Special Issue "Application Progress of Liposomes in Drug Development".

The second edition of the Special Issue entitled the "Application Progress of Liposomes in Drug Development" featured contributions predominantly focused on leveraging liposomes as enhancers and carriers in drug delivery in the context of cancer treatment, although this was not the initial intent of this Special Issue [...].

Tobacco consumption in Mozambique in 2005 and 2015.

INTRODUCTION: The burden related to smoking exposure is growing in many low-income settings. We aimed to quantify the use of smoked and smokeless tobacco in Mozambique in 2014/2015, and to compare the estimates with those obtained in 2005. METHODS: A cross sectional study was conducted in 2014/2015 on a representative sample of the Mozambican population aged 15 to 64 years, following the World Health Organization Stepwise Approach to Chronic Disease Risk Factor Surveillance (STEPS). Prevalence estimates with 95% confidence intervals were computed for different categories of tobacco consumption. The age-standardised prevalence in the age-group 25-64 years was compared with results from a STEPS survey conducted in 2005. RESULTS: Between 2005 and 2014/2015, the prevalence of daily smoking decreased from 9.1% to 3.4% (p < 0.05) in women and from 33.6% to 27.3% (p < 0.05) in men. There was a significant decrease in the daily consumption of hand-rolled cigarettes among women (from 3.1% to 1.4%, p < 0.05). Among men, there was a decrease in the prevalence of daily consumption of smokeless tobacco (from 3.5% to 1.0%, p < 0.05). In 2014/2015, both manufactured and hand-rolled cigarette consumption were more prevalent among men, while the use of smokeless tobacco was more common among women; the consumption of both hand-rolled cigarettes and smokeless tobacco were more prevalent in rural settings. DISCUSSION AND CONCLUSIONS: In Mozambique, there was a decrease in the prevalence of daily smokers in both genders and of daily consumption of smokeless tobacco among men between 2005 and 2014/2015. Efforts are needed to maintain the positive trends.

Antimicrobial Bacterial Metabolites: Properties, Applications and Loading in Liposomes for Site-specific Delivery.

The high levels of antibiotic resistance registered worldwide have become a serious health problem, threatening the currently available treatments for a series of infectious diseases. With antibiotics becoming less and less effective, it is becoming increasingly difficult and, in some cases, impossible to treat patients with even common infectious diseases, such as pneumonia. The inability to meet the ever-increasing demand to control microbial infection requires both the search for new antimicrobials and improved site-specific delivery. On the one hand, bacterial secondary metabolites are known for their diverse structure and antimicrobial potential and have been in use for a very long time in diverse sectors. A good deal of research is produced annually describing new molecules of bacterial origin with antimicrobial properties and varied applications. However, very few of these new molecules reach the clinical phase and even fewer are launched in the market for use. In this review article, we bring together information on these molecules with potential for application, in particular, for human and veterinary medicine, and the potential added value of the use of liposomes as delivery systems for site-specific delivery of these drugs with the synergistic effect to overcome the risk of antibiotic resistance.

Prevalence of Cardiovascular Risk Factors among Young Adults (18-25 Years) in Mozambique.

The life course development of cardiovascular diseases (CVDs) and the undergoing epidemiological transition in Mozambique highlight the importance of monitoring the cardiovascular risk profile in young adults. Therefore, this study aims to estimate the prevalence of CVD risk factors in a population aged 18-25 years living in Mozambique. A total of 776 young adults from a nationally representative sample were evaluated in 2014/2015 following the World Health Organization's STEPwise approach to chronic disease risk factor surveillance. Current smoking was the most prevalent among rural men (10.8%, 95%CI: 6.3-17.8), and drinking was most prevalent among urban men (38.6%, 95%CI: 29.3-48.8). The proportion of young adults not engaging in at least 75 min of vigorous physical activity per week ranged between 14.5% in rural men and 61.6% in urban women. The prevalence of being overweight/obese and hypertension were highest among urban women (21.6%, 95%CI: 14.7-30.6) and urban men (25.2%, 95%CI: 15.9-37.6), respectively. Education >8 years (vs. none) was independently associated with lower odds of being a current smoker, and increased monthly household income was associated with increased odds of low levels of physical activity. This study shows that important CVD risk factors are already common in the young adult population of Mozambique.

Liposomes: The Brave Old World.

