Why, when and how should hypertriglyceridemia be treated in the high-risk cardiovascular patient?

Recent epidemiology attests that hypertriglyceridemia may be a causal risk factor for cardiovascular disease (CVD). The specific atherogenicity of hypertriglyceridemia relates to the accumulation in plasma of triglyceride-rich lipoprotein remnants. Hypertriglyceridemia also drives a 'global' atherogenic dyslipidemic profile, which is frequent in high-risk cardiovascular patients, such as Type 2 diabetics. Elevated triglyceride in fasting or nonfasting blood samples should be a trigger for assessing atherogenic components of the lipid profile, particularly HDL-cholesterol, non-HDL-cholesterol and apoB. Residual risk of CVD remains high in statin-treated diabetic patients owing to persistent atherogenic dyslipidemia, which is not fully corrected by these agents nor by the addition of ezetimibe. Hypertriglyceridemia may then be targeted with niacin, fibrates or n-3 fatty acids, after correcting aggravating factors, especially obesity and hyperglycemia. Fibrates consistently decrease coronary events in dyslipidemic patients in outcome studies. New evidence supports adding fenofibrate to a statin in Type 2 diabetics with residual hypertriglyceridemia and low HDL-cholesterol; extrapolating from a recent meta-analysis, a 15% reduction in triglycerides could translate into a further 15% reduction in coronary events. Ongoing clinical trials may provide new evidence for adding niacin to a statin. The value of higher doses of n-3 fatty acids in reducing CVD risk remains to be demonstrated. The high triglyceride/low HDL nexus is an under-recognized risk factor for CVD that merits more detailed clinical assessment and treatment, particularly in patients with Type 2 diabetes already receiving a statin.     

Cytogenetic aberrations and their prognostic impact in chondrosarcoma.

Chondrosarcoma is the second most common primary malignancy of bone. Cytogenetic data are available from close to 100 cases, including all subtypes of chondrosarcoma. Specific chromosomal rearrangements have been identified only in extraskeletal myxoid chondrosarcoma (EMC). Strong prognostic factors are largely missing, although size and, in particular, histologic tumor grade have been implicated. In the present study, we investigated the genomic aberrations in 59 chondrosarcomas (six grade 1, 24 grade 2, and 29 grade 3, including dedifferentiated tumors), excluding EMC, by chromosome banding analysis and DNA flow cytometry and correlated the findings with clinical outcome. Hyperhaploid to near-diploid karyotypes were found in half of the cases, and there was a good correlation between cytogenetics and flow cytometry data; discrepancies were seen primarily in cases with normal karyotypes and in those with -Y as the sole anomaly. Abnormal karyotypes, excluding those with -Y as the only change, were found in 36 cases. No recurrent structural aberration was found, but a nonrandom pattern of aberrations was seen. Total or partial gains and losses were the dominant karyotypic features. Genomic imbalances found in at least 10 cases included -1p36, -1p13-p22, -4, -5q13-q31, -6q22-qter, +7p13-pter, -9p22-pter, -10p, -10q24-qter, -11p13-pter, -11q25, +12q15-qter, -13q21-qter, -14q24-qter, -18p, -18q22-qter, +19, +20pter-q11, +21q, and -22q13. At the latest follow-up, 19 patients had experienced distant metastases, and the 5-year metastasis-free survival rate was 0.69. By univariate analysis, malignancy grade and loss of material from 6q, 10p, 11p or 11q, 13q, and 22q were associated with impaired metastasis-free survival. Only -13q was an independent prognostic factor for metastasis, regardless of tumor grade or size.     

Redistribution of monocarboxylate transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus

Emerging evidence points to monocarboxylates as key players in the pathophysiology of temporal lobe epilepsy (TLE) with hippocampal sclerosis (mesial temporal lobe epilepsy, MTLE). Monocarboxylate transporters (MCTs) 1 and 2, which are abundantly present on brain endothelial cells and perivascular astrocyte endfeet, respectively, facilitate the transport of monocarboxylates and protons across cell membranes. Recently, we reported that the density of MCT1 protein is reduced on endothelial cells and increased on astrocyte plasma membranes in the hippocampal formation in patients with MTLE and in several animal models of the disorder. Because the perivascular astrocyte endfeet comprise an important part of the neurovascular unit, we now assessed the distribution of the MCT2 in hippocampal formations in TLE patients with (MTLE) or without hippocampal sclerosis (non-MTLE). Light microscopic immunohistochemistry revealed significantly less perivascular MCT2 immunoreactivity in the hippocampal formation in MTLE (n = 6) than in non-MTLE (n = 6) patients, and to a lesser degree in non-MTLE than in nonepilepsy patients (n = 4). Immunogold electron microscopy indicated that the loss of MCT2 protein occurred on perivascular astrocyte endfeet. Interestingly, the loss of MCT2 on astrocyte endfeet in MTLE (n = 3) was accompanied by an upregulation of the protein on astrocyte membranes facing synapses in the neuropil, when compared with non-MTLE (n = 3). We propose that the altered distribution of MCT1 and MCT2 in TLE (especially MTLE) limits the flux of monocarboxylates across the blood-brain barrier and enhances the exchange of monocarboxylates within the brain parenchyma.     

