A randomized controlled trial of electrocoagulation-enabled biopsy versus conventional biopsy in the diagnosis of endobronchial lesions. Although electrocoagulation at time of endobronchial biopsy can potentially reduce procedure-related bleeding during fiberoptic bronchoscopy (FOB), it can also impair quality of tissue specimen; credible data for either are lacking. To evaluate the impact of hot biopsy on the quality of tissue samples and to quantify the amount of procedure-related bleeding during endobronchial biopsy. In this single-center, prospective, single-blind, randomized controlled study we included adult patients referred for FOB and having endobronchial lesions. Patients were randomized to bronchial biopsy using an electrocoagulation-enabled biopsy forceps, with (EC+ group) or without (EC- group) application of electrocoagulation current (40 W for 10 s in a monopolar mode). Procedure-related bleeding was semi-quantified by observer description, as well as through a visual analogue scale. Overall quality of biopsy specimen and tissue damage were assessed and graded by a pulmonary pathologist blinded to FOB details. 160 patients were randomized to endobronchial biopsy with (n = 81) or without (n = 79) the application of electrocoagulation. There were no severe bleeding episodes in either group, and severity of bleeding in the EC+ and EC- groups was similar (median visual analogue scale scores of 14 and 16, respectively). Histopathological diagnosis was similar in the EC+ and EC- groups (77.8% and 82.3%, respectively). There was no significant difference in tissue quality between the two groups. Use of electrocoagulation-enabled endobronchial biopsy does not alter specimen quality and does not result in any significant reduction in procedure-related bleeding.


p27kip1: a new multiple endocrine neoplasia gene? Multiple endocrine neoplasias (MEN) are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Two types of MEN syndromes have long been known: MEN type 1 (MEN1) and MEN type 2 (MEN2), associated with a different spectrum of affected organs. MEN1 and MEN2 are caused by germline mutations in the MEN1 tumor suppressor gene and the RET proto-oncogene, respectively. Lately, a new type of MEN was identified (named MEN4) which is due to mutations in the CDKN1B gene, encoding for p27kip1 (p27), a cyclin-dependent kinase (Cdk) inhibitor that regulates the transition of cells from G1 to S phase. p27 is a non-canonical tumor suppressor since it is usually not somatically mutated in human cancers but it is often downregulated by post-translational mechanisms. The discovery of MEN4 has defined a new role for CDKN1B as a tumor susceptibility gene for multiple endocrine tumors. To date, six germline CDKN1B mutations have been found in patients with a MEN1-like phenotype but negative for MEN1 mutations. Due to the limited number of patients so far identified, the phenotypic features of MEN4 are not clearly defined. Here, we review the clinical and molecular characteristics of the MEN4 syndrome and summarize the main functions of p27 to better comprehend how their alteration can predispose to neuroendocrine tumors.


Systemic and cellular reflections on ageing and the circadian oscillator: a mini-review. From circulation to digestion to excretion, a circadian clock synchronizes most aspects of mammalian physiology with the solar day. During normal ageing, this daily coordination gradually erodes, and during pathological ageing such erosion is exacerbated. Recent experiments suggest that therapies aimed at sustaining circadian function increase quality of life in elderly patients. Hence, a better understanding of the interactions between the circadian clock and ageing - at both cellular and systemic levels - could lead to direct benefits for aged individuals.


Making decisions when no good choices exist: delivery of the survivor after intrauterine death of the co-twin in monochorionic twin pregnancies. Infertility therapies have markedly increased the incidence of multiple pregnancies and concomitantly monozygotic twinning. In utero death of one monozygotic twin predisposes the survivor to death and serious morbidity from hemodynamic collapse, thromboplastins, or microemboli. The optimal management of such cases, however, is unclear. We compared single-twin demise to similar clinical conundrums in the past to try to derive a model for the data needed to reach a consensus. The management of such pregnancies is very controversial as the clinician must balance the risks of damage to the survivor by temporizing against the risks of prematurity and the possible futility of damage already having occurred because it is impossible to precisely time and document when the damage occurs. While there is not yet a standard consensus, the trend is towards more aggressive management either by rapid delivery or transfusion to ameliorate possible damage, but the risks are still very high for the survivor. The trend is moving towards more aggressive management than previously. We pose several questions that still remain to be answered to derive a consensus as to management, but it is unlikely that the required data could ever be obtained in a rigorous, randomized fashion.


Efficacy of ustekinumab in palmoplantar psoriasis.


Male bias in the song control system despite female bias in song rate in streak-backed orioles (Icterus pustulatus). The song control system is a group of discrete interconnected nuclei found in the brains of all songbirds (suborder Passeri). Previous studies have reported a positive relationship between sex differences in song nucleus volumes and sex differences in song behavior across numerous songbird species, with species exhibiting greater sex differences in behavior also exhibiting greater sex differences in the brain. This body of comparative research, however, has failed to incorporate data from a bird species in which females sing more than males. In this study, we examine song nucleus volumes in both sexes of the streak-backed oriole (Icterus pustulatus), a New World blackbird with a female bias in song rate and similar song complexity between the sexes. Results from this neuroanatomical analysis are contrary to what was to be expected from previous research: despite the female bias in song rate, males have a significantly larger HVC and area X song nucleus volumes. Specifically, male HVC was 75% larger than that of females, and male area X was 64% larger than that of females. There was no significant sex difference in the size of the nucleus robustus arcopallialis. The lack of a positive relationship between song nuclei and singing behavior in these orioles demonstrates that our current understanding of song modulation via the song control system may be overly reliant on basic measures such as total volumes.


Coagulation in vertebrates with a focus on evolution and inflammation. The evolution of a thrombin-generating system that produces a gelatinous clot to prevent the loss of blood occurred in parallel with the evolution of inflammatory responses that depend on bradykinin generation. Bioinformatics approaches that inventory the presence or absence of genes involved in these two processes support the view that both became progressively more complex during the period between the divergence of jawless fish and the appearance of mammals. Although the roots of both systems may extend to protochordates, they arose quite independently.


Gangrenous cystitis: report of a case and review of the literature. Gangrenous cystitis is an extremely rare condition: only a total of 240 cases worldwide have been reported so far. Most of these cases have occurred in the preantibiotic era. After the advent and widespread use of antibiotics in clinical practice, only sporadic cases have been observed. We report a case of gangrenous cystitis in an 83-year-old woman who presented with symptoms of acute abdomen. The main causative factor was overdistension of the bladder due to urinary retention. The patient underwent total cystectomy and bilateral ureterocutaneostomy with a favorable outcome. The incidence, etiology, diagnosis, management and outcome of gangrenous cystitis are discussed.


Evolution of vertebrate hemostatic and inflammatory control mechanisms in blood-feeding arthropods. Arthropods evolved blood-feeding lifestyles on more than 20 independent occasions. A comparison of sialomes (secretory salivary gland protein family repertoires) corroborates this and indicates that unique protein families are found for different blood-feeding lineages. Closely related lineages considered to have evolved blood-feeding behavior independently might share similar sets of protein families in their sialomes. No orthologous relationships or conserved functional mechanisms have, however, been found for these apparently related protein family members. This implies that sialomes were already defined before the divergence of these related lineages, but that the functions involved in blood feeding evolved at a later stage. Protein families prone to lineage-specific expansion (gene duplication) tend to be abundant with specialized functions associated with various gene duplicates. A central theme that seems to emerge from comparative sialomic analysis is that of the convergent evolution of modulatory strategies that targets host defenses even if the molecular mechanisms differ.


Circulating levels of allopregnanolone, a neuroactive steroid, and leptin during treatment with valproic acid in children with epilepsy. Weight gain is a well-known unwanted effect of valproic acid (VPA) therapy. Studies on VPA-associated changes of homeostatic hormones remain limited and controversial. Allopregnanolone (AP) is a circulating neuroactive steroid involved in modulation of behavioral activities whose serum levels are increased in obese children. The aim of the present study was to determine whether VPA therapy affects leptin and AP circulating levels in prepubertal girls with epilepsy. One-hundred and one patients were divided into four groups: epileptic patients with VPA-associated obesity (n = 21); lean epileptic patients under VPA therapy (n = 35); healthy obese children (n = 23), and healthy lean children (n = 22). Patients with VPA-associated obesity had significantly enhanced blood concentrations of AP (p = 0.001) and leptin (p = 0.007) than lean subjects. There were no differences in leptin and AP plasma levels between patients with VPA-associated obesity and obese controls (p = 0.45 and p = 0.10, respectively), as there were no differences between lean patients under VPA therapy and lean healthy controls (p = 0.06). In patients under VPA therapy, both plasma leptin and AP levels were significantly correlated with BMI (r = 0.074, p = 0.02, and r = 0.084, p = 0.01, respectively). Plasma leptin concentrations were not correlated with AP levels (r = 0.023, p = 0.13). In conclusion, a correlation between obesity and neuroactive steroids was shown. It remains to be established whether the increased circulating level of AP is a secondary effect of anxiolytic-sedative processes occurring in subjects with obesity-related emotional and behavioral anomalies, or plays a central role in determining abnormal eating behaviors.


Estrogen receptors and signaling pathways in lactotropes and somatotropes. Estrogens are crucial determinants in the regulation of anterior pituitary function and maintenance of tissue homeostasis. Estrogen actions in this gland are exerted through both classical and non-classical mechanisms of action. This review summarizes the expression of classical α- and β-estrogen receptors and variant isoforms of estrogen receptors in anterior pituitary cell subpopulations. We also analyze estrogen receptor signaling pathways involved in estrogenic actions in the anterior pituitary gland, especially in lactotropes and somatotropes. Complex interactions between multiple signaling pathways are involved in estrogen regulation of hormone secretion, cell proliferation and cell death in this gland. Insight into these pituitary responses to estrogens would help to understand pituitary function and tumorigenesis.


Maintaining and promoting mobility and functional independence in older adults.


Laboratory review: the role of gait analysis in seniors' mobility and fall prevention. Walking is a complex motor task generally performed automatically by healthy adults. Yet, by the elderly, walking is often no longer performed automatically. Older adults require more attention for motor control while walking than younger adults. Falls, often with serious consequences, can be the result. Gait impairments are one of the biggest risk factors for falls. Several studies have identified changes in certain gait parameters as independent predictors of fall risk. Such gait changes are often too discrete to be detected by clinical observation alone. At the Basel Mobility Center, we employ the GAITRite electronic walkway system for spatial-temporal gait analysis. Although we have a large range of indications for gait analyses and several areas of clinical research, our focus is on the association between gait and cognition. Gait analysis with walking as a single-task condition alone is often insufficient to reveal underlying gait disorders present during normal, everyday activities. We use a dual-task paradigm, walking while simultaneously performing a second cognitive task, to assess the effects of divided attention on motor performance and gait control. Objective quantification of such clinically relevant gait changes is necessary to determine fall risk. Early detection of gait disorders and fall risk permits early intervention and, in the best-case scenario, fall prevention. We and others have shown that rhythmic movement training such as Jaques-Dalcroze eurhythmics, tai chi and social dancing can improve gait regularity and automaticity, thus increasing gait safety and reducing fall risk.


