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Abstract: Aim: Ovarian metastases from gastrointestinal tract malignancies have been considered an ominous finding with poor prognosis. The aim of this project was to determine the impact on survival, and potential cure, when cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are combined to treat peritoneal malignancy in women with Krukenberg tumours. Method: A retrospective analysis of prospectively collected data between January 2010 and July 2015. Female patients undergoing complete CRS (macroscopic tumour removal) and HIPEC for pseudomyxoma peritonei (PMP) of appendiceal origin, or colorectal peritoneal metastases (CPM) were included. Survival was estimated using the Kaplan–Meier method and survival rates compared using the log‐rank test. Results: In total, 889 patients underwent surgery for peritoneal malignancy, of whom 551 were female. Of these, 504/551 (91%) underwent complete CRS and HIPEC. Overall, 405/504 (80%) had at least one involved ovary removed either during CRS and HIPEC or at their index prereferral operation. Three hundred and fifty‐two patients (87%) had an appendiceal tumour and 53 (13%) had CPM. At a median follow up of 40 months, overall survival (OS) did not differ significantly between patients with or without ovarian involvement in women with a primary low‐grade appendiceal tumour or CPM. In women with high‐grade primary appendiceal pathology, OS was significantly lower in patients with ovarian metastases compared with those without ovarian involvement. Conclusion: Women with ovarian metastases from low‐grade appendiceal tumours or colorectal cancer treated with CRS and HIPEC have similar survival rates to patients without ovarian metastases. Long‐term survival and cure is feasible in patients amenable to complete tumour removal. [ABSTRACT FROM AUTHOR]

A study was conducted to explore the genetic polymorphism at ZuBeCa3 microsatellite and to estimate the association between microsatellite polymorphism and mammary cancer in dogs. Three genotypes namely AA, AB and BB were observed both in dogs affected by mammary cancer and in non-affected dogs. In the affected group, the frequency of genotype and allele was 0.63 for AA, 0.25 for AB and 0.12 for BB genotype, and 0.76 for A and 0.24 for B allele. In the nonaffected group, the frequency of AA, AB and BB genotype was 0.39, 0.38 and 0.23 and the frequency of A and B allele was 0.58 and 0.42, respectively. Histopathological observation classified the cancer-affected animals into three groups namely, malignant solid mammary carcinoma, malignant papillary adenocarcinoma and benign papillary adenoma in which the frequency of A allele was relatively more predominant in benign tumor group, which is more than 80%. Statistical tests showed significant differences ( P < 0.01) of allelic distribution between tumor-affected and non-affected group, which reveals the effect of polymorphism on occurrences of mammary cancer in dogs. Besides, χ2 test also reflected the significant effect of genotypes on occurrences of three groups of mammary cancer in dogs. [ABSTRACT FROM AUTHOR]

A 25-year-old male patient presented with palmoplantar keratoderma, dystrophic nails, severe plantar pain and oral leukokeratosis since birth. On genetic analysis, a heterozygous KRT6A gene missense mutation (c.1381G > A, p.Glu461Lys in exon 7) was identified by next-generation sequencing technology, consistent with pachyonychia congenita 6a. Oral simvastatin 40 mg was started once daily, and after 16 weeks of therapy, excellent improvement was noted in palmoplantar keratoderma and plantar pain. The maximum thickness of his foot callosity reduced by 4 mm on ultrasonography, and the Dermatology Life Quality Index score dropped significantly by eight points. These benefits may be attributed to inhibition of KRT6A gene expression, modulation of autophagy and mitophagy and Keap1-Nrf2 signalling activation; the latter two mechanisms of statins previously undiscussed in the context of pachyonychia congenita. Simvastatin and other statins are pathogenesis-targeted, disease-modifying therapy in pachyonychia congenita, therefore qualifying as a promising treatment avenue and warranting further clinical trials., (© 2022 Australasian College of Dermatologists.)