Liposomes have been known of for about 60 years, since they were discovered by A [...].

Changes in prevalence and the cascade of care for type 2 diabetes over ten years (2005-2015): results of two nationally representative surveys in Mozambique.

BACKGROUND: Sub-Saharan Africa is predicted to have the steepest increase in the prevalence of diabetes in the next 25 years. The latest Mozambican population-based STEPS survey (STEPS 2005) estimated a 2.9% prevalence of diabetes in the adult population aged 25-64 years. We aimed to assess the change in prevalence, awareness, and management of diabetes in the national STEPS survey from 2014/2015 compared to 2005. METHODS: We conducted an observational, quantitative, cross-sectional study following the WHO STEPS surveillance methodology in urban and rural settings, targeting the adult population of Mozambique in 2015. We collected sociodemographic data, anthropometric, and 12 hour fasting glucose blood samples in a sample of 1321 adults. The analysis consisted of descriptive measures of the prevalence of impaired fasting glucose (IFG), diabetes and related risk factors by age group, sex, and urban/rural residence and compared the findings to those of the 2005 survey results. RESULTS: The prevalence of IFG and diabetes was 4.8% (95CI: 3.6-6.3) and 7.4% (95CI: 5.5-10.0), respectively. These prevalence of IFG and diabetes did not differ significantly between women and men. The prevalence of diabetes in participants classified with overweight/obesity [10.6% (95CI: 7.5-14.6)] and with central obesity (waist hip ratio) [11.0% (95CI: 7.4-16.1)] was almost double the prevalence of their leaner counterparts, [6.3% (95CI, 4.0-9.9)] and [5.2% (95CI: 3.2-8.6)], respectively. Diabetes prevalence increased with age. There were 50% more people with diabetes in urban areas than in rural. Only 10% of people with diabetes were aware of their disease, and only 44% of those taking oral glucose-lowering drugs. The prevalence of IFG over time [2.0% (95CI: 1.1-3.5) vs 4.8% (95CI: 3.6-6.3)] and diabetes [2.9% (95CI: 2.0-4.2) vs 7.4% (95CI: 5.5-10.0)] were more than twofold higher in 2014/2015 than in 2005. However, awareness of disease and being on medication decreased by 3% and by 50%, respectively. Though this was not statistically significant. CONCLUSIONS: While the prevalence of diabetes in Mozambique has increased from 2005 to 2015, awareness and medication use have declined considerably. There is an urgent need to improve the capacity of primary health care and communities to detect, manage and prevent the occurrence of NCDs and their risk factors.

Elastic and Ultradeformable Liposomes for Transdermal Delivery of Active Pharmaceutical Ingredients (APIs).

Administration of active pharmaceutical ingredients (APIs) through the skin, by means of topical drug delivery systems, is an advanced therapeutic approach. As the skin is the largest organ of the human body, primarily acting as a natural protective barrier against permeation of xenobiotics, specific strategies to overcome this barrier are needed. Liposomes are nanometric-sized delivery systems composed of phospholipids, which are key components of cell membranes, making liposomes well tolerated and devoid of toxicity. As their lipid compositions are similar to those of the skin, liposomes are used as topical, dermal, and transdermal delivery systems. However, permeation of the first generation of liposomes through the skin posed some limitations; thus, a second generation of liposomes has emerged, overcoming permeability problems. Various mechanisms of permeation/penetration of elastic/ultra-deformable liposomes into the skin have been proposed; however, debate continues on their extent/mechanisms of permeation/penetration. In vivo bioavailability of an API administered in the form of ultra-deformable liposomes is similar to the bioavailability achieved when the same API is administered in the form of a solution by subcutaneous or epi-cutaneous injection, which demonstrates their applicability in transdermal drug delivery.

Risk Factors for Breast Cancer, Overall and by Tumor Subtype, among Women from Mozambique, Sub-Saharan Africa.

