Efficacy of convalescent plasma therapy for COVID-19: A systematic review and meta-analysis.

The purpose of this systematic review and meta-analysis was to examine clinical outcomes associated with convalescent plasma therapy in COVID-19 patients. We performed a literature search on PubMed, medRxiv, Web of Science, and Scopus to identify studies published up to December 10th, 2020 that examined the efficacy of convalescent plasma treatment for COVID-19. The primary endpoints were mortality, clinical improvement, and hospital length of stay. We screened 859 studies that met the search criteria, performed full-text reviews of 56 articles, and identified 15 articles that fulfilled inclusion criteria for meta-analysis. The odds of mortality were significantly lower in the convalescent plasma group compared to the control group (OR = 0.59 [95% CI = 0.44; 0.78], P < .001), although results from two key randomized controlled trials did not support the mortality benefit. The odds of clinical improvement were significantly higher in the convalescent plasma group compared to the control group (OR = 2.02 [95% CI = 1.54; 2.65], P < .001). There was no difference in hospital length of stay between the convalescent plasma group and the control group (MD = -0.49 days [95% CI = -3.11; 2.12], P = .713). In all, these data indicate that a mortality benefit with convalescent plasma is unclear, although there remain benefits with convalescent plasma therapy for COVID-19.

Interleukin-15 in autoimmunity.

Interleukin-15 (IL-15) is a member of the IL-2 family of cytokines, which use receptor complexes containing the common gamma (γc) chain for signaling. IL-15 plays important roles in innate and adaptative immune responses and is implicated in the pathogenesis of several immune diseases. The IL-15 receptor consists of 3 subunits namely, the ligand-binding IL-15Rα chain, the ß chain (also used by IL-2) and the γc chain. IL-15 uses a unique signaling pathway whereby IL-15 associates with IL-15Rα during biosynthesis, and this complex is 'trans-presented' to responder cells that expresses the IL-2/15Rßγc receptor complex. IL-15 is subject to post-transcriptional and post-translational regulation, and evidence also suggests that IL-15 cis-signaling can occur under certain conditions. IL-15 has been implicated in the pathology of various autoimmune diseases such as rheumatoid arthritis, autoimmune diabetes, inflammatory bowel disease, coeliac disease and psoriasis. Studies with pre-clinical models have shown the beneficial effects of targeting IL-15 signaling in autoimmunity. Unlike therapies targeting other cytokines, anti-IL-15 therapies have not yet been successful in humans. We discuss the complexities of IL-15 signaling in autoimmunity and explore potential immunotherapeutic approaches to target the IL-15 signaling pathway.

The effect of natural matrix biopolymer membrane on hard-to-heal venous leg ulcers: a pilot randomised clinical trial.

OBJECTIVE: The aim of this study was to evaluate the therapeutic effects of natural matrix biopolymer membrane (NMBM) in the treatment of venous leg ulcers (VLUs). METHOD: Patients exhibiting one or more VLU were assigned to a test group receiving NMBM or to a control group receiving conventional treatment. Patients exhibiting venous insufficiency-related ulcers within 0.1-170cm2 were included. Efficacy was assessed based on ulcer size and visual analogue scale (VAS) pain scores at baseline and at weeks one, two and four. Ulcer size and pain were compared between groups using a two-way ANOVA. RESULTS: In this study, 25 patients with 32 VLUs (NMBM group: 14 patients with 17 ulcers; control group: 11 patients with 15 ulcers) were included in the final analysis. At four weeks after baseline measurements, the mean percentage change in VLU area of patients in the NMBM group was 61.6% (95% CI: 40.3-82.9) compared with 84.1% (95% CI: 56.5-111.7) for control group patients. Additionally, the mean percentage change in VLU volume of NMBM group patients was 51.2% (95% CI: 31.8-70.6) compared with 84.0% (95% CI: 57.0-121.0) for control group patients. The NMBM group patients exhibited a mean decrease of 0.38 (95% CI: -0.85-1.61) in VAS pain score over four weeks, compared with a mean decrease of 0.13 (95% CI: -1.32-1.58) for control group patients. No significant differences in VLU area (p=0.210), volume (p=0.122) or VAS pain score (p=0.460) were shown between groups. CONCLUSION: NMBM was found to be as effective and safe as the control group treatments. This pilot study suggests NMBM can be used safely to promote ulcer healing.

