␤-Cell transcription factor genes are important in the pathophysiology of the ␤-cell, with mutations in hepatocyte nuclear factor (HNF)-1␣, HNF-4␣, insulin promoter factor (IPF)-1, HNF-1␤, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturityonset diabetes of the young (MODY) criteria was 63% HNF-1␣, 2% HNF-4␣, 0% IPF-1, 1% HNF-1␤, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients T ranscription factor genes play a crucial role in the normal development and function of the ␤-cell (1). This is highlighted by the identification of mutations in ␤-cell transcription factors as a cause of early-onset type 2 diabetes-most notably the distinct subtype maturity-onset diabetes of the young (MODY). MODY is characterized by an autosomal dominant mode of inheritance, ␤-cell dysfunction, and a young age of diagnosis (usually before 25 years) (2). Mutations in the transcription factors hepatocyte nuclear factor (HNF)-1␣ (3), HNF-4␣ (4), insulin promoter factor (IPF)-1 (5), HNF-1␤ (6), and NeuroD1 (7) all cause early-onset diabetes. These genes form crucial links in the cascade of transcription factors that control the appropriate expression of ␤-cell genes, such as insulin and GLUT2 (1,8,9).Mutations in different transcription factor genes appear to result in different clinical presentations. HNF-1␣ mutations are highly penetrant, with 63% of mutation carriers having diabetes by the age of 25 years, 78.6% by 35 years, and 95.5% by 55 years (10). Mutations in HNF-1␣ result in progressive ␤-cell dysfunction with increasing treatment requirements and greater risk of complications with age (11,12). Mutations in HNF-4␣ result in a similar progressive deterioration of ␤-cell function but appear to be associated with a later age of diagnosis (13-16). The predominant feature of patients with HNF-1␤ mutations appears to be renal dysfunction, which is often diagnosed before diabetes (6,(17)(18)(19). Mutations in IPF-1 (PDX-1) are not a common cause of MODY (20)(21)(22). Only one MODY family published to date has an IPF-1 mutation that clearly cosegregates with diabetes (5), although the average age at diagnosis in this family (35 years) was somewhat older than that in families with HNF mutations. The mutation in this family (P63fsdelC) had a severe dominant-negative effect in vitro (23). Two recent studies suggest that missense mutations in the coding region of the IPF-1 gene are more likely to represent predisposing alleles in more common forms of type 2 diabetes (24,25) rather than highly penetrant disease-causing alleles. Mutations in the NeuroD1/BETA2 gene have recently been reported as being associated with type 2 diabetes in two families, one of which meets MODY criteria (7). Studies of the HNF-3␤ (26-28) and NkX2.2 (29) ...

Abstract. Tooke JE, Hannemann MM (School of Postgraduate Medicine and Vascular Health Sciences,

It is hypothesised that vascular dysfunction, which characterises type 2 diabetes, may predate development of hyperglycaemia. 17 women with previous gestational diabetes mellitus, and thus at risk of developing type 2 diabetes, were matched with normal controls for body mass index, menstrual phase, smoking, age, blood pressure, and lipid profiles. All had normal glucose tolerance. Tests of microvascular and macrovascular function, including endothelium-dependent and -independent vasodilatation, were performed. Laser Doppler fluximetry of maximum skin microvascular hyperaemia in response to local heating of the dorsum of the foot to 42°C for 30 min was impaired in subjects compared to controls [subjects = 1.15 (0.73–1.73) V median (range) versus controls = 1.50 (0.95–2.29) V, p = 0.008]. There were no differences in laser Doppler perfusion imaging of responses to forearm skin iontophoresis of acetylcholine [subjects = 1.59 (0.32–2.55) V median (range) versus controls = 1.79 (0.72–2.06) V; p = 0.81] and sodium nitroprusside [subjects = 1.39 (0.8–3.14) V versus controls = 1.41 (0.34–2.19) V; p = 0.68], ultrasound estimation of brachial artery flow-mediated dilatation [subjects = 1.65 (–0.5–9.07)% versus controls = 2.77 (0.63–6.6)%; p = 0.42] and glyceryl trinitrate-induced dilatation [subjects = 15.20 (6.64–20.91)% versus controls = 15.92 (3.94–22.09)%; p = 0.48]. Microvascular maximum hyperaemia was impaired in the index group, suggesting the presence of a defect in vascular function. This defect was not explained by those aspects of endothelial function measured by the other techniques.

