Previously unreported abnormalities in Wolfram Syndrome Type 2

International audienceWolfram syndrome (WFS) is a rare autosomal recessive disease with non-autoimmune childhood onset insulin dependent diabetes and optic atrophy. WFS type 2 (WFS2) differs from WFS type 1 (WFS1) with upper intestinal ulcers, bleeding tendency and the lack ofdiabetes insipidus. Li-fespan is short due to related comorbidities. Only a few familieshave been reported with this syndrome with the CISD2 mutation. Here we report two siblings with a clinical diagnosis of WFS2, previously misdiagnosed with type 1 diabetes mellitus and diabetic retinopathy-related blindness. We report possible additional clinical and laboratory findings that have not been pre-viously reported, such as asymptomatic hypoparathyroidism, osteomalacia, growth hormone (GH) deficiency and hepatomegaly. Even though not a requirement for the diagnosis of WFS2 currently, our case series confirm hypogonadotropic hypogonadism to be also a feature of this syndrome, as reported before

Diabetes mellitus and hypertension: a dual threat

Purpose of review: The following is a review of the current concepts on the relationship between hypertension (HTN) and diabetes mellitus with a focus on the epidemiology and cardiovascular prognostic implications of coexistent HTN and diabetes mellitus, shared mechanisms underlying both conditions and pathophysiology of increased risk of cardiovascular disease, treatment of HTN in individuals with diabetes mellitus, and effects of anti-diabetic medications on blood pressure (BP). Recent findings: Diabetes mellitus and HTN often coexist in the same individual. They share numerous risk factors and underlying pathophysiologic mechanisms, most important of which are insulin resistance and inappropriate activation of the rennin-angiotensin-aldosterone system. Recently updated guidelines recommend a BP goal of 140/90 mmHg in most individuals with diabetes mellitus. A new class of anti-diabetic medications, sodium-glucose co-transporter 2 inhibitors, has shown favorable effects on BP. Summary: HTN affects the majority of individuals with diabetes mellitus. Coexistence of diabetes mellitus and HTN, especially if BP is not well controlled, dramatically increases the risk of morbidity and mortality from cardiovascular disease. BP control is an essential part of management of patients with diabetes mellitus, because it is one of the most effective ways to prevent vascular complications and death

Platelet-derived growth factor CC-mediated neuroprotection against HIV Tat involves TRPC-mediated inactivation of GSK 3beta.

Platelet-derived growth factor-CC (PDGF-CC) is the third member of the PDGF family, and has been implicated both in embryogenesis and development of the CNS. The biological function of this isoform however, remains largely unexplored in the context of HIV-associated dementia (HAD). In the present study, we demonstrate that exposure of human neuroblastoma cells SH-SY5Y to HIV transactivator protein Tat resulted in decreased intrinsic expression of PDGF-CC as evidenced by RT-PCR and western blot assays. Reciprocally, pretreatment of SH-SY5Y cells with PDGF-CC abrogated Tat-mediated neurotoxicity by mitigating apoptosis and neurite & MAP-2 loss. Using pharmacological and loss of function approaches we identified the role of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in PDGF-CC-mediated neuroprotection. We report herein a novel role about the involvement of transient receptor potential canonical (TRPC) channel 1 in modulation of calcium transients in PDGF-CC-mediated neuroprotection. Furthermore we also demonstrated PDGF-CC-mediated inactivation of the downstream mediator--glycogen synthase kinase 3β (GSK3β) evidenced by its phosphorylation at Ser-9. This was further validated by gain and loss of function studies using cells transfected with either the wild type or mutant GSK3β constructs. Intriguingly, pretreatment of cells with either the PI3K inhibitor or TRPC blocker resulted in failure of PDGF-CC to inactivate GSK3β, thereby suggesting the intersection of PI3K and TRPC signaling at GSK3β. Taken together our findings lead to the suggestion that PDGF-CC could be developed as a therapeutic target to reverse Tat-mediated neurotoxicity with implications for HAD

New-onset insulin-dependent diabetes due to nivolumab

Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab

PDGF receptor is involved in PDGF-CC neuroprotection.

