Raloxifeno e osteoporose: revisão de um novo modulador seletivo do receptor de estrógeno

Raloxifene is a selective estrogen receptor modulator of second generation with agonist effect in the bone, cardiovascular system, and antagonist effect in the breast and uterus. The tissue selectivity of raloxifene occurs due to several mechanisms such as different estrogen receptors, differential distribution of receptors, different protein transcriptional factors and receptor conformation after raloxifene binding. In bone, raloxifene increases the bone mass in the spine, femur and total body, prevents osteoporosis in postmenopausal women and reduces the incidence of vertebral fractures in 50% in women with osteoporosis. In the cardiovascular system, raloxifene decreases total cholesterol, LDL-cholesterol, fibrinogen and lipoprotein (a), without changes in triglycerides and HDL-cholesterol, however, it increases the subfraction HDL-C2. Raloxifene has antiproliferative activity in the breast, does not induce mastalgia and a reduction in the incidence of new cases of breast cancer has been found in women taking raloxifene in the large osteoporosis trials. In the uterus, raloxifene does not stimulate the endometrium and does not increase the incidence of vaginal bleeding or endometrial carcinoma. The most common adverse event with ralox-ifene is hot flashes and the most serious is venous thromboembolism with similar incidence as hormonal replacement therapy. Raloxifene is an alternative with evidence of selective beneficial effects in other tissues. Other potential benefits with raloxifene such as cardiovascular protection and breast cancer prevention are being investigated in long-term clinical trials.Raloxifeno é um modulador seletivo do receptor de estrógeno de segunda geração com ação agonista no osso e sistema cardiovascular e ação antagonista na mama e útero. Sua seletividade tecidual ocorre devido a diversos mecanismos como diferentes receptores de estrógenos, distribuição diferencial destes receptores, diferentes co-fatores protéicos transcricionais e diferente conformação do receptor após ligação de raloxifeno. No osso, raloxifeno aumenta a massa óssea na coluna, fêmur, corpo inteiro, é eficaz em prevenir osteoporose em mulheres na pós-menopausa e reduz a incidência de fraturas vertebrais em 50% em mulheres com osteoporose. No sistema cardiovascular, raloxifeno reduz o colesterol total, LDL-colesterol, fibrinogênio e lipoproteína (a), não tendo efeito nos triglicérides e HDL-colesterol total, porém aumenta a subfração HDL-C2. Raloxifeno tem atividade antiproliferativa na mama, não induz mastalgia e uma redução na incidência de novos casos de câncer de mama tem sido demonstrada em mulheres em uso de raloxifeno em grandes estudos clínicos para osteoporose. No útero, raloxifeno não estimula o endométrio e não aumenta a incidência de sangramento vaginal ou carcinoma endometrial. O evento adverso mais comum com raloxifeno são ondas de calor e o mais sério é o tromboembolismo venoso com incidência semelhante à terapia de reposição hormonal. Raloxifeno é uma alternativa para o tratamento e prevenção de osteoporose em mulheres na pós-menopausa com evidências de efeitos benéficos seletivos em outros órgãos. Outros benefícios potenciais de raloxifeno como proteção cardiovascular e prevenção de câncer de mama estão sendo investigados em grandes estudos clínicos a longo prazo.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de MedicinaEli Lilly do Brasil LtdaUNIFESP, EPMSciEL

Prospective study to measure the functional outcome of tibial plateau fractures

Background: Tibial plateau fractures are complex injuries of the knee. The tibial plateau is one of the most critical load-bearing areas in the human body. Early detection and appropriate treatment of these fractures are essential in minimizing patient's disability in range of movement, stability and reducing the risk of documented complications. The aim of the present study is to study the outcome of tibial plateau fractures and their management.Methods: This is prospective study which comprises of 50 patients with displaced tibial plateau fracture and were treated between January 2018 to December 2018 with minimal invasive percutaneous plate osteosynthesis and cortico-cancellous screw fixation. Statistical analysis was done by Chi-square test and IBM SPSS software.Results: In our study we included 50 cases, treated with surgical procedure, 30 cases gave excellent result, 16 cases came out with good result, fair in 3 cases and 1 case had poor result. High velocity injuries have poor outcome than low velocity injuries. A single case of malunion was noted in study. Four cases had knee joint stiffness.Conclusions: We conclude that functional outcome is good in operatively treated patients. Early physiotherapy plays key role in preventing knee stiffness, use of bone grafts and good fixation important for successful outcome

Menor incidência de hipoglicemia noturna com o uso de insulina lispro comparada à insulina humana regular no tratamento de pacientes com diabetes do tipo 1

