May Bacterial Infections Trigger Bullous Pemphigoid? Case Report and Review of Literature.

Bullous pemphigoid (BP) is an autoimmune blistering skin disease, mainly observed in the elderly. Infections have been suggested as possible disease triggers. However, infections may even heavily influence the disease clinical course and mortality. A 75-year-old woman was admitted to hospital for severe erythematosus blistering disease, accompanied by hyper-eosinophilia and hyper-IgE. The culture of bullous fluid was positive for Enterococcus faecalis, the blood culture was positive for Staphylococcus aureus, and the urine culture was positive for Proteus mirabilis and Escherichia coli. Moreover, circulating anti-BP180 IgG was present and the histopathological/ultrastructural examination of a lesional skin biopsy was compatible with BP. High eosinophil levels (up to 3170/µL) were found throughout the clinical course, while values below 1000/µL were associated with clinical improvement. The total IgE was 1273 IU/mL, and specific anti-G/V-penicillin/ampicillin IgE antibodies were positive. The patient had a complete clinical recovery in two months with methyl-prednisolone (40 then 20 mg/day) and low-dose azathioprine (50 mg/day) as a steroid-sparing agent. The steroid treatment was tapered until interruption during a one-year period and intravenous immunoglobulins have been administered for three years in order for azathioprine to also be interrupted. The patient stopped any treatment five years ago and, in this period, has always been in good health. In this case, the contemporaneous onset of different bacterial infections and BP is suggestive of bacterial infections acting as BP trigger(s), with allergic and autoimmune pathways contributing to the disease pathogenesis.

Migraine and cluster headache show impaired neurosteroids patterns.

BACKGROUND: Perturbation of neuronal excitability contributes to migraine. Neurosteroids modulate the activity of γ-aminobutyric acid A and N-methyl-d-aspartate receptors, and might be involved in the pathogenesis of migraine. Here, we measured plasma levels of four neurosteroids, i.e., allopregnanolone, epiallopregnanolone, dehydroepiandrosterone and deydroepiandrosterone sulfate, in patients affected by episodic migraine, chronic migraine, or cluster headache. METHODS: Nineteen female patients affected by episodic migraine, 51 female patients affected by chronic migraine, and 18 male patients affected by cluster headache were recruited to the study. Sex- and age-matched healthy control subjects (31 females and 16 males) were also recruited. Patients were clinically characterized by using validated questionnaires. Plasma neurosteroid levels were measured by liquid chromatography-tandem mass spectrometry. RESULTS: We found disease-specific changes in neurosteroid levels in our study groups. For example, allopregnanolone levels were significantly increased in episodic migraine and chronic migraine patients than in control subjects, whereas they were reduced in patients affected by cluster headache. Dehydroepiandrosterone and dehydroepiandrosterone sulfate levels were reduced in patients affected by chronic migraine, but did not change in patients affected by cluster headache. CONCLUSION: We have shown for the first time that large and disease-specific changes in circulating neurosteroid levels are associated with chronic headache disorders, raising the interesting possibility that fluctuations of neurosteroids at their site of action might shape the natural course of migraine and cluster headache. Whether the observed changes in neurosteroids are genetically determined or rather result from exposure to environmental or intrinsic stressors is unknown. This might also be matter for further investigation because stress is a known triggering factor for headache attacks in both migraineurs and cluster headache patients.

Changing the Approach to Anticoagulant Therapy in Older Patients with Multimorbidity Using a Precision Medicine Approach.

The ageing of the world population has resulted in an increase in the number of older patients with multimorbid conditions receiving multiple therapies. This emerging clinical scenario poses new challenges, which are mostly related to the increased incidence of adverse effects. This translates into poor clinical care, reduced cost-effectiveness of drug therapies, and social isolation of multimorbid patients due to reduced autonomy. A strategy to address these emerging challenges could involve the personalization of therapies based on the clinical, molecular, and genetic characterization of multimorbid patients. Anticoagulation therapy is a feasible model to implement personalized medicine since it generally involves older multimorbid patients receiving multiple drugs. In this study, in patients with atrial fibrillation, the use of the new generation of anticoagulation therapy, i.e., direct oral anti-coagulants (DOACs), is based on a preliminary assessment of the molecular targets of DOACS and any possible drug⁻drug interactions. Then, the genetic polymorphism of enzymes metabolizing DOACs is studied. After DOAC prescription, its circulating levels are measured. Clinical data are being collected to assess whether this personalized approach improves the safety and efficacy profiles of anticoagulation therapy using DOACs, thereby reducing the costs of healthcare for ageing multimorbid patients.

