Natural Functional Beverages as an Approach to Manage Diabetes.

Diabetes mellitus is a chronic disease, commonly associated with unhealthy habits and obesity, and it is becoming a serious health issue worldwide. As a result, new approaches to treat diabetes are required, and a movement towards more natural approaches is emerging. Consuming fruit and vegetables is advised to prevent diabetes since they contain several bioactive compounds. A simple and effective strategy to include them in the diets of diabetic and obese people is through beverages. This review aims to report the anti-diabetic potentials of different vegetable and fruit beverages. These functional beverages demonstrated in vitro potential to inhibit α-glucosidase and α-amylase enzymes and to improve glucose uptake. In vivo, beverage consumption showed a reduction of blood glucose, increase of insulin tolerance, improvement of lipid profile, control of obesity, and reduction of oxidative stress. This suggests the potential of vegetable- and fruit-based functional beverages to be used as a natural innovative therapy for the management of diabetes.

Factors associated with suicide attempts in the antecedent illness trajectory of bipolar disorder and schizophrenia.

BACKGROUND: Factors associated with suicide attempts during the antecedent illness trajectory of bipolar disorder (BD) and schizophrenia (SZ) are poorly understood. METHODS: Utilizing the Rochester Epidemiology Project, individuals born after 1985 in Olmsted County, MN, presented with first episode mania (FEM) or psychosis (FEP), subsequently diagnosed with BD or SZ were identified. Patient demographics, suicidal ideation with plan, self-harm, suicide attempts, psychiatric hospitalizations, substance use, and childhood adversities were quantified using the electronic health record. Analyses pooled BD and SZ groups with a transdiagnostic approach given the two diseases were not yet differentiated. Factors associated with suicide attempts were examined using bivariate methods and multivariable logistic regression modeling. RESULTS: A total of 205 individuals with FEM or FEP (BD = 74, SZ = 131) were included. Suicide attempts were identified in 39 (19%) patients. Those with suicide attempts during antecedent illness trajectory were more likely to be female, victims of domestic violence or bullying behavior, and have higher rates of psychiatric hospitalizations, suicidal ideation with plan and/or self-harm, as well as alcohol, drug, and nicotine use before FEM/FEP onset. Based on multivariable logistic regression, three factors remained independently associated with suicidal attempts: psychiatric hospitalization (OR = 5.84, 95% CI 2.09-16.33, p < 0.001), self-harm (OR = 3.46, 95% CI 1.29-9.30, p = 0.014), and nicotine use (OR = 3.02, 95% CI 1.17-7.76, p = 0.022). CONCLUSION: Suicidal attempts were prevalent during the antecedents of BD and SZ and were associated with several risk factors before FEM/FEP. Their clinical recognition could contribute to improve early prediction and prevention of suicide during the antecedent illness trajectory of BD and SZ.

Racial differences in pathways to care preceding first episode mania or psychosis: a historical cohort prodromal study.

Background: There is evidence suggesting racial disparities in diagnosis and treatment in bipolar disorder (BD) and schizophrenia (SZ). The purpose of this study is to compare psychiatric diagnoses and psychotropic use preceding a first episode of mania (FEM) or psychosis (FEP) in racially diverse patients. Methods: Using a comprehensive medical records linkage system (Rochester Epidemiology Project, REP), we retrospectively identified individuals diagnosed with BD or SZ and a documented first episode of mania or psychosis. Illness trajectory before FEP/FEM were characterized as the time from first visit for a mental health complaint to incident case. Pathways to care and clinical events preceding FEP/FEM were compared based on subsequent incident case diagnosis (BD or SZ) and self-reported race (White vs. non-White). Results: A total of 205 (FEM = 74; FEP = 131) incident cases were identified in the REP. Duration of psychiatric antecedents was significantly shorter in non-White patients, compared to White patients (2.2 ± 4.3 vs. 7.4 ± 6.6 years; p < 0.001) with an older age at time of first visit for a mental health complaint (15.7 ± 6.3 vs. 11.1 ± 6.0 years; p = 0.005). There were no significant differences by race in FEM pathway to care or age of first seeking mental health. Overall non-White patients had lower rates of psychotropic use. Conclusion: These data are unable to ascertain reasons for shorter duration of psychiatric antecedents and later age of seeking care, and more broadly first age of initial symptom presentation. If symptoms are confirmed to be earlier than first time seeking care in both groups, it would be important to identify barriers that racial minorities face to access timely psychiatric care and optimize early intervention strategies.

