Decreased differentiation capacity and altered expression of extracellular matrix components in irradiation-mediated senescent human breast adipose-derived stem cells.

Radiotherapy is widely used for the treatment of breast cancer. However, we have shown that ionizing radiation can provoke premature senescence in breast stromal cells. In particular, breast stromal fibroblasts can become senescent after irradiation both in vitro and in vivo and they express an inflammatory phenotype and an altered profile of extracellular matrix components, thus facilitating tumor progression. Adipose-derived stem cells (ASCs) represent another major component of the breast tissue stroma. They are multipotent cells and due to their ability to differentiate in multiple cell lineages they play an important role in tissue maintenance and repair in normal and pathologic conditions. Here, we investigated the characteristics of human breast ASCs that became senescent prematurely after their exposure to ionizing radiation. We found decreased expression levels of the specific mesenchymal cell surface markers CD105, CD73, CD44, and CD90. In parallel, we demonstrated a significantly reduced expression of transcription factors regulating osteogenic (i.e., RUNX2), adipogenic (i.e., PPARγ), and chondrogenic (i.e., SOX9) differentiation; this was followed by an analogous reduction in their differentiation capacity. Furthermore, they overexpress inflammatory markers, that is, IL-6, IL-8, and ICAM-1, and a catabolic phenotype, marked by the reduction of collagen type I and the increase of MMP-1 and MMP-13 expression. Finally, we detected changes in proteoglycan expression, for example, the upregulation of syndecan 1 and syndecan 4 and the downregulation of decorin. Notably, all these alterations, when observed in the breast stroma, represent poor prognostic factors for tumor development. In conclusion, we showed that ionizing radiation-mediated prematurely senescent human breast ASCs have a decreased differentiation potential and express specific changes adding to the formation of a permissive environment for tumor growth.

Increased Brain Serotonin Rather Than Increased Blood Acetaldehyde as a Common Denominator Behind Alleged Disulfiram-Like Reactions.

Several pharmaceutical agents are known to produce ethanol intolerance, which is often depicted as disulfiram-like reaction. As in the case with disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases, albeit this has not been confirmed in all cases by blood acetaldehyde measurements. Herein, cefamandole, cotrimoxazole, griseofulvin, procarbazine, and propranolol, which are reported to produce a disulfiram-like reaction, as well as disulfiram, were administered to Wistar rats and the hepatic activities of ethanol metabolizing enzymes along with the levels of brain monoamines were determined. Blood acetaldehyde was also evaluated after ethanol administration in rats pretreated with the abovementioned pharmaceutical products. Disulfiram, cefamandole, and procarbazine significantly increased blood acetaldehyde levels after ethanol administration, while on the contrary, cotrimoxazole, griseofulvin, and propranolol had no effect on blood acetaldehyde. Interestingly, all substances used, except disulfiram, increased the levels of brain serotonin. According to our findings, cotrimoxazole, griseofulvin, and propranolol do not produce a typical disulfiram-like reaction, because they do not increase blood acetaldehyde when given together with ethanol. On the other hand, all tested agents share the common property to enhance brain serotonin, whereas a respective effect of ethanol is well established. Hence, the ethanol intolerance produced by these agents, whether blood acetaldehyde concentration is elevated or not, could be the result of a "toxic serotonin syndrome," as in the case of the concomitant use of serotonin-active medications that provoke clinical manifestations similar to those of a disulfiram reaction.

Evidence for the efficacy of disulfiram and copper combination in glioblastoma multiforme - A propos of a case.

Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately this condition is incurable. Besides the dismal prognosis of GBM, financial factors have also presented challenges for advancing treatments. Taking into consideration the high cost of developing new anticancer drugs as well as the fact that GBM is a rare disease, thus further limiting financial incentive for drug development, it becomes obvious that there has been growing interest for repurposing candidates. One of the most promising drugs to repurpose for treating GBM is disulfiram (DSF). DSF is a relatively nontoxic drug used for more than sixty years in the treatment of chronic alcoholism with the ability to readily cross the blood-brain barrier. Repurposing DSF for use as an anticancer drug in general has recently become of interest because of its preclinically described anticancer effects against various human cancers. Interestingly, a number of these effects were shown to be copper (Cu)-dependent. The purpose of this paper was to review the existing literature surrounding preclinical and clinical data on the effects of DSF -alone or in combination with Cu- in GBM. In addition, we present the first case of a GBM patient safely treated with DSF/Cu combination along with standard therapy exhibiting remarkably increased progression-free (PFS) and overall survival (OS).

