Infections in Disorders of Immune Regulation.

Primary immune regulatory disorders (PIRDs) constitute a spectrum of inborn errors of immunity (IEIs) that are primarily characterized by autoimmunity, lymphoproliferation, atopy, and malignancy. In PIRDs, infections are infrequent compared to other IEIs. While susceptibility to infection primarily stems from antibody deficiency, it is sometimes associated with additional innate immune and T or NK cell defects. The use of immunotherapy and chemotherapy further complicates the immune landscape, increasing the risk of diverse infections. Recurrent sinopulmonary infections, particularly bacterial infections such as those associated with staphylococcal and streptococcal organisms, are the most reported infectious manifestations. Predisposition to viral infections, especially Epstein-Barr virus (EBV)-inducing lymphoproliferation and malignancy, is also seen. Notably, mycobacterial and invasive fungal infections are rarely documented in these disorders. Knowledge about the spectrum of infections in these disorders would prevent diagnostic delays and prevent organ damage. This review delves into the infection profile specific to autoimmune lymphoproliferative syndrome (ALPS), Tregopathies, and syndromes with autoimmunity within the broader context of PIRD. Despite the critical importance of understanding the infectious aspects of these disorders, there remains a scarcity of comprehensive reports on this subject.

Subcutaneous Immunoglobulin 16.5% (Cutaquig®) in Primary Immunodeficiency Disease: Safety, Tolerability, Efficacy, and Patient Experience with Enhanced Infusion Regimens.

PURPOSE: To achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens. METHODS: Three separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient's weekly dose. RESULTS: For Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy. CONCLUSIONS: SCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.

Infections in DNA Repair Defects.

DNA repair defects are heterogenous conditions characterized by a wide spectrum of clinical phenotypes. The common presentations of DNA repair defects include increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. Consequently, the characteristics of the infections may vary from mild upper respiratory tract infections to severe, opportunistic, and even fatal infections with bacteria, viruses, or fungi. Here, infections in 15 rare and sporadic DNA repair defects that are associated with immunodeficiencies are discussed. Because of the rarity of some of these conditions, limited information is available regarding infectious complications.

A Potentially Dangerous Industrial Projectile Lodged in the Leg of a Steel Factory Worker.

Penetrating injuries due to fragments energized by an explosive event are life/limb-threatening and are associated with poor clinical and functional outcomes. Penetrating injuries are commonly inflicted in attacks with explosive devices. The extremities, especially the leg, are the most commonly affected body areas, presenting a high risk of infection, slow recovery, and the threat of amputation. This report presents a case of a young factory worker who sustained an injury to the leg with a foreign body lodged near the neuro-vascular bundle. A 44-year-old gentleman sustained a projectile injury while working in a stainless steel factory from the rula (steel rolling) machine with a foreign body getting lodged in the leg in March 2019. He was initially managed with wound care and didn't report any functional impairment. Gradually patient developed numbness and claudication symptoms of the foot over the next couple of years. He was subsequently operated on in 2021 for removal of the stainless steel foreign body encased in dystrophic calcification close to the tibial nerve and posterior tibial vessels. Interestingly the entry point of the foreign body was on the anterolateral aspect of the leg. The foreign body was removed using the postero-lateral approach to the tibia with careful dissection close to the neurovascular bundle. At a follow-up of 3 months, the patient is symptom-free with significant improvement of limb function. The authors propose that the foreign body crossed the interosseous membrane to get lodged close to the posterior tibial neurovascular bundle. In such a scenario, the patient was extremely lucky to have survived an amputation or significant functional injury of the limb. Proper protective equipment is needed not only for the torso but also for extremities to protect industrial workers from such limb-threatening injuries. Moreover, primary care physicians should be sensitised for the proper management of such injuries.

Collagenous Gastritis in Primary Selective IgM Deficiency: Transition to EBV+ Gastric Adenocarcinoma.

