Showing papers by "Rappaport Faculty of Medicine published in 2011"

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Abstract: Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

The relevance of iron in the pathogenesis of Parkinson's disease.

Abstract: Alterations of iron levels in the brain has been observed and documented in a number of neurodegenerative disorders including Parkinson's disease (PD). The elevated nigral iron levels observed in PD may reflect a dysfunction of brain iron homeostasis. Under normal physiological conditions excess iron can be sequestrated in ferritin and neuromelanin. Alternatively, the excess iron may represent a component of brain iron deposition associated with ageing. The aetiology of idiopathic PD largely remains an enigma. However, intensive investigations have provided a host of putative mechanisms that might contribute to the pathogenesis underlying the characteristic degeneration of the dopaminergic neurons in the substantia nigra (SN). The mechanisms proposed include oxidative (and nitrative) stress, inflammation, excitotoxicity, mitochondrial dysfunction, altered proteolysis and finally apoptotic induced cell death. Iron-mediated cellular destruction is mediated primarily via reactive oxygen or/and nitrogen species induced oxidative stress. Furthermore, these pathogenic mechanisms appear to be closely interlinked to the cascade of events leading to cellular death. There are conflicting reports about the stage during disease progression at which nigral iron change occurs in PD. Some have found that there are no changes in iron content SN in asymptomatic incidental Lewy body disease, suggesting it may represent a secondary event in the cascade of neuronal degeneration. In contrast, others have found an elevation of iron in SN in pre-clinical stages. These discrepancies may be attributed to the occurrence of different sub-groups of the disease. This concurs with the notion that PD represents a group of related diseases with a number of potential pathogenic pathways.

Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells

Abstract: In view of the therapeutic potential of cardiomyocytes derived from induced pluripotent stem (iPS) cells (iPS-derived cardiomyocytes), in the present study we investigated in iPS-derived cardiomyocytes, the functional properties related to [Ca2+]i handling and contraction, the contribution of the sarcoplasmic reticulum (SR) Ca2+ release to contraction and the b-adrenergic inotropic responsiveness. The two iPS clones investigated here were generated through infection of human foreskin fibroblasts (HFF) with retroviruses containing the four human genes: OCT4, Sox2, Klf4 and C-Myc. Our major findings showed that iPS-derived cardiomyocytes: (i) express cardiac specific RNA and proteins; (ii) exhibit negative force–frequency relations and mild (compared to adult) post-rest potentiation; (iii) respond to ryanodine and caffeine, albeit less than adult cardiomyocytes, and express the SR-Ca2+ handling proteins ryanodine receptor and calsequestrin. Hence, this study demonstrates that in our cardiomyocytes clones differentiated from HFF-derived iPS, the functional properties related to excitation–contraction coupling, resemble in part those of adult cardiomyocytes.

Cardiomyocytes derived from human embryonic and induced pluripotent stem cells: comparative ultrastructure

Abstract: Induced pluripotent stem cells (iPSC) are generated from fully differentiated somatic cells that were reprogrammed into a pluripotent state. Human iPSC which can be obtained from various types of somatic cells such as fibroblasts or keratinocytes can differentiate into cardiomyocytes (iPSC-CM), which exhibit cardiac-like transmembrane action potentials, intracellular Ca2+ transients and contractions. While major features of the excitation-contraction coupling of iPSC-CM have been well-described, very little is known on the ultrastructure of these cardiomyocytes. The ultrastructural features of 31-day-old (post-plating) iPSC-CM generated from human hair follicle keratinocytes (HFKT-iPSC-CM) were analysed by electron microscopy, and compared with those of human embryonic stem-cell-derived cardiomyocytes (hESC-CM). The comparison showed that cardiomyocytes from the two sources share similar proprieties. Specifically, HFKT-iPSC-CM and hESC-CM, displayed ultrastructural features of early and immature phenotype: myofibrils with sarcomeric pattern, large glycogen deposits, lipid droplets, long and slender mitochondria, free ribosomes, rough endoplasmic reticulum, sarcoplasmic reticulum and caveolae. Noteworthy, the SR is less developed in HFKT-iPSC-CM. We also found in both cell types: (1) ‘Ca2+-release units’, which connect the peripheral sarcoplasmic reticulum with plasmalemma; and (2) intercellular junctions, which mimic intercalated disks (desmosomes and fascia adherens). In conclusion, iPSC and hESC differentiate into cardiomyocytes of comparable ultrastructure, thus supporting the notion that iPSC offer a viable option for an autologous cell source for cardiac regenerative therapy.

