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ID PMID Title PublicationDate abstract
17520258 Pulmonary veno-occlusive disease as a primary cause of pulmonary hypertension in a patient 2007 Oct Mixed connective tissue disease (MCTD) is a systemic disease seen in a group of patients with overlapping clinical features of lupus, scleroderma, polymyositis, and rheumatoid arthritis. A defining feature of MCTD is the presence of antibodies against the U1-ribonucleoprotein (U1-RNP) complex. Pulmonary hypertension is the major cause of death in MCTD. We report an autopsy case of MCTD with pulmonary hypertension. The U1-RNP antibody of this patient was 171.9 U (normal < 25.0 U). The immediate cause of death was attributed to acute pulmonary embolism at left lower lobe. A severe vasculopathy characterized by fibrotic occlusion of small veins and venules, associated with prominent capillary congestion, was consistent with pulmonary veno-occlusive disease (PVOD). This is the first case reported in which PVOD is the primary cause of pulmonary hypertension in MCTD.
17367264 The safety profile of cyclophosphamide in multiple sclerosis therapy. 2007 Mar Cyclophosphamide (Cyc) is an alkylating agent used to treat malignancies and autoimmune diseases, such as lupus nephritis, rheumatoid arthritis and immune-mediated neuropathies. Over the past 40 years, Cyc has also been applied to treat multiple sclerosis (MS) and the effective stabilisation of rapidly progressive forms of MS has been demonstrated in several studies. Cyc has a dose-dependent bimodal effect on the immune system. High doses have been demonstrated to induce an anti-inflammatory immune deviation (i.e., suppression of T helper 1 and enhancement of T helper 2 activity), affect CD4CD25(high) regulatory T cells and establish a state of marked immunosuppression. Data from the literature suggest that Cyc is particularly indicated in the treatment of young MS patients, suffering from a very active inflammatory disease characterised by frequent relapses and rapid accumulation of disability and displaying gadolinium-enhancing lesions on brain magnetic resonance. The most common Cyc-based therapeutic protocol applied in MS consists of monthly intravenous pulses for 1 year followed by bimonthly pulses for the second year, with or without prior infusion of corticosteroids. This protocol is usually well tolerated by the patients. Indeed, most of the side effects (mild alopecia, nausea and vomiting, cystitis) are dose dependent, transient and completely reversible. Definitive amenorrhoea is observed only in older female patients (aged > 40 years). Cyc has a safety and efficacy profile similar to that of mitoxantrone and can be used in patients whose disease is not controlled by IFN-beta or glatiramer acetate. Short course (6-12 months) of Cyc therapy can precede the initiation of immunomodulatory treatment in selected patients with an aggressive MS onset.
17252738 [Perspectives in clinical immunology]. 2006 Dec Since the last years the better knowledge of immunologic mechanisms underlying autoimmune phenomena and rejection of allotransplants has been accompanied by an impressive production of new drugs: new inhibitors of purine and pyrimidine synthesis, as mycophenolate mofetil and leflunomide respectively, new inhibitors of calcineurin, such as tacrolimus, and target of rapamycine, such as sirolimus. Moreover, the tremendous advance in the methodology of producing monoclonal antibodies and the genetic engineering of proteins has led to a wide variety of biological agents, many of them have been approved as important new therapies for autoimmune diseases and against graft rejection. Monoclonal antibodies targeting IL-2 cytokine receptor have been shown to be useful in decrease the incidence of rejection. Moreover, monoclonal antibodies are available which target inflammatory cytokines, such as TNFalpha and IL-1, while other monoclonal antibodies may cause immune cell depletion, such as anti CD20 rituximab, or cause disruption of co-stimuli, like CTLA4Ig abatacept in the treatment of rheumatoid arthritis and anti CD11 efalizumab in the treatment of psoriasis. The new biologic agents have induced salutary clinical effects and extended the therapeutic option of patients not responding to existing treatments. The future looks brighter than ever as the recorded success fuels efforts to optimize the use of the biologic agents and extend their use in other diseases.
17187716 [Anti-TNF alfa therapy in ankylosing spondylitis]. 2006 Mar Ankylosing spondylitis (AS) is an inflammatory chronic disease that affects young males and in more than 90% of cases is associated with HLA B27 antigen. Therapeutic options for those patients with spondyloarthropathies have been limited during the last decades. Infliximab and etanercept are both approved for the treatment of patients with active disease that does not respond to conventional therapies. Anti-TNF therapy is very effective in AS, and eventually can be more effective than in rheumatoid arthritis. In 2003 Assessments in Ankylosing Spondylitis Group (ASAS) published international recommendations about the use of these agents in AS, which can be used as guidance in taking decisions and elaborating guidelines. To define their utilization it is necessary more studies about efficacy, toxicity and about ways of use.
