Fibrosis and inflammatory cells in human chronic chagasic myocarditis: scanning electron microscopy and immunohistochemical observations

Several publications have shown that certain alleles at the HLA-DRB1, -DQA1, and -DQB1 loci are associated with insulin-dependent diabetes mellitus (IDDM). Many of these studies have claimed that HLA-DQalpha1Arg52 and DQbeta1Asp57 showed the strongest association with IDDM, but these results could not be confirmed in different populations. We have recently found that DRbeta1Lys71+ provided major susceptibility to IDDM and that DQbeta1Asp57- had an additive effect to DRbeta1Lys71+ [Zamani et al., 1994a: Eur J Hum Genet 2:177-184]. This was confirmed with haplotype analysis in multiplex IDDM families [Zamani et al., 1996a: J Med Genet 33:899-905]. Therefore, we have reanalyzed the data from the literature on the association of the human leucocyte antigen (HLA) DRB1, DQB1, and DQA1 with IDDM in different ethnic groups to determine whether different amino acids in the antigen binding cleft of HLA class II molecules play a preponderant role in the development of IDDM. The results showed that the DRbeta1Lys71+ allele provided the highest relative risk for IDDM in the Belgian, Danish, Greek Taiwanese, and Chinese population while this was not the case in Norwegians, Sardinians, and Algerians. Indeed, in the Sardinian and Algerian population the DRB1*0401 allele encoding Lys71+ is very rare. Nevertheless, the few positive cases were always in the patient group. We also measured the clinical relevance of the testing for DRbeta1Lys71, DQbeta1Asp57, and DQalpha1Arg52 by calculating a prevalence-corrected positive predictive value (PcPPV), a prevalence corrected negative predictive value (PcNPV), the sensitivity and specificity of these tests. The results indicated that the sensitivity of the test for DRbeta1Lys71+ was lower than for DQalpha1Ag52+ and DQbeta1Asp57-, while testing for DRbeta1Lys71+ was more specific than testing for DQbeta1Asp57- and DQalpha1Arg52+ and that the DRbeta1Lys71+ allele had a higher PcPPV than DQalpha1Arg52+ and DQbeta1Asp57- in all studied populations. These results also showed that testing for DRbeta1LyS71+/+ can be useful in IDDM risk assessment particularly in populations with a high prevalence (P) of IDDM such as the Danish (P[IDDM] = 0.65%). PcPPV for DRbeta1Lys71+/+ was 0.2313 in the Danish, indicating a 23.13% risk for an individual who is homozygous for the genotype DRbeta1Lys71+/+ to develop IDDM. Some mechanisms which might explain the role of these HLA class II alleles in susceptibility to IDDM are discussed.     

An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus

Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that beta-cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF alpha, and IFN alpha) and type 1 cytokines (IFN gamma, TNF beta, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGF beta). Cytokines (IL-1, TNF alpha, TNF beta and IFN gamma) may be directly cytotoxic to beta-cells by inducing nitric oxide and oxygen free radicals in the beta-cells. In addition, cytokines may sensitize beta-cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the beta-cells (an action of IFN gamma), and inducing Fas (CD95) expression on beta-cells (actions of IL-1, and possibly TNF alpha and IFN gamma). Transgenic expression of cytokines in beta-cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFN alpha, IFN gamma, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNF alpha. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4+ T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFN gamma-producing), but other islet-specific Th1 clones that produce TGF beta can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFN gamma genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFN gamma, also IL-1, TNF alpha, IL-2, and IL-6--by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs--significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF alpha, and IL-6) and type 1 cytokines (IFN gamma, IL-2 and IL-12) in IDDM development.     