Background and Objectives Understanding the pathophysiology of respiratory failure in coronavirus disease 2019 (COVID-19) is indispensable for development of therapeutic strategies. Since we observed similarities between COVID-19 and interstitial lung disease in connective tissue disease (CTD-ILD), we investigated features of autoimmunity in SARS-CoV-2-associated respiratory failure. Methods We prospectively enrolled 22 patients with RT-PCR-confirmed SARS-CoV-2 infection and 10 patients with non-COVID-19-associated pneumonia. Full laboratory testing was performed including autoantibody (AAB; ANA/ENA) screening using indirect immunofluorescence and immunoblot. Fifteen COVID-19 patients underwent high-resolution computed tomography. Transbronchial biopsies/autopsy tissue samples for histopathology and ultrastructural analyses were obtained from 4/3 cases, respectively. Results Thirteen (59.1%) patients developed acute respiratory distress syndrome (ARDS), and five patients (22.7%) died from the disease. ANA titers ≥1:320 and/or positive ENA immunoblots were detected in 11/13 (84.6%) COVID-19 patients with ARDS, in 1/9 (11.1%) COVID-19 patients without ARDS (p = 0.002) and in 4/10 (40%) patients with non-COVID-19-associated pneumonias (p = 0.039). Detection of AABs was significantly associated with a need for intensive care treatment (83.3 vs. 10%; p = 0.002) and occurrence of severe complications (75 vs. 20%, p = 0.03). Radiological and histopathological findings were highly heterogeneous including patterns reminiscent of exacerbating CTD-ILD, while ultrastructural analyses revealed interstitial thickening, fibroblast activation, and deposition of collagen fibrils. Conclusions We are the first to report overlapping clinical, serological, and imaging features between severe COVID-19 and acute exacerbation of CTD-ILD. Our findings indicate that autoimmune mechanisms determine both clinical course and long-term sequelae after SARS-CoV-2 infection, and the presence of autoantibodies might predict adverse clinical course in COVID-19 patients.

Epithelial ovarian cancer (EOC) frequently metastasises to the omentum, a process that requires pro-angiogenic activation of human omental microvascular endothelial cells (HOMECs) by tumour-secreted factors. We have previously shown that ovarian cancer cells secrete a range of factors that induce pro-angiogenic responses e.g. migration, in HOMECs including the lysosomal protease cathepsin D (CathD). However, the cellular mechanism by which CathD induces these cellular responses is not understood. The aim of this study was to further examine the pro-angiogenic effects of CathD in HOMECs i.e. proliferation and migration, to investigate whether these effects are dependent on CathD catalytic activity and to delineate the intracellular signalling kinases activated by CathD. We report, for the first time, that CathD significantly increases HOMEC proliferation and migration via a non-proteolytic mechanism resulting in activation of ERK1/2 and AKT. These data suggest that EOC cancer secreted CathD acts as an extracellular ligand and may play an important pro-angiogenic, and thus pro-metastatic, role by activating the omental microvasculature during EOC metastasis to the omentum.

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and has a poor prognosis due to relatively unspecific early symptoms, and thus often advanced stage, metastasized cancer at presentation. Metastasis of EOC occurs primarily through the transcoelomic route whereby exfoliated tumor cells disseminate within the abdominal cavity, particularly to the omentum. Primary and metastatic tumor growth requires a pool of proangiogenic factors in the microenvironment which propagate new vasculature in the growing cancer. Recent evidence suggests that proangiogenic factors other than the widely known, potent angiogenic factor vascular endothelial growth factor may mediate growth and metastasis of ovarian cancer. In this review we examine the role of some of these alternative factors, specifically cathepsin D and cathepsin L.

