Localisation of the central sulcus region in glioma patients with three-dimensional fluid-attenuated inversion recovery and volume rendering: comparison with functional and conventional magnetic resonance. Volume rendering (VR) of three-dimensional (3D) fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) images shows regional intensity differences, reflecting the central sulcus (CS) region and occipital cortex. The purpose of this study was to determine whether 3D FLAIR with VR could be used as an alternative method to localise the CS region in comparison with functional and conventional MR-imaging in patients with perirolandic glioma. Eleven patients with intracranial gliomas were studied with single-slab 3D FLAIR including VR and conventional T1-weighted imaging. In all patients, preoperative functional magnetic resonance imaging (fMRI) was performed with a motor paradigm of the hand. The hypo-intense central gyri on 3D FLAIR with VR were interpreted as the CS area. Localisation of the motor hand knob on anatomical images and fMRI results were used for identification of the primary motor cortex. Anatomical localisation of the motor hand knob on T1-weighted images was possible in 91% of both hemispheres. In 73% of the affected hemispheres (AH) and 91% of the unaffected hemispheres (UH) the hand knob and CS region could be identified on 3D FLAIR axial and VR images, respectively. With one exception, fMRI activation confirmed the CS region as observed with 3D FLAIR with VR. Volume rendering of 3D FLAIR MR images shows central hypo-intensities frequently corresponding with the CS region. Two-dimensional localisation of the CS region on conventional T1-weighted images and fMRI seems favourable compared to 3D FLAIR. However, in selected cases, especially where fMRI is not possible or feasible, volume rendering with 3D FLAIR may enhance the 3D visualisation of gliomas in relation to the CS region which can be used as an alternative method in the presurgical structural and functional evaluation of neurosurgical patients.


Novel strategies in brachial plexus repair after traumatic avulsion. Clinical trials in spinal cord injury (SCI) can be affected by many confounding variables including spontaneous recovery, variation in the lesion type and extend. However, the clinical need and the paucity of effective therapies has spawned a large number of animal studies and clinical trials for SCI. In this review, we suggest that brachial plexus avulsion injury, a longitudinal spinal cord lesion, is a simpler model to test methods of spinal cord repair. We explore reconstructive techniques currently explored for the repair of brachial plexus avulsion and focus on the use of olfactory ensheathing cell transplantation as an adjunct treatment in brachial plexus repair.


Temporary bilateral external carotid artery clamping to reduce blood loss during removal of calvarial meningioma: a technical note. Large calvarial lesions may bleed extensively during their removal. The main vascular supply to such lesions is from branches of the external carotid arteries (ECAs). Bilateral ECA embolisation has been described to reduce the vascularity, and therefore blood loss of such lesions during their surgical removal, but it is expensive and not easily available in developing countries. In addition, it is associated with significant morbidity. A case of a large calvarial meningioma, extending across the midline is presented in which both external carotids were temporarily clamped to reduce blood loss. Blood loss was low and the complications of permanent occlusion of the arteries avoided. This technique can be used for vascular calvarial lesions extending across the midline where embolisation is not feasible or has failed.


Stem cells in the adult human brain.

Stem cells in the adult human brain. The rapidly advancing field of stem cell research holds great promise for regenerative medicine. Regenerating brain tissue, while technically the most challenging application of stem cell biology, is also likely to reap the most reward for patients. Here, we review the current state of stem cell research in the field of human neuroscience and highlight aspects that will be of relevance to neurosurgeons.


The presigmoid approach for removal of tumours causing ventral compression of the brainstem. Surgical results and postoperative quality of life. To assess surgical results and quality of life after removal of tumours causing ventral compression of the brainstem using the presigmoid or combined presigmoid/retrosigmoid approaches. A review of all our patients operated on with removal of tumours causing ventral compression of the brainstem in whom either the presigmoid or combined presigmoid/retrosigmoid approaches were used. Post-operative quality of life was assessed using the SF-36 questionnaire. A total of 12 consecutive patients were included. A favourable complication profile was found. Cerebrospinal fluid leakage and secondary hydrocephalus were the most frequent complications. Post-operative scores from Karnofsky Performance Scale and ECOG after median 24 months were median 85 and 1, respectively, representing ability to carry on daily activities. Nevertheless, quality of life as assessed subjectively by SF-36 showed significantly reduced values as compared with normative values from Norwegian population. We found favourable surgical results when using the presigmoid approach alone or combined with the retrosigmoid route for large-sized extrinsic tumours causing ventral compression of the brainstem, both regarding complication profile, degree of tumour removal and functional outcome. However, impact of disease and surgery on quality of life appears to be more significant when assessed subjectively by the patients.


Bone marrow as a source of hematopoietic stem cells for human gene therapy of β-thalassemia. β-Thalassemia is a severe inherited anemia caused by insufficient production of β-globin chains. Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only cure, and is limited by donor availability and regimen-related toxicity and mortality. Gene therapy is a promising therapeutic tool for all thalassemic patients lacking a compatible donor and potentially provides transfusion independence in the absence of transplant-related complications, such as graft rejection and graft-versus-host disease. The issue of HSC procurement is critical in this setting because of the specific features of thalassemic syndromes, which include bone marrow (BM) expansion, ineffective erythropoiesis, and splenomegaly. Little is known about the efficiency of CD34(+) cell yield from steady-state BM harvests from thalassemic patients. We have collected data on safety and cell yield from 20 pediatric patients with β-thalassemia who underwent autologous BM harvest before allogeneic HSC transplantation, and from 49 age-matched sibling donors who also underwent BM harvest. The procedure was safe, as no significant adverse events occurred. In terms of cell yield, no difference was found between patients and normal donors in the number of CD34(+) cells and total nucleated cells harvested. Most importantly, no difference was found in the proportion of myeloid and erythroid progenitors, suggesting a similar repopulating capacity. On the basis of these results, we conclude that steady-state BM can be used as a safe and efficient source of HSC for gene therapy of β-thalassemia.


Recurrence of benign meningiomas: predictive value of proliferative index, BCL2, p53, hormonal receptors and HER2 expression. The biological behaviour of meningiomas and the risk of recurrence in individual cases cannot be predicted by using conventional histological criteria alone. A number of histologically benign meningiomas may recur, even after gross complete surgical removal. A retrospective immunohistochemical and statistical analysis of 60 patients with benign intracranial meningiomas (that have been grossly totally resected) was undertaken to determine the correlation of clinicopathological characteristics and expression of biological markers (proliferation index (PI) assessed by Ki67, hormonal receptors, p53, BCL2 and HER2, estrogen receptors, ER and progesterone receptors, PR) with prediction of recurrence. HER2 expression showed a significant inverse correlation with PR and a significant direct correlation with PI. PR-negative and HER2-positive cases showed a statistically significant higher mean PI than PR positive and HER2-negative cases. Univariate analysis showed that recurrence was significantly associated with male gender, cranial base location, the presence of bone and soft tissue invasion, some atypical histological features, higher PI, negative PR expression, and positive p53, BCL2 and HER2 expression. Multivariate analysis showed that the presence of bone and soft tissue invasion and/or the expression of p53 proved to be independent predictors of tumour recurrence. The presence of some atypical histological features and high PI were significant predictors of tumor recurrence, however, they were statistically excluded to avoid multicolinearity. Risk stratification based on histomorphology alone remains problematic. We conclude that soft tissue and bone invasion, some atypical histological features, p53 expression and high PI identify meningiomas with benign histological features but unfavourable clinical outcome. We suggest that those patients should be followed more closely for evidence of recurrent tumour or may be treated more aggressively at the time of diagnosis.


E13.5 retinal progenitors induce mouse bone marrow mesenchymal stromal cells to differentiate into retinal progenitor-like cells. Retinal progenitor cells (RPC) are an excellent resource for retinal replacement therapy but usually unavailable. We attempted to induce bone marrow mesenchymal stromal cells (BMSC) into RPC. BMSC and embryonic day 13.5 (E13.5) RPC derived from wild-type or enhanced green fluorescence protein (EGFP) transgenic (Egfp(+/+)) mice were co-cultured in a transwell or re-aggregation system. Gene and protein expressions were investigated by reverse transcription-polymerase chain reaction (PCR) and immunofluorescence, respectively. Spontaneous cell fusion was evaluated by Chloromethylbenzamido derivative of 1,1'- dioctadecyl-3,3,3',3' - tetramethylindocarbocyanine perchlorate (CM-DiI) labeling together with EGFP tracing. BMSC from both wild-type and Egfp(+/+) mice displayed similar spindle shapes. The undifferentiated BMSC already expressed immature neural markers but did not express Nfl, Gfap or the retina-related genes Pax6, Math5 and Brn3b. When co-cultured with E13.5 RPC in the transwell system, BMSC displayed transient expression of early retinal development genes, including Pax6, Math5 and Brn3b at 3 days, as well as long-term expression of Nfl (up to 21 days). No expression of the late photoreceptor gene rhodopsin could be detected at any time. In re-aggregation co-culture, E13.5 RPC induced EGFP-positive BMSC to express not only the early retinal development genes but also the late gene rhodopsin. Furthermore, a small fraction of BMSC could be induced to express the synaptophysin protein. Re-aggregation co-culture of CM-DiI-labeled BMSC and EGFP-positive E13.5 RPC displayed minimal co-localization of the two fluorescence signals. E13.5 RPC are capable of inducing BMSC towards an RPC fate. The differentiation is independent of cell fusion. Cytokines and cell-cell interactions exert this induction effect, but they have different functions.


