IMPORTANCE trial: a provisional study-design of a single-center, phase II, double-blinded, placebo-controlled, randomized, 4-week study to compare the efficacy and safety of intranasal esketamine in chronic opioid refractory pain.

Background:  Cancer is the second leading cause of death globally. Up to 86% of advanced cancer patients experience significant pain, while 10-20% live in chronic pain. Besides, increasing prescription of opioids resulted in 33,000 deaths in the US in 2015. Both reduce patients' functional status and quality of life. While cancer survival rates are increasing, therapeutic options for chronic opioid refractory pain are still limited. Esketamine is the s-enantiomer of ketamine, with superior analgesic effect and less psychotomimetic side effects. Intranasal esketamine was approved by the FDA for treatment-resistant depression. However, its use in chronic cancer pain has never been tested. Therefore, we propose a phase II, randomized, placebo-controlled trial to evaluate the efficacy and safety of intranasal esketamine in chronic opioid refractory cancer pain. Methods and analysis: We will recruit 120 subjects with chronic opioid refractory pain, defined as pain lasting more than 3 months despite optimal therapy with high dose opioids (>60 mg morphine equivalent dose/day) and optimal adjuvant therapy. Subjects will be randomized into two groups: intranasal esketamine (56mg) and placebo. Treatment will be administered twice a week for four consecutive weeks. The primary outcome is defined as reduction in the Numeric Pain Rating Scale (NPRS) after first application. Secondary outcomes include NPRS reduction after four weeks, the number of daily morphine rescue doses, functional status and satisfaction, and depression. Conclusion: This study may extend therapeutic options in patients with chronic pain, thus improving their quality of life and reducing opioid use. Trial registration: Clinical Trials.gov, NCT04666623. Registered on 14 December 2020.

A theoretical cell-killing model to evaluate oxygen enhancement ratios at DNA damage and cell survival endpoints in radiation therapy.

Radio-resistance induced under low oxygen pressure plays an important role in malignant progression in fractionated radiotherapy. For the general approach to predict cell killing under hypoxia, cell-killing models (e.g. the Linear-Quadratic model) have to be fitted to in vitro experimental survival data for both normoxia and hypoxia to obtain the oxygen enhancement ratio (OER). In such a case, model parameters for every oxygen condition needs to be considered by model-fitting approaches. This is inefficient for fractionated irradiation planning. Here, we present an efficient model for fractionated radiotherapy the integrated microdosimetric-kinetic model including cell-cycle distribution and the OER at DNA double-strand break endpoint (OERDSB). The cell survival curves described by this model can reproduce the in vitro experimental survival data for both acute and chronic low oxygen concentrations. The OERDSB used for calculating cell survival agrees well with experimental DSB ratio of normoxia to hypoxia. The important parameters of the model are oxygen pressure and cell-cycle distribution, which enables us to predict cell survival probabilities under chronic hypoxia and chronic anoxia. This work provides biological effective dose (BED) under various oxygen conditions including its uncertainty, which can contribute to creating fractionated regimens for multi-fractionated radiotherapy. If the oxygen concentration in a tumor can be quantified by medical imaging, the present model will make it possible to estimate the cell-killing and BED under hypoxia in more realistic intravital situations.

Development of a clinical laboratory data base of hyper and hypo alpha lipoproteins in Campinas-SP and neighboring region / Construção de um banco de dados clínico laboratorial de hiper e hipoalfalipoproteinêmicos em Campinas-SP e região

INTRODUCTION: The development of research for diagnosis, prevention and treatment of atherosclerotic cardiovascular disease is of utmost importance due to the fact that it is the main cause of morbidity and mortality in Brazil. OBJECTIVE: To demonstrate the phases of the selection process for candidates with the aim to develop a clinical-laboratorial database of hyper alpha lipoproteinemic patients (hyper A) - high density lipoprotein cholesterol (HDL-C) ≥ 68 mg/dl) and hypo alpha lipoproteinemic patients (hypo A) - HDL-C < 39 mg/dl. MATERIAL AND METHODS: The volunteers were contacted after selection of lipid profiles from individuals treated at the Sistema Único de Saúde (SUS), Campinas-SP and neighboring area. Afterwards, the selected patients went through blood collection, clinical examinations and answered questionnaires on dietary frequency and physical activity. After this preliminary evaluation, some individuals were convened to another blood collection and, subsequently, were submitted to an ultrasonographic exam of the carotid arteries. RESULTS: Only 0.6% and 0.3% from 598,288 lipid profiles were selected for hyper A and hypo A groups, respectively, including gender disparity. Lack of effective questionnaires (75%), missing calls (60%) and non-inclusion were the major hindrances in the construction of this database. DISCUSSION: The difficulties to obtain eligible candidates were also due to the low prevalence of both groups hypo A and hyper A and the high prevalence of pathologies that contribute to non-genetic variations of HDL-C. CONCLUSION: In spite of the obstacles in the development of this database, this study brought about several scientific publications. Furthermore, the development of molecular analyzes and functionality will shortly generate other findings, contributing to the diagnosis and follow-up of HDL dyslipidemias.