Background Human aging is associated with increased risk of thrombosis, but the mechanisms are poorly defined. We hypothesized that aging induces peroxide-dependent release of neutrophil extracellular traps that contribute to thrombin generation and thrombosis. Methods and Results We studied C57BL6J mice and littermates of glutathione peroxidase-1 transgenic and wild-type mice at young (4 month) and old (20 month) ages and a healthy cohort of young (18-39 years) or middle-aged/older (50-72 years) humans. In plasma, we measured thrombin generation potential and components of neutrophil extracellular traps (cell-free DNA and citrullinated histone). Aged wild-type mice displayed a significant increase in thrombin generation that was decreased in aged glutathione peroxidase-1 transgenic mice. Both aged wild-type and aged glutathione peroxidase-1 transgenic mice demonstrated similar elevation of plasma cell-free DNA compared with young mice. In contrast, plasma levels of citrullinated histone were not altered with age or genotype. Release of neutrophil extracellular traps from neutrophils in vitro was also similar between young and aged wild-type or glutathione peroxidase-1 transgenic mice. Treatment of plasma or mice with DNase 1 decreased age-associated increases in thrombin generation, and DNase 1 treatment blocked the development of experimental venous thrombi in aged C57BL6J mice. Similarly, thrombin generation potential and plasma cell-free DNA, but not citrullinated histone, were higher in middle-aged/older humans, and treatment of plasma with DNase 1 reversed the increase in thrombin generation. Conclusions We conclude that DNase 1 limits thrombin generation and protects from venous thrombosis during aging, likely by hydrolyzing cell-free DNA.

Recently, topical Tranexamic acid (TXA) has been used in melasma management. On detail search of literature, this may be the first study-assessing efficacy on combining of Topical TXA with GA peel in melasma. The aim of this study is to assess efficacy, safety, and improvement in quality of life index on combining 30% GA peel with 5% TXA solution topically in melasma of epidermal type. Sixty patients of epidermal melasma were included in the study and were categorized into two groups: Combination group was treated with 30% GA peel at 2 weekly intervals with 5% TXA solution applied twice daily and Control group was treated with only 30% GA peel every 2 weeks for 12 weeks. Melasma area severity index (MASI) was used for assessing clinical improvement. Hi-MELASQOL and HRQOL scales were used to measure Melasma related quality of life and were compared between both groups. At each visit, adverse effects were noted. A significantly decreasing trend was seen regarding the MASI score when compared within the group, but the difference was statistically not significant between the two groups at 12 weeks. However, significant reduction in MASI score was attained earlier in the combination group than the control group. Similarly, there was significant improvement in Hi-MELASQOL and HRQOL in both the groups, but the difference between them was statistically not significant. Side effects experienced by patients in both groups were trivial and did not require stoppage of therapy. This study concluded that topical TXA with GA peel has comparable result with GA peel alone, but the therapeutic response was achieved in patients of combination group earlier in comparison to control group patients., (© 2021 Wiley Periodicals LLC.)

Glycolic acid (GA), lactic acid (LA) and trichloroacetic acid (TCA) peels have been used in various combinations for treating melasma patients, but none of the studies have compared their therapeutic efficacy and improvement in quality of life (QOL) index with these three peeling agents in melasma. Our study aims to compare the clinical efficacy, safety, tolerability and improvement in QOL index between 30% GA, 92% LA, and 15% TCA peeling in epidermal melasma. Ninety patients were divided into three groups with 30 in each. First group was treated with 30% GA peel, second with 92% LA peel, and third with 15% TCA peel at every 2 weeks interval for 12 weeks. Melasma area severity index (MASI) and QOL index (Melasma quality of life and Health related quality of life index) were used for clinical evaluation. Patients were observed for side effects and tolerability. The mean MASI score after therapy was significantly lower in patients treated with GA and TCA peels as compared with the group receiving LA peel. However, there was no significant difference in the mean MASI scoring at 12 weeks between GA peel and TCA peel groups. The improvement in QOL index was higher among patients undergoing GA peel followed by TCA and LA peel. Adverse effects were noted mostly with TCA peels followed by GA and LA peel. Thus, GA and TCA peels were equally efficacious and more effective than LA peels. LA peel had minimum side effects and better tolerability than GA and TCA peels., (© 2020 Wiley Periodicals LLC.)

