Novel Benchmark Values for Open Major Anatomic Liver Resection in Non-cirrhotic Patients: A Multicentric Study of 44 International Expert Centers.

OBJECTIVE: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities. BACKGROUND: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures. METHODS: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient. RESULTS: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months. CONCLUSION: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens.

Defatting of Human Livers During Long-Term e x situ Normothermic Perfusion: Novel Strategy to Rescue Discarded Organs for Transplantation.

OBJECTIVE: To develop a protocol for the defatting of steatotic liver grafts during long-term ex situ normothermic machine perfusion. BACKGROUND: Despite the alarming increase in donor organ shortage, the highly prevalent fatty liver grafts are often discarded due to the risk of primary nonfunction. Effective strategies preventing such outcomes are currently lacking. An exciting new avenue is the introduction of ex situ normothermic machine perfusion (NMP), enabling a liver to remain fully functional for up to 2 weeks and providing a unique window of opportunity for defatting before transplantation. METHODS: Over a 5-year period, 23 discarded liver grafts and 28 partial livers from our resection program were tested during ex situ normothermic machine perfusion. The steatosis degree was determined on serial biopsies by expert pathologists, and triglyceride contents were measured simultaneously. RESULTS: Of 51 liver grafts, 20 were steatotic, with up to 85% macrovesicular steatosis, and were perfused for up to 12 days. Ten livers displayed marked (5 of which almost complete) loss of fat, while the other 10 did not respond to long-term perfusion. Successful defatting was related to prolonged perfusion, automated glucose control, circadian nutrition, and L-carnitine/fenofibrate supplementation. Pseudopeliotic steatosis and the associated activation of Kupffer/stellate cells were unexpected processes that might contribute to defatting. Synthetic and metabolic functions remained preserved for most grafts until perfusion ended. CONCLUSION: Ex situ long-term perfusion effectively reduces steatosis while preserving organ viability and may in the future allow transplantation of primarily unusable high-risk grafts, significantly increasing the number of organs available for transplantation.

Low-dose aspirin confers protection against acute cellular allograft rejection after primary liver transplantation.

This study investigated the effect of low-dose aspirin in primary adult liver transplantation (LT) on acute cellular rejection (ACR) as well as arterial patency rates. The use of low-dose aspirin after LT is practiced by many transplant centers to minimize the risk of hepatic artery thrombosis (HAT), although solid recommendations do not exist. However, aspirin also possesses potent anti-inflammatory properties and might mitigate inflammatory processes after LT, such as rejection. Therefore, we hypothesized that the use of aspirin after LT has a protective effect against ACR. This is an international, multicenter cohort study of primary adult deceased donor LT. The study included 17 high-volume LT centers and covered the 3-year period from 2013 to 2015 to allow a minimum 5-year follow-up. In this cohort of 2365 patients, prophylactic antiplatelet therapy with low-dose aspirin was administered in 1436 recipients (61%). The 1-year rejection-free survival rate was 89% in the aspirin group versus 82% in the no-aspirin group (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.63-0.94; p = 0.01). The 1-year primary arterial patency rates were 99% in the aspirin group and 96% in the no-aspirin group with an HR of 0.23 (95% CI, 0.13-0.40; p < 0.001). Low-dose aspirin was associated with a lower risk of ACR and HAT after LT, especially in the first vulnerable year after transplantation. Therefore, low-dose aspirin use after primary LT should be evaluated to protect the liver graft from ACR and to maintain arterial patency.

Transplantation of a human liver following 3 days of ex situ normothermic preservation.

Current organ preservation methods provide a narrow window (usually <12 hours) to assess, transport and implant donor grafts for human transplantation. Here we report the transplantation of a human liver discarded by all centers, which could be preserved for several days using ex situ normothermic machine perfusion. The transplanted liver exhibited normal function, with minimal reperfusion injury and the need for only a minimal immunosuppressive regimen. The patient rapidly recovered a normal quality of life without any signs of liver damage, such as rejection or injury to the bile ducts, according to a 1-year follow up. This inaugural clinical success opens new horizons in clinical research and promises an extended time window of up to 10 days for assessment of viability of donor organs as well as converting an urgent and highly demanding surgery into an elective procedure.