A reappraisal of Gaucher disease-diagnosis and disease management algorithms.

Abstract: Type 1 (non-neuronopathic) Gaucher disease was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed and it has become a prototype for treatments for related orphan diseases. There are currently four treatment options available to patients with Gaucher disease, nevertheless, almost 25% of Type 1 Gaucher patients do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. Diagnosis of Gaucher disease by enzyme testing is unequivocal, but the rarity of the disease and nonspecific and heterogeneous nature of Gaucher disease symptoms may impede consideration of this disease in the differential diagnosis. To help promote timely diagnosis and optimal management of the protean presentations of Gaucher disease, a consensus meeting was convened to develop algorithms for diagnosis and disease management for Gaucher disease.

Urinary Tract Infection in Postmenopausal Women

Abstract: Urinary tract infection (UTI) is the most common bacterial infection in women in general and in postmenopausal women in particular. Two groups of elderly women with recurrent UTI should be differentiated regarding age and general status: healthy, young postmenopausal women aged 50 to 70 years who are neither institutionalized or catheterized and elderly institutionalized women with or without a catheter. Bacteriuria occurs more often in elderly functionally impaired women, but in general it is asymptomatic. However, the risk factors associated with recurrent UTI in elderly women are not widely described. In a multivariate analysis it was found that urinary incontinence, a history of UTI before menopause, and nonsecretor status were strongly associated with recurrent UTI in young postmenopausal women. Another study described the incidence and risk factors of acute cystitis among nondiabetic and diabetic postmenopausal women. Independent predictors of infection included insulin-treated patients and a lifetime history of urinary infection. Borderline associations included a history of vaginal estrogen cream use in the past month, kidney stones, and asymptomatic bacteriuria at baseline. Another important factor in postmenopausal women is the potential role that estrogen deficiency plays in the development of bacteriuria. There are at least two studies showing a beneficial effect of estrogen in the management of recurrent bacteriuria in elderly women. One of these studies showed that vaginal estrogen cream reduced vaginal pH from 5.5±0.7 to 3.6±1.0, restored lactobacillus, and decreased new episodes of UTI. Another study reported similar results using an estriol vaginal ring. However, contradictory results are found in the literature. For example, additional studies found that the use of estriol-containing vaginal pessaries was less effective than oral nitrofurantoin macrocrystals in preventing UTI in postmenopausal women. Two other studies also did not find any benefit in the reduction of UTI by oral estrogen therapy. Unfortunately, the use of estrogen in preventing UTI in postmenopausal women remains questionable. New strategies have been researched for reducing the use of antibiotics in the prevention and treatment of UTI. Two of them are probiotics and cranberry juice or capsules. Although several studies regarding probiotics and cranberry juice or capsules have reported a reduction of episodes of UTI, there is no conclusive evidence that they are useful in the prevention of UTI in postmenopausal women. As for the optimal drug, dosage, and length of treatment for UTI in the elderly, there are no studies comparing these data with the treatment for young women.

Involvement of microparticles in diabetic vascular complications

Abstract: Type 2 diabetes mellitus (T2DM) is associated with increased coagulability and vascular complications. Circulating microparticles (MPs) are involved in thrombosis, inflammation, and angiogenesis. However, the role of MPs in T2DM vascular complications is unclear. We characterised the cell origin and pro-coagulant profiles of MPs obtained from 41 healthy controls and 123 T2DM patients with coronary artery disease, retinopathy and foot ulcers. The effects of MPs on endothelial cell coagulability and tube formation were evaluated. Patients with severe diabetic foot ulcers expressed the highest levels of MPs originated from platelet and endothelial cells and negatively-charged phospholipid-bearing MPs. MP coagulability, calculated from MP tissue factor (TF) and TF pathway inhibitor (TFPI) ratio, was low in healthy controls and in diabetic retinopathy patients ( 1.8, p≥0.002). MPs of all T2DM patients induced a more than two-fold increase in endothelial cell TF (antigen and gene expression) but did not affect TFPI levels. Tube networks were longest and most stable in endothelial cells that were incubated with MPs of healthy controls, whereas no tube formation occurred in MPs of diabetic patients with coronary artery disease. MPs of diabetic retinopathy and diabetic foot ulcer patients induced branched tube networks that were unstable and collapsed over time. This study demonstrates that MP characteristics are related to the specific type of vascular complications and may serve as a bio-marker for the pro- coagulant state and vascular pathology in patients with T2DM.

