Immunotherapy for type 1 diabetes.

INTRODUCTION: Despite advances in technology including the development of more sophisticated methods of monitoring blood glucose and delivering insulin, many individuals with type 1 diabetes continue to experience significant challenges in optimizing glycaemic control. Alternative treatment approaches to insulin are required. Increasing efforts have focused on developing treatments aimed at targeting the underlying disease process to modulate the immune system, maximize beta cell function and enhance endogenous insulin production and action. SOURCES OF DATA: Literature searches with keywords 'Type 1 diabetes and immunotherapy', publications relating to clinical trials of immunotherapy in type 1 diabetes. AREAS OF AGREEMENT: Insulin therapy is insufficient to achieve optimal glycaemic control in many individuals with type 1 diabetes, and new treatment approaches are required. Studies have showed promising results for the use of immunotherapy as a means of delaying disease onset and progression. AREAS OF CONTROVERSY: The optimal way of identifying individuals most likely to benefit from immunotherapies. GROWING POINTS: A better understanding of the natural history of type 1 diabetes has made it possible to identify individuals who have developed autoimmunity but have not yet progressed to clinical diabetes, offering opportunities not only to develop treatments that delay disease progression, but prevent its development in the first place. A consensus on how to identify individuals who may benefit from immunotherapy to prevent disease onset is needed. AREAS TIMELY FOR DEVELOPING RESEARCH: The development of optimal strategies for preventing and delaying progression of type 1 diabetes, and monitoring the response to immunointervention.

Neutrophils and secondary infections in COVID-19 induced acute respiratory distress syndrome.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is the cause of the current global pandemic and has affected more than 188 countries worldwide. Infection by the virus can have diverse clinical manifestations, with one of the most severe clinical manifestation being respiratory failure and the development of acute respiratory distress syndrome. Clinical manifestations of acute respiratory distress syndrome secondary to SARS-CoV-2 are also diverse with a lack of diagnostic tools to distinguish between primary viral infection and secondary bacterial infections. This was a single-centre, retrospective case-control study of bronchoalveolar lavage fluid cell counts, flow cytometry and culture results from mechanically ventilated patients with SARS-CoV-2 (COVID-19) pneumonia and acute respiratory distress syndrome. Neutrophils were the predominant cell type in bronchoalveolar fluid samples up to 2 weeks into mechanical ventilation. There also was a strong correlation between positive respiratory cultures and significant elevation in bronchoalveolar fluid neutrophil counts/percentages and serum C-reactive protein levels. Absolute levels of T cell subtypes correlated with reduced lung compliance measurements. Patients with SARS-CoV-2 and severe respiratory disease are at risk for secondary infections. In some COVID-19 patients, serum C-reactive protein and bronchoalveolar fluid neutrophils may be correlated with a secondary infection.

Cardiovascular and renal outcomes following percutaneous coronary intervention in a population with renal disease: a case-control study.

BACKGROUND: Patients with renal disease are less likely to undergo percutaneous coronary intervention (PCI) due to concerns about poor outcomes. AIM: We describe outcomes following PCI in individuals with chronic kidney disease (CKD), as compared with matched controls with comparable CKD who did not undergo PCI. We also identified factors predictive of poor outcomes following PCI amongst patients with CKD. DESIGN: Retrospective observational case-control study. METHODS: Cases were individuals with CKD (stages 1-5) undergoing PCI between 2008 and 2014. Controls were age, gender and creatinine-matched individuals not requiring PCI. We compared mortality between groups using Kaplan-Meier curves and Cox regression modelling. We assessed changes in serum creatinine using Wilcoxon Rank testing. We explored the relationship between biochemical and haematological measures (baseline creatinine, calcium, phosphate, calcium-phosphate product, parathyroid hormone, white cell count, haemoglobin, platelet count, c-reactive protein and total cholesterol) and post-PCI mortality, using logistic regression. RESULTS: We identified 144 cases and 144 controls. Mortality was significantly lower amongst cases compared with controls [hazard ratio 0.46 (95% confidence intervals 0.31, 0.69)]. PCI did not result in a significant change in renal function (P=0.52). Amongst cases, serum creatinine and calcium-phosphate product were predictors of mortality following PCI. CONCLUSION: Cases undergoing PCI had lower mortality, and PCI was not associated with accelerated CKD progression. On this data, PCI should not be deferred as a treatment option in patients with CKD. Serum creatinine and calcium-phosphate product predict mortality following PCI in this cohort, and may be useful in risk-stratifying patients with CKD being considered for PCI.

