Very low-calorie ketogenic diet (VLCKD) in the management of hidradenitis suppurativa (Acne Inversa): an effective and safe tool for improvement of the clinical severity of disease. Results of a pilot study.

BACKGROUND: Hidradenitis suppurativa (HS), an inflammatory-based dermatological condition often associated with obesity, poses significant challenges in management. The very low-calorie ketogenic diet (VLCKD) has shown efficacy in addressing obesity, related metabolic disorders, and reducing chronic inflammation. However, its effects on HS remain underexplored. In this prospective pilot study, we aimed to investigate the impact of a 28-day active phase of VLCKD on HS in a sample of treatment-naive women with HS and excess weight. METHODS: Twelve women with HS and overweight or obesity (BMI 27.03 to 50.14 kg/m2), aged 21 to 54 years, meeting inclusion/exclusion criteria and agreeing to adhere to VLCKD, were included. Baseline lifestyle habits were assessed. The Sartorius score was used to evaluate the clinical severity of HS. Anthropometric parameters (waist circumference, weight, height, and body mass index), body composition via bioelectrical impedance analysis, levels of trimethylamine N-oxide (TMAO), oxidized low-density lipoprotein (oxLDL), and derivatives of reactive oxygen metabolites (dROMs) were assessed at baseline and after 28 days of the active phase of VLCKD. RESULTS: VLCKD led to general improvements in anthropometric parameters and body composition. Notably, a significant reduction in the Sartorius score was observed after the intervention (Δ%: - 24.37 ± 16.64, p < 0.001). This reduction coincided with significant decreases in TMAO (p < 0.001), dROMs (p = 0.001), and oxLDL (p < 0.001) levels. Changes in the Sartorius score exhibited positive correlations with changes in TMAO (p < 0.001), dROMs (p < 0.001), and oxLDL (p = 0.002). CONCLUSION: The 28-day active phase of VLCKD demonstrated notable improvements in HS severity and associated metabolic markers, highlighting the potential utility of VLCKD in managing HS and its association with metabolic derangements in women with overweight or obesity.

The Burden of Pruritus Associated With CKD: A Mixed Methods Analysis Among Patients Undergoing Dialysis.

Rationale & Objective: Despite its prevalence and distress to patients, chronic kidney disease-associated pruritus (CKD-aP) is poorly characterized, which may contribute to the condition's underdiagnosis and inadequate management. This study aimed to understand the symptom experience of patients with CKD-aP and the extent to which pruritus impacts their lives. Study Design: Mixed methods study including one-on-one qualitative interviews and completion of the Skindex-10 Questionnaire (measuring itch-related quality of life). Setting & Participants: A total of 23 patients undergoing hemodialysis and reporting pruritus at 4 dialysis centers in the United States. Analytical Approach: Interviews followed a semistructured guide that included targeted and follow-up questions to elicit discussion of patients' symptoms of pruritus, including frequency and variability, impact on activities of daily living, and emotional and social functioning. Interviews were digitally audio-recorded. A coding dictionary was developed from transcripts to analyze themes and concepts. Results: Participants described their itch with various terms, including "numbness," "pain," and "tingling" on their skin. Itch affected multiple areas but especially the back, usually occurred daily, and was often worse at night. For some, itching was a constant experience. Patients relieved their itch through scratching and various off-label treatments; some reported skin damage from excessive scratching and most indicated treatments provided limited relief. Pruritus considerably disrupted physical function, including sleep, daily activities, social functioning and relationships, and emotional and psychological wellbeing. All participants reported being bothered by their itching during the past week on the Skindex-10 Questionnaire. Limitations: All participants were from the United States, so the findings may not be generalizable to other countries. Conclusions: Although symptom experience varies considerably, CKD-aP causes severe distress for many patients undergoing hemodialysis and can profoundly impair their quality of life. The results of this study show the impact of itch from patients' perspectives and highlight the need for greater awareness and better management of this condition. Plain-Language Summary: Patients with chronic kidney disease often experience itching, or pruritus, but its importance to patients is regularly overlooked. This study used one-on-one interviews to investigate patients' experiences of chronic kidney disease-associated pruritus and how it impacts their lives. We found that participants experienced itch on various body areas and used different words to describe their itch (eg, "numbness" and "pain"). Some reported skin damage from excessive scratching, and many used off-label treatments and other interventions (eg, rubbing alcohol and multiple showers daily), which provided limited relief. For many, itching was experienced daily and severely disrupted sleep, daily activities, interactions with others, and mental wellbeing. These findings reveal chronic kidney disease-associated pruritus severely impacts patients and highlights the need for improved management of this condition.

Modulatory influence of melatonin on apical periodontitis in Wistar rats fed a high-fat diet.