Blocking ADAM17 Function with a Monoclonal Antibody Improves Sepsis Survival in a Murine Model of Polymicrobial Sepsis.

Sepsis is the culmination of hyperinflammation and immune suppression in response to severe infection. Neutrophils are critical early responders to bacterial infection but can become highly dysfunctional during sepsis and other inflammatory disorders. The transmembrane protease ADAM17 (a disintegrin and metalloproteinase 17) is expressed by leukocytes and most other cells and has many substrates that regulate inflammation. We have reported that conditional knockout mice lacking ADAM17 in all leukocytes had a survival advantage during sepsis, which was associated with improved neutrophil effector functions. These and other findings indicate aberrant ADAM17 activity during sepsis. For this study, we evaluated for the first time the effects of an ADAM17 function blocking monoclonal antibody (mAb) on the pathogenesis of polymicrobial sepsis. Mice treated with the ADAM17 mAb MEDI3622 prior to sepsis induction exhibited significantly decreased mortality. When the ADAM17 mAb was combined with antibiotic administration, sepsis survival was markedly enhanced compared to either intervention alone, which was associated with a significant reduction in plasma levels of various inflammation-related factors. MEDI3622 and antibiotic administration after sepsis induction also significantly improved survival. Our results indicate that the combination of blocking ADAM17 as an immune modulator and appropriate antibiotics may provide a new therapeutic avenue for sepsis treatment.

Anti-ADAM17 monoclonal antibody MEDI3622 increases IFNγ production by human NK cells in the presence of antibody-bound tumor cells.

Several clinically successful tumor-targeting mAbs induce NK cell effector functions. Human NK cells exclusively recognize tumor-bound IgG by the FcR CD16A (FcγRIIIA). Unlike other NK cell activating receptors, the cell surface density of CD16A can be rapidly downregulated in a cis manner by the metalloproteinase ADAM17 following NK cell stimulation in various manners. CD16A downregulation takes place in cancer patients and this may affect the efficacy of tumor-targeting mAbs. We examined the effects of MEDI3622, a human mAb and potent ADAM17 inhibitor, on NK cell activation by antibody-bound tumor cells. MEDI3622 effectively blocked ADAM17 function in NK cells and caused a marked increase in their production of IFNγ. This was observed for NK cells exposed to different tumor cell lines and therapeutic antibodies, and over a range of effector/target ratios. The augmented release of IFNγ by NK cells was reversed by a function-blocking CD16A mAb. In addition, NK92 cells, a human NK cell line that lacks endogenous FcγRs, expressing a recombinant non-cleavable version of CD16A released significantly higher levels of IFNγ than NK92 cells expressing equivalent levels of wildtype CD16A. Taken together, our data show that MEDI3622 enhances the release of IFNγ by NK cells engaging antibody-bound tumor cells by blocking the shedding of CD16A. These findings support ADAM17 as a dynamic inhibitory checkpoint of the potent activating receptor CD16A, which can be targeted by MEDI3622 to potentially increase the efficacy of anti-tumor therapeutic antibodies.

The Applications of ELISpot in the Identification and Treatment of Various Forms of Tuberculosis and in the Cancer Immunotherapies.

ELISpot (enzyme-linked immunospot) is a powerful immunological tool for the detection of cytokine-secreting cells at a single-cell resolution. It is widely used for the diagnosis of various infectious diseases, e.g., tuberculosis and sarcoidosis, and it is also widely used in cancer immunotherapy research. Its ability to distinguish between active and latent forms of tuberculosis makes it an extremely powerful tool for epidemiological studies and contact tracing. In addition to that, it is a very useful tool for the research and development of cancer immunotherapies. ELISpot can be employed to assess the immune responses against various tumor-associated antigens, which could provide valuable insights for the development of effective therapies against cancers. Furthermore, it plays a crucial role to the evaluation of immune responses against specific antigens that not only could aid in vaccine development but also assist in treatment monitoring and development of therapeutic and diagnostic strategies. This chapter briefly describes some of the applications of ELISpot in tuberculosis and cancer research.

Clinical Applications of Flow Cytometry in Cancer Immunotherapies: From Diagnosis to Treatments.

