Long-lasting partnership between insulin resistance and endothelial dysfunction: role of metabolic memory

Background and Purpose

The persistence of deleterious effects of hyperglycaemia even after glucose normalization is referred to as ‘metabolic memory’. However, similar persistent effects of the metabolic consequences of a high fat diet (HFD) have not been described.

Experimental Approach

Rats were given a normal pellet diet (NPD) or a HFD for 3 months. The animals from the HFD group were then returned to the NPD to observe the long-term effects of insulin resistance. Endothelial dysfunction was assessed by carbachol-mediated vasorelaxation and eNOS phosphorylation.

Key Results

As expected, HFD consumption resulted in insulin resistance and endothelial dysfunction. Phosphorylation of eNOS at S1177 was decreased in HFD rats, compared with that in the NPD group. Rats on 3 months of HFD showed glucose intolerance and impaired insulin sensitivity and were then switched back to NPD (REV group). Levels of cholesterol and triglyceride, and adiposity returned to normal in REV rats. However, endothelium-dependent vascular responses to carbachol which were impaired in HFD rats, continued to be impaired in REV rats. Similarly, decreased eNOS phosphorylation after HFD was not improved after 1 or 6 months of REV.

Conclusions and Implications

Our data indicate that returning to NPD did not improve the insulin sensitivity or the endothelial dysfunction induced by HFD. Although some biochemical parameters responsible for insulin resistance and endothelial dysfunction were normalized, molecular and vascular abnormalities, involving NO, persisted for several months, highlighting the long-lasting effects of metabolic memory.     

Examining the Use of ICD-9 Diagnosis Codes for Primary Immune Deficiency Diseases in New York State

Purpose

To use International Classification of Disease Codes (ICD-9) codes to investigate primary immune deficiency (PID) in New York State.

Methods

We investigated the diagnosis of Primary Immune Deficiency (PID) in New York State (NYS) using the Statewide Planning and Research Cooperative System (SPARCS) database, a comprehensive data reporting system that collects ICD-9 codes for each patient hospitalized in NYS.

Results

From 2000–2004 there were 13,539,358 hospitalizations for 4,777,295 patients; of these, 2,361 patients (0.05 %) were diagnosed with one or more of the ICD-9 codes for PID. Antibody defects were the most common diagnoses made. The PID population had significantly more Caucasians, and fewer African American or Hispanic subjects compared to the general population. Subjects with PID codes were younger, had longer hospitalizations, were less likely to have Medicare and more likely to have Medicaid or Blue Cross insurance. Most hospitalizations were due to respiratory and infectious diseases. Most patients resided in the most populous counties, Kings, New York and Queens, but the distribution of home zip codes was not proportional to county populations.

Conclusions

These data provide useful information on incidence and complications of selected PID diagnoses in one large state.     

Outcomes of COVID-19 Complications and their Possibilities as Potential Triggers of Stroke

IntroductionThere is limited literature on coronavirus disease 2019 (COVID -19) complications such as thromboembolism, cardiac complications etc. as possible trigger for stroke. Hence, we aim to evaluate the prevalence and outcomes of COVID-19 related cardiovascular complications and secondary infection and their possibility as potential triggers for the stroke.MethodsData from observational studies describing the complications [acute cardiac injury (ACI), cardiac arrhythmias (CA), disseminated intravascular coagulation (DIC), septic shock, secondary infection] and outcomes of COVID‐19 hospitalized patients from December 1, 2019 to June 30, 2020, were extracted following PRISMA guidelines. Adverse outcomes defined as intensive care units, oxygen saturation less than 90%, invasive mechanical ventilation, severe disease, and in‐hospital mortality. The odds ratio and 95% confidence interval were obtained, and forest plots were created using random‐effects models. A short review of these complications as triggers of stroke was conducted.Results16 studies with 3480 confirmed COVID-19 patients, prevalence of ACI [38%vs5.9%], CA [26%vs5.3%], DIC [4%vs0.74%], septic shock [18%vs0.36%], and infection [30%vs12.5%] was higher among patients with poor outcomes. In meta-analysis, ACI [aOR:9.93(95%CI:3.95–25.00], CA [7.52(3.29–17.18)], DIC [7.36(1.24–43.73)], septic shock [30.12(7.56–120.10)], and infection [10.41(4.47–24.27)] had higher odds of adverse outcomes. Patients hospitalized with acute ischemic stroke and intracerebral hemorrhage, had complications like pulmonary embolism, venous thromboembolism, DIC, etc. and had poor outcomesConclusionThe complications like acute cardiac injury, cardiac arrhythmias, DIC, septic shock, and secondary infection had poor outcomes. Patients with stroke were having history of these complications. Long term monitoring is required in such patients to prevent stroke and mitigate adverse outcomes.     