OBJECTIVE: This study aimed to evaluate the influence of high-fat diet (HFD) and melatonin (MEL) treatment on the progression of inflammation and alveolar bone resorption (ABR) in rats with AP. DESIGN: Forty male Wistar rats were divided into four groups: apical periodontitis (AP), HFDAP, APMEL and HFDAPMEL. The animals were fed an HFD or standard diet for 107 days. On the 7th day, the rats were subjected to AP, and after 70 days, the rats in the MEL groups were treated with MEL for 30 days. Post treatment, the animals were euthanized, and their jaws were retrieved for evaluation of bone resorption, intensity of the inflammatory response, and immunohistochemical analysis including tartrate-resistant acid phosphatase (TRAP) and interleukin-1ß (IL-1ß) levels and tumor necrosis factor (TNF)-α expression. RESULTS: The APMEL group showed reduction in the inflammatory infiltrate and IL-1ß expression relation to HFDAP, while the TNF-α levels did not differ among the groups. The HFDAP group showed an increase in the ABR. MEL reduced the TRAP levels in the APMEL and HFDAPMEL groups. CONCLUSIONS: while MEL could reduce TRAP levels in the APMEL and HFDAPMEL groups, the reduction in the HFDAPMEL group was smaller than that in the APMEL group, demonstrating that the interaction between AP and HFD decreased the anti-resorptive effects of MEL.

Melatonin decreases IRF-3 protein expression in the gastrocnemius muscle, reduces IL-1ß and LPS plasma concentrations, and improves the lipid profile in rats with apical periodontitis fed on a high-fat diet.

To evaluate the effects of melatonin (MEL) on the expression of toll-like receptor-4 (TLR4); myeloid differentiation primary response protein-88 (MyD88); TIR-domain-containing adapter-inducing interferon-ß (TRIF); IFN regulatory-factor-3 (IRF-3); nuclear factor kappa-B (NF-κB); plasma concentrations of interleukin-1ß (IL-1ß) and lipopolysaccharide (LPS); and lipid profile of rats with apical periodontitis (AP) fed on a high-fat diet (HFD). Eighty 60-day-old rats were divided into eight groups: control, AP, HFD, HFDAP, CNMEL, APMEL, HFDMEL and HFDAPMEL. HFD groups were fed on a HFD for 107 days. On day 7, experimental AP was induced in the AP groups, and after 70 days, MEL (5 mg/kg) was administered to the MEL groups for 30 days. Plasma concentrations of LPS and IL-1ß were analyzed using enzyme-linked immunosorbent assay, and the lipid profile was analyzed using biochemical tests. The expression of proteins involved in the TLR4 pathway (TLR4, MyD88, TRIF, IRF-3 and NF-κB) in the gastrocnemius muscle (GM) was evaluated using western blotting and qRT-PCR. Treatment with MEL decreased IRF-3 protein expression in GM and IL-1ß plasma concentration in the APMEL and HFDMEL groups. Reduction in LPS plasma concentration was reported only in the HFDMEL group. Additionally, a decrease in LDL and an increase in HDL were observed in the HFDMEL and HFDAPMEL groups. Treatment with MEL exhibited anti-inflammatory and anti-hyperlipidemic effects attributed to HFD and AP by reducing the plasma concentrations of IL-1ß and LPS in addition to reducing IRF-3 protein expression in the GM, which is associated with the production of inflammatory cytokines.

Melatonin decreases plasma TNF-α and improves nonenzymatic antioxidant defence and insulin sensitivity in rats with apical periodontitis fed a high-fat diet.

AIM: To analyse the effects of melatonin (ME) treatment on oxidative stress and insulin resistance (IR) in rats with apical periodontitis (AP) fed a high-fat diet (HFD). METHODOLOGY: Eighty 60-day-old rats were divided into eight groups: control (CN), AP, HFD with AP (HFDAP), control with ME (CNME), AP with ME (APME), HFD with ME (HFDME) and HFD with AP+ME (HFDAPME). The animals from the HFD groups were fed a HFD throughout the experimental period. On day 7, the animals from the AP groups were subjected to experimental AP, and after 70 days, the ME groups were treated for 30 days. Glycaemia, insulinaemia, homeostatic model assessment for IR index, tumour necrosis factor-α (TNF-α), and interleukin-6 were analysed in plasma using biochemical tests and enzyme-linked immunosorbent assay. Thiobarbituric acid-reactive substances (TBARS), carbonyl protein (CP), superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione (GSH) and total antioxidant capacity (ferric reducing antioxidant power [FRAP]) were analysed in the gastrocnemius muscle. RESULTS: (1) Association of AP and HDF exacerbated IR, and ME treatment improved this alteration; (2) AP and HFD and their association showed increased TNF-α, and ME reversed it; (3) TBARS increased in the AP and HFDAP groups, and ME reversed only in the group with the association of disease and diet; (4) CP increased in all HFD groups and improved in the ME groups; (5) GSH activity decreased in all experimental groups, and ME increased this parameter only in the CN and AP groups; (6) FRAP did not change between the groups, but ME treatment increased its activity in the AP and HFD groups; (7) ME increased SOD in the CN and AP groups. CONCLUSION: Apical periodontitis and HFD promoted IR, and the association of AP with diet promoted IR exacerbation; this resistance might have been caused by an increase in TNF-α. AP promoted more intense changes in lipid oxidative damage than in protein oxidative damage. In non-enzymatic antioxidant defence, it was observed that both AP and HFD and their association promoted a decrease in GSH levels. Overall, ME treatment reversed changes such as oxidative stress and IR.

Effect of maternal true combined endodontic-periodontal lesion on insulin and inflammatory pathway in adult offspring.