Selective IgM deficiency (SIgMD) and isolated collagenous gastritis are two independent rare disorders. Our purpose is to report the 1st case of SIgMD and isolated collagenous gastritis and collagenous gastritis that has transitioned to EBV + gastric adenocarcinoma. Gastric biopsy tissue was analyzed by EBV-related encoded RNA in situ hybridization assay. Subsets of CD4, CD8, T follicular helper cells (TFH), and members of the "regulatory lymphocytes club" were measured with multiple panels of monoclonal antibodies and isotype controls by multicolor flow cytometry. The patient was diagnosed with SIgMD (extremely low serum IgM 9 mg/dl and normal IgG and IgA and exclusion of secondary causes of low IgM). Soon after SIgMD diagnosis, the patient developed collagenous gastritis and, 8 years later, developed gastric adenocarcinoma that was positive for EBV. An extensive immunological analysis revealed reduced naïve CD4 and CD8 effector memory T cells and increased naïve and central memory CD8 T cells. Among the circulating follicular helper T cells (cTFH), TFH1 and TFH2 were increased whereas TFH17 was decreased. CD4 Treg cells and TFR cells were increased, whereas Breg and CD8 Treg were comparable to control. In conclusion, SIgMD may be associated with isolated collagenous gastritis, and collagenous gastritis may transition to EBV + gastric adenocarcinoma. A role of regulatory lymphocytes in gastric cancer is discussed.

SARS-CoV-2-Associated T-Cell Responses in the Presence of Humoral Immunodeficiency.

We report perhaps the most comprehensive study of subsets of CD4+ and CD8+ and subsets of B cells in a mild symptomatic SARS-CoV-2+ immunocompetent patient and a common variable immunodeficiency disease (CVID) patient who had normal absolute lymphocyte counts and remained negative for SARS-CoV-2 IgG antibodies. Naïve (TN), central memory (TCM), effector memory (TEM), and terminally differentiated effector memory (TEMRA) subsets of CD4+ and CD8+ T cells, subsets of T follicular helper cells (cTFH, TFH1, TFH2, TFH17, TFH1/TFH17, and TFR), CD4 Treg, CD8 Treg, mature B cells, transitional B cells, marginal zone B cells, germinal center (GC) B cells, CD21low B cells, antibody-secreting cells (plasmablasts), and Breg cells were examined in patients and age-matched controls with appropriate monoclonal antibodies and isotype controls using multicolor flow cytometry. Different patterns of abnormalities (often contrasting) were observed in the subsets of CD4+ T, CD8+ T, B-cell subsets, and regulatory lymphocytes among the immunocompetent patient and CVID patient as compared to corresponding healthy controls. Furthermore, when data were analyzed between the 2 patients, the immunocompetent patient demonstrated greater changes in various subsets as compared to the CVID patient. These data demonstrate different immunological responses to SARS-CoV-2 infection in an immunocompetent patient and the CVID patient. A marked decrease in GC B cells and plasmablasts may be responsible for failure to make SARS-CoV-2 antibodies. The lack of SARS-CoV-2 antibodies with mild clinical disease suggests an important role of T-cell response in defense against SARS-CoV-2 infection.

Human pregnancy levels of estrogen and progesterone contribute to humoral immunity by activating TFH /B cell axis.

Circulating TFH (cTFH ) cells express CXCR5, PD-1, and, when activated, ICOS, and release IL-21. According to the production of IFN-γ, IL-4, and IL-17 and expression of FoxP3, these cells are also classified as cTFH 1, cTFH 2, cTFH 17, and cTFR cells, respectively. This CD4+ T-cell subset is pivotal to efficient humoral immunity, and pregnancy appears to favor IgG production. Here, not only pregnancy amplified the in vivo production of anti-HBsAg IgG in HBV immunized women, but the frequency of cTFH cells was directly correlated with estradiol levels. In vitro, pregnancy-related dose of 17-ß-estradiol (E2) directly increased the percentage of different cTFH subsets. While E2 and progesterone (P4) increased the proportion of differentiated TFH cells derived from naïve CD4+ T-cells, only E2 amplified the release of IL-21 in those cell cultures. In addition, E2 and P4 increased the proportion of memory B cells and plasma cells, respectively. In SEB-activated B/TFH cell co-cultures, E2, in the presence of P4, increased the production of total IgG. Finally, among the hormones, P4 was stronger in upregulating the percentage of IL-10+ TFR cells. Collectively, our findings suggested that E2 and P4 cooperate in the humoral immune response by favoring the expansion of different cTFH and B cell subsets.