The scope of flow cytometry is rapidly expanding in the diagnosis of various cancers, and it is being used routinely as an aid in classifying leukemias and lymphomas. There are several applications of flow cytometry to enumerate tumorigenic anomalies in patients. The unusual distribution of cells in various locations, their DNA content, cell proliferation rate, dysregulated expression of several surface receptors, and expression of tumor antigens are some examples that can be characterized by using different flow cytometry-based techniques. For instance, the differential diagnosis between chronic lymphocytic leukemia (CLL) and various other mature B-cell neoplasms can be made by immunophenotyping in combination with absolute counting of numerous cellular subsets or by enumerating their percent distributions. Flow cytometry has several advantages over conventional techniques which include the ability to acquire a multiparametric data in a relatively shorter time and facilitate the comparative analysis of specific cellular subsets in an efficient manner.In addition to diagnosis, there are several other applications of flow cytometry in the management of various cancers which include treatment monitoring or even selecting a personalized precision-based immunotherapy in synch with advanced genetic tests to increase the chances of favorable prognosis and complete remission. The detection of chimeric antigen receptors (CARs) on various engineered effector cells can also be determined along with their specificity in engaging the targets. Furthermore, the assessment of numerous immunological parameters, their effector functions and potencies including the proliferation dynamics, cytokine secretion profiles, and activation efficiencies can also be measured before starting immunotherapies in patients.This chapter is a brief overview of flow cytometry applications in the diagnosis and treatment strategies of various cancers.

Stepped approach for prediction of syndrome Z in patients attending sleep clinic: a north Indian hospital-based study.

PURPOSE: Syndrome Z is the occurrence of metabolic syndrome (MS) with obstructive sleep apnea. Knowledge of its risk factors is useful to screen patients requiring further evaluation for syndrome Z. METHODS: Consecutive patients referred from sleep clinic undergoing polysomnography in the Sleep Laboratory of AIIMS Hospital, New Delhi were screened between June 2008 and May 2010, and 227 patients were recruited. Anthropometry, body composition analysis, blood pressure, fasting blood sugar, and lipid profile were measured. MS was defined using the National Cholesterol Education Program (adult treatment panel III) criteria, with Asian cutoff values for abdominal obesity. RESULTS: Prevalence of MS and syndrome Z was 74% and 65%, respectively. Age, percent body fat, excessive daytime sleepiness (EDS), and ΔSaO(2) (defined as difference between baseline and minimum SaO(2) during polysomnography) were independently associated with syndrome Z. Using a cutoff of 15% for level of desaturation, the stepped predictive score using these risk factors had sensitivity, specificity, positive predictive value, and negative predictive value of 75%, 73%, 84%, and 61%, respectively for the diagnosis of syndrome Z. It correctly characterized presence of syndrome Z 75% of the time and obviated need for detailed evaluation in 42% of the screened subjects. CONCLUSIONS: A large proportion of patients presenting to sleep clinics have MS and syndrome Z. Age, percent body fat, EDS, and ΔSaO(2) are independent risk factors for syndrome Z. A stepped predictive score using these parameters is cost-effective and useful in diagnosing syndrome Z in resource-limited settings.

Activation of ADAM17 by IL-15 Limits Human NK Cell Proliferation.

Natural killer (NK) cells are innate cytotoxic lymphocytes that can recognize assorted determinants on tumor cells and rapidly kill these cells. Due to their anti-tumor effector functions and potential for allogeneic use, various NK cell platforms are being examined for adoptive cell therapies. However, their limited in vivo persistence is a current challenge. Cytokine-mediated activation of these cells is under extensive investigation and interleukin-15 (IL-15) is a particular focus since it drives their activation and proliferation. IL-15 efficacy though is limited in part by its induction of regulatory checkpoints. A disintegrin and metalloproteinase-17 (ADAM17) is broadly expressed by leukocytes, including NK cells, and it plays a central role in cleaving cell surface receptors, a process that regulates cell activation and cell-cell interactions. We report that ADAM17 blockade with a monoclonal antibody markedly increased human NK cell proliferation by IL-15 both in vitro and in a xenograft mouse model. Blocking ADAM17 resulted in a significant increase in surface levels of the homing receptor CD62L on proliferating NK cells. We show that NK cell proliferation in vivo by IL-15 and the augmentation of this process upon blocking ADAM17 are dependent on CD62L. Hence, our findings reveal for the first time that ADAM17 activation in NK cells by IL-15 limits their proliferation, presumably functioning as a feedback system, and that its substrate CD62L has a key role in this process in vivo. ADAM17 blockade in combination with IL-15 may provide a new approach to improve NK cell persistence and function in cancer patients.

Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: A systematic review.

Objectives: To systematically review the clinical literature reporting the use of Lopinavir/ritonavir (LPV/r) for the treatment of patients with Cornonavirus disease 19 (COVID-19) to assess the efficacy of LPV/r for the treatment of COVID-19.Methods: The authors systematically searched PubMed and MedRxiv databases for studies describing treatment of COVID-19 patients using LPV/r compared to other therapies. Articles were excluded if they were case reports, opinion editorials, preclinical studies, single-armed studies, not written in English, not relevant to the topic, or published before May 2020. The included outcomes were viral clearance as measured by reverse-transcription polymerase chain reaction (RT-PCR) negativity and/or improvement on chest computed tomography (CT), mortality, and adverse events.Results: Among 858 total studies, 16 studies met the inclusion criteria and were included in the qualitative review. These studies consisted of 3 randomized control trials, 3 open-label trials, and 10 observational studies. Most of these studies did not report positive clinical outcomes with LPV/r treatment.Conclusion: The systematic review revealed insufficient evidence of effectiveness and clinical benefit of LPV/r in the treatment of COVID-19 patients. Specifically, LPV/r does not appear to improve clinical outcome, mortality, time to RT-PCR negativity, or chest CT clearance in patients with COVID-19.

Corticosteroid therapy for COVID-19: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Corticosteroid treatment is an effective and common therapeutic strategy for various inflammatory lung pathologies and may be an effective treatment for coronavirus disease 2019 (COVID-19). The purpose of this systematic review and meta-analysis of current literature was to investigate the clinical outcomes associated with corticosteroid treatment of COVID-19. METHODS: We systematically searched PubMed, medRxiv, Web of Science, and Scopus databases through March 10, 2021 to identify randomized controlled trials (RCTs) that evaluated the effects of corticosteroid therapies for COVID-19 treatment. Outcomes of interest were mortality, need for mechanical ventilation, serious adverse events (SAEs), and superinfection. RESULTS: A total of 7737 patients from 8 RCTs were included in the quantitative meta-analysis, of which 2795 (36.1%) patients received corticosteroids plus standard of care (SOC) while 4942 (63.9%) patients received placebo and/or SOC alone. The odds of mortality were significantly lower in patients that received corticosteroids as compared to SOC (odds ratio [OR] = 0.85 [95% CI: 0.76; 0.95], P = .003). Corticosteroid treatment reduced the odds of a need for mechanical ventilation as compared to SOC (OR = 0.76 [95% CI: 0.59; 0.97], P = .030). There was no significant difference between the corticosteroid and SOC groups with regards to SAEs and superinfections. CONCLUSION: Corticosteroid treatment can reduce the odds for mortality and the need for mechanical ventilation in severe COVID-19 patients.

Prevalence of extensively drug-resistant tuberculosis among patients with multidrug-resistant tuberculosis: a retrospective hospital-based study.

BACKGROUND & OBJECTIVE: Extensively drug-resistant tuberculosis (XDR-TB) is a difficult-to-treat form of multidrug-resistant tuberculosis (MDR-TB). High rates of XDR-TB have been reported from India. We sought to ascertain the prevalence of XDR-TB among patients with MDR-TB treated at a tertiary care centre in New Delhi, India. METHODS: Case records of patients treated for MDR-TB at the All India Institute of Medical Sciences hospital, New Delhi, between 1997 and 2003 were retrospectively reviewed. All patients underwent a pretreatment drug-susceptibility testing (DST) to first- as well as second-line drugs. XDR-TB was defined as TB caused by bacilli showing resistance to rifampicin and isoniazid in addition to any fluoroquinolone and to at least one of the three following injectable drugs: capreomycin, kanamycin, and amikacin. RESULTS: A total of 211 laboratory-confirmed cases of MDR-TB were reviewed. The mean age of the patients was 33 +/- 12 yr. Fifty one (24%) patients were females. All patients were sero-negative for human immunodeficiency virus infection. Five of the 211 MDR-TB patients had XDR-TB. The prevalence of XDR-TB was 2.4 per cent among MDR-TB patients. INTERPRETATION & CONCLUSION: Our results showed that XDR-TB was rare among patients with MDR-TB treated between 1997 and 2003 at our centre. Unreported selection bias might have been responsible for the high prevalence of XDR-TB reported in previous hospital-based studies from India.