Early postoperative serum albumin levels as predictors of surgical outcomes in head and neck squamous cell carcinoma.

BACKGROUND: Malnutrition is a common issue in patients with head and neck squamous cell carcinoma and has a negative effect on surgical outcomes. OBJECTIVE: We attempted to determine which malnutrition diagnostic variables can be used as predictors of postoperative complications in patients with head and neck squamous cell carcinoma. METHODS: Forty-one patients undergoing surgery for head and neck squamous cell carcinoma were submitted to a prospective evaluation. Biochemical data, anthropometric measurements and evaluation of body composition were used in the nutritional analysis. RESULTS: Twenty-two patients (53.6%) developed complications. Serum albumin measured on the first postoperative day was the only variable that significantly differed between groups. A cut-off value of 2.8 g/dL distinguished between patients with a complicated and uncomplicated postoperative course. Normalization of albumin levels occurred more frequently and more rapidly in the noncomplicated group. CONCLUSION: Serum albumin measured on the first postoperative day was the only variable that was a predicter of postoperative complications after major head and neck squamous cell carcinoma surgery.

Early postoperative serum albumin levels as predictors of surgical outcomes in head and neck squamous cell carcinoma / Níveis de albumina sérica no pós‐operatório imediato como preditivo de resultados cirúrgicos em carcinoma de células escamosas de cabeça e pescoço

Abstract Background Malnutrition is a common issue in patients with head and neck squamous cell carcinoma and has a negative effect on surgical outcomes. Objective We attempted to determine which malnutrition diagnostic variables can be used as predictors of postoperative complications in patients with head and neck squamous cell carcinoma. Methods Forty-one patients undergoing surgery for head and neck squamous cell carcinoma were submitted to a prospective evaluation. Biochemical data, anthropometric measurements and evaluation of body composition were used in the nutritional analysis. Results Twenty-two patients (53.6%) developed complications. Serum albumin measured on the first postoperative day was the only variable that significantly differed between groups. A cut-off value of 2.8 g/dL distinguished between patients with a complicated and uncomplicated postoperative course. Normalization of albumin levels occurred more frequently and more rapidly in the noncomplicated group. Conclusion Serum albumin measured on the first postoperative day was the only variable that was a predicter of postoperative complications after major head and neck squamous cell carcinoma surgery.

Resumo Introdução A desnutrição é um problema comum em pacientes com carcinoma de células escamosas de cabeça e pescoço e tem um efeito negativo nos resultados cirúrgicos. Objetivo Tentamos determinar quais variáveis diagnósticas de desnutrição podem ser usadas como preditivos de complicações pós‐operatórias em pacientes com carcinoma de células escamosas de cabeça e pescoço. Método Quarenta e um pacientes submetidos à cirurgia de carcinoma de células escamosas de cabeça e pescoço foram submetidos a uma avaliação prospectiva. Dados bioquímicos, medidas antropométricas e avaliação da composição corporal foram usados na análise nutricional. Resultados Vinte e dois pacientes (53,6%) desenvolveram complicações. A dosagem de albumina sérica no primeiro dia pós‐operatório foi a única variável que diferiu significantemente entre os grupos. Um valor de corte de 2,8 g/dL distinguiu os pacientes com uma evolução pós‐operatória complicada e não complicada. A normalização dos níveis de albumina ocorreu mais frequentemente e mais rapidamente no grupo sem complicação pós‐operatória. Conclusão A albumina sérica medida no primeiro dia pós‐operatório foi a única variável capaz de predizer complicações pós‐operatórias após cirurgia de carcinoma de células escamosas de cabeça e pescoço de grande porte.

Long-term Normothermic Machine Preservation of Partial Livers: First Experience With 21 Human Hemi-livers.