Living environment and mobility of older adults. Older adults often elect to move into smaller living environments. Smaller living space and the addition of services provided by a retirement community (RC) may make living easier for the individual, but it may also reduce the amount of daily physical activity and ultimately reduce functional ability. With home size as an independent variable, the primary purpose of this study was to evaluate daily physical activity and physical function of community dwellers (CD; n = 31) as compared to residents of an RC (n = 30). In this cross-sectional study design, assessments included: the Continuous Scale Physical Functional Performance - 10 test, with a possible range of 0-100, higher scores reflecting better function; Step Activity Monitor (StepWatch 3.1); a physical activity questionnaire, the area of the home (in square meters). Groups were compared by one-way ANOVA. A general linear regression model was used to predict the number of steps per day at home. The level of significance was p < 0.05. Of the 61 volunteers (mean age: 79 ± 6.3 years; range: 65-94 years), the RC living space (68 ± 37.7 m(2)) was 62% smaller than the CD living space (182.8 ± 77.9 m(2); p = 0.001). After correcting for age, the RC took fewer total steps per day excluding exercise (p = 0.03) and had lower function (p = 0.005) than the CD. On average, RC residents take 3,000 steps less per day and have approximately 60% of the living space of a CD. Home size and physical function were primary predictors of the number of steps taken at home, as found using a general linear regression analysis.


Age-related effects on postural control under multi-task conditions. Changes in postural sway and gait patterns due to simultaneously performed cognitive (CI) and/or motor interference (MI) tasks have previously been reported and are associated with an increased risk of falling in older adults. The objectives of this study were to investigate the effects of a CI and/or MI task on static and dynamic postural control in young and elderly subjects, and to find out whether there is an association between measures of static and dynamic postural control while concurrently performing the CI and/or MI task. A total of 36 healthy young (n = 18; age: 22.3 ± 3.0 years; BMI: 21.0 ± 1.6 kg/m(2)) and elderly adults (n = 18; age: 73.5 ± 5.5 years; BMI: 24.2 ± 2.9 kg/m(2)) participated in this study. Static postural control was measured during bipedal stance, and dynamic postural control was obtained while walking on an instrumented walkway. Irrespective of the task condition, i.e. single-task or multiple tasks, elderly participants showed larger center-of-pressure displacements and greater stride-to-stride variability than younger participants. Associations between measures of static and dynamic postural control were found only under the single-task condition in the elderly. Age-related deficits in the postural control system seem to be primarily responsible for the observed results. The weak correlations detected between static and dynamic measures could indicate that fall-risk assessment should incorporate dynamic measures under multi-task conditions, and that skills like erect standing and walking are independent of each other and may have to be trained complementarily.


The interplay between cognitive and motor functioning in healthy older adults: findings from dual-task studies and suggestions for intervention. Reaching late adulthood is accompanied by losses in physical and mental resources, but lifestyle choices seem to have a considerable influence on the aging trajectory. This review deals with the interplay between cognitive and motor functioning in old age, focusing on two different lines of research, namely (a) dual-task studies requiring participants to perform a cognitive and a motor task simultaneously, and (b) intervention studies investigating whether increases in physical fitness also lead to improvements in cognitive performance. Dual-task studies indicate that healthy older adults show greater performance reductions in both domains than young adults when performing a cognitive and a motor task simultaneously. In addition, older adults often tend to protect their motor functioning at the expense of the cognitive task when the situation involves a threat to balance. This can be considered an adaptive behavior since fall-related injuries can have severe consequences. Fitness intervention studies which increased the aerobic fitness of previously sedentary older adults have demonstrated impressive performance improvements in the cognitive domain, especially for tasks involving executive control processes. These findings are interesting in light of cognitive intervention studies, which often fail to find significant transfer effects to tasks that have not been trained directly. The authors argue that future research should compare the effects of cognitive and aerobic fitness interventions in older adults, and they present a study design in which cognition and fitness are trained sequentially as well as simultaneously. Finally, methodological issues involved in this type of research and potential applications to applied settings are discussed.


Rationale for combined exercise and cognition-focused interventions to improve functional independence in people with dementia. Evidence suggests that exercise and some cognition-focused intervention approaches can be used to elicit functional improvements in older people and, to some degree, those diagnosed with dementia. Independently, the two intervention types have been found to improve functional performance in people with dementia. The mechanisms underpinning these improvements come from comparable and diverse pathways. This suggests that it may be beneficial for the two intervention types to be coupled as part of regular care in individuals with a range of cognitive impairments. The aims of this review are threefold. The first aim is to present evidence to support the use for combining exercise and cognition-focused interventions. This will be achieved by reviewing the mechanisms of both approaches in improving functional performance in older people and in people with dementia and summarising recent progress. The increased risk of depression, falls and cardiovascular disease risk in people with dementia will also be highlighted. The second aim is to discuss the parameters of the two approaches that should be considered when combining them in terms of possible efficient models, especially in relation to exercise protocols as this is where the current literature shows the most promising outcomes. Maximisation of the efficacy of preventative and treatment interventions which focus on both cognitive functioning and physical health should lead to improving and extending functional independence. Key aspects of any combined intervention would involve the inclusion of both cardiovascular and other types of exercises, including falls reduction, and exercises addressing memory and executive function via goal setting in the real-life context. The third aim is to explore some of the issues that may arise when attempting to incorporate interventions into the regular treatment of people with dementia. Consideration must also be given to caregivers and the education of health professionals as well as to the mode of intervention itself. Further research is necessary in order to discern the most effective types of both intervention models. Provision of combined interventions might enhance the improvements in functional independence in people with dementia over and above the interventions being used separately.


The effect of PACAP38 on MyD88-mediated signal transduction in ischemia-/hypoxia-induced acute kidney injury. toll-like receptor 4 (TLR4) and its adaptor protein MyD88 play an important role in ischemia/reperfusion (I/R) injury in the kidney, and pituitary adenylate cyclase-activating polypeptide (PACAP) could ameliorate renal I/R injury. primary cultures of proximal tubule epithelial cells (PTEC) were prepared from wild-type and MyD88(-/-) mice, and subjected to hypoxia in vitro. Acute kidney injury (AKI) was induced by I/R in vivo in wild-type mice only. hypoxia resulted in significant increases in cytokine production and apoptosis/necrosis in wild-type PTEC, but these responses were markedly blunted in MyD88(-/-) PTEC. Treatment with PACAP38 before or after hypoxia further suppressed the hypoxia-induced cytokine responses and apoptosis in both MyD88(+/+) and MyD88(-/-) PTEC cultures. PACAP38 significantly inhibited TLR4/MyD88/TRAF6 as well as TRIF and IRF3 expression in mouse kidney and PTEC, and inhibited the secretion and mRNA expression of cytokines in kidneys from mice after I/R, paralleling the cytokine responses in vitro. Moreover, treatment with PACAP38 protected mice from renal failure, histological damage, neutrophil influx and tubule cell apoptosis after I/R. our data reveal that the TLR4-mediated cytokine responses to hypoxia are primarily dependent on MyD88 signaling and highlight the pivotal role of MyD88-dependent mechanisms in the coordination of the innate immune responses to ischemic/hypoxic acute renal tubular injury. The renoprotective effect of PACAP in AKI involves both MyD88-dependent and -independent pathways.


Trophoblast glycoprotein: possible candidate mediating podocyte injuries in glomerulonephritis. trophoblast glycoprotein (Tpbg), a 72-kDa transmembrane glycoprotein, is known to regulate the phenotypes of epithelial cells by modifying actin organization and cell motility. Recently, a microarray study showed that Tpbg is upregulated in Thy1 glomerulonephritis (Thy1 GN). We hypothesized that Tpbg regulates cytoskeletal rearrangement and modulates phenotypic alteration in podocytes under pathological conditions. we examined Tpbg expression in Thy1 GN and Tpbg function in mouse podocytes. we demonstrated that Tpbg is upregulated in the injured podocytes of Thy1 GN. In vitro, immunofluorescence studies revealed that Tpbg colocalized with the focal adhesion protein, vinculin, in parallel with stress fiber formation. This colocalization was observed even when actin filaments were depolymerized with cytochalasin D. Tpbg localization at focal adhesions was induced by dominant-active RhoA and suppressed by the ROCK1 inhibitor Y-26732. In addition, transforming growth factor-β increased Tpbg expression at focal adhesions concurrently with rearrangement of stress fibers. Stress fiber formation was suppressed in differentiated podocytes transfected with full-length Tpbg. Furthermore, knockdown of Tpbg using small interfering RNA decreased podocyte motility. our findings suggest a novel role of Tpbg in the phenotypic alteration of injured podocytes, and we accordingly propose a new mechanism of glomerular injury in glomerulonephritis.


Sequential bilateral cochlear implantation in children: development of the primary auditory abilities of bilateral stimulation. The advantages of sequential bilateral cochlear implantation were assessed in 29 children with a severe to profound hearing loss. The effect of age at second implantation and the effect of duration of bilateral implant use on the outcomes in speech perception and directional hearing were investigated. The children received their second cochlear implant at an age ranging from 2.8 to 8.5 years. Measurements were carried out preoperatively and postoperatively after 6, 12 and 24 months of bilateral implant use. A matched control group of 9 children with a unilateral implant were also measured over time and were compared with the study group after 12 and 24 months. Speech reception in both quiet and in noise and lateralization were measured. After 24 months, a minimum audible angle task was carried out. Bilateral advantages with regard to speech reception in quiet and in noise were already present after 6 months of bilateral implant use and improved thereafter. After 24 months, speech reception in noise had significantly improved with bilateral implants compared to that of children with a unilateral implant. The percentage of children that could accurately lateralize increased from 57% after 6 months to 83% after 24 months. With regard to the minimum audible angle task, loudspeakers were placed on average at ±42°. Age at second implantation did not have an influence on all outcomes. From the results it can be concluded that the advantages of bilateral hearing occur after sequential bilateral implantation and that age at second implantation does not influence the amount of bilateral advantage. Furthermore, it can be concluded that longer periods of bilateral implant use lead to greater bilateral advantages.