Anaplastic large-cell lymphoma presenting primarily in bone in a patient with AIDS

beta-Cell-targeted expression of interferon-gamma (IFN-gamma) leads to pancreatitis and immune sensitization to beta-cells. This transgenic model is used to explore the possible role of locally produced IFN-gamma in loss of tolerance to beta-cell-specific antigens in insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to test if postnatal treatment with antibodies against IFN-gamma could inhibit morphological changes in the IFN-gamma transgenic pancreas, even though the transgene is expressed during embryogenesis. Treatment with a monoclonal rat anti-mouse IFN-gamma antibody for 6 weeks, starting from 5 to 7 days of age, completely inhibited IFN-gamma-induced morphological changes in the pancreas, and only a modest inflammatory reaction emerged after prolonged treatment for 12 weeks. The lack of morphological changes may reflect the ability of nonterminally differentiated neonatal pancreatic cells to compensate for transgene-induced pathological alterations occurring in utero prior to the antibody treatment. We conclude that inflammation and altered pancreas morphology in the transgenic mice is the result of the biological actions of IFN-gamma and not by disrupted islet development due to transgene overexpression in the pancreatic beta-cells. Furthermore, our treatment schedule can serve as a model for future intervention studies in the transgenic mice, elaborating the role of IFN-gamma in localized inflammatory reactions, IDDM in particular.     

Association between the angiotensin-converting enzyme-insertion/deletion polymorphism and diabetic nephropathy: a methodologic appraisal and systematic review

Recent studies have implicated a variant of the angiotensin-converting enzyme gene (ACE), associated with increased activity of this enzyme, in the development and progression of diabetic nephropathy. This study provides a systematic review of all cross-sectional, case-control, and cohort studies in patients with insulin-dependent (IDDM) or non-insulin-dependent (NIDDM) diabetes mellitus of any race, examining the relationship between the ACE-insertion/deletion polymorphism and nephropathy. Nineteen studies in 21 populations published between 1994 and 1997 presenting data on 5336 patients were reviewed. Two investigators independently assessed the studies on methodologic quality, performance of study, and association between the ACE-insertion/deletion polymorphism and nephropathy. Separate analyses of the relationship between genotype and allele frequencies were performed for patients with IDDM and NIDDM by race, using Peto's odds ratio. In Caucasians with IDDM, pooling was not performed due to heterogeneity of the studies, but among the homogeneous studies, no association was detected. Likewise, no association was observed in Caucasian patients with NIDDM (odds ratio [OR], 1.10; 95% confidence interval [95% CI], 0.83 to 1.45). In Asian patients with NIDDM, the risk of nephropathy was increased in the presence of the DD or ID genotype (OR, 1.88; 95% CI, 1.42 to 2.85). Although this analysis fails to confirm an association between the ACE-insertion/deletion genotype and nephropathy in Caucasians with NIDDM or IDDM, a role for this genetic marker in Asian patients cannot be ruled out. However, due to methodologic limitations of individual studies, no definite conclusions can be drawn from this analysis. Clearly, more rigorous methodology needs to be applied in future studies.     

Correction of diabetic nod mice with insulinomas implanted within Baxter immunoisolation devices

Insulin replacement by injection is clearly not a cure for Insulin Dependent Diabetes Mellitus (IDDM). Replacement of the destroyed islets by pancreas or islet allograft transplantation can achieve the good metabolic control required to prevent diabetic complications, but tissue supply is limited. The problem of islet supply to treat the 1 million IDDM patients in the USA could be overcome by using immortalized islet beta-cells as a donor source. However, before either allogeneic or xenogeneic immortalized beta-cells are used, some major problems have to be overcome: control of immortalized cell growth, allograft or xenograft rejection and recurrence of autoimmunity. To tackle these problems we have used a cell impermeable immunoisolation device containing mouse insulinoma cells. Transplantation of devices with insulinomas from NOD mice carrying the Rat-insulin promoter regulated SV40 T-Antigen transgene (RIP-TAg), normalized the blood glucose levels of diabetic NOD mice. Insulinomas from allogeneic CBA/NOD-RIP-TAg mice were also capable of normalizing diabetic NOD mice. Not only were non-fasting blood glucoses normalized but when given an intraperitoneal injection of glucose, the corrected mice had a near normal clearance of glucose from the blood. When the devices were removed from normalized mice they became diabetic again, demonstrating that the immunoisolation device was capable of protecting against both alloimmune and autoimmune destruction. The results with allogeneic mouse beta-cells suggest the possibility that immortalized human beta-cells could be an effective source of tissue to correct diabetes in IDDM patients without the use of immunosuppression.     

