A frequent mutation in the lipoprotein lipase gene (D9N) deteriorates the biochemical and clinical phenotype of familial hypercholesterolemia

The D9N substitution is a common mutation in the lipoprotein lipase (LPL) gene. This mutation has been associated with reduced levels of HDL cholesterol and elevated triglycerides (TG) in a wide variety of patients. We investigated the influence of this D9N mutation on lipid and lipoprotein levels and risk for cardiovascular disease (CVD) in patients with familial hypercholesterolemia (FH). A total of 2091 FH heterozygotes, all of Dutch extraction, were screened for the D9N mutation using standard polymerase chain reaction techniques, followed by specific enzyme digestion. A total of 94 FH subjects carried the D9N mutation at a carrier frequency of 4.5%. Carriers of other common LPL mutations, such as the N291S and the S447X were excluded. Clinical data on 80 FH individuals carrying the D9N were available and were compared with a FH control group matched for age, sex, and body mass index (n=203). Analysis revealed significantly higher TG (P=0.01) and lower HDL-cholesterol levels (P=0.002). Dyslipidemia was more pronounced in D9N carriers with higher body mass index. Moreover, FH patients carrying this common LPL mutation were at higher risk for CVD, (odds ratio=2.8; 95% CI, 1.43 to 5.32; P=0.002). The common D9N LPL mutation leads to increased TG and decreased HDL plasma levels in patients with FH. These effects are most apparent in those FH heterozygotes with an increased body mass index. Furthermore, this mutation, present in 4.5% of Dutch FH heterozygotes, leads to increased risk for CVD.     

Apolipoprotein B gene variants are involved in the determination of serum cholesterol levels: a study in normo- and hyperlipidaemic individuals

We have investigated the frequencies of 3 restriction fragment length polymorphisms (RFLPs) of the apolipoprotein B (apo B) gene in normo- and hyperlipidaemic individuals. In individuals with type III hyperlipidaemia, the allele frequency for the RFLP detected with XbaI was significantly different from the allele frequency in normolipidaemic individuals and in those with other types of hyperlipidaemia. No significant difference in allele frequency was found among these groups for the RFLPs detected with MspI or EcoRI. Within a sample of 62 normolipidaemic individuals, homozygotes for the X2 allele (cutting site) of the XbaI RFLP had a significantly higher serum cholesterol level than homozygotes for the XI allele, with individuals of the genotype X1X2 having an intermediate value (X2X2 mean 5.71 mmol/l, X1X1 mean 4.81 mmol/l, X1X2 mean 5.30 mmol/l). There were also significant differences in serum triglyceride levels in individuals with different XbaI genotypes. In these normolipidaemic individuals there was no correlation between the EcoRI and MspI RFLP genotypes and levels of any serum lipid variable. Information from the XbaI and EcoRI RFLPs was used in conjunction to define apo B haplotypes. These haplotypes are a more precise measure of the genotypic variation, and they explain a greater fraction of the serum cholesterol and triglyceride levels than the single-site polymorphisms considered separately. This study suggests that variations in the gene for apo B are associated with the determination of serum cholesterol and triglyceride levels both in patients with type III hyperlipidaemia and in the normal population.     

Activity in orbitofrontal neuronal ensembles reflects inhibitory control

Stopping, or inhibition, is a form of self‐control that is a core element of flexible and adaptive behavior. Its neural origins remain unclear. Some views hold that inhibition decisions reflect the aggregation of widespread and diverse pieces of information, including information arising in ostensible core reward regions (i.e., outside the canonical executive system). We recorded activity of single neurons in the orbitofrontal cortex (OFC) of macaques, a region associated with economic decisions, and whose role in inhibition is debated. Subjects performed a classic inhibition task known as the stop signal task. Ensemble decoding analyses reveal a clear firing rate pattern that distinguishes successful from failed inhibition and that begins after the stop signal and before the stop signal reaction time (SSRT). We also found a different and orthogonal ensemble pattern that distinguishes successful from failed stopping before the beginning of the trial. These signals were distinct from, and orthogonal to, value encoding, which was also observed in these neurons. The timing of the early and late signals was, respectively, consistent with the idea that neuronal activity in OFC encodes inhibition both proactively and reactively.     

The Effect of a Hypertension Self-Management Intervention on Diabetes and Cholesterol Control

Background

Most patient chronic disease self-management interventions target single-disease outcomes. We evaluated the effect of a tailored hypertension self-management intervention on the unintended targets of glycosylated hemoglobin (HbA_1c) and low-density lipoprotein cholesterol (LDL-C).

Methods

We evaluated patients from the Veterans Study to Improve the Control of Hypertension, a 2-year randomized controlled trial. Patients received either a hypertension self-management intervention delivered by a nurse over the telephone or usual care. Although the study focused on hypertension self-management, we compared changes in HbA_1c among a subgroup of 216 patients with diabetes and LDL-C among 528 patients with measurements during the study period. Changes in these laboratory values over time were compared between the 2 treatment groups using linear mixed-effects models.