Prevalence and prognosis of mild anemia in non-dialysis chronic kidney disease: a prospective cohort study in outpatient renal clinics. we evaluated prevalence and prognosis of mild anemia, defined as Hb (g/dl) 11-13.5 in males and 11-12 in females, in a prospective cohort of stage 3-5 chronic kidney disease (CKD) patients. we enrolled 668 consecutive patients in 25 renal clinics during 2003. Patients with frank anemia (Hb <11 or erythropoiesis-stimulating agents) at enrolment were excluded. Mild anemia was evaluated at two visits planned with an interval of 18 ± 6 months to identify four categories: no anemia at both visits, mild anemia at visit 1 resolving at visit 2 (RES), mild anemia persisting at both visits (PER), and progression from no anemia or mild anemia at visit 1 to mild or frank anemia at visit 2 (PRO). mild anemia was present in 41.3% at visit 1 and 34.1% at visit 2. We identified PER in 22% patients, RES in 10%, and PRO in 26%. In the subsequent 40 months, 125 patients developed end-stage renal disease (ESRD) and 94 died. At competing risk model, PER predicted ESRD (hazard ratio, HR, 1.82, 95% confidence interval, CI, 1.01-3.29) while PRO predicted both ESRD (HR 1.81, 95% CI 1.02-3.23) and death (HR 1.87, 95% CI 1.04-3.37). in non-dialysis chronic kidney disease, mild anemia is prevalent and it is a marker of risk excess when persistent or progressive over time.


A pilot study of rituximab in immune-mediated inner ear disease. Immune-mediated inner ear disease (IMED) is a cause of rapidly progressive auditory dysfunction. Patients are often responsive to high-dose corticosteroids and the disease is believed to be mediated by an antibody to inner ear proteins. To date, no therapies have proven effective as corticosteroid-sparing agents. Rituximab is a monoclonal antibody that depletes B cells, resulting in a reduction in autoantibody production. For that reason, rituximab was evaluated in a small pilot study in patients with IMED to see if there was a signal suggesting benefit. In all, 5/7 patients met the primary endpoint of an improvement in pure tone average (500-3000 Hz) by 10 dB in at least one ear, or an improvement in word identification score by at least 12% at 24 weeks, both relative to screening precorticosteroid values after 1 course of treatment. No significant adverse events were reported. The results of this study suggest further evaluation of rituximab as a treatment for IMED is indicated.


Cochlear implants in forty-eight children with cochlear and/or vestibular abnormality. CT and MRI scans for 48 children with cochlear and/or vestibular abnormality were classified in decreasing severity; common cavity, Mondini plus enlarged vestibular aqueduct, Mondini dysplasia alone and enlarged vestibular aqueduct alone. No significant relationship between degree of cochlea abnormality and surgical issues (cerebrospinal fluid gusher, depth of insertion, number of electrodes) or speech perception/language outcomes was found. A significant relationship was observed between cerebrospinal fluid gusher and partial electrode insertion, fewer active electrodes and poorer sentence understanding. Optimum language outcomes were associated with younger age at implant.


Pharmacokinetics of dexamethasone solution following intratympanic injection in guinea pig and sheep. Information on inner ear pharmacokinetics is limited in the literature, especially in large animals and in humans. A preliminary study was designed to explore the differences in inner ear exposure between guinea pigs and sheep following a single intratympanic injection of a 2% dexamethasone sodium phosphate solution. In both species, significant levels of dexamethasone were observed in the perilymph within 1 h, and decreasing by 50- to 100-fold within 12 h. Overall, the exposure to dexamethasone in the inner ear was significantly lower in sheep by 17- to 27-fold than in guinea pigs. Systemic and CNS exposure were minimal in both species as indicated by the low drug levels observed in plasma and CSF. Altogether, the preliminary evidence presented herein suggests the sheep as a practical and acceptable animal model to study the inner ear pharmacokinetics of drug candidates in large mammals and its potential towards extrapolation to human exposure.


Proinflammatory activation of peripheral blood mononuclear cells in patients with vestibular neuritis. Vestibular neuritis (VN) is characterized by acute vertigo with spontaneous nystagmus and is often accompanied by vegetative symptoms. While the pathogenetic process leading to this disease is widely unknown, increasing evidence exists that a proinflammatory environment is responsible for the induction and progression of VN. Twelve patients with acute VN and 12 healthy, age-matched individuals were included in this study. In addition to routine blood parameters, plasma levels of soluble CD40 receptor/ligand (sCD40/sCD40L) were determined by ELISA. Moreover, peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density gradient. Afterwards, in CD14 (monocytes), CD68 (macrophages), CD3 (T lymphocytes) or CD19 (B lymphocytes) subpopulations, proinflammatory [CD40, tumor necrosis factor-α (TNF-α), and COX-2], proapoptotic [caspase-3, and poly(adenosine diphosphate ribose) polymerase] and proadhesive (CD38) proteins were measured by 2-color fluorescence-activated cell sorter analyses. In comparison to healthy individuals, patients with acute VN revealed significantly elevated plasma levels of C-reactive protein, whereas plasma levels of sCD40 and sCD40L, as well as cholesterol/triglyceride status were similar. However, we found a significant elevation of the percentage of proinflammatory CD40+, TNF-α+, COX-2+ or CD38+ PBMCs. Elevation of proinflammatory and proadhesive proteins in PBMCs of patients with acute VN in parallel with an acute phase response may contribute to disease induction and progression and, thus, may be suggested as a novel therapeutic target.


Hyperventilation-induced nystagmus in patients with vestibular neuritis in the acute and follow-up stages. Our purposes were to characterize hyperventilation-induced nystagmus (HVIN) in patients with unilateral vestibular neuritis (VN) through follow-up examinations and to determine the effects of hyperventilation on vestibular imbalance in patients with VN. The horizontal eye movements in 35 patients with acute VN were recorded. The eye movements were analyzed and the maximum value of slow-phase eye velocity (SPV) was obtained during and after hyperventilation. Nineteen of 35 patients underwent follow-up examinations around 7 weeks later. When spontaneous nystagmus was present, the SPV of spontaneous nystagmus was subtracted from that of HVIN. A maximum SPV of HVIN of ≥4°/s was considered abnormal. The direction and SPV of HVIN were analyzed. The incidence of HVIN in patients with VN was significantly higher in the acute stage (18 of 35; 51%) than the follow-up stage (4 of 19; 21%). The direction of HVIN present in the follow-up stage was entirely towards the contralesional side (contralesional HVIN). However, the direction of HVIN in the acute stage was mixed, towards the contralesional side (10 of 35; 28%) and towards the ipsilesional side (8 of 35; 23%). The SPVs (49 ± 56°/s) of ipsilesional HVIN were significantly greater than the contralesional HVIN in the acute stage (8 ± 3°/s). Robust nystagmus (SPV ≥ 25°/s) was entirely ipsilesional HVIN, which was observed only in the acute stage. Our findings indicate that hyperventilation can result in aggravation of vestibular imbalance in the acute and follow-up stages in different ways. Hyperventilation resulted in contralesional HVIN in both the acute and follow-up stages, each in approximately a fourth of the patients, which suggests a disruption of central static compensatory mechanisms. However, ipsilesional HVIN was elicited only in the acute stage (in approximately a fourth of the patients). About half of the patients with ipsilesional HVIN showed robust responses, which is a characteristic finding, suggesting a transient intense increase in vestibular activity on the lesional side.


Proinflammatory and proadhesive activation of lymphocytes and macrophages in sudden sensorineural hearing loss. Even though sudden sensorineural hearing loss (SHL) is a quite frequent disease, the pathogenetic processes leading to it are widely unknown. There is increasing evidence that immunomodulatory cells, especially T lymphocytes, might be involved. Twelve patients with acute SHL and 12 healthy, age-matched individuals were included in this study. In addition to routine blood parameters, plasma levels of tumor necrosis factor alpha (TNF-α), soluble CD40 (sCD40) and sCD40 ligand (sCD40L) were determined by ELISA. Moreover, peripheral blood mononuclear cells were isolated by Ficoll density gradient. Afterwards, in subpopulations--identified by CD14 (monocytes), CD68 (macrophages), CD3 (T lymphocytes) or CD19 (B lymphocytes) immunoreactivity--proinflammatory (CD40, TNF-α or cyclooxygenase-2) and proadhesive (CD38) proteins were measured by 2-color fluorescence-activated cell sorter analyses. In comparison with healthy individuals, patients with acute SHL revealed elevated plasma levels of sCD40 and sCD40L and a significantly decreased percentage (36%) of lymphocytes, especially of T lymphocytes (28%). Additionally, in patients with acute SHL the percentage of proinflammatory CD40, TNF-α, cyclooxygenase-2 or CD38-positive T or B lymphocytes was significantly increased. Our data suggest an enhanced extravasation of proadhesive and proinflammatory lymphocytes from the peripheral circulation, which may contribute to SHL disease induction as well as progression and, thus, may be suggested as a novel therapeutical target.


Post-stroke apathy and hypoperfusion in basal ganglia: SPECT study. Although apathy has been reported as one of the neuropsychiatric symptoms following stroke, there are few studies on regional cerebral blood flow (rCBF) in stroke patients with apathy. The present study compared rCBF between apathetic and non-apathetic patients after stroke. We recruited 102 patients with cerebral infarction within 1 month after stroke and performed neuropsychiatric assessments that included the apathy scale. rCBF was quantitatively measured using N-isopropyl-p-(123)I-iodoamphetamine single-photon emission computed tomography. Thirty-seven patients (36%) had apathy. The apathetic group showed lower cognitive function and a higher depressive state than the non-apathetic group. rCBF in the basal ganglia was reduced for the apathetic group compared with the non-apathetic group. Furthermore, lesions in the left basal ganglia were associated with hypoperfusion in bilateral basal ganglia and the presence of apathy. These findings demonstrate that apathy is a frequent symptom among stroke patients and that hypoperfusion caused by basal ganglia lesions may contribute to post-stroke apathy.


