Pituitary Society Delphi Survey: An international perspective on endocrine management of patients undergoing transsphenoidal surgery for pituitary adenomas.

PURPOSE: In adults and children, transsphenoidal surgery (TSS) represents the cornerstone of management for most large or functioning sellar lesions with the exception of prolactinomas. Endocrine evaluation and management are an essential part of perioperative care. However, the details of endocrine assessment and care are not universally agreed upon. METHODS: To build consensus on the endocrine evaluation and management of adults undergoing TSS, a Delphi process was used. Thirty-five statements were developed by the Pituitary Society's Education Committee. Fifty-five pituitary endocrinologists, all members of the Pituitary Society, were invited to participate in two Delphi rounds and rate their extent of agreement with statements pertaining to perioperative endocrine evaluation and management, using a Likert-type scale. Anonymized data on the proportion of panelists' agreeing with each item were summarized. A list of items that achieved consensus, based on predefined criteria, was tabulated. RESULTS: Strong consensus (≥ 80% of panelists rating their agreement as 6-7 on a scale from 1 to 7) was achieved for 68.6% (24/35) items. If less strict agreement criteria were applied (ratings 5-7 on the Likert-type scale), consensus was achieved for 88% (31/35) items. CONCLUSIONS: We achieved consensus on a large majority of items pertaining to perioperative endocrine evaluation and management using a Delphi process. This provides an international real-world clinical perspective from an expert group and facilitates a framework for future guideline development. Some of the items for which consensus was not reached, including the assessment of immediate postoperative remission in acromegaly or Cushing's disease, represent areas where further research is needed.

Increased risk of preneoplastic colonic lesions and colorectal carcinoma in acromegaly: multicenter case-control study.

PURPOSE: Current international guidelines recommend colonoscopy in patients with acromegaly at the time of diagnosis, even though the risk of developing colorectal neoplasm is still controversial. The main objective of this Argentine multicenter study was to analyze through screening colonoscopy the presence of advanced neoplastic lesions considered as precancerous, in patients with acromegaly compared to a control group. METHODS: This is a case-control retrospective study. Full length colonoscopy of 70 acromegalic patients and 128 control subjects were studied. Polyps were classified into non pre-cancerous lesions and advance neoplastic lesions which included advanced adenomas (preneoplastic) and colorectal carcinomas. RESULTS: Thirty three out of 70 acromegalic patients and 32 out of 128 subjects controls presented polyps in the colonoscopy [47.1% vs 25%, p = 0.002, OR 2.68]. Non precancerous polyps were found in 11 (15.7%) and 23 (17.9%) (p = 0.690), while advanced neoplastic lesions were found in 22 (31.4%) and 9 (7.0%) (p = 0,0001 - OR: 6.06) patients and controls respectively. Advanced adenomas and colorectal carcinomas were found in 18 (27.3%) and 9 (7.0%) (p = 0,0006-OR: 4,57), and 4 (5.7%) and 0 (0.0%) p = 0.0063) of patients and controls respectively. The presence of insulin resistance was the only statistically significant associated factor among acromegalic patients with and without colonic polyps. CONCLUSIONS: Our findings show an increased risk of preneoplastic colonic lesions and colorectal carcinoma in patients with chronic and sustained GH excess compared to a control group. This supports the recommendation to perform screening colonoscopy at diagnosis of acromegaly.

Pituitary society guidance: pituitary disease management and patient care recommendations during the COVID-19 pandemic-an international perspective.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain that has caused the coronavirus disease 2019 (COVID-19) pandemic, has presented healthcare systems around the world with an unprecedented challenge. In locations with significant rates of viral transmission, social distancing measures and enforced 'lockdowns' are the new 'norm' as governments try to prevent healthcare services from being overwhelmed. However, with these measures have come important challenges for the delivery of existing services for other diseases and conditions. The clinical care of patients with pituitary disorders typically involves a multidisciplinary team, working in concert to deliver timely, often complex, disease investigation and management, including pituitary surgery. COVID-19 has brought about major disruption to such services, limiting access to care and opportunities for testing (both laboratory and radiological), and dramatically reducing the ability to safely undertake transsphenoidal surgery. In the absence of clinical trials to guide management of patients with pituitary disease during the COVID-19 pandemic, herein the Professional Education Committee of the Pituitary Society proposes guidance for continued safe management and care of this population.