Bacterial ATP-driven transporters of transition metals: physiological roles, mechanisms of action, and roles in bacterial virulence

Abstract: Maintaining adequate intracellular levels of transition metals is fundamental to the survival of all organisms. While all transition metals are toxic at elevated intracellular concentrations, metals such as iron, zinc, copper, and manganese are essential to many cellular functions. In prokaryotes, the concerted action of a battery of membrane-embedded transport proteins controls a delicate balance between sufficient acquisition and overload. Representatives from all major families of transporters participate in this task, including ion-gradient driven systems and ATP-utilizing pumps. P-type ATPases and ABC transporters both utilize the free energy of ATP hydrolysis to drive transport. Each of these very different families of transport proteins has a distinct role in maintaining transition metal homeostasis: P-type ATPases prevent intracellular overloading of both essential and toxic metals through efflux while ABC transporters import solely the essential ones. In the present review we discuss how each system is adapted to perform its specific task from mechanistic and structural perspectives. Despite the mechanistic and structural differences between P-type ATPases and ABC transporters, there is one important commonality: in many clinically relevant bacterial pathogens, transporters of transition metals are essential for virulence. Here we present several such examples and discuss how these may be exploited for future antibacterial drug development.

Genetic spectrum of hereditary neuropathies with onset in the first year of life

Abstract: Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.

Host Response to Short-term, Single-Agent Chemotherapy Induces Matrix Metalloproteinase-9 Expression and Accelerates Metastasis in Mice

Abstract: Mounting evidence suggests that bone marrow-derived cells (BMDC) contribute to tumor growth, angiogenesis, and metastasis. In acute reactions to cancer therapy, several types of BMDCs are rapidly mobilized to home tumors. Although this host reaction to therapy can promote tumor regrowth, its contribution to metastasis has not been explored. To focus only on the effects of chemotherapy on the host, we studied non-tumor-bearing mice. Plasma from animals treated with the chemotherapy paclitaxel induced angiogenesis, migration, and invasion of tumor cells along with host cell colonization. Lesser effects were seen with the chemotherapy gemcitabine. Conditioned medium from BMDCs and plasma from chemotherapy-treated mice each promoted metastatic properties in tumor cells by inducing matrix metalloproteinase-9 (MMP9) and epithelial-to-mesenchymal transition. In mice in which Lewis lung carcinoma cells were injected intravenously, treatment with paclitaxel, but not gemcitabine or vehicle, accelerated metastases in a manner that could be blocked by an MMP9 inhibitor. Moreover, chimeric mice reconstituted with BMDC where MMP9 activity was attenuated did not support accelerated metastasis by carcinoma cells that were pretreated with chemotherapy before their introduction to host animals. Taken together, our findings illustrate how some chemotherapies can exert prometastatic effects that may confound treatment outcomes.

Selective inhibitors of monoamine oxidase type B and the "cheese effect".

Abstract: Potentiation of the cardiovascular and other effects of dietary tyramine by monoamine oxidase (MAO) inhibitors (cheese effect) has been a major limitation to clinical use of these drugs. The discovery that MAO exists in two distinct isoforms, MAO-A and MAO-B, together with the development of selective inhibitors of each isoform, enabled the understanding that selective inhibition of MAO-A, or inhibition of both isoforms, will cause cheese effect, but selective inhibition of MAO-B can be elicited without dangerous pressor reaction. This development has permitted the introduction of selective MAO-B inhibitors to clinical medicine for treatment of Parkinson's disease. This review describes the basic mechanisms involved in cheese effect, as well as providing information on tyramine levels in a variety of foodstuff, and surveys clinical information from tyramine pressor testing with the selective MAO-B inhibitors, selegiline and rasagiline.

Treating obstructive sleep apnea with hypoglossal nerve stimulation.