Bioresponsive hyperbranched polymers for siRNA and miRNA delivery. This work presents the novel use of reducible hyperbranched (rHB) polymers for delivery of RNA interference (RNAi) therapeutics. Cationic poly(amido amine) hyperbranched polymers that contain different contents of reducible disulfide to nonreducible linkages (0%, 17%, 25%, and 50%) were used to form interpolyelectrolyte polyplexes with siRNA and precursor miRNA (pre-miRNA). Atomic force microscopy (AFM) revealed rHB complexes of ∼100 nm in size, which exhibited redox-activated disassembly in the presence of dithiothreitol (DTT). The complexes were avidly internalized and showed no cellular toxicity in an endogenous enhanced green fluorescence protein (EGFP) expressing H1299 human lung cancer cell line. The highest specific EGFP gene silencing (∼75%) was achieved with rHB (17%)/siRNA complexes at a weight-to-weight (w/w) ratio of 40 that correlated with the ability for this polymer to successfully transfect pre-miRNA. Evaluation of temporal silencing levels over 72 h revealed incremental knockdown that reached a maximum at 72 h for the rHB (50%) complexes, in contrast to maximum knockdown at 24 h that remained relatively consistent, thereafter, for the rHB (17%), rHB (25%), and non-rHB complexes. The role of particle disassembly for intracellular targeting and modulation of gene silencing addressed in this work are important considerations in the development of this and other next-generation delivery systems.


3D and 4D sonography and magnetic resonance in the assessment of normal and abnormal CNS development: alternative or complementary. Advanced transvaginal neurosonography has revealed normal and abnormal intracranial morphology. Transvaginal three-dimensional (3D) sonography demonstrates bony structure, multiplanar analysis of inside detailed morphology, tomographic ultrasound imaging in any cutting sections, 3D sonoangiography and volume calculation of ventricles and/or intracranial lesions. Longitudinal assessment of normal and abnormal central nervous system (CNS) development is done by serial scanning. However, the transvaginal high-frequency approach has several limitations due to lack of penetration and cranial bone ossification with advanced gestational age. Magnetic resonance neuroimaging enabled observation of the whole intracranial cavity, brainstem and cortical gyral/sulcal development. On the other hand, neuro-sonography has advantages in detecting intracranial calcification, vascular abnormalities, intratumoral vascularity and bone dysplasia. Moreover, 3D ultrasound demonstrates extra CNS abnormalities, strongly associated with CNS abnormalities. Any less-invasive modalities can be used for a CNS anomaly screening scan and ultrasound is no doubt the first choice. Once CNS abnormality is suspected, it is suggested to use the different technologies according to what is looked for in each abnormal CNS case. Of course, MR and 3D ultrasound imaging should be complementary as well as alternative.


Isolation of Cryptococcus magnus and Cryptococcus chernovii from nasal cavities of pediatric patients with acute lymphoblastic leukemia. We report the isolation of Cryptococcus magnus and Cryptococcus chernovii in cultures inoculated with nasal specimens of pediatric cancer patients with acute lymphoblastic leukemia. The phenotypic characteristics of the isolates are described and their identity confirmed by sequencing of rDNA. Both species were resistant to caspofungin, anidulafungin, 5-flucytosine and itraconazole, but susceptible to amphotericin B, posaconazole and voriconazole. To the best of our knowledge, the isolation of these two species from nasal cavities has not been reported previously.


Predicting survival of periviable fetuses using NICHD fetal heart rate categories. To evaluate whether National Institute of Child Health and Human Health and Development (NICHD) fetal heart rate categories were predictive of neonatal survival in periviable pregnancies. We reviewed the charts of 57 infants delivered at 23 and 24 weeks' gestation. Fetal heart rate tracings were evaluated following the NICHD 2008 criteria, using the acceleration height of 10 bpm and duration of 10 s. Multiple logistic regression analyses were performed using survival, fetal morbidities, and cord pH <7.1 as dependent variables. Independent variables included fetal heart rate category, mode of delivery, resuscitation, and histological chorioamnionitis. Outcomes of infants delivered at 23 and 24 weeks were also compared. In 23-week pregnancies, fetal heart rate category 2 was associated with improved short-term survival compared to category 3 (OR 1.3, 95% CI 0.11-15.7). Cesarean delivery and histological chorioamnionitis were not predictive of survival [(OR 0.5, 95% CI 0.04-7.1, and OR 0.4, 95% CI 0.02-6.85), respectively]. Long-term survival for infants born at 23 and 24 weeks was 8% and 56%, respectively. The NICHD fetal heart rate category during labor may be associated with survival for infants born at 23 and 24 weeks of gestation. Cesarean delivery was not associated with improved survival.


Evaluation and clinical application of changes in thyroid hormone and TSH levels in critically ill full-term newborns. The term "euthyroid sick syndrome" (ESS) has been used to describe a pattern of thyroid hormone changes during the course of critical illness in adult patients without thyroid disease, often associated with reduced thyroid hormone secretion. To describe the thyroid hormone profile in full-term newborns critically ill compared with thyroid hormone profile of healthy infants, and determine if alterations could be related to the severity of the disease and outcome. A cross-sectional, observational, and prospective study of full-term infants admitted to the neonatal intensive care unit (NICU) of the Hospital de Pediatría J.P. Garrahan between July 2007 and April 2008. Serum T3, T4, and thyroid stimulating hormone (TSH) levels were measured at admission and severity of the disease was evaluated through SNAP, lactic acid, respiratory assistance and number of organs affected. Sick newborns showed significantly lower T3 and T4 levels compared with healthy infants [T3: -0.97 μg/dL (95% CI -0.89, -1.13) and T4: -4.37 μg/dL (95% CI -2.95, -5.78)]. Only 29 out of 94 (31%) infants presented a normal profile; 37 (39%) infants showed isolated low T3 levels, 20 (21%) infants had low T3 and T4 levels and eight (9%) infants had low TSH, T3, and T4. Of this latter group, five of eight (62%) children died suggesting a significantly higher risk of death for patients with low T3 associated with low T4 and TSH [Risk ratio (RR) 10.75 95% CI 3.93, 29]. Full-term sick newborns frequently have lower thyroid hormone levels than healthy ones. These observed thyroid hormones changes might be related to the underlying disease and could be used as a prognostic marker of the severity and fatal outcome of the patient.


Epidemiology of congenital syphilis in a South Bronx population: a follow-up study. Despite widespread prenatal serological screening, the Centers for Disease Control recently reported that from 2005 to 2008, congenital syphilis increased by 23%, many being born to black women in the southern United States. We collected data on the epidemiology of this condition in our institution for the past 18 years (January 1, 1991-December 31, 2008). There has been a marked decrease in the incidence of active infection since the 1990s. Through the 18 years period reviewed, only 21 cases of active neonatal infection were documented among 699 babies who had a positive rapid plasma reagin test. Of these 21 cases, only one was symptomatic. As compared to previous studies, poor prenatal care has still the greatest correlation with active infection. This study might contribute towards the reinforcement of current programs and the formulation of newer strategies towards control and elimination of this condition.


Cell and molecular physiology diversity of channels, carriers, and pumps.


Transport and metabolism of (±)-praeruptorin A in Caco-2 cell monolayers. (±)-Praeruptorin A (dl-PA) is one of the main pyranocoumarins of Peucedani Radix and the chemical marker for quality control of the herb in China. This study investigated the transport and metabolism of dl-PA, for the first time, in Caco-2 cell monolayers. PA enantiomers of dl-PA in the transport study were simultaneously determined using a simple and rapid enantio-selective high performance liquid chromatography-UV method. Both dextrorotatory (d-PA) and levorotatory (l-PA) enantiomers traversed Caco-2 monolayer rapidly in both directions (absorptive P(app): 2.01-3.03 × 10(-5) cm/s; secretory P(app): 1.58-1.96 ×10(-5) cm/s) mainly via passive diffusion. Higher transport rates of dPA were observed in both directions. PA enantiomers were incompletely recovered after the transport study. Nonspecific binding to the Transwell inserts, irreversible binding to cellular components and metabolism within the cells accounted for the loss. dl-PA was partially hydrolyzed in Caco-2 monolayers and yielded two stereoisomers via removal of the acetyl group from C-4' position. Both phenylmethylsulphonyl fluoride (a nonspecific esterase inhibitor) and bis(p-nitrophenyl) phosphate sodium salt (a specific inhibitor of carboxylesterases) completely abolished dl-PA hydrolysis. In summary, PA enantiomers were rapidly transported across Caco-2 cells and partially hydrolyzed by carboxylesterases during permeation. These findings provide mechanistic understanding of in vivo pharmacokinetic properties of dl-PA.


Amniotic mesenchymal stem cells enhance normal fetal wound healing. Fetal wound healing involves minimal inflammation and limited scarring. Its mechanisms, which remain to be fully elucidated, hold valuable clues for wound healing modulation and the development of regenerative strategies. We sought to determine whether fetal wound healing includes a hitherto unrecognized cellular component. Two sets of fetal lambs underwent consecutive experiments at midgestation. First, fetuses received an intra-amniotic infusion of labeled autologous amniotic mesenchymal stem cells (aMSCs), in parallel to different surgical manipulations. Subsequently, fetuses underwent creation of 2 symmetrical, size-matched skin wounds, both encased by a titanium chamber. One of the chambers was left open and the other covered with a semipermeable membrane that allowed for passage of water and all molecules, but not any cells. Survivors from both experiments had their wounds analyzed at different time points before term. Labeled aMSCs were documented in all concurrent surgical wounds. Covered wounds showed a significantly slower healing rate than open wounds. Paired comparisons indicated significantly lower elastin levels in covered wounds at the mid time points, with no significant differences in collagen levels. No significant changes in hyaluronic acid levels were detected between the wound types. Immunohistochemistry for substance P was positive in both open and covered wounds. We conclude that fetal wound healing encompasses an autologous yet exogenous cellular component in naturally occurring aMSCs. Although seemingly not absolutely essential to the healing process, amniotic cells expedite wound closure and enhance its extracellular matrix profile. Further scrutiny into translational implications of this finding is warranted.


Pregnane X receptor-mediated induction of Cyp3a by black cohosh. Black cohosh (BC) has been widely applied for the treatment of menopausal symptoms. However, increasing concerns about herb-drug interactions demand the need for studies on the influence of BC on cytochrome 450. Cyp3a11 in liver was induced by 7-fold in wild-type mice treated with 500 mg/kg black cohosh for 28 days compared with the control group as assessed by quantitative real-time PCR; no difference was found in small intestine and kidney, suggesting that up-regulation of Cyp3a11 by black cohosh was liver-specific. Western blot, activity assays, and pharmacokinetic analyses established dose- and time-dependent induction of Cyp3a11. To determine the mechanism of Cyp3a11 induction, including the role of pregnane X receptor (PXR) in vivo and in vitro, respectively, in Pxr-null, PXR-humanized, and double transgenic CYP3A4/hPXR mice, cell-based luciferase assays were employed revealing that mouse PXR played a direct role in the induction of Cyp3a11; human PXR was not activated by black cohosh. Overall, these findings demonstrate that induction of Cyp3a11 is liver-specific and involved only mouse PXR, not the human counterpart. Thus, the incidence of herb-drug interaction in patients administered black cohosh may not be mediated by human PXR and CYP3A4.