Novel CD3Z and CD3E Deficiency in Two Unrelated Females

Journal of Clinical Immunology -     

Comparison of 68Ga-DOTANOC PET/CT with cardiac MRI in patients with clinical suspicion of cardiac sarcoidosis

Annals of Nuclear Medicine - 68Ga-DOTA-NaI-octreotide (DOTANOC) is a promising new alternative to 18F-fluorodeoxyglucose (FDG) for imaging inflammation in cardiac sarcoidosis. The aim of the study...     

mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity

The epithelial Na⁺ channel (ENaC) is essential for Na⁺ homeostasis, and dysregulation of this channel underlies many forms of hypertension. Recent studies suggest that mTOR regulates phosphorylation and activation of serum/glucocorticoid regulated kinase 1 (SGK1), which is known to inhibit ENaC internalization and degradation; however, it is not clear whether mTOR contributes to the regulation of renal tubule ion transport. Here, we evaluated the effect of selective mTOR inhibitors on kidney tubule Na⁺ and K⁺ transport in WT and Sgk1^–/– mice, as well as in isolated collecting tubules. We found that 2 structurally distinct competitive inhibitors (PP242 and AZD8055), both of which prevent all mTOR-dependent phosphorylation, including that of SGK1, caused substantial natriuresis, but not kaliuresis, in WT mice, which indicates that mTOR preferentially influences ENaC function. PP242 also substantially inhibited Na⁺ currents in isolated perfused cortical collecting tubules. Accordingly, patch clamp studies on cortical tubule apical membranes revealed that mTOR inhibition markedly reduces ENaC activity, but does not alter activity of K⁺ inwardly rectifying channels (ROMK channels). Together, these results demonstrate that mTOR regulates kidney tubule ion handling and suggest that mTOR regulates Na⁺ homeostasis through SGK1-dependent modulation of ENaC activity.     

Persistent BK Viremia Does Not Increase Intermediate-Term Graft Loss but Is Associated with De Novo Donor-Specific Antibodies

There are limited data regarding intermediate-term outcomes in patients with persistent BK viremia. Other viral infections have been implicated in the development of allosensitization through heterologous immunity, but the relationship between BK viremia and donor-specific antibodies (DSAs) is unexplored. In 2008, we initiated routine post-transplant BK viremia and DSA screening at our center; 785 kidney or kidney–pancreas transplant recipients were included in our study. Of these recipients, 132 (17%) recipients developed BK viremia during the study period. The median duration of BK viremia was 140 days (interquartile range=40–393 days), and persistent BK viremia was defined as lasting ≥140 days. Kaplan–Meier curves were generated to assess differences in patient and allograft survival on the basis of BK viremia status; survival was modeled using Cox proportional hazard regression. After a median follow-up of 3 years, there was no significant difference in terms of patient (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.28 to 2.49) or allograft survival (HR, 0.80; 95% CI, 0.37 to 1.73) between patients with and without BK viremia, which was confirmed in a time-varying analysis. In our logistic regression model, persistent BK viremia was strongly associated with the development of class II (HR, 2.55; 95% CI, 1.30 to 4.98) but not class I (HR, 1.13; 95% CI, 0.46 to 2.77) DSAs. These data suggest that persistent BK viremia does not negatively affect intermediate-term patient or allograft survival but is associated with increased risk for de novo DSA, although the exact mechanism is unclear.     

Recurrent myocardial infarction secondary to Prinzmetal’s variant angina

Prinzmetal’s variant angina describes chest pain secondary to reversible coronary artery vasospasm in the context of both diseased and non-diseased coronary arteries. Symptoms typically occur when the patient is at rest and are associated with transient ST-segment elevation. Acute episodes respond to glyceryl trinitrate, but myocardial infarction and other potentially fatal complications can occur, and long-term management can be challenging. Although it is not well understood, the underlying mechanism appears to involve a combination of endothelial damage and vasoactive mediators. In this case, a 35-year-old woman with myocardial infarction secondary to coronary artery vasospasm experienced recurrent chest pain. Coronary angiography revealed severe focal stenosis in the mid left anterior descending artery, which completely resolved after administration of intracoronary glyceryl trinitrate. The patient was discharged on nitrates and calcium channel blockers. The patient re-presented with another myocardial infarction, requiring up-titration of medical therapy.     

Unilateral pupillary mydriasis from nebulized ipratropium bromide: A false sign of brain herniation in the intensive care unit

Although there are many causes of anisocoria in the intensive care setting, the development of unilateral mydriasis in patients with intracranial hemorrhage or tumor is a neurological emergency, as it may herald the onset of uncal herniation. We describe two patients with a hemiparesis from neurosurgical disorder who subsequently developed a fixed and dilated pupil. The pupillary abnormality was caused by nebulized ipratropium bromide in both cases, and resolved when the medication was discontinued. Nebulized ipratropium may leak from the mask into ipsilateral eye and cause mydriasis in patients with facial weakness. This benign cause of anisocoria in the intensive care setting is distinguished from uncal herniation by the laterality of neurologic findings, and lack of mental status change, ptosis, and extraocular movement impairment.