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Lipoprotein lipase (LPL) is a key enzyme involved with hydrolysis and removal of triglycerides from plasma. LPL deficiency is a rare condition with an estimated prevalence of 1 in 106. It is characterized biochemically by elevated triglycerides and lowered HDL in the plasma and clinically by a constellation of signs and symptoms during childhood including failure to thrive, lipemia retinalis, eruptive xanthomas, hepatosplenomegaly, and acute pancreatitis. Nearly 100 mutations in the LPL gene have been associated with LPL deficiency. Here we report 2 unrelated pedigrees with LPL deficiency from 2 novel disease-causing LPL mutations: a Gly159Glu missense mutation in exon 5 and a 4-bp ACGG deletion at the 3' boundary of exon 2. We present molecular findings of these 2 cases and review the biochemical, clinical, and genetic features of LPL deficiency.

Metabolic syndrome (MetS) is a common complex trait consisting of the clustering of abdominal obesity, hypertension, dyslipidemia, and dysglycemia. MetS is found in about 25% of the population in the United States and is associated with increased risk for type 2 diabetes and cardiovascular disease. Despite research into possible genetic influences for MetS, no consistently reproducible genetic markers have been obtained, partially due to lack of agreement on the definition of the phenotype. Because phenotypic precision is essential for genomic interrogation, the evolving discipline of clinical phenomics, which uses objective and systematic acquisition of phenotypic data (ie, "deep phenotyping"), may help evaluate the genetic influences of MetS. This article reviews evidence that MetS has a genetic component and the potential applicability of clinical phenomics for the genetic evaluation of MetS using the example of hierarchical cluster analysis of phenotypic components of lipodystrophy syndromes, which serve as monogenic models of MetS.

Metabolic syndrome (MetS) is a common phenotype, affecting about 24% of the US population. It is associated with an increased risk for type 2 diabetes and cardiovascular disease. Although there is no universally accepted definition for MetS, affected individuals commonly have a cluster of features, including abdominal obesity, hypertension, dyslipidemia, and dysglycemia. Recently, there has been extensive interest in potential genetic contributions to MetS. At present, no single gene or cluster of genes has been consistently replicated for MetS among different populations, likely due to the complex interplay between gene and environment necessary for expression of this phenotype. We review recent studies regarding the genetic contributions to MetS.

Objective: To determine visceral adiposity (VAT), subcutaneous adiposity (SAT), and regional body adipose differences between HIV-infected and non-HIV-infected subjects in relation to body mass index (BMI) and World Health Organization BMI categories., Design, Setting, and Participants: Analyses were conducted of 306 HIV-infected and 107 community-derived HIV-negative subjects evaluated for metabolic studies between 1999 and 2006. Analyses were stratified by gender. Additional analyses were performed stratifying subjects by metabolic syndrome status., Results: HIV-infected men and women demonstrated decreased total extremity fat by 1.1 kg and 0.85 kg, respectively, relative to non-HIV-infected control subjects. VAT was increased among HIV-infected men and women in the normal (18.5 to 24.9 kg/m2) and overweight (25.0 to 29.9 kg/m2) categories relative to control subjects but not among those in the obese category (> or =30.0 kg/m2). In contrast, abdominal SAT was reduced among HIV-infected men in the normal and overweight categories but was similar among HIV-infected women and control subjects in these categories. Abdominal SAT was increased among HIV-infected women in the obese category relative to control subjects. Similar results were obtained limiting the analysis to HIV-infected (n = 204) and control subjects (n = 89) without the metabolic syndrome., Conclusions: Peripheral lipoatrophy is a consistent finding among HIV-infected men and women with metabolic abnormalities. Relative increases in VAT are most pronounced among male and female HIV-infected subjects in the normal weight and overweight categories. Gender differences in abdominal SAT accumulation are observed, with preservation of SAT among HIV-infected women relative to control subjects.