Spironolactone-induced pemphigoid

BACKGROUND: Sporadic observations would suggest that certain drugs play a role in the development of pemphigoid. A recent case-control study on long-term drug use associated with pemphigoid was unable to confirm the suspected role of these drugs, but did demonstrate a significant association between the development of pemphigoid and use of spironolactone. CASE REPORT: An 82-year-old patient had bullous erythematous lesions on the left thigh suggestive of pemphigoid. Histology and direct cutaneous immunofluorescence confirmed the diagnosis. The patient had been taking alimemazine, adrafinil, flunarizine, spironolactone and furosemide as long-term treatment. Spironolactone alone was withdrawn. The cutaneous lesions regressed and have not recurred during the 18-month follow-up. DISCUSSION: The causal effect of spironolactone in this case of pemphigoid is quite plausible. This hypothesis is favored by the agreement with epidemiological data. Other observations are however required before the causal role of spironolactone in development of pemphigoid can be confirmed.     

Molecular beacons: a new approach for semiautomated mutation analysis

IDDM is a polygenic and autoimmune disorder in which subsets of white blood cells (WBCs) are engaged in the destruction of beta-cells of the pancreas. The mechanisms that account for the abnormal behavior of these cells in IDDM are not fully understood. By measuring the mean length of telomeres of WBCs from patients with IDDM, we tested the concept that telomeres might play a role in IDDM. We examined the lengths of the terminal restriction fragments (TRFs) of DNA of WBCs from 234 white men comprising 54 patients with IDDM, 74 patients with NIDDM, and 106 control subjects. When adjusted for age, the TRF length from WBCs of patients with IDDM was significantly shorter than that of nondiabetic control subjects (mean +/- SE: 8.6 +/- 0.1 vs. 9.2 +/- 0.1, P = 0.002). No significant difference was observed between the TRF length from WBCs of patients with NIDDM versus nondiabetic subjects. Neither the duration nor the complications of IDDM (i.e., nephropathy and hypertension) had an effect on the TRF length of WBCs from patients with IDDM. The shortened TRF length of WBCs of patients with IDDM likely reflects a marked reduction in the TRF length of subsets of WBCs that play a role in the pathogenesis of IDDM.     

Exceptional stability of the HLA-DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC molecule associated with protection from insulin-dependent diabetes mellitus

HLA-DQ alleles are closely associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM) but the immunologic mechanisms involved are not understood. Structural studies of the IDDM-susceptible allele, HLA-DQA1*0301/DQB1*0302, have classified it as a relatively unstable dimer, particularly at neutral pH. This is reminiscent of studies in the nonobese diabetic mouse, in which I-A(g7) is relatively unstable, in contrast to other murine I-A alleles, suggesting a correlation between unstable MHC class II molecules and IDDM susceptibility. We have addressed this question by analysis of dimer stability patterns among various HLA-DQ molecules. In EBV-transformed B-lymphoblastoid cell lines and PBL, the protein encoded by the IDDM-protective allele HLA-DQA1*0102/DQB1*0602 was the most SDS stable when compared with other HLA-DQ molecules, including HLA-DQA1*0102/DQB1*0604, a closely related allele that is not associated with protection from IDDM. Expression of six different HLA-DQ allelic proteins and three different HLA-DR allelic proteins in the bare lymphocyte syndrome cell line, BLS-1, revealed that HLA-DQA1*0102/DQB1*0602 is SDS stable even in the absence of HLA-DM, while other HLA class II molecules are not. These results suggest that the molecular property of HLA-DQ measured by resistance to denaturation of the alphabeta dimer in SDS may play a role in IDDM protection.     

Occupational allergy to latex--life threatening reactions in health care workers. Report of three cases

During the analysis of risk factors in relation to primary liver cancer, we noticed an association between the confirmed (as opposed to probable) pathologic diagnosis of liver cancer and a positive history of hepatitis. This report pursues the observation using data from the Selected Cancers Study. Study subjects included 168 men who lived in areas covered by eight cancer registries in the U.S., and were pathologically diagnosed with confirmed or probable primary liver cancer during 1984-1988. The results showed that men with confirmed primary liver cancer were six times more likely to have a hepatitis diagnosed within 3 years before liver cancer detection, compared with those with probable primary liver cancer. Further analyses showed that men with a confirmed primary liver cancer or with a recent hepatitis more likely had a tissue specimen obtained from a surgery, and less likely had one from an aspiration. Upon adjustment for type of specimen, the association between pathological confirmation of primary liver cancer and recent hepatitis persisted. The results raised questions whether recent hepatitis and its pathologic changes influence choice of tissue-collecting procedure and ultimate pathological diagnosis of primary liver cancer. Other factors that might be related to the findings also need to be examined in future studies.     