OBJECTIVE: The aim of this study was to maintain long-term full function and viability of partial livers perfused ex situ for sufficient duration to enable ex situ treatment, repair, and regeneration. BACKGROUND: Organ shortage remains the single most important factor limiting the success of transplantation. Autotransplantation in patients with nonresectable liver tumors is rarely feasible due to insufficient tumor-free remnant tissue. This limitation could be solved by the availability of long-term preservation of partial livers that enables functional regeneration and subsequent transplantation. METHODS: Partial swine livers were perfused with autologous blood after being procured from healthy pigs following 70% in-vivo resection, leaving only the right lateral lobe. Partial human livers were recovered from patients undergoing anatomic right or left hepatectomies and perfused with a blood based perfusate together with various medical additives. Assessment of physiologic function during perfusion was based on markers of hepatocyte, cholangiocyte, vascular and immune compartments, as well as histology. RESULTS: Following the development phase with partial swine livers, 21 partial human livers (14 right and 7 left hemi-livers) were perfused, eventually reaching the targeted perfusion duration of 1 week with the final protocol. These partial livers disclosed a stable perfusion with normal hepatic function including bile production (5-10 mL/h), lactate clearance, and maintenance of energy exhibited by normal of adenosine triphosphate (ATP) and glycogen levels, and preserved liver architecture for up to 1 week. CONCLUSION: This pioneering research presents the inaugural evidence for long-term machine perfusion of partial livers and provides a pathway for innovative and relevant clinical applications to increase the availability of organs and provide novel approaches in hepatic oncology.

Síndrome congénito de Klippel-Trenaunay-Weber: caso clínico / Congenital Klippel-Trenaunay-Weber syndrome: clinical case

RESUMEN: El síndrome de Klippel-Trenaunay-Weber (SKTW) es una enfermedad congénita poco frecuente caracterizada por hipertrofia de un miembro que afecta a los huesos y a las partes blandas, con extensos angiomas planos, várices y otras anomalías vasculares, como fístulas arteriovenosas. Su incidencia es de 1:100.000 personas. El objetivo fue describir un caso raro de SKTW bilateral, confirmado con hallazgos clínicos e imagenológicos en un niño de 9 años de edad, de sexo masculino, con antecedentes de sangrado digestivo bajo, herniorrafía inguinal izquierda y orquidopexia ipsilateral. En ambos miembros inferiores se identificaron lesiones hemangiomatosas e hipertrofia muscular y edema en miembro inferior izquierdo con ausencia de segundo y tercer dedos del pie izquierdo por antecedente quirúrgico de amputación. Adicionalmente, presentaba adenopatías cervicales e inguinales. Dentro de los hallazgos radiográficos importantes, se observó una cortical ósea delgada en el fémur del miembro inferior izquierdo. El SKTW afecta típicamente a los miembros inferiores de forma unilateral; este es un caso infrecuente de afección bilateral (con predominio izquierdo). Algunos pacientes, registran compromiso visceral con hemorragia digestiva baja, además de alteraciones genitourinarias, presentes en el 30% de los casos. La presentación de adenopatías es inusual.

SUMMARY: Klippel-Trenaunay-Weber syndrome (KTWS) is a rare congenital disease characterized by limb hypertrophy affecting bones and soft tissues, with extensive flat angiomas, varicose veins, and other vascular abnormalities, such as arteriovenous fistulas. Its incidence is 1: 100,000 people. The aim of this work was to describe a rare case of bilateral KTWS, confirmed with clinical and imaging findings in a 9-year-old male, with a history of lower gastrointestinal bleeding, left inguinal herniorrhaphy and ipsilateral orchidopexy. In both lower limbs, hemangiomatous lesions and muscle hypertrophy were identified, and in the left lower limb edema was identified with absence of the second and third toes due to a surgical history of amputation. Additionally, the patient presented cervical and inguinal lymphadenopathy. Among the important radiographic findings, in the left lower limb femur a thin bony cortex was observed. KTWS typically affects the lower limbs unilaterally; this is an infrequent case of bilateral affection (predominantly left). Some patients have visceral involvement with lower gastrointestinal bleeding, as well as genitourinary alterations, present in 30 % of cases. The presentation of lymphadenopathy is unusual.