Stroke history and Chagas disease are independent predictors of silent cerebral microembolism in patients with congestive heart failure. Chagas disease is endemic in South and Central America, where 18 million individuals are infected by Trypanosoma cruzi, causing congestive heart failure (CHF) and cardioembolic stroke. Transcranial Doppler (TCD) is able to detect real-time microembolic signals (MES) to the brain vessels and may represent a surrogate marker of stroke risk. We aimed to determine predictors of MES in a population of patients with CHF. Consecutive CHF patients from a university-based cardiomyopathy clinic underwent TCD recording of the middle cerebral artery for 60 min by a single investigator who was blinded to all clinical data including cardiomyopathy etiology. Predictors of MES were sought by multivariable logistic regression analysis. From April 2004 to February 2009, 144 patients were studied, including 62 (44.6%) patients with Chagas disease. MES were detected in 9 (6.2%) patients and were more frequent in patients with Chagas disease than in patients with other causes of CHF (12.9 vs. 1.2%, p = 0.005). In multivariate analysis corrected for age and left-ventricular ejection fraction, predictors of MES were Chagas disease (odds ratio = 1.15, 95% confidence interval = 1.05-1.26, p = 0.004) and stroke history (odds ratio = 1.27, 95% confidence interval = 1.08-1.50, p = 0.005). Chagas disease and stroke history are risk factors for MES independent of cardiac disease severity. Other mechanisms besides structural cardiac disease may be operative, increasing embolic risk in Chagas disease.


Little association between intracranial arterial stenosis and lacunar stroke. Atheromatous middle cerebral artery (MCA) stenosis could cause lacunar stroke by occluding lenticulostriate artery origins, but atheroma is common, and previous studies lacked suitable controls. We aimed to determine if intracranial atheroma was more common in lacunar than in cortical ischaemic stroke. We recruited patients with lacunar stroke and controls with mild cortical stroke, confirmed the stroke subtype with magnetic resonance imaging and used transcranial Doppler ultrasound imaging to record flow velocity and focal stenoses in the basal intracranial arteries 1 month after stroke. We compared ipsi- and contralateral MCA mean flow velocities between stroke subtypes and tested for associations using linear mixed models. Amongst 67 lacunar and 67 mild cortical strokes, mean age 64 and 67 years, respectively, we found no difference in MCA mean flow velocity between cortical and lacunar patients. Increasing age and white matter lesion scores were independently associated with lower MCA flow velocities (0.2 cms(-1) fall in velocity per year increase in age, p = 0.045; 3.75 cms(-1) fall in flow velocity per point increase in white matter lesion score, p = 0.004). We found no intracranial arterial stenoses. MCA atheromatous stenosis is unlikely to be a common cause of lacunar stroke in white populations. Falling velocities with increasing white matter lesion scores may reflect progressive brain tissue loss leaving less tissue to supply.


Stroke in asymptomatic Trypanosoma cruzi-infected patients. The knowledge about the natural history of stroke in Chagas disease is incomplete. Vascular risk factors and stroke subtypes of asymptomatic Trypanosoma cruzi-infected patients with no clinical evidence of heart failure were assessed. They were compared with chronic chagasic cardiomyopathy patients who suffered a stroke and with a control group of 60 T. cruzi-noninfected stroke patients. Eighty-six consecutive chagasic stroke patients (mean age: 57.4 years; 64% females) were studied. 38.4% of chagasic stroke patients had asymptomatic T. cruzi infection. Smoking was more frequent in asymptomatic chagasic stroke patients (21.2 vs. 5.7%; p = 0.04). Prevalence of hypertension, diabetes and prior stroke was similar in both groups. Small-vessel infarction (15.6 vs. 3.8%) and large-vessel atherosclerosis (9.4 vs. 3.8%) were significantly more frequent in asymptomatic than in symptomatic T. cruzi-infected stroke patients (p = 0.001). Nevertheless, their frequency was even higher in T. cruzi-noninfected stroke patients (36.7 and 13.3%, respectively). Apical aneurysm (27.3%), left atrial dilatation (12.1%), left ventricle hypokinesia (9.4%) and right bundle branch block (36.4%) were also detected in asymptomatic T. cruzi-infected stroke patients. Ischemic stroke may be the first manifestation of Chagas disease in asymptomatic patients with mild left ventricle dysfunction. Other noncardioembolic stroke subtypes can occur in asymptomatic T. cruzi-infected patients.


Toll-like receptor 4 immunohistochemical expression is enhanced in macrophages of symptomatic carotid atherosclerotic plaques. A growing body of evidence supports a role for Toll-like receptor 4 (TLR4), a primary receptor of the innate immune system, in atherosclerosis initiation and progression. Carotid atheroma macrophages (MACs) and smooth muscle cells (SMCs) express TLR4; nevertheless, correlations with epidemiological and clinical variables and especially cerebrovascular symptomatology remain unsettled. Carotid atherosclerotic plaques were obtained by standard carotid endarterectomy on 157 patients with carotid artery disease (84 asymptomatic - 73 symptomatic). TLR4 expression in MACs and SMCs of carotid atheroma was detected by immunohistochemistry techniques. TLR4 positivity, overexpression and intensity of immunostaining in MACs and SMCs were correlated with cerebrovascular symptomatology, epidemiological and clinical variables. MAC TLR4 positivity was noted in 129 (82.2%) patients. Patients receiving statins had significantly lower TLR4 expression. Rates of MAC TLR4 positivity were higher among symptomatic patients (odds ratio, OR = 5.1; 95% confidence interval, CI = 1.8-14.3; p < 0.001); the association was stronger for transient ischemic attacks. TLR4 overexpression was also significantly enhanced among symptomatic patients (OR = 2.3; 95% CI = 1.02-5.03; p < 0.05). No correlations were detected between SMC TLR4 expression and cerebrovascular symptoms. In multivariate models adjusting for age, gender, body mass index, hyperlipidemia and smoking, MAC TLR4 positivity was associated with a cerebrovascular event during the last 6 months (OR = 4; 95% CI = 1.2-13.3; p = 0.02). Symptomatic carotid artery plaques are characterized by increased expression of TLR4 in macrophages supporting a potential role for TLR4 in the pathophysiology and clinical presentation of cerebrovascular disease. Further investigation is warranted.


Characteristics and outcome of ischemic stroke patients who are free of symptoms at 24 hours following thrombolysis. A part of ischemic stroke patients score 0 on the National Institutes of Health Stroke Scale (NIHSS) within 24 h following thrombolysis. Their clinical characteristics and long-term outcome are poorly studied. We report a single-center assessment of such patients. The cohort comprises 874 consecutive patients from the Helsinki Stroke Thrombolysis Registry, out of whom 113 scored 0 on 24-hour NIHSS. We analyzed their baseline demographic, clinical and radiological characteristics and 3-month outcome (modified Rankin Scale, mRS). Associations between the study parameters were tested by multivariate analysis. Patients with a 24-hour NIHSS score = 0 (n = 113) were younger than the rest of the population (n = 761; median: 65.6 vs. 71.5 years; p < 0.001), their NIHSS score on admission was lower (median: 5 vs. 10; p < 0.001), as was their glucose level (median: 6.2 vs. 6.7 mmol/l; p = 0.02). The onset-to-treatment time was similar in both groups (median: 120 vs. 115 min; p = 0.89). Patients with a 24-hour NIHSS score = 0 more often achieved an excellent outcome (mRS scores: 0-1; 81 vs. 31%; p < 0.001) and had lower mortality (1.8 vs. 11.8%; p < 0.01). One third of these patients had a brain infarction visible on 24-hour imaging. Lower baseline NIHSS score and younger age were independently associated with 24-hour NIHSS score = 0, which, in turn, was independently associated with excellent 3-month outcome. Patients with an NIHSS score = 0 at 24 h following thrombolysis are younger, have milder symptoms and have a lower glucose level on admission. They achieve more often excellent outcome and lower mortality. Still, 8% of them required help in daily activities or were dead at 3 months (mRS scores: 3-6).


Utility of the Kurashiki Prehospital Stroke Scale for hyperacute stroke. Our aim was to confirm the utility of paramedics using the Kurashiki Prehospital Stroke Scale (KPSS), with a maximum score of 13, for patients who may be eligible for administration of intravenous tissue plasminogen activator (IV t-PA). The subjects comprised acute stroke and transient ischemic attack (TIA) patients transferred to our hospital by paramedics. We analyzed correlations between KPSS and the National Institutes of Health Stroke Scale (NIHSS). Patients admitted within 3 h of onset were categorized into 2 groups: KPSS ≥4 and KPSS <4. We compared the proportion of patients receiving IV t-PA between the groups. Among 430 consecutive patients (mean age = 73 years; 266 men), paramedics recorded KPSS for 256 patients (59.5%). Excellent correlation was observed between KPSS and NIHSS in all 256 patients (R = 0.766; p < 0.001) and in 94 patients (ischemic stroke and TIA with symptoms on admission) admitted within 3 h of onset (R = 0.706; p < 0.001). Among these 94 patients, IV t-PA was more frequently given in the KPSS ≥4 group (30 of 58 patients, 51.7%) than in the KPSS <4 group (5 of 36 patients, 13.9%; p < 0.001). Arterial occlusion was more frequently observed in the KPSS ≥4 group (57.9 vs. 31.4%, p = 0.018). KPSS ≥4 was independently associated with administration of IV t-PA (odds ratio = 4.7; 95% confidence interval = 1.5-14.6, p = 0.008). Reliable concordance between KPSS and NIHSS was found in acute stroke and TIA patients. KPSS ≥4 represents a good score to indicate prospective t-PA patients among those admitted within 3 h of stroke onset.


Common carotid artery intima-media thickness: the Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study results. Measurement of far wall common carotid artery intima-media thickness (CCAIMT) has emerged as a predictor of incident cardiovascular events. The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study was the first large-scale population-based assessment of both CCAIMT and cardiovascular risk factor prevalence in 7 Latin American cities; the relationship between CCAIMT and cardiovascular risk markers was assessed in these urban Latin American centers. CARMELA was a cross-sectional, population-based, observational study using stratified, multistage sampling. The participants completed a questionnaire, were evaluated in a clinical visit and underwent carotid ultrasonography. Clinical measurements were obtained by health personnel trained, certified and supervised by CARMELA investigators. Mannheim intima-media thickness consensus guidelines were followed for measurement of CCAIMT. In all cities and for both sexes, CCAIMT increased with higher age. CCAIMT was greater in the presence of cardiovascular risk factors than in their absence. In all cities, there was a statistically significant linear trend between increasing CCAIMT and a growing number of cardiovascular risk factors (p < 0.001). After adjustment for age and sex, metabolic syndrome was strongly associated with increased CCAIMT (p < 0.001 in all cities), as were hypercholesterolemia, obesity and diabetes (p < 0.001 in most cities). By multivariate analysis, hypertension was independently associated with an increase in CCAIMT in all cities (p < 0.01). CARMELA was the first large-scale population study to provide normal CCAIMT values according to age and sex in urban Latin American populations and to show CCAIMT increases in the presence of cardiovascular risk factors and metabolic syndrome.