Both CD31(+) and CD31⁻ naive CD4(+) T cells are persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy. Naive T cell recovery is critical for successful immune reconstitution after antiretroviral therapy (ART), but the relative contribution of CD31(+) and CD31⁻ naive T cells to immune reconstitution and viral persistence is unknown. In a cross-sectional (n = 94) and longitudinal (n = 10) study of human immunodeficiency virus (HIV)-infected patients before and after ART, we examined the ratio of CD31(+) to CD31⁻ naive CD4(+) T cells. In the longitudinal cohort we then quantified the concentration of HIV-1 DNA in each cell subset and performed single-genome amplification of virus from memory and naive T cells. Patients receiving ART had a higher proportion of CD31(+) CD4(+) T cells than HIV-1-infected individuals naive to ART and uninfected control subjects (P < .001 and .007, respectively). After 24 months of ART, the proportion of CD31(+) naive CD4(+) T cells did not change, the concentration of HIV-1 DNA in memory CD4(+) T cells significantly decreased over time (P < .001), and there was no change in the concentration of HIV-1 DNA in CD31(+) or CD31⁻ naive CD4(+) T cells (P = .751 and .251, respectively). Single-genome amplification showed no evidence of virus compartmentalization in memory and naive T cell subsets before or after ART. After ART, both CD31(+) and CD31⁻ naive CD4(+) T cells expand, and both subsets represent a stable, persistent reservoir of HIV-1.


Inactivated seasonal influenza vaccines increase serum antibodies to the neuraminidase of pandemic influenza A(H1N1) 2009 virus in an age-dependent manner. Levels of preexisting antibodies to the hemagglutinin of pandemic influenza A(H1N1) 2009 (hereafter pandemic H1N1) virus positively correlate with age. The impact of contemporary seasonal influenza vaccines on establishing immunity to other pandemic H1N1 proteins is unknown. We measured serum antibodies to the neuraminidase (NA) of pandemic H1N1 in adults prior to and after vaccination with seasonal trivalent inactivated influenza vaccines. Serum antibodies to pandemic H1N1 NA were observed in all age groups; however, vaccination elevated levels of pandemic H1N1 NA antibodies predominately in elderly individuals (age, ⩾60 years). Therefore, contemporary seasonal vaccines likely contribute to reduction of pandemic H1N1-associated disease in older individuals.


A norovirus vaccine on the horizon?

A norovirus vaccine on the horizon?


Adjuvanted intranasal Norwalk virus-like particle vaccine elicits antibodies and antibody-secreting cells that express homing receptors for mucosal and peripheral lymphoid tissues. Noroviruses cause significant morbidity and mortality from acute gastroenteritis in all age groups worldwide. We conducted 2 phase 1 double-blind, controlled studies of a virus-like particle (VLP) vaccine derived from norovirus GI.1 genotype adjuvanted with monophosphoryl lipid A (MPL) and the mucoadherent chitosan. Healthy subjects 18-49 years of age were randomized to 2 doses of intranasal Norwalk VLP vaccine or controls 21 days apart. Study 1 evaluated 5-, 15-, and 50-μg dosages of Norwalk antigen, and study 2 evaluated 50- and 100-μg dosages. Volunteers recorded symptoms for 7 days after dosing, and safety was followed up for 180 days. Blood samples were collected for serological profile, antibody secreting cells (ASCs), and analysis of ASC homing receptors. The most common symptoms were nasal stuffiness, discharge, and sneezing. No vaccine-related serious adverse events occurred. Norwalk VLP-specific immunoglobulin G and immunoglobulin A antibodies increased 4.8- and 9.1-fold, respectively, for the 100-μg dosage level. All subjects tested who received the 50- or 100-μg vaccine dose developed immunoglobulin A ASCs. These cells expressed molecules associated with homing to mucosal and peripheral lymphoid tissues. The intranasal monovalent adjuvanted Norwalk VLP vaccine was well tolerated and highly immunogenic and is a candidate for additional study.


Staphylococcal superantigens cause lethal pulmonary disease in rabbits. The Centers for Disease Control and Prevention (CDC) and others reported that methicillin-resistant S. aureus (MRSA) are significant causes of serious human infections, including pulmonary illnesses. We investigated the role played by superantigens in lung-associated lethal illness in rabbits. A rabbit model was established to investigate the potential role played by superantigens, staphylococcal enterotoxin B (SEB), staphylococcal enterotoxin C (SEC), and toxic shock syndrome toxin-1 (TSST-1). Rabbits received intrabronchial community-associated (CA) MRSA strains USA200 (TSST-1(+)), MW2 (SEC(+)), c99-529 (SEB(+)), or purified superantigens. Some rabbits were preimmunized against superantigens or treated with soluble high-affinity T cell receptors (Vβ-TCR) to neutralize SEB and then challenged intrabronchially with CA-MRSA or superantigens. Rabbits challenged with CA-MRSA or superantigens developed fatal, pulmonary illnesses. Animals preimmunized against purified superantigens, or treated passively with Vβ-TCRs and then challenged with CA-MRSA or superantigens, survived. Lung histological analysis indicated that nonimmune animals developed lesions consistent with necrotizing pneumonia after challenge with CA-MRSA or purified superantigens. Superantigen-immune animals or animals treated with soluble Vβ-TCRs did not develop pulmonary lesions. Superantigens contribute to lethal pulmonary illnesses due to CA-MRSA; preexisting immunity to superantigens prevents lethality. Administration of high-affinity Vβ-TCR with specificity for SEB to nonimmune animals protects from lethal pulmonary illness resulting from SEB(+) CA-MRSA and SEB.


Immune responses to Helicobacter pylori infection in Bangladeshi children during their first two years of life and the association between maternal antibodies and onset of infection. A birth cohort of 238 children in Bangladesh was monitored during the initial 2 years of life to analyze immune responses against Helicobacter pylori in relation to infection and spontaneous eradication and to evaluate a possible association between maternal antibodies and protection against early onset of infection. H. pylori infection was determined by a stool antigen test and serologic testing. Immune responses were analyzed in depth in 50 children. Of the stool antigen-positive children, 90% developed ≥4-fold increased antibody levels against H. pylori in serum immunoglobulin (Ig) A, 73% developed increases in serum IgG levels, and 81% developed increases in stool IgA/total IgA levels after, as compared with before, the onset of infection. Good agreement between different immune responses was observed after 6 months of age. Before that time, transplacentally derived IgG and breast milk IgA antibodies interfered with the children's serum IgG and stool IgA responses. Children infected during the first year of life had significantly lower preinfection serum IgG titers than those infected during the second year of life. Infants infected during the first month of life were fed breast milk that contained levels of H. pylori IgA antibodies that were significantly lower than the levels in breast milk fed to infants infected at 6 months of age. Children who experienced spontaneous eradication of infection developed significantly higher serum IgA antibody levels after infection than did children with continuous infection.


Acupressure as a non-pharmacological intervention for traumatic brain injury (TBI). Acupressure is a complementary and alternative medicine (CAM) treatment using fingertips to stimulate acupoints on the skin. Although suggested to improve cognitive function, acupressure has not been previously investigated with a controlled design in traumatic brain injury (TBI) survivors, who could particularly benefit from a non-pharmacological intervention for cognitive impairment. A randomized, placebo-controlled, single-blind design assessed the effects of acupressure (eight treatments over 4 weeks) on cognitive impairment and state of being following TBI, including assessment of event-related potentials (ERPs) during Stroop and auditory oddball tasks. It was hypothesized that active acupressure treatments would confer greater cognitive improvement than placebo treatments, perhaps because of enhanced relaxation response induction and resulting stress reduction. Significant treatment effects were found comparing pre- to post-treatment change between groups. During the Stroop task, the active-treatment group showed greater reduction in both P300 latency (p = 0.010, partial η² = 0.26) and amplitude (p = 0.011, partial η² = 0.26), as well as a reduced Stroop effect on accuracy (p = 0.008, partial η² = 0.21) than did the placebo group. Additionally, the active-treatment group improved more than did the placebo group on the digit span test (p = 0.043, Cohen's d = 0.68). Together, these results suggest an enhancement in working memory function associated with active treatments. Because acupressure emphasizes self-care and can be taught to novice individuals, it warrants further study as an adjunct treatment for TBI.


Circulating antibody-secreting cells during acute respiratory syncytial virus infection in adults. The specificity and duration of circulating human antibody-secreting cells (ASCs) after vaccination have been well described, but characteristics of ASCs during acute respiratory infections have not been well studied. Circulating antigen-specific ASCs were measured at 3 time points (enrollment, days 10-16, and days 22-45) in 40 adults during respiratory syncytial virus (RSV) infection. Of the 40 patients, 36 (90%) had detectable circulating RSV F protein-specific ASCs within 11 days after illness onset. The magnitude of the RSV-specific ASCs was 1-1500 spots per 10⁶ peripheral blood mononuclear cells (mean frequency [± standard deviation], 200 ± 256 spots per 10⁶ peripheral blood mononuclear cells). ASCs were detected on day 8-16 and day 22-45 after symptom onset in 78% and 48% of subjects, respectively. Subjects shedding virus for >10 days were more likely to have a positive response to ASC enzyme-linked immunospot assay at the late time point than those shedding for ≤10 days (8 of 12 subjects vs 2 of 11 subjects; P = .02). The kinetics of ASC circulation during acute mucosal viral infections was more prolonged than that we had observed after a single intramuscular injection with inactivated influenza vaccine in a study reported elsewhere. The association between the duration of virus shedding and the persistence of detectable viral-specific ASCs suggests that ongoing antigen persistence induces a prolonged temporal pattern of ASC generation.