Evaluación de la capacidad funcional en escolares con fisiología de corazón univentricular / Assessment of functional capacity among students with univentricular heart

Se realizó un estudio transversal en escolares con corazón univentricular en estadio pos-bypass total de ventrículo derecho con el objetivo de determinar la capacidad funcional basal mediante el test de marcha en 6 minutos e identificar posibles factores determinantes. Participaron 30 pacientes con una mediana de edad de 12 años. Dieciocho pacientes fueron de sexo masculino. La mediana de distancia recorrida fue de 551,3 metros, un 84 % de la distancia teórica para población pediátrica sana. Las variables talla, presión arterial sistólica pretest y saturación arterial de oxígeno de reposo se asociaron significativamente con la distancia recorrida en el modelo de regresión lineal múltiple. No hubo asociación significativa en los metros caminados respecto de las variables sexo, estado nutricional, dignóstico cardiológico inicial, número de cirugías previas y edad al momento del bypass total de ventrículo derecho

A cross-sectional study was done in students with univentricular heart after undergoing total cavopulmonary connection (Fontan procedure) to establish their baseline functional capacity based on the six-minute walk test and identify potential determining factors. Thirty patients were included; their median age was 12 years old. Eighteen patients were males. The median distance walked was 551.3 meters, 84 % of the theoretical distance for a healthy pediatric population. Height, pre-test systolic blood pressure, and resting arterial oxygen saturation showed a significant association with the distance walked in the multiple linear regression model. No significant association was observed in the meters walked in terms of the following outcome measures: sex, nutritional status, baseline cardiological diagnosis, number of prior surgeries, and age at the time of Fontan procedure

Yeast as a Model to Understand Actin-Mediated Cellular Functions in Mammals-Illustrated with Four Actin Cytoskeleton Proteins.

The budding yeast Saccharomyces cerevisiae has an actin cytoskeleton that comprises a set of protein components analogous to those found in the actin cytoskeletons of higher eukaryotes. Furthermore, the actin cytoskeletons of S. cerevisiae and of higher eukaryotes have some similar physiological roles. The genetic tractability of budding yeast and the availability of a stable haploid cell type facilitates the application of molecular genetic approaches to assign functions to the various actin cytoskeleton components. This has provided information that is in general complementary to that provided by studies of the equivalent proteins of higher eukaryotes and hence has enabled a more complete view of the role of these proteins. Several human functional homologues of yeast actin effectors are implicated in diseases. A better understanding of the molecular mechanisms underpinning the functions of these proteins is critical to develop improved therapeutic strategies. In this article we chose as examples four evolutionarily conserved proteins that associate with the actin cytoskeleton: 1) yeast Hof1p/mammalian PSTPIP1, 2) yeast Rvs167p/mammalian BIN1, 3) yeast eEF1A/eEF1A1 and eEF1A2 and 4) yeast Yih1p/mammalian IMPACT. We compare the knowledge on the functions of these actin cytoskeleton-associated proteins that has arisen from studies of their homologues in yeast with information that has been obtained from in vivo studies using live animals or in vitro studies using cultured animal cell lines.

Artroplastía parcial de cadera con banda de tensión en fracturas de fémur proximal en pacientes ancianos / Partial hip arthroplasty with tension band in proximal femur fractures in older patients

RESUMEN: Las fracturas intertrocantéricas en adulto mayor presentan gran dificultad para lograr una cicatrización ósea estable y una fijación en la artroplastía, para la recuperación completa y funcional del anciano. En pacientes adultos mayores sin stock óseo, se recomienda realizar anexo a la artroplastía de cadera, la colocación de una banda de tensión, con la finalidad de brindar mayor estabilidad a los fragmentos y sustentación a la artroplastía primaria, con el objetivo de lograr un retorno a la calidad de vida normal. A las cuatro semanas de la cirugía, se evidencia una mejora en la escala funcional alcanzando una puntuación media de 83, considerandose un buen resultado. En los controles subsecuentes se evidencia una media en la escala de Harris de 87. Los pacientes volvieron a su nivel de actividad preoperatoria, más de la mitad de los pacientes fueron capaces de caminar sin apoyos, y finalmente, no se reportaron complicaciones en los controles postquirúrgicos al seguimiento de un año.

