Acanthosis Nigricans Associated with Insulin Resistance

The association of acanthosis nigricans, skin tags, diabetes mellitus due to insulin resistance, and obesity in adolescents and young adults represents a well defined syndrome. Hyperandrogenism may also be present. The endocrine origin of this condition is beyond doubt. Insulin and insulin-like growth factor-1, and their receptors on keratinocytes are obviously involved in the complex regulations leading to the peculiar epidermal hyperplasia. This condition is unrelated to other types of acanthosis nigricans, including the congenital and the paraneoplastic types. Control of obesity contributes largely to reverse the whole process, essentially by reducing both insulin resistance and compensatory hyperinsulinemia. Several drugs including metformin, octreotide, retinoids and topical colecalciferol (vitamin D(3)) analogs are also beneficial in clearing acanthosis nigricans.     

Differential psychostimulant-induced activation of neural circuits in dopamine transporter knockout and wild type mice

Dopamine (DA) is a neurotransmitter that has been implicated in a wide variety of psychiatric disorders that include attention deficit-hyperactivity disorder (ADHD), schizophrenia, and drug abuse. Recently, we have been working with a mouse in which the gene for the DA transporter (DAT) has been disrupted. This mouse is hyperactive in the open field, displays an inability to inhibit ongoing behaviors, and is deficient on learning and memory tasks. Psychostimulants such as amphetamine and methylphenidate attenuate the hyperlocomotion of the mutants, but stimulate activity of the wild type (WT) controls. The objective of the present study is to examine the neural basis for the differential responses to psychostimulants in these mice. WT and DAT knockout (KO) animals were given vehicle or methylphenidate, amphetamine, or cocaine and brain sections were immunostained for Fos. In WT mice, methylphenidate induced Fos-like immunoreactivity (Fos-LI) in the mesostriatal and mesolimbocortical DA pathways that included the anterior olfactory nucleus, frontal association cortex, orbitofrontal cortex, cingulate cortex, caudate-putamen, globus pallidus, claustrum, lateral septum, nucleus accumbens, basolateral and central nuclei of the amygdala, bed nucleus of stria terminalis, subthalamic nucleus, substantia nigra, ventral tegmental area, and dorsal raphe. Additional areas of activation included the granular dentate gyrus, Edinger-Westphal nucleus, and periaqueductal gray. While the mutants showed little response in most of these same areas, the anterior olfactory nucleus, caudal caudate-putamen, lateral septum, basolateral and central nuclei of the amygdala, and bed nucleus of stria terminalis were activated. Amphetamine and cocaine produced similar changes to that for methylphenidate, except these psychostimulants also induced Fos-LI in the nucleus accumbens of the KO animals. Since the DAT gene is disrupted in the KO mouse, these findings suggest that dopaminergic mechanisms may mediate the WT responses, whereas non-dopaminergic systems predominate in the mutant. In the mutants, it appears that limbic areas and non-dopaminergic transmitter systems within these brain regions may mediate responses to psychostimulants. Inasmuch as the KO mouse may represent a useful animal model for ADHD and because psychostimulants such as cocaine are reinforcing to these animals, our results may provide some useful insights into the neural mechanisms-other than DA-that may contribute to the symptoms of ADHD and/or drug abuse in human patients.     

Maternal serum unconjugated estriol as a predictor for Smith-Lemli-Opitz syndrome and other fetal conditions

OBJECTIVE: To assess the clinical value of low maternal serum unconjugated estriol (E3) level for diagnosing Smith-Lemli-Opitz syndrome and other fetal clinical conditions in pregnant members of a large health maintenance organization. METHODS: We studied serum unconjugated E3 levels in 120,071 gravidas having California Expanded Alpha-Fetoprotein prenatal screening at 15-20 weeks' gestation during a 5-year period. RESULTS: Of the 120,071 women, 323 (0.27%) had low unconjugated E3 levels (less than or equal to 0.2 ng/mL, or 0.15 multiples of the median). Excluding women who were screened too early or who had indeterminate screening results, 103 (0.08%) women with unexplained low unconjugated E3 level remained; of these 103 women, 33 had negative screening results and 68 had positive screening results, and two were tested too late for interpretation. Intrauterine fetal death occurred in 39 (57%) of the 68 women with low unconjugated E3 and positive screening results and occurred in two (6%) of the 33 women with low unconjugated E3 levels and negative screening results, a significant difference (P <.001). Two cases of Smith-Lemli-Opitz syndrome were identified and the patients did not survive the neonatal period; one was a therapeutic abortion for severe oligohydramnios, and the other died at age 48 hours. Low unconjugated E3 level also predicted presence of steroid sulfatase deficiency, a much more common X-linked skin disorder characterized by ichthyosis. CONCLUSION: Low maternal serum unconjugated E3 diagnosed more cases of steroid sulfatase deficiency and undetected intrauterine fetal death than Smith-Lemli-Opitz syndrome (1:60,000 prevalence), although the clinical importance of having this information prenatally is uncertain.     