Analyzer-based imaging of spinal fusion in an animal model.

Analyzer-based imaging (ABI) utilizes synchrotron radiation sources to create collimated monochromatic x-rays. In addition to x-ray absorption, this technique uses refraction and scatter rejection to create images. ABI provides dramatically improved contrast over standard imaging techniques. Twenty-one adult male Wistar rats were divided into four experimental groups to undergo the following interventions: (1) non-injured control, (2) decortication alone, (3) decortication with iliac crest bone grafting and (4) decortication with iliac crest bone grafting and interspinous wiring. Surgical procedures were performed at the L5-6 level. Animals were killed at 2, 4 and 6 weeks after the intervention and the spine muscle blocks were excised. Specimens were assessed for the presence of fusion by (1) manual testing, (2) conventional absorption radiography and (3) ABI. ABI showed no evidence of bone fusion in groups 1 and 2 and showed solid or possibly solid fusion in subjects from groups 3 and 4 at 6 weeks. Metal artifacts were not present in any of the ABI images. Conventional absorption radiographs did not provide diagnostic quality imaging of either the graft material or fusion masses in any of the specimens in any of the groups. Synchrotron-based ABI represents a novel imaging technique which can be used to assess spinal fusion in a small animal model. ABI produces superior image quality when compared to conventional radiographs.

Salmonella pathogenicity island 2-encoded type III secretion system mediates exclusion of NADPH oxidase assembly from the phagosomal membrane.

Salmonella typhimurium requires a type III secretion system encoded by pathogenicity island (SPI)-2 to survive and proliferate within macrophages. This survival implies that S. typhimurium avoids or withstands bactericidal events targeted to the microbe-containing vacuole, which include intraphagosomal production of reactive oxygen species (ROS), phagosomal acidification, and delivery of hydrolytic enzymes to the phagosome via fusion with lysosomes. Recent evidence suggests that S. typhimurium alters ROS production by murine macrophages in an SPI-2-dependent manner. To gain insights into the mechanism by which S. typhimurium inhibits intraphagosomal ROS production, we analyzed the subcellular distribution of NADPH oxidase components during infection of human monocyte-derived macrophages by wild-type (WT) or several SPI-2 mutant strains of S. typhimurium. We found that the membrane component of the NADPH oxidase, flavocytochrome b(558), was actively excluded or rapidly removed from the phagosomal membrane of WT-infected monocyte-derived macrophages, thereby preventing assembly of the NADPH oxidase complex and intraphagosomal production of superoxide anion. In contrast, the NADPH oxidase assembled on and generated ROS in phagosomes containing SPI-2 mutant S. typhimurium. Subversion of NADPH oxidase assembly by S. typhimurium was accompanied by increased bacterial replication relative to that of SPI-2 mutant strains, suggesting that the ability of WT S. typhimurium to prevent NADPH oxidase assembly at the phagosomal membrane represents an important virulence factor influencing its intracellular survival.

VAMP3 null mice display normal constitutive, insulin- and exercise-regulated vesicle trafficking.

To investigate the physiological function of the VAMP3 vesicle SNARE (v-SNARE) isoform in the regulation of GLUT4 vesicle trafficking, we generated homozygotic VAMP3 null mice by targeted gene disruption. The VAMP3 null mice had typical growth rate and weight gain, with normal maintenance of fasting serum glucose and insulin levels. Analysis of glucose disposal and insulin sensitivity demonstrated normal insulin and glucose tolerance, with no evidence for insulin resistance. Insulin stimulation of glucose uptake in isolated primary adipocytes was essentially the same for the wild-type and VAMP3 null mice. Similarly, insulin-, hypoxia-, and exercise-stimulated glucose uptake in isolated skeletal muscle did not differ significantly. In addition, other general membrane trafficking events including phagocytosis, pinocytosis, and transferrin receptor recycling were also found to be unaffected in the VAMP3 null mice. Taken together, these data demonstrate that VAMP3 function is not necessary for either regulated GLUT4 translocation or general constitutive membrane recycling.