This study investigated the direct roles of hydrogen peroxide (H 2 O 2 ) in kidney aging using transgenic mice overexpressing glutathione peroxidase-1 (GPX1 TG). We demonstrated that kidneys in old mice recapitulated kidneys in elderly humans and were characterized by glomerulosclerosis, tubular atrophy, interstitial fibrosis, and loss of cortical mass. Scavenging H 2 O 2 by GPX1 TG significantly reduced mitochondrial and total cellular reactive oxygen species (ROS) and mitigated oxidative damage, thus improving these pathologies. The potential mechanisms by which ROS are increased in the aged kidney include a decreased abundance of an anti-aging hormone, Klotho, in kidney tissue, and decreased expression of nuclear respiratory factor 2 (Nrf2), a master regulator of the stress response. Decreased Klotho or Nrf2 was not improved in the kidneys of old GPX1 TG mice, even though mitochondrial morphology was better preserved. Using laser capture microdissection followed by label-free shotgun proteomics analysis, we show that the glomerular proteome in old mice was characterized by decreased abundance of cytoskeletal proteins (critical for maintaining normal glomerular function) and heat shock proteins, leading to increased accumulation of apolipoprotein E and inflammatory molecules. Targeted proteomic analysis of kidney tubules from old mice showed decreased abundance of fatty acid oxidation enzymes and antioxidant proteins, as well as increased abundance of glycolytic enzymes and molecular chaperones. GPX1 TG partially attenuated the remodeling of glomerular and tubule proteomes in aged kidneys. In summary, mitochondria from GPX1 TG mice are protected and kidney aging is ameliorated via its antioxidant activities, independent and downstream of Nrf2 or Klotho signaling., (© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background Hyperhomocysteinemia is a risk factor for ischemic stroke; however, a targeted treatment strategy is lacking partly because of limited understanding of the causal role of homocysteine in cerebrovascular pathogenesis. Methods and Results In a genetic model of cystathionine beta synthase (CBS) deficiency, we tested the hypothesis that elevation in plasma total homocysteine exacerbates cerebrovascular injury and that memantine, a N-methyl-D-aspartate receptor antagonist, is protective. Mild or severe elevation in plasma total homocysteine was observed in Cbs+/- (6.1±0.3 μmol/L) or Cbs-/- (309±18 μmol/L) mice versus Cbs+/+ (3.1±0.6 μmol/L) mice. Surprisingly, Cbs-/- and Cbs+/- mice exhibited similar increases in cerebral infarct size following middle cerebral artery ischemia/reperfusion injury, despite the much higher total homocysteine levels in Cbs-/- mice. Likewise, disruption of the blood brain barrier was observed in both Cbs+/- and Cbs-/- mice. Administration of the N-methyl-D-aspartate receptor antagonist memantine protected Cbs+/- but not Cbs-/- mice from cerebral infarction and blood brain barrier disruption. Our data suggest that the differential effect of memantine in Cbs+/- versus Cbs-/- mice may be related to changes in expression of N-methyl-D-aspartate receptor subunits. Cbs-/- , but not Cbs+/- mice had increased expression of NR2B subunit, which is known to be relatively insensitive to homocysteine. Conclusions These data provide experimental evidence that even a mild increase in plasma total homocysteine can exacerbate cerebrovascular injury and suggest that N-methyl-D-aspartate receptor antagonism may represent a strategy to prevent reperfusion injury after acute ischemic stroke in patients with mild hyperhomocysteinemia.