Abstract: Purpose of review Obstructive sleep apnea (OSA) is a common disorder characterized by recurrent pharyngeal collapse secondary to sleep-induced hypotonia of peri-pharyngeal structures. Therapy for OSA is sometimes poorly tolerated and not always effective. The current study reviews a new treatment modality, hypoglossus stimulation, recently evaluated by multiple physiological studies and currently assessed by several clinical studies. Recent findings A phase-I, implantable hypoglossus nerve stimulation multicenter study was published in 2001. Significant reduction in apnea-hypopnea index (AHI) was reported in seven of the eight implanted OSA patients, but technical faults precluded prolonged follow-up. Over the past 2 years, three new hypoglossus nerve stimulation systems have been evaluated in more than 60 OSA patients. In adequately selected patients, a more than 50% reduction in AHI was observed. Usually, a decrease in OSA severity from moderate-severe to mild-minimal can be achieved. Summary Ongoing research, including recent initiation of a large multicenter phase-III study, suggests that hypoglossus nerve stimulators are likely to be available as a new treatment modality within a few years. Additional data are needed to define which OSA patients are most likely to benefit from hypoglossus nerve stimulation. Continuous refinement of electrodes design is likely to improve stimulation efficacy in coming years.

Heparanase levels are elevated in the urine and plasma of type 2 diabetes patients and associate with blood glucose levels.

Abstract: Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans. Utilizing an ELISA method capable of detection and quantification of heparanase, we examined heparanase levels in the plasma and urine of a cohort of 29 patients diagnosed with type 2 diabetes mellitus (T2DM), 14 T2DM patients who underwent kidney transplantation, and 47 healthy volunteers. We provide evidence that heparanase levels in the urine of T2DM patients are markedly elevated compared to healthy controls (1162±181 vs. 156±29.6 pg/ml for T2DM and healthy controls, respectively), increase that is statistically highly significant (P<0.0001). Notably, heparanase levels were appreciably decreased in the urine of T2DM patients who underwent kidney transplantation, albeit remained still higher than healthy individuals (P<0.0001). Increased heparanase levels were also found in the plasma of T2DM patients. Importantly, urine heparanase was associated with elevated blood glucose levels, implying that glucose mediates heparanase upregulation and secretion into the urine and blood. Utilizing an in vitro system, we show that insulin stimulates heparanase secretion by kidney 293 cells, and even higher secretion is observed when insulin is added to cells maintained under high glucose conditions. These results provide evidence for a significant involvement of heparanase in diabetic complications.

The heparanase system and tumor metastasis: is heparanase the seed and soil?

Abstract: Tumor metastasis, the leading cause of cancer patients' death, is still insufficiently understood. While concepts and mechanisms of tumor metastasis are evolving, it is widely accepted that cancer metastasis is accompanied by orchestrated proteolytic activity executed by array of proteases. While matrix metalloproteinases (MMPs) attracted much attention, other proteases constitute the tumor milieu, of which a large family consists of cysteine proteases named cathepsins. Like MMPs, some cathepsins are often upregulated in cancer and, once secreted or localized to the cell surface, can degrade components of the extracellular matrix. In addition, cathepsin L is held responsible for processing and activation of heparanase, an endo-β-glucuronidase capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans, activity that is strongly implicated in cell dissemination associated with tumor metastasis, angiogenesis, and inflammation. In this review, we discuss recent progress in heparanase research focusing on heparanase-related molecules namely, cathepsin L and heparanase 2 (Hpa2), a heparanase homolog.

Assessment of disease-severity scoring systems for patients with sepsis in general internal medicine departments

Abstract: Introduction: Due to the increasing burden on hospital systems, most elderly patients with non-surgical sepsis are admitted to general internal medicine departments. Disease-severity scoring systems are used for stratification of patients for utilization management, performance assessment, and clinical research. Some widely used scoring systems for septic patients are inappropriate when rating non-surgical patients in a non-intensive care unit (ICU) environment mainly because their calculations require types of data that are frequently unavailable. This study aimed to assess the fitness of four scoring systems for septic patients hospitalized in general internal medicine departments: modified early warning score (MEWS), simple clinical score (SCS), mortality in emergency department sepsis (MEDS) score, and rapid emergency medicine score (REMS). Methods: We prospectively collected computerized data of septic patients admitted to general internal medicine departments in our community-based university hospital. We followed 28-day in-hospital mortality, overall inhospital mortality, and 30- and 60-day mortality. Using a logistic regression procedure we calculated the area under ROC curve (AUC) for every scoring system. Results: Between February 1 st , 2008 and April 30 th , 2009 we gathered data of 1,072 patients meeting sepsis criteria on admission to general internal medicine departments. The 28-day mortality was 19.4%. The AUC for the MEWS was 0.65-0.70, for the SCS 0.76-0.79, for the MEDS 0.73-0.75, and for the REMS, 0.74-0.79. Using Hosmer-Lemeshow statistics, a lack of fit was found for the MEDS model. All scoring systems performed better than calculations based on sepsis severity. Conclusions: The SCS and REMS are the most appropriate clinical scores to predict the mortality of patients with sepsis in general internal medicine departments.