Pediatric Sjögren Syndrome: Case Report On A Rare Entity.

Pediatric Sjögren's Syndrome (SS) is an auto-immune disorder of unknown prevalence with significant risk of comorbidity. In contrast to the classical dyad of xerostomia and xeropthalmia frequently seen in adults, in children and adolescents, recurrent parotiditis and sialadenitis are more often the presenting symptoms. We describe the case of a previously healthy 16-year-old girl with recurrent cervical lymphadenopathy and parotid swelling. Over the course of nine months, extensive investigation established chronic bilateral recurrent sialadenitis of unknown cause. The patient's clinic and complementary exams favor a primary SS diagnosis; however, she later meets classification criteria for Systemic Lupus Erythematosus. Although currently clinically stable under hydroxychloroquine with minor parotid swelling and eye redness, long term multidisciplinary follow-up will be needed to manage the patient's disease. This report aims to bring awareness to this diagnostic challenge and to the need for pediatric criteria for SS.

Juvenile Paget's Disease: Report of a successful treatment throughout the complete growth of a patient with a missense TNFRSF11B mutation.

INTRODUCTION: Juvenile Paget's Disease (JPD) is an ultra-rare inherited osteopathy featuring markedly accelerated bone turnover. Several clinical characteristics have been reported, including bone deformities developing in childhood and hearing loss. CASE REPORT: We report the case of a 2 ¾-year-old girl that presented with progressive bowing of both legs since the age of 2, lower limb pain and frequent falls with one consequent femur fracture. Plain radiographs revealed osteoectasia of the long bone's diaphysis, and laboratory tests showed extremely high serum total alkaline phosphatase levels. A missense mutation on the gene TNFRSF11B was identified in homozygosity, and the diagnosis of JPD was made. Treatment with bisphosphonates was initiated early and markedly improved lower limb bowing and pain. The patient reached adulthood with normal height, minor bone deformities, and no functional impairment. Despite the good skeletal symptom's response, bisphosphonates failed to prevent or improve sensorineural hearing loss. CONCLUSIONS: In this clinical case, early treatment with bisphosphonates was effective for the treatment of JPD skeletal deformities. New therapeutic strategies need to be developed to better control the extraskeletal manifestations of JPD.

Association of body mass index with Juvenile Idiopathic Arthritis disease activity: a Portuguese and Brazilian collaborative analysis.

OBJECTIVE: To investigate the relationship between body mass index (BMI) and disease activity in patients with Juvenile Idiopathic Arthritis (JIA). METHODS: Patients with JIA, aged ≤18 years, registered at the Rheumatic Diseases Portuguese Register (Reuma.pt) in Portugal and Brazil were included. Age- and sex-specific BMI percentiles were calculated based on WHO growth standard charts and categorized into underweight (P <3), normal weight (3≤P≤85), overweight (85

97). Disease activity was assessed by Juvenile Arthritis Disease Activity Score (JADAS-27). Uni- and multivariate analyses were performed. RESULTS: A total of 275 patients were included. The prevalence of underweight, normal weight, overweight and obesity was 6.9%, 67.3%, 15.3% and 10.5%, respectively. Underweight patients had significantly higher number of active joints (p <0.001), patient's/parent's global assessment of disease activity (PGA) (p=0.020), physician's global assessment of disease activity (PhGA) (p <0.001), erythrocyte sedimentation rate (ESR) (p=0.032) and overall higher JADAS-27 (p <0.001), compared to patients with normal weight, overweight and obesity. In the multivariate regression, underweight persisted significantly associated with higher disease activity, compared to normal weight (B=-9.430, p <0.001), overweight (B=-9.295, p=0.001) and obesity (B=-9.120, p=0.001), when adjusted for age, gender, country, ethnicity, JIA category and therapies used. The diagnosis of RF- (B=3.653, p=0.006) or RF+ polyarticular JIA (B=5.287, p=0.024), the absence of DMARD therapy (B=5.542, p <0.001) and the use of oral GC (B=4.984, p=0.002) were also associated with higher JADAS-27. CONCLUSION: We found an independent association between underweight and higher disease activity in patients with JIA. Further studies are needed to understand the underlying mechanisms of this association.