BACKGROUND: Breast cancer incidence is rising in Africa, but there are scare data regarding risk factors in this region. We assessed the relation between risk factors and the occurrence of breast cancer, overall and by tumor subtype in women from Mozambique. METHODS: The associations between education, number of births, height, weight, body mass index (BMI), and breast cancer risk among 138 cases (participants from the Moza-BC cohort) and 638 controls from the general population (from a World Health Organization stepwise approach to surveillance survey), recruited during 2014 to 2017, were investigated. Adjusted ORs (aOR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression. RESULTS: Multiparity (≥6 vs. 0-1 live births) was a protective factor for the development of hormone receptor (HR)-positive (aOR = 0.22; 95% CI, 0.08-0.64) and HR-positive/HER2-negative tumors (aOR = 0.20; 95% CI, 0.06-0.68), whereas a higher educational level (≥8 vs. 0 schooling years) increased breast cancer risk across all subtypes (overall aOR = 1.98; 95% CI, 1.04-3.80). Higher weight and BMI were associated with a higher breast cancer risk among postmenopausal women (per 1-kg increase: aOR = 1.05; 95% CI, 1.02-1.08; per 1-kg/m2 increase: aOR = 1.11; 95% CI, 1.04-1.18, respectively), but were protective in premenopausal women (aOR = 0.98; 95% CI, 0.96-0.99; aOR = 0.95; 95% CI, 0.91-0.99, respectively), regardless of subtype. Higher height increased the risk of HR-negative tumors in postmenopause (per 10-cm increase: aOR = 2.81; 95% CI, 1.41-6.03). CONCLUSION: These results demonstrate the etiological heterogeneity of breast cancer among native African women, namely regarding the differential effect of multiparity, education, and body parameters in breast cancer risk. IMPACT: As the prevalence of obesity grows, these findings are important to inform public health policies on cancer prevention, by highlighting obesity as a modifiable risk factor for breast cancer among African women.

HCC Detection on Surveillance US: Comparing Focused Liver Protocol Using US LI-RADS Technical Guidelines to a General Complete Abdominal US Protocol.

OBJECTIVE: Focused US examinations of the liver in the routine hepatocellular carcinoma (HCC) screening reduce the time spent on evaluating other structures deemed irrelevant to the clinical setting. It is still unknown, however, if such a strategy may additionally improve the frequency of nodules detection. We aimed to assess the impact of an HCC surveillance program in high-risk patients by means of targeted liver US following LI-RADS technical guidelines in comparison to a complete upper abdominal scan. METHODS: In this IRB-approved, single-center, prospective study, patients at high-risk for HCC enrolled from 06/2016 to 09/2019 were randomly assigned to 1 of the 2 institutional protocols: Group A (targeted liver US) or Group B (complete upper abdominal scan). Twenty examiners with similar experience in abdominal US were randomly assigned to perform the examinations exclusively in 1 of the groups (10 in each group). Frequency of hepatic nodules between groups was compared by using Fisher's exact test. RESULTS: Four hundred and sixty-five patients were enrolled, with no significant differences in both groups regarding sex, age, etiology of liver disease, MELD scores, and alpha-fetoprotein levels. A significantly higher frequency of nodules detection was found in Group A (230 patients; 23 nodules detected; 10% of the sample) in comparison to Group B (235 patients; 3 nodules; 1.3% of the sample) (p <.001). Five patients in Group A and 1 in Group B were positive for HCC after full diagnostic work-up. CONCLUSION: Adopting an HCC screening program based on targeted liver US improved the detection of hepatic nodules among high-risk individuals.

An Epidemiological Study of Stroke Hospitalizations in Maputo, Mozambique A High Burden of Disease in a Resource-Poor Country

Already a major cause of death and disability in high-income countries, the burden of stroke in sub-Saharan Africa is also expected to be high. However, specific stroke data are scarce from resource-poor countries. We studied the incidence, characteristics, and short-term consequences of hospitalizations for stroke in Maputo, Mozambique. Methods­Over 12 months, comprehensive data from all local patients admitted to any hospital in Maputo with a new stroke event were prospectively captured according to the World Health Organization's STEPwise approach to stroke surveillance program. Disability levels (pre- and posthospital discharge) and short-term case-fatality (in-hospital and 28 days) were also studied. Results­Overall, 651 new stroke events (mean age 59.113.2 years and 53% men) were captured by the registry with 601 confirmed by CT scan (83.4%) or necropsy (8.9%). Crude and adjusted (world reference population) annual incidence rates of stroke were 148.7 per 100 000 and 260.1 per 100 000 aged 25 years, respectively. Of these, 531 (81.6%) represented a first-ever stroke event comprising 254 ischemic (42.0%) and 217 (36.1%) an intracerebral hemorrhage. Before admission, 561 patients (86.2%) had hypertension and 271 (41.6%) had symptoms for 24 hours. In-hospital and 28-day case-fatality were 33.3% and 49.6% (72.3% for hemorrhagic stroke), respectively. From almost no preadmission disability, 64.4% of 370 survivors at 28 days had moderate-to-severe disability. Conclusions­The burden of disease associated with stroke is high in Maputo, emphasizing the importance of primary prevention and improvement of the standards of care in a developing country under epidemiological transition

Non-Steroidal Anti-Inflammatory Drugs Loaded Liposomes for Topical Treatment of Inflammatory and Degenerative Conditions.