Nutrition support and clinical outcome in advanced cancer patients.

Newly diagnosed cancer patients are frequently found suffering from a metastatic disease, which poses additional challenges to the delivery of effective therapies. Chemotherapy and radiotherapy are associated with side effects which reduce tolerance to treatment and likelihood of tumour response. Identifying preventable factors of reduced response to therapy would translate into better care of cancer patients. Among other factors, malnutrition, as diagnosed by non-volitional weight loss, and cachexia, as revealed by sarcopenia, are universally recognised negative prognostic factors. Less certainty exists on the role of nutrition therapy in improving cancer patients' body composition and clinical outcome. The reasons for the lack of convincing evidence are manifold, mostly related to the poor design of nutritional trials. Metastatic cancer patients should receive a quantitatively and qualitatively adequate diet, and in case of reduced tolerance of food, artificial nutrition is indicated. Most importantly, nutritional care should target the underlying mechanisms of reduced food intake/impaired anabolic response, and aim at minimising the impact of catabolic crisis, to maximise the recovery phase. The combined and early use of supplemental energies and proteins, as well as modulators of inflammatory response has been shown to improve nutritional status and may also benefit clinical outcome. When part of early palliative care, nutrition therapy improves cancer patients' quality of life and may prolong survival at a fraction of the costs of developing new drugs.

Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential.

Migraine is an important socioeconomic burden and is ranked the sixth cause of years of life lost because of disability in the general population and the third cause of years of life lost in people younger than 50 years. The cornerstone of pharmacological treatment is represented by the acute therapy. The serotonin (5-hydroxytryptamine [5-HT]) receptor subtype 1B/1D agonists, called triptans, are nowadays the first-line acute therapy for patients who experience moderate-to-severe migraine attacks. Unfortunately, a high percentage of patients are not satisfied with this acute treatment, either for lack of response or side effects. Moreover, their mechanism of action based on vasoconstriction makes them unsuitable for patients with previous cardio- and cerebrovascular diseases and for those with uncontrolled hypertension. Since the introduction of triptans, no other acute drug class has passed all developmental stages. The research for a new drug lacking vasoconstrictive effects led to the development of lasmiditan, a highly selective 5-HT1F receptor agonist with minimized interactions with other 5-HT receptor subtypes. Lasmiditan is considered to be the first member of a new drug category, the neurally acting anti-migraine agent (NAAMA). Phase II and III trials had shown superiority compared to placebo and absence of typical triptan-associated adverse events (AEs). Most of the AEs were related to the central nervous system, depending on the high permeability through the blood-brain barrier and mild to moderate severity. The results of ongoing long-term Phase III trials will determine whether lasmiditan will become available in the market, and then active triptan comparator studies will assess patients' preference. Future studies could then explore the safety during pregnancy and breastfeeding or the risk that overuse of lasmiditan leads to medication overuse headache.

Assessing pathophysiology of cancer anorexia.

PURPOSE OF REVIEW: Cancer anorexia is a negative prognostic factor and is broadly defined as the loss of the interest in food. However, multiple clinical domains contribute to the phenotype of cancer anorexia. The characterization of the clinical and molecular pathophysiology of cancer anorexia may enhance the efficacy of preventive and therapeutic strategies. RECENT FINDINGS: Clinical trials showed that cancer anorexia should be considered as an umbrella encompassing different signs and symptoms contributing to appetite disruption in cancer patients. Loss of appetite, early satiety, changes in taste and smell are determinants of cancer anorexia, whose presence should be assessed in cancer patients. Interestingly, neuronal correlates of cancer anorexia-related symptoms have been revealed by brain imaging techniques. SUMMARY: The pathophysiology of cancer anorexia is complex and involves different domains influencing eating behavior. Limiting the assessment of cancer anorexia to questions investigating changes in appetite may impede correct identification of the targets to address.

Does nutrition support have a role in managing cancer cachexia?

PURPOSE OF REVIEW: Cachexia is a negative prognostic factor in cancer patients. The pathogenesis is related to a variable combination of reduced food intake and metabolic changes. However, whether nutritional support may contribute to effectively prevent and treat cachexia remains a debated issue. RECENT FINDINGS: Consistent evidence demonstrates that anabolic windows of opportunity occur during the clinical trajectory of cancer patients. Also, the use of specific nutrients, namely omega-3 fatty acids, may enhance the efficacy of nutritional support when tumor-driven inflammatory response is high. Of greater interest, it is now becoming clearer that the use of nutritional support at key time points in the clinical journey of cancer patients (i.e., perioperative period) may extend its clinical benefits beyond those on nutritional status. SUMMARY: Nutritional support plays a role in managing cancer cachexia, when it is timely delivered, when it provides adequate amounts of calories and proteins, and when it is part of a concurrent palliative care approach. Specific nutrients, that is, omega-3 fatty acids, may help in those cancer patients with high-inflammatory response, and may also contribute to positively influence long-term clinical outcomes.