BACKGROUND: Maternal periodontal disease (PED) and apical periodontitis (AP) are associated insulin resistance (IR), increased tumor necrosis factor-α (TNF-α) levels, and alterations in insulin signaling (IS) in the gastrocnemius muscle (GM) of adult offspring. TNF-α stimulates I kappa B kinase (IKK) and c-Jun N-terminal protein kinase (JNK), resulting in IS attenuation. However, studies that investigated the maternal true endodontic-periodontal lesion (EPL) in offspring are scarce, and in this case, the impact could be even higher. This study aimed to evaluate the effects of EPL on the IR, IS, and inflammatory pathways on the offspring GM. METHODS: Female Wistar rats were distributed into control, AP, PED, and EPL groups. After 30 days of oral inflammation induction, rats from all groups were allowed to mate with healthy rats. The body weight of the offspring was assessed from birth to 75 days of age. After 75 days, the following measurements were performed: glycemia, insulinemia, IR, TNF-α content, and IKKα/ß, JNK, pp185 (Tyr), and IRS-1 (Ser) phosphorylation status in the GM. RESULTS: Maternal PED and EPL were associated with low birth weights. All maternal oral inflammations promoted IR and IS impairment in the GM and only maternal PED and EPL caused an increase in TNF-α content and IKKα/ß phosphorylation status in the GM of offspring. The offspring of the rats with EPL group showed worsening of metabolic changes when compared with offspring of rats with AP or PED. CONCLUSION: Association of maternal AP and PED promoted a more pronounced worsening in the health of the adult offspring.

Assessment of redox state and biochemical parameters of salivary glands in streptozotocin-induced diabetic male rats treated with mate tea (Ilex paraguariensis).

OBJECTIVE: The study aimed to assess the effects of mate tea [Ilex paraguariensis] on the redox state and biochemical parameters of salivary glands in diabetic male rats. DESIGN: Twenty-four male Wistar rats (3 months old) were randomly divided into groups (n = 8 per group): control rats that received water (C); diabetic rats that received water (D); diabetic rats treated with mate tea (DMT). The treated streptozotocin-induced diabetic rats were given mate tea powder by intragastric gavage at a dose of 20 mg/kg daily for 28 days. Content of total protein, amylase, oxidative lipid damage, measured as thiobarbituric acid reactive substances (TBARs), oxidative protein damage, measured as protein carbonyl, total antioxidant capacity, uric acid, reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were examined by the spectrophotometric method in the parotid and submandibular glands. RESULTS: The D group showed lower total protein, amylase, TBARs, protein carbonyl, total antioxidant capacity, GSH, uric acid, and GPx than the C group in both salivary glands, as well as higher SOD and CAT activities. The DMT group showed higher total protein, amylase, total antioxidant capacity, GSH, uric acid, and GPx than the D group in both salivary glands. Moreover, mate tea increased SOD in the parotid gland and CAT in the submandibular gland of diabetic rats but did not influence TBARs and protein carbonyl in either salivary gland compared to D group. CONCLUSION: Mate tea increased tissue protein synthesis and improved antioxidant defenses in the salivary glands of streptozotocin-induced diabetic male rats.

Apical periodontitis promotes insulin resistance and alters adaptive immunity markers in rats.

OBJECTIVE: Apical periodontitis (AP) is a chronic or acute inflammatory disease usually developed from endodontic infections, predominantly due to gram-negative anaerobic bacteria invading the dental pulp. This study aimed to evaluate lymphocyte markers to assess the involvement of adaptive immunity in insulin resistance (IR) in a rat model of AP.Design.Forty-five male Wistar albino rats were divided into 3 groups (control, 1AP and 4AP). AP was induced in the upper right first molar (1AP), and in the first and second upper and lower right molars (4AP). The spleen was collected to evaluate the expression of transcription factors involved in lymphocyte polarization, including T-bet (Th1), GATA3 (Th2), and FOXP3 (Treg). Blood samples were assessed for serum cytokine levels transcribed by the respective lymphocyte polarizations, INF-γ (Th1), IL-4 (Th2) and TGF-ß (Treg). In addition, glucose and insulin levels were measured to evaluate IR by the HOMA-IR method. RESULTS: The results showed higher T-bet expression on AP groups, along with lower GATA3 and FOXP3 expression in the 1AP, in addition to increased GATA3 and decreased FOXP3 expression in the 4AP group compared to the CN group. There was no difference in the INF-γ levels, while IL-4 was decreased in the AP groups. Taken together, these results suggest that the adaptive immune system, with a predominance of the Th1 polarization, may be involved in the development of IR in rats with AP. CONCLUSIONS: AP promotes increase in the expression of T-bet (4AP) and decrease of FOXP3 expressions and IL-4 levels (1AP and 4AP). However, depending on the number of lesions (1 or 4 lesions), the expression of GATA3 appears differently. Thus, innate immunity and adaptive immunity may contribute to the IR observed in rats with AP.

Effect of resistance training on osteopenic rat bones in neonatal streptozotocin-induced diabetes: Analysis of GLUT4 content and biochemical, biomechanical, densitometric, and microstructural evaluation.