Phenotypically defined subpopulations of circulating follicular helper T cells in common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by low immunoglobulin G and IgA/IgM, decreased switched memory B cells, impaired response to vaccine, and an increased susceptibility to infections and autoimmunity. TFH cells play an important role in germinal center reaction where it supports isotype switching, somatic hypermutation, generation of memory B cells, and differentiation of B cells to plasma cells. The objective was to study the distribution of three subsets of TFH cells and their relationship with autoimmune diseases associated with CVID. METHODS: TFH cells have been divided into TFH 1 (interleukin 21 [IL-21] and interferon γ), TFH 2 (IL-21 and IL-4), and TFH 17 (IL-21 and IL-17) cells. Mononuclear cells from 25 patients with CVID and age and gender-matched controls were stained with various monoclonal antibodies (anti-CD4 APC, anti-CXCR5 FITC, anti-CCR6 PerCP, and anti-CXCR3 PE) and isotype controls and analyzed for TFH 1 (CD4+ CXCR5+ CXCR3+ CCR6- ), TFH 2 (CD4+ CXCR5+ CXCR3- CCR6- ), and TFH 17 (CD4+ CXCR5+ CXCR3- CCR6+ ) cells by multicolor flow cytometry. Twenty thousand cells were acquired and analyzed by FlowJo software. Statistical analysis of comparison of patients and healthy controls was performed by paired t test using PRISM 7 software. RESULTS: TFH 2 and TFH 17 cells subpopulations of TFH cells were significantly decreased (P < .003 and P < .006, respectively) in CVID as compared with controls. No significant difference was observed in any of TFH cell subpopulations between CVID with and those without autoimmunity group. CONCLUSION: Alterations in TFH cell subpopulation may play a role in defects in B cell compartment in CVID.

Phenotypic and Functional Analysis of T Follicular Cells in Common Variable Immunodeficiency.

INTRODUCTION: One of the most frequent abnormalities of B cells in common variable immunodeficiency (CVID) is reduced number of class-switched memory B cells, suggesting an impaired germinal center response. Therefore, due to its pivotal role in regulating the development of humoral immunity, the objective of this study was to evaluate the role of circulating T follicular helper (cTFH) and circulating T follicular regulatory (cTFR) cells in the pathogenesis of CVID. METHODS: cTFH and cTFR cells from CVID patients and healthy subjects were phenotypically characterized by flow cytometry. cTFH and memory B cells from CVID patients and healthy subjects were isolated and cocultured. RESULTS: Our results showed a reduced proportion of cTFH17 cells in patients with CVID and an increased ratio of cTFH/cTFR cells in CVID patients with autoimmune diseases. Furthermore, the proportion of IL-21-producing cTFH cells was directly related to the proportion of CD27+ IgD- B cells. Interestingly, coculture assay showed that CVID-derived cTFH cells are able to help memory B cells from healthy controls to produce immunoglobulins. CONCLUSIONS: The proportions of cTFH17 and cTFR cells are altered in CVID patients; however, the cTFH function in assisting B cells to produce antibodies in vitro is preserved.

In vitro Effects of CD8+ Regulatory T Cells on Human B Cell Subpopulations.

BACKGROUND: CD8+ regulatory T cells (CD8+ Tregs) are relatively recently described T cell subsets that have been shown to regulate various T cell responses and appear to play a role in autoimmunity. However, their effects on B cells have not been explored. OBJECTIVES: In this investigation we examine the effect of CD8+ Tregs on various subsets of peripheral B cells include naïve B cells, transitional B cells, marginal zone B cells, IgM memory B cells, class switched memory B cells, and plasmablasts, and on the expression of B cell-activating factor receptor (BAFF-R). METHODS: CD8+ T cells were first purified and then activated with anti-CD3/CD28 beads to generate CD8+ Tregs. Purified CD19+ B cells were cultured alone or with sorted CD8+ Tregs (CD8+CD183+CCR7+CD45RA-) and activated with anti-CD40 monoclonal antibody and CpG. B cell subsets and the expression of BAFF-R on naïve and memory B cells were analyzed using various monoclonal antibodies and corresponding control isotypes. Ten thousand cells were acquired and analyzed by FACSCalibur using the FlowJo software. RESULTS: CD8+ Tregs selectively and significantly suppressed plasmablasts without any significant effect on other B cell subsets or on the expression of BAFF-R. CONCLUSION: CD8+ Tregs may play a role in autoimmunity by regulating antibody production via suppression of plasmablasts.

Pregnancy favors circulating IL-21-secreting TFH -like cell recovery in ARV-treated HIV-1-infected women.