Clinical and metabolic effects of drospirenone-estradiol in menopausal women: a prospective study. To describe the effects of low-dose hormonal replacement therapy (HRT) on quality of life, metabolic parameters and blood pressure in postmenopausal women. Postmenopausal women untreated with HRT or sex steroids in the previous 12 months were randomized to treatment with 17β-estradiol (1 mg/day) plus drospirenone (2 mg/day) (E2+DRSP) or to calcium (controls). Quality of life was evaluated by the Women's Health Questionnaire (WHQ) at baseline and after 6 and 12 weeks of treatment. Anthropometric, metabolic and blood pressure measurements were performed before and after 3 months of treatment. WHQ domain scores for vasomotor and somatic symptoms, anxiety/fears, depressed mood, sexual behavior and sleep problems decreased significantly in the E2+DRSP group relative to both baseline and control values (p < 0.05). Body mass index was unchanged, while waist circumference decreased significantly (p < 0.001) after E2+DRSP treatment. Significant decreases were also observed after E2+DRSP treatment for blood insulin values, insulin resistance (estimated by homeostasis model assessment) and systolic blood pressure (p < 0.001, all). In subjects with systolic blood pressure < 130 mmHg at baseline, no changes in systolic values were registered, while women with baseline high-normal systolic blood pressure (130-139 mmHg) showed significant decreases (p < 0.0069). E2+DRSP did not modify diastolic blood pressure values. In the calcium-treatment group, there were no significant changes in WHQ scores or in anthropometric, metabolic or blood pressure measurements. In postmenopausal women, E2+DRSP administration improves vasomotor symptoms and general aspects of quality of life and may positively influence cardiovascular risk factors.


Factors associated with non-compliance with hormone therapy cessation before screening mammography. To evaluate factors associated with non-compliance with discontinuation of hormone therapy (HT) within a study on the effect of HT cessation on mammography performance. This randomized, controlled trial was conducted at Group Health, a health plan in Washington State, USA. Eligibility included: age 45-80 years; due for screening ('study') mammogram; and prior screening mammogram while using HT. We randomized 1704 women to no cessation (n = 567), 1-month (n = 570), or 2-month cessation (n = 567), and called participants before cessation to review instructions. We collected self-reported data at randomization (baseline) and before the study mammogram, including symptoms and compliance. This analysis includes women randomized to 1-month or 2-month cessation with complete baseline and follow-up questionnaires (n = 883). Most participants were using unopposed estrogen (63.3%) and intended to continue HT (90%); 9.6% were non-compliant with HT cessation. Comparing 2-month vs. 1-month cessation, the age and body mass index (BMI)-adjusted relative risk (RR) for non-compliance was 1.72 (95% confidence interval (CI) 1.12-2.60). Baseline variables associated with non-compliance included: age ≤55 vs. >55 years (RR 2.34; 95% CI 1.34-4.41); BMI < 25 vs. BMI ≥30 kg/m 2 (RR 1.63; 95% CI 1.01-2.63); unopposed estrogen vs. estrogen plus progestin (RR 1.59; 95% CI 1.01-2.51); using HT to manage sleep (RR 1.80; 95% CI 1.20-2.71); severe vs. no night sweats (RR 1.68; 95% CI 1.03-2.74); and night sweats that interfered with sleep (RR 1.78; 95% CI 1.02-3.11). Non-compliance with HT cessation before screening mammogram was associated with younger age, lower BMI, symptom severity and use of unopposed estrogen. Alternatives for menopause symptom management are needed to assist women with HT cessation.


Health care in the 2010 congressional election.


Writing new rules for insurers--progress on the medical loss ratio.


A "broader regulatory scheme"--the constitutionality of health care reform.


Images in clinical medicine. Air in the middle of the abdomen.


Resurrection of a stem-cell funding barrier--Dickey-Wicker in court.


Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).


Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. It has been suggested that clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite. We genotyped patients from two large, randomized trials that showed that clopidogrel, as compared with placebo, reduced the rate of cardiovascular events (the primary efficacy outcome) among patients with acute coronary syndromes and among patients with atrial fibrillation. Patients were genotyped for three single-nucleotide polymorphisms (*2, *3, *17) that define the major CYP2C19 alleles. Among 5059 genotyped patients with acute coronary syndromes, clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome, irrespective of the genetically determined metabolizer phenotype (P=0.12 for heterogeneity). The effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles (rate among carriers, 8.0% with clopidogrel vs. 11.6% with placebo; hazard ratio with clopidogrel, 0.69; 95% confidence interval [CI], 0.49 to 0.98; rate among noncarriers, 9.5% vs. 13.0%; hazard ratio, 0.72; 95% CI, 0.59 to 0.87). In contrast, gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers (rate of primary outcome among carriers, 7.7% vs. 13.0%; hazard ratio, 0.55; 95% CI, 0.42 to 0.73; rate among noncarriers, 10.0% vs. 12.2%; hazard ratio, 0.85; 95% CI, 0.68 to 1.05; P=0.02 for interaction). The effect of clopidogrel on bleeding did not vary according to genotypic subgroups. Among 1156 genotyped patients with atrial fibrillation, there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype, loss-of-function carrier status, or gain-of-function carrier status. Among patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00249873.).


Tiotropium bromide step-up therapy for adults with uncontrolled asthma. Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed. In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison). The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003). When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).


Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. Inflammatory myofibroblastic tumor (IMT) is a distinctive mesenchymal neoplasm characterized by a spindle-cell proliferation with an inflammatory infiltrate. Approximately half of IMTs carry rearrangements of the anaplastic lymphoma kinase (ALK) locus on chromosome 2p23, causing aberrant ALK expression. We report a sustained partial response to the ALK inhibitor crizotinib (PF-02341066, Pfizer) in a patient with ALK-translocated IMT, as compared with no observed activity in another patient without the ALK translocation. These results support the dependence of ALK-rearranged tumors on ALK-mediated signaling and suggest a therapeutic strategy for genomically identified patients with the aggressive form of this soft-tissue tumor. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).


Clinical practice. Recurrent miscarriage.


Images in clinical medicine. A foreign body.


EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers, and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way. Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.).


Case records of the Massachusetts General Hospital. Case 33-2010. A 22-year-old woman with blurred vision and renal failure.


Crizotinib--latest champion in the cancer wars?


Products at risk.

Products at risk.


Anticholinergics for patients with asthma?


Stenting versus endarterectomy for carotid-artery stenosis.


A school-based intervention for diabetes risk reduction.


Molecular architecture of the Goodpasture autoantigen.


Valproic acid use in pregnancy and congenital malformations.


Early Alzheimer's disease.

Early Alzheimer's disease.


Genetic disorders of renal phosphate transport.


Acupuncture for chronic low back pain.

Acupuncture for chronic low back pain.


Management of Clostridium difficile infection: thinking inside and outside the box. Treatment of Clostridium difficile infection (CDI) has relied on 2 antimicrobial agents, metronidazole and vancomycin, since the recognition of this disease entity. While effective, these "inside the box" approaches to CDI management have the disadvantage of further microbial disruption of the host indigenous microflora. "Outside the box" therapies use non-antimicrobial approaches to management and are theoretically less prone to causing recurrent CDI episodes. Recent advances in understanding of "inside the box" approaches include appreciation of the decreased efficacy of metronidazole overall and the superior efficacy of vancomycin for treatment of severe CDI, as well as a new agent under development, fidaxomicin, which appears to be equal in efficacy to vancomycin but with less risk of subsequent CDI recurrences. Several "outside the box" approaches have also entered clinical development, including use of monoclonal antibodies, active vaccination, luminal toxin binders, and nontoxigenic C. difficile. These reports provide optimism that more-effective management of CDI is forthcoming.


Incidence of cleft lip and palate in Uganda. The purpose of the study was to estimate the need for resources for cleft repairs in Uganda by determining the overall incidence of oral-facial clefts and the ratio of isolated cleft lip to isolated cleft palate to cleft lip and palate. A 1-year prospective study was implemented in seven hospitals and health centers with maternity units in and around Kampala. All live babies were examined for cleft lip and/or palate at birth. The birth of a baby with a cleft was communicated to the research coordinator by maternity staff, and the babies were assessed within 24 hours of delivery. Maternity data (live births) for each center were collected monthly to determine the denominator. Over the course of 1 year (February 1, 2008 to January 31, 2009), 26,186 babies were delivered. Nineteen babies had a cleft lip and/or palate, giving an incidence of 0.73 in 1000; 12 of the 19 babies (63.2%) had a cleft lip and palate, six (31.2%) had an isolated cleft lip, and only one (5.3%) had an isolated cleft palate. The ratio of boys to girls was 1.1∶1. The incidence of clefts in this study was 0.73 in 1000. With an estimated 1100 babies born with a cleft per year, this would result in the need for 1800 cleft repairs for babies in Uganda (695 babies needing two repairs each). These data will be helpful to advocate for and plan the necessary resources to effectively treat this condition.


Current definitions of central line-associated bloodstream infection: is the emperor wearing clothes?


Risk of postdischarge infection with vancomycin-resistant enterococcus after initial infection or colonization. Postdischarge risks of vancomycin-resistant Enterococcus (VRE) infection among carriers are unknown. We conducted a retrospective cohort study of 199 patients newly detected as VRE carriers. Fifteen patients (8%) developed 27 VRE infections in the 18 months after detection. Among 10 postdischarge infections, 2 involved bacteremia and 3 resulted in readmission.


Neonatologists' perceptions of antimicrobial resistance and stewardship in neonatal intensive care units.