INTRODUÇÃO: O desenvolvimento de pesquisa para diagnóstico e prevenção da doença aterosclerótica cardiovascular no Brasil é de grande importância por esta ser a principal causa de morbimortalidade no país. OBJETIVO: Demonstrar as etapas do processo de seleção de voluntários para a construção de um banco de dados clínico-laboratorial de indivíduos hiperalfalipoproteinêmicos (hiper A) - colesterol da lipoproteína de alta densidade (HDL-C) ≥ 68 mg/dl - e hipoalfalipoproteinêmicos (hipo A) - HDL-C < 39 mg/dl. MATERIAL E MÉTODOS: Os voluntários são contatados a partir de resultados de perfis lipídicos de indivíduos atendidos pelo Sistema Único de Saúde (SUS) de Campinas-SP e região e, se selecionados, são convidados para coleta de sangue, exames clínicos e responder a questionários de atividade física e de frequência alimentar. Após essa avaliação, os indivíduos podem ser convocados para nova coleta de sangue e, posteriormente, para a ultrassonografia de carótidas. RESULTADOS: Entre 598.288 perfis lipídicos recebidos das redes públicas, apenas 0,6% e 0,3% compuseram os nossos grupos hiper A e hipo A, com disparidade entre os gêneros. A falta de questionários efetivos (75%), das chamadas não atendidas (60%) e a não inclusão foram os pontos mais difíceis na construção do banco de dados. DISCUSSÃO: A dificuldade de obtenção de voluntários elegíveis também se deve à baixa prevalência de hipo A e hiper A e à alta prevalência de patologias que contribuem para variações não genéticas do HDL-C. CONCLUSÃO: Apesar das dificuldades na criação da base de dados, este estudo gerou várias publicações e, com o desenvolvimento das análises moleculares e da funcionalidade, muitas outras seguirão em curto período, fatos contribuintes para o diagnóstico e o acompanhamento das dislipidemias envolvendo a HDL.

Tratamento pós-menopausa reduz a atividade da catalase e atenua o risco cardiovascular / Postmenopausal therapy reduces catalase activity and attenuates cardiovascular risk

FUNDAMENTO: A menopausa pode levar a alterações na saúde feminina, com mudanças no estado oxidativo de mulheres pós-menopausadas, para as quais são limitadas as informações relativas à influência da hormonioterapia (HT) sobre as atividades das enzimas antioxidantes. OBJETIVO: Avaliar a influência da HT sobre a atividade da catalase, concentrações de lipídeos e lipoproteínas, proteína de transferência de colesteril éster, substâncias reativas ao ácido tiobarbitúrico, nitratos, proteína C-reativa ultrassensível e espessura da carótida em mulheres pós-menopausadas. MÉTODOS: Foram alocadas 94 mulheres para um de quatro grupos com ou sem HT. O último grupo foi subdividido em mulheres sendo tratadas com estrógeno e outras com estrógeno mais progestágeno. Foram realizadas medidas de parâmetros bioquímicos plasmáticos e da espessura da íntima-média da carótida. RESULTADOS: A HT antagonizou a redução na atividade da catalase após a menopausa, mas não teve efeito sobre os níveis da proteína de transferência de colesteril éster, substâncias reativas ao ácido tiobarbitúrico, peróxido lipídico, nitrato e proteína C reativa ultrassensível, nem sobre a espessura da íntima-média da carótida. A análise multivariada mostrou que a HT baseada em estrógeno atenuou a relação entre os fatores de risco cardiovasculares e a espessura da íntima-média da carótida comum. CONCLUSÃO: Este estudo mostra que a HT em mulheres pós-menopausadas produz efeitos antioxidantes e antiateroscleróticos benéficos por melhorar as concentrações séricas de lipídios e lipoproteínas, aumentar a atividade da catalase sérica e atenuar a associação entre os fatores de risco cardiovasculares e a aterosclerose precoce.