SUMMARY: The intertrochanteric fractures in the elderly are very difficult to achieve stable bone healing and fixation in arthroplasty for complete and functional recovery of the elderly. In elderly patients without bone stock, it is recommended to make an attachment to the hip arthroplasty the placement of tension band with the purpose of providing greater stability to the fragments and support to the primary arthroplasty with the aim of a return to the normal quality of life, in the results at 4 weeks post-surgery an improvement in the functional scale is evidenced having as average score 83 taken as good results. In the subsequent controls a mean on the Harris scale of 87 was evidenced, the patients returned to their level of preoperative activity, more than half of the patients were able to walk without support, no complications were reported in the postoperative follow-up controls. of 1 year of patients.

Garlic: kinetic drying and thermodynamic properties / Alho: cinética de secagem e propriedades termodinâmicas

Dehydrated garlic is an importance spice in pre-cooked and processed food products, but studies of the drying variables of this product are scarce. Thus, this work aimed to model and study the kinetics of garlic drying at three different temperatures (40, 50 and 60 °C) and analyze the thermodynamic parameters during the process. The drying was analyzed using pre-established mathematical models for agricultural products and equations that describe the thermodynamics of product dehydration. The best mathematical adjustment for all drying temperatures was the Midilli equation. The moisture ratio was seen to decrease during the process for all situations. The effective diffusivity increased with increasing temperature. The enthalpy change was positive during the process and decreased with increasing temperature. The study entropy was negative, indicating a non-spontaneous reaction. In addition, the Gibbs free energy increased with increasing drying temperature. The thermodynamic standards were satisfactory and correctly described the moisture loss by the garlic samples.

O alho desidratado é um tempero de suma importância em produtos pré-cozidos e processados, no entanto, o estudo das variáveis de secagem desse produto é escasso. Diante disso, objetivou-se com esse trabalho estudar a cinética e a modelagem da secagem de alho, em três temperaturas distintas (40, 50 e 60 °C), e analisar os parâmetros termodinâmicos durante o processo. O estudo da secagem foi feito por meio de modelos matemáticos pré-estabelecidos para produtos agrícolas e por equações que descrevem a termodinâmica da desidratação de produtos. O melhor ajuste matemático foi à equação de Midilli para todas as temperaturas de secagem. A razão de umidade apresentou-se decrescente durante o processo para todas as situações. A difusividade efetiva aumentou com o aumento da temperatura. A variação de entalpia apresentou-se positiva durante o processo de secagem e diminui com o aumento da temperatura. A entropia estudada foi negativa, indicando uma reação não-espontânea. E a energia livre de Gibbs aumentou com a elevação da temperatura de secagem. Os padrões termodinâmicos foram satisfatórios e descreveram como ocorreu a perda de umidade pelas amostras de alho.

Timing of surgical antimicrobial prophylaxis: a phase 3 randomised controlled trial.

BACKGROUND: Based on observational studies, administration of surgical antimicrobial prophylaxis (SAP) for the prevention of surgical site infection (SSI) is recommended within 60 min before incision. However, the precise optimum timing is unknown. This trial compared early versus late administration of SAP before surgery. METHODS: In this phase 3 randomised controlled superiority trial, we included general surgery adult inpatients (age ≥18 years) at two Swiss hospitals in Basel and Aarau. Patients were randomised centrally and stratified by hospital according to a pre-existing computer-generated list in a 1:1 ratio to receive SAP early in the anaesthesia room or late in the operating room. Patients and the outcome assessment team were blinded to group assignment. SAP consisted of single-shot, intravenous infusion of 1·5 g of cefuroxime, a commonly used cephalosporin with a short half-life, over 2-5 min (combined with 500 mg metronidazole in colorectal surgery). The primary endpoint was the occurrence of SSI within 30 days of surgery. The main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01790529. FINDINGS: Between Feb 21, 2013, and Aug 3, 2015, 5580 patients were randomly assigned to receive SAP early (2798 patients) or late (2782 patients). 5175 patients (2589 in the early group and 2586 in the late group) were analysed. Median administration time was 42 min before incision in the early group (IQR 30-55) and 16 min before incision in the late group (IQR 10-25). Inpatient follow-up rate was 100% (5175 of 5175 patients); outpatient 30-day follow-up rate was 88·8% (4596 of 5175), with an overall SSI rate of 5·1% (234 of 4596). Early administration of SAP did not significantly reduce the risk of SSI compared with late administration (odds ratio 0·93, 95% CI 0·72-1·21, p=0·601). INTERPRETATION: Our findings do not support any narrowing of the 60-min window for the administration of a cephalosporin with a short half-life, thereby obviating the need for increasingly challenging SAP timing recommendations. FUNDING: Swiss National Science Foundation, Hospital of Aarau, University of Basel, Gottfried und Julia Bangerter-Rhyner Foundation, Hippocrate Foundation, and Nora van Meeuwen-Häfliger Foundation.