AIMS: To investigate the effect of resistance training-RT on glycemia, expression of the glucose transporter-GLUT4, bone mineral density-BMD, and microstructural and biomechanical properties of osteopenic rat bones in neonatal streptozotocin-induced diabetes. MAIN METHODS: Sixty-four 5-day-old male rats were divided into two groups: control and diabetic rats injected with vehicle or streptozotocin, respectively. After 55 days, densitometric analysis-DA of the tibia was performed. These groups were subdivided into four subgroups: non-osteopenic control-CN, osteopenic control-OC, non-osteopenic diabetic-DM, and osteopenic diabetic-OD. The OC and OD groups were suspended by their tails for 21 days to promote osteopenia in the hindlimb; subsequently, a second DA was performed. The rats were subdivided into eight subgroups: sedentary control-SC, sedentary osteopenic control-SOC, exercised control-EC, exercised osteopenic control-EOC, sedentary diabetic-SD, sedentary osteopenic diabetic-SOD, exercised diabetic-ED, and exercised osteopenic diabetic-EOD. For RT, the rats climbed a ladder with weights secured to their tails for 12 weeks. After RT, a third DA was performed, and blood samples, muscles, and tibias were assessed to measure glycemia, insulinemia, GLUT4 content, bone maximum strength, fracture energy, extrinsic stiffness, BMD, cancellous bone area, trabecular number, and trabecular width. KEY FINDINGS: After RT, glycemia, GLUT4 content, BMD, and bone microstructural and biomechanical properties were improved in diabetic rats (osteopenic and non-osteopenic). However, RT had no effect on these parameters in the EC and SC groups. SIGNIFICANCE: These results suggest that RT improves GLUT4 content, BMD, and microstructural and biomechanical properties of bone in osteopenic and non-osteopenic diabetic rats and is effective in controlling glycemia.

Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.

Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice. As expected, 24-month-old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8-month-old (adult) mice (all p < 0.05). To investigate the influence of late-in-life exercise training, additional cohorts of 21-month-old mice did (old-ETR) or did not (old-SED) complete a 3-month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old-ETR vs. old-SED mice at 24 months (all p < 0.05). Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced (all p < 0.05) in hearts from old-ETR vs. old-SED mice. These data provide the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.

Effect of maternal apical periodontitis on the final step of insulin signalling and inflammatory pathway in the adult male offspring of rats.

AIM: To evaluate the final step of insulin signalling, inflammatory pathway (related to the inhibition of insulin signalling), peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) protein content and DNA methylation in the Slc2a4 gene promoter region in the skeletal muscle of adult male offspring of rats with apical periodontitis (AP) in a single tooth or in four teeth. METHODOLOGY: Female Wistar rats were distributed into three groups: a control group, a group with one tooth with AP and a group with four teeth with AP. Thirty days after induction of AP, female rats from all groups were mated with healthy male rats. When male offspring reached 75 days of age, the following analyses were performed in the gastrocnemius muscle (GM): insulin-stimulated Akt serine and threonine phosphorylation status; NF-κB p50 and p65 subunits phosphorylation status; GLUT4, TNF-α and PGC-1α protein content by Western blotting; GLUT4 and TNF-α gene expression by real-time polymerase chain reaction (PCR); and DNA methylation in the Slc2a4 gene promoter region by restriction digestion and real-time PCR. Analysis of variance was performed, followed by Tukey's post hoc test. p values <.05 were considered to be statistically significant. RESULTS: Maternal AP in four teeth decreased insulin-stimulated Akt serine and threonine phosphorylation status, reduced GLUT4 gene expression and its protein content, and increased NF-κB p50 and p65 subunits phosphorylation status in the GM of adult offspring. There were no alterations in the parameters analysed in the GM of adult offspring of rats with AP in a single tooth. In addition, maternal AP did not affect TNF-α gene expression and its protein content, PGC-1α protein content and DNA methylation in the Slc2a4 gene promoter region in the GM of adult offspring. CONCLUSIONS: Maternal AP in four teeth was associated with impairment in the final step of insulin signalling in the GM of adult male offspring in rats. An increase in NF-κB activity may be involved in this decrease in insulin signalling. This study demonstrates the impact of maternal AP on the health of offspring, demonstrating the importance of maintaining adequate maternal oral health to prevent diseases in adult offspring in rats.

Maternal Apical Periodontitis Increases Insulin Resistance and Modulates the Antioxidant Defense System in the Gastrocnemius Muscle of Adult Offspring.