Do vascular risk factors explain the association between socioeconomic status and stroke incidence: a meta-analysis. Reduced socioeconomic status (SES) is associated with an increased risk of stroke, although the mechanism is not clear. It may be that those with lower SES have a greater burden of classic vascular risk factors. Our aim was to quantify the extent to which classic vascular risk factors explain the association between SES and stroke incidence. We conducted a systematic review and meta-analysis of studies examining the association of SES and stroke incidence, where classic vascular risk factors were considered. Searching MEDLINE, EMBASE and the Cochrane Library from 1980 onwards we identified 17 studies, 12 of these studies provided sufficient information to allow a meta-analysis. From each study the increased risk of stroke incidence, where the lowest socioeconomic category was compared with the highest, was recorded and pooled. The stroke incidence risks, adjusted for grouped classic risk factors, were also pooled. Review Manager 5 software was used for all analyses and results were analysed using hazard ratios (HR, 95% confidence interval, 95% CI) with a random effects model. Those with a lower SES were more likely to have a stroke (HR 1.67; 95% CI 1.46-1.91). Additional risk was reduced, but not eliminated, when classic vascular risk factors were adjusted for (HR 1.31; 95% CI 1.16-1.48). Low SES is associated with an increased risk of stroke that is partly explained by known classic vascular risk factors.


The dilemma of diastole.

The dilemma of diastole.


Enamel erosion in dietary acids: inhibition by food proteins in vitro. The aim of this study was to investigate the effects of two common food proteins on human enamel erosion in vitro. Erosion was measured by non-contact profilometry in citric, malic and lactic acids at pH 2.8, 3.2 and 3.8 and five commercially available soft drinks, in the presence of a salivary pellicle. Whole milk casein or hen egg ovalbumin was added to the acid solutions and drinks at 0.2% w/v, and the effect on erosion was determined by comparison with the corresponding solution without protein. Casein significantly reduced erosion in all but two solutions. The effects of the individual subfractions of casein in citric acid at pH 3.2 were similar to that of whole casein. Ovalbumin reduced erosion in some solutions, but the magnitude of the reduction was less than that with casein. A greater proportional reduction in erosion was seen in citric acid than in malic or lactic acids. We postulate that the mechanism involves adsorption of proteins to the pellicle or the enamel surface, forming a protein film with enhanced erosion-inhibiting properties. The citrate ion may play an active stabilising role, since erosion reduction was less in the other acids. In conclusion, casein and, to a lesser extent, ovalbumin show promise as potential anti-erosive additives to drinks.


Review of effects of physical activity on strength, balance, mobility and ADL performance in elderly subjects with dementia. Elderly individuals with dementia are vulnerable for a decline in physical functioning and basic activities of daily living (BADL) which can lead to a decline in autonomy and participation. This study reviews the effect of physical activity on physical functioning and BADL in elderly subjects with dementia. A systematic search of the literature was performed. Key words related to the elderly, dementia, exercise interventions and physical outcome measures were used. Sixteen studies were included. It was found that physical activity was beneficial in all stages of dementia. Multicomponent interventions (e.g. a combination of endurance, strength and balance) led to larger improvements in gait speed, functional mobility and balance, compared to progressive resistance training alone. BADL and endurance improved but were only assessed in multicomponent interventions. Lower-limb strength improved equally in multicomponent interventions and progressive resistance training. Multicomponent interventions can improve physical functioning and BADL in elderly subjects regardless of the stage of dementia. The best results were obtained in the interventions with the largest training volume. However, the small number of high-quality studies, and heterogeneity of the participants and interventions prevent us from drawing firm conclusions. Recommendations are given with respect to methodological issues, further research and practical guidelines.


Restless legs syndrome and pregnancy: a questionnaire study in the Poitiers District, France. To perform a large and detailed epidemiologic study on restless legs syndrome (RLS) during pregnancy in a European country. A cross-sectional questionnaire survey. The questionnaire was distributed by the medical staff in different outpatient waiting rooms (obstetrics and gynecology department of the university hospital, obstetrics and gynecology department of a private clinic, private midwives, private obstetrician-gynecologists, radiological centers before fetal ultrasound examination and general practitioners) in a French town and its surrounding area (200,000 inhabitants): A woman was considered affected if she met the International RLS Study Group criteria for RLS diagnosis. 1,022 pregnant women living in a French town were included. 24% of women were affected by RLS during their pregnancy. The disease was strongly related to the third trimester of pregnancy and had a significant impact on sleep leading to severe nocturnal and diurnal consequences with a high consumption of sleep medication. RLS affects one quarter of pregnant women, essentially during the third trimester and represents an important public health issue with sleep medication intake.


Cortical and non-cortical myoclonus of Creutzfeldt-Jakob disease.


Stressed patients, stressed physicians and the need for mind-body medicine.


Combined use of pulsed arterial spin-labeling and susceptibility-weighted imaging in stroke at 3T. In acute stroke it is no longer sufficient to detect simply ischemia, but also to try to evaluate reperfusion/recanalization status and predict eventual hemorrhagic transformation. Arterial spin labeling (ASL) perfusion may have advantages over contrast-enhanced perfusion-weighted imaging (cePWI), and susceptibility weighted imaging (SWI) has an intrinsic sensitivity to paramagnetic effects in addition to its ability to detect small areas of bleeding and hemorrhage. We want to determine here if their combined use in acute stroke and stroke follow-up at 3T could bring new insight into the diagnosis and prognosis of stroke leading to eventual improved patient management. We prospectively examined 41 patients admitted for acute stroke (NIHSS >1). Early imaging was performed between 1 h and 2 weeks. The imaging protocol included ASL, cePWI, SWI, T2 and diffusion tensor imaging (DTI), in addition to standard stroke protocol. We saw four kinds of imaging patterns based on ASL and SWI: patients with either hypoperfusion and hyperperfusion on ASL with or without changes on SWI. Hyperperfusion was observed on ASL in 12/41 cases, with hyperperfusion status that was not evident on conventional cePWI images. Signs of hemorrhage or blood-brain barrier breakdown were visible on SWI in 15/41 cases, not always resulting in poor outcome (2/15 were scored mRS = 0-6). Early SWI changes, together with hypoperfusion, were associated with the occurrence of hemorrhage. Hyperperfusion on ASL, even when associated with hemorrhage detected on SWI, resulted in good outcome. Hyperperfusion predicted a better outcome than hypoperfusion (p = 0.0148). ASL is able to detect acute-stage hyperperfusion corresponding to luxury perfusion previously reported by PET studies. The presence of hyperperfusion on ASL-type perfusion seems indicative of reperfusion/collateral flow that is protective of hemorrhagic transformation and a marker of favorable tissue outcome. The combination of hypoperfusion and changes on SWI seems on the other hand to predict hemorrhage and/or poor outcome.


Chelidonium majus--an integrative review: traditional knowledge versus modern findings. Chelidonium majus L. (family Papaveraceae), or greater celandine, is an important plant in western phytotherapy and in traditional Chinese medicine. Crude extracts of C. majus as well as purified compounds derived from it exhibit a broad spectrum of biological activities (antiinflammatory, antimicrobial, antitumoral, analgesic, hepatoprotective) that support some of the traditional uses of C. majus. However, herbal medicine also claims that this plant has several important properties which have not yet been scientifically studied: C. majus is supposed to have diuretic, antitussive and eye-regenerative effects. On the other hand, C. majus also has scientifically proven effects, e.g. anti-osteoporotic activity and radioprotection, which are not mentioned in traditional sources. Moreover, recent controversy about the hepatoprotective versus hepatotoxic effects of Chelidonium majus has renewed the interest of the medical community in this plant. This review is intended to integrate traditional ethno-medical knowledge and modern scientific findings about C. majus in order to promote understanding of its therapeutic actions as well as its toxic potential.


Effects of homeopathic medicines on mood of adults with histories of coffee-related insomnia. The purpose of this within-subjects feasibility study was to determine whether two different homeopathic remedies, Nux Vomica (NV) and Coffea Cruda (CC), exert effects on subjective mood ratings in healthy adults with a history of coffee-induced insomnia. The impact of individual personality traits, anxiety sensitivity or Type A cynical hostility, and homeopathic constitutional type (HTYPE-NV, HTYPE-CC), on remedy effects was examined to evaluate differential responsivity, in accord with clinical claims. Young adults of both sexes (ages 18-31) with above-average scores on standardized personality scales for either cynical hostility or anxiety sensitivity, and a history of coffee-induced insomnia, participated in the month-long study. At-home polysomnographic recordings were obtained on successive pairs of nights once per week for a total of 8 recordings (nights 1, 2, 8, 9, 15, 16, 22, 23). Subjects (N = 59) received placebo pellets on night 8 (single-blind) and verum pellets in 30c doses of one of two homeopathic remedies, NV or CC, on night 22 (doubleblind). Subjects completed the Profile of Mood States Scales at bedtime. The remedies produced differential effects on anger and overall mood, with improved mood following CC administration. A similar trend for depression was observed. Anxiety sensitive subjects experienced less tension following CC, whereas hostile subjects receiving CC became more tense. The high HTYPE-CC receiving CC experienced less vigor. The high HTYPE-CC receiving NV experienced more vigor.


Are sham acupuncture interventions more effective than (other) placebos? A re-analysis of data from the Cochrane review on placebo effects. A recent Cochrane review on placebo interventions for all kinds of conditions found that 'physical placebos' (which included sham acupuncture) were associated with larger effects over no-treatment control groups than 'pharmacological placebos'. We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other 'physical placebos'. All trials included in the Cochrane review as investigating 'physical placebos' were classified as investigating either (sham) acupuncture or other physical placebos. The latter group was further subclassified into groups of similar interventions. Data from the Cochrane review were re-entered into the RevMan 5 software for meta-analysis. The primary analysis was a random-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos. Out of a total of 61 trials which reported a continuous outcome measure, 19 compared sham acupuncture and 42 compared other physical placebos with a no-treatment control group. The trials re-analyzed were highly heterogeneous regarding patients, interventions and outcomes measured. The pooled standardized mean difference was -0.41 (95% confidence interval -0.56, -0.24) between sham acupuncture and no treatment and -0.26 (95% CI -0.37, -0.15) between other physical placebos and no treatment (p value for subgroup differences = 0.007). Significant differences were also observed between subgroups of other physical placebos. Due to the heterogeneity of the trials included and the indirect comparison our results must be interpreted with caution. Still, they suggest that sham acupuncture interventions might, on average, be associated with larger effects than pharmacological and other physical placebos.