Osteocondroma escapular: un caso infrecuente / Scapular osteochondroma: an infrequent case

El osteocondroma de la escápula es un tumor beningno muy raro por su ubicación, que produce dolor y disfunción mecánica de la articulación cuando se establece en la superficie ventral de la escápula, afecta principalmente a los varones en los períodos del crecimiento óseo, entre 10 y 30 años de edad, representan el 14,4 % de todos los tumores de la escápula y el 49 % de los tumores benignos de la escápula. Surgen en las regiones metafisarias de los huesos largos (fémur, húmero, tibia), causando irritación mecánica que conduce a impotencia funcional, bursitis, e incluso fractura de la escápula, pocos casos en huesos planos han sido descritos. El diagnostico se realiza con la valoración física, clínica y exámenes complementarios, debiendo ser confirmado por el histopatológo previa biopsia. La indicación quirúrgica incluye la disfunción mecánica de una articulación o tendón en relación con el tamaño de la lesión, y del cambio sarcomatoso siendo el procedimiento de elección la escisión quirúrgica abierta. A continuación se describe el caso de una joven de 11 años a quien se diagnosticó un osteocondroma subescapular, previabiopsia escisional.

Osteochondroma of the scapulais a rare benign tumor in view of its location, which produces pain and mechanical dysfunction of the joint when it is on the ventral surface of the scapula, mainly affecting men during bone growth periods, betweenthe ages of 10 and 30, accounting for 14.4 % of allscapula tumors and 49 % of benign tumors of thescapula. They arise in the metaphyseal regions ofthe long bones (femur, humerus, tibia), causing mechanical irritation leading to functional impotence,bursitis, and fracture of the scapula. Few cases inflat bones have been described. Diagnosis is made with physical, clinical and complementary examinations, and must be confirmed by prior histopathology biopsy. The surgical indication includes mechanical dysfunction of a joint or tendon in relationto the size of the lesion, sarcomatous change being the procedure of choice in open surgical excision. The case of an 11-year-old girl who was diagnosed with a subscapular osteochondroma after previous excisional biopsy, is described below.

Keeping the eIF2 alpha kinase Gcn2 in check.

The protein kinase Gcn2 is present in virtually all eukaryotes and is of increasing interest due to its involvement in a large array of crucial biological processes. Some of these are universally conserved from yeast to humans, such as coping with nutrient starvation and oxidative stress. In mammals, Gcn2 is important for e.g. long-term memory formation, feeding behaviour and immune system regulation. Gcn2 has been also implicated in diseases such as cancer and Alzheimer's disease. Studies on Gcn2 have been conducted most extensively in Saccharomyces cerevisiae, where the mechanism of its activation by amino acid starvation has been revealed in most detail. Uncharged tRNAs stimulate Gcn2 which subsequently phosphorylates its substrate, eIF2α, leading to reduced global protein synthesis and simultaneously to increased translation of specific mRNAs, e.g. those coding for Gcn4 in yeast and ATF4 in mammals. Both proteins are transcription factors that regulate the expression of a myriad of genes, thereby enabling the cell to initiate a survival response to the initial activating cue. Given that Gcn2 participates in many diverse processes, Gcn2 itself must be tightly controlled. Indeed, Gcn2 is regulated by a vast network of proteins and RNAs, the list of which is still growing. Deciphering molecular mechanisms underlying Gcn2 regulation by effectors and inhibitors is fundamental for understanding how the cell keeps Gcn2 in check ensuring normal organismal function, and how Gcn2-associated diseases may develop or may be treated. This review provides a critical evaluation of the current knowledge on mechanisms controlling Gcn2 activation or activity.