Insulin lispro is a human insulin analog of rapid onset of action and duration, which mimics the physiological insulin profile after a meal. We have evaluated the safety and efficacy of lispro insulin in comparison with human regular insulin in a crossover, multicenter, randomized trial in 25 type 1 diabetic patients in use of human NPH and regular insulin (median age = 16 years). After administration of lispro or regular insulin for 2 months, the patients were transferred for the other insulin for two more months, maintaining the basal NPH insulin regimen. There was no difference in the postprandial glucose excursion and glycated hemoglobin A1c comparing the 2 groups (lispro and regular). The relative percentage decrease in glycemia was significantly greater with lispro insulin after lunch, in the first phase of the study (p<0.02). The total number of hypo-glycemic episodes was not different comparing both groups. However, there was a significant difference in the nocturnal hypoglycemia incidence with initial administration of lispro (p<0.05). With initial administration of regular insulin, there was an increase in the incidence of nocturnal hypoglycemia (p=0.038), with a subsequent reduction of hypoglycemia with insulin lispro (p=0.04). In the end of the study, 68% of the patients referred preference and better feeling with lispro, compared to regular insulin. Insulin lispro was a safe and efficacious option, with lower incidence of nocturnal hypoglycemia in type 1 diabetics. An optimization of the basal insulin regimen is necessary to improve glucose control with the use of rapid-action insulin.Insulina lispro é um análogo da insulina humana de ação e duração rápida, que mimeíiza o perfil fisiológico da insulina após uma refeição. Avaliamos a segurança e eficácia da insulina lispro em comparação com a insulina humana regular em um estudo multicêntrico, randomizado e cruzado em 27 diabéticos tipo 1 em uso de insulina humana NPH e regular (idade mediana = 16 anos). Após uso de insulina lispro ou regular por 2 meses, fez-se a transferência para a outra insulina por mais 2 meses mantendo-se a insulina NPH basal. Não houve diferença em relação à excursão prandial da glicemia da hemoglobina glicosilada A1C, comparando-se os 2 grupos (lispro e regular). O decréscimo percentual relativo da glicemia foi significantemente maior com insulina lispro no período do almoço, na primeira fase do estudo (p<0,02). O número total de episódios hipoglicêmicos não foi diferente, comparando os 2 grupos. Houve, porém, uma redução significante na incidência de hipoglicemia noturna e na madrugada com o uso inicial de lispro (p<0,05). Com o uso inicial de insulina regular, houve incremento na incidência de hipoglicemia noturna (p=0,038), com redução posterior na incidência da hipoglicemia com insulina lispro (p=0,04). Ao final do estudo, 68% dos pacientes referiram preferência e maior comodidade com insulina lispro em relação à insulina regular. A insulina lispro se mostrou uma opção segura e eficaz, com menor incidência de hipoglicemia noturna em diabéticos tipo 1. Uma otimização do regime de insulina basal é necessária para melhora do controle glicêmico, quando em uso de uma insulina de ação rápida.Universidade Federal do CearáUniversidade de São Paulo Faculdade de MedicinaUniversidade Federal de São Paulo (UNIFESP)Laboratório Eli Lilly do BrasilUNIFESPSciEL

Influences of obese (ob/ob) and diabetes (db/db) genotype mutations on lumber vertebral radiological and morphometric indices: Skeletal deformation associated with dysregulated systemic glucometabolism

BACKGROUND: Both diabetes and obesity syndromes are recognized to promote lumbar vertebral instability, premature osteodegeneration, exacerbate progressive osteoporosis and increase the propensity towards vertebral degeneration, instability and deformation in humans. METHODS: The influences of single-gene missense mutations, expressing either diabetes (db/db) or obese (ob/ob) metabolic syndromes on vertebral maturation and development in C57BL/KsJ mice were evaluated by radiological and macro-morphometric analysis of the resulting variances in osteodevelopment indices relative to control parameters between 8 and 16 weeks of age (syndrome onset @ 4 weeks), and the influences of low-dose 17-B-estradiol therapy on vertebral growth expression evaluated. RESULTS: Associated with the indicative genotypic obesity and hyper-glycemic/-insulinemic states, both db/db and ob/ob mutants demonstrated a significant (P ≤ 0.05) elongation of total lumbar vertebrae column (VC) regional length, and individual lumbar vertebrae (LV1-5) lengths, relative to control VC and LV parameters. In contrast, LV1-5 width indices were suppressed in db/db and ob/ob mutants relative to control LV growth rates. Between 8 and 16 weeks of age, the suppressed LV1-5 width indices were sustained in both genotype mutant groups relative to control osteomaturation rates. The severity of LV1-5 width osteosuppression correlated with the severe systemic hyperglycemic and hypertriglyceridemic conditions sustained in ob/ob and db/db mutants. Low-dose 17-B-estradiol therapy (E2-HRx: 1.0 ug/ 0.1 ml oil s.c/3.5 days), initiated at 4 weeks of age (i.e., initial onset phase of db/db and ob/ob expressions) re-established control LV 1–5 width indices without influencing VC or LV lengths in db/db groups. CONCLUSION: These data demonstrate that the abnormal systemic endometabolic states associated with the expression of db/db and ob/ob genomutation syndromes suppress LV 1–5 width osteomaturation rates, but enhanced development related VC and LV length expression, relative to control indices in a progressive manner similar to recognized human metabolic syndrome conditions. Therapeutic E2 modulation of the hyperglycemic component of diabetes-obesity syndrome protected the regional LV from the mutation-induced osteopenic width-growth suppression. These data suggest that these genotype mutation models may prove valuable for the evaluation of therapeutic methodologies suitable for the treatment of human diabetes- or obesity-influenced, LV degeneration-linked human conditions, which demonstrate amelioration from conventional replacement therapies following diagnosis of systemic syndrome-induced LV osteomaturation-associated deformations

