Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy

Subclinical hypothyroidism (sHT) is associated with enhanced cardiovascular risk. To test the hypothesis that patients with sHT are characterized by endothelial dysfunction and impaired nitric oxide (NO) availability, in 14 patients [serum cholesterol, 218 +/- 41 mg/dl (5.6 +/- 0.9 mM)] and 28 euthyroid subjects, subdivided into groups A and B [serum cholesterol, 170 +/- 19 mg/dl (4.4 +/- 0.5 mM) and 217 +/- 21 mg/dl (5.6 +/- 0.5 mM), respectively], we studied the forearm blood flow (strain-gauge plethysmography) response to intrabrachial acetylcholine, an endothelium-dependent vasodilator, at baseline and during infusion of N(G)-monomethyl-L-arginine (L-NMMA), a NO synthase inhibitor. Response to sodium nitroprusside and minimal forearm vascular resistances were also evaluated. In sHT patients, vasodilation to acetylcholine was reduced, compared with group B (+358 +/- 29% vs. +503 +/- 19%, P = 0.0003) and group A (663 +/- 65%, P = 0.02 vs. group B and P = 0.0002 vs. sHT). L-NMMA blunted the vasodilation to acetylcholine in groups A and B (49.1 +/- 6.3% and 42.7 +/- 5.5% maximal forearm blood flow reduction, respectively, P < 0.0001 vs. acetylcholine), whereas it was ineffective in sHT patients (12.8 +/- 2.5%). Response to sodium nitroprusside and minimal vascular resistances were similar. In sHT (n = 9) patients, 6 months of euthyroidism by levothyroxine replacement increased acetylcholine-vasodilation and restored L-NMMA inhibition. Patients with sHT are characterized by endothelial dysfunction resulting from a reduction in NO availability, an alteration partially independent of dyslipidemia and reversed by levothyroxine supplementation.     

Plasma levels of cell adhesion molecules during hyperinsulinemia and modulation of vasoactive mediators

Endothelial expression of cell adhesion molecules (CAMs) plays an important role in atherosclerosis. Atherosclerosis is increased in hyperinsulinemic states, but whether insulin per se is proatherogenic remains unclear. To investigate the effects of hyperinsulinemia on CAM expression, plasma levels of ICAM-1, VCAM-1 and E-selectin were measured before and after forearm infusion of insulin in healthy subjects. Insulin administration for 2h resulted in significant hyperinsulinemia, whereas no significant change was observed in soluble CAMs (all p > 0.05). Because insulin stimulates endothelial release of both endothelin-1 (ET-1) and nitric oxide (NO), which may modulate the expression of CAMs, we also investigated the response of CAMs to ET-1 receptor blockade, alone and in combination with NO synthesis inhibition. ET-1 receptor blockade during hyperinsulinemia resulted in a vasodilator response, but did not affect soluble CAMs (all p > 0.05). Superimposition of NO inhibition by L-NMMA reversed the vasodilator effect of ET-1 blockade, without affecting soluble CAMs (all p > 0.05). In conclusion, acute hyperinsulinemia, alone or during ET-1 and NO pathway blockade, does not affect soluble CAMs. These results do not support a direct effect of insulin on endothelial cells to affect leukocyte adhesiveness to the vascular wall.     

Chronic endogenous fungal endophthalmitis: diagnostic and treatment challenges: A case report