A Case of Deficiency of Adenosine Deaminase 2: 28 years of Diagnostic Challenges.

Deficiency of adenosine deaminase 2 (DADA2) is a unique monogenic autoinflammatory disease caused by autosomal recessive loss-of-function mutations in the CECR1 gene which presents as childhood-onset small- and medium-vessel vasculitis. Previously, many of these patients were misdiagnosed and thought to have clinical features of systemic polyarteritis nodosum, which negatively influenced its outcome, since TNF inhibitors seem to have efficacy on the vasculitic phenotype of DADA2. We present a case of a 28-year-old woman with a lifelong unknown syndrome and unique clinical manifestations recently recognized as DADA2. The first manifestation, at 3 months of age, was an episode of facial paralysis during which renovascular hypertension was diagnosed. Later, she developed episodes of prolonged fever, polyarthritis, Raynaud's phenomenon, gastrointestinal bleeding, and intracerebral hemorrhage. This inflammatory state ultimately led to the development of amyloid A amyloidosis and renal insufficiency.

Neurophysiological comparative response to clinical and surgical treatment of the ulnar neuropathy in leprosy / Padrões neurofisiológicos da resposta tardia ao tratamento clínico e cirúrgico da neuropatia ulnar na hanseníase

Leprosy neuropathy may develop into subacute and chronic inflammatory scenarios, called reactions, which may cause entrapments in the anatomic tunnels. Objective: This study describes the late nerve conduction findings in patients with ulnar neuropathy at the elbow that were submitted to clinical and surgery treatments. Methods: A total of 27 nerves of 21 patients with borderline leprosy during type 1 (reversal) reaction were selected in a non- competing retrospective cohort for three years. The nerves with treated clinically active neuropathy (Group A1) were randomized for inclusion of surgical treatment (Group A2) after one month of clinical treatment without clear signs of clinical and neurophysiological improvement. Fifteen nerves were randomly chosen for surgery while 12 were clinically treated, after steroids treatment without expected response. Nerve conduction was measured before and after treatment on four occasions. Results: The authors observed significant improvement in the following variables in the surgically treated nerves: compound motor action potential amplitude (CMAP) at elbow and above elbow and conduction velocity (CV) along the forearm. Conclusion: The improvement of CMAP amplitudes and conduction velocity (CV) along the forearm express the late effect of nerve decompression. Persistence of temporal dispersion (TD) along the elbow was related to the new reaction or to incomplete surgical solution. However, moderate reduction in CV along the elbow, without TD, was considered an indication of na expected partial remyelination. Previous gradation of the nerve lesion based on the CMAP amplitude was related to the most severe results

A neuropatia de hanseníase pode desenvolver quadros inflamatórios subagudos e crônicos denominados reações, os quais podem evoluir para compressões nos túneis anatômicos. Objetivo: Descrever os achados de condução nervosa (CN) tardios em pacientes com neuropatia ulnar no cotovelo submetidos aos tratamentos clínico e cirúrgico. Método: Vinte e sete nervos de 21 pacientes foram selecionados em uma coorte retrospectiva não-concorrente por um a três anos, sendo formados dois grupos. Após o tratamento clínico sem sinais inequívocos de melhora os nervos foram randomizados para manter o tratamento clinico (Grupo A1) ou adicionar a descompressão do nervo (Grupo A2). Resultados: Os autores observaram melhora significativa nas seguintes variáveis no Grupo A2, tratado com a adição da descompressão cirúrgica, amplitude do potencial de ação motor composto (PAMC) no cotovelo e acima do cotovelo e velocidade de condução (VC) ao longo do antebraço. Conclusão: O ganho em amplitudes dos PAMCs no cotovelo e acima do cotovelo e da velocidade de condução (VC) ao longo do antebraço são a expressão do efeito tardio da descompressão do nervo ulnar. A persistência de dispersão temporal (DT) através do cotovelo foi relacionada a nova reação ou solução cirúrgica incompleta. Entretanto, a persistência de redução moderada da VC através do cotovelo sem a DT foi discutida e considerada como remielinização parcial esperada. A graduação previa da lesão do nervo baseada na amplitude dos PAMCs apresentou relação direta aos resultados menos favoráveis

High glucose induces O-GlcNAc glycosylation of the vitamin D receptor (VDR) in THP1 cells and in human macrophages derived from monocytes.