Topical administration of drugs presents some advantages over other routes; the drug can be administered in the anatomical region to be treated, limiting the systemic distribution and side effects. However, the structure of the skin makes it a highly effective barrier to drug permeation. Amongst the strategies to overcome this obstacle, liposomes are interesting vehicles for delivering the drugs into the skin, the synovial cavity or other regions affected by inflammatory or degenerative conditions. Liposomes are lipid carriers of nanometric size formed by phospholipid bilayers. They have the advantages of preparation feasibility and biological compatibility associated with the possibility of carrying either lipophylic and/or hydrophylic compounds, and have been extensively used in various drug delivery systems, for drug targeting, controlled release and permeation enhancement of drugs. Conventional liposomes are not very stable and not suitable for dermal administration after topical application, since they accumulate on the skin surface due to the rigidity of the lipid layers and suffer dehydration, culminating in their fragmentation. Other formulations have emerged in the meantime, such as transfersomes, niosomes or ethosomes. The present work consists of a review on the published scientific papers regarding the development of liposomal formulations containing non-steroidal anti-inflammatory drugs for the purpose of relieving the symptomatology of inflammatory and degenerative ailments. The exposition summarizes data relating to liposome type, composition, preparation method, liposome characterization, topical vehicle used, in vitro permeation studies performed, in vivo anti-inflammatory assays carried out and results obtained in the different studies published in the last five years.

Prevalence of overweight and obesity in Mozambique in 2005 and 2015.

OBJECTIVE: The ongoing demographic, nutritional and epidemiological transitions in sub-Saharan Africa highlight the importance of monitoring overweight and obesity. We aimed to assess the prevalence of overweight and obesity in Mozambique in 2014/2015 and compare the estimates with those obtained in 2005. DESIGN: Cross-sectional study conducted in 2014/2015, following the WHO Stepwise Approach to Chronic Disease Risk Factor Surveillance (STEPS). Prevalence estimates with 95 % CI were computed for different categories of BMI and abdominal obesity, along with age-, education- and income-adjusted OR. The age-standardized prevalence in the age group 25-64 years was compared with results from a STEPS survey conducted in 2005. SETTING: Mozambique. PARTICIPANTS: Representative sample of the population aged 18-64 years (n 2595). RESULTS: Between 2005 and 2014/2015, the prevalence of overweight and obesity increased from 18·3 to 30·5 % (P < 0·001) in women and from 11·7 to 18·2 % (P < 0·001) in men. Abdominal obesity increased among women (from 9·4 to 20·4 %, P < 0·001), but there was no significant difference among men (1·5 v. 2·1 %, P = 0·395). In 2014/2015, the prevalence of overweight and obesity was more than twofold higher in urban areas and in women; in the age group 18-24 years, it was highest in urban women and lowest in rural men. CONCLUSIONS: In Mozambique, there was a steep increase in the prevalence of overweight and obesity among adults between 2005 and 2014/2015. Overweight and obesity are more prevalent in urban areas and among women, already affecting one in five urban women aged 18-24 years.

Cervical cancer screening uptake in women aged between 15 and 64 years in Mozambique.

