In this study, the authors examined the catabolic cascade in osteoarthritis (OA). OA is primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. The authors investigated the role of zinc (Zn(2+)) homeostasis, Zn(2+) transporters, and Zn(2+)-dependent transcription factors in OA pathogenesis. Among Zn(2+) transporters, the Zn(2+) importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn(2+) in chondrocytes. ZIP8- mediated Zn(2+) influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn(2+) influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn(2+)/ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. The authors conclude that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis. This could have potential implications when translated into the clinical setting. Cell. February 2014. PMID: 24529376.

This study used the Florida birth registry data to investigate the associations between air pollutants (NO2, SO2, PM(2.5), O3 and CO) and the risks of HDP in 22,041 pregnant women in Jacksonville, Florida, USA from 2004 to 2005. The authors examined whether air pollution exposure during different time windows defined by trimesters and the entire pregnancy had different effects on HDP. The single-pollutant logistic regression model showed that exposure to four pollutants during the full pregnancy period was significantly associated with prevalence of HDP after adjusting for covariates: NO2 (OR=1.21, 95% CI 1.09 to 1.35), PM2.5 (OR=1.24, 95% CI 1.08 to 1.43), SO2 (OR=1.13, 95% CI 1.01 to 1.25) and CO (OR=1.12, 95% CI 1.03 to 1.22) per IQR increase. Similar effects were observed when first trimester exposure to NO2, SO2 and CO, and second trimester exposures to PM2.5 were examined. Consistent results were confirmed in multiple-pollutant models. The authors conclude that exposure to high levels of air pollution during early pregnancy and the full gestational period was associated with increased prevalence of HDP in Florida, USA. J Epidemiol Community Health. January 2014. PMID: 24022815

This review identifies factors that mediate the emergence of RNA viruses such as influenza A virus (IAV). Phylogenetic inference is crucial to reconstructing the origins and tracing the flow of IAV within and between hosts. The authors show that explicitly allowing IAV host lineages to have independent rates of molecular evolution is necessary for reliable phylogenetic inference of IAV and that methods that do not do so, including ‘relaxed’ molecular clock models, can be positively misleading. A phylogenomic analysis using a host-specific local clock model recovers extremely consistent evolutionary histories across all genomic segments and demonstrates that the equine H7N7 lineage is a sister clade to strains from birds-as well as those from humans, swine and the equine H3N8 lineage-sharing an ancestor with them in the mid to late 1800s. On the basis of these phylogenies and the synchrony of these key nodes, we infer that the internalgenes of avian influenza virus (AIV) underwent a global selective sweep beginning in the late 1800s, a process that continued throughout the twentieth century and up to the present. The resulting western hemispheric AIV lineage subsequently contributed most of the genomic segments to the 1918 pandemic virus and, independently, the 1963 equine H3N8 panzootic lineage. Nature. February 2014. PMID: 24531761.

This study was performed to determine whether a personalized sex-specific intervention, WAIPointes (WAI stands for Who Am I), could reduce central obesity in women undergoing perimenopausal transition. Eighty-three of 103 women aged 35 to 55 years and experiencing symptoms of the menopausal transition completed a 6-month WAIPointes demonstration project; 75 consented to data review. Sex-specific history was obtained on visit 1; directed physical examination for body mass index, body fat percentage, waist circumference, and blood pressure were performed at each of four or five subsequent monthly visits. Other tests were ordered as necessary to determine risk stratification. Participants were assessed for menopause status, and they reported activity and menopausal symptoms at each visit. Personalized strategies for health improvement were developed in partnership. Women served as their own controls. Data from visit 2 were compared with data from visit 4. The results showed that the intervention reduced waist circumference and diastolic blood pressure and improved self-reported menopausal symptoms and physical activity levels. The authors conclude that the WAIPointes program offers potential as an effective officebased clinical intervention to reduce cardiovascular risk factors and symptoms of menopause in women during the menopausal transition. Menopause. February 2014. PMID: 24518150.

The authors investigated the effects of increasing grape seed extract doses on the severity of chemotherapy in a rat model and its coincident impact on chemotherapeutic effectiveness in colon cancer cells. Female Dark Agouti rats were gavaged with grape seed extract (400–1000 mg/kg) or water (day 3–11) and were injected intraperitoneally with 5-Fluorouracil (150 mg/kg) or saline (control) on day 9 to induce mucositis. Daily metabolic data were collected and rats were sacrificed on day 12. Intestinal tissues were collected for histological and myeloperoxidase analyses. Caco-2 cell viability was examined in response to grape seed extract in combination with 5-Fluorouracil by 3-(4,5-Dimethylthiazol-2yl)-2,5- diphenyl-tetrazoliumbromide) assay. The results showed that compared with 5-Fluorouracil controls, grape seed extract (400–1000 mg/ kg) significantly decreased the histological damage score (P<0.05) in the jejunum. Grape seed extract (1000 mg/kg) increased jejunal crypt depth by 25% (P<0.05) in 5-Fluorouracil treated rats compared to 5-Fluorouracil controls, and attenuated the 5-Fluorouracil -induced reduction of mucosal thickness (25%, P<0.05). Grape seed extract (600 mg/kg) decreased myeloperoxidase activity by 55% (P<0.01) compared to 5-Fluorouracil controls. The authors conclude that grape seed extract may represent a new therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting on the viability of colon cancer cells. PLoS One. January 2014. PMID: 24465501.