Spiradenocarcinoma with low-grade basal cell adenocarcinoma pattern: report of a case with varied morphology and wild type TP53

We present a patient with a 2-cm spiradenocarcinoma of the left arm resembling low-grade salivary gland basal cell adenocarcinoma. In addition to showing attributes of conventional spiradenoma, the benign component showed prominent areas of cystic change with focal apocrine differentiation, glands with and without mucinous differentiation, clear cell change and focal adenoid cystic carcinoma-like areas. The malignant component was composed of nodules of basaloid cells arranged in sheets with variable tendency to luminal differentiation. The nuclear atypia was low-grade, and the mitotic index was high in the malignant component (to 8/10 high power fields). Immunohistochemically, there was diffuse but variable positivity for cytokeratin 7 in both the benign and malignant components. Epithelial membrane antigen was focally positive, highlighting cells with ductal (luminal) differentiation. Expression of p63 was observed in 50 and 80% of the cells in the benign and malignant components, respectively. Calponin was negative. The proliferative index (MIB-1/Ki-67) was <3% in the benign component and up to 10% in the malignant component. Although the malignant component displayed patchy areas with nuclear p53 immunoreactivity with variable intensity, no mutation in the TP53 gene was identified.     

The Prevalence of Autism Spectrum Disorders in Toddlers: A Population Study of 2-Year-Old Swedish Children

Autism Spectrum Disorder (ASD) is more common than previously believed. ASD is increasingly diagnosed at very young ages. We report estimated ASD prevalence rates from a population study of 2-year-old children conducted in 2010 in Gothenburg, Sweden. Screening for ASD had been introduced at all child health centers at child age 21/2 years. All children with suspected ASD were referred for evaluation to one center, serving the whole city of Gothenburg. The prevalence for all 2-year-olds referred in 2010 and diagnosed with ASD was 0.80%. Corresponding rates for 2-year-olds referred to the center in 2000 and 2005 (when no population screening occurred) were 0.18 and 0.04%. Results suggest that early screening contributes to a large increase in diagnosed ASD cases.     

A new screening programme for autism in a general population of Swedish toddlers

The evidence from early intervention studies of autism has emphasised the need for early diagnosis. Insight into the early presentation of autism is crucial for early recognition, and routine screening can optimise the possibility for early diagnosis. General population screening was conducted for 2.5-year-old children at child health centres in Gothenburg, Sweden, and the efficacy of the screening instruments in predicting a clinical diagnosis of autism was studied. The tools used for autism screening comprised the Modified Checklist for Autism in Children (M-CHAT) and an observation made by trained nurses of the child's joint attention abilities (JA-OBS). From the new screening procedure a "definitive" suspicion of autism spectrum disorder (ASD) was raised in 64 individuals in the study population of 3999 young children. Fifty-four of these were clinically assessed in detail. Forty-eight children had a confirmed diagnosis of ASD, three had severe language disorder, and three (6%) were classified as having typical development. The Positive predictive Value (PPV) for the combination of M-CHAT and the JA-OBS was 90%. The combination of instruments used showed promise for early detection of autism as a routine in the developmental programme at child health centres. Trained medical staff is a basic requirement and enables earlier detection and the use of screening tools beyond routine population screening regardless of the age at which a suspicion of autism is raised.     

Synthesis and evaluation of a set of para-substituted 4-phenylpiperidines and 4-phenylpiperazines as monoamine oxidase (MAO) inhibitors

A series of para-substituted 4-phenylpiperidines/piperazines have been synthesized and their affinity to recombinant rat cerebral cortex monoamine oxidases A (MAO A) and B (MAO B) determined. Para-substituents with low dipole moment increased the affinity to MAO A, whereas groups with high dipole moment yielded compounds with no or weak affinity. In contrast, the properties affecting MAO B affinity were the polarity and bulk of the para-substituent, with large hydrophobic substituents producing compounds with high MAO B affinity. In addition, these compounds were tested in freely moving rats and the effect on the post-mortem neurochemistry was measured. A linear correlation was demonstrated between the affinity for MAO A, but not MAO B, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) in the striatum.