Cervical cancer is the most common cancer in Mozambique, reflecting the high prevalence of both human papillomavirus and HIV infections. A national screening program for cervical cancer was started in 2009, using the visual inspection with acetic acid and cryotherapy, targeting women aged 30-55 years. We aimed to estimate the self-reported prevalence and determinants of cervical cancer screening uptake in Mozambique. A cross-sectional study of a representative sample of the women aged 15-64 years (n=1888) was carried out in 2014/2015 following the WHO-Stepwise Approach to Chronic Disease Risk Factor Surveillance. The prevalence of screening uptake using visual inspection with acetic acid or cervical cytology, at least once in a lifetime, was 3.0% [95% confidence interval (CI): 2.2-4.1]; the prevalence was the lowest in the center region (1.4%) and the highest in the capital city of Maputo (11.1%). Among women aged 30-55 years, the prevalence was 3.4% (95% CI: 2.3-5.2) and the factors independently associated with a greater frequency of screening uptake were education (≥8 schooling years vs. none: prevalence ratio=5.57, 95% CI: 1.34-23.16) and use of oral contraceptives (prevalence ratio=2.33, 95% CI: 1.05-5.15). This was the first national Mozambican survey on cervical cancer screening uptake ever carried out and it showed a very low prevalence of screening, even in the more urban and affluent areas. There is an urgent need to raise public awareness of cervical cancer screening and to increase the number of screening units and trained personnel throughout the country.

Hypertension in Mozambique: trends between 2005 and 2015

To assess the current prevalence, awareness, treatment and control of arterial hypertension in Mozambican population, including adolescents and young adults, and to appraise their trends over the past decade, for the 25­64 years old population. Methods: A cross-sectional study of a representative sample of the population aged 15­64 years (n = 2965) was conducted in 2014­2015, following the Stepwise Approach to Chronic Disease Risk Factor Surveillance. Data from a survey conducted in 2005 using the same methodological approach was used to assess trends in the age group of 25­64 years. Results: The prevalence of hypertension increased significantly, from 33.1 to 38.9% (P = 0.048), whereas awareness (2005 vs. 2014­2015: 14.8 vs. 14.5%, P = 0.914) and treatment among the aware (2005 vs. 2014­2015: 51.9 vs. 50.1%, P = 0.770) remained similar. Control among the treated increased (from 39.9 to 44.5%, P = 0.587), although not significantly. Mean blood pressure values increased (SBP: from 132.1 to 134.6 mmHg, P = 0.089; DBP: from 78.2 to 82.5 mmHg, P < 0.001). Among participants aged 15­24 years, in 2014­2015 the prevalence of hypertension was 13.1% (95% confidence interval: 9.8­16.4). Conclusion: Our findings show that the prevalence of hypertension in Mozambique is among the highest in developing countries, both in adults and adolescents, portraying an ample margin for reduction of the morbidity and mortality burden because of high blood pressure.

Knowledge and behaviors regarding salt intake in Mozambique.

BACKGROUND/OBJECTIVES: Health education and regulatory measures may contribute to lower population salt intake. Therefore, we aimed to describe knowledge and behaviors related to salt intake in Mozambique. SUBJECTS/METHODS: A cross-sectional evaluation of a representative sample of the population aged 15-64 years (n = 3116) was conducted in 2014/2015, following the Stepwise Approach to Chronic Disease Risk Factor Surveillance, including a 12-question module for evaluation of dietary salt. RESULTS: Three dimensions were identified in the questionnaire, named "self-reported salt intake", "knowledge of health effects of salt intake", and "behaviors for control of salt intake". A total of 7.4% of the participants perceived that they consumed too much/far too much salt and 25.9% reported adding salt/salty seasoning often/always to prepared foods. The proportion considering that it was not important to decrease the salt contents of their diet was 8%, and 16.9% were not aware that high salt intake could be deleterious for health. Prevalences of lack of behaviors for reducing salt intake ranged from 74.9% for not limiting consumption of processed foods, to 95% for not buying low salt alternatives. There were few differences according to socio-demographic variables, but awareness of hypertension was, in general, associated with better knowledge and less frequent behaviors likely to contribute to a high salt intake. CONCLUSIONS: Most Mozambicans were aware that high salt intake can cause health problems, but the self-reported salt intake and behaviors for its control show an ample margin for improvement. This study provides evidence to guide population level salt-reducing policies.

Hypertension in Mozambique: trends between 2005 and 2015.