Somatization: a debilitating syndrome in primary care.

Somatization is a significant problem for clinical medicine. Unlike somatization disorder, which is relatively rare, abridged somatization, a less severe form of somatization, is prevalent in primary care clinics. The authors examined the clinical status and functioning of patients diagnosed with a depression or anxiety disorder comorbid with abridged somatization and compared them with patients diagnosed with a depression or anxiety disorder alone. The authors examined severity of physical functioning and psychopathology in relation to diagnostic status. Patients diagnosed with both abridged somatization and a depression or anxiety disorder were more physically impaired and more anxious than those diagnosed with a depression or anxiety disorder alone. The results suggest that abridged somatization frequently coexists with depression and anxiety and thus complicates the presentation of these disorders.

The role of the neutrophil and phagocytosis in infection caused by Helicobacter pylori.

Recent advances in our understanding of Helicobacter pylori-phagocyte interactions indicate that these organisms actively modulate phagocyte function in order to retard phagocytosis, while simultaneously inducing a strong respiratory burst. The central players in this dynamic include H. pylori neutrophil activating protein and factors that are associated with the cag pathogenicity island type IV secretion apparatus. Additionally, catalase, alkyl hydroperoxide reductase, and factors that are unique to type I strains allow bacteria to resist phagocytic killing.

Cognitive behavior therapy for somatization disorder: a preliminary investigation.

Patients diagnosed with somatization disorder have high rates of disability and often prove refractory to treatment. This preliminary investigation examines the effect of a 10-session cognitive behavior therapy (CBT) protocol on the physical discomfort and disability of severely impaired somatizers. The severity of patients' physical discomfort and disability was assessed at baseline, post-treatment, and eight months following treatment. Patients reported significant improvement in symptomatology and physical functioning between baseline and post-treatment as well as between baseline and follow-up. The findings suggest that CBT might benefit patients diagnosed with somatization disorder and should be subjected to a controlled treatment trial.

Efficacy and specificity of bFGF increased collateral flow in experimental peripheral arterial insufficiency.

Angiogenic growth factors could prove to be useful in managing peripheral arterial insufficiency. The present study was designed to evaluate the dose response of basic fibroblast growth factor (bFGF), the efficacy of critical routes and dosing regimens, and the specificity of action in rats with peripheral arterial insufficiency. Bilateral ligation of femoral arteries greatly reduces blood flow capacity to the calf muscles but does not impair resting flow needs. Collateral blood flow to calf muscles was determined 16 days postocclusion, during treadmill running, with (85)Sr and (141)Ce microspheres, in blinded-randomized trials that included intra-arterial and intravenous infusions and subcutaneous injections of recombinant human bFGF. Peak blood flow of 75-80 ml. min(-1). 100 g(-1) for calf muscle was observed at a bFGF dose of 5 microg. kg(-1). day(-1) (ia for 14 days) compared with 50 ml. min(-1). 100 g(-1) for vehicle groups. Similar increases in collateral blood flow were observed with short-term or prolonged and continuous or intermittent delivery of bFGF by any route. Collateral blood flows were similar in corresponding muscles across both limbs. Vascular remodeling induced by bFGF required attendant vascular occlusion, inasmuch as vessels in the normal nonoccluded vascular tree were unresponsive to circulating bFGF. Improvement in collateral blood flow with exogenous bFGF is robust, amenable to short-term administration, and requires vascular occlusion to be effective.

The abused child as parent: the structure and content of physically abused mothers' perceptions of their babies.