PROBLEM: Pregnancy appears to favor maternal antibody production. In contrast, by damaging follicular helper T cells (TFH ), HIV-1 infection compromises protective humoural immune response. Therefore, we aimed to investigate the frequency of different TFH -like cells in HIV-infected pregnant women (PW) before and after antiretroviral (ARV) therapy. METHOD OF STUDY: Peripheral blood mononuclear cells, CD4+ T and B cells, were obtained from asymptomatic HIV-1-infected non-PW and PW just before and after ARV therapy. In some experiments, healthy HIV-1-negative PW were also tested. The frequency of different TFH -like cell subsets was determined by flow cytometry. The plasma titers of IgG anti-tetanus toxoid (TT), anti-HBsAg, and anti-gp41 were determined by ELISA. The in vitro production of total IgG, IL-21, and hormones (estrogen and progesterone) was quantified also by ELISA. RESULTS: Our results demonstrate that antiretroviral (ARV) therapy was more efficient in elevating the percentage of circulating IL-21-secreting TFH cells in HIV-1-infected pregnant women (PW) than in non-pregnant patients (nPW). Moreover, in co-culture systems, CD4+ T cells from ART-treated PW were more efficient in assisting B cells to produce IgG production. The in vivo anti-HBsAg IgG titers after ARV therapy were also significantly higher in PW, and their levels were directly associated with both IL-21+ TFH frequency and plasma concentration of estrogen. CONCLUSION: In summary, our results suggest that pregnancy favors the recovery of TFH -like cells after ARV therapy in HIV-1-infected women, which could help these mothers to protect their newborns from infectious diseases by transferring IgG across the placenta.

Biochemical findings in sudden unexpected death in epilepsy: Hospital based case-control study.

PURPOSE: A review study on the biochemistry of epilepsy showed that in epileptic patients, serum glucose and cholesterol concentrations are low, sodium is unaffected, potassium increases, glucose is high and mild hypocalcemia. We have conducted a biochemical study on sudden unexpected death in epilepsy (SUDEP) cases in an attempt to establish the characteristic biochemical values to diagnose these deaths. METHODS: This was a hospital based case-control study done at All India Institute of Medical Sciences, New Delhi for one year. Twenty SUDEP cases and 20 age- and sex-matched controls were included in the study. Femoral blood, cerebrospinal fluid, vitreous humor, and pericardial fluid were biochemically analyzed for sodium, potassium, calcium, glucose, N-acetyl- cysteine activated creatine kinase (CK-NAC) and isoenzyme CK-MB. RESULT: Serum sodium, CK-MB and CK-NAC level was found significantly increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. Likewise, in CSF, sodium and CK-NAC was found increased and potassium level was found decreased in SUDEP cases. In vitreous humor, sodium and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. In pericardial fluid, sodium, CK-NAC and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. CONCLUSION: It concludes that high sodium level and low potassium level could be associated with SUDEP. However, this is a small size study, a larger study is needed to verify the findings. Furthermore, it is difficult to conclude whether these findings are exclusive to SUDEP.

Role of non-invasive markers in prediction of esophageal varices and variceal bleeding in patients of alcoholic liver cirrhosis from central India.

BACKGROUND/AIMS: Alcohol is the leading cause of liver cirrhosis, which results in portal hypertension and subsequently, culminates into esophageal varices and esophgeal variceal bleeding. Esophagogastroduodenoscopy is gold standard for diagnosis of varices. Non-invasive markers based on clinical, laboratory - ultrasonographic parameters can be utilised for prediction of risk of esophageal varices - variceal bleed in alcoholic cirrhosis from central India. MATERIALS AND METHODS: This was a cross sectional observational study. Child Turcot Pugh scores, MELD, AST ALT Ratio(AAR), AST Platelet Ratio Index(APRI), FIB-4 index and Platelet count-Spleen diameter(PC/SD) ratio were calculated for all patients and correlated with esophagogastroduodenoscopy findings. Short term follow up was done for variceal bleeding. RESULTS: Total 202 male patients were included with mean age of 43.77±9.95 years. 188(93%) patients had esophageal varices. 61(30.19%) patients had variceal bleeding. On univariate analysis platelet count, APRI, spleen bipolar diameter, and PC/SD ratio were significantly associated with varices. For prediction of esophageal varices, only PC/SD ratio was significant and showed area under the curve of 65.6% at cut-off of <997. CTP score, FIB-4, APRI, and PC/SD ratio were significant for variceal bleeding. At cut-off <985 PC/SD ratio had sensitivity of 82% and specificity of 63% with AUC of 78% for prediction of variceal bleeding. Also, FIB-4 and APRI had diagnostic accuracy of 64% and 61% with AUC of 74% and 72% respectively for bleed. CONCLUSION: FIB-4 and PC/SD may be useful among armamentarium of non-invasive markers for predicting esophageal varices and risk of variceal bleeding in alcoholic liver cirrhosis.