Rationale:Endogenous fungal endophthalmitis (EFE) is a sight-threatening complication of systemic fungemia. As the prevalence rises, treatment remains a challenge especially when there is a failure in first-line treatment or drug-resistant fungus. This case report studies a case of chronic EFE, focusing on the diagnostic procedures, treatment options, monitoring parameters and the treatment outcomePatient concerns:A 64-year-old man with underlying well controlled diabetes mellitus was treated with 2 weeks’ course of intravenous antifungal fluconazole for pyelonephritis as his blood culture grew Candida albicans. Concurrently, he complained of 3 months of bilateral painless progressive blurring of vision. At presentation, his visual acuity (VA) was light perception both eyes. Ocular examination revealed non granulomatous inflammation with dense vitritis of both eyes.Diagnosis:He was diagnosed with EFE but the condition responded poorly with the medications.Interventions:He was treated with intravitreal (IVT) amphotericin B and fluconazole was continued. Vitrectomy was performed and intraoperative findings included bilateral fungal balls in the vitreous and retina with foveal traction in the left eye. Postoperatively, vision acuity was 6/24, N8 right eye and 2/60, N unable for left eye with extensive left macular scar and hole. Vitreous cultures were negative. He received multiple IVT amphotericin B and was started on topical steroid eye drops for persistent panuveitis with systemic fluconazole. Ocular improvement was seen after switching to IVT and topical voriconazole. Despite this, his ocular condition deteriorated and he developed neovascular glaucoma requiring 3 topical antiglaucoma agents. Panretinal photocoagulation was subsequently performed.Outcomes:At 3 months’ follow-up, his vision acuity remained at 6/24 for right eye and 2/60 for the left eye. There was no recurrence of inflammation or infection in both eyes.Lessons:Voriconazole could serve as a promising broad spectrum tri-azole agent in cases of failure in first-line treatment or drug-resistant fungus.     

Shortened Telomere Length in Sputum Cells of Bronchiectasis Patients is Associated with Dysfunctional Inflammatory Pathways

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta?=????1.167, P_Adj?=?2.75?×?10^?4). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients.

     

Engagement of the inhibitory receptor CD158a interrupts TCR signaling,preventing dynamic membrane reorganization in CTL/tumor cell interaction

Renal cell carcinoma (RCC) infiltrating lymphocytes (TILs) express killer cell immunoglobulinlike receptors (KIRs) that inhibit the antitumor CD8(+) T-cell lysis. In the present study, to better examine the functional consequences of KIR engagement on cytotoxic T lymphocyte (CTL)/tumor interaction, we have investigated the influence of KIR CD158a on early steps of T-cell activation. We show that coengagement of T-cell receptor (TCR) and CD158a by tumor cells inhibited tyrosine phosphorylation of early signaling proteins ZAP-70 and LAT, lipid raft coalescence, and TCR/CD3 accumulation at the CTL/tumor cell interface. In addition, the guanine exchange factor Vav was not phosphorylated, and no actin cytoskeleton rearrangement was observed. Our data indicate a role of KIR CD158a in the dynamic events induced by TCR triggering, preventing CTL membrane reorganization, and subsequent completion of CTL activation program. Accordingly, the expression of CD158 by TILs may favor tumor cell escape to the immune response.     

Carcinoma of colon presenting as fever of unknown origin

Fever of unknown origin (FUO) is defined as fever of more than 38.3 degrees C, the cause of which remains elusive after 1 week of intensive investigation. Most cases of FUO are restricted to infections, malignancies, and inflammatory diseases. FUO was previously reported as the presenting symptom of a few solid tumors such as lymphoma, renal cell carcinoma, and hepatocellular carcinoma. Colon carcinoma manifesting as FUO has been rarely reported. We describe three female patients who presented with classical FUO and microcytic anemia. As a control, we retrospectively evaluated 28 matched patients with carcinoma of colon and no fever. The evaluation included review of patient files, clinical and laboratory data, and pathologic specimens. In the three patients (mean age, 58 years) who presented with FUO and had left-sided colon carcinoma and microcytic anemia, pathologic evaluation of the tumor tissues demonstrated a severe organized inflammatory process forming abscesses in the pericolic fat. The 28 control matched patients showed no such histopathologic changes. In patients presenting with FUO, especially those who present with microcytic anemia, even with no bowel disturbances or elevated carcinoembryonic antigen levels, diagnostic workup should include a search for occult colorectal carcinoma. In our three cases, it appears that microabscesses in the pericolic fat are the cause of fever.