Aortocaval Fistula in Rat: A Unique Model of Volume-Overload Congestive Heart Failure and Cardiac Hypertrophy

Abstract: Despite continuous progress in our understanding of the pathogenesis of congestive heart failure (CHF) and its management, mortality remains high. Therefore, development of reliable experimental models of CHF and cardiac hypertrophy is essential to better understand disease progression and allow new therapy developement. The aortocaval fistula (ACF) model, first described in dogs almost a century ago, has been adopted in rodents by several groups including ours. Although considered to be a model of high-output heart failure, its long-term renal and cardiac manifestations are similar to those seen in patients with low-output CHF. These include Na+-retention, cardiac hypertrophy and increased activity of both vasoconstrictor/antinatriureticneurohormonal systems and compensatory vasodilating/natriuretic systems. Previous data from our group and others suggest that progression of cardiorenal pathophysiology in this model is largely determined by balance between opposing hormonal forces, as reflected in states of CHF decompensation that are characterized by overactivation of vasoconstrictive/Na+-retaining systems. Thus, ACF serves as a simple, cheap, and reproducible platform to investigate the pathogenesis of CHF and to examine efficacy of new therapeutic approaches. Hereby, we will focus on the neurohormonal, renal, and cardiac manifestations of the ACF model in rats, with special emphasis on our own experience.

Stimulus-Specific Adaptation: Can It Be a Neural Correlate of Behavioral Habituation?

Abstract: Habituation is the most basic form of learning, yet many gaps remain in our understanding of its underlying neural mechanisms. We demonstrate that in the owl's optic tectum (OT), a single, low-level, relatively short auditory stimulus is sufficient to induce a significant reduction in the neural response to a stimulus presented up to 60 s later. This type of neural adaptation was absent in neurons from the central nucleus of the inferior colliculus and from the auditory thalamus; however, it was apparent in the OT and the forebrain entopallium. By presenting sequences that alternate between two different auditory stimuli, we show that this long-lasting adaptation is stimulus specific. The response to an odd stimulus in the sequence was not smaller than the response to the same stimulus when it was first in the sequence. Finally, we measured the habituation of reflexive eye movements and show that the behavioral habituation is correlated with the neural adaptation. The finding of a long-lasting specific adaptation in areas related to the gaze control system and not elsewhere suggests its involvement in habituation processes and opens new directions for research on mechanisms of habituation.

Scleroderma overlap syndrome.

Abstract: Background Overlap syndrome is an entity that satisfies the criteria of at least two connective tissue diseases (CTD). These conditions include systemic sclerosis (SSc), dermatomyositis or polymyositis, Sjogren's syndrome, rheumatoid arthritis and systemic lupus erythematosus. A combined pathology has impact on the clinical features, diagnosis and treatment. Objectives To analyze the features of SSc patients with overlap syndrome registered in the European (EUSTAR) database at our center and to review the literature focusing on clinical and diagnostic issues and new treatments. Methods We studied the medical records of 165 consecutive SSc patients and reviewed cases with scleroderma overlap syndrome. A PubMed search for the period 1977 to 2009 was conducted using the key words "overlap syndrome", "systemic sclerosis", "connective tissue disease" and "biological agents." Results Forty patients satisfied the criteria for scleroderma overlap syndrome. The incidence of additional connective tissue diseases in the whole group and in the overlap syndrome group respectively was: dermatomyositis or polymyositis 11.5% and 47.5%, Sjogren's syndrome 10.3% and 42.5%, rheumatoid arthritis 3.6% and 15.4%, and systemic lupus erythematosus 1.2% and 5.0%. Coexistence of SSc and another CTD aggravated the clinical course, especially lung, kidney, digestive, vascular and articular involvement. Coexisting non-rheumatic complications mimicked SSc complications. An additional rheumatic or non-rheumatic disease affected treatment choice. Conclusions The definition of scleroderma overlap syndrome is important, especially in patients who need high-dose corticosteroids for complications of a CTD. The use of novel biological therapies may be advocated in these patients to avoid the hazardous influences of high-dose steroids, especially renal crisis. In some overlap syndrome cases, biological agents serve both conditions; in others one of the conditions may limit their use. In the absence of formal clinical trials in these patients a cautious approach is preferred.