OBJECTIVE: The major aim of the study was to provide an empirical answer to the following question: Does a mother's history of being physically abused as a child have a discernible impact on the structure and content of her perceptions and beliefs concerning her own child? METHOD: Free-response memories and current descriptions of babies, self, and significant others such as parents were compared longitudinally in two groups of mothers when their babies were 6 months, 1 year, and 2 years old. One group of mothers consisted of individuals who reported being physically abused as children; the control group consisted of mothers who were not physically abused. The two groups were comparable with respect to age of baby, race, and socioeconomic status. RESULTS: Abused mothers were found to differ significantly from control mothers in the structure and content of their free-response perceptions of their own babies. More specifically, abused mothers lagged behind controls in how well-differentiated were their negative perceptions of their babies. Differentiation in this study is operationally defined as the number of unique clusters that underlie a mother's perceptions of her baby, when social perception data is analyzed using cluster analysis (HICLAS). The greater the number of clusters observed, the greater is the differentiation. On the other hand, abused mothers were comparable to controls with respect to differentiation of positive perceptions of babies. CONCLUSIONS: The findings constitute a discovery about the structural organization of social cognition in mothers at-risk for child abuse. Implications of the findings for theory and future research are briefly discussed, as are limitations of the current study.

Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages.

Helicobacter pylori colonizes the gastric epithelium of approximately 50% of the world's population and plays a causative role in the development of gastric and duodenal ulcers. H. pylori is phagocytosed by mononuclear phagocytes, but the internalized bacteria are not killed and the reasons for this host defense defect are unclear. We now show using immunofluorescence and electron microscopy that H. pylori employs an unusual mechanism to avoid phagocytic killing: delayed entry followed by homotypic phagosome fusion. Unopsonized type I H. pylori bound readily to macrophages and were internalized into actin-rich phagosomes after a lag of approximately 4 min. Although early (10 min) phagosomes contained single bacilli, H. pylori phagosomes coalesced over the next approximately 2 h. The resulting "megasomes" contained multiple viable organisms and were stable for 24 h. Phagosome-phagosome fusion required bacterial protein synthesis and intact host microtubules, and both chloramphenicol and nocodazole increased killing of intracellular H. pylori. Type II strains of H. pylori are less virulent and lack the cag pathogenicity island. In contrast to type I strains, type II H. pylori were rapidly ingested and killed by macrophages and did not stimulate megasome formation. Collectively, our data suggest that megasome formation is an important feature of H. pylori pathogenesis.

Museums, friends, and lovers in the New South: Laura's Web, 1909-1931.

Laura Bragg, a member of the first graduating class at Simmons College, journeyed to Charleston as a New Woman in 1909. As the first woman director of a major scientific museum in the United States, Bragg transformed the Charleston Museum into a public education institution and became an innovative leader in museum education. This article documents Bragg's contributions within the context of antebellum culture where the Southern Belle was placed on a Victorian pedestal and Boston marriages were an unknown phenomenon. Using extensive and hitherto unpublished correspondence, the authors detail Bragg's lesbian relationships and describe her network within the homosexual male community during the era of the Charleston Renaissance.

NADPH oxidase activation and assembly during phagocytosis.

Generation of superoxide (O2-) by the NADPH-dependent oxidase of polymorphonuclear leukocytes is an essential component of the innate immune response to invading microorganisms. To examine NADPH oxidase function during phagocytosis, we evaluated its activation and assembly following ingestion of serum-opsonized Neisseria meningitidis, serogroup B (NMB), and compared it with that elicited by serum-opsonized zymosan (OPZ). Opsonized N. meningitidis- and OPZ-dependent generation of reactive oxygen species by polymorphonuclear leukocytes peaked early and then terminated. Phosphorylation of p47phox coincided with peak generation of reactive oxygen species by either stimulus, consistent with a role for p47phox phosphorylation during NADPH oxidase activation, and correlated with phagosomal colocalization of flavocytochrome b558 (flavocytochrome b) and p47phox and p67phox (p47/67phox). Termination of respiratory burst activity did not reflect dephosphorylation of plasma membrane- and/or phagosome-associated p47phox; in contrast, the specific activity of phosphorylated p47phox at the phagosomal membrane increased. Most significantly, termination of oxidase activity paralleled the loss of p47/67phox from both NMB and OPZ phagosomes despite the continued presence of flavocytochrome b. These data suggest that 1) the onset of respiratory burst activity during phagocytosis is linked to the phosphorylation of p47phox and its translocation to the phagosome; and 2) termination of oxidase activity correlates with loss of p47/67phox from flavocytochrome b-enriched phagosomes and additional phosphorylation of membrane-associated p47phox.