Setting the stage to quit smoking in Bipolar Disorder patients: brief advice in clinical practice. / Preparando el escenario para dejar de fumar en el paciente con Trastorno Bipolar: intervención breve en la práctica clínica.

Tobacco consumption is the main preventable factor of mortality in smokers with bipolar disorder (BD), and any possible solutions are often blocked by prejudices over desire, and the possibilities and risks for these patients in giving up tobacco consumption. Adults with BD were recruited at 8 Mental Health Centres. Smokers were evaluated before and after a brief intervention based on the 3 A's and classified into a 'Stage of Change' (SOC) and their 'Readiness to Change' (RTC). A multiple linear regression was used to analyze the progression in their RTC and the independent effect of different variables (pharmacological treatment, history of psychotic symptoms, current anxiety symptoms, willingness, self-perceived capacity to quit smoking and subjective perception of cognitive functioning). Of 212 stable patients diagnosed with BD, current smokers (n=101; 47.6%) were included in the intervention phase, and 80.2% completed it. At baseline, 75.2% were considering the idea of giving up smoking and, after the brief intervention, 30.9% of the patients progressed in their SOC. A significant increase in the level of RTC was observed (53.3 vs 59.3, P=0.019). Perception of cognitive performance (ß=-0.35;P=0.002), the degree of willing to quit (ß=0.32;P=0.008), self-perceived capacity to quit tobacco smoking (ß=-0.30;P=0.012), the patient's age (ß=-0.72;P=0.004), the age of onset of smoking (ß=0.48;P=0.022) and years as a smoker (ß=0.48;P=0.025) were all factors that significantly influenced the chances of improving after the short intervention. Smokers with BD consider the idea of quitting and a brief intervention developed in the every day mental health care setting improves the level of readiness. The neurocognitive dysfunction associated with BD may limit patients' readiness to quit smoking.

El consumo de tabaco es el principal factor prevenible de mortalidad en pacientes con trastorno bipolar (TB), y las posibles soluciones se encuentran bloqueadas por prejuicios acerca del deseo, posibilidades y riesgos al dejar el consumo de tabaco en estos pacientes. En 8 Centros de Salud Mental se reclutaron consecutivamente pacientes con TB. Los fumadores fueron evaluados antes y después de una intervención breve basada en las 3 As y clasificados según los "estadios de cambio" (EC) y su "disposición para el cambio" (DC). Mediante una regresión lineal múltiple se analizó la evolución del DC y su efecto sobre otras variables independientes (tratamiento farmacológico, historias de síntomas psicóticos, presencia de síntomas de ansiedad, deseo de abandono, capacidad auto-percibida y la percepción subjetiva de funcionamiento cognitivo). Se incluyeron 212 pacientes con TB estabilizados, los fumadores activos (n=101; 47.6%) pasaron a la fase de intervención, y un 80.2% la completaron. Basalmente, 75.2% consideraban la idea de dejar de fumar, después de la intervención breve, el 30.9% de los pacientes progresó en su EC. Se observó un incremento significativo del nivel de DC (53.3 vs 59.3, P=0.019). La autopercepción del rendimiento cognitivo (ß=-0.35;P=0.002), el deseo de abandono (ß=0.32;P=0.008), la autopercepción de la capacidad para dejar de fumar (ß=-0.30;P=0.012), la edad del paciente (ß=-0.72;P=0.004), la edad de inicio del tabaquismo (ß=0.48;P=0.022) y los años fumando (ß=0.48;P=0.025) fueron los factores que influyeron significativamente en la posibilidad de cambio tras la intervención breve. Los fumadores con TB consideran la idea de dejar de fumar y una intervención breve desarrollada en el marco de la atención a la salud mental diaria, mejoraría el nivel de preparación. La disfunción neurocognitiva asociada con el TB podría limitar la disposición de los pacientes a dejar de fumar.