Results

For the patients with diabetes, the hypertension self-management intervention resulted in a 0.46% reduction in HbA_1c over 2 years compared with usual care (95% confidence interval, 0.04%-0.89%; P = .03). For LDL-C, there was a minimal 0.9 mg/dL between-group difference that was not statistically significant (95% confidence interval, −7.3-5.6 mg/dL; P = .79).

Conclusions

There was a significant effect of the self-management intervention on the unintended target of HbA_1c,but not LDL-C. Chronic disease self-management interventions might have “spill-over” effects on patients' comorbid chronic conditions.     

Virtual Rhesus Labyrinth Model Predicts Responses to Electrical Stimulation Delivered by a Vestibular Prosthesis

Journal of the Association for Research in Otolaryngology - To better understand the spread of prosthetic current in the inner ear and to facilitate design of electrode arrays and stimulation...     

Subtalar dislocation: Evaluation and management in the emergency department

Subtalar dislocations are sufficiently uncommon to be unfamiliar but require appropriate recognition and management to effect a good outcome. These dislocations benefit from urgent reduction that is essential to limiting sustained disability. Most can be reduced by closed manipulation at the time of presentation. Three cases of subtalar dislocations are presented followed by a discussion of the subject.     

小儿淋巴管瘤的MRI诊断

目的分析小儿淋巴管瘤的磁共振表现及其病理基础。方法对６例经手术病理证实的、年龄７天至７岁的小儿淋巴管瘤患者的磁共振表现进行回顾性分析。结果淋巴管瘤磁共振表现为Ｔ１ＷＩ上呈与肌肉相似或稍高的信号，Ｔ２ＷＩ上高于脂肪信号。５例瘤内可见低信号分隔，１例瘤内见血管流空影，３例见明显包膜，３例边界不清。２例病理诊断为海绵状淋巴管瘤，４例诊断为囊状淋巴管瘤。结论磁共振成像可较好地显示肿瘤的大小、形态及范围，从而指导手术治疗。     

Urinary Nuclear Matrix Protein as a Marker for Transitional Cell Carcinoma of the Urinary Tract

Purpose

The purpose of this trial was to evaluate an immunoassay for urinary nuclear matrix protein, NMP22,^* as an indicator for transitional cell carcinoma of the urinary tract.

Materials and Methods

Three groups of subjects participated in this trial of NMP22: 1--175 with transitional cell carcinoma, 2--117 with benign urinary tract conditions and 3--375 healthy volunteers. Each subject provided a single (3 voids) urine sample for analysis at the time of study entry. Each sample was assayed for the level of NMP22.

Results

In normal healthy volunteers and in subjects with benign conditions median NMP22 levels were 2.9 and 3.3 units per ml., respectively. Median urinary NMP22 levels in patients with transitional cell carcinoma were significantly greater than in comparison subjects. Patients with active transitional cell carcinoma had significantly greater median urinary NMP22 levels than those with no evidence of disease (6.04 versus 4.11 units per ml., p = 0.027, 1-tailed Mann-Whitney U test). We noted no effect of tumor grade, extent of disease or exposure to intravesical therapy on urinary NMP22 levels.

Conclusions

NMP22 is a promising urinary tumor marker for monitoring transitional cell carcinoma. Nuclear matrix proteins are a new class of tumor markers that represent the basis for the development of assays with increased efficacy for the detection and treatment of cancer.     

Regulating a novel drug: An evaluation of changes in use of Salvia divinorum in the first year of Florida's ban

BackgroundA plant with dissociative and psychoactive properties began to attract the attention of the media and United States policymakers following a well-publicized suicide in 2006 and reports that the plant served as a ‘legal high’ and substitute for cannabis. As a result, Salvia divinorum and its active ingredient, salvinorin A, were classified as Schedule I substances by the Florida Legislature on July 1, 2008. As of yet, no research has explored the efficacy of this policy or similar policies in other jurisdictions.MethodsThree self-report studies collected from young adults both prior to and following the policy's implementation are employed to investigate the potential relationship between the policy and usage rates. In addition, law enforcement personnel from the state's most populated areas were interviewed to determine the extent to which they were encountering salvia in their work.ResultsIt was indicated that less than two-thirds of those surveyed were aware of the drug's legal status. Lifetime prevalence of salvia use was largely unchanged. However, the rates of self-reported past year and past month use in Florida were significantly lower following the scheduling. Though use of Salvia divinorum appears to have decreased, perceptions of peer use increased markedly. Law enforcement officers and laboratories reported rarely, if ever, dealing with cases of salvia possession.ConclusionsData suggests the classification of Salvia divinorum as a Schedule I drug was followed by a substantial reduction in recreational use. We caution that other factors may have influenced use, that the efficacy of scheduling novel substances is likely to vary by drug type, that such a reduction in reported use may only exist transiently until a sophisticated illicit market develops to replace the legitimate one, and that a state's success in regulating salvia may be related to their regulation of and enforcement of other drug prohibitions.