17069520 Epratuzumab in the therapy of oncological and immunological diseases. 2006 Oct B cells play an important role in the pathogenesis of certain lymphomas and leukemias, as well as many autoimmune diseases. Antagonistic B-cell antibodies are thus gaining an increasing role in the management of these diseases. The first antibody target in this regard was CD20, with the development and introduction of rituximab in the management of B-cell malignancies, as well as rheumatoid arthritis. A second candidate target is CD22. The first antagonistic antibody to this B-cell marker, epratuzumab, appears to function, in contrast to CD20 antibodies, more by modulation of B cells rather than by their high depletion in circulation. Originally developed for the treatment of non-Hodgkin's lymphoma, epratuzumab has now been found to be effective, with a very good safety profile, in two prototype autoimmune diseases: systemic lupus erythematosus and primary Sjögren's syndrome. Recent studies have demonstrated the activity and safety of epratuzumab in non-Hodgkin's lymphoma patients who have relapsed or are refractive to conventional therapy, including rituximab, and has also shown good activity in follicular and diffuse large B-cell lymphoma in combination with rituximab. As such, this new investigative antibody may have a significant market potential owing to the multitude of diseases and patients who may benefit from a CD22, B-cell antibody immunotherapy that is complementary to the known effects and role of CD20 antibodies, but can usually be administered within 1 h and depletes approximately 50% of circulating B cells.
17020529 Phosphodiesterase 7A: a new therapeutic target for alleviating chronic inflammation? 2006 Over the last fifteen years there has been much excitement in the idea that targeting phosphodiesterase (PDE) 4 with small molecule inhibitors could lead to the discovery of novel, steroid-sparing compounds with utility in treating a multitude of diseases associated with chronic inflammation. However, dose-limiting side effects, of which nausea and vomiting are the most common are worrisome, have hampered their clinical development. Indeed, a fundamental obstacle that still is to be overcome by the pharmaceutical industry is to make compounds that dissociate beneficial from the adverse events. Unfortunately, both of these activities of PDE4 inhibitors represents an extension of their pharmacology and improving the therapeutic ratio has proved to be a major challenge. Several strategies have been considered, with some degree of success, but compounds with an optimal pharmacophore still have not been reported. An alternative approach to targeting PDE4 is to inhibit other cAMP PDE families that are also expressed in immune and pro-inflammatory cells in the hope that the beneficial activity can be retained at the expense of side effects. One such candidate is PDE7A. In this article we review the literature on PDE7A and explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, lupus, rheumatoid arthritis and multiple sclerosis.
16983459 An estimate of the worldwide prevalence and disability associated with osteoporotic fractu 2006 Dec OBJECTIVE: The aim of this study was to quantify the global burden of osteoporotic fracture worldwide. METHODS: The incidence of hip fractures was identified by systematic review and the incidence of osteoporotic fractures was imputed from the incidence of hip fractures in different regions of the world. Excess mortality and disability weights used age- and sex-specific data from Sweden to calculate the Disability Adjusted Life Years (DALYs) lost due to osteoporotic fracture. RESULTS: In the year 2000 there were an estimated 9.0 million osteoporotic fractures of which 1.6 million were at the hip, 1.7 million at the forearm and 1.4 million were clinical vertebral fractures. The greatest number of osteoporotic fractures occurred in Europe (34.8%). The total DALYs lost was 5.8 million of which 51% were accounted for by fractures that occurred in Europe and the Americas. World-wide, osteoporotic fractures accounted for 0.83% of the global burden of non-communicable disease and was 1.75% of the global burden in Europe. In Europe, osteoporotic fractures accounted for more DALYs lost than common cancers with the exception of lung cancer. For chronic musculo-skeletal disorders the DALYs lost in Europe due to osteoporosis (2.0 million) were less than for osteoarthrosis (3.1 million) but greater than for rheumatoid arthritis (1.0 million). CONCLUSION: We conclude that osteoporotic fractures are a significant cause of morbidity and mortality, particularly in the developed countries.