Impact of childhood trauma on risk of relapse requiring psychiatric hospital admission for psychosis.

Relapse in psychosis typically necessitates admission to hospital placing a significant financial burden on the health service. Exposure to childhood trauma is associated with an increased risk of psychosis, however, the extent to which this influences relapse is unclear. This report summarises current research investigating the influence of childhood trauma on relapse requiring psychiatric hospital admission for psychosis. Seven studies were included; two revealed a positive association between childhood trauma and relapse admission, two studies found a negative relationship and three found no significant difference. Inconsistent current evidence suggests a need for further research in this area.

The Alcohol Intolerance Produced by Isoniazid Is Not Due to a Disulfiram-Like Reaction Despite Aldehyde Dehydrogenase Inhibition.

BACKGROUND/AIMS: Isoniazid (ISO) has been reported to inhibit the hepatic aldehyde dehydrogenase (ALDH) and to cause a disulfiram (DIS)-like reaction, albeit there are no reports demonstrating increased blood acetaldehyde levels after co-administration of ISO with alcohol. The aim of our study was to clarify whether the alcohol intolerance produced by ISO is indeed due to a typical DIS-like reaction. METHODS: DIS and ISO were administered to Wistar rats and the hepatic ethanol (ETH) metabolizing enzyme activities along with the levels of brain monoamines were determined. Blood acetaldehyde levels were also evaluated after co-administration of ETH with DIS or ISO. RESULTS: Despite inhibition of the hepatic ALDH, ISO did not result in elevated blood acetaldehyde levels after ETH administration, probably due to the induction of cytochrome P450 2E1 which theoretically leads to an increased elimination rate of acetaldehyde preventing its accumulation. Moreover, ISO produced some minor, but statistically significant, alterations in central monoaminergic neurotransmission. CONCLUSION: Our results demonstrate for the first time that despite ALDH inhibition ISO does not provoke a typical DIS-like reaction since it does not increase blood acetaldehyde levels after co-administration with ETH. The possibility that the ETH intolerance observed in ISO treatment is a central synergistic effect cannot be excluded.

Metformin in Type 2 Diabetes: Evidence for its Beneficial Effects on Frailty and Sarcopenia.

This narrative review aimed to discuss the potential interplay among frailty syndrome, sarcopenia and metformin in type 2 diabetes mellitus (T2DM). There is emerging evidence on the potential protective role of metformin on both frailty and sarcopenia. However, results are not always consistent. Thus, further research is needed to provide a definitive answer on any role of metformin in improving frailty and/or sarcopenia in T2DM.

Folic Acid and Diabetic Foot Ulcers.

Diabetic foot ulcers (DFUs) remain a major cause of morbidity. This narrative mini-review aimed to investigate the potential role of folic acid (FA) in DFUs. Individuals with DFUs exhibit lower levels of FA and lower daily intake, compared to those without DFUs. There is preliminary evidence that FA administration may contribute to improved DFUs healing. In this context, regular evaluation of dietary FA intake may prove important towards reduction or even prevention of DFUs. However, data are still limited and further research is required to enable definitive conclusions and any recommendations.

Frailty, sarcopenia and diabetic kidney disease: where do we stand?

The aim of this narrative non-systematic review was to investigate the potential interplay among frailty syndrome, sarcopenia and diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients. Data derived from a limited number of studies underline that DKD is a significant risk factor for frailty. On the other hand, frailty syndrome poses a higher risk for end-stage renal disease (ESRD) in subjects with DKD. In addition, frailty seems to affect the cognitive function and social life of DKD individuals, whilst as DKD deteriorates, there is a higher prevalence of sarcopenia which is a fundamental frailty factor. As a result, it is shown that a bidirectional relation is established between these entities, as diabetes mellitus (DM) affects the components of frailty and sarcopenia and vice versa. This vicious cycle is created through multiple pathophysiologic mechanisms, including the anabolic role of insulin, low-grade inflammation, cytokines and endothelial function, prompting further investigation in this area. Specific nutritional and exercise interventions are imperative to be established in order to ameliorate potential adverse outcomes, concerning these entities.

Vitamin E and diabetic foot ulcers.

This narrative mini-review discusses vitamin E levels in subjects with diabetic foot ulcers (DFUs). Vitamin E may be reduced in subjects with DFUs, but this finding is inconsistent. Its administration appears to benefit patients with DM, delaying the onset of complications, including DFU. There is also evidence that it may promote DFU healing. Nonetheless, further studies are required to confirm these promising results and estimate vitamin E administration's cost-effectiveness.