This review article discusses industrial chemicals as causes of developmental neurotoxicity. Neurodevelopmental disabilities, including autism, attention-deficit hyperactivity disorder, dyslexia, and other cognitive impairments, affect millions of children worldwide, and some diagnoses seem to be increasing in frequency. Industrial chemicals that injure the developing brain are among the known causes for this rise in prevalence. In 2006, the authors did a systematic review and identified five industrial chemicals as developmental neurotoxicants: lead, methylmercury, polychlorinated biphenyls, arsenic, and toluene. Since 2006, epidemiological studies have documented six additional developmental neurotoxicants— manganese, fluoride, chlorpyrifos, dichlorodiphenyltrichloroethane, tetrachloroethylene, and the polybrominated diphenyl ethers. The authors postulate that even more neurotoxicants remain undiscovered. To control the pandemic of developmental neurotoxicity, they propose a global prevention strategy. Untested chemicals should not be presumed to be safe to brain development, and chemicals in existing use and all new chemicals must therefore be tested for developmental neurotoxicity. To coordinate these efforts and to accelerate translation of science into prevention, the authors propose the urgent formation of a new international clearinghouse. The Lancet Neurology. March 2014. PMID: N/A

This trial examined health care utilization (HCU) and costs following brief cognitive behavioural treatment for insomnia (bCBTi). The authors reviewed medical records of outpatients treated in a behavioural sleep medicine clinic based in an accredited sleep disorder center. Six indicators of HCU and costs were obtained: estimated total and outpatient costs, estimated primary care visits, CPT costs, number of office visits, and number of medications. All patients completed more than 1 session of bCBTi. Those who attended greater than 3 were considered completers and completers with significant sleep improvements were considered responders. The results showed that for both completers and responders, all HCU and cost variables, except number of medications, significantly decreased or trended towards decrease at post-treatment. Completers had an average decrease in CPT costs of $200 and estimated total costs of $75. Responders had average decreases in CPT costs of $210. The authors conclude that bCBTi can reduce HCU and costs. Response to bCBTi resulted in greater reduction of HCU and costs. The findings highlight the need for greater dissemination of bCBTi for several reasons: a high percentage of completers responded to treatment, as few as 3 sessions can result in significant improvements insomnia, and bCBTi can be delivered by novice clinicians. J Clin Sleep Med. February 2014. PMID: 24532995

This study analyzed the risk of clinical trial failure during non-small cell lung cancer (NSCLC) drug development. NSCLC drug development was investigated using publically available resources. Analysis was conducted in regard to treatment indication, compound classification, and mechanism of action. The results showed that six hundred seventy-six clinical trials that included 199 unique compounds met the inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than industry aggregate rates. Over half of the biomarkers used in NSCLC have not yet been approved by the Food and Drug Administration in any indication. Biomarker targeted therapies (62%) and receptor targeted therapies (31%) were found to have the highest success rates. The risk-adjusted cost for NSCLC clinical drug development was calculated to be U.S. $1.89 billion. The authors conclude that biomarker use alone in this indication results in a six-fold increase in clinical trial success whereas receptor targeted therapies did so by almost threefold. Physicians who enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that use biomarkers and receptor targeted therapies. J Thorac Oncol. February 2014. PMID: 24419412.

This review evaluated the role of dietary components in pancreatic cancer. Pancreatic cancer has a poor prognosis with a 5-year survival rate of less than 5%. The authors performed searched in PubMed using the terms “pancreatic cancer”, together with “nutrition”, “diet”, “dietary factors”, “lifestyle”, “smoking”, “alcohol” and “epidemiology”. The results showed that fruits, particularly citrus, and vegetable consumption may be beneficial. The consumption of whole grains has been shown to reduce pancreatic cancer risk and fortification of whole grains with folate may confer further protection. Red meat, cooked at high temperatures, should be avoided, and replaced with poultry or fish. Total fat should be reduced. The use of curcumin and other flavonoids should be encouraged in the diet. There is no evidence for benefit from vitamin D supplementation. There may be benefit for dietary folate. Smoking and high Body Mass Index have both been inversely associated with pancreatic cancer risk. The authors conclude that there is evidence to encourage the use of whole grain in the staple diet and supplementation within the diet of folate, curcumin and other flavanoids. Carefully designed randomized trials are required to further elucidate these important matters. Anticancer Res. January 2014. PMID: 24403441.

Known as the PIONEER trial, this study was a prospective, multinational, epidemiological study of epidermal growth factor receptor (EGFR) mutations in patients from Asia with newly diagnosed advanced lung adenocarcinoma. Eligible patients had untreated stage IIIB/IV adenocarcinoma. EGFR mutation status of tumor samples was determined. The results showed that of 1482 patients from seven Asian regions, 43.4% of patients were female, median age was 60 years (range, 17-94), and 52.6% of patients were never-smokers. EGFR mutation status was evaluable in tumors from 1450 patients (97.8%) (746 [51.4%] positive; 704 [48.6%] negative). Country, sex, ethnicity, smoking status, pack-years (all p < 0.001), disease stage (p = 0.009), and histology type (p = 0.016) correlated significantly with EGFR mutation frequency. Mutation frequency was 61.1% in females, 44.0% in males; lower in patients from India (22.2%) compared with other areas (47.2%- 64.2%); highest among neversmokers (60.7%); and decreased as pack-year number increased (>0-10 pack-years, 57.9%; >50 pack-years, 31.4%) (similar trend by sex). Ethnic group (p < 0.001) and packyears (p < 0.001) had statistically significant associations with mutation frequency (multivariate analysis); sex was not significant when adjusted for smoking status. The authors conclude that there is high EGFR mutation frequency (51.4% overall) in tumors from Asian patients with adenocarcinoma. J Thorac Oncol. February 2014. PMID: 24419411.