Research Spotlight

Christensen, K. E., W. Hou, R. H. Bahous, L. Deng, O. V. Malysheva, E. Arning, T. Bottiglieri, M. A. Caudill, L. A. Jerome-Majewska and R. Rozen (2016). “Moderate folic acid supplementation and mthfd1-synthetase deficiency in mice, a model for the r653q variant, result in embryonic defects and abnormal placental development.” Am J Clin Nutr 104(5): 1459-1469.

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BACKGROUND: Moderately high folic acid intake in pregnant women has led to concerns about deleterious effects on the mother and fetus. Common polymorphisms in folate genes, such as methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (MTHFD1) R653Q, may modulate the effects of elevated folic acid intake. OBJECTIVES: We investigated the effects of moderate folic acid supplementation on reproductive outcomes and assessed the potential interaction of the supplemented diet with MTHFD1-synthetase (Mthfd1S) deficiency in mice, which is a model for the R653Q variant. DESIGN: Female Mthfd1S+/+ and Mthfd1S+/- mice were fed a folic acid-supplemented diet (FASD) (5-fold higher than recommended) or control diets before mating and during pregnancy. Embryos and placentas were assessed for developmental defects at embryonic day 10.5 (E10.5). Maternal folate and choline metabolites and gene expression in folate-related pathways were examined. RESULTS: The combination of FASD and maternal MTHFD1-synthetase deficiency led to a greater incidence of defects in E10.5 embryos (diet x maternal genotype, P = 0.0016; diet x embryonic genotype, P = 0.054). The methylenetetrahydrofolate reductase (MTHFR) protein and methylation potential [ratio of S-adenosylmethionine (major methyl donor):S-adenosylhomocysteine) were reduced in maternal liver. Although 5-methyltetrahydrofolate (methylTHF) was higher in maternal circulation, the methylation potential was lower in embryos. The presence of developmental delays and defects in Mthfd1S+/- embryos was associated with placental defects (P = 0.003). The labyrinth layer failed to form properly in the majority of abnormal placentas, which compromised the integration of the maternal and fetal circulation and presumably the transfer of methylTHF and other nutrients. CONCLUSIONS: Moderately higher folate intake and MTHFD1-synthetase deficiency in pregnant mice result in a lower methylation potential in maternal liver and embryos and a greater incidence of defects in embryos. Although maternal circulating methylTHF was higher, it may not have reached the embryos because of abnormal placental development; abnormal placentas were observed predominantly in abnormally developed embryos. These findings have implications for women with high folate intakes, particularly if they are polymorphic for MTHFD1 R653Q.

Cass, I., L. R. Duska, S. V. Blank, G. Cheng, N. C. duPont, P. J. Frederick, E. K. Hill, C. M. Matthews, T. L. Pua, K. S. Rath, R. Ruskin, P. H. Thaker, A. Berchuck, B. S. Gostout, D. M. Kushner and J. M. Fowler (2016). “Stress and burnout among gynecologic oncologists: A society of gynecologic oncology evidence-based review and recommendations.” Gynecol Oncol 143(2): 421-427.

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Burnout and compassion fatigue are endemic among healthcare providers. It has been estimated that half of all medical students, residents and attending physicians experience burnout, and that physicians suffer more burnout than do other American workers [7], [8] and [9]. Conflicting data suggest that primary care physicians on the ‘front line’ experience the lowest job satisfaction and the highest burnout, while the oncology, trauma and surgical literature show that physicians dealing with the most acutely ill patients have a high prevalence of burnout. In a meta-analysis of burnout among healthcare professionals that care for patients with cancer, the prevalence of emotional exhaustion was 36%, depersonalization 34% and low sense of personal accomplishment 25%, with severe involvement in up to 51% of surveyed subjects [10]. Forty percent of surgical oncologists, 35% of medical oncologists and 64% of obstetrician gynecologists were estimated to have symptoms of burnout in specialty specific surveys [11], [12] and [13]. While it is to be expected that caring for extremely ill and dying patients is emotionally draining, it is alarming that doing so causes potential harm to the physician as well.

Filardo, G., G. Ailawadi, B. D. Pollock, B. da Graca, D. M. Sass, T. K. Phan, D. E. Montenegro, V. Thourani and R. Damiano (2016). “Sex differences in the epidemiology of new-onset in-hospital post-coronary artery bypass graft surgery atrial fibrillation: A large multicenter study.” Circ Cardiovasc Qual Outcomes: 2016 Oct [Epub ahead of print].