Genetic Variants and Hamstring Injury in Soccer: An Association and Validation Study.

PURPOSE: This study aimed to investigate the association of candidate single nucleotide polymorphisms (SNP) with noncontact hamstring muscle injuries in elite soccer players and to create and validate a model to assess the risk of hamstring injury. METHODS: A total of 107 elite male outfield players were prospectively followed for six seasons. Players were genotyped for 37 SNP previously investigated in relation to musculoskeletal injuries. The association of SNP, previous injury, age, level of play, position, and anthropometric data with 129 hamstring injuries (413 observations) was investigated in the discovery phase (2010-2015), and a multivariable Cox frailty model was created using forward selection. The model's discriminative ability was tested in the validation phase (2015-2016, 31 injuries, 98 observations) using Harrell's C index. RESULTS: Five SNP were found to be significantly associated with hamstring injury in a multivariable model: matrix metalloproteinase 3 rs679620 (A vs G, hazard ratio [HR] = 2.06, 95% confidence interval [CI] = 1.51-2.81), tenascin C rs2104772 (A vs T, HR = 1.65, 95% CI = 1.17-2.32), interleukin 6 rs1800795 (GG vs GC + CC, HR = 1.68, 95% CI = 1.11-2.53), nitric oxide synthase 3 rs1799983 (G vs T, HR = 1.35, 95% CI = 1.01-1.79), and hypoxia-inducible factor-1α rs11549465 (CC vs CT, HR = 2.08, 95% CI = 1.00-4.29). Age also entered the model (≥24 vs <24 yr, HR = 2.10, 95% CI = 1.29-3.42). The model showed acceptable discrimination in the discovery phase (C index = 0.74), but not in the validation phase (C index = 0.52). CONCLUSION: Genetic variants appear to be involved in the etiology of hamstring injuries but were not found to have predictive value by themselves. Further research, increasing the number of genetic variants and including environmental factors in complex multifactorial risk models, is necessary.

Riesgo aumentado de lesiones colónicas preneoplásicas en acromegalia: estudio multicéntrico caso control. Resultados preliminares / Increased risk of pre-cancerous bowel lesions in acromegaly: Multicentre case-control study. Preliminary results

Introducción: El riesgo de desarrollar neoplasias colónicas en pacientes acromegálicos y su relación directa con los niveles elevados de GH/IGF-1 no están bien establecidos y continúan siendo motivo de controversia en la literatura mundial. El objetivo de este trabajo fue evaluar el riesgo de desarrollar lesiones neoplásicas avanzadas (LNA) (adenomas mayores a 1 cm, componente velloso mayor del 75% y/o displasia de alto grado), en pacientes con acromegalia, comparado con un grupo control. Materiales y métodos: Estudio multicéntrico caso-control retrospectivo. Ciento treinta y siete pacientes con acromegalia que realizaron videocolonoscopia (VCC) fueron incluidos inicialmente, aunque solo 69 cumplieron criterios de inclusión. Sesenta y dos controles fueron obtenidos: por cada caso (paciente con acromegalia) 2 «controles¼ fueron seleccionados aleatorizadamente e igualados por edad y sexo. El riesgo se expresó en odds ratio (OR) y su correspondiente intervalo de confianza (IC) del 95%. La significación estadística fue considerada una p < 0,05. Resultados: De los 69 pacientes con VCC completa y datos adecuados para su análisis, 28 presentaron VCC positiva con hallazgos de pólipos (40%) y 41 VCC negativa o normal (60%). Dentro del grupo con VCC positiva, 14 presentaron LNA (20%) y solo un paciente presentó diagnóstico de cáncer colorrectal. Para el análisis caso-control se incluyó a 31 pacientes frente al grupo control (n = 62) que cumplieron con los criterios de inclusión. La presencia de pólipos colónicos, adenomas y LNA en los pacientes con acromegalia fue de 19/31 (61,9%), 14/31 (45,16%) y 10/31 (32,25%), y en el grupo control de 18/62 (29,03%), 11/62 (17,74%) y 4/62 (6,45%), respectivamente. El riesgo de adenomas y LNA fue mayor en el grupo de acromegalia en comparación con el grupo control, siendo ambos resultados estadísticamente significativos: adenomas OR 2,54 (IC 1,22-5,25) p = 0,005, LNA OR: 7,3 (2,4-25), p = 0,00. Conclusión: La acromegalia se asocia a un mayor riesgo de lesiones colónicas preneoplásicas. Este hallazgo justifica el cribado con VCC al diagnóstico en pacientes con acromegalia.