OBJECTIVE: To assess the current prevalence, awareness, treatment and control of arterial hypertension in Mozambican population, including adolescents and young adults, and to appraise their trends over the past decade, for the 25-64 years old population. METHODS: A cross-sectional study of a representative sample of the population aged 15-64 years (n = 2965) was conducted in 2014-2015, following the Stepwise Approach to Chronic Disease Risk Factor Surveillance. Data from a survey conducted in 2005 using the same methodological approach was used to assess trends in the age group of 25-64 years. RESULTS: The prevalence of hypertension increased significantly, from 33.1 to 38.9% (P = 0.048), whereas awareness (2005 vs. 2014-2015: 14.8 vs. 14.5%, P = 0.914) and treatment among the aware (2005 vs. 2014-2015: 51.9 vs. 50.1%, P = 0.770) remained similar. Control among the treated increased (from 39.9 to 44.5%, P = 0.587), although not significantly. Mean blood pressure values increased (SBP: from 132.1 to 134.6 mmHg, P = 0.089; DBP: from 78.2 to 82.5 mmHg, P < 0.001). Among participants aged 15-24 years, in 2014-2015 the prevalence of hypertension was 13.1% (95% confidence interval: 9.8-16.4). CONCLUSION: Our findings show that the prevalence of hypertension in Mozambique is among the highest in developing countries, both in adults and adolescents, portraying an ample margin for reduction of the morbidity and mortality burden because of high blood pressure.

Practical Considerations of Real Life of Hepatocellular Carcinoma in a Tertiary Center of Brazil

ABSTRACT Background. Hepatocellular carcinoma (HCC) is the most common malignancy that develops in cirrhotic livers. Its clinical and epidemiological characteristics and mortality rates vary according to geographical region. The objective of this study was to evaluate the clinical profile, epidemiological characteristics, laboratory parameters, treatment and survival of patients with HCC. Material and methods. Patients with HCC seen between 2000 and 2012 were studied. The Kaplan-Meier method was used for survival analysis according to variables in question. Results. The study included 247 patients with a mean age of 60 ± 10 years. There was a predominance of males (74%). The main etiologies of HCC were HCV infection (55%), excessive alcohol consumption (12%), and HBV infection (8%). Liver cirrhosis was present in 92% of cases. The mean tumor number and diameter were 2 and 5 cm, respectively. Patients meeting the Milan criteria corresponded to 43% of the sample. Liver transplantation was performed in 22.4% of patients of the Milan subset and in 10% of the whole sample. The overall mean survival was 60 months, with a 1-, 3- and 5-year survival probability of 74%, 40% and 29%, respectively. Lower survival was observed among patients with alcoholic etiology. Survival was higher among patients submitted to liver transplantation (P < 0.001), TACE (P < 0.001), or any kind of treatment (P < 0.001). However, no difference was found for surgical resection (P = 0.1) or sorafenib (P = 0.1). Conclusion. Patients with HCC were mainly older men diagnosed at an advanced stage. Treatment was associated with better overall survival, but few patients survived to be treated.

Practical Considerations of Real Life of Hepatocellular Carcinoma in a Tertiary Center of Brazil.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignancy that develops in cirrhotic livers. Its clinical and epidemiological characteristics and mortality rates vary according to geographical region. The objective of this study was to evaluate the clinical profile, epidemiological characteristics, laboratory parameters, treatment and survival of patients with HCC. MATERIAL AND METHODS: Patients with HCC seen between 2000 and 2012 were studied. The Kaplan-Meier method was used for survival analysis according to variables in question. RESULTS: The study included 247 patients with a mean age of 60 ± 10 years. There was a predominance of males (74%). The main etiologies of HCC were HCV infection (55%), excessive alcohol consumption (12%), and HBV infection (8%). Liver cirrhosis was present in 92% of cases. The mean tumor number and diameter were 2 and 5 cm, respectively. Patients meeting the Milan criteria corresponded to 43% of the sample. Liver transplantation was performed in 22.4% of patients of the Milan subset and in 10% of the whole sample. The overall mean survival was 60 months, with a 1-, 3- and 5-year survival probability of 74%, 40% and 29%, respectively. Lower survival was observed among patients with alcoholic etiology. Survival was higher among patients submitted to liver transplantation (P &lt; 0.001), TACE (P &lt; 0.001), or any kind of treatment (P &lt; 0.001). However, no difference was found for surgical resection (P = 0.1) or sorafenib (P = 0.1). CONCLUSION: Patients with HCC were mainly older men diagnosed at an advanced stage. Treatment was associated with better overall survival, but few patients survived to be treated.

Motor Learning Requires Purkinje Cell Synaptic Potentiation through Activation of AMPA-Receptor Subunit GluA3.

