Hemodynamic effects of somatostatin in insulin-dependent diabetic subjects

Summary The aim of the present study was to evaluate possible hemodynamic effects of somatostatin in insulin-dependent diabetic subjects. For this purpose, 7 insulin-requiring juvenile-onset diabetics were submitted to a short-term infusion of cyclic somatostatin (250 μg/h, over 2 h) or saline in randomized order. Somatostatin infusion resulted in a progressive and significant decrease in heart rate, stroke volume, cardiac index and velocity circumferential fiber; on the other hand, left ventricular ejection time was augmented by somatostatin. None of these effects was seen in the saline control study. We conclude that somatostatin exerts a negative inotropic effect in insulin-dependent diabetes.     

Fibronectin binding to thrombin-stimulated platelets: evidence for fibrin(ogen) independent and dependent pathways

Plasma fibronectin binds in a specific and saturable manner to thrombin- stimulated platelets. gamma-Thrombin stimulated 80% as much fibronectin binding to platelets as alpha-thrombin with conversion of less than or equal to 1% of platelet fibrinogen to fibrin. Afibrinogenemic and normal platelets bound similar quantities of fibronectin in the presence of calcium or magnesium-ethylene glycol tetra-acetic acid (EGTA). These observations indicate that fibronectin can interact with platelets without involvement of fibrin or fibrinogen. Nevertheless, two different effects of fibrin(ogen) on fibronectin binding were observed. First, exogenous fibrinogen inhibited fibronectin binding to thrombin-stimulated platelets. This inhibition was unidirectional, as fibronectin did not inhibit fibrinogen binding to ADP or thrombin- stimulated cells. Second, formaldehyde-fixed cells with surface- associated fibrin bound significant quantities of fibronectin. This interaction required calcium and did not occur on fixed cells with or without surface-bound fibrinogen. A portion of the ligand bound to fixed cells with surface-associated fibrin was modified to form a derivative with a molecular weight identical to that of the fibronectin subunit cross-linked to the alpha-chain of fibrin. This high mol wt derivative was also observed to a variable extent with living cells in the presence of magnesium or calcium but not in the presence of magnesium-EGTA. Thus, fibronectin binds to platelets by at least two mechanisms: (1) a fibrin(ogen)-independent pathway that requires divalent ions and is inhibited by exogenous fibrinogen; and (2) a fibrin-dependent pathway with an absolute calcium requirement. With nonaggregated, thrombin-stimulated platelets, the former pathway appears to predominate.     

Risk factors for early and late mortality in hospitalized older patients: the continuing importance of functional status

BACKGROUND: Prognostic information collected at hospital admission may be useful in defining care objectives and in deciding on therapy for older people. The aim of our study was to identify admission risk factors for in-hospital and postdischarge mortality. METHODS: The study included 987 patients aged 70 years and older admitted to the geriatric ward of San Giovanni Battista Hospital in Torino during 1995 and 1996. Demographic, clinical, and functional variables were collected on admission to hospital and examined as potential risk factors for mortality during hospitalization and at 5 years of follow-up. RESULTS: During their hospital stay, 147 patients (14.9%) died. Risk factors independently associated with in-hospital mortality included functional impairment (Activities of Daily Living [ADL]) (OR [odds ratio] 1.73, CI [confidence interval] 95% 1.02-2.95), dependence related to medical conditions (OR 2.18, CI 95% 1.39-3.42), cerebrovascular disease (OR 3.23, CI 95% 1.64-6.37), cancer (OR 4.52, CI 95% 1.99-10.24), albumin 3.0-3.4 g/dl (OR 4.51, CI 95% 2.76-7.35), albumin <3.0 g/dl (OR 6.83, CI 95% 3.59-13.0), creatinine 1.5-3 mg/dl (OR 2.23, CI 95% 1.36-3.65), creatinine >3 mg/dl (OR 2.55, CI 95% 1.10-5.93), and fibrinogen >/=452 mg/dl (OR 1.91, CI 95% 1.26-2.89). During the 5-year follow-up, 553 patients (67.7%) died. Variables independently associated with mortality in multivariate analysis were age 75-84 years (HR [hazard ratio] 1.40, CI 95% 1.10-1.78), >/=85 years (HR 2.08, CI 95% 1.59-2.72), male sex (HR 1.50, CI 95% 1.24-1.81), ADL dependency (HR 1.24, CI 95% 1.01-1.52), >/=5 errors on Short Portable Mental Status Questionnaire (HR 1.34, CI 95% 1.10-1.63), dependence on Dependence Medical Index (HR 1.36, CI 95% 1.10-1.67), presence of cancer (HR 2.58, CI 95% 1.80-3.71), hemoglobin /=2 (HR 1.49, CI 95% 1.14-1.95). CONCLUSIONS: A complete functional and clinical evaluation at hospital admission permits identification of patients at higher risk of early and long-term mortality.     

Mental health need: use of administrative data and record linkage to inform mental health policy and practice

Background

With mental ill-health on the rise globally, it is crucial to investigate whether the needs of individuals with mental ill-health are fully addressed. Attempts to measure negative consequences of unmet needs have been limited by the use of cross-sectional study designs or self-report measures. We aimed to investigate the interplay between perceived mental ill-health and unmet need in relation to mental health on a population level.