Background: The risk of developing cancerous lesions in the colon of acromegaly patients and their direct relationship with elevated growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels is not well established, and is still controversial in the international literature. The objective of this study was to evaluate the risk of developing advanced neoplastic lesions (ALN: greater than 1 cm adenomas, villous component greater than 75% and/or high grade dysplasia) in patients with acromegaly compared to a control group. Materials and methods: A multicentre, retrospective case-control study was conducted initially on 137 patients with acromegaly (cases) who underwent videocolonoscopy (VCC), although only 69 met inclusion criteria. Sixty-two controls were obtained, and for each case two "controls" were randomly selected and matched by age and gender. Risk was expressed as odds ratio (OR) and its corresponding 95% con"dence interval (CI). P values < .05 were considered statistical significantly. Results: Of the 69 acromegaly patients with a completed VCC and adequate data for their analysis, 28 had a positive VCC with findings of polyps (40%), and 41 VCC negative with no lesions (60%). Within the group with positive VCC, 14 were ALN (20%) and one a colorectal cancer. In the case-control analysis, 31 cases were to be analysed against the control group (n = 62). The presence of colonic polyps, adenomas, and ALN in patients with acromegaly was 19/31 (61.9%), 14/31 (45.16%), and 10/31 (32.25%), respectively, and in the control group, it was 18/62 (29.03%), 11/62 (17.74%), and 4/62 (6.45%), respectively. The risk of adenomas and ALN was higher in the acromegaly group compared to the control group: adenomas OR: 2.54 (95% CI 1.22-5.25) P=.005, ALN OR: 7.3 (2.4-25) P=.00. Conclusion: This preliminary case control study showed an increased risk of pre-cancerous colprectal lesions in patients with acromegaly, supporting the VCC screening at diagnosis.

Comorbidities in Patients With Primary Sjögren's Syndrome and Systemic Lupus Erythematosus: A Comparative Registries-Based Study.

OBJECTIVE: To compare the prevalence of the main comorbidities in 2 large cohorts of patients with primary Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE), with a focus on cardiovascular (CV) diseases. METHODS: This was a cross-sectional multicenter study where the prevalence of more relevant comorbidities in 2 cohorts was compared. Patients under followup from SJOGRENSER (Spanish Rheumatology Society Registry of Primary SS) and RELESSER (Spanish Rheumatology Society Registry of SLE), and who fulfilled the 2002 American-European Consensus Group and 1997 American College of Rheumatology classification criteria, respectively, were included. A binomial logistic regression analysis was carried out to explore potential differences, making general adjustments for age, sex, and disease duration and specific adjustments for each variable, including CV risk factors and treatments, when appropriate. RESULTS: A total of 437 primary SS patients (95% female) and 2,926 SLE patients (89% female) were included. The mean age was 58.6 years (interquartile range [IQR] 50.0-69.9 years) for primary SS patients and 45.1 years (IQR 36.4-56.3 years) for SLE patients (P < 0.001), and disease duration was 10.4 years (IQR 6.0-16.7 years) and 13.0 years (IQR 7.45-19.76 years), respectively (P < 0.001). Smoking, dyslipidemia, and arterial hypertension were associated less frequently with primary SS (odds ratio [OR] 0.36 [95% confidence interval (95% CI) 0.28-0.48], 0.74 [95% CI 0.58-0.94], and 0.50 [95% CI 0.38-0.66], respectively) as were life-threatening CV events (i.e., stroke or myocardial infarction; OR 0.57 [95% CI 0.35-0.92]). Conversely, lymphoma was associated more frequently with primary SS (OR 4.41 [95% CI 1.35-14.43]). The prevalence of severe infection was lower in primary SS than in SLE (10.1% versus 16.9%; OR 0.54 [95% CI 0.39-0.76]; P < 0.001). CONCLUSION: Primary SS patients have a consistently less serious CV comorbidity burden and a lower prevalence of severe infection than those with SLE. In contrast, their risk of lymphoma is greater.