The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein inhibitor torcetrapib has led to considerable doubt about the value of raising high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These results have underscored the intricacy of HDL metabolism, with functional quality perhaps being a more important consideration than the circulating quantity of HDL. As a result, HDL-based therapeutics that maintain or enhance HDL functionality warrant closer investigation. In this article, we review the complexity of HDL metabolism, discuss clinical-trial data for HDL-raising agents, including possible reasons for the failure of torcetrapib, and consider the potential for future HDL-based therapies.

Background: 5-hydroxyindoleacetic acid (5-HIAA) excretion is commonly measured for biochemical detection of carcinoid tumours. A 77-year-old woman was referred for elevated 24 h urine 5-HIAA excretion (510 micromol/day; normal is less than 45 micromol/day) and serum chromogranin A (CgA) (72.1 U/L; normal is less than 18 U/L), both subsequently normalized after discontinuation of 5-hydroxytryptophan (5-HTP). 5-HTP, a precursor of serotonin, is not commonly listed as a substance that increases 5-HIAA levels in urine. The effect of 5-HTP on CgA has not been previously described., Objectives: To determine whether, and to what extent, oral 5-HTP increases urine 5-HIAA excretion and serum CgA levels in healthy volunteers., Patients and Methods: A randomized, prospective, double-blind, placebo-controlled crossover study, with a four-day washout period, was performed in a general community setting. Eight healthy subjects aged 22 to 58 years were recruited by advertising. Bedtime ingestion of 5-HTP 100 mg/day was compared with placebo ingestion for 10 days. Twenty-four hour urine excretion of 5-HIAA and serum CgA were the main outcome measures., Results: Median (range) urinary 5-HIAA excretion was 204 micromol/day (22 micromol/day to 459 micromol/day) during 5-HTP intake, compared with 18 micromol/day (12 micromol/day to 36 micromol/day) during placebo intake (P=0.017). 5-HTP did not affect clinical symptoms or serum CgA levels., Conclusions: Oral 5-HTP increases urinary 5-HIAA excretion with considerable interindividual variation. In a small number of subjects, oral 5-HTP did not affect serum CgA levels. Therefore, increased 5-HIAA levels with normal CgA levels may suggest 5-HTP ingestion. The use of over-the-counter 5-HTP should be excluded as the cause of increased urinary 5-HIAA levels before initiating diagnostic tests to search for a carcinoid tumour. 5-HTP should be added to popular references as a substance that may cause increased 5-HIAA excretion.

During routine cadaveric dissection, we encountered multiple muscular anomalies in a 58-year-old embalmed male cadaver. All the variations were encountered on the flexor compartment of right upper limb. The anomalies include an axillary arch (Aa) in the axilla, a third head of biceps brachii (Thb) in the arm, a reverse palmaris longus (Rpl) and a Gantzer's muscle (Gm) in the forearm and an unusually large palmaris brevis muscle (Pbm) in the palm. Anatomical description is achieved by measuring the length, width and attachments of the above-mentioned variants. The morphological and clinical significance of the anomalous muscles are discussed.

Background: Alstrom syndrome (AS) is a rare autosomal recessive disease characterized by multiorgan dysfunction. The key features are childhood obesity, blindness due to congenital retinal dystrophy, and sensorineural hearing loss. Associated endocrinologic features include hyperinsulinemia, early-onset type 2 diabetes, and hypertriglyceridemia. Thus, AS shares several features with the common metabolic syndrome, namely obesity, hyperinsulinemia, and hypertriglyceridemia. Mutations in the ALMS1 gene have been found to be causative for AS with a total of 79 disease-causing mutations having been described., Case Presentation: We describe the case of a 27-year old female from an English (Caucasian) kindred. She had been initially referred for hypertriglyceridemia, but demonstrated other features suggestive of AS, including blindness, obesity, type 2 diabetes, renal dysfunction, and hypertension. DNA analysis revealed that she is a compound heterozygote with two novel mutations in the ALMS1 gene - H3882Y and V424I. Examination of her family revealed that her phenotypically unaffected mother and younger sister also had heterozygous mutations in the ALMS1 gene. In addition to presenting these novel molecular findings for AS, we review the clinical and genetic features of AS in the context of our case., Conclusion: Two novel mutations in the ALMS1 gene causative for AS have been reported here, thereby increasing the number of reported mutations to 81 and providing a wider basis for mutational screening among affected individuals.