Questionable effectiveness of the QuantiFERON-TB Gold Test (Cellestis) as a screening tool in healthcare workers. The Center for Disease Control and Prevention recommends the use of QuantiFERON TB Gold test (QFTG; Cellestis) in all situations where the tuberculin skin test (TST) is used. In November 2007, our institution replaced its screening-tool TST with the QFTG in-tube assay (QFT-GIT) for annual screening of latent tuberculosis infection among healthcare workers (HCWs). This study evaluated the effectiveness of QFT-GIT test as screening tool in HCWs at our institution. This retrospective study reviewed medical records of all HCWs who underwent screening with QFT-GIT from January 2008 through December 2008. Among the 6,530 HCWs screened with QFT-GIT from January through December 2008, 287 had a positive test result. Of the 287, 123 had positive TST results in the past, meaning that 164 HCWs had newly diagnosed latent tuberculosis infection by QFT-GIT. Of the 164 HCWs, 135 were retested by QFT-GIT and were simultaneously tested with TST within 4 weeks after the initial QFT-GIT. Of these 135 HCWs, 66 reverted to negative results and results remained positive for 69 with QFT-GIT. Only 2 HCWs had a positive TST result. The disagreement between QFT-GIT and TST results and the high reversion rate with QFT-GIT raise concerns about the effectiveness of QFT-GIT as a sole screening test in HCWs.


Geographic access to hospice in the United States. Despite a 41% increase in the number of hospices since 2000, more than 60% of Americans die without hospice care. Given that hospice care is predominantly home based, proximity to a hospice is important in ensuring access to hospice services. We estimated the proportion of the population living in communities within 30 and 60 minutes driving time of a hospice. We conducted a cross-sectional study of geographic access to U.S. hospices using the 2008 Medicare Provider of Services data, U.S. Census data, and ArcGIS software. We used multivariate logistic regression to identify gaps in hospice availability by community characteristics. As of 2008, 88% of the population lived in communities within 30 minutes and 98% lived in communities within 60 minutes of a hospice. Mean time to the nearest hospice was 15 minutes and the range was 0 to 403 minutes. Community characteristics independently associated with greater geographic access to hospice included higher population density, higher median income, higher educational attainment, higher percentage of black residents, and the state not having a Certificate of Need policy. The percentage of each state's population living in communities more than 30 minutes from a hospice ranged from 0% to 48%. Recent growth in the hospice industry has resulted in widespread geographic access to hospice care in the United States, although state and community level variation exists. Future research regarding variation and disparities in hospice use should focus on barriers other than geographic proximity to a hospice.


Should herbs take all the blame? Causality assessment of a serious thrombocytopenia event. With the increasing use of herbal medicines, the causality assessment of adverse drug-related reactions becomes more complicated because of the concomitant use of herbs and conventional medications. Epidemiological causal inference can be a central feature of such judgment but may be insufficient. Other scientific considerations include study design, bias, confounding, and measurement issues. The approach of this study is to establish an active safety surveillance system for finished herbal products (FHPs) and to review each adverse event regularly. A single case of serious thrombocytopenia was found in 136 subjects taking FHPs on a clinical trial for 12 weeks, for which the cause was sought. Because at the end of the first month the patient's platelet counts were normal and the thrombocytopenia developed after the co-medication with conventional drugs, it was suspected that the thrombocytopenia might not be attributed to the use of FHP. This report summarizes the criteria of causality assessment under mixed use of herbs and conventional medicine and recommends a feasible process for careful evaluation of adverse drug reactions related to all herbal medicine.


Protein synthesis, degradation, and retention: mechanisms of indeterminate growth in cephalopods. This study is the first to examine the underlying process of growth in a cephalopod, the southern dumpling squid (Euprymna tasmanica), to ascertain the mechanism by which indeterminate growth is achieved in this live-fast, die-young group of animals. This is the first study to estimate rates of protein synthesis and growth of squid from 7 to 140 d of age, providing an understanding of both the pattern and the process of growth throughout the lifetime of a squid species. Younger and smaller individuals had greater rates of protein synthesis and protein synthesis retention efficiency, as well as more RNA, than did older and larger individuals. Variation in growth rates among older, larger individuals was a function of individuals with faster growth rates having greater protein synthesis retention efficiency and also greater concentrations of protein. Critically, growth did not cease in the adults and, with an average of 10% of protein synthesized being retained, the mechanism to support the nonasymptotic growth model of cephalopods is provided.


C-reactive protein can influence the proliferation, apoptosis, and monocyte chemotactic protein-1 production of human umbilical vein endothelial cells. C-reactive protein (CRP) has been shown to be closely associated with coronary heart disease. The serum CRP concentrations of chronic periodontitis (CP) patients were increased due to periodontal inflammation. CRP may be a potential key mediator associating CP with coronary heart disease. This study aimed to investigate the effects of CRP on human endothelial cells in vitro. CRP ranging from 0 to 10 μg/mL was adopted to imitate the chronic inflammatory conditions of periodontitis. The influences of CRP on proliferation, apoptosis, and monocyte chemotactic protein-1 (MCP-1) production of human umbilical vein endothelial cells (HUVECs) were studied through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and enzyme-linked immunosorbent assay analysis, respectively. Compared to the blank control, 2.5 and 5.0 μg/mL CRP significantly suppressed cell proliferation by 6.9% and increased apoptosis by 10.2% and 14.6%, respectively (p<0.05). Concentrations of 7.5 and 10.0 μg/mL CRP also induced 2.3% HUVEC proliferation suppression (p>0.05) and significantly increased apoptosis ratio compared to that of the blank control. CRP could promote MCP-1 production of HUVECs in a concentration-dependent manner. The MCP-1 production of 10.0 μg/mL CRP group was about 15.3% higher than that of the control group. It is concluded that low concentrations of CRP, which appears in CP, inhibits cell proliferation, promotes cell apoptosis, and increases MCP-1 production in endothelium, which may initiate self-repairing function of vascular endothelium following vascular injury process.


Targeting the glycoprotein 130 receptor subunit to control pain and inflammation. The glycoprotein 130 (gp130) is a shared signal-transducing-membrane-associated receptor for several hematopoietic cytokines. Its activation is implicated in pain and in a variety of diseases via signaling of proinflammatory cytokines. These include interleukin-6 (IL-6) subfamily cytokines, many of which play important roles in the pathogenesis of diseases such as rheumatoid arthritis, Castleman's disease, and Kaposi's sarcoma. Several strategies have been developed to block gp130-receptor-mediated signaling. These include the application of monoclonal antibodies, the creation of mutant form(s) of the gp130 with increased binding affinity for such ligands as IL-6/sIL-6R complex, and the generation of antagonists by selective mutagenesis of the specific cytokine/gp130 receptor binding site(s). Other strategies include targeting gp130-mediated signaling pathways such as that involving signal transducer and activator of transcription-3. This review provides a summary of the latest research pertaining to the role of gp130 in the pathogenesis of inflammatory and other diseases in which the gp130 receptor is implicated. An overview of antagonists targeting the gp130 receptor is included with particular emphasis on their mechanism of action and their limitations and potential for therapeutic application.


Localization and characterization of rat transmembrane protein 225 specifically expressed in testis. Testis is the one and only location of spermatogenesis and sexual hormone production. Spermatogenesis is a complicated physiological process regulated by many genes specifically and differentially expressed in the testis. In this study, Transmembrane Protein 225 (TMEM225), which is specifically expressed in rat testis, has been identified. TMEM225 was cloned from the testis cDNA library and was mapped to chromosome 8q22 by browsing the University of California Santa Cruz genomic database. It contains an open reading frame with a length of 696 bp, encoding a protein with four putative transmembrane helices. TMEM225 mRNA expression was evaluated by reverse transcription-polymerase chain reaction and in situ hybridization. In addition, the subcellular location of TMEM225 was evaluated. The results obtained highlighted age related specific expression of TMEM225 in testis, specifically during the adult period after age of 13 months. In situ hybridization analysis indicated that TMEM225 mRNA was mainly expressed in spermatocyte cells and round spermatids. Green fluorescence protein localization analysis showed that rat TMEM225 mainly surrounded the nuclear membrane, with a minority distribution in the cytoplasm, and the distribution of TMEM225 was affected by the deletion of N-terminal transmembrane domain. As the expression phase is not related to the first wave of spermatozoon development, our data presented here suggest that TMEM225 may play an important role in sperm degeneration but not in spermatogenesis.


A new comparative metric for estimating heterothermy in endotherms. A major focus in the study of endothermic thermoregulation has been the description of thermoregulatory patterns used by various species and/or populations. Compared with ectotherms, relatively few attempts have been made to study the thermoregulation of endotherms in an adaptive framework. We believe that one of the main factors limiting this area of research has been the lack of an appropriate metric to directly compare body temperature (T(b)) variation across all endothermic species. Thus, we present a simple comparative metric, the heterothermy index (HI), to quantify the expression of heterothermy by endotherms during a given time frame. Key advantages of HI are that (1) it represents a new analytical technique that has different strengths than the metrics commonly used to describe variation in T(b), (2) it allows for evaluation of nonenergetic costs and benefits that affect the expression of heterothermy, and (3) it has the potential to unify research on homeotherms and heterotherms through quantitative comparative analyses that examine the entire continuum of thermoregulatory patterns. In short, we suggest that our metric provides a means to overcome one of the hurdles presently slowing the advancement of research on endothermic thermoregulation beyond the simple description of thermoregulatory patterns.


Ezh2 expression in astrocytes induces their dedifferentiation toward neural stem cells. Recently, we have demonstrated the expression of the polycomb group protein Ezh2 in embryonic and adult neural stem cells. Although Ezh2 remained highly expressed when neural stem cells differentiate into oligodendrocyte precursor cells, it is downregulated during the differentiation into neurons or astrocytes. This is in accordance with the differentiation repressive role Ezh2 is thought to play in the maintenance and self-renewal of stem cells. To establish the importance of downregulation of Ezh2 for becoming astrocytes, we have studied the effect of forced Ezh2 expression in postnatal mouse astrocytes. Upon forced expression of this polycomb group protein, cultured astrocytes retracted their cell extensions and became proliferating round/bipolar cells that occasionally formed small neurosphere-like clusters. Analysis of the expression profile of these Ezh2-expressing astrocytes reveal downregulation of typical astrocytic genes, like GFAP and S100, and upregulation of genes that are generally expressed in neural stem cells, like nestin, Sox2, musashi, and CD133. However, these neural stem cell-like cells lack a differentiation potential, indicating that overexpression of Ezh2 alone is insufficient for a complete dedifferentiation.