Applicability of an agility test in young players in the soccer field / Aplicabilidade de um teste de agilidade em jovens futebolistas em campo / Aplicabilidad de un test de agilidad en futbolistas jóvenes en el campo

INTRODUCTION: in soccer, agility is a relevant parameter that is defined as the ability to change the direction of the body rapidly and is a result of a combination of strength, speed, balance and coordination. OBJECTIVE: to demonstrated the reliability and validity of the modified Barrow test in soccer players aged 10 to 14 years, analyze its relationship with age, maturation, experience and body size and test the effectiveness of the protocol for distinguishing performance changes during a 10-month competitive season. METHODS: fifty-one adolescent Basque soccer players were enrolled. Age, maturation, experience, body size, vertical jump and 15-m sprint were measured. The reliability of the test was analyzed using replicate tests in a subgroup n = 34. Another subgroup of 33 players n =18, under-11, 10.4 ± 0.3 years; n = 15 under-13, 12.0 ± 0.8 years was evaluated at the beginning and the end of the season. RESULTS: the reliability of the test was good change in mean = -0.5%, 95% CI -1.2 to 0.2, SD=0.14; coefficient of variation = 0.9%, 95% CI - 0.7 to 1.5, SD=0.25. Chronological age and adiposity were significant predictors of agility performance P<0.01. An improvement in performance was observed over a 10-month soccer season, with a significant group effect P<0.01. CONCLUSION: the agility test demonstrated logic and validity, and proved to be a reliable and objective instrument for assessing adolescent soccer players. .

INTRODUÇÃO: a agilidade é um parâmetros relevante de desempenho no futebol, que pode de ser definido como a capacidade de alterar a direção do corpo com rapidez, sendo resultado da combinação de força, velocidade, equilíbrio e coordenação. OBJETIVO: demonstrar a confiabilidade e a validade do teste de Barrow modificado em jogadores de futebol com idade entre 10 e 14 anos, analisar sua relação com idade, amadurecimento, experiência e tamanho do corpo e comprovar a efetividade do protocolo para distinguir as mudanças no desempenho ao longo de uma temporada de 10 meses de competição. MÉTODOS: participaram 51 jovens jogadores de futebol bascos. Foram realizadas as seguintes mensurações: idade, maturação, experiência, composição corporal, salto vertical e corrida de velodidade de 15 metros. A confiabilidade do teste foi analisada pela repetição das medidas em um subgrupo de 34 jogadores n =18 sub-11, 10,4 ± 0,3 anos; n = 15 sub-13, 12,0 ± 0,8 anos. RESULTADOS: a confiabilidade do teste foi boa mudanças da média = -0,5%, IC 95% - 1,2 a 0,2, DP = 0,14; coeficiente de variação = 0,9%; IC 95% - 0,7 a 1,5, DP = 0,25. A idade cronológica e a adiposidade foram preditores do desempenho de agilidade P < 0,01. Foi observada melhora significante no desempenho durante os 10 meses de temporada, com efeito de grupo significante P < 0,01. CONCLUSÃO: o teste de agilidade demonstrou lógica e validade, além de ser um instrumento confiável e objetivo para avaliar a agilidade em jogadores de futebol adolescentes. .

