Citations

ABSTRACT Background Sunlight has profound impacts on physical and mental health, beyond vision, including effects on circadian rhythms, alertness, mood, and sleep. A family history of any mood disorders is strongly associated with psychiatric disorders including bipolar disorder. The purpose of this study was to evaluate the association between a family history of any mood disorder in patients with bipolar I disorder and solar insolation at varied international onset locations. Methods Data for this analysis were available from 5842 patients with a diagnosis of bipolar I disorder obtained at 83 collection sites in both hemispheres. This included 4752 patients from 71 collection sites in the northern hemisphere and 1090 patients from 12 collection sites in the southern hemisphere. Patient data variables were obtained from records or interviews. Solar insolation data were obtained from The National Aeronautics and Space Administration (NASA) Power database for each onset location, and the ratio of the mean monthly minimum/mean monthly maximum solar insolation was calculated. Typically, the ratio is largest near the equator (little yearly change in solar insolation) and smallest near the poles (large yearly change in solar insolation). Results A significant relationship was found between a family history of any mood disorder, the ratio of the mean monthly minimum/mean monthly maximum solar insolation, and gender. The odds of a family history of mood disorder increased as patient location nears the poles and decreased near the equator. Female gender also increased the odds of having a family history of a mood disorder. Conclusions This study highlighted the association between family history, solar insolation, and gender in international patients with bipolar I disorder. Given the profound effects of sunlight on human health, the family of patients with bipolar disorder who live in the same location with the same solar insolation, and especially females, may be at increased risk for a mood disorder.

Abstract Background: The fastest growing cause of cancer related death is hepatocellular carcinoma (HCC), in part due to the rising prevalence of nonalcoholic steatohepatitis (NASH). HCC cases are expected to increase during 2015-2030. Cholecystokinin (CCK), blood levels are increased in those consuming high fat diets and CCK receptors have been identified in normal liver, fibroblasts, and immune cells. Hypothesis: We hypothesize that CCK receptor blockade could decrease NASH and prevent HCC in a mouse model.Methods: We examined whether CCK receptor blockade with proglumide could decrease NASH in the choline deficient ethionine supplemented (CDE)-diet mouse model. Two cohorts of Female C57BL/6 mice (N=65) mice were examined: (1) a preventive study in which mice were treated for 12 and 18 weeks to determine if proglumide could prevent NASH and HCC and (2) a ‘reversal study’ in which histologic and biochemical NASH was induced on a 75% CDE high fat diet for 12 weeks followed by treatment with proglumide for 6 weeks (until week 18) while remaining on the CDE diet to determine if CCK-receptor blockade could reverse NASH once established. Control mice received the same high fat diet with choline and half received proglumide therapy. Results: Alanine aminotransferase, aspartate aminotransferases, and bilirubin were increased in mice on the CDE/Regular (untreated water) diet and these values returned to near normal with proglumide therapy in the prevention study and also reversed after NASH was established. Histologic scoring showed significant decreased inflammation, fibrosis and steatosis in mice on the high fat CDE diet when treated with proglumide. 35% of the mice (N=23) at week 18 developed HCC or dysplastic nodules on the CDE diet while none of the mice in the CDE/proglumide prevention (N=15) or reversal therapy groups (N=15) had HCC. Mice on the lard-control diet had fatty livers at week 18 but no evidence of NASH histologically or biochemically and no HCC. Fibrosis was decreased in mice treated with proglumide as evidence by Masson’s trichrome stain and Western blot for FAP. Gene expression of the liver’s collagen-4, TGFβR11, PDGH-Rβ, and collagen-1α1 as determined by qRT-PCR decreased with proglumide treatment. Control diet fed mice had normal serum tests and fibrosis biomarkers. Conclusion: This data supports our novel hypothesis that CCK receptors play a role in NASH-associated HCC. CCK receptor blockade decreased histologic and biochemical evidence of NASH and prevented HCC. Since proglumide has already been tested in human subjects for peptic ulcer disease decades ago and is known to be orally bioavailable, results of our study could easily be translated into a clinical trial in human subjects to improve NASH to prevent HCC. Supported by AGA Research Foundation, Ruesch Foundation, and a grant from NIH, TL1TR001431 Citation Format: Martha D. Gay, Victor Ciofoaia, Sandeep Nadella, Hong Cao, Matthew Huber, Robin D. Tucker, Narayan Shivapurkar, Bhaskar Kallakury, Alexander H. Kroemer, Jill P. Smith. Cholecystokinin receptor antagonist proglumide reverses nonalcoholic steatohepatitis and prevents hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2728.

ObjectiveTo confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.MethodData were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth‐cohort, family history, polarity of first episode and country physician density.ResultsThere was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth‐cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth‐cohort (all estimated coefficientsP< 0.001).ConclusionA large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LEDlighting, mobile devices backlit withLEDs) may influence adaptability to a springtime circadian challenge.