CYP3A isoforms in Ewing's sarcoma tumours: an immunohistochemical study with clinical correlation

Ewing's sarcoma is an aggressive malignancy of bone and soft tissue with high incidence of metastasis and resistance to chemotherapy. Cytochrome P450 (CYP) monooxygenases are a family of enzymes that are involved in the metabolism of exogenous and endogenous compounds, including anti‐cancer drugs, and have been implicated in the aggressive behaviour of various malignancies. Tumour samples and clinical information including age, sex, tumour site, tumour size, clinical stage and survival were collected from 36 adult and paediatric patients with Ewing's sarcoma family tumours. Tissue microarrays slides were processed for immunohistochemical labelling for CYP3A4, CYP3A5 and CYP3A7 using liver sections as positive control. The intensity of staining was scored as negative, low or high expression and was analysed statistically for any association with patients' clinical information. Four cases were later excluded due to inadequate viable tissue. CYP3A4 staining was present in 26 (81%) cases with high expression noted in 13 (40%) of 32 cases. High expression was significantly associated with distant metastases (P < 0.05). CYP3A5 and CYP3A7 were expressed in 5 and 13 cases respectively (15.6%, 40.6%). There was no association between the expression of CYP3A isoforms and age, sex, tumour size, or location (pelvic or extra‐pelvic). None of the biomarkers showed any correlation with overall or disease‐free survival. In conclusion, expression of CYP3A isoforms is noted in Ewing's sarcoma tumours and high CYP3A4 expression may be associated with metastasis. Additional studies are needed to further investigate the role of CYP3A4 in the prognosis of these tumours.     

Functional Magnetic Resonance Imaging of Motor Cortex Activation in Schizophrenia

Previous fMRI studies of sensorimotor activation in schizophrenia have found in some cases hypoactivity, no difference, or hyperactivity when comparing patients with controls; similar disagreement exists in studies of motor laterality. In this multi-site fMRI study of a sensorimotor task in individuals with chronic schizophrenia and matched healthy controls, subjects responded with a right-handed finger press to an irregularly flashing visual checker board. The analysis includes eighty-five subjects with schizophrenia diagnosed according to the DSM-IV criteria and eighty-six healthy volunteer subjects. Voxel-wise statistical parametric maps were generated for each subject and analyzed for group differences; the percent Blood Oxygenation Level Dependent (BOLD) signal changes were also calculated over predefined anatomical regions of the primary sensory, motor, and visual cortex. Both healthy controls and subjects with schizophrenia showed strongly lateralized activation in the precentral gyrus, inferior frontal gyrus, and inferior parietal lobule, and strong activations in the visual cortex. There were no significant differences between subjects with schizophrenia and controls in this multi-site fMRI study. Furthermore, there was no significant difference in laterality found between healthy controls and schizophrenic subjects. This study can serve as a baseline measurement of schizophrenic dysfunction in other cognitive processes.

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Pathogenic mitochondrial mt-tRNAAla variants are uniquely associated with isolated myopathy

Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA^Ala variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA^Ala levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA^Ala variants. Previously described mt-tRNA^Ala mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene.     

Size dependent platelet subpopulations: relationship of platelet volume to ultrastructure, enzymatic activity, and function

A method for the separation of platelets on the basis of their size has been developed using counterflow centrifugation. Platelets were separated, free of plasma proteins and other cells, into seven subpopulations. The smallest-sized platelets, designated as Fraction 1, had a mean platelet volume (MPV) of 3.94 ± 0.60 μm³ (SD). Each successive fraction had a progressively larger MPV. The MPV for the largest-sized platelets, designated Fraction 7, was 8.19 ± 0.64 μm³. The MPV for the original platelets prior to fractionation was 6.57 ± 0.61 μm³. The mean density of Fraction 1 platelets was 1.067 ± 0.002 g/cm³, while Fraction 7 had a mean density of 1.072 ± 0.001 g/cm³. Transmission electron microscopy demonstrated that Fraction 1 had 4.3 ± 0.9 dense bodies per platelet, and Fraction 7 had 12.6 ± 2.4 dense bodies per platelet. Platelet LDH activity showed that the Fraction 1 platelets had 4.77 ± 0.92 iu per 10¹⁰ platelets; Fraction 7 platelets had 14.88 ± 1.23 iu per 10¹⁰ platelets. The LDH activity in the platelets before separation into subpopulations was 9.47 ± 1.45 iu per 10¹⁰ platelets.     

Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis

Background: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population.

Methods: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed.

Results: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea.

Conclusion: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide’s overall safety.     

The influence of an intense cardiovascular disease risk factor modification program

In an effort to make intensive lifestyle modification programs more accessible to patients with cardiovascular disease, the Ornish Program was offered at eight independent medical centers located across the United States. The purpose of this study was to determine if one of these independent sites was able to replicate outcomes produced by the original Ornish Program. Fifty program participants from six different cohorts provided baseline, 3- and 12-month data consisting of blood lipids, body fat, blood pressure, anginal pain, quality of life, stress, depression, social support, and hostility. A pooled analysis showed significant reductions in almost all physiological and psychosocial variables with most reductions persisting for at least 12 months. These findings suggest that cardiovascular disease patients who choose to participate in an independent, intensive lifestyle modification program can experience significant improvements in both physiological and psychosocial cardiovascular disease risk factors.     

Innate control of adaptive immunity via remodeling of lymph node feed arteriole

The adaptive immune system relies on rare cognate lymphocytes to detect pathogen-derived antigens. Na?ve lymphocytes recirculate through secondary lymphoid organs in search of cognate antigen. Here, we show that the na?ve-lymphocyte recirculation pattern is controlled at the level of innate immune recognition, independent of antigen-specific stimulation. We demonstrate that inflammation-induced lymphocyte recruitment to the lymph node is mediated by the remodeling of the primary feed arteriole, and that its physiological role is to increase the efficiency of screening for rare antigen-specific lymphocytes. Our data reveal a mechanism of innate control of adaptive immunity: by increasing the pool of na?ve lymphocytes for detection of foreign antigens via regulation of vascular input to the local lymph node.