INTRODUCTION: Maternal apical periodontitis (AP) is associated with insulin resistance (IR) in adult offspring. Oxidative stress has been linked to IR. This study investigated insulin sensitivity (IS) and oxidative stress in the gastrocnemius muscle (GM) of adult offspring of rats with AP. METHODS: Fifteen female Wistar rats were distributed into a control group, a group with 1 tooth with AP, and a group with 4 teeth with AP. Thirty days after AP induction, female rats were mated with healthy male rats. When male offspring reached 75 days of age, glycemia, insulinemia, and IS were determined. In the GM, the oxidative damage products (thiobarbituric acid reactive substances and carbonyl protein) and activities of enzymatic (superoxide dismutase, catalase, and glutathione peroxidase) and nonenzymatic (glutathione and total antioxidant capacity) antioxidants were quantified. Analysis of variance was performed followed by the Tukey post hoc test (P < .05). RESULTS: Maternal AP was associated with decreased IS and changes in antioxidant activities (reduced superoxide dismutase and increased catalase, glutathione peroxidase, and glutathione) and decreased thiobarbituric acid reactive substance concentration in the GM of their adult offspring. However, maternal AP does not appear to affect glycemia, carbonyl protein concentration, and the nonenzymatic total antioxidant capacity in the GM of this offspring. CONCLUSIONS: Maternal AP modulates the antioxidant defense system in the GM of their adult offspring, attenuating lipid peroxidation in this tissue. This reflects part of an adaptive response of the offspring to the stimulation of the maternal chronic oral inflammatory process in which the organism acts by decreasing oxidative tissue damage in the postnatal stage. The present study improves knowledge about the impact of maternal oral inflammation on healthy offspring.

Toxinas Algales en el Mar Argentino: nuevos hallazgos, nuevos desafíos / Algal Toxins in the Argentine Sea: new findings, new challenges

Resumen Las floraciones de algas nocivas son un problema cada vez más frecuente a nivel mundial que ocasiona severos daños sobre la salud pública, pérdidas económicas en acuicultura, perjuicios al turismo y episodios de mortalidad de poblaciones naturales de peces, aves y mamíferos marinos. Las toxinas son producidas por el fitoplancton y se acumulan en moluscos bivalvos que se alimentan por filtración del agua siendo estos los principales vectores de intoxicación humana. En el Mar Argentino, se han reportado toxinas marinas de origen microalgal asociadas con cuatro síndromes de intoxicación por moluscos. Los síndromes más graves por su extensión, frecuencia, toxicidad y organismos afectados, son los originados por el dinoflagelado Alexandrium cate-nella responsable de la Intoxicación Paralizante por Moluscos la cual ha ocasionado numerosas muertes humanas. Seguidamente, la más leve, en cuanto a gravedad y frecuencia, ha sido la Intoxicación Diarreica por Moluscos. En contraste, el ácido domoico, conocido como toxina amnésica de moluscos, no ha producido hasta ahora intoxicaciones humanas. Recientemente, se amplió el rango de toxinas para la región al registrarse las toxinas y los dinoflagelados productores de la Intoxicación Azaspirácidos por Moluscos. Además, se han detectado las potencialmente tóxicas Yessotoxinas y Espirolidos, cuyos mecanismos de acción y toxicidad están siendo aún evaluados a nivel mundial. Estas toxinas emergentes para la región, representan un riesgo potencial para la salud e inconvenientes socioeconómicos por el cierre de los sitios de explotación de moluscos. Ciertamente presentan un nuevo desafío, pues la detección y cuantificación sólo puede realizarse por medio de métodos basados en HPLC - espectrometría de masas, lo cual dificulta el monitoreo en laboratorios regionales en el país. La herramienta clave de manejo es la prevención, a través de políticas, regulaciones y sistemas de monitoreo y control de cada grupo de toxinas. A través de estas mejoras, se anticipa que no sólo disminuirá el número de afectados por estas intoxicaciones, si no que se podrán realizar vedas más eficientes, asegurando un equilibrio que proteja tanto la salud pública como el desarrollo de la industria pesquera.

Abstract Harmful algal blooms are an increasingly common problem worldwide, causing severe damage to public health, economic losses in aquaculture, damage to tourism and mortality events of natural populations of fish, birds and marine mammals. The toxins are produced by phytoplankton and accumulated in bivalve molluscs that feed on water filtration, being these main vectors of human intoxication. In the Argentine Sea marine toxins of microalgal origin have been reported associated with four shellfish poisoning syn-dromes. The most serious due to their extension, frequency, toxicity and affected organisms are those caused by the dinoflagellate Alexandrium catenella responsible for the Paralytic shellfish poisoning that has caused numerous human deaths. Then, the mildest, in severity and frequency, is the Diarrhetic shellfish poisoning. In contrast, domoic acid, known as Amnesic shellfish toxin, has not produced human intoxications yet. Recently, toxins and dinoflagellate species causing Azaspiracid shellfish poisoning have been re-corded, expanding the range of toxins for the region. In addition, the potentially toxic Yessotoxins and Spirolides have been detected, whose mechanism of action and toxicity is still being evaluated worldwide. These emerging toxins represent a potential risk to public health and socioeconomic activities due to the eventual closure of mollusc exploitation sites. They certainly present a new challenge, since detection and quantification can only be carried out using methods based on HPLC - mass spectrometry, which makes monitor-ing in regional laboratories difficult. Prevention through policies, regulations, and monitoring and control systems of each toxin group is the key management tool. These preventive measures are expected to contribute to reducing the number of poisonings and to ap-plying more efficient fisheries closures, ensuring a balance that protects both public health and the development of the fishing industry.

Molecular bases of responses to abiotic stress in trees.