Can you combine herbal therapy with physical agents in the treatment of venous leg ulcers? Evaluation of healing and antimicrobiological effects: a pilot study. Venous leg ulcers are an important and common health problem. The aim of this study was to determine the effects of herbal therapies alone or in combination with physical therapy in the treatment of venous ulcers, as well as their antibacterial effects. Our study included 60 patients (3 groups, 20 patients each) with non-infected venous leg ulcers. The patients were treated with herbal therapy alone (group HTC), with a combination of electro-ionizing radiation and herbal therapy (group ERHT) or with a combination of polarized light and herbal therapy (group PLHT). Surface area and score of venous leg ulcers were followed clinically at baseline and at the end of 1, 3, 5, and 7 weeks of treatment. Comparing the results within the HTC, PLHT, and ERHT groups we found that the physical agents and herbal therapy significantly accelerated the healing of venous leg ulcers and reduced bacterial flora (p < 0.05). Comparing the results between the tested groups revealed no statistically significant difference (p > 0.05). Our results demonstrate healing and antibacterial effects of combined physical and herbal therapies, but no superiority of the combined treatment for venous leg ulcers as compared to treatment by herbal therapy alone.


Topical treatment of necrotising herpes zoster with betulin from birch bark. Betulin, a pentacyclic triterpene, is the main constituent of the outer bark of birches (Betula alba). In recent years, anti-microbial, anti-inflammatory and differentiation-promoting effects of betulin have been described. A betulin-based emulsion without preservatives and detergent emulsifiers can be prepared from birch bark extract. We report the successful treatment with betulin emulsion of a severe necrotising herpes zoster in an immunosuppressed patient who had not responded to a conventional topical treatment. The betulin emulsion was directly applied to the wounds without causing any side effects. The presented case report demonstrates impressive skin tolerance and wound-healing properties of the betulin emulsion. These should be further evaluated.


Person-centred medicine: towards a definition.


Research initiatives in Europe.

Research initiatives in Europe.


Early enteral fat supplementation with microlipid® and fish oil in the treatment of two premature infants with short bowel. The infusion of Intralipid® is a main risk factor for parenteral nutrition-associated cholestasis in infants with short bowel syndrome. Early provision of enteral fat to reduce the use of Intralipid while providing adequate fat for the growth of infants with short bowel has not been reported. We present 2 cases of premature infants with short bowel who received early supplementation of enteral Microlipid® and fish oil. This approach allowed us to discontinue Intralipid shortly after initiating feedings. The infants tolerated Microlipid/fish oil well without adverse reactions, had appropriate weight gain and ostomy output. They underwent bowel reanastomosis 3 weeks after enteral feeding began, and were discharged on full oral feedings. In case 1, the infant did not develop parenteral nutrition-associated cholestasis; in case 2, cholestasis had developed before initiating feeds, but was not aggravated by enteral fat and was improving prior to discharge.


Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Congenital diaphragmatic hernia (CDH) is associated with high mortality and morbidity. To date, there are no standardized protocols for the treatment of infants with this anomaly. However, protocols based on the literature and expert opinion might improve outcome. This paper is a consensus statement from the CDH EURO Consortium prepared with the aim of achieving standardized postnatal treatment in European countries. During a consensus meeting between high-volume centers with expertise in the treatment of CDH in Europe (CDH EURO Consortium), the most recent literature on CDH was discussed. Thereafter, 5 experts graded the studies according to the Scottish Intercollegiate Guidelines Network (SIGN) Criteria. Differences in opinion were discussed until full consensus was reached. The final consensus statement, therefore, represents the opinion of all consortium members. Multicenter randomized controlled trials on CDH are lacking. Use of a standardized protocol, however, may contribute to more valid comparisons of patient data in multicenter studies and identification of areas for further research.


Fecal expression of human β-defensin-2 following birth. Newborns display high intestinal permeability and a naive adaptive immune system, but infections are rare, indicating strong innate defense mechanisms. To measure the kinetics of fecal β-defensin-2 (HBD2), an inducible endogenous antimicrobial peptide produced by intestinal epithelial cells, in full-term and preterm infants. As a first step of this bicentric study, we enrolled 30 healthy full-term infants and 20 healthy preterm infants, with fecal samples collected at days 3, 7, 12 and 30 in full-term infants and at days 15, 30 and 60 in preterm infants. As a second step, we enrolled 10 preterm infants with intestinal distress, either necrotizing enterocolitis (NEC) Bell's stage III (n = 3) or isolated rectal bleeding (n = 7) and 20 controls, cross-matched for gestational age and age at sampling. HBD2 decreased significantly from day 3 to day 7 (227 ng/g; 14-440 vs. 117 ng/g; 30-470, p = 0.01) then moderately until day 30 (84 ng/g; 10-500) in healthy full-term infants. Healthy preterm infants showed similar high levels between days 15 and 60 (82 ng/g; 30-154 and 85 ng/g; 26-390, respectively). No significant variation of fecal HBD2 levels was observed between infants with clinical features of intestinal distress (77 ng/g, 2-1,271) and cross-matched controls (56 ng/g, 31-164). However, 2/3 infants with NEC and 1/7 infants with isolated rectal bleeding had HBD2 levels above the maximal level observed in controls. The kinetics of fecal HBD2 in the neonatal period indicate that this inducible defensin can be detected at high level in the feces of full-term and preterm infants, independently of gestational age or mode of feeding. The potential role of fecal HBD2 in detecting NEC is suggested.


Moderate physical training attenuates the effects of perinatal undernutrition on the morphometry of the splenic lymphoid follicles in endotoxemic adult rats. Physical training is a well-known inducer of positive physiological adaptations. The effects of moderate physical training on the morphometry of splenic lymphoid follicles of endotoxemic rats submitted to a perinatal low-protein (LP) diet were evaluated. Male Wistar rats were divided into two groups according to their mother's diet (17% casein, control, C) and, undernourished (8% casein, LP diet). On postnatal day 63, the animals were submitted to moderate physical training (8 weeks, 5 days·week⁻¹, 60 min·day⁻¹, at 70% of VO(₂max)). After the physical training period, half of each group received an injection of either lipopolysaccharide (LPS) or saline. Plasma corticosterone concentration, blood differential leukocyte counts and splenic morphometric parameters were analyzed. In undernourished toxemic (LP + LPS), LPS increased plasma corticosterone concentrations, but not in previously trained (LP + T + LPS) animals. Neutrophilia and lymphopenia in response to LPS was more pronounced in pups from undernourished mothers (LP + LPS). LP + LPS animals showed a higher increment (47.4%) in the number of lymphoid follicles, a reduction in the number and size of the splenic follicles, and in the marginal zone area. Those alterations were attenuated in trained animals (LP + T + LPS). Physical training attenuates the effects of nutritional programming on the splenic microanatomy by a mechanism that involves the hypothalamic-pituitary-adrenal axis.


Influence of cell cycle checkpoints and p53 function on the toxicity of temozolomide in human pancreatic cancer cells. Though an increased efficacy of carmustine and temozolomide (TMZ) has been demonstrated by inactivation of O(6)-methylguanine-DNA methyltransferase (MGMT) with O(6)-benzyl-guanine (BG) in human pancreatic tumors refractive to alkylating agents, the regulatory mechanisms have not been explored. The effects of TMZ and BG on apoptosis, cell growth, the mitotic index, cell cycle distribution, and protein expression were studied by TUNEL, cell counting, flow cytometry, and Western blot analysis, respectively. The wt-p53 human pancreatic tumor cell line Capan-2 and p53-efficient mouse embryonic fibroblasts (MEFs) were more responsive to treatment with TMZ + BG than mutant p53 Capan-1 and p53-null MEFs. S phase delay with a subsequent G2/M arrest was observed in Capans in response to BG + TMZ. The G1-to-S transition delay in Capan-2 was associated with p53-dependent apoptosis and was distinctly different from the presumed mismatch repair (MMR) killing operative during the G2/M arrest. The effect of p53 on BG + TMZ toxicity was supported by a marked change in apoptosis when p53 function was restored/inactivated. There was an early induction of MMR proteins in p53-efficient lines. p53 provokes a classic proapoptotic response by delaying G1-to-S progression, but it may also facilitate cell killing by enhancing MMR-related cell cycle arrest and cell death.


Chronic pancreatitis-like changes detected by endoscopic ultrasound in subjects without signs of pancreatic disease: do these indicate age-related changes, effects of xenobiotics, or early chronic pancreatitis? The threshold number of endoscopic ultrasound (EUS) criteria for diagnosing chronic pancreatitis (CP) is variable. The presence of more than three abnormal ductular or parenchymal features is typically used, but the diagnostic significance of fewer EUS criteria is currently unclear. The aim of this study was to determine the prevalence of EUS features of CP in patients without pancreaticobiliary disease and to analyze the association with specific factors of interest. Over a 24-month period, 2,614 patients underwent EUS for an indication unrelated to pancreaticobiliary disease. Main outcome measurements wereunivariate and multivariate analysis between any EUS abnormality and demographic data and habits. 82 patients (16.8%) showed at least one ductular or parenchymal abnormality. 38 patients presented with only one abnormal feature, 26 patients with two, 12 patients with three, 4 patients with four, and 2 patients with five. Low-level alcohol consumption significantly increased the risk of hyperechoic parenchymal foci, main pancreatic duct (MPD) dilatation and wall hyperechogenicity. Smoking was associated with an increased risk of hyperechoic parenchymal foci. Male gender and advanced age were significantly associated with an increased risk of MPD dilatation. Long-term smoking and alcohol consumption, although at a low dose, induces CP-like changes. These abnormalities might represent either a clinically silent CP or a toxic effect of smoking and alcohol. Conversely, MPD dilation might represent a normal age-related variant or, alternatively, an effect of chronic low-level alcohol consumption. and IAP.


Fatty acid composition of plasma lipid classes in chronic alcoholic pancreatitis. Supplementation of n-3 long-chain polyunsaturated fatty acids (LCPUFA) is considered as adjuvant therapy in acute pancreatitis. We investigated plasma fatty acid status in chronic pancreatitis (CP). Patients with alcoholic CP (n = 56, gender: 33/23 male/female, age: 60.0 [14.0] years (median [IQR]), who reported giving up alcohol consumption several years ago and 51 control subjects were included into the study. The fatty acid composition of plasma phospholipids (PL), triacylglycerols (TG) and sterol esters (STE) was analyzed. The sum of monounsaturated fatty acids was significantly higher in patients with CP than in controls (PL: 12.83 [3.35] vs. 12.20 [1.95], TG: 40.51 [6.02] vs. 37.52 [5.80], STE: 20.58 [7.22] vs. 17.54 [3.48], CP vs. control, % weight/weight, median [IQR], p < 0.05). Values of arachidonic acid were significantly lower in patients with CP than in controls (PL: 10.57 [3.56] vs. 11.66 [3.25], STE: 8.14 [2.63] vs. 9.24 [2.86], p < 0.05). Values of eicosapentaenoic acid and docosahexaenoic acid did not differ and there was no difference in the ratio of n-3 to n-6 LCPUFA. Our present data do not furnish evidence for the supplementation of n-3 LCPUFA to the diet of CP patients in relatively good clinical condition.