Antibiotics and risk of subsequent first-time acute myocardial infarction

CONTEXT: Increasing evidence supports the hypothesis of a causal association between certain bacterial infections and increased risk of developing acute myocardial infarction. If such a causal association exists, subjects who used antibiotics active against the bacteria, regardless of indication, might be at lower risk of developing acute myocardial infarction than nonusers. OBJECTIVE: To determine whether previous use of antibiotics decreases the risk of developing a first-time acute myocardial infarction. DESIGN: Population-based case-control analysis. SETTING: The United Kingdom-based General Practice Research Database comprising 350 general practices. PATIENTS: A total of 3315 case patients aged 75 years or younger with a diagnosis of first-time acute myocardial infarction between 1992 and 1997 and 13139 controls without myocardial infarction matched to cases for age, sex, general practice attended, and calendar time. MAIN OUTCOME MEASURES: Use of antibiotics among those who did or did not have a first-time acute myocardial infarction. RESULTS: Cases were significantly less likely to have used tetracycline antibiotics (adjusted odds ratio [OR], 0.70; 95% confidence interval [CI], 0.55-0.90) or quinolones (adjusted OR, 0.45; 95% CI, 0.21-0.95). No effect was found for previous use of macrolides (primarily erythromycin), sulfonamides, penicillins, or cephalosporins. CONCLUSIONS: The findings from this large case-control analysis provide further, albeit indirect, evidence for an association between bacterial infections with organisms susceptible to tetracycline or quinolone antibiotics and the risk of acute myocardial infarction. These results of preliminary nature should stimulate more research to further explore the role of infections in the etiology of acute myocardial infarction.     

Cellular and molecular basis of estrogen's neuroprotection. Potential relevance for Alzheimer's disease

Alzheimer's disease (AD) is one of the most common types of dementia among the aged population, with a higher prevalence in women. The reason for this latter observation remained unsolved for years, but recent studies have provided evidence that a lack of circulating estrogen in postmenopausal women could be a relevant factor. Moreover, follow-up studies among postmenopausal women who had received estrogen-replacement therapy (ERT), suggested that they had a markedly reduced risk of developing AD. In addition, studies among older women who already had AD indeed confirmed that a decrease in estrogen levels was likely to be an important factor in triggering the pathogenesis of the disease. In this review article, we will discuss the evidence suggesting that estrogen may have a protective role against AD, mainly through its action as: a trophic factor for cholinergic neurons, a modulator for the expression of apolipoprotein E (ApoE) in the brain, an antioxidant compound decreasing the neuronal damage caused by oxidative stress, and a promoter of the physiological nonamyloidogenic processing of the amyloid precursor protein (APP), decreasing the production of the amyloid-beta-peptide (A beta), a key factor in the pathogenesis of AD.     

Infection and coronary atherosclerosis: the role Chlamydia pneumonia]

The role of inflammatory reactions in the pathogenesis of atherosclerosis is widely accepted. Recently, an increasing body of evidence has linked infections to atherosclerosis. It is hypothesized that infections could interact with other risk factors of vascular disease, enhancing the endothelial damage and the production of atherosclerotic plaques. Several different infectious agents have been related to the atherosclerosis genesis: mainly herpesvirus, Helicobacter pylori and Chlamydia pneumoniae. Several lines of evidence strongly link C. pneumoniae to atherosclerosis. Consequently, several studies evaluating the effectiveness of antibiotic treatment in the reduction of cardiac ischemic events in patients with C. pneumoniae seropositivity have been performed. These studies support a causative role for C. pneumoniae. This article reviews the recent evidence linking infections to atherosclerosis, with emphasis on the role of C. pneumoniae on the atherosclerotic plaque.     