Trees are constantly exposed to climate fluctuations, which vary with both time and geographic location. Environmental changes that are outside of the physiological favorable range usually negatively affect plant performance and trigger responses to abiotic stress. Long-living trees in particular have evolved a wide spectrum of molecular mechanisms to coordinate growth and development under stressful conditions, thus minimizing fitness costs. The ongoing development of techniques directed at quantifying abiotic stress has significantly increased our knowledge of physiological responses in woody plants. However, it is only within recent years that advances in next-generation sequencing and biochemical approaches have enabled us to begin to understand the complexity of the molecular systems that underlie these responses. Here, we review recent progress in our understanding of the molecular bases of drought and temperature stresses in trees, with a focus on functional, transcriptomic, epigenetic, and population genomic studies. In addition, we highlight topics that will contribute to progress in our understanding of the plastic and adaptive responses of woody plants to drought and temperature in a context of global climate change.

Evaluating minimal important differences and responder definitions for the asthma symptom diary in patients with moderate to severe asthma.

BACKGROUND: The Asthma Symptom Diary was developed to assess severity of symptoms in patients with moderate to severe asthma, and has evidence supporting reliability and validity. Only limited information is available on sensitivity to change and responder definitions for the Asthma Symptom Diary. OBJECTIVES: Main study objectives were to evaluate sensitivity to change and provide responder definitions for clinically meaningful effects for the Asthma Symptom Diary. METHODS: This is a secondary analysis of Phase II clinical trial data in patients with moderate to severe asthma, Asthma Symptom Diary (ASD) was collected daily during the 24-week study. The Asthma Control Questionnaire and the Patient Global Assessment were collected at baseline, and week 12 and 24. Analysis of covariance (ANCOVA) models were used to evaluate sensitivity to change in Asthma Symptom Diary scores after 12 and 24 weeks of treatment. Anchor-based methods, using Asthma Control Questionnaire and Patient Global Assessment defined anchors, were used to identify minimal important differences and various responder criteria for changes in mean 7-day ASD score, symptomatic days, and minimal symptom days. RESULTS: Sample was 59% female, 81% White, with a mean age of 47.3 (SD = 13.6) years. ANCOVAs demonstrated significant differences in baseline to week 12 and week 24 changes in mean 7-day Asthma Symptom Diary scores and symptomatic days by Asthma Control Questionnaire (all p < 0.001) and Patient Global Assessment anchors (all p < 0.001). Meaningful responders, from the patient's perspective, were defined as improvements of 0.5-0.6 points (SD = 0.6; scale range 0 to 4) in mean 7-day Asthma Symptom Diary scores, and as a reduction of 2 to 3 Asthma Symptom Diary-based symptomatic days. CONCLUSION: The Asthma Symptom Diary was responsive to changes in clinical status in patients with moderate to severe asthma. Responder definitions were identified, including symptomatic days, for evaluating individual level treatment effects in clinical trials.

Effect of maternal periodontitis on GLUT4 and inflammatory pathway in adult offspring.

BACKGROUND: Maternal periodontal disease leads to low birth weight (LBW), insulin resistance (IR), increased TNF-α levels, and alterations in insulin signaling in adult offspring. TNF-α has been associated with the stimulation of IKKß/NF-κB, resulting in the decreased expression of GLUT4. Another mechanism that may be involved in decreasing GLUT4 expression is DNA methylation. This study aimed to evaluate in the adult offspring of rats with periodontal disease: IR, inflammatory pathways, DNA methylation, and expression of GLUT4. METHODS: Female Wistar rats were distributed into control and experimental periodontal disease groups. Seven days after induction of periodontal disease, both groups were mated with healthy male rats. After weaning, male offspring were distributed into control offspring (CN-o) and periodontal disease offspring (PED-o) groups. Body weights were measured from 0-75 days of age. At day 75, the following were measured in the offspring: IR (HOMA-IR index); TNF-α and NF-κBp65 content in the gastrocnemius muscle (GM) by western blotting; IKKα/ß, JNK, ERK 1/2, NF-κBp65, and NF-κBp50 phosphorylation status in the GM by western blotting; DNA methylation by restriction digest and real-time PCR(qAMP); and expression of GLUT4 mRNA in the GM by real-time PCR. RESULTS: LBW, IR, increases in TNF-α, IKKα/ß, ERK 1/2, NF-κBp65, and NF-κBp50 decreased expression of GLUT4 mRNA were observed in the PED-o rats. No differences were identified in JNK phosphorylation status and DNA methylation in the evaluated regions of the GLUT4-encoding gene Slc2a4. CONCLUSION: Maternal periodontal disease causes LBW, IR, activation of inflammatory pathways, and decreased GLUT4 expression in the GM of adult offspring.

The importance of drug safety and tolerability in the development of new immunosuppressive therapy for transplant recipients: The Transplant Therapeutics Consortium's position statement.

The Transplant Therapeutics Consortium (TTC) is a public-private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug-development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug-development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process-accelerating tools. The TTC has identified 2 major areas of emphasis: new biomarkers or endpoints for determining the efficacy of new therapies and new tools to assess the safety or tolerability of new therapies. This article presents the rationale and planned approach to develop new tools to assess safety and tolerability of therapies for transplant patients. We also discuss how similar efforts might support the continued development of patient-reported outcome measures in the future.