Cachexia: clinical features when inflammation drives malnutrition.

Cachexia is a clinically relevant syndrome which impacts on quality of life, morbidity and mortality of patients suffering from acute and chronic diseases. The hallmark of cachexia is muscle loss, which is triggered by disease-associated inflammatory response. Cachexia is a continuum and therefore a staging system is needed. Initially, a three-stage system (i.e. pre-cachexia, cachexia and refractory cachexia) was proposed. More recent evidence supports the use of a five-stage classification system, based on patient's BMI and severity of weight loss, to better predict clinical outcome. Also, large clinical trials in cancer patients demonstrated that cachexia emerging during chemotherapy has greater influence on survival than weight loss at baseline. Therefore, becoming widely accepted is the importance of routinely monitoring patients' nutritional status to detect early changes and diagnose cachexia in its early phases. Although cachexia is associated with the presence of anabolic resistance, it has been shown that sustained yet physiological hyperaminoacidaemia, as well as the use of specific nutrients, is able to overcome impaired protein synthesis and revert catabolism. More importantly, clinical evidence demonstrates that preservation of nutritional status during chemotherapy or improvement of body weight after weight loss is associated with longer survival in cancer patients.

Dose response biology of resveratrol in obesity.

Obesity is a major health problem throughout the world, and it is increasing both in prevalence and severity. Pharmaceutical approaches developed for the treatment of obesity, despite short-term benefits, often are associated with rebound weight gain after the cessation of drug use and serious side effects deriving from the medication can occur. Resveratrol has been well recognized as an anti-obesity substance for its lipid-lowering function as well as calorie-restriction effect. This polyphenol induces hormetic dose responses in a wide range of biological models, affecting numerous endpoints of biomedical and therapeutic significance. From an hormetic standpoint, we will discuss the potential relevance of resveratrol in the management of obesity and related comorbid conditions, emphasizing its ability to control simultaneously various pathological mechanisms associated with obesity.

Osteoporosis and alzheimer pathology: Role of cellular stress response and hormetic redox signaling in aging and bone remodeling.

Alzheimer's disease (AD) and osteoporosis are multifactorial progressive degenerative disorders. Increasing evidence shows that osteoporosis and hip fracture are common complication observed in AD patients, although the mechanisms underlying this association remain poorly understood. Reactive oxygen species (ROS) are emerging as intracellular redox signaling molecules involved in the regulation of bone metabolism, including receptor activator of nuclear factor-κB ligand-dependent osteoclast differentiation, but they also have cytotoxic effects that include lipoperoxidation and oxidative damage to proteins and DNA. ROS generation, which is implicated in the regulation of cellular stress response mechanisms, is an integrated, highly regulated, process under control of redox sensitive genes coding for redox proteins called vitagenes. Vitagenes, encoding for proteins such as heat shock proteins (Hsps) Hsp32, Hsp70, the thioredoxin, and the sirtuin protein, represent a systems controlling a complex network of intracellular signaling pathways relevant to life span and involved in the preservation of cellular homeostasis under stress conditions. Consistently, nutritional anti-oxidants have demonstrated their neuroprotective potential through a hormetic-dependent activation of vitagenes. The biological relevance of dose-response affects those strategies pointing to the optimal dosing to patients in the treatment of numerous diseases. Thus, the heat shock response has become an important hormetic target for novel cytoprotective strategies focusing on the pharmacological development of compounds capable of modulating stress response mechanisms. Here we discuss possible signaling mechanisms involved in the activation of vitagenes which, relevant to bone remodeling and through enhancement of cellular stress resistance provide a rationale to limit the deleterious consequences associated to homeostasis disruption with consequent impact on the aging process.

Cellular stress response, redox status, and vitagenes in glaucoma: a systemic oxidant disorder linked to Alzheimer's disease.

