Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

Insulin plays a central role in regulating energy metabolism, including hepatic transport of very low-density lipoprotein (VLDL)-associated triglyceride. Hepatic hypersecretion of VLDL and consequent hypertriglyceridemia leads to lower circulating high-density lipoprotein levels and generation of small dense low-density lipoproteins characteristic of the dyslipidemia commonly observed in metabolic syndrome and type 2 diabetes mellitus. Physiological fluctuations of insulin modulate VLDL secretion, and insulin inhibition of VLDL secretion upon feeding may be the first pathway to become resistant in obesity that leads to VLDL hypersecretion. This review summarizes the role of insulin-related signaling pathways that determine hepatic VLDL production. Disruption in signaling pathways that reduce generation of the second messenger phosphatidylinositide (3,4,5) triphosphate downstream of activated phosphatidylinositide 3-kinase underlies the development of VLDL hypersecretion. As insulin resistance progresses, a number of pathways are altered that further augment VLDL hypersecretion, including hepatic inflammatory pathways. Insulin plays a complex role in regulating glucose metabolism, and it is not surprising that the role of insulin in VLDL and lipid metabolism will prove equally complex.     

Increased metastasis and mortality from cutaneous squamous cell carcinoma in patients with chronic lymphocytic leukemia

In patients with chronic lymphocytic leukemia, squamous cell carcinoma behaves aggressively. Our purpose was to compare squamous cell carcinoma metastasis and mortality between patients with chronic lymphocytic leukemia and control subjects. Medical records were assessed retrospectively for 28 patients with chronic lymphocytic leukemia who underwent surgical excision of cutaneous squamous cell carcinoma and for 56 matched control subjects. The rate of metastasis and mortality from cutaneous squamous cell carcinoma were determined on a per-patient basis. Three of 28 patients with chronic lymphocytic leukemia had metastasis and died of metastatic disease. No metastases or deaths occurred among the 56 control subjects. Compared with control subjects, chronic lymphocytic leukemia patients with cutaneous squamous cell carcinoma were more likely to have metastasis (P = .0031) and die of metastasis (P = .0033). No significant association was detected between metastasis and history of chemotherapy administration for chronic lymphocytic leukemia. Among patients with chronic lymphocytic leukemia, surveillance for skin cancer and a decreased threshold for biopsy of suspect lesions are warranted.     

Effectiveness of serial increases in amino-terminal pro-B-type natriuretic peptide levels to indicate the need for mechanical circulatory support in children with acute decompensated heart failure

We sought to determine prospectively whether serial assessment of the natriuretic peptide prohormone, amino-terminal pro-B-type natriuretic peptide (NT-pro-BNP), correlated with clinical severity and outcomes in children hospitalized for acute decompensated heart failure (ADHF). Patients (>1 month of age) admitted from 2005 to 2007 with ADHF requiring intravenous vasoactive/diuretic therapy for ADHF were eligible. Serum NT-pro-BNP levels were obtained within 24 hours of admission and at prespecified intervals, and clinical caregivers were blinded to these levels. End points included hospital discharge, death or cardiac transplantation, and care escalation including the need for mechanical circulatory support (MCS) was noted. Twenty-four patients were enrolled: 22 survived to hospital discharge and 2 died. Ten required MCS (of which 6 underwent cardiac transplantation). Two patients underwent transplantation without MCS. For the entire cohort, NT-pro-BNP levels peaked at days 2 to 3 after admission, with a subsequent gradual decrease until discharge. However, for those who did require MCS, NT-pro-BNP failed to decrease consistently until after MCS initiation. At discharge, NT-pro-BNP levels were significantly decreased from admission levels but remained well above normal for all patients. Single-point NT-pro-BNP levels on admission did not correlate with independently assessed clinical scores of heart failure severity or predict the need for MCS in this cohort. In conclusion, serial NT-pro-BNP levels demonstrated an incremental trend after 48 hours in patients who went on to require MCS but decreased in all other patients and may therefore assist the decision to initiate or avoid MCS after admission for pediatric ADHF.     

Peer Reviewed: Geographic and Sociodemographic Disparities in Drive Times to Joint Commission–Certified Primary Stroke Centers in North Carolina,South Carolina,and Georgia

Introduction

Timely access to facilities that provide acute stroke care is necessary to reduce disabilities and death from stroke. We examined geographic and sociodemographic disparities in drive times to Joint Commission–certified primary stroke centers (JCPSCs) and other hospitals with stroke care quality improvement initiatives in North Carolina, South Carolina, and Georgia.

Methods

We defined boundaries for 30- and 60-minute drive-time areas to JCPSCs and other hospitals  by  using geographic information systems (GIS) mapping technology and calculated the proportions of the population living in these drive-time areas by sociodemographic characteristics. Age-adjusted county-level stroke death rates were overlaid onto the drive-time areas.