Avaliação do mecanismo epigenético por metilação do DNA e da expressão de GLUT4 em tecido muscular esquelético de ratos adultos, proles de ratas com doença periodontal / Evaluation of the epigenetic mechanism by DNA methylation and GLUT4 expression in skeletal muscle tissue of adult rats, prole of rats with periodontal disease

Atualmente, está bem estabelecido que o ambiente fetal está ligado à saúde materna, e estímulos ou agressões anormais durante a vida intra-uterina podem resultar em mudanças na fisiologia e metabolismo da prole, aumentando o risco de doenças na vida adulta. Tal fenômeno é conhecido como programação fetal. Alterações na metilação do DNA e expressão gênica são consideradas mecanismos moleculares responsáveis por esta programação. Estudos anteriores demonstraram que a doença periodontal (DP) materna promove resistência insulínica, aumento nas concentrações plasmáticas de citocinas, redução do conteúdo de GLUT4 e do seu índice de translocação para membrana plasmática em sua prole adulta. E citocinas, como por exemplo, o TNF-α, têm sido relacionadas com a redução da expressão de GLUT4 por meio da ativação do fator de transcrição nuclear κappa B (NF-κB). Além disso, esta citocina pode estimular algumas serinas quinases, incluindo IκB quinase (IKK), c-Jun amino-terminal kinase (JNK) e quinases reguladas por sinais extracelulares (ERKs) que estão envolvidas na resistência insulínica. Tais achados evidenciam a necessidade de realizar mais estudos para verificar os mecanismos envolvidos nestas alterações. Portanto, os objetivos do presente estudo foram avaliar em ratos adultos, proles de ratas com DP: 1) massa corpórea ao longo de 75 dias de idade; 2) glicemia e insulinemia; 3) expressão do RNAm da proteína transportadora de glicose GLUT4 e do IRS1 em muscular esquelético gastrocnêmio (MG); 4) o grau de metilação do DNA na região promotora do gene do GLUT4 em MG; 5) fosforilação das proteínas JNK, IKKα/ß, ERK 1/2, NF-κBp65 e NF-κBp50 e seus conteúdos totais em MG; 6) conteúdo total de TNF-α em MG. As ratas foram divididas em dois grupos: 1) com doença periodontal (DP), no qual esta doença foi induzida por meio de ligadura com fio de seda ao redor do 1º molar inferior; 2) ratas controle (CN). Após 7 dias da colocação da ligadura, as ratas de ambos os grupos foram colocadas para acasalamento, verificou-se diariamente, por esfregaço vaginal, o dia da copulação. As ratas prenhas foram separadas em caixas individuais. Quando os filhotes machos destas ratas completaram 75 dias, realizaram-se os experimentos: 1) glicemia e insulinemia; 2) expressão do RNAm do GLUT4 e do IRS1 em MG; 3) o grau de metilação do DNA na região promotora do gene do GLUT4 em MG; 4) fosforilação das proteínas JNK, IKKα/ß, ERK 1/2, NF-κBp65 e NF-κBp50 e seus conteúdos totais em MG; 5) conteúdo total de TNF-α em MG. Os resultados demonstraram que a doença periodontal materna promove na sua prole adulta baixo peso ao nascimento (BPN), resistência insulínica, aumento do conteúdo total de TNF-α em MG, aumento do grau de fosforilação de IKKα/ß, ERK 1/2, NF-κBp65 (grau de fosforilação e conteúdo) e NF-κBp50 em MG, diminuição na expressão gênica da proteína transportadora de glicose GLUT4 e aumento na expressão gênica do IRS1; porém não promove nessa prole alteração no grau de metilação do DNA na região promotora do gene do GLUT4, e no grau de fosforilação da proteína JNK em MG. Portanto, este estudo é de fundamental importância para o entendimento de alguns dos mecanismos envolvidos na relação entre a doença periodontal materna e resistência à insulina na prole adulta. Além disso, mostra que a saúde bucal materna ideal pode ajudar a prevenir doenças futuras na prole adulta(AU)