16899858 Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in patients with 2006 Aug BACKGROUND: Diffuse alveolar damage (DAD) is a relatively common finding on surgical lung biopsy and can result from a variety of causes. METHODS: We studied nine consecutive patients with connective tissue disease (CTD) and DAD diagnosed on surgical lung biopsy to examine this association and clinical implications. RESULTS: The median age was 63 years (range, 35 to 76 years), and seven of the patients were women (78%). Underlying CTDs included rheumatoid arthritis in five patients, polymyositis in two patients, and one patient each with systemic sclerosis and mixed CTD. In seven patients (78%), CTD had been diagnosed before the onset of DAD; six of these patients had a preexisting interstitial lung disease (ILD) related to their CTD. DAD was the presenting manifestation leading to a new CTD diagnosis in two patients (22%). CT of the chest revealed ground-glass opacities and/or consolidation bilaterally with or without honeycombing. In all patients, surgical lung biopsy revealed DAD for which no cause could be identified other than the underlying CTD. Seven patients (78%) were receiving mechanical ventilatory support at the time of the surgical lung biopsy. Four patients (44%) survived to hospital discharge and included one patient with preexisting ILD and all three patients without chronic ILD. CONCLUSION: We conclude that DAD can complicate the clinical course of patients with CTD-related chronic ILD, or can occasionally occur as a presenting manifestation of CTDs. When DAD occurs in patients with CTDs, the outcome appears to be worse for those with preexisting chronic ILD compared to those without ILD.
16896987 Antipolymer antibody is not associated with fibromyalgia in Korean female patients. 2006 Nov To examine the levels of antipolymer antibody (APA) in Korean female patients with fibromyalgia (FM) and to determine whether the levels of APA correlate with FM severity. Serum samples from patients with FM (n = 69), patients with rheumatoid arthritis (RA) (n = 71), and controls (n = 75) were assayed for APA. All of the subjects were female, and the controls were age-matched healthy volunteers. FM tender point counts and scores were examined, and FM patients were asked to complete a Korean version of the Fibromyalgia Impact Questionnaire (FIQ), the State-Trait Anxiety Inventory (STAI), and the Beck Depression Inventory (BDI). APA-positive samples were detected in five (7.2%) of the 69 FM patients, seven (9.9%) of the 71 RA patients, and four (5.3%) of the 75 controls. The prevalence of seropositivity and the level of APA in FM patients did not differ from those in RA patients and controls. The proportion positive for APA was not higher for FM patients with severe symptoms than for FM patients with mild symptoms. There was a negative association between the APA level and age. The APA level in FM patients was not correlated with age at diagnosis, age at symptom onset, disease duration, education, tender point counts and scores, FIQ, STAI, or BDI. The prevalence of APA in Korean FM patients was quite low. Owing to the low prevalence of APA in this study, the APA assay did not distinguish FM patients with severe symptoms from those with mild symptoms.
16848318 A new sesquiterpene lactone from the roots of Lasianthus acuminatissimus. 2006 May AIM: To study the active constituents for the treatment of rheumatoid arthritis from the ethyl acetate extracts of the roots of Lasianthus acuminatissimus Merr. METHODS: Various chromatographic techniques were used to separate and purify the constituents. Their structures were established on the basis of 1D, 2D NMR and HRMS spectroscopic analyses and their preliminary evaluation of anti-inflammation effect on the release of beta-glucuronidase was carried out. RESULTS: Eight compounds were isolated and identified as lasianthuslactone A (1), codonolactone (2), 2,5-dimethoxy-1, 4-benzoquinone (3), uncargenin A (4), nonadecyl alcohol (5), 13-docosenoic acid (6), tetracosanoic acid (7) and beta-sitosterol (8). Compound 3 showed a significant inhibitory effect on release of beta-glucuronidase rat polymorphous nuclear leukocytes activated by platelet activating factor (PAF). CONCLUSION: Compound 1 is a new one, the others were isolated from the plant for the first time and 3 is one of active anti-inflammation compound in the plant.