The mouse alpha-albumin (afamin) promoter is differentially regulated by hepatocyte nuclear factor 1α and hepatocyte nuclear factor 1β. Alpha-albumin (AFM), a member of the albumin gene family that also includes albumin, alpha-fetoprotein, and vitamin D-binding protein, is expressed predominantly in the liver and activated at birth. Here, we identify two hepatocyte nuclear factor 1 (HNF1)-binding sites in the AFM promoter that are highly conserved in different mammals. These two sites bind HNF1α and HNF1β. The distal site (centered at -132, relative to AFM exon 1) is more important than proximal site (centered at -58), based on HNF1 binding and mutational analysis in transfected cells. Our data indicate that HNF1α is a more potent activator of AFM promoter than is HNF1β. However, HNF1β can act in a dominant manner to inhibit HNF1α-dependent transactivation of the AFM promoter when both proteins are expressed together. This suggests that the differential timing with which the albumin family genes are activated in the liver may be influenced by their responsiveness to HNF1α and HNF1β. Our comparison of HNF1-binding sites in the promoters in the albumin family of genes indicates that the primordial albumin-like gene contained two HNF1 sites; one of these sites was lost from the albumin promoter, but both sites still are present in other members of this gene family.


Effects of extracellular matrix density and mesenchymal stem cells on neovascularization in vivo. Aberrant angiogenesis is common to a variety of diseases in which alterations in tissue mechanical properties also occur. A fundamental understanding of the interdependence of angiogenesis and tissue structural properties may enhance the development of therapeutic strategies. We previously established that increasing extracellular matrix density inhibits capillary morphogenesis in three-dimensional tissues in vitro, and that addition of human mesenchymal stem cells (MSCs) partially rescues a healthy angiogenic phenotype. This study's goal was to investigate if these effects can be recapitulated in vivo. Human umbilical vein endothelial cells, MSCs, or a mixture of both was suspended in fibrin gel precursor solutions of 5, 10, and 15 mg/mL concentrations and injected subcutaneously into SCID mice. Neovascularization was assessed in tissue constructs retrieved at 3, 7, and 21 days by quantifying vessel numbers, perfusion, thickness, maturity, and perivascular collagen deposition. The data show that changing extracellular matrix density inhibits capillary morphogenesis in vivo in a manner consistent with that observed in vitro. Delivery of both human umbilical vein endothelial cells and MSCs produced more robust and mature vessels than delivery of either cell type alone in all tissue concentrations.


Biophysical properties and oxygenation potential of high-molecular-weight glutaraldehyde-polymerized human hemoglobins maintained in the tense and relaxed quaternary states. Recent clinical evaluation of commercial glutaraldehyde-polymerized hemoglobins (PolyHbs) as transfusion solutions has demonstrated several adverse side effects. Chief among these is the hypertensive effect. Fortunately, previous studies have shown that the hypertensive effect can be attenuated by removing free hemoglobin (Hb) and low-molecular-weight (low-MW) PolyHbs from the PolyHb mixture. In this work, polymerized human Hb (PolyhHb) solutions were synthesized in two distinct quaternary states with high MW and subjected to extensive diafiltration to remove free Hb and low-MW PolyhHb components (<500 kDa). The resultant PolyhHb solutions possessed high MW, distinct quaternary state, distinct reactivities with O(2) and CO, similar NO deoxygenating rate constants, distinct autoxidation rate constants, high viscosity, and low colloid osmotic pressure. To preliminarily assess the ability of PolyhHb solutions to oxygenate surrounding tissues fed by a blood vessel, we evaluated the ability of PolyhHbs to transport O(2) to cultured hepatocytes in a mathematical model of a hollow fiber bioreactor. The structure of individual hollow fibers in the bioreactor is similar to that of a blood vessel and provides an easy way to assess the oxygenation potential of PolyhHbs without the need for expensive and time-consuming animal studies. It was observed that PolyhHbs with low O(2) affinities were more effective in oxygenating cultured hepatocytes inside the bioreactor than high O(2) affinity PolyhHbs. Taken together, our results show that it is possible to synthesize high-MW PolyhHbs with no free Hb and low-MW PolyhHb components that are capable of transporting O(2) to cultured cells/tissues.


Combined gene therapy with hypoxia-inducible factor-1α and heme oxygenase-1 for therapeutic angiogenesis. Transfection with either hypoxia-inducible factor-1α (HIF-1α) or heme oxygenase-1 (HO-1) gene can induce neovascularization in ischemic tissues. Although expression of transfected HIF-1α gene occurs rapidly, the expressed HIF-1α protein degrades quickly, limiting its therapeutic efficacy. Meanwhile, expressed HO-1 protein does not rapidly undergo degradation, but gene expression occurs a couple of days after transfection, resulting in apoptosis and a delay in angiogenesis in ischemic tissues at the incipient period of HO-1 gene transfection. We hypothesize that combined delivery of HIF-1α and HO-1 gene will enhance antiapoptosis and neovascularization in ischemic tissue compared with HIF-1α or HO-1 single-gene therapy. To test this hypothesis, ischemic mouse hindlimbs were treated with HIF-1α and/or HO-1 gene therapy. The combined gene therapy proved superior to both single-gene therapies, resulting in rapid expression of HIF-1α gene and long-term maintenance of expressed HO-1 protein. The apoptosis in the ischemic region was significantly less, and angiogenic growth factor secretion and angiogenesis were greater in the combined gene therapy than in either of the single-gene therapies. Our results suggest that a combined gene therapy of HIF-1α and HO-1 enhances the transfection of both genes and improves angiogenesis compared with either single-gene therapy.


Takotsubo cardiomyopathy in acute coronary syndrome; clinical features and contribution of cardiac magnetic resonance during the acute and convalescent phase. Takotsubo cardiomyopathy (TTC) is a diagnostic entity that is increasingly being recognized. Data from cardiac magnetic resonance (CMR) imaging and its impact on differential diagnosis are limited. After 26 months, coronary angiography revealed normal coronary arteries and left ventriculography and/or echocardiography left ventricular dysfunction with apical ballooning in 20 patients with acute coronary syndrome (ACS). Four patients were excluded from CMR and in three patients an alternative diagnosis was revealed. Thirteen patients (all female; 60 ± 8 years) with TTC underwent a multisequential CMR, in which all showed myocardial oedema with an elevated T2 ratio in the apical region (2.4 ± 0.4; p < 0.001 vs. healthy controls), and five patients an elevated global relative enhancement (gRE; 3.7 ± 1.4; p < 0.05 vs. healthy controls). No late gadolinium enhancement (LGE) was detected on CMR. Follow-up after 132 ± 33 days showed a normalized left ventricular ejection fraction, myocardial mass, T2 ratio, and gRE in all patients. TTC is a small but definite group among patients with ACS and normal coronary arteries. CMR allows differentiating TTC from other causes such as myocarditis and cardiomyopathies, as well as to identify the transient increase of myocardial mass and resolution of myocardial oedema as the systolic dysfunction improves. Therefore, CMR might add valuable information for the differential diagnoses and therapeutic decision-making in patients with suspected TTC.


Plants used for the treatment of diabetes in Jordan: a review of scientific evidence. Diabetes is a serious disease which has reached epidemic proportions in many parts of the world. Despite the tremendous developments in medicinal chemistry, traditional medicine is still a common practice for the treatment of diabetes. In Jordanian traditional medicine, 69 plant species are used by diabetic patients to reduce glucose levels in blood. The aim of the present study is to report these plants and link their traditional use with scientific evidence confirming their claimed activity. The plant part(s) used, method(s) of preparation, common Arabic names, and other ethnopharmacological uses are also listed. The literature and databases (SciFinder, PubMed, ScienceDirect and Scirus) have been thoroughly investigated and the plants used have been grouped according to the reported scientific evidence. Results showed that 40 plants have been reported to possess hypoglycemic activities in in vivo/in vitro experiments. Five plant species did not exhibit in vivo hypoglycemic activity, while 24 plants had not been studied for such an activity. Twenty plants had been screened for their α-amylase/α-glucosidase inhibitory activities. The reported in vivo and in vitro hypoglycemic as well as α-amylase/α-glucosidase inhibitory activities of these plants are discussed. Additional in vitro and in vivo studies are needed to test the hypoglycemic activity of the plants with claimed antidiabetic activity which has not yet been evaluated. Identification of the active ingredients of potent plants might generate lead compounds in drug discovery and development.


Diel patterns of nitrogen excretion, plasma constituents, and behavior in the gulf toadfish (Opsanus beta) in laboratory versus outdoor mesocosm settings. Nitrogen excretion by the gulf toadfish (Opsanus beta) is of interest because of its high proportion of urea excretion compared with that of other teleosts. To better understand the factors influencing the timing of nitrogen excretion, the ratio of excreted urea∶ammonia, and the effector molecules regulating these processes, gulf toadfish were subjected to a series of experiments that moved them progressively from internal laboratory to outdoor mesocosm settings while assessing their behavior, nitrogen excretion patterns, levels of plasma hormones/effectors, and other parameters. In confined flux chambers in both laboratory and outdoor settings, toadfish nitrogen excretion was largely observed as urea pulses, with no apparent diel patterns to the pulses. Unrestrained toadfish in mesocosms exhibited distinctly nocturnal behavior, remaining exclusively in shelters during the day but taking several forays out into the mesocosm at night. In contrast to nitrogen excretion patterns in chambers, urea and ammonia were coexcreted in mesocosms and ratios for urea∶ammonia were very close to 1∶1 for both fed and fasted toadfish. The majority of measured excretion (and corresponding declines in plasma urea levels) occurred during two distinct periods of pulsing during daylight hours (0600-1000 and 1600-1800 hours). The declines in plasma urea associated with excretion were preceded by/coincided with declines in plasma cortisol. No day/night or hourly patterns in plasma serotonin (5-hydroxytryptamine [5-HT]) were observed, but there was a strong positive correlation among all samples between plasma urea and 5-HT. There was also a negative correlation between plasma cortisol and 5-HT. As expected for a nocturnally active species, plasma melatonin was significantly lower in daylight hours. A variety of enzyme activities (glutamine synthetase, glutaminase) and mRNA levels (glutamine synthetase, urea transporter, and Rhesus proteins) showed no significant variation over a diel cycle. Unlike prior laboratory studies, our results show that gulf toadfish in a natural setting have a distinctly diurnal pattern of nitrogen excretion and that ammonia and urea are coexcreted. The decline in plasma cortisol associated with urea pulses noted in prior laboratory studies was not as evident in the natural setting.