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BACKGROUND: New-onset atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG) is associated with increased morbidity and poorer long-term survival. Although many studies show differences in outcome in women versus men after CABG, little is known about the sex-specific incidence and characteristics of post-CABG AF. METHODS AND RESULTS: Overall, 11 236 consecutive patients without preoperative AF underwent isolated CABG from 2002 to 2010 at 4 US academic medical centers and 1 high-volume specialty cardiac hospital. Data routinely collected for the Society of Thoracic Surgeons database were augmented with details on new-onset post-CABG AF events detected via continuous in-hospital ECG/telemetry monitoring. Unadjusted incidence of post-CABG AF was 29.5% (3312/11 236) overall, 30.2% (2485/8214) in men, and 27.4% (827/3022) in women. After adjustment for Society of Thoracic Surgeons-recognized risk factors, women had significantly lower risk for post-CABG AF (odds ratio [95% confidence interval]=0.75 [0.64-0.89]), shorter first, longest, and total duration of AF episodes (mean difference [95% confidence interval]=-2.7 [-4.7 to -0.8] hours; -4.1 [-6.9 to -1.2] hours; -2.4 [-2.5 to -2.3] hours, respectively). At 48 hours, AF-free probabilities were 77% for women and 72% for men (P<0.001). Number of episodes (P=0.18), operative mortality (P=0.048), stroke (P=0.126), and discharge in AF (P=0.234) did not differ significantly by sex. CONCLUSIONS: These novel data on sex-specific characteristics of new-onset AF after isolated CABG show that women had lower adjusted risk for post-CABG AF and experienced shorter episodes. Investigation of sex-specific impacts on outcomes is needed to identify optimal strategies for prevention and management to ensure all patients achieve the best possible outcomes.

Gupta, A. K., J. Carviel and W. Abramovits (2016). “Treating alopecia areata: Current practices versus new directions.” Am J Clin Dermatol: 2016 Oct [Epub ahead of print].

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Alopecia areata (AA) is non-scarring hair loss resulting from an autoimmune disorder. Severity varies from patchy hair loss that often spontaneously resolves to severe and chronic cases that can progress to total loss of scalp and body hair. Many treatments are available; however, the efficacy of these treatments has not been confirmed, especially in severe cases, and relapse rates are high. First-line treatment often includes corticosteroids such as intralesional or topical steroids for mild cases and systemic steroids or topical immunotherapy with diphenylcyclopropenone or squaric acid dibutylester in severe cases. Minoxidil and bimatoprost may also be recommended, usually in combination with another treatment. Ongoing research and new insights into mechanisms have led to proposals of innovative therapies. New directions include biologics targeting immune response as well as lasers and autologous platelet-rich plasma therapy. Preliminary data are encouraging, and it is hoped this research will translate into new options for the treatment of AA in the near future.

Hicks, D. A., C. E. Galimanis, P. G. Webb, M. A. Spillman, K. Behbakht, M. C. Neville and H. K. Baumgartner (2016). “Claudin-4 activity in ovarian tumor cell apoptosis resistance and migration.” BMC Cancer 16(1): 788.

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BACKGROUND: Claudin-4 is a transmembrane protein expressed at high levels in the majority of epithelial ovarian tumors, irrespective of subtype, and has been associated with tumor cells that are both chemoresistant and highly mobile. The objective of this study was to determine the functional role that claudin-4 plays in apoptosis resistance and migration as well as the therapeutic utility of targeting claudin-4 activity with a small mimic peptide. METHODS: We examined claudin-4 activity in human ovarian tumor cell lines (SKOV3, OVCAR3, PEO4) using in vitro caspase and scratch assays as well as an in vivo mouse model of ovarian cancer. Claudin-4 activity was disrupted by treating cells with a small peptide that mimics the DFYNP sequence in the second extracellular loop of claudin-4. Claudin-4 expression was also altered using shRNA-mediated gene silencing. RESULTS: Both the disruption of claudin-4 activity and the loss of claudin-4 expression significantly increased tumor cell caspase-3 activation (4 to 10-fold, respectively) in response to the apoptotic inducer staurosporine and reduced tumor cell migration by 50 %. The mimic peptide had no effect on cells that lacked claudin-4 expression. Female athymic nude mice bearing ZsGreen-PEO4 ovarian tumors showed a significant decrease in ovarian tumor burden, due to increased apoptosis, after treatment with intraperitoneal injections of 4 mg/kg mimic peptide every 48 h for three weeks, compared to control peptide treated mice. CONCLUSION: Claudin-4 functionally contributes to both ovarian tumor cell apoptosis resistance and migration and targeting extracellular loop interactions of claudin-4 may have therapeutic implications for reducing ovarian tumor burden.