Chronic alcohol intake increases the severity of pancreatitis induced by acute alcohol administration, hyperlipidemia and pancreatic duct obstruction in rats. The mechanism of alcoholic pancreatitis is still unknown. It is of special interest why only about 5% of all alcoholics develop an episode of pancreatitis. We evaluated the role of long-term alcohol intake in the pathogenesis of alcoholic pancreatitis in rats. To evaluate the effect of long-term alcohol intake, rats were fed either a Lieber-DeCarli control diet (CD) or a Lieber-DeCarli alcohol diet (AD) for 6 weeks. Then, rats were infused over 2 h with either Ringer's solution (CO) or ethanol (E). In additional animals, alcoholic pancreatitis was induced by ethanol combined with hyperlipidemia and temporary pancreatic duct obstruction (EFO). Controls received Ringer's solution combined with hyperlipidemia and temporary pancreatic duct obstruction (RFO). Intravital microscopy (pancreatic perfusion and leukocyte adhesion), alcohol concentrations, amylase, lipase, cholesterine and triglyceride levels in plasma, myeloperoxidase activity and histology were evaluated at different time intervals. In those animals which received the Lieber-DeCarli control diet, capillary perfusion was reduced in the E group and further reduced in the EFO group as compared to the controls (CO, RFO; p < 0.01). Leukocyte adhesion was significantly increased in rats receiving E (p < 0.01), and was further increased in the combination group EFO (p < 0.01). EFO induced histologically evident acute pancreatitis. The additional administration of a long-term alcohol diet further increased microcirculatory disturbances and pancreatic injury significantly (EFO-AD > EFO-CD). This study shows that alcoholic pancreatitis is induced by the combination of ethanol and individual cofactors. Chronic alcohol abuse intensifies these changes. Therefore, long-term alcohol intake seems to be a major factor in the pathogenesis of alcoholic pancreatitis.


Effects of hydroxyethyl starch, gelatin and dextran on endothelium-derived relaxation in porcine coronary arteries. In a pilot study we could show that hydroxyethyl starch (HES) induced a significant reduction of endothelium-dependent relaxation (EDR) and the endothelium-derived hyperpolarizing factor (EDHF). In this follow-up study we investigated whether this effect of HES was dose-dependent and whether it could be replicated with other colloids like dextran (DX) and gelatin (GL). Rings of fresh porcine coronary arteries were consecutively tested with or without HES, DX or GL (5, 10, or 20 mg/ml). Indomethacin was added in all measurements to eliminate prostacyclin effects. Prostaglandin F₂α was used for contraction and bradykinin (BK, 10⁻¹⁰ to 10⁻⁵ M) for inducing EDR. After blocking nitric oxide (NO) by N-nitro-L-arginine (L-NNA), the experiments were repeated to assess the EDHF-mediated relaxation response to BK. HES induced a reduction in EDR for the BK concentrations of 10⁻⁸ and 10⁻⁷ M (n = 10; p < 0.05). After NO blockage with L-NNA, the relaxation response was reduced especially for the BK concentrations of 10⁻⁶ and 10⁻⁵ M (p < 0.05). GL showed a reduction in EDR with or without NO blockage with L-NNA especially for the BK concentrations of 10⁻⁶ and 10⁻⁵ M (n = 14; p < 0.05). DX induced a significant reduction in EDR for the BK concentrations of 10⁻⁷ and 10⁻⁶ M (n = 12; p < 0.05). After NO blockage with L-NNA, the relaxation response was reduced especially for the BK concentrations of 10⁻⁶ and 10⁻⁵ M (p < 0.05). For clinically relevant concentrations of HES, DX and GL a significant reduction in both NO-induced and NO-/prostacyclin-independent EDR can be found in epicardial coronary arteries of the pig.


Effects of papaverine on twitches in mouse diaphragm. This study examined the inhibitory effects of papaverine on twitches directly elicited by electrical stimulation of the mouse diaphragm. Papaverine (3-100 μM) inhibited twitches in a dose-dependent manner. Papaverine increased the cyclic adenosine monophosphate (cAMP) but not cyclic guanosine monophosphate (cGMP) content. IBMX, Db-cAMP and 8-br-cGMP did not affect twitches, whereas verapamil and NaCN inhibited twitches. Increases in extracellular Ca²+ removed the twitch inhibition caused by verapamil but not that caused by papaverine. Papaverine (30 and 100 μM) and NaCN (1 mM) decreased creatine phosphate and ATP contents. These results suggest that the relaxing effects of papaverine on mouse diaphragm are mainly due to inhibition of aerobic energy metabolism.


Contribution of cyclooxygenase-dependent mechanisms to contractile responses to donepezil in the rat urinary bladder. Donepezil, an inhibitor of acetylcholinesterase, is used to improve cholinergic neurotransmission and cognitive function in Alzheimer's disease. In the present study, contractile effects of donepezil on the rat urinary bladder were examined and compared with those of the nonselective cholinesterase inhibitor neostigmine. Both donepezil and neostigmine produced concentration-dependent contractile responses of the isolated rat urinary bladder strips. The neostigmine-induced contractions were abolished by atropine. However, donepezil produced contractions of urinary bladders partly through atropine-insensitive mechanisms. The atropine-resistant component of donepezil-induced contraction was significantly reduced by the cyclooxygenase inhibitor indomethacin. These results suggest that cyclooxygenase-derived prostanoids contribute, at least in part, to contractile effects of donepezil in the rat urinary bladder.


Outcomes of empirical eating disorder phenotypes in a clinical female sample: results from a latent class analysis. To empirically classify phenotypes of eating disorders (ED) using latent class analysis (LCA), and to validate this classification based on clinical outcomes. LCA was applied to 968 inpatients. The resultant classes were validated by clinical outcomes including mortality. A 5-class solution showed the best fit. The symptoms of latent class 1 (LC1; 26% of the sample) resembled anorexia nervosa (AN), bingeing-purging (AN-B/P) subtype; those of LC2 (23%) resembled bulimia nervosa; those of LC3 (11%) were close to AN-B/P without weight and body concerns; those of LC4 resembled restrictive anorexia nervosa (RAN) without weight and body concerns, and those of LC5 RAN. A history of hospitalization for ED was significantly more frequent for LC3 and LC4. The lowest BMI at admission were presented in LC4. LC1 showed the highest level of psychological disturbances and LC4 the lowest. LC3 and LC4 differed from LC1 and LC5 by higher percentages of treatment dropout (64.9 vs. 57.2 and 55.7 vs. 47.5%, respectively; overall p = 0.001). Survival rates tended to be different between the LC (p = 0.09). Subgroups of AN patients with low weight and body concerns seem more severe at hospitalization and more difficult to manage, with a higher rate of treatment dropout than the 'typical' AN patients.


Differential responses to emotional interference in paranoid schizophrenia and bipolar mania. Studies on emotional biases towards threat-related stimuli in schizophrenia and bipolar disorder have provided, so far, inconsistent results. The aim of the present study was to investigate emotional interference in acute schizophrenic and manic patients and its clinical correlates by using a card version of the Emotional Stroop Task designed with neutral, paranoid, depressive and manic words. Thirty paranoid schizophrenia patients, 30 manic patients and 60 healthy controls were compared on the Emotional Stroop Test. Response times (RT) were collected for each card. Interference indices were calculated by subtracting the RT for the neutral card from the RT for the depressive, paranoid and manic cards. The schizophrenic and manic patient groups showed an increased interference effect when the emotional valence was relating to the disorder-specific psychopathology. In addition, the paranoid interference index correlated with positive symptoms in schizophrenic patients. By contrast, no correlation was evidenced between interference indices and mood symptoms in the manic group. Among schizophrenic patients, paranoid interference might be a state-related emotional abnormality associated with persecutory delusions. In mania, we suggest that emotional biases towards depressive as well as manic information might be trait features of the emotional hyperreactivity involved in the vulnerability to bipolar disorder.


The relationship between personality organization and psychiatric classification in chronic pain patients. The present study investigated the relationship between psychiatric classification and personality organization (PO) in a secondary/tertiary clinical sample of chronic pain patients (CPPs). Forty-three patients were administered the Structured Clinical Interview for DSM-IV (SCID I+II) and the Structured Interview of Personality Organization (STIPO). The prevalence of axis I and axis II disorders was correlated with the STIPO level of PO. The STIPO dimensional ratings of patients without personality disorder (PD) were compared to those of patients diagnosed with one or more PDs. Axis I comorbidity was high (93%), and 63% of the patients met the criteria for at least one axis II diagnosis. Twenty-five patients (58%) were diagnosed as borderline PO, with high-level impairments in the dimensions 'coping/rigidity', 'primitive defenses' and 'identity'. Higher axis I and axis II comorbidity corresponded with greater severity of PO impairment. No difference was found between the dimensional ratings of patients without PD and those of patients with one or more PDs. The assessment of PO is a crucial issue for diagnosis and treatment planning in CPPs, since it represents a measure of structural impairment that is to a considerable extent independent of axis I and II diagnoses. Moreover, the STIPO dimensional rating focuses on the most salient dysfunctions at a given time.


Gender, depressive symptoms and patterns of alcohol use among college students. Serious alcohol-related negative consequences are associated with a number of drinking behaviors among college students. Thus, it is critical to identify students who are at greater risk for hazardous drinking. Although some studies have shown that depressive symptoms may be associated with alcohol use in this population, findings are not consistent. The current study extends previous research by investigating the relationship between depressive symptoms, daily alcohol use and compulsive drinking among college students and whether gender moderates these relationships. The participants were 904 college students (495 females; mean age = 20.07 ± 1.85 years) who filled out questionnaires that focused on drinking behaviors and severity of depressive symptoms. Gender moderated the relationship between depressive symptoms and daily alcohol consumption. In male college students, worse depressive symptoms were associated with increased daily alcohol use and with greater risk for compulsive drinking. In female college students, worse depressive symptoms increased the risk for compulsive drinking, but not for greater daily alcohol use. Results suggest that prevention programs aimed at decreasing harmful alcohol use among college students must take into consideration the role of both gender and depressive symptoms in the development of problematic drinking behaviors.