Amyloid deposits, constituted of amyloid beta (Aß) aggregates, are a characteristic feature of several neurodegenerative diseases, such as Alzheimer's, mild cognitive impairment and Parkinson's disease. They also have been recently implicated in the pathogenesis of retinal damage, as well as age-related macular degeneration and glaucoma. Glaucoma is a progressive optic neuropathy characterized by gradual degeneration of neuronal tissue due to retinal ganglion cell loss, associated to visual field loss over time resulting in irreversible blindness. Accumulation of Aß characterizes glaucoma as a protein misfolding disease, suggesting a pathogenic role for oxidative stress in the pathogenesis of retinal degenerative damage associated to glaucoma. There is a growing body of evidence demonstrating a link between Alzheimer's disease and glaucoma. Further, several heat shock proteins (HSPs) members have been implicated both in neurodegenerative diseases and glaucomatous apoptosis. To maintain redox homeostasis vitagenes, as integrated mechanisms, operate actively to preserve cell survival under condition of stress. Vitagenes encode for sirtuin, thioredoxin and HSPs. The present study was designed to investigate cellular stress response mechanisms in the blood of patients with glaucoma, compared to control subjects. Levels of vitagenes HSP-72, heme oxygenase-1, as well as F2-isoprostanes were significantly higher in the blood of patients with glaucoma than in controls. Furthermore, in the same experimental group increased expression of Trx and sirtuin 1 were measured. Our results sustain the importance of redox homeostasis disruption in the pathogenesis of glaucoma and highlights the opportunity that new therapies that prevents neurodegeneration through non-immunomodulatory mechanisms might be synergistically associated with current glaucoma therapies, thus unraveling important targets for novel cytoprotective strategies.

Inflammation and immune response in acute aortic dissection.

OBJECTIVE: The aim of our study was to evaluate the lymphocyte subpopulations and the cytokines in the peripheral blood of patients with type-A Stanford acute aortic dissection (AAD group) and to determine whether inflammatory cells are present at the site of aortic dissection. METHODS: Thirty-five consecutive patients with type-A Stanford dissection were evaluated for haemochrome and lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+, CD4+CD25+, CD16+CD56+, CD4+CD28-, CD8+CD28-) by flow cytometry. C-reactive protein (CRP), tumour necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (IFN-γ), and monocyte chemoattractant protein (MCP)-1 were measured by ELISA. In addition, immunohistochemical staining with cell type-specific antibodies was performed to study the inflammatory cells detected inside the aortic wall. RESULTS: In the AAD group, a significant increase in natural killer (NK) (P = 0.032), B cells (P = 0.022), and CD8+CD28- (P = 0.045) subpopulations was observed, whereas there was a significant decrease in total T lymphocytes (P = 0.004) and T helper fractions (P = 0.005). Moreover, a significant increase in CRP (P < 0.0001), IL-6 (P < 0.0001), IL-8 (P < 0.0001), IL-10 (P < 0.0001), TNF-α (P < 0.0001), and MCP-1 (P < 0.001) was observed; macrophages represented the main population detected inside the media. CONCLUSIONS: Our results strongly support the hypothesis of a pivotal role of innate immunity in type-A Stanford AAD.

Colon OCTN2 gene expression is up-regulated by peroxisome proliferator-activated receptor gamma in humans and mice and contributes to local and systemic carnitine homeostasis.

In the large intestine organic cation transporter type-2 (OCTN2) is recognized as a transporter of compounds such as carnitine and colony sporulation factor, promoting health of the colon intestinal epithelium. Recent reports suggest that OCTN2 expression in small intestine is under control of peroxisome proliferator-activated receptor-alpha (PPARalpha). However, PPARalpha contribution to colonic OCTN2 expression remains controversial. Here we examined the transcriptional regulation of colon OCTN2 gene by PPARgamma. To exclude any additional modulation of other PPAR to OCTN2 expression, we used both in vivo and in vitro PPAR-null models and specific PPAR inhibitors. The PPARgamma agonists thiazolidinediones increased both OCTN2 mRNA and protein expression in colonic epithelial cell lines independently by PPARalpha expression. The induction was blocked only by PPARgamma antagonists or by gammaORF4, a PPARgamma isoform with dominant negative activity, suggesting a PPARgamma-dependent mechanism. A conserved noncanonical PPAR-responsive element was found by computational analysis in the first intron of human OCTN2 gene and validated by EMSA assay. Promoter-reporter assays further confirmed transcriptional functionality of the putative PPAR response element, whereas selective mutation caused complete loss of responsiveness to PPARgamma activation. Finally, adenovirus-mediated overexpression of constitutively active PPARgamma mutant increased colon OCTN2 expression in PPARalpha(-/-) mice. Interestingly, animals overexpressing colon PPARgamma showed a significant increase in plasma carnitine, thus demonstrating the functional contribution of large intestine to systemic carnitine homeostasis. This study reveals a PPARgamma-dependent absorption machinery in colon that is likely involved in the health of colon epithelium, in the microbiota-host interactions and in the absorption of nutraceuticals and drugs.