Zinc Levels and Diabetic Foot Ulcers: A Mini Review.

The aim of this nonsystematic mini review was to discuss serum levels of zinc in subjects with diabetic foot ulcers (DFUs). Most studies have reported low zinc levels in subjects with DFUs. Furthermore, there is some evidence that oral zinc supplementation may have a positive and beneficial impact on DFUs healing. Nonetheless, findings have so far not provided definitive answers. More studies are needed to clarify the role of zinc and its supplementation in this setting.

Magnesium and Diabetic Foot Ulcers: A Mini Review.

There is accumulating evidence that magnesium, an important mineral having a pivotal role in many physiological functions, may be important in development and healing of diabetic foot ulcers (DFUs). In this non-systematic mini review, we discuss the role of magnesium in DFUs, as well as the effects of magnesium administration in DFUs. Reduced Mg levels appear to be associated with DFUs. Moreover, Mg administration may be beneficial for the outcome of DFUs. Further investigation is imperative in order to shed more light on these findings.

Vitamin B12 and Diabetic Foot: Α Mini-Review.

This narrative mini-review article aimed to investigate the potential association of vitamin B12 levels with diabetic neuropathy (DN) and diabetic foot ulcers (DFUs). It was demonstrated that B12 deficiency seems to be related to DFUs in cases of metformin administration and bariatric surgery. B12 supplementation with dietary measures and agents may improve DN and quality of life (QoL). However, data are still preliminary and more experience is needed.

Sarcopenia, Frailty and Diabetic Foot: A Mini Narrative Review.

The aim of this narrative mini review was to investigate the potential association of the diabetic foot (DF) with sarcopenia and frailty. Data is still limited, but it appears that DF patients may be more prone to frailty. In addition, patients with DF and sarcopenia exhibit more frequently foot ulcers and amputations, as well as increased mortality rates post-operatively. Further studies are now needed to see how these realizations may be used in clinical practice, aiming to improve DF outcomes.

Association between sleep insufficiency and dyslipidemia: a cross-sectional study among Greek adults in the primary care setting.

Objective: To investigate the potential association between sleep insufficiency and dyslipidemia (DL) in the primary care setting using self-reported questionnaires. Material and Methods: 957 adults aged between 19 and 86 years old from the rural area of Thrace, Greece were enrolled in this cross-sectional study. Multistage stratifed cluster sampling was used and the subjects were classifed into three groups according to sleep duration [short (<6h), normal (6-8h), and long (>8h) sleep duration]. DL was defined by a positive response to the question "Have you ever been told by a doctor or health professional that your blood cholesterol or triglyceride levels were high?", or if they were currently taking antilipidemic agents. Sleep quality, utilizing Epworth sleepiness scale, Athens insomnia scale, Pittsburgh sleep quality index and Berlin questionnaire, was also examined. Results: DL prevalence was significantly associated with short sleep duration (aOR=2.18, p<0.001) and insomnia (aOR=1.43, p=0.050), while its relation with poor sleep quality (aOR=1.31, p=0.094) and risk for obstructive sleep apnea (aOR=1.32, p=0.097) were of marginal statistical significance. Concerning insomnia subtypes, DL was significantly associated with difficulties maintaining sleep (aOR=2.99, p<0.001) and early morning awakenings (aOR=1.38, p=0.050), but not difficulties initiating sleep (aOR=1.18, p=0.328). Conclusion: This study reveals an association between sleep pathology and DL. Thus, early pharmacological and cognitive or behavioral interventions that improve sleep are deemed necessary in order to decrease DL burden.

Exploring the association between sleep insufficiency and self-reported cardiovascular disease among northeastern Greeks.

Objective: To explore the association of sleep characteristics with cardiovascular disease (CVD) using self-reported questionnaires. Material and Methods: 957 adults between 19 and 86 years old were enrolled in this cross-sectional study. The participants were classified into three groups [short (<6h), normal (6-8h), and long (>8h) sleepers] by using multistage stratified cluster sampling. CVD was defined by a positive response to the questions: "Have you been told by a doctor that you have had a heart attack or angina or stroke or have you undergone bypass surgery?". Sleep quality, utilizing Epworth sleepiness scale, Athens insomnia scale, Pittsburgh sleep quality index and Berlin questionnaire, was also examined. Results: Prevalence of CVD was 9.5%. Individuals with CVD exhibited reduced sleep duration by 33 min (p<0.001) and sleep efficiency by 10% (p<0.001). In multivariable logistic regression analysis, adjusting for subjects' sociodemographic, lifestyle habits and health related characteristics, short sleep duration was almost three times more frequent in patients with CVD (aOR=2.86, p<0.001 in the entire sample; aOR=2.68, p=0.019 in women and aOR=2.57, p=0.009 in men). Furthermore, CVD was significantly associated with excessive daytime sleepiness (aOR=2.02, p=0.026), insomnia (aOR=1.93, p=0.010), poor sleep quality (aOR=1.90, p=0.006) and increased risk of obstructive sleep apnea (aOR=2.08, p=0.003). Conclusion: Our study highlights a strong correlation of sleep insufficiency with CVD and promotes early pharmacological or cognitive behavioral interventions in order to protect cardiovascular health.