It is well established that the fetal environment is linked to maternal health, and abnormal stimuli or aggressions during intrauterine life can result in changes in the physiology and metabolism of offspring, increasing the risk of disease in adult life, this phenomenon is known as fetal programming. Changes in DNA methylation and gene expression are considered molecular mechanisms responsible for this programming. Previous studies have demonstrated that maternal periodontal disease (PD) promotes insulin resistance, increased plasma concentrations of cytokines, reduced GLUT4 content and its plasma membrane translocation index in its adult offspring. And cytokines, such as TNF-α, have been linked to reduced GLUT4 expression through the activation of nuclear transcription factor kappa B (NF-κB). In addition, this cytokine can stimulate some serine kinases including IκB kinase (IKK), c-Jun amino-terminal kinase (JNK) and extracellular signal­regulated kinases (ERKs) that are involved in insulin resistance. These findings evidenced the need for further studies to verify the mechanisms involved in these changes. Therefore, the objectives of the present study were to evaluate in adult rats, offspring of rats with PD: 1) birth weight and during the 75 days of age; 2) glycemia and insulinemia; 3) GLUT4 and IRS1 mRNA expression in skeletal muscle gastrocnemius (MG); 4) the degree of DNA methylation in the promoter region of the GLUT4 gene in MG; 5) phosphorylation of JNK, IKKα/ß, ERK 1/2, NF-κBp65 and NF-κBp50 proteins and their total contents in MG; 6) TNF-α content in MG. Female Wistar rats were distributed into a control group and an experimental periodontal disease group, in which the disease is induced by ligation with silk thread around the 1st molar. Seven days after ligature placement, animals from both groups mated and daily vaginal smears were taken to verify the presence of sperm. Pregnant rats were kept in individual cages. The body weights of the offspring were measured once weekly from birth until 75 days of age. When male offspring of these rats completed 75 days, the experiments were performed: 1) glycemia and insulinemia; 2) GLUT4 and IRS1 mRNA expression in skeletal muscle gastrocnemius (MG); 3) the degree of DNA methylation in the promoter region of the GLUT4 gene in MG; 4) phosphorylation of JNK, IKKα/ß, ERK 1/2, NF-κBp65 and NF-κBp50 proteins and their total contents in MG; 5) TNF-α content in MG. The results demonstrated that maternal periodontal disease promotes in its adult offspring low birth weight (LBW), insulin resistance, increased TNF-α content in MG, increased IKKα/ß, ERK 1/2, NF-κBp65 (phosphorylation status and content) and NF-κBp50 phosphorylation status in the MG, decrease in gene expression of GLUT4 and increase in IRS1 gene expression; but does not promote in this progeny change in the degree of DNA methylation in the promoter region of the GLUT4 gene, and JNK phosphorylation status in MG. Therefore, this study is of fundamental importance for the understanding of some of the mechanisms involved in the relationship between maternal periodontal disease and insulin resistance in adult offspring. In addition, it shows that ideal maternal oral health can help prevent future illnesses in adult offspring(AU)

Validation of the shortened Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS).

BACKGROUND: The rare disease, Hunter Syndrome (mucopolysaccharidosis type II; MPS II), characterized by iduronate-2-sulfatase deficiency, has heterogeneous symptoms often including cognitive impairment (CI). To evaluate physical functioning and daily activity limitations of patients with MPS II, the multidomain shortened Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) questionnaire was previously developed and preliminarily validated. Here we gather data in a dedicated prospective longitudinal observational study using direct responses to the shortened instrument and assess its psychometric properties further. METHODS: Interview data were collected from eligible self-reporting patients (≥ 12 years of age) or caregivers of patients using respective versions of the instrument at baseline and 2-4 weeks later. Internal consistency, test-retest reliability, convergent and discriminant validity, and validity of known groups were assessed. Participants also completed Child Health Questionnaire (CHQ), Health Utilities Index Mark 3, and Global Impression of Severity (GIS) questionnaires. RESULTS: All patients were male, consisting of 31 caregiver-reported patients (aged 3-26 years) and 20 self-reported patients (aged 12-58 years). Most (77.4%) caregiver-reported patients had CI. Both questionnaire versions demonstrated good internal consistency and test-retest reliability; Cronbach's alpha and intra-class correlation coefficients were > 0.70. Spearman's correlations demonstrated good convergent validity with moderate (> 0.3) to high (> 0.6) correlations of the HS-FOCUS total score with physical functioning, role/social-physical, and bodily pain domains of CHQ. The tool also differentiated between MPS II severity levels based on GIS scores. CONCLUSIONS: The shortened HS-FOCUS questionnaire was found to be a valid and reliable tool to assess the physical functioning impact of MPS II.

Melatonin promotes reduction in TNF levels and improves the lipid profile and insulin sensitivity in pinealectomized rats with periodontal disease.

AIM: This study aimed to investigate the effects of melatonin (ME) on insulin resistance (IR) and signaling (IS), proinflammatory cytokine levels, and lipid profiles in pinealectomyzed (PNX) rats with periodontal disease (PD). MAIN METHODS: One hundred and forty-four rats (age = 40 days) were distributed into 8 groups: 1) control (CN); 2) PD only; 3) PNX only; 4) PNX and PD (PNXPD); 5) CN treated with ME (CNM); 6) PD treated with ME (PDM); 7) PNX treated with ME(PNXM); 8) PNX and PD treated with ME(PNXPDM). The PNX groups were subjected to pinealectomy at 40 and at 60 days of age. The animals were then subjected to PD induction in the mandibular first molars. After PD induction, the ME replacement therapy (MERT-5 mg/kg body weight) was performed using water for 28 days. After this period, the plasma concentration of glucose, insulin, TNF, IL-6, triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol, and VLDL-cholesterol and the HOMA-IR index were determined. Akt serine phosphorylation status in the white adipose tissue, gastrocnemius muscle, and rat liver were also evaluated. KEY FINDINGS: PD, PNX, and PNXPD groups showed an increase in IR with elevated plasma levels of insulin and TNF compared to CN group. PNX and PNXPD groups presented alteration in lipid profile compared to CN group. MERT improved all of the analyzed parameters. No difference was observed in the IS among different groups. SIGNIFICANCE: The results suggest that MERT efficiently prevents IR, improves lipid profile, and increases plasma levels of insulin and TNF in PD and PNX rats.