Polymorphisms in MICB are associated with human herpes virus seropositivity and schizophrenia risk

Viral infection may be a risk factor for schizophrenia and has been associated with decreased cognitive functioning in patients. We report associations of SNPs at MICB (MHC class I polypeptide-related sequence B, chromosome 6p21) with cytomegalovirus and herpes simplex virus 1 seropositivity. We previously found associations with schizophrenia on chromosome 6p21 among patients seropositive for cytomegalovirus (CMV) and herpes simplex virus 1 (HSV1). To localize the associations further, we genotyped 26 SNPs spanning 100 kb in a sample of 236 Caucasian schizophrenia patients and 240 controls. Based on suggestive associations, we selected five SNPs at MICB to assay among two additional Caucasian samples that had been serotyped for CMV and HSV1: a case-control sample recruited in Baltimore (n=272 cases, 108 controls), and a case-parent trio sample recruited in Pittsburgh (n=221). Among Baltimore control individuals there were significant associations with antibody status for infectious agents: rs1051788 with HSV1 seropositivity (p=0.006) and rs2523651 with cytomegalovirus seropositivity (p=0.001). The former association was also detectable among the parents of cases recruited in Pittsburgh (p=0.024). Neither viral association was noted among the schizophrenia cases. With respect to schizophrenia risk, significant transmission distortion was noted at rs1051788 and rs1055569 among the case-parent trios regardless of antibody status (p=0.014 and 0.036 respectively). A similar trend for association with schizophrenia liability at rs1051788 in the Baltimore sample did not attain statistical significance. There are a number of explanations for the associations, including chance variation, as well as gene-virus interactions. Further replicate studies are warranted, as are functional studies of these polymorphisms.     

Prefrontal-hippocampal-fusiform activity during encoding predicts intraindividual differences in free recall ability: an event-related functional-anatomic MRI study

The ability to spontaneously recall recently learned information is a fundamental mnemonic activity of daily life, but has received little study using functional neuroimaging. We developed a functional MRI (fMRI) paradigm to study regional brain activity during encoding that predicts free recall. In this event-related fMRI study, ten lists of fourteen pictures of common objects were shown to healthy young individuals and regional brain activity during encoding was analyzed based on subsequent free recall performance. Free recall of items was predicted by activity during encoding in hippocampal, fusiform, and inferior prefrontal cortical regions. Within-subject variance in free recall performance for the ten lists was predicted by a linear combination of condition-specific inferior prefrontal, hippocampal, and fusiform activity. Recall performance was better for lists in which prefrontal activity was greater for all items of the list and hippocampal and fusiform activity were greater specifically for items that were recalled from the list. Thus, the activity of medial temporal, fusiform, and prefrontal brain regions during the learning of new information is important for the subsequent free recall of this information. These fronto-temporal brain regions act together as a large-scale memory-related network, the components of which make distinct yet interacting contributions during encoding that predict subsequent successful free recall performance.     

Discovery of VU6028418: A Highly Selective and Orally Bioavailable M4 Muscarinic Acetylcholine Receptor Antagonist

Herein, we report the SAR leading to the discovery of VU6028418, a potent M₄ mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.     

Obesity among individuals with serious mental illness

OBJECTIVE: To study the distribution and correlates of body mass index (BMI) among individuals with serious mental illness. METHOD: A total of 169 participants were recruited from randomly selected out-patients receiving community-based psychiatric care and were interviewed with items from the National Health and Nutrition Examination Survey (NHANES) III. Their BMI was compared with that of 2404 matched individuals from the NHANES data set. RESULTS: The distribution of BMI in the psychiatric sample significantly differed from that of the comparison group; 50% of women and 41% of men were obese compared with 27% and 20% in the comparison group. Within the psychiatric sample, higher BMI was associated with current hypertension and diabetes, a wish to weigh less, and reduced health-related functioning. CONCLUSION: Obesity is more prevalent among individuals with serious mental illness than in demographically matched individuals from the US general population. Among persons with mental illness, obesity is associated with co-occurring health problems.     

Health status of individuals with serious mental illness

We examined indices of the health of persons with serious mental illness. A sample of 100 adults with schizophrenia and 100 with major mood disorder were recruited from randomly selected outpatients who were receiving community-based psychiatric treatment. Participants were surveyed about health indicators using items from the National Health and Nutrition Examination Study III and the National Health Interview Survey. Their responses were compared with those of matched samples from the general population surveys. A total of 1% of persons with serious mental illness, compared with 10% from the general population sample, met criteria for all 5 of selected health indicators: nonsmoker, exercise that meets recommended standards, good dentition, absence of obesity, and absence of serious medical co-occurring illness. Within the mentally ill group, educational level, but not a diagnosis of schizophrenia versus mood disorder, was independently associated with a composite measure of health behaviors. We conclude that an examination of multiple health indicators may be used to measure overall health status in persons with serious mental illness.     

Concentrations of individual fine particulate matter components in the USA around July 4th

Fireworks emit particulate matter (PM) air pollution. Laboratory and epidemiologic studies have linked exposure to PM with cardiovascular and respiratory effects. Although it was reported that the mass of total PM with a nominal mean aerodynamic diameter less than or equal to 2.5 μm (PM_2.5) is elevated on July 4th and 5th, no studies to date have used national, multi-year air quality monitoring data to determine which individual PM_2.5 components increase due to July 4th fireworks. To evaluate this, we compiled and analyzed 24-h average PM_2.5 air quality measurements collected by the Environmental Protection Agency’s Chemical Speciation Network monitors positioned at 379 urban sites across the USA over the years 2000 to 2014. By combining all individual daily mean PM_2.5 concentrations recorded and viewing the arithmetic mean concentrations over time, we observed sharp and statistically significant increases in the concentrations of the firework-related chemicals barium, chlorine, copper, magnesium, potassium, and strontium on July 4th, which persisted through July 5th. There were also modest, but still statistically significant, increases of the concentrations of the firework-related components aluminum, arsenic, antimony, chromium, phosphorous, sulfur, titanium, and zinc on July 4th. Concentrations of elemental and organic carbon, calcium, cesium, iron, nickel, and sodium did not significantly increase on July 4th. These findings provide important information about changes in ambient air quality around Independence Day in the USA.