16793911 Paneth cells: leukocyte-like mediators of innate immunity in the intestine. 2006 Sep Paneth cells are secretory intestinal epithelial cells located at the base of the crypts of Lieberkühn in the small intestine. They display prominent cytoplasmic granules, containing antibacterial proteins such as lysozyme, secretory phospholipase A2 type IIA, and alpha-defensins, which are released into the intestinal lumen in response to a range of stimuli. In this, they resemble circulating leukocytes, which also elaborate and secrete lysozyme and alpha-defensins as part of an antibacterial defense function, and the resemblance is sustained at other levels. The cells also strongly and specifically express the NOD2 gene product, one of an emerging family of critical, intracellular mediators of innate immune responses, which is also highly expressed in peripheral blood mononuclear cells, and they express RNA for tumor necrosis factor alpha, a major myelomonocytic cell-derived cytokine, which has a crucial role in the pathogenesis of diseases such as rheumatoid arthritis and Crohn's disease (CD). Thus, these cells, which are derived from the pluripotent intestinal epithelial stem-cell lineage, are sessile, resident host-defense cells, which may share with leukocytes the beneficial function of secreting antimicrobial peptides, as well as the potentially harmful capacity for promoting inflammation and tissue damage. Paneth cells are most abundant in the distal small intestine, which is the region most frequently affected by CD, and there is great interest in the potential role of these cells in this condition. This brief review summarizes current knowledge and speculates on how the study of these fascinating cells might be advanced.
16640655 Interleukin-6 trans-signalling in chronic inflammation and cancer. 2006 May Interleukin-6 (IL-6) is a cytokine, which plays an important role in many chronic inflammatory diseases. IL-6 belongs to a family of 10 cytokines, which all act via receptor complexes containing the cytokine receptor subunit gp130. On cells, IL-6 first binds to a specific membrane-bound IL-6R and the complex of IL-6 and IL-6R interacts with gp130 leading to signal initiation. Whereas gp130 is widely expressed throughout the body, the IL-6R is only found on some cells including hepatocytes and some leucocytes. A soluble form of the IL-6R is an agonist capable of transmitting signals through interaction with the gp130 protein. In vivo, the IL-6/soluble IL-6R complex stimulates several types of target cells, which are unresponsive to IL-6 alone, as they do not express the membrane-bound IL-6R. We have named this process trans-signalling. We provided evidence that a soluble form of the IL-6 family signalling receptor subunit gp130 is the natural inhibitor of IL-6 trans-signalling responses. We showed that in chronic inflammatory diseases such as inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma as well as in colon cancer, IL-6 trans-signalling is critically involved in the maintenance of the disease state. Moreover, in all these animal models, the progression of the disease can be interrupted by specifically interfering with IL-6 trans-signalling using recombinant-soluble gp130Fc protein. The pathophysiologic mechanisms by which the IL-6/soluble IL-6R complex perpetuates the inflammatory state are discussed.
16638417 Atopic dermatitis and systemic autoimmune diseases: a descriptive cross sectional study. 2006 Mar 30 Atopic dermatitis (AD) has a Th2 (T-helper 2) immune-reactivity pattern. However, the majority of systemic autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and insulin dependent diabetes mellitus show a Th1 (T-helper 1) reactivity pattern. From this, one may hypothesize that AD and the Th1 autoimmune diseases could be inversely associated and AD may be more common in the minority of autoimmune diseases with a Th2 overactivity pattern such as systemic lupus erythematosus. A cross sectional study was designed. Our patients were enrolled from a general university hospital (all systemic autoimmune patients in every medical ward based on definite diagnoses in their medical records). Information on atopic dermatitis was obtained by questionnaires and physical examination by a dermatologist. A total of 63 patients were studied; 17.5 percent of cases had atopic dermatitis in the past or present. There were 31 patients 49.2 %) who carried a diagnosis known to be associated with Th1 reaction, and 21 patients (33.3 %) who had a disease associated with Th2-type reactivity. In 11 patients (17.5 %) the T-cell reaction type was not definitively classified. The relative frequency of AD was 9.7 percent (3 of 31 cases) in Th1-related autoimmune diseases, 28.6 percent (6 of 21 cases) in Th2-related autoimmune diseases and 18.2 percent (2 of 11 cases) in the unclassified category, a difference not statistically significant. Although the power of this study is not high enough to show a statistical significance, AD seems to be uncommon in patients with autoimmune diseases associated with Th1 overactivity.