BACKGROUND: Menopause can lead to alterations in women's health, with changes in the oxidative status of postmenopausal women in whom information regarding the influence of hormone therapy (HT) on antioxidant enzyme activities is limited. OBJECTIVE: To evaluate the influence of HT on catalase activity; concentrations of lipids and lipoprotein, cholesteryl ester transfer protein, thiobarbituric acid-reactive substances, nitrates, high-sensitivity C-reactive protein and carotid thickness in postmenopausal women. METHODS: Ninety-four consecutive women were allocated to one of four groups, without HT and with HT. The latter group was subdivided into women using estrogen and those using estrogen plus progestogen therapy. Plasma biochemical parameters and common carotid intima-media thickness measurements were performed. RESULTS: HT antagonized the decrease in catalase activity after menopause, but had no effect on the levels of cholesteryl ester transfer protein, thiobarbituric acid-reactive substances, lipid peroxide, nitrate, high-sensitivity C-reactive protein, or on the common carotid intima-media thickness. Multivariate analysis showed that estrogen-based HT attenuated the relationship between cardiovascular risk factors and the intima-media thickness of the common carotid. CONCLUSION: This study indicates that HT in postmenopausal women produces beneficial antioxidant and anti-atherosclerotic effects by ameliorating the plasma lipid and lipoprotein profiles, increasing plasma catalase activity and attenuating the association between cardiovascular risk factors and early atherosclerosis.

Postmenopausal therapy reduces catalase activity and attenuates cardiovascular risk.

BACKGROUND: Menopause can lead to alterations in women's health, with changes in the oxidative status of postmenopausal women in whom information regarding the influence of hormone therapy (HT) on antioxidant enzyme activities is limited. OBJECTIVE: To evaluate the influence of HT on catalase activity; concentrations of lipids and lipoprotein, cholesteryl ester transfer protein, thiobarbituric acid-reactive substances, nitrates, high-sensitivity C-reactive protein and carotid thickness in postmenopausal women. METHODS: Ninety-four consecutive women were allocated to one of four groups, without HT and with HT. The latter group was subdivided into women using estrogen and those using estrogen plus progestogen therapy. Plasma biochemical parameters and common carotid intima-media thickness measurements were performed. RESULTS: HT antagonized the decrease in catalase activity after menopause, but had no effect on the levels of cholesteryl ester transfer protein, thiobarbituric acid-reactive substances, lipid peroxide, nitrate, high-sensitivity C-reactive protein, or on the common carotid intima-media thickness. Multivariate analysis showed that estrogen-based HT attenuated the relationship between cardiovascular risk factors and the intima-media thickness of the common carotid. CONCLUSION: This study indicates that HT in postmenopausal women produces beneficial antioxidant and anti-atherosclerotic effects by ameliorating the plasma lipid and lipoprotein profiles, increasing plasma catalase activity and attenuating the association between cardiovascular risk factors and early atherosclerosis.

Oxidized low-density lipoproteins and their antibodies: relationships with the reverse cholesterol transport and carotid atherosclerosis in adults without cardiovascular diseases.

BACKGROUND: Metabolic predictors and the atherogenicity of oxidized LDL (oxLDL) and the specific antibodies against oxLDL (oxLDL Ab) are unclear and controversial. METHODS: In 107 adults without atherosclerotic manifestations, we measured oxLDL and oxLDL Ab, and also the activities of CETP, PLTP, lipases and the carotid intima-media thickness (cIMT). Comparisons were performed for the studied parameters between the lowest and the highest tertile of oxLDL and oxLDL Ab, and the relationships between studied variables were evaluated. RESULTS: Subjects with higher oxLDL Ab present reduced hepatic lipase activity and borderline increased cIMT. In the highest oxLDL tertile, besides the higher levels of total cholesterol, LDL-C and apoB100, we found reduced CETP activity and higher cIMT. A significant correlation between oxLDL Ab and cIMT, independent of oxLDL, and a borderline correlation between oxLDL and cIMT independent of oxLDL Ab were found. In the multivariate analysis, apoAI was a significant predictor of oxLDL Ab, in contrast to regulation of oxLDL by apoB100, PLTP and inverse of CETP. CONCLUSIONS: In adults without atherosclerotic disease, the metabolic regulation and carotid atherosclerosis of oxLDL Ab and oxLDL groups, characterized a dual trait in oxLDL Ab, as a contributor to carotid atherosclerosis, much less so than oxidized LDL, and with a modest atheroprotective role.

Post-menopausal hormone therapy reduces autoantibodies to oxidized apolipoprotein B100.

