Novel markers of cell kinetics to evaluate progression from cirrhosis to hepatocellular carcinoma.

BACKGROUND: We investigated cell cycle kinetics of nodular lesions in cirrhosis to differentiate hepatocellular carcinoma (HCC) from its precursor lesions. METHODS: Twelve small HCC, 10 regenerative (RN), six large regenerative (LRN), and five dysplastic nodules (DN), identified in explant cirrhotic livers of five consecutive patients transplanted at Royal Free Hospital in 2002. Immunoperoxidase for MCM2, geminin and Ki67 was performed and the percentage of positive cells counted. RESULTS: The proportion of cells expressing MCM2 was more than those expressing Ki67, which in turn was more than those expressing geminin (overall median=16%, 2% and 0.5%, respectively, P<0.001). There was a statistically significant trend of increasing Ki67 expression (P=0.006), from RN to HCC; this trend was not statistically significant for geminin (P=0.18) or MCM2 (P=0.51). The median percentage of cells expressing Ki67 was 1% in RN, 0.5% in LRN, 2.2% in DN and 5.4% in HCC. The combination of these markers identified four different cell kinetics patterns: 'resting' (G0 cells: MCM2 -ve, Ki67 -ve, geminin -ve); 'licensed' (MCM2 +ve, Ki67 -ve, geminin -ve); 'slowly growing' (G1 phase arrest, MCM2 +ve, Ki67 +ve, low (0.4%) geminin) and expanding (MCM2 +ve, Ki67 +ve, geminin +ve) nodules. CONCLUSIONS: The combination of MCM2, geminin and Ki67 could represent a valuable tool in the understanding of HCC progression in cirrhosis.     

Rifaximin,a pregnane X receptor (PXR) activator regulates apoptosis in a murine model of breast cancer

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized and divided among four groups of six animals each. Group I (control 0.9% normal saline, 3 ml kg⁻¹, p.o.); Group II (toxic control, MNU 47 mg kg⁻¹, i.v.); Group III (RFX, 25 mg kg⁻¹, p.o.); Group IV (RFX, 50 mg kg⁻¹, p.o.). Toxicity was induced by single i.v. injection of MNU. MNU treatment was evident with increased alveolar bud count, differentiation score, up-regulated inflammatory enzyme markers (COX, LOX, NO and H₂S) and oxidative stress markers (TBAR''s, protein carbonyl, SOD, catalase and Ach). The mammary gland surface architecture was studied using SEM, carmine staining and H&E staining. The treatment with RFX elicited noticeable restoration of the overall histological architecture in the experimental animals similar to the control. In the MNU treated toxic group, the levels of oxidative stress markers significantly increased in comparison to the control, which was subsequently restored after RFX treatment. Furthermore, RFX up regulated the levels of caspase 3 and caspase 8, when compared to the MNU treated animals. MNU associated toxicity was also ascertained, when determined for UCHL-1, COX, NF-κBp65, BAD, and BCL-xl expression, while RFX demonstrated modulation of the same.

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats.     

Changes in Caries Experience,Untreated Caries,Sealant Prevalence,and Preventive Behavior Among Third-Graders in New York State, 2002–2004 and 2009–2012

ObjectiveThis study assessed changes in caries experience, untreated caries, sealant prevalence, and preventive behavior among third-grade children in New York State to monitor progress toward state health objectives.MethodsWe analyzed children''s data from the 2002–2004 (n=10,865) and 2009–2012 (n=6,758) New York State Oral Health Survey. We calculated differences in weighted percentages and 95% confidence intervals for caries experience, untreated caries, sealant prevalence, and preventive behavior. We used logistic regression procedures to assess the independent effects and interaction terms on dental caries experience.ResultsThe percentage of children with dental caries and untreated caries decreased from 54.1% and 33.0% in 2002–2004 to 45.2% and 23.6% in 2009–2012, respectively. While this decrease was not uniform across income subgroups, the prevalence of sealants, a key measure of the use of preventive services, increased significantly from 16.7% to 36.0% among lower-income children.ConclusionsMeasurable improvement in reducing dental caries prevalence among third-grade children has been made in New York State, but this improvement was not uniform across subgroups. Specifically, disease prevalence among lower-income children remained high, underscoring the need to strengthen existing programs and identify additional policy and programmatic interventions.Researchers generally agree that the prevalence and severity of dental caries among U.S. and New York State (NYS) school-age children declined steadily from the 1970s to the 1990s. Although this trend has continued for older children in more recent years, this trend is uncertain among younger children aged 2–8 years.^1–3 Findings from analyses of 1988–1994 and 1999–2004 national surveys show that declines in dental caries observed in earlier decades among younger children may have plateaued or dental caries may even be increasing among subgroups of younger children.⁴ Because of the persistent higher disease rate, especially in low-income groups, prevention of tooth decay among children has become the focus of many prevention efforts.^5,6 Since 2001, the Centers for Disease Control and Prevention (CDC) and the Health Resources and Services Administration have provided grants and technical assistance to NYS to strengthen the infrastructure and capacity to promote fluoridation and improve its quality, as well as to strengthen school-based preventive and early treatment programs.Changes have also been made to increase insurance coverage for dental services and improve annual dental visits.^7,8 Child Health Plus, the state Children''s Health Insurance Program (CHIP), was implemented in 1997 to provide public health insurance for near-poor children from families previously not eligible for Medicaid. According to a U.S. Government Accounting Office report, nationally, Medicaid and CHIP beneficiaries, children in particular, showed increases in the use of dental services (from 28% in 1996 to 37% in 2010), but still visited the dentist less frequently than privately insured children (58% in 2010).⁹ In NYS, the Medicaid program enhanced the fee structure for dental procedures in 2000. In addition, professional organizations, advocacy groups, and foundations have made a concerted effort to promote prevention and access to care. The professional recommendation to initiate first dental visit shifted from age 3 to age 1 around 2003.¹⁰ To assess the collective effect of these and other efforts in NYS, we examined data on caries experience, untreated caries, sealant prevalence, and preventive behavior among third-grade children from the 2002–2004 and 2009–2012 NYS Oral Health Survey.     

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 -