Estrogen receptors mediate estradiol's effect on sensitization and CPP to cocaine in female rats: role of contextual cues.

Preclinical studies show that estradiol enhances sensitization to cocaine in females by mechanisms not fully understood. These studies consistently show that ovariectomized (OVX) rats exhibit little or no sensitization to cocaine compared to OVX rats administered estradiol. In this study we varied the dose of cocaine (10, 15, and 30mg/kg), the length of cocaine treatment (from 5 to 10days) and the context of cocaine injections to determine if these factors play a role on estradiol's effects on cocaine sensitization. Because OVX rats are hormonally compromised, they are not representative of the natural state of the animal, and thus the physiological context of these studies remains unclear. To address this issue, we blocked ERs in gonadally intact females by icv administration of the antiestrogen ICI-182,780. Varying the dose or length of exposure to cocaine does not alter estradiol's effect on cocaine sensitization. In contrast, a highly context-dependent sensitization protocol results in robust sensitization even in OVX rats. Interestingly, using this protocol, sensitization in OVX rats diminished with time, suggesting that estradiol is necessary for the maintenance of cocaine sensitization. Blocking brain ERs with ICI completely abolishes the development and expression of cocaine sensitization in gonadally intact female rats, even when tested in a highly context-dependent sensitization protocol. Given these findings, we propose that activation of brain ERs is required for the development and maintenance of sensitization and CPP.

Changes in natural killer cell subsets in pediatric liver transplant recipients.

NK cells are important in the immune response against tumors and virally infected cells. A balance between inhibitory and activating receptors controls the effector functions of NK cells. We examined the fate of circulating NK cells and the expression of the NK cell-activating receptors in pediatric liver transplant recipients. Blood specimens were collected from 38 pediatric liver transplant recipients before transplant, and at one wk, one, three, six, and nine months, and one yr post-transplant. PBMCs were isolated and analyzed for the levels of NK cell activation receptors NKp30, NKp46, and NKG2D in the CD56(dim) CD16(+) and CD56(bright) CD16(+/-) subsets of NK cells. We demonstrated that there is a significant decrease in the percentage of circulating NK cells post-transplant (pretransplant 7.69 ± 1.54 vs. one wk post-transplant 1.73 ± 0.44) in pediatric liver transplant recipients. Interestingly, NKp30 expression is significantly increased, while NKp46 and NKG2D levels remain stable on the NK cells that persist at one wk post-transplant. These data indicate that the numbers and subsets of circulating NK cells are altered in children after liver transplantation.

Sepse fatal após instilação intravesical de BCG: relato de caso / Fatal sepsis after intravesical instillation of BCG: case report

A instilação intravesical do bacilo de Calmette-Guérin (BCG) é o tratamento de escolha para carcinoma de bexiga in situ ou tumores superficiais de bexiga de alto grau não invasivos. Este tratamento geralmente é bem tolerado, mas podem ocorrer complicações graves. Paciente idoso, coronariopata, portador de carcinoma superficial de bexiga de alto grau recidivado foi submetido à instilação intravesical de BCG, evoluindo com choque séptico. Recebeu antibioticoterapia de amplo espectro, tuberculostáticos, corticóide, aminas vasoativas, suporte ventilatório e tratamento hemodialítico, sem melhora. Faleceu nove dias após a instilação intravesical de BCG por insuficiência de múltiplos órgãos.