A comprehensive approach to the prevention of bronchopulmonary dysplasia

Abstract: The current bronchopulmonary dysplasia (BPD) is seen in infants born extremely premature, with less severe respiratory distress syndrome (RDS) and who received prenatal steroids-"new BPD". The pathophysiology of BPD is based on an impairment of lung maturation with prenatal and postnatal multi-hit insults and genetic susceptibility. This multifactorial pathophysiology of BPD suggests that no single "magic bullet" will prevent it. Thus, to avoid BPD we need to implement a complex and comprehensive strategy. This strategy is based on ventilatory and non-ventilatory measures. The ventilatory route allows an individualized endotracheal intubation approach. Early lung recruitment with nasal respiratory support (nasal continuous positive airway pressure [NCPAP] or nasal intermittent positive pressure ventilation [NIPPV] / synchronized NIPPV [SNIPPV]) and the INSURE (intubation, surfactant and early extubation) approach are discussed. Initial treatment with NCPAP did not reduce the rate of BPD compared to endotracheal ventilation and surfactant administration. While NIPPV/SNIPPV may have short-term advantages over NCPAP, the effect on BPD needs to be further studied. During hospitalization the respiratory goals should aim for adequate oxygenation, permissive hypercapnia, and gentle ventilation. However, these goals were found to have short-term benefits but did not reduce significantly the rate of BPD. Selective use of a short course of low dose corticosteroids can be considered after the first or second week of life in infants who are unable to be weaned from the ventilator and are at high risk for BPD. Non-ventilatory measures include early nutritional support with fluid restriction, caffeine and consideration of vitamin A. Hemodynamic significant patent ductus arteriosus (PDA) may be associated with BPD, but medical or surgical treatment of PDA were not shown to decrease BPD. Each component and the strategy as a whole needs to be further studied in large randomized prospective studies or by meta-analyses, especially in the target population of extremely premature infants who are the most prone to BPD.

Placental volume and three‐dimensional power Doppler analysis in prediction of pre‐eclampsia and small for gestational age between Week 11 and 13 weeks and 6 days of gestation

Abstract: Objective To assess three-dimensional placental volume measurement and three-dimensional power Doppler (3D-PD) indices between 10 weeks and 6 days and 13 weeks and 6 days in predicting pregnancy-induced hypertension (PIH) and small for gestational age (SGA). Methods Three hundred and eight women undergoing fetal nuchal translucency measurement were prospectively assessed using three-dimensional ultrasound in order to measure placental volume and 3D-PD indices: vascularization index (VI), flow index (FI) and vascularization flow index (VFI), using the VOCAL software. The outcome was scored as normal, PIH, SGA or both. Results Eight women developed PIH and ten delivered SGA; and 17 developed PIH or SGA. The age, gestational age at the examination or delivery, number of the pregnancy and the nuchal translucency, were similar in all groups. The placental volume, FI and VFI were similar between the groups. The VI was significantly lower when PIH developed (7.86 ± 3.92 vs. 12.02 ± 7.09 in the normal group, P = 0.035). The crown-rump length (CRL) was significantly smaller in the group where either PIH or SGA developed compared to normal outcome (54.29 ± 6.50 and 59.04 ± 8.89, respectively, P = 0.02). Conclusion Placental volume is not appropriate for early prediction of PIH or SGA, whereas the VI may be of some potential in detection of PIH. The significance of small CRL in these patients should be further tested. Copyright © 2011 John Wiley & Sons, Ltd.