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy.

Human NK cell antitumor activities involve Ab-dependent cell-mediated cytotoxicity (ADCC), which is a key mechanism of action for several clinically successful tumor-targeting therapeutic mAbs. Human NK cells exclusively recognize these Abs by the Fcγ receptor CD16A (FcγRIIIA), one of their most potent activating receptors. Unlike other activating receptors on NK cells, CD16A undergoes a rapid down-regulation in expression by a proteolytic process following NK cell activation with various stimuli. In this review, the role of a disintegrin and metalloproteinase-17 (ADAM17) in CD16A cleavage and as a regulatory checkpoint is discussed. Several studies have examined the effects of inhibiting ADAM17 or CD16A cleavage directly during NK cell engagement of Ab-coated tumor cells, which resulted in strengthened Ab tethering, decreased tumor cell detachment, and enhanced CD16A signaling and cytokine production. However, the effects of either manipulation on ADCC have varied between studies, which may be due to dissimilar assays and the contribution of different killing processes by NK cells. Of importance is that NK cells under various circumstances, including in the tumor microenvironment of patients, down-regulate CD16A and this appears to impair their function. Considerable progress has been made in the development of ADAM17 inhibitors, including human mAbs that have advantages of high specificity and increased half-life in vivo. These inhibitors may provide a therapeutic means of increasing ADCC potency and/or antitumor cytokine production by NK cells in an immunosuppressive tumor microenvironment, and if used in combination with tumor-targeting Abs or NK cell-based adoptive immunotherapies may improve their efficacy.

Expression of a Recombinant High Affinity IgG Fc Receptor by Engineered NK Cells as a Docking Platform for Therapeutic mAbs to Target Cancer Cells.

Anti-tumor mAbs are the most widely used and characterized cancer immunotherapy. Despite having a significant impact on some malignancies, most cancer patients respond poorly or develop resistance to this therapy. A known mechanism of action of these therapeutic mAbs is antibody-dependent cell-mediated cytotoxicity (ADCC), a key effector function of human NK cells. CD16A on human NK cells has an exclusive role in binding to tumor-bound IgG antibodies. Though CD16A is a potent activating receptor, it is also a low affinity IgG Fc receptor (FcγR) that undergoes a rapid downregulation in expression by a proteolytic process involving ADAM17 upon NK cell activation. These regulatory processes are likely to limit the efficacy of tumor-targeting therapeutic mAbs in the tumor environment. We sought to enhance NK cell binding to anti-tumor mAbs by engineering these cells with a recombinant FcγR consisting of the extracellular region of CD64, the highest affinity FcγR expressed by leukocytes, and the transmembrane and cytoplasmic regions of CD16A. This novel recombinant FcγR (CD64/16A) was expressed in the human NK cell line NK92 and in induced pluripotent stem cells from which primary NK cells were derived. CD64/16A lacked the ADAM17 cleavage region in CD16A and it was not rapidly downregulated in expression following NK cell activation during ADCC. CD64/16A on NK cells facilitated conjugation to antibody-treated tumor cells, ADCC, and cytokine production, demonstrating functional activity by its two components. Unlike NK cells expressing CD16A, CD64/16A captured soluble therapeutic mAbs and the modified NK cells mediated tumor cell killing. Hence, CD64/16A could potentially be used as a docking platform on engineered NK cells for therapeutic mAbs and IgG Fc chimeric proteins, allowing for switchable targeting elements and a novel cancer cellular therapy.

Angiotensin converting enzyme genotype affects development and course of sarcoidosis in Asian Indians.

BACKGROUND AND OBJECTIVES: Studies of serum angiotensin converting enzyme (SACE) activity and its association with ACE gene insertion/deletion (I/D) polymorphism in relation to sarcoidosis have yielded variable results. This has been attributed to possible ethnic differences. Present study was designed to evaluate the relationship between I/D polymorphism and susceptibility to develop sarcoidosis and its effect on SACE activity and disease course in Asian Indian patients with sarcoidosis. METHODS: ACE genotyping was performed in 72 consecutive patients with sarcoidosis and 199 controls (96 normal healthy individuals and 103 tuberculosis patients taken as disease controls). SACE activity was determined in all patients with sarcoidosis. Various parameters were compared amongst patients with different genotypes as well as between sarcoidosis and control groups. RESULTS: Gene frequency of I and D in control group was 0.6 and 0.4, whereas in patients with sarcoidosis it was 0.35 and 0.65 respectively (p < 0.001). For individuals with D allele (DD&ID genotypes), odds ratios for developing sarcoidosis were 9.0 (95% CI: 3.4; 23.7) and 5.5 (95% CI: 2.2; 13.6) respectively considering individuals with II genotype as reference. Mean SACE activity was highest in patients with DD genotype and followed an order of DD > ID > II. Good response to initial corticosteroids was seen in 6 of 6 (100%) patients with II genotype whereas in only 32 of 37 (84%) with ID and 16 of 25 (64%) with DD (p = 0.013). INTERPRETATION AND CONCLUSION: In Asian Indian population 'D' allele is associated with an increased risk for development of sarcoidosis and patients with 'D' allele show poor response to corticosteroids.