Intracellular niches for extracellular bacteria: lessons from Helicobacter pylori.

Helicobacter pylori colonizes the gastric epithelium of humans and plays a causative role in peptic ulcer disease and perhaps gastric cancer. H. pylori proliferates in the mucus layer over the epithelium and is not cleared by the host immune response. Although the mucus layer is the major reservoir of H. pylori in vivo, a growing body of evidence suggests that H. pylori can persist in multiple intracellular locales. Clinical isolates of H. pylori invade epithelial monolayers at least as well as Shigella. The intracellular organisms are cytotoxic, and bacterial microcolonies form on the exposed basement membrane. Both mononuclear phagocytes and neutrophils phagocytose unopsonized H. pylori. However, the internalized organisms are not killed efficiently and our recent data suggest that H. pylori disrupts phagosome maturation. Collectively, the data support the hypothesis that intracellular H. pylori represent a reservoir of organisms that contributes to bacterial persistence, host tissue damage, and treatment failure.

Self-complexity and the persistence of depression.

Self-complexity, a measure of the structure of cognition involving the self, was used to predict the persistence of depression in patients diagnosed with major depression. Self-descriptions offered by depressed patients were analyzed using a clustering algorithm to model cognitive structure. Indices of positive and negative self-complexity, derived from the resulting models, were used to predict depressive symptomatology 9 months after the onset of a major depression. Negative self-complexity uniquely predicted subsequent levels of depression even after the effects of initial levels of depression, self-evaluation, and dysfunctional attitudes were statistically removed. Highly complex negative self-representation appears to be associated with poor recovery from a major depressive episode. Future studies examining the relationship between cognition and psychopathology should investigate, in addition to its content, the formal and structural properties of cognition.

Transient association of the nicotinamide adenine dinucleotide phosphate oxidase subunits p47phox and p67phox with phagosomes in neutrophils from patients with X-linked chronic granulomatous disease.

Optimal microbicidal activity of polymorphonuclear leukocytes (PMNs) requires recruitment of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to the phagosome. In this study, we used a synchronized phagocytosis assay and immunofluorescence microscopy (IFM) to examine the association of cytosolic NADPH oxidase subunits with phagosomes containing opsonized zymosan (OpZ). Ingestion of OpZ began within 30 seconds of particle binding and forming phagosomes were enriched for both F-actin and the actin-binding protein p57. NADPH oxidase subunits p47phox and p67phox were also recruited to forming phagosomes and were retained on mature phagosomes for at least 15 minutes. Colocalization of F-actin, p57, and p47phox on phagosomes was confirmed by immunoblotting. Translocation of p67phox, but not p57, to forming phagosomes was deficient in PMNs lacking p47phox. Surprisingly, we found that in PMNs from six individuals with X-linked chronic granulomatous disease (CGD), p47phox and p67phox accumulated in the periphagosomal area during ingestion of OpZ. However, in marked contrast to normal PMNs, p47phox and p67phox were shed from nascent phagosomes along with F-actin and p57 once OpZ was internalized (approximately 5 minutes). These data support a model in which flavocytochrome b is required for stable membrane binding of p47phox and p67phox, but not their association with the cytoskeleton or transport to the cell periphery.

Buspirone: future directions.

The Food and Drug Administration approved the use of buspirone for generalized anxiety disorder (GAD) in 1986. Since then, numerous studies have examined the efficacy and safety of buspirone for patients with not only generalized feelings of anxiety, but also panic disorder, major depressive disorder, obsessive-compulsive disorder, body dysmorphic disorder, social phobia, posttraumatic stress disorder, selective serotonin reuptake inhibitor-induced adverse events, dementia, behavioral disturbances, attention deficit-hyperactivity disorder, and tobacco dependency. Although relatively few placebo-controlled trials have been conducted on patients with problems other than GAD, an ever-growing body of research suggests future directions for the use of buspirone. This article reviews the body of research relating to new uses for buspirone.