The population genetics of chronic kidney disease: insights from the MYH9–APOL1 locus

Abstract: Many rare kidney disorders exhibit a monogenic, Mendelian pattern of inheritance. Population-based genetic studies have identified many genetic variants associated with an increased risk of developing common kidney diseases. Strongly associated variants have potential clinical uses as predictive markers and may advance our understanding of disease pathogenesis. These principles are elegantly illustrated by a region within chromosome 22q12 that has a strong association with common forms of kidney disease. Researchers had identified DNA sequence variants in this locus that were highly associated with an increased prevalence of common chronic kidney diseases in people of African ancestry. Initial research concentrated on MYH9 as the most likely candidate gene; however, population-based whole-genome analysis enabled two independent research teams to discover more strongly associated mutations in the neighboring APOL1 gene. The powerful evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are highly associated with an increased risk of kidney disease. We describe the data sources, process of discovery, and reasons for initial misidentification of the candidate gene, as well as the lessons that can be learned for future population genetics research.

Recently diagnosed axial spondyloarthritis: gender differences and factors related to delay in diagnosis.

Abstract: A cohort of patients with recently diagnosed axial spondyloarthritis (SpA) was characterized with emphasis on gender differences and factors leading to delay in diagnosis. Clinical, laboratory, and imaging data of 151 consecutive patients diagnosed with ankylosing spondylitis or undifferentiated SpA in 2004–2009 and satisfying the new ASAS classification criteria for axial SpA, was collected and analyzed. Seventy-nine men and 72 women were enrolled. Both groups (men and women) had similar age of onset of disease-related symptoms, as well as similar delay time to diagnosis, follow-up duration and frequency of anti-TNF treatment. Inflammatory back pain, as a first symptom related to SpA, was reported more often by men, while women had more pelvic, heel, and widespread pain (WP) during the course of the disease. At the time of diagnosis, men were more limited in chest expansion and showed increased occiput-to-wall distance compared to women. Elevated erythrocyte sedimentation rate and/or C-reactive protein were detected in a similar proportion of men and women. Presence of WP in women almost doubled the delay in the diagnosis of SpA. No other differences in disease presentation or burden were demonstrated to correlate with delay in diagnosis.

Cytokine Levels as Potential Biomarkers for Predicting the Development of Posttraumatic Stress Symptoms in Casualties of Accidents

Abstract: Background:Traumatic injuries are usually associated with increased secretion of pro-inflammatory cytokines, and are sometimes followed by the development of acute stress symptoms (ASS) and posttraumatic stress symptoms (PTSS).Aims:To measure serum pro- and anti-inflammatory cytokines in accident casualties and to associate it with ASS at hospitalization, and with PTSS 1 month later.Methods:Participants were 48 patients, aged 20–60, hospitalized following various orthopedic injuries including bone fractures, and 13 healthy volunteers matched for gender. At hospitalization (Time 1), 30 ml heparinized venous blood were drawn and cytokines levels in serum were assessed; participants filled out the Acute Stress Disorder Inventory (ASDI), COPE, and injury-related questionnaires. One month later (Time 2), 26 participants filled out the Posttraumatic Disorder Symptom Scale (PDS).Results:High serum levels of IL-6, IL-8, and TGF-β and low levels of serum IL-4 and IL-10 were found in injured patients as compared wi...

Colon stem cell and crypt dynamics exposed by cell lineage reconstruction.

Abstract: Stem cell dynamics in vivo are often being studied by lineage tracing methods. Our laboratory has previously developed a retrospective method for reconstructing cell lineage trees from somatic mutations accumulated in microsatellites. This method was applied here to explore different aspects of stem cell dynamics in the mouse colon without the use of stem cell markers. We first demonstrated the reliability of our method for the study of stem cells by confirming previously established facts, and then we addressed open questions. Our findings confirmed that colon crypts are monoclonal and that, throughout adulthood, the process of monoclonal conversion plays a major role in the maintenance of crypts. The absence of immortal strand mechanism in crypts stem cells was validated by the age-dependent accumulation of microsatellite mutations. In addition, we confirmed the positive correlation between physical and lineage proximity of crypts, by showing that the colon is separated into small domains that share a common ancestor. We gained new data demonstrating that colon epithelium is clustered separately from hematopoietic and other cell types, indicating that the colon is constituted of few progenitors and ruling out significant renewal of colonic epithelium from hematopoietic cells during adulthood. Overall, our study demonstrates the reliability of cell lineage reconstruction for the study of stem cell dynamics, and it further addresses open questions in colon stem cells. In addition, this method can be applied to study stem cell dynamics in other systems.