Ectodomain Shedding by ADAM17: Its Role in Neutrophil Recruitment and the Impairment of This Process during Sepsis.

Neutrophils are specialized at killing bacteria and are recruited from the blood in a rapid and robust manner during infection. A cascade of adhesion events direct their attachment to the vascular endothelium and migration into the underlying tissue. A disintegrin and metalloproteinase 17 (ADAM17) functions in the cell membrane of neutrophils and endothelial cells by cleaving its substrates, typically in a cis manner, at an extracellular site proximal to the cell membrane. This process is referred to as ectodomain shedding and it results in the downregulation of various adhesion molecules and receptors, and the release of immune regulating factors. ADAM17 sheddase activity is induced upon cell activation and rapidly modulates intravascular adhesion events in response to diverse environmental stimuli. During sepsis, an excessive systemic inflammatory response against infection, neutrophil migration becomes severely impaired. This involves ADAM17 as indicated by increased levels of its cleaved substrates in the blood of septic patients, and that ADAM17 inactivation improves neutrophil recruitment and bacterial clearance in animal models of sepsis. Excessive ADAM17 sheddase activity during sepsis thus appears to undermine in a direct and indirect manner the necessary balance between intravascular adhesion and de-adhesion events that regulate neutrophil migration into sites of infection. This review provides an overview of ADAM17 function and regulation and its potential contribution to neutrophil dysfunction during sepsis.

Diagnostic accuracy of ascitic fluid IFN-gamma and adenosine deaminase assays in the diagnosis of tuberculous ascites.

In this study, we evaluated the diagnostic accuracy and cost-effectiveness of ascitic fluid interferon-gamma (IFN-gamma) and adenosine deaminase (ADA) assays in the diagnosis of tuberculous ascites. Ascitic fluid from patients with proven tuberculosis (TB) (n = 31) and non-TB ascites (n = 88) was analyzed for IFN-gamma and ADA levels. Areas under the receiver operative characteristic (ROC) curves (AUCs) for the two biologic markers were compared. Levels of ascitic fluid IFN-gamma, median (range): 560 (104-1600) pg/mL vs. 4.85 (0-320) pg/mL (p < 0.001), and ADA, median (range): 58 (16-331) IU/L vs. 10 (0-59) IU/L (p = 0.001), were significantly different between TB and non-TB groups. IFN-gamma and ADA assays showed equal sensitivity (0.97) and differed marginally in specificity (0.97 vs. 0.94). Difference in AUCs was not significant (0.99 vs. 0.98, p < 0.62). For differentiating TB from non-TB ascites, optimal cutoff points were 112 pg/mL for IFN-gamma and 37 IU/L for ADA. The accuracy of the ADA assay was similar to that of the IFN-gamma assay in differentiating of TB from non-TB ascites. Because both material and human costs of the ADA assay are far less than those of the IFN-gamma assay, the former is probably the most appropriate diagnostic test for analysis of peritoneal fluid in resource- limited settings.

Targeting ADAM17 in leukocytes increases neutrophil recruitment and reduces bacterial spread during polymicrobial sepsis.