A case of an old woman with Sj?gren's syndrome associated with insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) is thought to result from the autoimmune destruction of the insulin-dependent beta cells of the pancreas. Sj?gren's syndrome is also an autoimmune disease characterized by the destruction of the lacrimal and salivary glands that leads to keratoconjunctivitis sicca and xerostomia. But it is a very rare case that a patient with Sj?gren's syndrome developed IDDM. We present a case of a 65-year old woman with Sj?gren's syndrome who developed diabetic ketoacidosis due to IDDM. Recent studies have revealed that there was molecular mimicry between glutamic acid decarboxylase (GAD) and coxsackievirus. Furthermore, some reports have shown that sialadenitis was represented in IDDM model mice. This case shows the possibility that a causal relationship between IDDM and Sj?gren's syndrome may exist.     

Recombinant cytokines and pulmonary host defense

The recent discovery of several cytokines and their purification using recombinant DNA technology has uncovered their role as critical factors in pulmonary host defense. The importance of tumor necrosis factor, interferon-gamma, and granulocyte-colony stimulating factor in lung infections was first elucidated in animal models and has been confirmed with neutralization studies. This article reviews these three cytokines, their recent use in human subjects, and their potential use in the future.     

Leukaemia and Sellafield: is there a heritable link?

The demonstration of a statistical association between paternal preconceptional irradiation and childhood leukaemia appeared to provide a satisfactory explanation for the excess of cases in the village of Seascale, close to the Sellafield nuclear installation, and became the basis of two legal claims for compensation. In the ensuing scientific debate the biological plausibility of a causal interpretation of this association focused on the heritability of leukaemia and a comparison of the genetic risks implied by this finding with current information on the induction of genetic damage by irradiation. After a wide ranging review of the mechanistic issues it is concluded that there is no genetic basis for a causal relationship and this, together with recent appraisals of epidemiological studies, suggests that the association between childhood leukaemia and paternal preconceptional irradiation exposure is most likely to be a chance finding.     

Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status

Persistent humoral autoimmunity to the enzyme glutamic acid decarboxylase (GAD) has been described in a substantial proportion of patients with insulin-dependent diabetes mellitus (IDDM) of long duration. The source of the stimulus for this autoimmune reactivity is still unknown. Because the GAD 65 isoform is mainly expressed in pancreatic beta-cells and in the nervous system we investigated in the present study of the largest number of well characterized patients with longstanding IDDM (n = 105; median duration: 21 years; range: 10-46 years) the presence of autoantibodies to GAD 65 and their relationship to a residual C-peptide response or peripheral and autonomic neuropathy. Additionally we studied the HLA-DR status relative to GAD 65 antibodies in 86 out of the 105 individuals. One hundred healthy control subjects and 100 recent onset IDDM patients were also studied for GAD 65 antibodies. GAD 65 antibodies were detected in a radioligand-binding-assay with recombinant human GAD 65 and were present in 32% of the long-term diabetic patients, 82% of the recent onset IDDM patients and in 3% of the healthy control subjects. A preserved C-peptide response to i.v. glucagon (Hendriksen criteria) was observed in 23% of the long-term IDDM patients. Autonomic neuropathy and peripheral neuropathy was identified using criteria based on both symptoms and formal testing giving a frequency of 67% vs 79%. The HLA specific DR 4/X was observed in 47% and HLA-DR 3/X in 22% of the long-term IDDM patients. Patients who were heterozygous for DR3/DR4 were found in 23% of the cases. GAD 65 antibodies were significantly less frequent in the long-term IDDM patients compared to recent onset IDDM (p < 0.001), and diabetes duration showed a significant negative correlation with GAD 65 antibody index levels (r = 0.22, p < 0.01). Interestingly, GAD 65 antibodies were not significantly correlated either with residual beta-cell function or neuropathy and no particular HLA-DR status was associated with persistent GAD 65 antibodies. In conclusion neither residual beta-cell function nor diabetic neuropathy or a certain HLA-DR specificity are exclusively associated with persistent autoimmunity directed to GAD 65 in longstanding IDDM. The stimulus for the persistent humoral immune response and its significance for the disease process and its complications remain to be established.     