Childhood trauma and psychopathology among alcohol-dependent men: no interaction with temperament and character. The aim of this study was to evaluate possible interactions between childhood trauma, temperament, character, and psychopathology among alcohol-dependent men. Participants were 156 alcohol-dependent men consecutively admitted to a dependency treatment unit. The Childhood Abuse and Neglect Questionnaire, the Temperament and Character Inventory, and the Symptom Checklist-Revised were administered to all participants. Childhood abuse and neglect did not have any effect on temperament and character scores in multivariate analysis. Whereas childhood abuse had a significant main effect on all types of clinical psychopathology except depression and psychoticism scores, childhood neglect only had a significant main effect on depression scores. There was no interaction between childhood abuse and neglect on these analyses. Among alcohol-dependent men, childhood abuse and neglect contribute to general psychopathology through distinct clinical consequences, independently of temperamental and characterological features.


Morphogenetic targets and genetics of undescended testis. Although important advances in testicular physiology have been achieved, the aetiology of human cryptorchidism remains mostly unknown. Next to sex steroidal signaling pathways, morphogenetic genes are specifically involved in the testicular descent via gubernacular development. Mutations in the human genes encoding insulin-like factor 3 (INSL3) and its Leu-rich repeat-containing G protein-coupled receptor 8 (LGR8), homeobox A10 (HOXA10), zinc finger 214 (ZNF214) and 215 (ZNF215) have occasionally been identified but do not seem to be a frequent cause of cryptorchidism. On the other hand, common polymorphisms in these genes have recently been investigated as contributing risk factors for idiopathic isolated (nonsyndromic) cryptorchidism.


An XY agonadal Oldenburg warmblood horse exhibiting a male phenotype. In a 1.5-year-old Oldenburg horse, a clitoris-like structure instead of a penis was identified in the prepuce. The external genital organs did not show any abnormalities at visual inspection except that exteriorization of the penis was not possible, not even under general anesthesia. The horse's owner observed a continuous dripping of urine and a tendency to mild colics beginning 2 weeks after birth. Testosterone concentration was 0.01 ng/ml and therefore under the threshold for geldings, and the horse did not respond to the application of gonadotropin-releasing hormone (GnRH). The inner genital consisted of a male urinary tract. Gonads and accessory male glands were missing. Residual structures of a female genital tract were not observed. Abnormalities of the mesentery could be found which might explain the recurrent colics of this horse. A cytogenetic examination revealed a 2n = 64,XY-karyotype and a positive result for the SRY-PCR. This is the first report on an agonadal horse with a male karyotype and a pseudohermaphrodite phenotype.


Feasibility and activity of sorafenib and sunitinib in advanced penile cancer: a preliminary report. We describe our experience with sorafenib and sunitinib in the treatment of chemotherapy-refractory advanced penile squamous cell carcinoma (SCC). Between May 2008 and June 2009, 6 advanced penile cancer patients were treated with sorafenib or sunitinib in our center. All of them had previously received at least two chemotherapy regimens. Tumor responses were evaluated by radiologic assessment and serum SCC antigen change. Immunohistochemical staining of CD34 and Ki-67 was performed in 3 paired tumor tissues before and after treatment. In the 6 patients, 1 partial response and 4 stable diseases were observed. Three patients showed pain response and had an improvement in quality of life. After molecular-targeted therapies, reduction in microvessel density and Ki-67 labeling index was observed in paired specimens. Serum SCC antigen levels were decreased in 5 patients after 1 week of medication. The patient who achieved partial response had an SCC antigen reduction of nearly 95% after treatment with sunitinib. Serious adverse events were fatal infection and rupture of the femoral vessel, which were unlikely related to the medication. The feasibility and activity of sorafenib and sunitinib in our series suggest that this approach may be a promising alternative in chemotherapy-refractory advanced penile SCC.


Heat shock protein 90 regulates IκB kinase complex and NF-κB activation in angiotensin II-induced cardiac cell hypertrophy. Heat shock protein 90 (HSP90), one of the most abundant proteins in the cardiac cells is essential for cell survival. Previous studies have shown that angiotensin II induces cardiac cell hypertrophy. However, the role of HSP90 in the angiotensin II-induced cardiac hypertrophy is unclear. In this study, we showed that HSP90 regulated angiotensin II-induced hypertrophy via maintenance of the IκB kinase (IKK) complex stability in cardiac cells. An HSP90 inhibitor, geldanamycin (GA), significantly suppressed angiotensin II-induced [³H]leucine incorporation and atrial natriuretic factor expression in cardiac cells. GA also inhibited the NF-κB activation induced by angiotensin II. Importantly, treatment with GA caused a degradation of IKKα/β; on the other hand, a proteasome-specific inhibitor restored the level of IKKα/β. We also found that GA prevented HSP90-IKKs complex induced by angiotensin II in cardiac cells. The small interfering RNA (siRNA)-mediated knockdown of HSP90 expression significantly inhibited angiotensin II-induced cell hypertrophy and NF-κB activation. These results suggest that angiotensin II-induced cardiac hypertrophy requires HSP90 that regulates the stability and complex of IKK.


Premature infants and vaccination.

Premature infants and vaccination.


Caring about rabies: a deadly, neglected disease.


Haemophilus influenzae type b conjugate vaccines: considerations for vaccination schedules and implications for developing countries. Prior to widespread vaccination, Haemophilus influenzae type b was a leading cause of severe childhood bacterial infection, including meningitis, worldwide. Over the last decade the world has taken great strides towards controlling Hib disease through routine use of conjugate vaccines in developed and developing countries. Currently there is no consensus on the appropriate schedule by which to use Hib vaccine. Vaccination schedules around the world vary greatly, particularly between high and low income countries. Questions remain as to the most effective and efficient schedule of primary doses, the need for a booster dose, and the implications of using combination vaccines. Here, we present a synthesis of data supporting various Hib vaccine schedules, with a focus on the implications for developing countries.


The global pertussis initiative: Meeting report from the Regional Latin America Meeting, Costa Rica, 5-6 December, 2008. Pertussis remains endemic across the world, with an estimated 279,000 deaths in 2002, the majority in infants under 1 year of age. Worldwide epidemiologic data indicates increasing infection rates in older children and adults, which act as a source of infection to young infants. The Global Pertussis Initiative (GPI) is an expert scientific forum, which has published consensus recommendations for the monitoring, prevention, and treatment of the disease. This paper reports the proceedings of a regional meeting, held in Costa Rica in December 2008. The meeting gathered information on regional epidemiological, diagnostic capabilities and the ability to introduce GPI recommended vaccine strategies in Latin America. The capacity of Latin American countries to conduct vaccination programs is high and there is considerable government support. Whole-cell pertussis vaccines are used across Latin America, which appear to be quite effective. A 4-dose schedule is typically used (2, 4, 6, and 18 months), and a booster given at 4 to 6 years of age, with coverage often above 90%, but with regions of low coverage due to political and geographical difficulties. Adequate surveillance is lacking in many countries, giving insufficient data to guide vaccination policy. Improvements are being made, with countries such as Costa Rica, Panama, and Argentina introducing polymerase chain reaction (PCR) diagnosis. Those countries that do not currently use a preschool booster should launch one. Implementing vaccination programs in adolescents and/or adults to reduce exposure to infants would be beneficial and possible in most countries, given their current infrastructure.


Immunogenicity and safety of a novel AS03(A)-adjuvanted H1N1 2009 pandemic influenza vaccine in adults in Japan. This study evaluated the immunogenicity and safety of a novel H1N1 2009 pandemic vaccine(A/California/7/2009) in Japanese adults. Following Dose 1, seroprotection rate (HI titre ≥1:40) was 95%, seroconversion rate was 94% and the geometric mean titre (GMT) was 230.3 (geometric mean fold rise [GMFR]: 26.3). Following Dose 2, seroprotection rate as well as seroconversion rate were 100%; HI antibody GMT rose to 485 (GMFR: 55.4). European and United States regulatory acceptance criteria for immunogenicity were met and exceeded following each dose of the vaccine. Solicited symptoms recorded during the 7-day post-vaccination follow-up period were of mild to moderate intensity (Grade 3: ≤4% of subjects). The most frequently reported solicited symptoms after both doses were pain at the injection site, fatigue and muscle ache. Unsolicited adverse events causally related to vaccination were reported in 18 subjects; none were of Grade 3 intensity. There were no serious adverse events. This open-label, single-group, multi-center Phase II study enrolled 100 healthy subjects aged 20-64 years(stratification [1:1] by age: 20-40 years and 41-64 years) to receive 21 days apart, two doses of a monovalent, split-virion AS03(A)-adjuvanted H1N1 2009 pandemic vaccine (3.75 μg hemagglutinin [HA]). Blood samples collected before vaccination and 21 days after each dose were analyzed using hemagglutination inhibition (HI) assay. A single dose of AS 03A-adjuvanted, 3.75 μg HA H1N1 2009 pandemic influenza vaccine was highly immunogenic in Japanese adults with a clinically acceptable safety profile, thereby making it a potential candidate for mitigating A/H1N1-associated morbidity and mortality.


Evaluation of vaccination results in high-risk patients included in hepatitis B vaccination program. Hepatitis B infection is one of the infectious diseases quite common in Turkey and around the world. Hepatitis B virus infection is a significant health problem which may cause chronic hepatitis, cirrhosis and hepatocellular carcinoma. With the introduction of Hepatitis B vaccine, a significant progress has been made in the prevention of HBV infections. The purpose of the study was to evaluate the characteristics of the individuals included in the risk group who admitted to our vaccination clinic, as well as their immune responses following the vaccination. Among the patients admitted to the vaccination clinic of our hospital between January 2003-December 2005 and that were included in the risk group (patients who have family members with chronic Hepatitis B infection, healthcare workers, hemodialysis patients etc.), those who were included in the vaccination program by examining the results of HBs Ag, anti-HBc and anti-HBs were evaluated in terms of their characteristics (age, gender, smoking etc.) and results of Anti-HBs score. A total of 958 people were included in the vaccination program. Upon evaluation in terms of risk factors, presence of patients with chronic hepatitis B infection in the family was found to be 80.6% (772/958), being healthcare worker was 9.2% (88/958), HCV positivity and chronic liver disease was 3.0% (29/958), being a hemodialysis patient was 2.8% (27/958), and being an oncology patient was 2.1% (20/958). Post-vaccination immune response could be evaluated in 69.8% (669/958) of patients and no responsiveness to vaccine was detected only in 8.1% (54/669) of them. Of the non-responders, 64.8% (35/54) were hemodialysis and oncology patients. Anti-HBs positivity rate following hepatitis B vaccination program was found compatible with the results of previous studies. With this vaccine of considerably high effectiveness, immunization of the entire community including primarily the risk groups should be targeted.


Assessment of HPV vaccines: from the burden of disease to the health technology assessment approach.