A rapid and robust recruitment of circulating neutrophils at sites of infection is critical for preventing bacterial spread. The efficiency of this process, however, is greatly diminished during sepsis, a severe systemic inflammatory response to infection. The proteolytic activity of a disintegrin and metalloprotease-17 is induced in the cell membrane of leukocytes upon their activation, resulting in the conversion of membrane to soluble TNF-α and the release of assorted receptors from the surface of neutrophils important for their effector functions. We show that conditional knockout mice lacking a disintegrin and metalloprotease-17 in all leukocytes had a survival advantage when subjected to polymicrobial sepsis. Bacteremia and the levels of circulating proinflammatory cytokines, key determinants of sepsis severity, were significantly reduced in conditional a disintegrin and metalloprotease-17 knockout mice during sepsis. Although cecal bacterial microbiota and load were similar in unmanipulated conditional a disintegrin and metalloprotease-17 knockout and control mice, peritoneal spread of bacteria was significantly reduced in conditional a disintegrin and metalloprotease-17 knockout mice following sepsis induction, which was associated with an amplified recruitment of neutrophils. Taken together, our findings suggest that extensive a disintegrin and metalloprotease-17 induction during sepsis may tip the balance between efficient and impaired neutrophil recruitment.

Regulation of CXCR2 expression and function by a disintegrin and metalloprotease-17 (ADAM17).

The chemokine receptor CXCR2 is expressed at high levels on circulating neutrophils and is critical for directing their migration to sites of inflammation. CXCR2 surface levels are rapidly modulated by 2 mechanisms-cell internalization and recycling upon ligand binding-and by a metalloprotease activity following overt neutrophil activation by nonligand stimuli. The latter process has only been described in human neutrophils, and essentially, nothing is known about its functional relevance and the specific protease involved. We show that targeting ADAM17 in mouse and human neutrophils blocks CXCR2 down-regulation induced by nonligand stimuli but not by chemokine ligands. This was determined by use of a selective ADAM17 inhibitor, an ADAM17 function-blocking antibody, and ADAM17 gene-targeted mice. CXCR2 is known to undergo a marked down-regulation during various inflammatory disorders, and this is associated with impaired neutrophil recruitment. We show that blocking ADAM17 activity reduced CXCR2 down-regulation on circulating neutrophils and enhanced their recruitment during acute inflammation, which was reversed by a CXCR2 inhibitor. Taken together, our findings demonstrate that unlike CXCR2 internalization, ADAM17 induction down-regulates the receptor in an irreversible manner and may serve as a master switch in controlling CXCR2 function, but may also contribute to neutrophil dysfunction during excessive inflammation.

Prevalence and risk factors of syndrome Z in urban Indians.

BACKGROUND: Syndrome Z is defined as the co-occurrence of obstructive sleep apnea (OSA) and metabolic syndrome. There is a paucity of information on the magnitude of syndrome Z in the community and the factors associated with it. METHODS: We conducted a two-stage, cross-sectional, community-based study in four different socioeconomic zones of the South Delhi district, India, from April 2005 through June 2007. In stage 1, a systematic random sample of subjects of either gender aged 30-65 years were administered a questionnaire by door-to-door survey. Subjects that responded were classified as habitual and non-habitual snorers. In stage 2, all the habitual and 10% of randomly selected non-habitual snorers were invited for overnight polysomnography and evaluation for metabolic syndrome. The National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria were used to define metabolic syndrome. RESULTS: Of the 2860 subjects approached, 2505 (88%) completed stage 1; 452 (18%) were habitual snorers. In stage 2, OSA (defined as apnea-hypopnea index > or =5) was observed in 94 (32.4%) of 290 habitual snorers and 3 (4%) of 75 non-habitual snorers. Seventy (77%) of the 91 habitual snorers with OSA also had metabolic syndrome; none of the non-habitual snorers with OSA had metabolic syndrome. The estimated population prevalence of metabolic syndrome was 43% [95% CI: (41.0-44.9%)] and syndrome Z was 4.5% (95% CI: 3.7-5.3). On multivariable analysis, age [OR: 1.05 (1.00-1.09)], male gender [OR: 5.64 (2.06-15.49)], percent body fat [OR: 1.08 (1.04-1.13)] and DeltaSaO(2) (%) (defined as the difference between baseline and minimum SaO(2) during overnight sleep study) [OR: 5.80 (2.36-14.26), 17.70 (5.97-52.17) and 57.1 (19.12-170.40) for 10-20%, 20-30% and >30% reduction respectively as compared to <10% reduction] were independently associated with syndrome Z. CONCLUSIONS: To the best of our knowledge, this is the first population-based study on the prevalence and risk factors of syndrome Z, and it reveals that a considerable proportion of community-dwelling northern Indian adults have syndrome Z. Age, male gender, percent body fat and severity of nocturnal desaturation were independent risk factors for syndrome Z.