Protective effects of the aqueous extract of Scutellaria baicalensis against acrolein-induced oxidative stress in cultured human umbilical vein endothelial cells.  Scutellaria baicalensis Georgi (Labiatae) (SbG), one of the fifty fundamental herbs of Chinese herbology, has been reported to have anti-asthmatic, antifungal, antioxidative, and anti-inflammatory activities.  This study was designed to determine the protective effects of the extract of SbG against the acrolein-induced oxidative stress in cultured human umbilical vein endothelial cells (HUVEC).  The MTT reduction assay was employed to determine cell viability. The total cellular glutathione (GSH) level was detected using a colorimetric GSH assay kit. Cellular GSH production was conducted by detecting the mRNA expression levels of γ-glutamylcysteine ligase catalytic subunit and modifier subunit.  Concentration-dependent cytotoxic effects of acrolein were observed while SbG could effectively protect the acrolein-induced oxidative damage. The protective mechanism was investigated, showing that the increased GSH content in the SbG-incubated HUVE cells was associated with the protective effects of SbG-treated cells. Further RT-PCR data confirmed the elevated mRNA expressions of GSH synthesis enzymes.  The current study strongly indicated that SbG could be a potential antioxidant against oxidative stress in treating cardiovascular diseases.


Intrafollicular and serum levels of leptin during in vitro fertilization cycles: comparison between the effects of recombinant follicle-stimulating hormones and human menopausal gonadotrophin. To compare the effect of recombinant follicle-stimulating hormones (r-FSH) and human menopausal gonadotrophin (hMG) on leptin levels in serum and follicular fluid (FF) during in vitro fertilization IVF/ET treatment, and to investigate whether leptin levels in the follicular fluid and/or serum are correlated with IVF success. Sixty-three patients undergoing IVF cycle were subdivided into two groups. r-FSH was used to for controlled ovarian hyperstimulation in 29 patients (Group A) while, hMG was used in 34 patients (Group B). Our main outcomes were serum and FF leptin on the day of oocyte collection. The two groups were comparable in age, body mass index (BMI), indications for IVF/ET, E2 level on human chorionic gonadotrophin day, number of retrieved oocytes, fertilization rate, number of transferred embryos and pregnancy rate. Serum and FF leptin levels were similar between the two study groups. Additionally, no correlation was found between levels of leptin in either serum or FF and cycle results such as: number of retrieved oocytes, fertilization rate and pregnancy rate. r-FSH and hMG have been found to have comparable effects on leptin levels in the serum and the FF of patients undergoing IVF/ET. Additionally, leptin levels in both serum and FF on day of retrieval have no correlation to IVF/ET outcome.


Optimizing soy isoflavones effect in postmenopausal women: the impact of timing on climacteric symptoms. The most common complaints during climacteric are vasomotor symptoms. A circadian rhythm has been observed when hot flashes start; however, not much information is available in this field. To analyze whether the time (morning/evening) of administration of a compound containing 60 mg of dry soy seed extract (glycine max) with 40% of total isoflavones, primrose oil and α-tocopherol modifies the effect on the climacteric syndrome. Multicentric, observational, open, prospective, longitudinal and cross-sectional study. Subjects and methods. One thousand six hundred eighty-two postmenopausal women with climacteric symptoms were allocated in two groups in order to receive the treatment in the morning (Group 1) or in the evening (Group 2), switching administration time after 3 months. Clinical evaluation was carried out at 0, 3 and 6 months of follow-up using Blatt-Kupperman and Greene scales. 233 (13.9%) women dropped out from the study. Both administration times improved the climacteric symptoms after 3 and 6 months of treatment, showing a reduction in the scores of Blatt-Kupperman and Greene scales (p < 0.001). No differences between both groups during the follow-up were identified. The time of administration of isoflavones does not modify its effect on climacteric symptoms.


Changes in hemostatic parameters after oral and transdermal hormone therapy in postmenopausal women. Hormone therapy (HT) can be prothrombotic risk factor. We compared the effects of oral HT (o-HT) and transdermal HT (t-HT) on the kinetic of clot formation and fibrinolysis in postmenopausal women after 6 months HT using a multiparameter test. We observed that after HT, the level of fibrinogen was higher than in controls (Fg 3.12 g/l vs. 4.24 g/l (o-HT); 3,7 g/l (t-HT); p < 0.001) and values of velocity of polymerization in o-HT group were increased (95.84 mOD/min vs. 146.50 mOD/min, p < 0.001) compared to controls. Maximum absorbance of formed clots was higher in o-HT group (0.279 vs. 0.312, p < 0.001) than in controls, but in t-HT group was lowest (0.268). Fibrin lysis half-time increased in both HT groups (controls 17.16 min vs. 31.43 min (o-HT); 23.34 min (t-HT) p < 0.001) compared to values in controls. The results of our study show that o-HT caused the changes in clot formation and fibrinolysis than t-HT in postmenopausal women. The increased level of fibrinogen and its accelerated kinetics of polymerization as well as a lower rate of clot lysis may partly explain the increase in venous thrombosis and cardiovascular events reported after the use of HT, especially the oral form of that.


Anti-inflammatory activity of Penstemon gentianoides and Penstemon campanulatus. Penstemon gentianoides (Kunth) Poir. and Penstemon campanulatus (Cav.) Willd. (Plantaginaceae) are important medicinal plants in Mexico used by indigenous people for their anti-inflammatory effects and to also reduce rheumatic pains. In addition to radical scavenging activity, the anti-inflammatory activity of the extracts, fractions and compounds of these plants were investigated and reported here for the first time. The anti-inflammatory activities of MeOH, CH(2)Cl(2), and ethyl acetate extracts and iridoid, flavonoids, and phenylpropanoids from Penstemon gentianoides and P. campanulatus were studied in the TPA-induced mouse ear edema model. In addition, antioxidant activity against DPPH, crocin and β-carotene were investigated. All extracts were tested and a selection of known compounds significantly (p <0.05) inhibited mouse ear edema. The results showed that CH(2)Cl(2) extracts of roots and stems from P. gentianoides and ethyl acetate extracts of leaves from P. gentianoides and P. campanulatus, as well as luteolin, diosmetin, penstemide and verbascoside produced the most positive results. Of all substances tested, the CH(2)Cl(2) extract of P. gentianoides roots was the most powerful inhibitor (ED(50)=0.07 mg/ear), with activity comparable to that of indomethacin. These extracts, compounds purified, as well as known compounds, inhibited oxidation of β-carotene and crocin. These findings showed that the iridoid monoterpenes, flavonoids and phenylpropanoids present in these plants species may all contribute to the observed anti-inflammatory activity. Additionally, the observed antioxidant activity is correlated with the anti-inflammatory activity of these plants and the phytochemicals derived from them.


BRCA1 and BRCA2 heterozygosity in embryonic stem cells reduces radiation-induced Rad51 focus formation but is not associated with radiosensitivity. The breast cancer susceptibility genes BRCA1 (breast cancer 1) and BRCA2 (breast cancer 2) encode proteins involved in double-strand break (DSB) repair, whose functions include facilitating homologous recombination through interactions with Rad51, the human homologue of bacterial RecA. Homozygous deficiency inhibits Rad51 focus formation and enhances radiosensitivity, but the effects of heterozygosity have not been investigated in detail. The purpose of this work was to examine the effect of heterozygosity on Rad51 activation and clonogenicity following X-irradiation (XR). We used quantitative assessment of immunofluorescent foci to assess Rad51 activation in wild type mouse embryonic fibroblasts (MEF) and in paired mutant and wild type BRCA1 and BRCA2 embryonic stem cells (ES cells). We measured radiosensitivity in the same cell lines using clonogenic survival assays. ES cells exhibit higher numbers of cells with Rad51 foci post radiation than MEF, likely due to differences in cell cycle distribution. Compared to wild type cells, BRCA1 and BRCA2 heterozygous ES cells demonstrate lower numbers of Rad51 foci per nucleus 4 and 24 hours post radiation. This was not associated with significantly enhanced radiosensitivity. BRCA1/2 heterozygosity in ES cells is associated with a subtle reduction in Rad51 foci formation that is not associated with increased XR induced cytotoxicity.


The alteration of asymmetric dimetilarginine (ADMA) levels in cardiac and gastrocnemius muscles following radioactive iodine application in guinea pigs and the effect of L-carnitine on this alteration. Tissue levels of asymmetric dimetilarginine (ADMA) and symmetric dimetilarginine (SDMA) were investigated in cardiac ventricle and gastrocnemius muscles of guinea pigs treated with radioactive iodine (RAI) alone or in combination with L-carnitine (LC). Group 1 received no treatment (control group). Group 2 received a total dose of 30 mCi⁻¹kg⁻¹ body weight iodine-131 alone. Group 3 received 200 mg⁻¹kg⁻¹ of LC for 10 days alone. Group 4 received 200 mg⁻¹kg⁻¹ of LC plus RAI therapy. Free thyroid hormones, ADMA and SDMA concentrations were measured. Serum free thyroid hormone concentrations were found decreased in the RAI and LC-RAI groups after RAI application. A significant decrease in ADMA and SDMA concentration was observed in ventricle muscle following RAI application. The LC-RAI group had significantly decreased ADMA levels in ventricle muscle compared with those of the control group. Similarly, SDMA concentrations in ventricle and gastrocnemius muscles of the LC-RAI groups were significantly lower than those of the control groups. Our results indicated that RAI appears to exert an inhibitory effect on ADMA and SDMA levels of ventricular muscle. LC administration when given adjuvant to RAI therapy may cause a marked decrease in ADMA concentrations of both ventricular and gastrocnemius muscles.