Specificity of autoantibodies in autoimmune thrombocytopenia

In 42 patients with autoimmune thrombocytopenia (AITP) and a positive direct platelet suspension immunofluorescence test (PSIFT), the antigenic specificity of the autoantibodies was studied. Because the autoantibodies were often not detectable in the serum and additional HLA antibodies may disturb the reaction pattern with the platelet panel, we used eluates prepared from the patients' platelets for this study. Thirty-five patients had antibodies equally reactive with normal platelets, irrespective of their antigenic make-up, but not with the platelets from two Glanzmann's disease patients. Absorption and elution experiments in two patients showed that his was probably not due to the presence of a combination of anti-Zwa and anti-Zwb antibodies. Thus, the majority of autoantibodies against platelets seems to be directed against antigenic determinants not present on Glanzmann's disease platelets, but perhaps located on the platelet-membrane glycoproteins IIb and/or IIIa. In ten patients, antibodies of no, or still unknown, specificity were detected. Three of these had additional antibodies not reactive with the platelets of the two Glanzmann patients.     

Molecular and cellular effects of antisickling concentrations of alkylureas

Alkylureas are capable of inhibiting sickling in vitro and the gelation of solutions of hemoglobin S at concentrations between 0.05 and 0.1 M with increasing effectiveness that is directly proportional to the length of the alkyl chain (butyl greater than propyl greater than ethyl greater than methyl). 6The inhibitory effect is independent of pH between 6.5 and 7.5 and is a process driven by entropy. The alkylureas at concentrations of 0.1 M have minimal effects on several erythrocyte functions. Oxygen equilibria, osmotic fragility, reduced glutathione content, and glutathione reductase activity are totally unaffected, while pyruvic kinase activity is decreased only by butylurea by about 20%, and glucose-6-phosphate dehydrogenase activity is decreased progressively to a maximum of 30% in direct proportion to the length of the alkyl chain. Alkylureas not only inhibit sickling but are also capable of desickling erythrocytes that have been maintained in the deoxygenated state. They have little effect on several erythrocyte functions at antisickling concentrations, but their toxicity must be evaluated before they can be examined as potential therapeutic agents for the treatment or prevention of acute episodes in sickle cell anemia.     

T-cell receptor gene rearrangement in T-cell large granular leukocyte leukemia: preferential V alpha but diverse J alpha usage in one of five patients

T-gamma lymphoproliferative disease (T-gamma LPD) is a chronic disorder of mature T cells that is associated with neutropenia and autoimmune phenomena. Although the progression of the lymphoproliferation is indolent, it is often associated with a monoclonal proliferation of T- cell-type large granular lymphocytes (LGL) that manifest multiple in vitro suppressor and cytotoxic activities. We considered the possibility that the granulocytopenia or anemia might represent an autoimmune disorder mediated by the monoclonal LGL via T-cell receptor (TCR) recognition of an antigen involved in hematopoiesis. Therefore, in an effort to characterize the usage of the TCR alpha- and beta-chain genes in patients with T-gamma LPD, we cloned and sequenced TCR alpha- and beta-chain mRNAs derived from the T-cell type LGL of five patients. The five patients studied did not use a common V alpha nor a common J alpha segment. However, an unusual finding was observed in one of the patients where the occurrence of a single variable-diversity-junctional (VDJ) rearrangement of the beta chain confirmed the monoclonal origin of the LGL proliferation. In accord with this evidence for monoclonality, many of the cells studied used a common V alpha (V alpha 19.1). In contrast to this common V alpha usage, there was a marked diversity of the J alpha segments and N-region addition that were associated with the V alpha 19.1 segment. This pattern of common V alpha usage associated with different N and J alpha segments suggests an immune-mediated selection process affecting the TCR alpha chain occurring after the transformation event that established the clone. We suggest that the T-cell-type LGL malignant clone might have developed autoreactivity conferred by the selected TCR alpha chain and that this autoreactivity might be implicated in this patient's anemia.     

CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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Lactobacillus rhamnosus CNCM I-3690 and the commensal bacterium Faecalibacterium prausnitzii A2-165 exhibit similar protective effects to induced barrier hyper-permeability in mice

Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-α confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I-3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities.     

In systemic sclerosis macrovascular damage of hands digital arteries correlates with microvascular damage

Objective

To assess morphology and blood flow of the proper palmar digital arteries (PPDA) by Color Doppler Ultrasonography (CDUS) and its relationship with nailfold videocapillaroscopy (NVC), skin blood perfusion and digital arteries pulsatility of hands in SSc patients and healthy controls.

Methods

CDUS, NVC, Laser Doppler Perfusion Imaging (LDPI) and photoplethysmography (PPG) were performed in 36 systemic sclerosis (SSc) patients and 20 healthy controls.

Results

CDUS was pathologic in 69% of patients with SSc and in none of healthy controls (p < 0.0001). SSc patients with low vascular damage (early capillaroscopic pattern) have a normal morphology of PPDA, but the blood flow, evaluated by peak systolic velocity (PSV) and end diastolic velocity (EDV), is reduced and vascular resistance, measured by resistive index (RI) and pulsatility index (PI), increased. At this stage the LDPI mean perfusion and digital artery pulsatility, evaluated by PPG, were reduced. The US changes appear with microvasculare damage progression (active and late capillaroscopic patterns), while the PPDA blood flow progressively decreases (PSV and EDV decreased, RI and PI increased). The macrovascular damage correlates with disease duration. Anti-topoisomerase I represents an independent predictive factor for macrovascular damage. We not observed any association between digital ulcer history, pulmonary fibrosis and US findings.

Conclusion

PPDA blood flow dysfunction is already present in early disease. Structural macrovascular damage progresses with worsening of SSc microangiopathy.