Transition of Macrophages to Fibroblast-Like Cells in Healing Myocardial Infarction.

BACKGROUND: Macrophages and fibroblasts are 2 major cell types involved in healing after myocardial infarction (MI), contributing to myocardial remodeling and fibrosis. Post-MI fibrosis progression is characterized by a decrease in cardiac macrophage content. OBJECTIVES: This study explores the potential of macrophages to express fibroblast genes and the direct role of these cells in post-MI cardiac fibrosis. METHODS: Prolonged in vitro culture of human macrophages was used to evaluate the capacity to express fibroblast markers. Infiltrating cardiac macrophages was tracked in vivo after experimental MI of LysM(Cre/+);ROSA26(EYFP/+) transgenic mice. The expression of Yellow Fluorescent Protein (YFP) in these animals is restricted to myeloid lineage allowing the identification of macrophage-derived fibroblasts. The expression in YFP-positive cells of fibroblast markers was determined in myocardial tissue sections of hearts from these mice after MI. RESULTS: Expression of the fibroblast markers type I collagen, prolyl-4-hydroxylase, fibroblast specific protein-1, and fibroblast activation protein was evidenced in YFP-positive cells in the heart after MI. The presence of fibroblasts after MI was evaluated in the hearts of animals after depletion of macrophages with clodronate liposomes. This macrophage depletion significantly reduced the number of Mac3+Col1A1+ cells in the heart after MI. CONCLUSIONS: The data provide both in vitro and in vivo evidence for the ability of macrophages to transition and adopt a fibroblast-like phenotype. Therapeutic manipulation of this macrophage-fibroblast transition may hold promise for favorably modulating the fibrotic response after MI and after other cardiovascular pathological processes.

IgAλ monoclonal gammopathy of undetermined significance (MGUS) associated with primary selective IgM deficiency.

Selective IgM deficiency (SIgMD) and IgA MGUS in a young woman are two rare disorders. IgA MGUS has not been described in patients with SIgMD. We present the first comprehensive analysis of various subsets of CD4+ T, CD8+ T cells, and B cells in a young woman with SIgMD and IgAλ MGUS. Analysis of B cell subsets revealed increased proportions of transitional B cells, germinal center (GC) B cells, B regulatory cells (Breg), and plasmablasts (PB), and decreased proportions of marginal zone (MZ) B cells. BAFF-R expression on both naïve and memory B cells was increased. CD4+ and CD8+ effector memory cells were decreased, whereas CD4+ and CD8+ naïve T cells were increased. These abnormalities in B cell subsets and plasmablasts are not observed in SIgMD, therefore appears be influenced by MGUS. No correlation was observed with changes in the levels of monoclonal IgA and serum IgM levels over nine years follow-up suggesting that SIgMD is likely to be primary rather than secondary to MGUS. These observations also suggest that IgAλ MGUS and perhaps other MGUS may occur at a young age in association with selective IgM deficiency. The abnormalities in B cell subsets may have a predictive value for progression to multiple myeloma.

Granuloma-like lesion at subcutaneous immunoglobulin site in a common variable immunodeficiency patient.

Immunoglobulin therapy is the main stay in the treatment of primary antibody deficiencies. Granulomatous lesions are common complication in patients with common variable immunodeficiency (CVID). We present the first case of cutaneous granuloma-like lesion at site of subcutaneous immunoglobulin injections in a patient with CVID. These lesions resolve overtime following switching treatment to intravenous immunoglobulin. Unlike granulomas associated with CVID, granulomatous lesion in this patient did not require any specific therapy, and resolved over a period of 4 weeks following switching subcutaneous immunoglobulin to intravenous immunoglobulin.

Safety and tolerability of subcutaneous immunoglobulin 20% in primary immunodeficiency diseases from two continents.