Objective: To evaluate dietary intake and its relationship to lipid parameters in HIV-infected patients with metabolic abnormalities., Method: We prospectively determined dietary intake (4-day food records or 24-h recall) in 356 HIV-infected patients and 162 community-derived HIV-negative controls evaluated for metabolic studies between 1998-2005. Differences in dietary intake between HIV-infected patients and non-HIV-infected controls, in relation to the established 2005 USDA (United States Department of Agriculture) Recommended Dietary Guidelines, were determined. The relationship between dietary fat intake and serum lipid levels among HIV-infected individuals was also evaluated., Results: Assessment of dietary intake in this group of HIV-infected patients demonstrated increased intake of total dietary fat (P < 0.05), saturated fat (P = 0.006), and cholesterol (P = 0.006) as well as a greater percentage of calories from saturated fat (P = 0.002) and from trans fat (P = 0.02), despite similar caloric intake to the control individuals. A significantly higher percentage of HIV-infected patients were above the 2005 USDA Recommended Dietary Guidelines for saturated fat (> 10%/day) (76.0% HIV vs. 60.9% controls, P = 0.003), and cholesterol (> 300 mg/day) (49.7% HIV vs. 37.9% controls, P = 0.04). Saturated fat intake was strongly associated with triglyceride level [triglyceride level increased 8.7 mg/dl (parameter estimate) per gram of increased saturated fat intake, P = 0.005] whereas total fat was inversely associated with triglyceride level [triglyceride level decreased 3.0 mg/dl (parameter estimate) per gram of increased total fat intake, P = 0.02] among HIV-infected individuals., Conclusions: Increased intake of saturated fat is seen and contributes to hypertriglyceridemia among HIV-infected patients who have developed metabolic abnormalities. Increased saturated fat intake should be targeted for dietary modification in this population.

Background: Given the relative lack of treatment options for mild to moderate scoliosis, when the Cobb angle measurements fall below the 25-30 degrees range, conservative manual therapies for scoliosis treatment have been increasingly investigated in recent years. In this case series, we present 3 specific cases of scoliosis., Case Presentation: Patient presentation, examination, intervention and outcomes are detailed for each case. The types of scoliosis presented here are left thoracic, idiopathic scoliosis after Harrington rod instrumentation, and a left thoracic scoliosis secondary to Scheuermann's Kyphosis. Each case carries its own clinical significance, in relation to clinical presentation. The first patient presented for chiropractic treatment with a 35 degrees thoracic dextroscoliosis 18 years following Harrington Rod instrumentation and fusion. The second patient presented with a 22 degrees thoracic levoscoliosis and concomitant Scheuermann's Disease. Finally, the third case summarizes the treatment of a patient with a primary 37 degrees idiopathic thoracic levoscoliosis. Each patient was treated with a novel active rehabilitation program for varying lengths of time, including spinal manipulation and a patented external head and body weighting system. Following a course of treatment, consisting of clinic and home care treatments, post-treatment radiographs and examinations were conducted. Improvement in symptoms and daily function was obtained in all 3 cases. Concerning Cobb angle measurements, there was an apparent reduction in Cobb angle of 13 degrees , 8 degrees , and 16 degrees over a maximum of 12 weeks of treatment., Conclusion: Although mild to moderate reductions in Cobb angle measurements were achieved in these cases, these improvements may not be related to the symptomatic and functional improvements. The lack of a control also includes the possibility of a placebo effect. However, this study adds to the growing body of literature investigating methods by which mild to moderate cases of scoliosis can be treated conservatively. Further investigation is necessary to determine whether curve reduction and/or manipulation and/or placebo was responsible for the symptomatic and functional improvements noted in these cases.