Background: Maximum skin hyperaemia (MH) induced by heating skin to ≧42°C is impaired in individuals at risk of diabetes and cardiovascular disease. Interpretation of these findings is hampered by the lack of clarity of the mechanisms involved in the attainment of MH. Methods: MH was achieved by local heating of skin to 42–43°C for 30 min, and assessed by laser Doppler fluximetry. Using double-blind, randomized, placebo-controlled crossover study designs, the roles of prostaglandins were investigated by inhibiting their production with aspirin and histamine, with the H₁ receptor antagonist cetirizine. The nitric oxide (NO) pathway was blocked by the NO synthase inhibitor, N^G-nitro-L-arginine methyl esther (L-NAME), and enhanced by sildenafil (prevents breakdown of cGMP). Results: MH was not altered by aspirin, cetirizine or sildenafil, but was reduced by L-NAME: median placebo 4.48 V (25th, 75th centiles: 3.71, 4.70) versus L-NAME 3.25 V (3.10, 3.80) (p = 0.008, Wilcoxon signed rank test). Inhibition of NO production (L-NAME) resulted in a more rapid reduction in hyperaemia after heating (p = 0.011), whereas hyperaemia was prolonged in the presence of sildenafil (p = 0.003). The increase in skin blood flow was largely confined to the directly heated area, suggesting that the role of heat-induced activation of the axon reflex was small. Conclusion: NO, but not prostaglandins, histamine or an axon reflex, contributes to the increase in blood flow on heating and NO is also a component of the resolution of MH after heating.

Background: Understanding the pathophysiology of respiratory failure (ARDS) in coronavirus disease 2019 (COVID-19) patients is of utmost importance for the development of therapeutic strategies and identification of risk factors. Since we observed clinical and histopathological similarities between COVID-19 and lung manifestations of connective tissue disease (CTD-ILD) in our clinical practice, aim of the present study is to analyze a possible role of autoimmunity in SARS-CoV-2-associated respiratory failure. Methods: In this prospective, single-center trial, we enrolled 22 consecutive patients with RT-PCR-confirmed SARS-CoV-2 infection hospitalized in March and April, 2020. We performed high-resolution computed tomography (HR-CT) and full laboratory testing including autoantibody (AAB) screening (anti-ANA, SS-B/La, Scl-70, Jo-1, CENP-B, PM-Scl). Transbronchial biopsies as well as post mortem tissue samples were obtained from 3 and 2 cases, respectively, and subsequent histopathologic analysis with special emphasis on characterization of interstitial lung disease was performed. Results: Twelve of 22 patients (54.5%) were male and median age was 69.0 (range: 28-88). 11 (50.0%) patients had to be undergo intensive care unit (ICU) treatment. Intubation with ventilation was required in 10/22 cases (46%). Median follow-up was 26 days. Clinical and serological parameters were comparable to previous reports. Radiological and histopathological findings were highly heterogeneous including patterns reminiscent of CTD-ILD. AAB titers ≥1:100 were detected in 10/11 (91.9%) COVID-19 patients who required ICU treatment, but in 4/11 (36.4%) patients with mild clinical course (p=0.024). Patients with AABs tended to require invasive ventilation and showed significantly more severe complications (64.3% vs. 12.5%, p=0.031). Overall COVID-19-related mortality was 18.2% among hospitalized patients at our institution. Conclusion: Our findings point out serological, radiological and histomorphological similarities between COVID-19-associated ARDS and acute exacerbation of CTD-ILD. While the exact mechanism is still unknown, we postulate that SARS-CoV-2 infection might trigger or simulate a form of organ-specific autoimmunity in predisposed patients. The detection of autoantibodies might identify patients who profit from immunosuppressive therapy to prevent the development of respiratory failure.