The Burkholderia pseudomallei Type III Secretion System and BopA Are Required for Evasion of LC3-Associated Phagocytosis

Burkholderia pseudomallei is the causative agent of melioidosis, a fatal infectious disease endemic in tropical regions worldwide, and especially prevalent in southeast Asia and northern Australia. This intracellular pathogen can escape from phagosomes into the host cytoplasm, where it replicates and infects adjacent cells. We previously demonstrated that, in response to B. pseudomallei infection of macrophage cell line RAW 264.7, a subset of bacteria co-localized with the autophagy marker protein, microtubule-associated protein light chain 3 (LC3), implicating autophagy in host cell defence against infection. Recent reports have suggested that LC3 can be recruited to both phagosomes and autophagosomes, thereby raising questions regarding the identity of the LC3-positive compartments in which invading bacteria reside and the mechanism of the autophagic response to B. pseudomallei infection. Electron microscopy analysis of infected cells demonstrated that the invading bacteria were either free in the cytosol, or sequestered in single-membrane phagosomes rather than double-membrane autophagosomes, suggesting that LC3 is recruited to B. pseudomallei-containing phagosomes. Partial or complete loss of function of type III secretion system cluster 3 (TTSS3) in mutants lacking the BopA (effector) or BipD (translocator) proteins respectively, resulted in delayed or no escape from phagosomes. Consistent with these observations, bopA and bipD mutants both showed a higher level of co-localization with LC3 and the lysosomal marker LAMP1, and impaired survival in RAW264.7 cells, suggesting enhanced killing in phagolysosomes. We conclude that LC3 recruitment to phagosomes stimulates killing of B. pseudomallei trapped in phagosomes. Furthermore, BopA plays an important role in efficient escape of B. pseudomallei from phagosomes

Small-Molecule Inhibitor of the Shigella flexneri Master Virulence Regulator VirF

This is the publisher's version, also available electronically from http://iai.asm.org/content/81/11/4220VirF is an AraC family transcriptional activator that is required for the expression of virulence genes associated with invasion and cell-to-cell spread by Shigella flexneri, including multiple components of the type three secretion system (T3SS) machinery and effectors. We tested a small-molecule compound, SE-1 (formerly designated OSSL_051168), which we had identified as an effective inhibitor of the AraC family proteins RhaS and RhaR, for its ability to inhibit VirF. Cell-based reporter gene assays with Escherichia coli and Shigella, as well as in vitro DNA binding assays with purified VirF, demonstrated that SE-1 inhibited DNA binding and transcription activation (likely by blocking DNA binding) by VirF. Analysis of mRNA levels using real-time quantitative reverse transcription-PCR (qRT-PCR) further demonstrated that SE-1 reduced the expression of the VirF-dependent virulence genes icsA, virB, icsB, and ipaB in Shigella. We also performed eukaryotic cell invasion assays and found that SE-1 reduced invasion by Shigella. The effect of SE-1 on invasion required preincubation of Shigella with SE-1, in agreement with the hypothesis that SE-1 inhibited the expression of VirF-activated genes required for the formation of the T3SS apparatus and invasion. We found that the same concentrations of SE-1 had no detectable effects on the growth or metabolism of the bacterial cells or the eukaryotic host cells, respectively, indicating that the inhibition of invasion was not due to general toxicity. Overall, SE-1 appears to inhibit transcription activation by VirF, exhibits selectivity toward AraC family proteins, and has the potential to be developed into a novel antibacterial agent

A study to link grab sampling frequency to effluent variability and costs

The nature of variation in BOD5 values from grab samples taken from three secondary wastewater treatment plants is studied by applying Spectral and Cross-spectral analysis. The important periodicities in the data are identified, and it was found that most of the significant periodicities were below a frequency of 0.33 cycles/day. For Plant 3, a weekly cycle was found in the influent BOD load. An analysis of the costs of sampling reveals that it is expensive to detect a high percentage of pollution violations. By recognizing the periodicities, the sampling interval can be increased to 2 or 3 days, and still provide adequate pollution control thus reducing the sampling costs.Industrial Engineering, Department o