INTRODUCCIÓN: en futbol, la agilidad es un parámetro relevante. Así, este parámetro está definido como la capacidad para cambiar de direcciones de forma rápida y es el resultado de una combinación de fuerza, velocidad, equilibrio y coordinación. OBJETIVO: demostrar la validez y confiabilidad del test modificado de Barrow en jóvenes jugadores de futbol de 10 a 14 años, analizar la relación con la edad, maduración, experiencia y tamaño corporal y comprobar la efectividad del protocolo para distinguir cambios de rendimiento durante una temporada competitiva de 10 meses. MÉTODOS: participaron 55 jugadores adolescentes vascos. Se realizaron las siguientes mediciones: edad, maduración, experiencia, composición corporal, salto vertical y sprint de 15 metros. La confiabilidad del test fue analizada mediante test replicado en un subgrupo de 34 jugadores. Otro subgrupo de 33 jugadores n = 18 sub-11, 10,4 ± 0,3 años; n = 15 sub-13, 12,0 ± 0,8 años fue analizado al principio y al final de la temporada. RESULTADOS: la confiabilidad del test fue buena cambios en la media = -0,5%, 95% IC - 1,2 a 0,2, ES-d = 0,14; el coeficiente de variación fue 0,9%, 95% IC - 0,7 a 1,5, ES-d = 0,25. La edad cronológica y la adiposidad fueron predictores del rendimiento de la agilidad P < 0,01. Se observó una mejora importante del rendimiento durante los 10 meses de temporada con un efecto de grupo significativo P < 0,01. CONCLUSIÓN: el test de agilidad demostró lógica y validez además de ser un instrumento confiable y objetivo para evaluar la agilidad en jugadores de futbol adolescentes. .

Influence of nutrient intake on antioxidant capacity, muscle damage and white blood cell count in female soccer players.

BACKGROUND: Soccer is a form of exercise that induces inflammatory response, as well as an increase in free radicals potentially leading to muscle injury. Balanced nutritional intake provides important antioxidant vitamins, including vitamins A, C and E, which may assist in preventing exercise-related muscle damage. The purpose of the present study was to determine the effect of macro/micronutrient intake on markers of oxidative stress, muscle damage, inflammatory and immune response in female soccer players. METHODS: Twenty-eight female players belonging to two soccer teams of the same professional soccer club participated in this study after being informed about the aims and procedures and after delivering written consent. Each team completed an 8-day dietary record and played one competition match the same week. Participants were divided into two groups: the REC group (who complied with recommended intakes) and the NO-REC group (who were not compliant). Laboratory blood tests were carried out to determine hematological, electrolytic and hormonal variables, as well as to monitor markers of cell damage and oxidative stress. Blood samples were obtained 24 h before, immediately after and 18 h after official soccer matches. Student t-test or Mann-Whitney U-test was used to compare both groups throughout the match. RESULTS: At rest, we observed that the REC group had higher levels of total antioxidant status (TAS), glutathione peroxidase (GPx), and lower levels of creatine kinase (CK) and lactate dehydrogenase (LDH) in comparison to the NO-REC group. Immediately after the match, levels of TAS, GPx, superoxide dismutase (SOD), LDH and % lymphocytes were higher and the % of neutrophils were lower in the REC group compared to the NO-REC group. These differences were also maintained 18 h post-match, only for TAS and GPx. CONCLUSIONS: Our data reveal an association between nutritional intake and muscle damage, oxidative stress, immunity and inflammation markers. The benefit of the intake of specific nutrients may contribute to preventing the undesirable physiological effects provoked by soccer matches.

Influencia del color de fondo y el tipo de lente en la toma de fotografía extraoral / Influencia del color de fondo y el tipo de lente en la toma de fotografía extraoral

Disponer de evidencias médicas basadas en fotografías clínicas extraorales de alta calidad, esuna labor que necesita destreza, conocimiento de la técnica y un entorno adecuado. Hoy endía muchos odontólogos capturan imágenes de forma no estandarizada, y con gran desconocimientosobre el tema.

MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor.