A phase I/II study to evaluate the effect of fractionated hemibody irradiation in the treatment of osseous metastases--RTOG 88-22

Previous studies have indicated that certain alleles of HLA-DR and -DQ genes were strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM), and the role of DQ molecule in IDDM has been suggested. To further clarify the association of DQ alleles with IDDM, we determined the nucleotide sequences of full-length cDNA from 13 DQA1 alleles and 14 DQB1 alleles. The sequencing analysis revealed sequence polymorphisms outside the hypervariable region of DQ genes. We then analyzed the DQA1 and DQB1 polymorphisms along with that of DRB genes in 86 B-lymphoblastoid cell lines (B-LCLs) from various ethnic groups and in healthy unrelated Japanese and Norwegian individuals. The allelic and haplotypic distributions in each population revealed the characteristic haplotypic formation in the HLA class II region. HLA genes in 139 Japanese and 100 Norwegian IDDM patients were analyzed. DQB1*0301 was negatively associated with IDDM in both ethnic groups, irrespective of associated DRB1 and DQA1 alleles. In DQB1*0302 positive populations, which represented a positive association with IDDM in both ethnic groups, DRB1*0401, *0404, *0802 haplotypes increased in the patients, whereas DRB1*0406 haplotype decreased. Considering about the hierarchy in DRB1 alleles with IDDM susceptibility (DRB1*0401>*0404>*0403 in Norwegian and DRB1*0802>*0403>*0406 in Japanese), the genetic predisposition to IDDM is suggested to be defined by the combination of DR-associated susceptibility and DQ-associated susceptibility and by the DQ-associated resistance which is a dominant genetic trait.     

Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus (IDDM) is a disease that results from autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. The autoimmune response against islet beta-cells is believed to result from a disorder of immunoregulation. According to this concept, a T helper 1 (Th1) subset of T cells and their cytokine products, i.e. Type 1 cytokines--interleukin 2 (IL-2), interferon gamma (IFNgamma), and tumor necrosis factor beta (TNFbeta), dominate over an immunoregulatory (suppressor) Th2 subset of T cells and their cytokine products, i.e. Type 2 cytokines--IL-4 and IL-10. This allows Type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Type 1 cytokines activate (1) cytotoxic T cells that interact specifically with beta-cells and destroy them, and (2) macrophages to produce proinflammatory cytokines (IL-1 and TNFalpha), and oxygen and nitrogen free radicals that are highly toxic to islet beta-cells. Furthermore, the cytokines IL-1, TNFalpha, and IFNgamma are cytotoxic to beta-cells, in large part by inducing the formation of oxygen free radicals, nitric oxide, and peroxynitrite in the beta-cells themselves. Therefore, it would appear that prevention of islet beta-cell destruction and IDDM should be aimed at stimulating the production and/or action of Type 2 cytokines, inhibiting the production and/or action of Type 1 cytokines, and inhibiting the production and/or action of oxygen and nitrogen free radicals in the pancreatic islets.     

Cognitive function in mammals: the evolutionary perspective

The work of behavioural pharmacologists has concentrated on small animals, such as rodents and pigeons. The validity of extrapolation of their findings to humans depends upon the existence of parallels in both physiology and psychology between these animals and humans. This paper considers the question whether there are in fact substantial cognitive parallels between, first, different non-human groups of vertebrates and, second, non-humans and humans. Behavioural data from 'simple' tasks, such as habituation and conditioning, do not point to species differences among vertebrates. Using examples that concentrate on the performance of rodents and birds, it is argued that, similarly, data from more complex tasks (learning-set formation, transitive inference, and spatial memory serve as examples) reveal few if any cognitive differences amongst non-human vertebrates. This conclusion supports the notion that association formation may be the critical problem-solving process available to non-human animals; associative mechanisms are assumed to have evolved to detect causal links between events, and would therefore be relevant in all ecological niches. In agreement with this view, recent advances in comparative neurology show striking parallels in functional organisation of mammalian and avian telencephalon. Finally, it is argued that although the peculiarly human capacity for language marks a large cognitive contrast between humans and non-humans, there is good evidence-in particular, from work on implicit learning--that the learning mechanisms available to non--humans are present and do play an important role in human cognition.     

Ovarian cancer in infertility patients

The possibility that ovulation induction increases the risk of ovarian cancer remains unproven. However, recent studies suggest that both infertility and endometriosis may be independent risk factors. Despite the various case reports and epidemiological studies performed the association between the use of infertility drugs and ovarian cancer remains weak. The fact that the women who were the first to use ovulation agents are now reaching mid-life means that future studies should show whether any association exists. Hence, there is a need now for large prospective trials to be performed to establish whether an association between ovulation induction agents and ovarian cancer truly exists.