Results

Approximately 55% of the population lived within a 30-minute drive time to a JCPSC; 77% lived within a 60-minute drive time. Disparities in percentage of the population within 30-minute drive times were found by race/ethnicity, education, income, and urban/rural status; the disparity was largest between urban areas (70% lived within 30-minute drive time) and rural areas (26%). The rural coastal plains had the largest concentration of counties with high stroke death rates and the fewest JCPSCs.

Conclusion

Many areas in this tri-state region lack timely access to JCPSCs. Alternative strategies are needed to expand provision of quality acute stroke care in this region. GIS modeling is valuable for examining and strategically planning the distribution of hospitals providing acute stroke care.     

Phenotypic and genomic analysis of serotype 3 Sabin poliovirus vaccine produced in MRC-5 cell substrate

The cell substrate has a pivotal role in live virus vaccines production. It is necessary to evaluate the effects of the cell substrate on the properties of the propagated viruses, especially in the case of viruses which are unstable genetically such as polioviruses, by monitoring the molecular and phenotypical characteristics of harvested viruses. To investigate the presence/absence of mutation(s), the near full-length genomic sequence of different harvests of the type 3 Sabin strain of poliovirus propagated in MRC-5 cells were determined. The sequences were compared with genomic sequences of different virus seeds, vaccines, and OPV-like isolates. Nearly complete genomic sequencing results, however, revealed no detectable mutations throughout the genome RNA-plaque purified (RSO)-derived monopool of type 3 OPVs manufactured in MRC-5. Thirty-six years of experience in OPV production, trend analysis, and vaccine surveillance also suggest that: (i) different monopools of serotype 3 OPV produced in MRC-5 retained their phenotypic characteristics (temperature sensitivity and neuroattenuation), (ii) MRC-5 cells support the production of acceptable virus yields, (iii) OPV replicated in the MRC-5 cell substrate is a highly efficient and safe vaccine. These results confirm previous reports that MRC-5 is a desirable cell substrate for the production of OPV.     

Effect of rosuvastatin on hepatic production of apolipoprotein B-containing lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster, was employed to investigate the efficacy and mechanisms of action of rosuvastatin, a HMG-CoA reductase inhibitor, in ameliorating metabolic dyslipidemia in insulin-resistant states. Fructose feeding for a 2-week period induced insulin resistance and a significant increase in hepatic secretion of VLDL. This was followed by a fructose-enriched diet with or without 10 mg/kg rosuvastatin for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride in both groups (n=6, p<0.001). However, there was a significant decline (30%, n=8, p<0.05) in plasma triglyceride levels following rosuvastatin feeding (10 mg/kg). A significant decrease (n=6, p<0.05) was also observed in VLDL-apoB production in hepatocytes isolated from drug-treated hamsters, together with an increased apoB degradation (n=6, p<0.05). Similar results were obtained in parallel cell culture experiments in which primary hepatocytes were first isolated from chow-fed hamsters, and then treated in vitro with 15 microM rosuvastatin for 18 h. Rosuvastatin at 5 microM caused a substantial reduction in synthesis of unesterified cholesterol and cholesterol ester (98 and 25%, n=9, p<0.01 or p<0.05) and secretion of newly synthesized unesterified cholesterol, cholesterol ester, and triglyceride (95, 42, and 60% reduction, respectively, n=9, p<0.01 or p<0.05). This concentration of rosuvastatin also caused a significant reduction (75% decrease, n=4, p<0.01) in the extracellular secretion of VLDL-apoB100, accompanied by a significant increase in the intracellular degradation of apoB100. There was a 12% reduction (not significant, p>0.05) in hepatic MTP and no changes in ER-60 (a chaperone involved in apoB degradation) protein levels. Taken together, these data suggest that the assembly and secretion of VLDL particles in hamster hepatocytes can be acutely inhibited by rosuvastatin in a process involving enhanced apoB degradation. This appears to lead to a significant amelioration of hepatic VLDL-apoB overproduction observed in the fructose-fed, insulin-resistant hamster model.     

Applications of SMILE-extracted lenticules in ophthalmology

AIM: To review recent innovations, challenges, and applications of small incision lenticule extraction (SMILE) extracted lenticule for treating ocular disorders. METHODS: A literature review was performed in the PubMed database, which was last updated on 30 December 2021. There was no limit regarding language. The authors evaluated the reference lists of the collected papers to find any relevant research. RESULTS: Due to the simplicity and accuracy of modern femtosecond lasers and the extensive development of SMILE surgery, many healthy human corneal stromal lenticules were extracted during surgery, motivating some professionals to investigate the SMILE lenticule reusability in different ocular disorders. In addition, new approaches had been developed to preserve, modify, and bioengineer the corneal stroma, leading to the optimal use of discarded byproducts such as lenticules from SMILE surgery. The lenticules can be effectively re-implanted into the autologous or allogenic corneas of human subjects to treat refractive errors, corneal ectasia, and corneal perforation and serve as a patch graft for glaucoma drainage devices with better cosmetic outcomes. CONCLUSION: SMILE-extracted lenticules could be a viable alternative to human donor corneal tissue.