16484987 Analysis of chromosome 5q31-32 and psoriasis: confirmation of a susceptibility locus but n 2006 May We have previously reported a region on chromosome 5q as a possible susceptibility region for psoriasis. This cytokine cluster-rich region has also been suggested as a susceptibility locus in other autoimmune or inflammatory diseases including Crohn's disease (CD) and rheumatoid arthritis (RA). Three specific single-nucleotide polymorphisms (SNPs) have been reported to associate with RA and CD and to change the functional activity of two organic cation transporters, solute carrier family 22 member 4/5 (SLC22A4) and (SLC22A5). In this study, we have analyzed these SNPs for an association with psoriasis. We have also performed a denser linkage analysis of this region with an additional 31 microsatellite markers. We were not able to detect any association with any of the three SNPs analyzed. However, our linkage result supports the involvement of this region in the etiology of psoriasis. We obtained a peak non-parametric linkage value of 3.1 for marker D5S436 in a subgroup of patients with joint complaints. This result supports the findings in another study of psoriasis patients originating from Iceland in which the authors obtained a peak logarithm of the odds score of 2.6 for marker D5S2090, only 2 Mb from D5S436. This suggests a psoriasis susceptibility locus on chromosome 5q32 that is involved in the arthritic phenotype of the disease.
18803896 Frequency of depression and anxiety in patients attending a rheumatology clinic. 2008 Sep OBJECTIVE: This study was done to find out the frequency of anxiety and depression among patients with common rheumatic disorders and determine the possible relationship of different demographic and clinical variables with anxiety and depression. STUDY DESIGN: Cross-sectional, analytical study. PLACE AND DURATION OF STUDY: The study was carried out at Fauji Foundation Hospital, Rawalpindi, during April to August 2006. METHODOLOGY: Patients attending the rheumatology outpatient department, with more than 2 years duration of rheumatic disorder were selected. A proforma regarding the demographic details was filled for all the patients. A physician made the assessment regarding the rheumatological disorder. Urdu version of Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depression. Clinical assessment was done by two psychiatrists according to International Classification of Diseases-10 (ICD-10). Data was analyzed on SPSS10 and p-value was calculated using Chi-square test as test of significance. RESULTS: There were 108 patients mostly females (90%), mean age 44.7 + 11 years, majority (72%) were married and 51% were uneducated. Almost 80% of the patients had rheumatoid arthritis. Two-third of the patients had persistent symptoms. According to the HADS, scoring 56% of the patients had more than the cut off score for depression and 65.7% patients had scores falling in the category of cases. Regarding the clinical diagnosis, 42% of the patients were found to be depressed. Considering the factors which might be associated with depression or anxiety; only gender was found to be significantly associated with depression (p=0.03). CONCLUSION: Depression and anxiety is high in patients being treated for chronic rheumatological disorders. A close liaison between rheumatologist and mental health professionals could prove beneficial for these patients.
18778113 The impact of PEGylation on biological therapies. 2008 The term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency. In order to benefit from these favorable pharmacokinetic consequences, a variety of therapeutic proteins, peptides, and antibody fragments, as well as small molecule drugs, have been PEGylated. This paper reviews the chemical procedures and the conditions that have been used thus far to achieve PEGylation of biomedical molecules. It also discusses the importance of structure and size of PEGs, as well as the behavior of linear and branched PEGs. A number of properties of the PEG polymer--e.g. mass, number of linking chains, the molecular site of PEG attachment--have been shown to affect the biological activity and bioavailability of the PEGylated product. Releasable PEGs have been designed to slowly release the native protein from the conjugates into the blood, aiming at avoiding any loss of efficacy that may occur with stable covalent PEGylation. Since the first PEGylated drug was developed in the 1970s, PEGylation of therapeutic proteins has significantly improved the treatment of several chronic diseases, including hepatitis C, leukemia, severe combined immunodeficiency disease, rheumatoid arthritis, and Crohn disease. The most important PEGylated drugs, including pegademase bovine, pegaspargase, pegfilgrastim, interferons, pegvisomant, pegaptanib, certolizumab pegol, and some of the PEGylated products presently in an advanced stage of development, such as PEG-uricase and PEGylated hemoglobin, are reviewed. The adaptations and applications of PEGylation will undoubtedly prove useful for the treatment of many previously difficult-to-treat conditions.
18698171 IL-17 and the Th17 lineage in systemic lupus erythematosus. 2008 Sep PURPOSE OF REVIEW: Systemic lupus erythematosus etiology includes both genetic and environmental factors. Evidence suggests that many genetic loci in humans and mouse models contribute to the occurrence and clinical presentation of lupus. This large array of different genes affects many aspects of immune cell function, including the activation and functional differentiation of B cells, T cells, dendritic cells and other immune cells. In particular, the T-cell components that contribute to systemic lupus erythematosus pathogenesis are incompletely defined. RECENT FINDINGS: A major paradigm shift in understanding how CD4+ T cells contribute to autoimmunity recently occurred with the discovery of a new T-cell population that produces the cytokine IL-17 (IL-17A), termed 'Th17'. Although Th17 cells contribute to autoimmune disease in rheumatoid arthritis and Crohn's disease, their role in systemic lupus erythematosus is far less clear. SUMMARY: In this review, we focus on an emerging role for the cytokine IL-17 and the cells that produce it in contributing to lupus in particular based on recent findings in animal models.