The receptor tyrosine kinase c-Met is an attractive target for therapeutic blockade in cancer. Here, we describe MK-2461, a novel ATP-competitive multitargeted inhibitor of activated c-Met. MK-2461 inhibited in vitro phosphorylation of a peptide substrate recognized by wild-type or oncogenic c-Met kinases (N1100Y, Y1230C, Y1230H, Y1235D, and M1250T) with IC(50) values of 0.4 to 2.5 nmol/L. In contrast, MK-2461 was several hundredfold less potent as an inhibitor of c-Met autophosphorylation at the kinase activation loop. In tumor cells, MK-2461 effectively suppressed constitutive or ligand-induced phosphorylation of the juxtamembrane domain and COOH-terminal docking site of c-Met, and its downstream signaling to the phosphoinositide 3-kinase-AKT and Ras-extracellular signal-regulated kinase pathways, without inhibiting autophosphorylation of the c-Met activation loop. BIAcore studies indicated 6-fold tighter binding to c-Met when it was phosphorylated, suggesting that MK-2461 binds preferentially to activated c-Met. MK-2461 displayed significant inhibitory activities against fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor, and other receptor tyrosine kinases. In cell culture, MK-2461 inhibited hepatocyte growth factor/c-Met-dependent mitogenesis, migration, cell scatter, and tubulogenesis. Seven of 10 MK-2461-sensitive tumor cell lines identified from a large panel harbored genomic amplification of MET or FGFR2. In a murine xenograft model of c-Met-dependent gastric cancer, a well-tolerated oral regimen of MK-2461 administered at 100 mg/kg twice daily effectively suppressed c-Met signaling and tumor growth. Similarly, MK-2461 inhibited the growth of tumors formed by s.c. injection of mouse NIH-3T3 cells expressing oncogenic c-Met mutants. Taken together, our findings support further preclinical development of MK-2461 for cancer therapy.

Cell damage, antioxidant status, and cortisol levels related to nutrition in ski mountaineering during a two-day race.

The aim of this study was to measure the effect of nutrition on cell damage, antioxidant enzymes, and cortisol during a two-day ski mountaineering competition. Twenty-one male skiers participated in the study. Creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (AP), cortisol and C-reactive protein (CRP), glutathione peroxidase (GPx) and reductase activities (GR) and C-reactive protein (CRP) levels, total antioxidant status, and cortisol levels were measured in serum the day before and immediately after the race. Their diet was also analysed during the competition. Enzymes and cortisol levels significantly increased after the competition. CK and LDH and cortisol levels were negatively correlated to total energy, protein, and fat intake. Intake of vitamin A, B1, B2, B6 and niacin was negatively correlated to LDH and AP. A negative correlation was also found between CK activity and Na, Fe, and Zn intake. Cortisol levels were negatively correlated to the intake of vitamins C, B1 and B2, and niacin. A positive correlation was found between serum GPx and intake of energy, carbohydrates, proteins, A and B vitamins, and folic acid. Skiers with the lowest nutrient intake during the competition were the ones who showed greater cell damage and lower antioxidant enzyme activity and cortisol levels, which may impair performance and also cause injuries and accidents. Particularly, skiers should have high intakes of total energy, macronutrients, vitamins A and B, Na, Zn, and Fe in order to decrease the deleterious effect of strenuous exercise. Key pointsA two-day ski mountaineering race produced muscle cell damage and oxidative stress and an increase in cortisol levels.There was a marked insufficient intake of carbohydrates which has been shown to affect performanceThose skiers with lowest nutrient intake showed greater cell damage, lower antioxidant activity and higher cortisol levels.Nutrition should be carefully monitored and assessed in order to minimize the mentioned blood changes to avoid fatigue, injuries and also accidents in this type of sport; particularly when skiers must carry their own food.

A role for the scaffolding adapter GAB2 in breast cancer.

The scaffolding adapter GAB2 maps to a region (11q13-14) commonly amplified in human breast cancer, and is overexpressed in breast cancer cell lines and primary tumors, but its functional role in mammary carcinogenesis has remained unexplored. We found that overexpression of GAB2 (Grb2-associated binding protein 2) increases proliferation of MCF10A mammary cells in three-dimensional culture. Coexpression of GAB2 with antiapoptotic oncogenes causes lumenal filling, whereas coexpression with Neu (also known as ErbB2 and HER2) results in an invasive phenotype. These effects of GAB2 are mediated by hyperactivation of the Shp2-Erk pathway. Furthermore, overexpression of Gab2 potentiates, whereas deficiency of Gab2 ameliorates, Neu-evoked breast carcinogenesis in mice. Finally, GAB2 is amplified in some GAB2-overexpressing human breast tumors. Our data suggest that GAB2 may be a key gene within an 11q13 amplicon in human breast cancer and propose a role for overexpression of GAB2 in mammary carcinogenesis. Agents that target GAB2 or GAB2-dependent pathways may be useful for treating breast tumors that overexpress GAB2 or HER2 or both.