Chronic hyperglycemia increases the carbon flux through the hexosamine pathway, allowing the accumulation of UDP-GlcNAc. UDP-GlcNAc is the sugar donor for the enzyme-mediated protein glycosylation event known as OGlcNAcylation. This posttranslational modification targets several transcription factors implicated in glucose toxicity, insulin resistance, and diabetes. Vitamin D plays an important role in glucose homeostasis and insulin secretion through transcriptional mechanisms mediated by its receptor (VDR). Vitamin D deficiency has been associated with higher susceptibility to bacterial diseases in diabetic patients. However, it has not been explored whether VDR is subject to OGlcNAcylation or whether high glucose affects its transcriptional or biological activities. The aim of this study was to evaluate the effect of hyperglycemia on VDR OGlcNAcylation and its effects on vitamin D-mediated transcription. We predicted potential OGlcNAcylation sites using free software. Our results showed that hyperglycemia (30 mM) induces the OGlcNAcylation of VDR in THP1 cells and in human macrophages derived from monocytes (MDM). This condition did not hamper the vitamin D-dependent activation of LL-37 gene expression, and even did not impair the macrophage bactericidal activity. Our study provides new insight into vitamin D receptor posttranslational modification that may have relevance on the physiological responses of long-term hyperglycemia.

Genetic Screening of Mutations Associated with Fabry Disease in a Nationwide Cohort of Juvenile Idiopathic Arthritis Patients.

Fabry's disease (FD) is a lysosomal storage disorder associated with an alpha-galactosidase A deficiency. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients with established diagnosis is unknown, but as musculoskeletal pain may be an important complaint at presentation, misdiagnosed cases are anticipated. With this study, we aim to calculate the frequency of FD-associated mutations in a cohort of JIA patients. Children with JIA from a national cohort were selected. Clinical and laboratorial information was recorded in the Portuguese rheumatic diseases register (http://Reuma.pt). Molecular genetic testing to detect GLA gene mutations was performed. After the multiplex polymerase chain reactions technique for DNA amplification, direct sequencing of the complete sequence of GLA gene was completed. From a cohort of 292 patients with JIA (188 females, 104 males), mutations were identified in 5 patients (all female). Four patients had the mutation D313Y, a rare GLA variant, which is associated with low enzymatic levels in plasma, but normal lysosomal levels. One patient presented the missense mutation R118C, which was previously described in Mediterranean patients with FD. This is the first screening of FD mutations in a cohort of JIA patients. No "classic" pathogenic FD mutations were reported. The late-onset FD-associated mutation, R118C, was found in a frequency of 0.34% (1/292).

Congenital Milium of the Nipple.

A 12-month-old girl presented with an asymptomatic, pearly nodule on the left nipple that had been present from birth and was currently 3 mm in diameter and growing. Assuming the diagnosis of congenital primary milium of the nipple, we took a "wait and see" approach. After 3 months, the pearl disappeared without any scarring.

IL10 low-frequency variants in Behçet's disease patients.

AIM: To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility. METHODS: To identify IL10 low-frequency variants, a discovery group of 50 Portuguese BD patients were Sanger-sequenced in a 7.7 kb genomic region encompassing the complete IL10 gene, 0.9 kb upstream and 2 kb downstream, and two conserved regions in the putative promoter. To assess if the novel variants are BD- and/or Portuguese-specific, they were assayed in an additional group of BD patients (26 Portuguese and 964 Iranian) and controls (104 Portuguese and 823 Iranian). RESULTS: Rare IL10 coding variants were not detected in BD patients, but we identified 28 known single nucleotide polymorphisms with minor allele frequencies ranging from 0.010 to 0.390, and five novel non-coding variants in five heterozygous cases. ss836185595, located in the IL10 3' untranslated region, was also detected in one Iranian control individual and therefore is not specific to BD. The remaining novel IL10 variants (ss836185596 and ss836185602 in intron 3, ss836185598 and ss836185604 in the putative promoter region) were not found in the replication dataset. CONCLUSION: This study highlights the importance of screening the whole gene and regulatory regions when searching for novel variants associated with complex diseases, and the need to develop bioinformatics tools to predict the functional impact of non-coding variants and statistical tests which incorporate these predictions.