Background: Alcoholic steatohepatitis (ASH) is caused in part by the effects of ethanol (EtOH) on hepatic methionine metabolism., Methods: To investigate the phenotypic and epigenetic consequences of altered methionine metabolism in this disease, we studied the effects of 4-week intragastric EtOH feeding with and without the methyl donor betaine in cystathionine beta synthase (CβS) heterozygous C57BL/6J mice., Results: The histopathology of early ASH was induced by EtOH feeding and prevented by betaine supplementation, while EtOH feeding reduced and betaine supplementation maintained the hepatic methylation ratio of the universal methyl donor S-adenosylmethionine (SAM) to the methyltransferase inhibitor S-adenosylhomocysteine (SAH). MethylC-seq genomic sequencing of heterozygous liver samples from each diet group found 2 to 4% reduced methylation in gene bodies, but not promoter regions of all autosomes of EtOH-fed mice, each of which were normalized in samples from mice fed the betaine-supplemented diet. The transcript levels of nitric oxide synthase (Nos2) and DNA methyltransferase 1 (Dnmt1) were increased, while those of peroxisome proliferator receptor-α (Pparα) were reduced in EtOH-fed mice, and each was normalized in mice fed the betaine-supplemented diet. DNA pyrosequencing of CβS heterozygous samples found reduced methylation in a gene body of Nos2 by EtOH feeding that was restored by betaine supplementation and was correlated inversely with its expression and positively with SAM/SAH ratios., Conclusions: The present study has demonstrated relationships among EtOH induction of ASH with aberrant methionine metabolism that was associated with gene body DNA hypomethylation in all autosomes and was prevented by betaine supplementation. The data imply that EtOH-induced changes in selected gene transcript levels and hypomethylation in gene bodies during the induction of ASH are a result of altered methionine metabolism that can be reversed through dietary supplementation of methyl donors., (Copyright © 2014 by the Research Society on Alcoholism.)

In vertebrates and invertebrates, relationships between diet and health are controlled by a conserved signalling pathway responsive to insulin-like ligands. In invertebrate models for example, forkhead transcription factor family O (FOXO) transcription factors in this pathway regulate the rate of aging in response to dietary cues, and in vertebrates, obesity and age-induced deficits in the same pathway are thought to contribute to dysregulation of hepatic gluconeogenesis through genes such as phosphoenolpyruvate carboxykinase (PEPCK). Recently, we have begun to screen for dietary constituents capable of regulating this pathway in our cell culture model. Here, we identify three black tea theaflavins, theaflavin 3-O-gallate, theaflavin 3'-O-gallate, theaflavin 3,3'di-O-gallate and thearubigins as novel mimics of insulin/IGF-1 action on mammalian FOXO1a, PEPCK and moreover we provide evidence that the effects on this pathway of the green tea constituent (-)-epigallocatechin gallate depend on its ability to be converted into these larger structures. With the exception of water, tea is the most popular drink globally, but despite this, little is known about the biological availability of black tea polyphenols in vivo or the molecular target(s) mediating the effects presented here. Further investigation in these two areas might provide insight into how age-related metabolic disease may be deferred.

Fifty patients of both sexes with clinically suspected cosmetic dermatitis were subjected to patch testing with a cosmetic and fragrance series, approved by the Contact and Occupational Dermatosis Forum of India (CODFI), and with selected allergens from the Indian Standard Series (ISS). Most of these patients were young adults between 10-29 years; the mean age was 27.5 years. The majority of the patients had cosmetic dermatitis of <1 year duration (68%). The occupational profiles of the patients included students (46%), housewives (18%), teachers (10%) and laborers (4%). A miscellaneous group, comprised of tailors, farmers, staff nurses, beauticians, jewellers and engineers, accounted for the remaining 22%. The most commonly involved site was the face, followed by the forehead, neck and scalp. Patch testing of these patients revealed that, out of the 50 subjects tested, thirty-three (66%) reacted to one or more allergens. Fragrance components were the most common offending allergen (51.5%) followed by preservatives (39.3%), paraphenylenediamine (PPD) (21.2%), and cetrimide and tertiary butyl hydroquinone (12.1% each), in descending order of frequency. Hence, patch testing, with the standard series supplemented by personal cosmetics; should be considered for patients with cosmetic dermatitis to determine the offending allergen so as to avoid further contact with that allergen.

Forty patients with psoriasis and forty healthy controls were enrolled to study the levels of total blood thiols (an important part of the body's antioxidant defence system) and plasma malondialdehyde (a lipid peroxidation product). The levels of total blood thiols in psoriatic patients in the acute phase were significantly lower than those in controls, but total blood thiol levels in psoriatic patients in the remission phase were not significantly different from those in controls. There was a significant difference between levels of total blood thiols of patients in the acute phase and in remission. The levels of plasma MDA were significantly raised in psoriatic patients in the acute phase as compared to those in controls and in patients in remission. The differences in levels of plasma MDA were not significant between control subjects and patients in remission. These findings suggest a role of oxidative stress in the etiopathogenesis of psoriasis.