<p>(<b>A</b>) Expression of PDGF-αR and βR in SH-SY5Y cells by RT-PCR. (<b>B</b>) SH-SY5Y cells were exposed to PDGF-CC (50 ng/ml) for 30 min in presence or absence of tyrosine kinase inhibitor STI-571 (1 µM). Phosphorylation of PDGF-αR & βR was detected by co-immunoprecipitation. (<b>C</b>) Cell viability of SH-SY5Y cells exposed to PDGF-CC and/or Tat in presence or absence of tyrosine STI-571 was assessed by MTT assay. Figure is a representative of three independent experiments. All data in these figures are presented as mean ± SEM of three individual experiments. *p<0.05 vs control, #p<0.05 vs Tat-treated group, %p<0.05 vs PDGF-CC plus Tat-treated group.</p

TRPC 1 channel is critical for PDGF-CC-mediated neuroprotection.

<p>(<b>A</b>) SH-SY5Y cells were labeled with Fluo-4 prior to treatment with PDGF-CC followed by recording of the fluorescence density representing the level of intracellular Ca²⁺. A representative change of fluorescence intensity is shown in the lower panel. The arrow indicates the time of addition of PDGF-CC. Number in upper panel shows the recording time. (<b>B</b>) Change in intracellular Ca²⁺ induced by PDGF-CC (50 ng/ml) in the presence of absence of pharmacological inhibitors (STI-571, 1 µM; EGTA, 2 mM; SKF96365, 20 µM; 2APB, 100 µM; U73122, 1 µM). All the data in these figures are presented as mean ± SEM of three individual experiments. ***p<0.001 vs control; ##p<0.01 vs PDGF-CC-treated group. (<b>C</b>) Cell viability in SH-SY5Y cells pretreated with SKF96365 (20 µM) by MTT assay. All the data in these figures are presented as mean ± SEM of three individual experiments. *p<0.05 vs control, #p<0.05 vs Tat-treated group. (<b>D</b>) SH-SY5Y cells were transfected with 100 nM siRNA targeting TRPC1, 5 or 6. After 24 h cells were lysed, mRNA was isolated and subjected to RT-PCR. Arrow indicates the RT-PCR product bands. (<b>E</b>) SH-SY5Y cells seeded in 96-well plate were transfected with TRPC 1, 5 or 6 siRNAs (100 nM) for 24 h later followed by treatment of cells with PDGF-CC and/or Tat. MTT assay was conducted to detect cell viability. All the data in these figures are presented as mean ± SEM of three individual experiments. *p<0.05 vs control; ##p<0.01 vs Tat-treated group.</p

Down-regulation of PDGF-CC in neurons exposed to Tat.

<p>SH-SY5Y cells or rat primary neurons were exposed to 14 nM Tat for the indicated times, followed by RNA isolation and assessment of PDGF-CC using real-time PCR (<b>A</b>), RT-PCR (<b>B</b>), or western blot (<b>C</b>). In panels B and C, SH-SY5Y cells were treated for 24 h and monitored for PDGF-CC RNA and protein. Figure shown is a representative of three independent experiments. All data in these figures are presented as mean ± SEM of three individual experiments. *p<0.05, **p<0.01, ***p<0.001 vs control.</p

Schematic illustration demonstrating putative signaling pathways involved in PDGF-CC-mediated neuroprotection.

<p>PDGF-CC-mediated engagement of the PDGF receptor stimulates the PLC/PI3R pathway, which in turn, activates TRPC channels resulting in elevation of [Ca²⁺] transient. The elevation of [Ca²⁺] is required for PDGF induced PI3K/Akt pathway leading to inactivation of GSK3β signal. The inactivated GSK3β fails to induce the degradation of β-catenin resulting in accumulation of β-catenin in the cytoplasm, followed by its translocation into nucleus and subsequent induction of expression of genes associated with the cell survival.</p