Tris(pentafluorophenyl)borane as an efficient catalyst in the guanylation reaction of amines.

Tris(pentafluorophenyl)borane, [B(C6F5)3], has been used as an efficient catalyst in the guanylation reaction of amines with carbodiimide under mild conditions. A combined approach involving NMR spectroscopy and DFT calculations was employed to gain a better insight into the mechanistic features of this process. The results allowed us to propose a new Lewis acid-assisted Brønsted acidic pathway for the guanylation reaction. The process starts with the interaction of tris(pentafluorphenyl)borane and the amine to form the corresponding adduct, [(C6F5)3B-NRH2] , followed by a straightforward proton transfer to one of the nitrogen atoms of the carbodiimide, (i)PrN[double bond, length as m-dash]C[double bond, length as m-dash]N(i)Pr, to produce, in two consequent steps, a guanidine-borane adduct, [(C6F5)3B-NRC(N(i)PrH)2] . The rupture of this adduct liberates the guanidine product RNC(N(i)PrH)2 and interaction with additional amine restarts the catalytic cycle. DFT studies have been carried out in order to study the thermodynamic characteristics of the proposed pathway. Significant borane adducts with amines and guanidines have been isolated and characterized by multinuclear NMR in order to study the N-B interaction and to propose the existence of possible Frustrated Lewis Pairs. Additionally, the molecular structures of significant components of the catalytic cycle, namely 4-tert-butylaniline-[B(C6F5)3] adduct and both free and [B(C6F5)3]-bonded 1-(phenyl)-2,3-diisopropylguanidine, and respectively, have been established by X-ray diffraction.

Análisis monoinstitucional del impacto en control local de la braquiterapia intersticial de alta tasa en fracción única de 7 Gy / A single-institution analysis of the effect on local control of high-dose rate brachytherapy boost in a single 7 Gy fraction

Objetivo. Evaluar el impacto de la sobreimpresión con fracción única de braquiterapia de alta tasa en estadios iniciales del cáncer de mama en términos de control local, supervivencia global y toxicidad. Pacientes y métodos. Tras un tratamiento conservador, 137 pacientes, con una edad media de 57 años, recibieron sobreimpresión con braquiterapia de alta tasa en fracción única de 7 Gy entre enero de 2002 y diciembre de 2012. Recibieron quimioterapia el 70% y hormonoterapia el 67%. Resultados. Con un seguimiento medio de casi 8 años, la supervivencia global a los 5 y 10 años fue de 89,5 y 87,7%, respectivamente, con una supervivencia libre de recaída local a los 5 años del 99,3%. Los factores favorecedores de recaída local fueron el tamaño tumoral, la presencia de carcinoma in situ, un margen próximo y un grado iii. La toxicidad aguda fue poco frecuente y de rápida resolución. La fibrosis moderada fue el efecto secundario tardío predominante. Conclusiones. La sobreimpresión con braquiterapia intersticial en fracción única de 7 Gy en estadios iniciales del cáncer de mama es una técnica bien tolerada, con toxicidades tardías aceptables, que permite un excelente control local tumoral acortando el tiempo de tratamiento (AU)

Objective. To evaluate the impact of single fraction boost high-dose rate brachytherapy for breast cancer in early stages in terms of local control, overall survival and toxicity. Patients and methods. After conservative treatment 137 patients, mean age was 57 years, received high-dose rate brachytherapy boost in only fraction of 7 Gy between January 2002 and December 2012. Chemotherapy was used in 70% of the patients and hormone treatment in 67%. Results. At a mean follow-up 90 months, at 5 and 10 years the overall survival was 89.5 and 87.7%, respectively, and local recurrence free survival was 99.3% at 5 years. The risk factors for local recurrence were tumor size, carcinoma in situ, involved margins and grade iii. Acute toxicity was rare and rapid resolution. Moderate fibrosis was the most common late effect. Conclusions. High-dose rate brachytherapy boost in only fraction of 7 Gy to the tumour bed in early stage breast cancer is well tolerated with long term aceptable toxicities and improved local tumor control with a short duration of treatment (AU)