Cortactin regulates cell migration through activation of N-WASP.

Cortactin is an actin-associated scaffolding protein that regulates cell migration. Amplification of the human gene, EMS1, has been detected in breast, head and neck tumors, where it correlates with increased invasiveness. Cortactin can regulate actin dynamics directly via its N-terminal half, which can bind and activate the Arp2/3 complex. The C-terminal portion of cortactin, however, is thought to have limited function in its regulation of the actin polymerization machinery. In this report, we identify a role for the cortactin C-terminus in regulating cell migration and, more specifically, actin dynamics. Overexpression of either full-length cortactin or cortactin C-terminus is sufficient to enhance migration of mammary epithelial cells. In vitro, cortactin binds to and activates, via its SH3 domain, a regulator of the Arp2/3 complex, neural Wiskott Aldrich Syndrome protein (N-WASP). This in vitro activation of N-WASP is likely to be important in vivo, as cortactin-enhanced migration is dependent upon N-WASP. Thus, our results suggest that cortactin has multiple mechanisms by which it can recruit and modulate the actin machinery and ultimately regulate cell migration.

Detection and purification of instructive extracellular matrix components with monoclonal antibody technologies.

Historically, Mabs have been one of the most productive and reliable methods for the identification of adhesion receptors and adhesive ECM ligands. In large part, this is because Mabs can identify the function of the adhesion components within the context of the complex ECM or the cell surface. There are now many isoforms of laminin, collagen, and other ECM components that have been identified by molecular and Mab approaches. It is not clear when and where these isoforms are expressed at the protein level, nor what unique functions each ECM isoform may serve within the context of tissue. Undoubtedly, specific in vitro assays in combination with specific Mabs will help illuminate the instructive roles of ECM components for reporter cells within in vitro models and tissue. Delineation of cell responses to the instructive ECM will require additional high-resolution technologies including DNA microarrays and targeted disruption of ECM components.

Experiencia en pacientes con serología positiva para el virus de inmunodeficiencia humana (H.I.V.) en la Unidad de Clínica Médica del Hospital Vélez Sársfield / Experience in patients with human immunodeficiency virus (H.I.V.) positive serology in the medical clinic unit to Vélez Sársfield Hospital

Se presenta la experiencia en la atención de pacientes con serología positiva para el HIV en una Unidad de Clínica Médica de un Hospital de Buenos Aires. Fueron internados 38 pacientes que registraron un total de 63 internaciones en un período de 4 años. El primer caso se presentó en 1990. El 92,1 por ciento eran varones y el 7,9 por ciento mujeres (p<0,01). La edad promedio fue de 30,2ñ 7,1 años. Entre los factores de riesgo prevalecieron la drogadicción endovenosa (72 por ciento), la heterosexualidad promiscua (66 por ciento) y la homosexualidad (34 por ciento). Parte de la población estudiada provenía de la Unidad Penitenciaria 2 (Villa Devoto), en quienes se halló una tríada de riesgo característica: homosexualidad, drogadicción endovenosa y tatuajes múltiples. Las manifestaciones al ingreso fueron poliadenomegalias (66 por ciento), síndrome de vías respiratorias (50 por ciento) y síndrome de impregnación (42 por ciento). El laboratorio de ingreso mostró anemia en el 55 por ciento de los casos, leucopenia en el 45 por ciento y plaquetopenia en el 39 por ciento. La evolución de la enfermedad estuvo relacionada con la presencia de una o más enfermedades. En nuestro medio predominaron las neumonías a Pneumocystis carinii (34 por ciento), tuberculosis (26 por ciento) y hepatitis viral C (26 por ciento). La mortalidad durante el período de internación fue del 15 por ciento (6 casos). La misma se debió a la falta de respuesta al tratamiento instituido y a la concurrencia, en todos los casos, de dos o más enfermedades en forma simultánea.