Aim: This pooled analysis evaluated the safety and tolerability of the subcutaneous immunoglobulin 20% product, Ig20Gly, in primary immunodeficiency diseases using data from two Phase II/III studies conducted in North America and Europe. Patients & materials/methods: Patients received Ig20Gly (volumes, ≤60 ml/site; rates, ≤60 ml/h/site). Adverse events (AEs), tolerability and infusion parameters were assessed. Results: Patients (2-83 years; N = 122) received 6676 Ig20Gly infusions. No causally related serious or severe AEs were reported. Thirty-five patients (28.7%) reported 232 causally related local AEs. Twenty-seven patients (22.1%) reported 165 causally related systemic AEs. There was no association between the infusion volume or rate and causally related local AEs. Conclusion: Ig20Gly was well tolerated in a broad population of patients with primary immunodeficiency diseases.

Diet and inflammatory bowel disease: The Asian Working Group guidelines.

INTRODUCTION: These Asian Working Group guidelines on diet in inflammatory bowel disease (IBD) present a multidisciplinary focus on clinical nutrition in IBD in Asian countries. METHODOLOGY: The guidelines are based on evidence from existing published literature; however, if objective data were lacking or inconclusive, expert opinion was considered. The conclusions and 38 recommendations have been subject to full peer review and a Delphi process in which uniformly positive responses (agree or strongly agree) were required. RESULTS: Diet has an important role in IBD pathogenesis, and an increase in the incidence of IBD in Asian countries has paralleled changes in the dietary patterns. The present consensus endeavors to address the following topics in relation to IBD: (i) role of diet in the pathogenesis; (ii) diet as a therapy; (iii) malnutrition and nutritional assessment of the patients; (iv) dietary recommendations; (v) nutritional rehabilitation; and (vi) nutrition in special situations like surgery, pregnancy, and lactation. CONCLUSIONS: Available objective data to guide nutritional support and primary nutritional therapy in IBD are presented as 38 recommendations.

Association of menstruation cycle with completed suicide: a hospital-based case-control study.

The purpose of the study was to determine the phases of the menstrual cycle in the reproductive age group of females who committed suicide as compared with a control group of females who died from causes other than suicide. The study included 86 cases in the suicidal group and 80 cases in the non-suicidal group. The menstrual phase was decided by the gross and histological examination of the uterus and ovary at autopsy. Deaths were more common during the secretory phase (56.9%) in the suicidal group, while in the non-suicidal group, death occurred more commonly in the proliferative phase (66.3%). In reference to proliferative phase, deaths were more in the secretory phase and menstrual phase in the suicidal group, adjusted odd's ratio (OR) being 3.7 (p = 0.042) and 4.7 (p = 0.032), respectively. Corpus luteum was present in the right ovary of 43 and 14 victims of suicidal and non-suicidal deaths, respectively, while it was in the left ovary of 3 and 11 victims of suicidal and non-suicidal death, respectively. Odd's ratio was 10.3 for corpus luteum to be in the right ovary in comparison with the left ovary for the suicidal group (p = 0.001). This study revealed that suicidal chances in a woman are significantly more in the menstrual phase and the secretory phase of the menstrual cycle. The presence of corpus luteum in the right ovary is associated with an increased risk of suicide, but the reason is not known.

Molecular changes associated with increased TNF-α-induced apoptotis in naïve (TN) and central memory (TCM) CD8+ T cells in aged humans.

BACKGROUND: Progressive T cell decline in aged humans is associated with a deficiency of naïve (TN) and central memory (TCM) T cells. We have previously reported increased Tumor necrosis factor-α (TNF-α)-induced apoptosis in TN and TCM T cells in aged humans; however, the molecular basis of increased apoptosis remains to be defined. Since expression of TNF receptors (TNFRs) was reported to be comparable in young and aged, we investigated signaling events downstream of TNFRs to understand the molecular basis of increased TNF-α-induced apoptosis in aged TN and TCM CD8+ cells. RESULTS: The expression of TRAF-2 and RIP, phosphorylation of JNK, IKKα/ß, and IκBα, and activation of NF-κB activation were significantly decreased in TN and TCM CD8+ cells from aged subjects as compared to young controls. Furthermore, expression of A20, Bcl-xL, cIAP1, and FLIP-L and FLIP-S was significantly decreased in TN and TCM CD8+ cells from aged subjects. CONCLUSIONS: These data demonstrate that an impaired expression/function of molecules downstream TNFR signaling pathway that confer survival signals contribute to increased apoptosis of TN and TCM CD8+ cells in aged humans.