Anterior partial fundoplication for gastroesophageal reflux disease

Background This study examined the effect of anterior partial fundoplication on reflux symptoms and dysphagia in gastroesophageal reflux disease.Patients and methods Perioperative results in 249 patients were evaluated retrospectively for 93 conventional and prospectively for 156 laparoscopic procedures. The patients were followed up by standardized questionnaire. Median clinical follow-up period was 9 months (range 6–44) after laparoscopic and 88 months (range 15–194) following partial open fundoplication.Results The median operating time was 58 and 115 min for laparoscopic and open partial fundoplication. Intraoperative complications were rare (1%) for both approaches. After introduction of the laparoscopic procedure the morbidity rate was reduced (mean 3.2% vs. 1.3%) at a shorter postoperative hospital stay (10 vs. 5 days). No reflux symptoms were found in 71.4% patients after conventional and in 69% after laparoscopic partial fundoplication, dysphagia did not develop in 86% and 85%, respectively, and 66% and 82% received no medications. Among the patients with reflux symptoms 6.5% and 0.9% underwent revision surgery. Satisfaction with the surgical outcome was expressed by 78% and 85% of patients, respectively.Conclusions Anterior partial fundoplication achieves effective medium- and long-term control of reflux symptoms. Technically easy to perform and associated with few complications, the procedure is superior to fundoplication with respect to the development of postoperative dysphagia and therefore represents a viable alternative to fundoplication.     

Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis

Context  Cholinesterase inhibitors are the primary treatment for the cognitive symptoms of Alzheimer disease (AD). Cholinergic dysfunction is also associated with neuropsychiatric and functional deficits, but results from randomized controlled trials of cholinesterase inhibitors are conflicting. Objective  To conduct a systematic review and meta-analysis to quantify the efficacy of cholinesterase inhibitors for neuropsychiatric and functional outcomes in patients with mild to moderate AD. Data Sources  We performed a literature search of trials using MEDLINE (January 1966–December 2001), Dissertations Abstracts On-line, PSYCHINFO, BIOSIS, PubMed, and the Cochrane Controlled Trials Register. We retrieved English- and non–English-language articles for review and collected references from bibliographies of reviews, original research articles, and other articles of interest. We searched for both published and unpublished trials, contacting researchers and pharmaceutical companies. Study Selection  We included 29 parallel-group or crossover randomized, double-blind, placebo-controlled trials of outpatients who were diagnosed as having mild to moderate probable AD and were treated for at least 1 month with a cholinesterase inhibitor. Sixteen trials included neuropsychiatric and 18 included functional measures. Data Extraction  Two investigators (N.H.T. and J.H.) independently extracted study methods, sources of bias, and outcomes. Neuropsychiatric outcomes were measured with the Neuropsychiatric Inventory (NPI, 0-120 points) and the Alzheimer Disease Assessment Scale, noncognitive (ADAS-noncog, 0-50 points) and were analyzed with the weighted mean difference method. Functional outcomes were measured with several activities of daily living (ADL) and instrumental activities of daily living (IADL) scales and analyzed with the standardized mean difference method. Data Synthesis  For neuropsychiatric outcomes, 10 trials included the ADAS-noncog and 6 included the NPI. Compared with placebo, patients randomized to cholinesterase inhibitors improved 1.72 points on the NPI (95% confidence interval [CI], 0.87-2.57 points), and 0.03 points on the ADAS-noncog (95% CI, 0.00-0.05 points). For functional outcomes, 14 trials used ADL and 13 trials used IADL scales. Compared with placebo, patients randomized to cholinesterase inhibitors improved 0.1 SDs on ADL scales (95% CI, 0.00-0.19 SDs), and 0.09 SDs on IADL scales (95% CI, 0.01 to 0.17 SDs). There was no difference in efficacy among various cholinesterase inhibitors. Conclusions  These results indicate that cholinesterase inhibitors have a modest beneficial impact on neuropsychiatric and functional outcomes for patients with AD. Future research should focus on how such improvements translate into long-term outcomes such as patient quality of life, institutionalization, and caregiver burden.      

Identification of a new Leu354Pro mutation responsible for factor XIII deficiency

We report a new homozygous CTG-->CCG (Leu-->Pro) mutation at codon 354 in the factor XIIIA gene of a patient suffering from FXIII deficiency. Leu354 lies in a pocket within the core domain of the FXIIIA molecule, with its side chain pointing into the structure of the barrel 1 domain. Replacement of leucine with a proline residue gives rise to steric hindrance between the proline ring and the surrounding residues, and rearrangement of these residues would be necessary for proline to be accommodated at this position. Using PCR-RFLP, we have demonstrated the absence of this mutation from 220 normal alleles. Together, these data suggest that Leu354Pro is likely to be the disease-causing mutation in this factor XIII deficient family.     

Validity of the Fagerstrom test for nicotine dependence and of the Heaviness of Smoking Index among relatively light smokers

Aims. To assess the validity of the Fagerstrom test for nicotine dependence (FTND, six items) and of a short-form of this questionnaire, the Heaviness of Smoking Index (HSI, two items), in a population of relatively light smokers. Design. Comparison of item content with published definitions of addiction. Test-retest reliability and multiple tests of construct validity, based on a secondary analysis of a cohort study conducted between November 1995 and June 1996. Setting. University of Geneva, Switzerland. Participants. Students (82%), academic (12%) and administrative staff (6%): 643 smokers at baseline and 482 smokers at follow-up. Measurements. French-language versions of the FTND and HSI, smoking status, saliva cotinine level, self-efficacy for quitting smoking and other variables related to addiction with cigarettes. Findings. A literature review showed that both composite scales fail to assess several recognised aspects of tobacco dependence. In this population of relatively light smokers (average: 12 cigarettes per day), both tests had important floor effects with, respectively, 55% and 63% of participants with scores equal to 0 or 1 on these scales. In addition, two of the FTND items (Difficult-to-refrain and Hate-most-to-give-up) had poor psychometric properties. Even though FTND and HSI correlated about as expected with criterion variables, the number of cigarettes smoked per day performed better than either composite scale on most validation criteria. Conclusion. In a population of relatively light smokers, FTND and HSI seem to measure little more than the number of cigarettes per day. Designing a new and more broadly applicable test of addiction to cigarettes is a research priority.