Sitosterolemia is a rare autosomal recessive disorder of lipoprotein metabolism characterized by xanthomas and increased plasma concentrations of plant sterols, such as sitosterol. Causative mutations occur in either the ABCG5 or ABCG8 gene, each of which encodes a sterol half-transporter expressed in the intestine. We report five Canadian subjects with nonsense mutations in these half-transporters: four related Caucasian subjects were homozygous for the ABCG8 S107X mutation, and one unrelated Japanese-Canadian subject was homozygous for a complex insertion/deletion (I/D) mutation in ABCG5 exon 3. A female subject with each mutation was symptomatic with coronary atherosclerosis: a 5-year-old ABCG8 S107X homozygote and a 75-year-old ABCG5 exon 3 I/D homozygote; these represent the extreme ends of the spectrum of vascular involvement in sitosterolemia. The largest reductions in plasma concentrations of sitosterol and LDL-cholesterol were seen with ezetimibe or bile acid sequestrant treatment, and less dramatic reductions were seen with statin drug treatment. These findings extend the range of clinical phenotypes in sitosterolemia caused by nonsense mutations in either ABCG5 or ABCG8.

Objectives: Amyloidosis results from local or systemic extracellular deposition of insoluble protein fibrils and is associated with certain rare mutations in APOA1 encoding apolipoprotein (apo) A-I., Design and Methods: In a patient with renal-predominant amyloidosis with neuropathy, we found the APOA1 G26R mutation., Conclusions: While the spectrum of APOA1 mutations provides no particular mechanistic insights, molecular diagnosis may still be important due to clinical differences between amyloidosis resulting from mutation in APOA1 vs. other genes.

Adult chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by production of autoreactive antibodies to platelet antigens. It is now becoming clear that autoantibody production, in general, is regulated by T helper (Th) cells. Several recent studies have examined potential defects in T cell function in this disease and have demonstrated that patients with ITP possess abnormal lymphocyte activation and Th1/Th2-mediated cytokine production. Although the underlying cause(s) of aberrant T cell function in this disease are not known, studies from other models of autoimmune disease indicate that defects in T cell transmembrane signalling can be causally linked to abnormal T cell activation and cytokine production. This review will present some of the major T cell signalling pathways and discuss how altered T cell signalling may be linked to autoimmunity with an emphasis on ITP. Recent preliminary findings of a potential defect in the signal transduction apparatus in lymphocytes from three patients with ITP will also be presented.

Forty organic dyspepsia patients and 40 functional dyspepsia patients, endoscopically diagnosed, were recruited from a gastroenterology outpatient unit and were age- and sex-matched with an equal number of patient controls. A diet history of typical eating patterns for a 7-day period was taken and food portions quantified using a photographic atlas. An interviewer-assisted questionnaire was used to identify present eating habits, dietary patterns reported to exacerbate or relieve symptoms and alterations in eating habits as a result of symptoms. Females with organic or functional dyspepsia reported significantly lower energy intakes (P < 0.01) than controls. Females with organic dyspepsia had significantly lower intakes of fat, carbohydrate, fibre and a wide range of micronutrients compared to controls. Females with functional dyspepsia had significantly lower intakes of fat, sugars and vitamin C (P < 0.05) than controls. Organic dyspepsia patients (male and female) had significantly lower intakes of alcohol and vitamin C than controls (P < 0.05). Patients with organic dyspepsia had higher intakes of milk and lower intakes of fresh fruit and/or fruit juice than controls. The main difference in eating pattern noted was that a significantly lower percentage (P < 0.05) of functional dyspepsia patients than controls regularly ate three meals per day. Large numbers of dyspepsia patients in both groups associated certain eating habits and the consumption of specific foods with exacerbation of dyspeptic symptoms and over 80% of both groups reported food avoidance as a result of this.(ABSTRACT TRUNCATED AT 250 WORDS)