18682433 Detection of a complete autoimmune regulator gene deletion and two additional novel mutati 2008 Nov OBJECTIVE: Autoimmune polyglandular syndrome type 1 (APS-1) is characterised by multiple autoimmune diseases. Detection of autoimmune regulator (AIRE) gene mutations facilitates timely and precise diagnosis. DESIGN: AIRE mutation detection was performed in a cohort of 11 patients. Two did not meet clinical APS-1 criteria and several started with atypical presentation. METHODS: Sequencing and TaqMan genotyping were used to identify AIRE mutations. Complete AIRE deletion was confirmed and framed by real-time PCR, long-range amplification and analysis of the microsatellite markers. RESULTS: Seven different mutations were detected, three were novel: c.892G>A in exon 8, silent mutation c.462A>T in exon 3 most likely affecting splicing, and a complete deletion of a single AIRE allele ((?_68)_(1567-14_?)del). Novel (chronic otitis) and rare (systemic juvenile rheumatoid arthritis, autoimmune bronchiolitis, epilepsy) clinical presentations were observed. CONCLUSIONS: AIRE mutation detection was valuable in the diagnostics of APS-1 in patients with atypical presentation. Chronic otitis media possibly broadened the cluster of APS-1 manifestations.
18678279 Cytotoxic and genotoxic effects of methotrexate in germ cells of male Swiss mice. 2008 Aug Methotrexate (MTX) is an anti-metabolite drug widely used in the treatment of neoplastic disorders, rheumatoid arthritis and psoriasis. Developed as an analogue of folic acid, it inhibits purine and pyrimidine synthesis that accounts for its therapeutic efficacy as well as for its toxicities. MTX has narrow therapeutic index and its toxicity has been reported in various organ systems including gastrointestinal, haematologic and central nervous system. The objective of the present study is to investigate the germ cell toxicity induced by MTX in male Swiss mice. MTX was administered intraperitoneally (ip) at the doses of 5, 10, 20 and 40 mg/kg to mice (20-25 g) weekly once (wk) for 5 and 10 weeks. The animals were sacrificed 1 week after receiving the last treatment of MTX. The germ cell toxicity was evaluated using testes weight (wt), sperm count, sperm head morphology, sperm comet assay, histology, TUNEL and halo assay in testis. MTX treatment significantly reduced the sperm count and increased the occurrence of sperm head abnormalities in a dose dependent manner. It induced the testicular toxicity as evident from the histology of testis. Sperm comet, TUNEL and halo assay in testis also revealed significant DNA damage after MTX treatment. On the basis of the present study, it can be concluded that MTX induced germ cell toxicity in mice.
18533027 Worldwide population differentiation at disease-associated SNPs. 2008 Jun 4 BACKGROUND: Recent genome-wide association (GWA) studies have provided compelling evidence of association between genetic variants and common complex diseases. These studies have made use of cases and controls almost exclusively from populations of European ancestry and little is known about the frequency of risk alleles in other populations. The present study addresses the transferability of disease associations across human populations by examining levels of population differentiation at disease-associated single nucleotide polymorphisms (SNPs). METHODS: We genotyped ~1000 individuals from 53 populations worldwide at 25 SNPs which show robust association with 6 complex human diseases (Crohn's disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, coronary artery disease and obesity). Allele frequency differences between populations for these SNPs were measured using Fst. The Fst values for the disease-associated SNPs were compared to Fst values from 2750 random SNPs typed in the same set of individuals. RESULTS: On average, disease SNPs are not significantly more differentiated between populations than random SNPs in the genome. Risk allele frequencies, however, do show substantial variation across human populations and may contribute to differences in disease prevalence between populations. We demonstrate that, in some cases, risk allele frequency differences are unusually high compared to random SNPs and may be due to the action of local (i.e. geographically-restricted) positive natural selection. Moreover, some risk alleles were absent or fixed in a population, which implies that risk alleles identified in one population do not necessarily account for disease prevalence in all human populations. CONCLUSION: Although differences in risk allele frequencies between human populations are not unusually large and are thus likely not due to positive local selection, there is substantial variation in risk allele frequencies between populations which may account for differences in disease prevalence between human populations.