Accumulating evidence indicates that cerebellar long-term potentiation (LTP) is necessary for procedural learning. However, little is known about its underlying molecular mechanisms. Whereas AMPA receptor (AMPAR) subunit rules for synaptic plasticity have been extensively studied in relation to declarative learning, it is unclear whether these rules apply to cerebellum-dependent motor learning. Here we show that LTP at the parallel-fiber-to-Purkinje-cell synapse and adaptation of the vestibulo-ocular reflex depend not on GluA1- but on GluA3-containing AMPARs. In contrast to the classic form of LTP implicated in declarative memory formation, this form of LTP does not require GluA1-AMPAR trafficking but rather requires changes in open-channel probability of GluA3-AMPARs mediated by cAMP signaling and activation of the protein directly activated by cAMP (Epac). We conclude that vestibulo-cerebellar motor learning is the first form of memory acquisition shown to depend on GluA3-dependent synaptic potentiation by increasing single-channel conductance.

Liver transplantation for carcinoma hepatocellular in Aão Paulo: 414 cases by the Milan/Brazil criteria / O transplante hepático por hepatocarcinoma na era meld em São Paulo: análise de 414 casos transplantados pelo critério de Milão/Brasil

ABSTRACT Background: The criterion of Milan (CM) has been used as standard for indication of liver transplantation (LTx) for hepatocellular carcinoma (HCC) worldwide for nearly 20 years. Several centers have adopted criteria expanded in order to increase the number of patients eligible to liver transplantation, while maintaining good survival rates. In Brazil, since 2006, the criterion of Milan/Brazil (CMB), which disregards nodules <2 cm, is adopted, including patients with a higher number of small nodules. Aim: To evaluate the outcome of liver transplantation within the CMB. Methods: The medical records of patients with HCC undergoing liver transplantation in relation to recurrence and survival by comparing CM and CMB, were analyzed. Results: 414 LTx for HCC, the survival at 1 and 5 years was 84.1 and 72.7%. Of these, 7% reached the CMB through downstaging, with survival at 1 and 5 years of 93.1 and 71.9%. The CMB patient group that exceeded the CM (8.6%) had a survival rate of 58.1% at five years. There was no statistical difference in survival between the groups CM, CMB and downstaging. Vascular invasion (p<0.001), higher nodule size (p=0.001) and number of nodules >2 cm (p=0.028) were associated with relapse. The age (p=0.001), female (p<0.001), real MELD (p<0.001), vascular invasion (p=0.045) and number of nodes >2 cm (p<0.014) were associated with worse survival. Conclusions: CMB increased by 8.6% indications of liver transplantation, and showed survival rates similar to CM.

RESUMO Racional: O critério de Milão (CM) vem sendo utilizado como padrão para indicação do transplante hepático (TxH) por hepatocarcinoma (HCC) em todo mundo há quase 20 anos. Diversos centros têm adotado critérios expandidos com intuito de aumentar o número de pacientes candidatos ao transplante, mantendo bons índices de sobrevida. No Brasil, desde 2006, o critério de Milão/Brasil (CMB), que desconsidera nódulos <2 cm, é adotado, incluindo pacientes com maior número de nódulos pequenos. Objetivo: Avaliar o resultado do transplante hepático dentro do CMB. Métodos: Foram analisados os prontuários dos pacientes com HCC submetidos ao TxH em relação à recidiva e sobrevida através da comparação entre CM e CMB. Resultados: Em 414 TxH por HCC, a sobrevida em 1 e 5 anos foi de 84,1 e 72,7%. Destes, 7% atingiram o CMB através de downstaging, com sobrevida em 1 e 5 anos de 93,1 e 71,9%. O grupo de pacientes do CMB que excederam o CM (8,6%) teve sobrevida de 58,1% em cinco anos. Não houve diferença estatística na sobrevida entre os grupos CM, CMB e downstaging. A invasão vascular (p<0,001), tamanho do maior nódulo (p=0,001) e número de nódulos >2 cm (p=0,028) associaram-se com recidiva. A idade (p=0,001), sexo feminino (p<0,001), MELD real (p<0,001), invasão vascular (p=0,045) e o número de nódulos >2 cm (p<0,014) estiveram associados com a piora na sobrevida. Conclusões: O CMB aumentou em 8,6% as indicações de TxH e apresentou índices de sobrevida semelhantes ao CM.