Body size and growth from birth to 2 years and risk of overweight at 7-9 years. To assess the potential association between growth during the first 2 years of life and the risk of overweight in childhood. Overweight status of 1 582 French children aged 7-9 years in 2000 was estimated, using measured weight and height data collected retrospectively. Overweight was estimated using measured weight and height. Linear mixed models identified six growth parameters associated with later overweight: weight, length and body mass index (BMI) attained at 1 year, average monthly weight and length gain, and average variation in monthly weight gain. In the combined logistic regression model, the risk of overweight in boys at 7-9 years was associated with average monthly weight gain (odds ratio [OR] for 100 g=2.06, 95% confidence interval [CI]: 1.22, 3.48) and BMI at 1 year (OR for 1 kg/m(2)=1.83, CI: 1.33, 2.51), while in girls, it was associated with weight at 1 year (OR for 1 kg=2.24, CI: 1.37, 3.66), BMI at 1 year (OR for 1 kg/m(2)=1.58, CI: 1.05, 2.39) and average variation in monthly weight gain (OR for 1 g=1.13, CI: 1.04, 1.22). This study showed the simultaneous association of large infant size at 1 year and early rapid infant growth along with overweight at 7-9 years, as well as involvement of early growth velocity variations. Early infancy, a phase of very rapid growth, constitutes a critical period for the onset of overweight.


Treatment of cancer during pregnancy with monoclonal antibodies: a real challenge.


Canakinumab: a human anti-IL-1β monoclonal antibody for the treatment of cryopyrin-associated periodic syndromes. The cryopyrin-associated periodic syndromes (CAPS) are a group of rare inherited inflammatory diseases associated with overproduction of IL-1β. Canakinumab, developed by Novartis AG (Basel, Switzerland), is an intravenously or subcutaneously administered, fully human monoclonal antibody that neutralizes the bioactivity of human IL-1β. Canakinumab has promising clinical safety and pharmacokinetic properties, and has demonstrated potential for the treatment of CAPS. Canakinumab was recently granted EU orphan drug status for systemic-onset juvenile idiopathic arthritis, and early clinical trials have established that administration of canakinumab every 2 weeks is both safe and effective. Subcutaneous canakinumab (approved formulation) offers some advantages over the existing IL-1β-blocking treatment, anakinra, which must be injected daily and is often not well tolerated by patients. The long-term safety of all targeted anti-IL-1 therapies in CAPS remains an unanswered question owing to the relatively short clinical experience with these agents; as canakinumab produces sustained IL-1 suppression, vigilance is necessary to diagnose the development of adverse events, especially any associated infections.


Tocilizumab for the treatment of rheumatoid arthritis. Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody, which binds to circulating soluble IL-6 receptor and membrane-expressed IL-6 receptor, inhibiting IL-6 binding to both forms of IL-6 receptor. Several Phase III clinical trials demonstrate the clinical efficacy of tocilizumab as monotherapy or with disease-modifying anti-rheumatic drugs for adult patients with moderately to severely active rheumatoid arthritis. Tocilizumab in combination with methotrexate after 24 weeks of treatment could induce disease remission in 30% of patients with rheumatoid arthritis refractory to anti-TNF antagonist therapy. The most common adverse reactions reported in clinical studies are upper respiratory tract infection, nasopharyngitis, headache, hypertension and mild, reversible increases in alanine aminotransferase enzymes. Serious adverse reactions include infections, gastrointestinal perforations and hypersensitivity reactions, including anaphylaxis. The clinical efficacy and safety of tocilizumab has led to the approval of this innovative drug for the treatment of rheumatoid arthritis in more than 70 countries worldwide.


3,4-diaminopyridine for the treatment of Lambert-Eaton myasthenic syndrome. The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease in which antibodies against voltage-gated calcium channels inhibit cholinergic neurotransmission. LEMS is clinically characterized by muscle weakness and autonomic dysfunction. 3,4-diaminopyridine (3,4-DAP) blocks potassium channels in nerve terminals, resulting in an increase in acetylcholine release. This article describes the four randomized placebo-controlled trials of 3,4-DAP in patients with LEMS. All trials demonstrated a significant effect on muscle strength and compound muscle action potential amplitude. Furthermore, the safety and tolerability of 3,4-DAP are reviewed. The side effects of 3,4-DAP are generally mild and most frequently consist of paresthesias, but epileptic seizures and arrhythmias have been described in patients using high doses. Given the efficacy and safety of 3,4-DAP in LEMS, this drug is the mainstay for symptomatic treatment of LEMS.


Certolizumab pegol: a new biologic targeting rheumatoid arthritis. The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis. This is mostly due to targeted biologic agents that have changed the outcome of this disease. Certolizumab pegol (Cimzia(®), UCB Inc., GA, USA), which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn's disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy. This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease-modifying antirheumatic drugs and other biologic agents. Treatment recommendations are beyond the scope of this review; however, with many options available, there will be annotations on current trends in the care of this chronic disease.


Illuminating the latest advances in innate immunity on the island of the sun god. The latest Aegean Conferences workshop on innate immunity (Rhodes, Greece) discussed recent developments that suggest that innate immune mechanisms are not restricted to providing first-line defense or instructing the development of adaptive immunity, but additionally permeate and influence diverse physiological and homeostatic processes.


Finding the right time for weaning off immunosuppression in solid organ transplant recipients. Solid organ transplantation (SOT) requires lifelong immunosuppression (IS) to prevent rejection and graft loss. The currently adopted immunosuppressive protocols are numerous and are based on the administration of at least two molecules with diverse mechanisms of action. Owing to the fact that the majority of immunosuppressants act non-selectively, the immune system is normally oversuppressed, and as a result is less able to both defend the host against infection and to control the spread of malignant cells. Consequently, long-term IS is burdened by chronic toxicity, which may be highly invalidating and may significantly influence patient's quality of life, compliance to treatment, overall success rate, and patient and graft survival. In an ideal scenario, SOT recipients should initially receive just enough IS to favor the onset of clinical operational tolerance (COT), a condition where the immune system of the host does not attack the graft in the absence of any immunosuppressant. COT has been documented after liver transplantation (LT) and renal transplantation (RT). First, COT was accidentally detected in patients who were nonadherent to treatment and who spontaneously decided to stop all IS without any medical guidance or surveillance. Later, it was described in recipients who required IS withdrawal following the occurrence of malignant diseases. Based on strikingly convincing experimental data, several tolerogenic protocols have recently been applied in patients but overall the results have been disappointing. The current literature demonstrates that COT can be safely achieved in stable LT recipients, with completely different strategies. Importantly, the onset of an episode of acute rejection during the attempt of IS withdrawal would not worsen the clinical outcome. On the contrary, COT remains a major challenge after RT because the onset of acute rejection will substantiate in graft loss. Currently, a major field of investigation aims to define markers of COT, which will allow the selection of individuals who are more prone to develop COT. Preliminary results in both RT and LT have just been announced; however, these markers will require validation in prospective studies.


ABO blood group incompatibility: a diminishing barrier to successful kidney transplantation? Blood type-incompatible transplantation has gained wide acceptance over the last decade. This is largely the result of B-cell-directed therapies aimed at modulating anti-blood group antibodies, which were the cause of the poor outcomes originally seen. Now rituximab (anti-CD20 and anti-B cell) has largely replaced splenectomy in preconditioning protocols, allowing for the wider implementation of ABO-incompatible transplants. Plasma exchange followed by intravenous immunoglobulin is also critical for the success of ABO-incompatible transplants. In this article, we describe the important contributions immunomodulatory drugs and antibody reduction therapies have made in achieving excellent outcomes in what was once an impenetrable barrier to transplantation.


Treatment of lupus nephritis.

Treatment of lupus nephritis. Renal involvement in systemic lupus erythematosus patients is a severe disease manifestation characterized by various clinical and histopathological alterations. The revised International Society of Nephrology/Renal Pathology Society 2003 classification defines the subclasses of lupus nephritis (LN) according to their pathological glomerular patterns, which has a crucial impact on the prognosis and treatment options for LN patients. There are widely accepted therapeutic agents available, such as cyclophosphamide, mycophenolate mofetil, azathioprine and corticosteroids. Several trials have tried to determine a gold standard for induction and maintenance therapy in LN, and the place of newer drugs, biologicals, has been investigated. We review recently reported data on current treatment regimens in LN, in particular in the context of the International Society of Nephrology/Renal Pathology Society 2003 classification.


Current understanding and management of giant cell arteritis and polymyalgia rheumatica. Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are linked conditions that occur in the elderly. GCA is a vasculitis of large- and medium-sized vessels causing critical ischemia. It is a medical emergency owing to the high incidence of neuro-ophthalmic complications. PMR is an inflammatory disease characterized by abrupt-onset pain and stiffness of the shoulder and pelvic girdle muscles. Both conditions are associated with a systemic inflammatory response and constitutional symptoms. The pathogeneses are unclear. The initiating step may be the recognition of an infectious agent by activated dendritic cells. The key cell type involved is CD4(+) T cells and the key cytokines are IFN-γ (implicated in granuloma formation) and IL-6 (key to the systemic response). The pathogenesis of PMR may be similar to that of GCA, however, PMR exhibits less clinical vascular involvement. The mainstay of therapy is corticosteroids, and disease-modifying therapy is indicated in relapsing disease. This article reviews recent guidelines on early recognition, investigations and management of these diseases, as well as advances in imaging.


How genetic variation affects patient response and outcome to therapy for psoriasis. Psoriasis is a prevalent chronic inflammatory condition that affects the skin. There are many treatments available for psoriasis but they are not universally effective and some have associated toxicities. Pharmacogenetics and pharmacogenomics explore the relationship between individual genetic variation and drug effect to allow targeted 'personalized' therapy for patients. There has been very limited pharmacogenetic research regarding psoriasis, with most limited to small retrospective case-control studies looking at single-nucleotide polymorphisms in candidate genes involved in drug pharmacokinetics. We review the pharmacogenetic investigation of treatments for psoriasis to date, including emerging pharmacogenomic studies. In addition, we discuss how such genetic data could be incorporated into routine clinical practice and future areas for development in this field.