In vitro metabolism of MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl] methyl]benzamide], a peroxisome proliferator-activated receptor alpha/gamma agonist. II. Identification of metabolites by liquid chromatography-tandem mass spectrometry.

The in vitro metabolism of MK-0767 [(+/-)-5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl] methyl]benzamide], a novel 2,4-thiazolidinedione (TZD)-containing peroxisome proliferator-activated receptor alpha/gamma agonist, was studied in rat, dog, monkey, and human liver microsomes and hepatocytes, as well as in recombinant human CYP3A4-containing microsomes. Twenty-two metabolites (some at trace levels) were detected by liquid chromatography-tandem mass spectrometry analysis. All appeared to be phase I metabolites except for a glucuronide conjugate of a hydroxylated metabolite that was detected at trace levels. A constant neutral loss scan experiment performed on a triple quadrupole mass spectrometer proved to be very useful for resolving the metabolites from endogenous compounds. It was observed that the initial site of metabolism of MK-0767 was at the TZD ring leading to two major metabolites, namely the 5-hydroxy-TZD metabolite (M24) and the mercapto metabolite (M22). The latter was formed via the cleavage of the TZD ring with the elimination of the carbonyl adjacent to the sulfur atom. The structure of M24 was established by accurate mass measurements and NMR analysis. This hydroxy-TZD metabolite might represent an important precursor for a group of metabolites formed by TZD ring opening and subsequent loss of the sulfur moiety. The mercapto metabolite, on the other hand, is probably the key precursor for the TZD ring-opened metabolites with retention of the sulfur, even though the detailed mechanism of the ring scission remains to be characterized. From these studies, it was concluded that the TZD ring was the major site of metabolism of MK-0767. All the metabolites produced in vitro from human preparations were detected in the corresponding preparations from the nonclinical species.     

Mutant huntingtin impairs immune cell migration in Huntington disease

In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.     

Erratum to: Depression,anxiety, and quality of life in a large cohort of patients with rheumatic diseases: common,yet undertreated

Clinical Rheumatology -     

Additional Diagnostic Yield of Adding Serology to PCR in Diagnosing Viral Acute Respiratory Infections in Kenyan Patients 5 Years of Age and Older

The role of serology in the setting of PCR-based diagnosis of acute respiratory infections (ARIs) is unclear. We found that acute- and convalescent-phase paired-sample serologic testing increased the diagnostic yield of naso/oropharyngeal swabs for influenza virus, respiratory syncytial virus (RSV), human metapneumovirus, adenovirus, and parainfluenza viruses beyond PCR by 0.4% to 10.7%. Although still limited for clinical use, serology, along with PCR, can maximize etiologic diagnosis in epidemiologic studies.     

Acute noise stress impairs feedback processing

We examined the impact of acute noise stress on the feedback-related negativity (FRN) and whether this effect depended on stressor predictability. Participants performed a gambling task in a silence and a noise condition with either predictable or unpredictable noise. FRN amplitude was measured in three ways, either neglecting (mean amplitude) or correcting for overlap with other components (base-to-peak; mean amplitude minus average mean amplitude of surrounding peaks). Notably, results differed between measures. Valence and magnitude both affected the FRN. These effects were additive on the mean amplitude and base-to-peak measures, but interactive on the mean amplitude corrected for both peaks measure. Acute noise stress specifically modulated valence and magnitude effects on the FRN, although evidence differed between measures as to whether valence and/or magnitude were processed differently. These findings indicate that acute stress impairs cognitive control by the anterior cingulate cortex. Stressor predictability added little to the explanation of effects.     

Spectrophotometric dental colour measurement to assess age in living adults

The aim of this study was to evaluate the usefulness of spectrometrically measured colour parameters of teeth for age estimation in living adults. A total of 329 teeth were selected (162 upper central incisors and 167 upper canines) from 52 men and 50 women aged between 20 and 86 years. Colour measurements were performed in vivo on the vestibular surface of the teeth using a portable contact Spectro-color device. Colorimetric variables (L*, a*, b*), chromaticity coordinates (x, y, z), and indexes of whiteness (WIC, Z%, WI) and yellowness (YI) were calculated. The accuracy of colour values to estimate the age was determined by Receiver Operating Characteristic analysis. A more powerful age discrimination was obtained with upper incisors than with upper canines. Areas under the ROC curve ranged from 0.7 to 0.8 for all dental colour parameters measured in upper central incisors except for the variables L* and Z%, with sensitivity values ranging from 56% to 93% and specificity values from 38% to 92%. We conclude that spectrophotometric dental colour measurement may be an objective and useful tool to estimate age and meets medical ethical standards for application in living adults. However, further research is needed to study the effect of ethnicity and other factors on tooth colour.     

Hypoxia and its therapeutic possibilities in paediatric cancers

In tumours, hypoxia—a condition in which the demand for oxygen is higher than its availability—is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients.Subject terms: Tumour biomarkers, Paediatric cancer, Cancer microenvironment, Cancer therapy     

Polycystic Ovary Syndrome and Depression in New Zealand Adolescents

ObjectiveTo determine whether adolescents with polycystic ovary syndrome (PCOS) are more depressed than adolescent girls in the community and to examine factors associated with depression.DesignAn observational study comparing clinical and community samples.SettingTwo specialist reproductive endocrine clinics in Auckland, New Zealand.Participants102 girls aged 14-19 presenting for clinical assessment, fulfilling the Rotterdam consensus for PCOS. The comparison group was 1349 girls from a school-based survey of New Zealand youth.InterventionsClinically significant depression was identified by the long and short form Reynolds Adolescent Depression Scale. BMI, androgen levels, oral contraceptive use, objective symptom severity, age, ethnicity, and socioeconomic grouping were recorded.Main Outcome MeasuresClinically significant depression in the PCOS and community samples. Potential determinants of depression.ResultsClinically significant depression in adolescent girls with PCOS was not increased compared with the community sample (OR 1.3; 95%CI 0.7-2.7, P = .42). Within the PCOS cohort, depression was correlated with increased BMI (P = .01) and possibly acne (P = .08).ConclusionsLean adolescent girls with PCOS did not have more clinically significant depression than girls in the community. Within the PCOS cohort, however, there was a clear association between higher depression scores and elevated BMI. There is a potentially important interaction between obesity and depression in PCOS.