The aim of the study was to verify whether post-menopausal hormone replacement therapy (HRT) modifies autoantibody titers against oxidized low-density lipoprotein (LDL) (anti-LDLoxi), against epitopes of oxidized apolipoprotein B100 and common carotid intima-media thickness (IMT) in these women. Sixty-eight women in pre-menopause (PMW) and 216 in post-menopause (POMW) were recruited; eighty-three had undergone HRT for at least 12 months, where 48 received conjugated estrogens alone (EHRT) and 35 received conjugated estrogen and medroxyprogesterone acetate (CHRT). ELISA was used to determine autoantibodies. Lipoprotein lipase (LPL), hepatic lipase (HL), cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activities were assayed by radiometric methods. IMT was measured using Doppler ultrasound. Anti-oxidized LDL and anti-D antibodies increased by 40% (p ≤ 0.003) and 42% (p ≤ 0.006), respectively, with menopause. There was a surprising and significant 7% reduction in anti-D2 antibody titers with HRT (p ≤ 0.050), indicating a positive effect of treatment on the immune response to oxidized LDL. Combined HRT decreased activities of HL and LPL. HRT did not change common carotid IMT, which was increased by 32% as expected after menopause (p ≤ 0.030). This study describes, for the first time, the protective effect of HRT on decreasing autoantibody titers against oxidized apolipoprotein B in LDL.

A reduction of CETP activity, not an increase, is associated with modestly impaired postprandial lipemia and increased HDL-cholesterol in adult asymptomatic women.

BACKGROUND: The relationship between CETP and postprandial hyperlipemia is still unclear. We verified the effects of varying activities of plasma CETP on postprandial lipemia and precocious atherosclerosis in asymptomatic adult women. METHODS: Twenty-eight women, selected from a healthy population sample (n = 148) were classified according to three CETP levels, all statistically different: CETP deficiency (CETPd ≤ 4.5%, n = 8), high activity (CETPi ≥ 23.8, n = 6) and controls (CTL, CETP ≥ 4.6% and ≤ 23.7%, n = 14). After a 12 h fast they underwent an oral fat tolerance test (40 g of fat/m² of body surface area) for 8 hours. TG, TG-rich-lipoproteins (TRL), cholesterol and TRL-TG measurements (AUC, AUIC, AR, RR and late peaks) and comparisons were performed on all time points. Lipases and phospholipids transfer protein (PLTP) were determined. Correlation between carotid atherosclerosis (c-IMT) and postprandial parameters was determined. CETP TaqIB and I405V and ApoE-ε3/ε2/ε4 polymorphisms were examined. To elucidate the regulation of increased lipemia in CETPd a multiple linear regression analysis was performed. RESULTS: In the CETPi and CTL groups, CETP activity was respectively 9 and 5.3 higher compared to the CETPd group. Concentrations of all HDL fractions and ApoA-I were higher in the CETPd group and clearance was delayed, as demonstrated by modified lipemia parameters (AUC, AUIC, RR, AR and late peaks and meal response patterns). LPL or HL deficiencies were not observed. No genetic determinants of CETP deficiency or of postprandial lipemia were found. Correlations with c-IMT in the CETPd group indicated postprandial pro-atherogenic associations. In CETPd the regression multivariate analysis (model A) showed that CETP was largely and negatively predicted by VLDL-C lipemia (R² = 92%) and much less by TG, LDL-C, ApoAI, phospholipids and non-HDL-C. CETP (model B) influenced mainly the increment in ApoB-100 containing lipoproteins (R² = 85% negatively) and phospholipids (R² = 13%), at the 6(th)h point. CONCLUSION: The moderate CETP deficiency phenotype included a paradoxically high HDL-C and its sub fractions (as earlier described), positive associations with c-IMT, a postprandial VLDL-C increment predicting negatively CETP activity and CETP activity regulating inversely the increment in ApoB100-containing lipoproteins. We hypothesize that the enrichment of TG content in triglyceride-rich ApoB-containing lipoproteins and in TG rich remnants increases lipoproteins' competition to active lipolysis sites,reducing their catabolism and resulting on postprandial lipemia with atherogenic consequences.

Sex-dependent variables in the modulation of postalimentary lipemia.