A Rare Case of Dulaglutide-Associated Angioedema in a Male Patient.

Dulaglutide is an injectable glucagon-like peptide-1 receptor agonist approved for the treatment of adults with type 2 diabetes. Angioedema is defined as self-limiting edema, localized in the deeper layers of the skin and mucosa. Angioedema can be hereditary or acquired which can be allergic due to reactions to foods, insect bites and stings, and latex, drug-induced, caused by physical stimuli and associated with lupus erythematosus and hypereosinophilia. Angioedema represents a rare adverse event of glucagon-like peptide-1 receptor agonists. The only glucagon-like peptide-1 receptor agonist that has been mentioned to induce angioedema in literature is exenatide. We report the first case of dulaglutide-associated angioedema in a 72-year-old male in order to point out to the clinicians this potential rare side effect of this drug and its clinical significance.

Down-Regulation of the Proteoglycan Decorin Fills in the Tumor-Promoting Phenotype of Ionizing Radiation-Induced Senescent Human Breast Stromal Fibroblasts.

Down-regulation of the small leucine-rich proteoglycan decorin in the stroma is considered a poor prognostic factor for breast cancer progression. Ionizing radiation, an established treatment for breast cancer, provokes the premature senescence of the adjacent to the tumor stromal fibroblasts. Here, we showed that senescent human breast stromal fibroblasts are characterized by the down-regulation of decorin at the mRNA and protein level, as well as by its decreased deposition in the pericellular extracellular matrix in vitro. Senescence-associated decorin down-regulation is a long-lasting process rather than an immediate response to γ-irradiation. Growth factors were demonstrated to participate in an autocrine manner in decorin down-regulation, with bFGF and VEGF being the critical mediators of the phenomenon. Autophagy inhibition by chloroquine reduced decorin mRNA levels, while autophagy activation using the mTOR inhibitor rapamycin enhanced decorin transcription. Interestingly, the secretome from a series of both untreated and irradiated human breast cancer cell lines with different molecular profiles inhibited decorin expression in young and senescent stromal fibroblasts, which was annulled by SU5402, a bFGF and VEGF inhibitor. The novel phenotypic trait of senescent human breast stromal fibroblasts revealed here is added to their already described cancer-promoting role via the formation of a tumor-permissive environment.

Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis.

RATIONALE: Stress is a risk factor for psychosis and treatments which mitigate its harmful effects are needed. Cannabidiol (CBD) has antipsychotic and anxiolytic effects. OBJECTIVES: We investigated whether CBD would normalise the neuroendocrine and anxiety responses to stress in clinical high risk for psychosis (CHR) patients. METHODS: Thirty-two CHR patients and 26 healthy controls (HC) took part in the Trier Social Stress Test (TSST) and their serum cortisol, anxiety and stress associated with public speaking were estimated. Half of the CHR participants were on 600 mg/day of CBD (CHR-CBD) and half were on placebo (CHR-P) for 1 week. RESULTS: One-way analysis of variance (ANOVA) revealed a significant effect of group (HC, CHR-P, CHR-CBD (p = .005) on cortisol reactivity as well as a significant (p = .003) linear decrease. The change in cortisol associated with experimental stress exposure was greatest in HC controls and least in CHR-P patients, with CHR-CBD patients exhibiting an intermediate response. Planned contrasts revealed that the cortisol reactivity was significantly different in HC compared with CHR-P (p = .003), and in HC compared with CHR-CBD (p = .014), but was not different between CHR-P and CHR-CBD (p = .70). Across the participant groups (CHR-P, CHR-CBD and HC), changes in anxiety and experience of public speaking stress (all p's < .02) were greatest in the CHR-P and least in the HC, with CHR-CBD participants demonstrating an intermediate level of change. CONCLUSIONS: Our findings show that it is worthwhile to design further well powered studies which investigate whether CBD may be used to affect cortisol response in clinical high risk for psychosis patients and any effect this may have on symptoms.