Intravesical instillation of bacillus Calmette-Guérin (BCG) is the treatment of choice for carcinoma in situ and non-invasive high-grade superficial tumors of the urinary bladder. This treatment is well tolerated overall, but serious complications can occur. An elderly man with coronary disease and recurrent high-grade superficial carcinoma of the bladder underwent intravesical instillation of BCG and developed septic shock. He received wide range antibiotics, tuberculostatic and vasoactive drugs, corticosteroids, mechanical ventilation and renal replacement therapy without improvement. He died nine days after the intravesical instillation of BCG because of multiple organ failure.

[Association of chronic pulmonary obstructive disease (COPD) and complications in head and neck surgery]. / Associação de doença pulmonar obstrutiva crônica (DPOC) e complicações em cirurgia de cabeça e pescoço.

UNLABELLED: COPD presents in a variety of forms patients with head and neck cancer; it may affect therapeutic decision-making or postoperative outcomes due to its complications. AIM: To correlate the severity of COPD in patients with head and neck SCC treated with surgery, who present postoperative complications. METHOD: A retrospective analysis of 31 patients undergoing en bloc resections, from 2008 to 2009. All cases were evaluated and classified using the GOLD scale. The COPD grade, intubation period, ICU stay and hospital stay were studied. RESULTS: The mean age was 64.8 years; COPD was mild in 24 cases, moderate in 6 and severe in 1 case. ICU stay was 2.7 days and the intubation period was 1,12 days. The mean hospital stay was 24.4 days. There was no relation between COPD grade and brochopneumonia, intubation period, ICU stay and hospital stay. CONCLUSION: Patients with head and neck SCC have a tendency to acquire COPD; its severity was not related with postoperative pulmonary complications, prolonged intubation period, ICU stay and hospital stay.

Associação de doença pulmonar obstrutiva crônica (DPOC) e complicações em cirurgia de cabeça e pescoço / Association of chronic pulmonary obstructive disease (COPD) and complications in head and neck surgery

A DPOC está presente em graus variados em pacientes portadores de câncer de cabeça e pescoço e pode influenciar na decisão terapêutica ou alterar a evolução no PO por eventuais complicações relacionadas. OBJETIVO: Correlacionar o grau de DPOC em pacientes com de CEC de cabeça e pescoço tratados com cirurgia com complicações no PO. MÉTODO: Estudo retrospectivo de pacientes submetidos a cirurgias em monobloco entre 2008 e 2009. Todos os pacientes foram avaliados e classificados pela escala de GOLD. Foram relacionados o grau de DPOC, tempo de intubação, permanência em UTI e tempo de internação. RESULTADOS: O n foi 31 casos com idade média de 64,8 anos. O grau de DPOC foi leve em 24 casos, moderado em 6 e grave em 1. A permanência em UTI no PO imediato foi 2,7 e o tempo de intubação foi 1,12 dias. A média de internação foi 24,4 dias. Não houve correlação entre grau de DPOC e incidência de broncopneumonia, tempo de IOT, permanência em UTI e permanência hospitalar. CONCLUSÃO: Os pacientes com CEC de vias aerodigestivas superiores têm uma tendência a apresentar DPOC cuja gravidade não teve relação com complicações pulmonares no PO, tempo prolongado de intubação, permanência em UTI ou tempo de internação.

COPD presents in a variety of forms patients with head and neck cancer; it may affect therapeutic decision-making or postoperative outcomes due to its complications. AIM: To correlate the severity of COPD in patients with head and neck SCC treated with surgery, who present postoperative complications. METHOD: A retrospective analysis of 31 patients undergoing en bloc resections, from 2008 to 2009. All cases were evaluated and classified using the GOLD scale. The COPD grade, intubation period, ICU stay and hospital stay were studied. RESULTS: The mean age was 64.8 years; COPD was mild in 24 cases, moderate in 6 and severe in 1 case. ICU stay was 2.7 days and the intubation period was 1,12 days. The mean hospital stay was 24.4 days. There was no relation between COPD grade and brochopneumonia, intubation period, ICU stay and hospital stay. CONCLUSION: Patients with head and neck SCC have a tendency to acquire COPD; its severity was not related with postoperative pulmonary complications, prolonged intubation period, ICU stay and hospital stay.