OBJECTIVE: To quantify in young adults the sex-dependent differences in lipemic responses to a fat meal, we measured the association of these responses with markers of atherosclerosis and determined their metabolic regulators. METHODS: Forty-nine normolipidemic volunteers, 25 women and 24 men, were matched according to age, body mass index, waist circumference, diet, physical activity, and apolipoprotein-E phenotyping. After receiving a standardized fat meal (40 g of fat/m2 of body surface area), serial blood samples were drawn for laboratory analysis. Common carotid intima-media thickness was measured. RESULTS: The lipemic responses were much greater in men than in women for plasma triacylglycerol (TAG), cholesterol, and TAG in TAG-rich lipoproteins, non-esterified fatty acids, phospholipids, and apolipoprotein-B100. Men presented with increased blood pressure, carotid intima-media thickness, TAG, hepatic lipase, and insulin and lower high-density lipoprotein cholesterol, apolipoprotein-AI, and non-esterified fatty acid concentrations. Only in men did carotid intima-media thickness correlate marginally with titers of autoantibodies to epitopes of oxidized low-density lipoprotein; in addition, phospholipids and cholesteryl esters were negatively related to autoantibodies. Multivariate analysis indicated that age (R2 = 45%), waist circumference (R2 = 19%), phospholipids (R2 = 39%), non-esterified fatty acids (R2 = 29%), insulin (R2 = 17%), lipoprotein lipase activity (R2 = 16%), and cholesteryl ester transfer protein (an exploratory variable; R2 = 6%) are strong determinants of postalimentary lipemia in women and that only insulin (R2 = 55%) and phospholipids (R2 = 37%) are determinants in men. CONCLUSIONS: We have provided data explaining that postalimentary lipemia is differently regulated by sex. Several risk factors for coronary heart disease and significant associations with atherosclerosis biomarkers were found only in men.

Prostatic atrophy: evidence for a possible role of local ischemia in its pathogenesis.

Prostatic atrophy may be histologically and at ultrasound similar to adenocarcinoma causing diagnostic confusion, its frequency increases with age but the etiopathogenesis is unknown. Based on a systematic study in autopsies previously done by one of us, ischemia due to local intense arteriosclerosis seems to be a potential factor for its pathogenesis. Absent blood flow in areas of prostatic atrophy might be a further evidence for a possible role of ischemia. From a total of 298 patients biopsied and studied by gray-scale and color Doppler transrectal ultrasound in the period 1998 to 2001, 33 patients had suspicious lesions (37 hypoechoic nodules and 3 heterogeneous lesions) showing prostatic atrophy as the only diagnosis on all these biopsied lesions. Adenocarcinoma, high-grade intraepithelial neoplasia or other atypical lesions were absent in all patients. On color Doppler the suspicious areas showed absent flow in 24/40 (60%), present flow in 12/40 (30%), and increased flow in 4/40 (10%) of the lesions. Absent flow in the majority of the lesions studied may be a further evidence for a possible role of local ischemia in the etiopathogenesis of prostatic atrophy.

Botriomicose: relato de um caso / Botryomycosis: a case report

Os autores relatam um caso de botriomicose com tumoração da parede abdominal anterior. Ela é de origem bacteriana e acomete tanto o tecido cutâneo quanto o visceral, e a áreas expostas como mãos e pés são as mais atingidas. No caso em questão se estendia por toda a parede abdominal anterior, com trajetos fistulosos, comprometendo o tecido subcutâneo, músculos, gordura pré-peritoneal, não havendo planos de clivagem com alças instestinais, atingindo região pancreática e bexiga. O diagnóstico final foi feito por exame histopatológico e bacteriológico da lesão.

O uso do sistema prognosticador apache II (classificaçäo da severidade da doença) no pós-trauma de pacientes submetidos à nutriçäo enteral / The use of apache II (a severity of disease classification system) in trauma care patients under enteral nutrition

O sistema de classificaçäo da severidade da doença APACHE II foi testado a fim de identificar os pacientes graves suscetíveis de apresentar intolerância digestiva, a partir da administraçäo de dieta enteral polimérica. Foi realizado um estudo prospectivo em 40 pacientes na fase de recuperaçäo de traumas diversos que receberam suporte nutricional enteral. Quando o score do APACHE II da admissäo foi utilizado isoladamente, näo foi possível prever quais pacientes poderiam desenvolver intolerância digestiva. Contudo, quando um score deAPACHE II ò 10 foi associado a uma administraçäo de dieta ò 1.500Kcal com piora e/ou estagnaçäo do quadro clínico, observou-se, para esses critérios, uma sensibilidade de 83,3 por cento e uma especificidade de 78,5//com um Odds ratio (O.R.) de 3,87. Esses achados sugerem que o sistema APACHE II, nessa casuística, associado a outros fatores pode constituir-se num guia eficaz de prediçäo dos pacientes suscetíveis de apresentar intolerância digestiva