Kcnj16 (Kir5.1) gene ablation causes subfertility and increases the prevalence of morphologically abnormal spermatozoa

The ability of spermatozoa to swim towards an oocyte and fertilize it depends on precise K+ permeability changes. Kir5.1 is an inwardly-rectifying potassium (Kir) channel with high sensitivity to intracellular H+ (pHi) and extracellular K+ concentration [K+ ]o, and hence provides a link between pHi and [K+ ]o changes and membrane potential. The intrinsic pHi sensitivity of Kir5.1 suggests a possible role for this channel in the pHi-dependent processes that take place during fertilization. However, despite the localization of Kir5.1 in murine spermatozoa, and its increased expression with age and sexual maturity, the role of the channel in sperm morphology, maturity, motility, and fertility is unknown. Here, we confirmed the presence of Kir5.1 in spermatozoa and showed strong expression of Kir4.1 channels in smooth muscle and epithelial cells lining the epididymal ducts. In contrast, Kir4.2 expression was not detected in testes. To examine the possible role of Kir5.1 in sperm physiology, we bred mice with a deletion of the Kcnj16 (Kir5.1) gene and observed that 20% of Kir5.1 knock-out male mice were infertile. Furthermore, 50% of knock-out mice older than 3 months were unable to breed. By contrast, 100% of wild-type (WT) mice were fertile. The genetic inactivation of Kcnj16 also resulted in smaller testes and a greater percentage of sperm with folded flagellum compared to WT littermates. Nevertheless, the abnormal sperm from mutant animals displayed increased progressive motility. Thus, ablation of the Kcnj16 gene identifies Kir5.1 channel as an important element contributing to testis development, sperm flagellar morphology, motility, and fertility. These findings are potentially relevant to the understanding of the complex pHi-and [K+ ]o-dependent interplay between different sperm ion channels, and provide insight into their role in fertilization and infertility

Skeletal muscle is a primary target of SOD1G93A-mediated toxicity

The antioxidant enzyme superoxide dismutase 1 (SOD1) is a critical player of the antioxidative defense whose activity is altered in several chronic diseases, including amyotrophic lateral sclerosis. However, how oxidative insult affects muscle homeostasis remains unclear. This study addresses the role of oxidative stress on muscle homeostasis and function by the generation of a transgenic mouse model expressing a mutant SOD1 gene (SOD1(G93A)) selectively in skeletal muscle. Transgenic mice developed progressive muscle atrophy, associated with a significant reduction in muscle strength, alterations in the contractile apparatus, and mitochondrial dysfunction. The analysis of molecular pathways associated with muscle atrophy revealed that accumulation of oxidative stress served as signaling molecules to initiate autophagy, one of the major intracellular degradation mechanisms. These data demonstrate that skeletal muscle is a primary target of SOD1(G93A) -mediated toxicity and disclose the molecular mechanism whereby oxidative stress triggers muscle atrophy

Expresión Inmunohistoquímica del Carcinoma de mama: prevalencia del triple negativo

10 p.El carcinoma de mama representa la principal causa de muerte por cáncer en mujeres. 1, 2. Los cánceres de mama constituyen un grupo heterogéneo de neoplasias malignas con diversas características clínico-patológicas y moleculares, que tienen un pronóstico y respuesta al tratamiento variados. Generalmente se los clasifica de acuerdo a la inmunoexpresión de receptores hormonales (estrógeno y progesterona) y del receptor del factor de crecimiento 2 de la epidermis humana (HER2). Esto se traduce en tres grandes grupos: · Tumores que expresan receptores hormonales: son aquellos positivos para receptores de estrógenos (ER) y/o progesterona (PR). · Tumores que expresan el receptor HER2: sin embargo no poseen receptores hormonales. ·Tumores triple-negativo. El cáncer de mama triple negativo (CMTN) se define como la ausencia de tinción del receptor de estrógeno, progesterona y HER2/neu (receptor 2 del factor de crecimiento epidérrmico humano). El CMTN es insensible a la terapia anti HER2, como el trastuzumab, y al tratamiento endocrino con tamoxifeno. 3 A pesar de que esta agrupación es simplista, posee un importante valor pronóstico y se utiliza ampliamente para guiar la conducta terapéutica (1). El objetivo de la presente comunicación es estudiar y cuantificar la prevalencia del CMTN. Material y Métodos: Se realizó un estudio retrospectivo de 50 casos de carcinoma de mama, de pacientes asistidas en el HUMN, durante el período 2007-2011. Los materiales utilizados fueron fijados en formol acuoso al 10%. Se estudió la expresión inmunohistoquímica con el método Avidina-Biotina-Peroxidasa (ABP), con marcadores para estrógenos, progesterona y HER2/neu. Se incluyeron piezas quirúrgicas con diagnóstico de carcinoma ductal y lobulillar tanto in situ como invasor, positivos para ER y/o PR, así como tumores que expresaron sólo HER-2/neu y los tumores triple negativos.http://www.revistamorfologia.com.ar/assets/files/Rev-ArgMorfol20132_2.pdfFil: Fonseca, Ismael B. Universidad Nacional de Córdoba. Hospital Universitario Maternidad y Neonatología. Facultad de Ciencias Médicas. Cátedra II de Patología; ArgentinaFil: Luque, Carolina. Universidad Nacional de Córdoba. Hospital Universitario Maternidad y Neonatología. Facultad de Ciencias Médicas. Cátedra II de Patología; Argentina.Fil: Szulc, Sonia Irene. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Cátedra II Patología; Argentina.Fil: Collard, Antonela. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Cátedra de Patología; Argentina.Fil: Altamirano Brasca, Belia Rocío. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Cátedra de Patología; Argentina.Fil: Spitale, Luis Santos. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Cátedra II de Patología. Hospital Nacional de Clínicas. Anatomía Patológica; Argentina.Patologí

The impact of minimally-invasive esophagectomy operative duration on post-operative outcomes

BackgroundEsophagectomy, an esophageal cancer treatment mainstay, is a highly morbid procedure. Prolonged operative time, only partially predetermined by case complexity, may be uniquely harmful to minimally-invasive esophagectomy (MIE) patients for numerous reasons, including anastomotic leak, tenuous conduit perfusion and protracted single-lung ventilation, but the impact is unknown. This multi-center retrospective cohort study sought to characterize the relationship between MIE operative time and post-operative outcomes.MethodsWe abstracted multi-center data on esophageal cancer patients who underwent MIE from 2010 to 2021. Predictor variables included age, sex, comorbidities, body mass index, prior cardiothoracic surgery, stage, and neoadjuvant therapy. Outcomes included complications, readmissions, and mortality. Association analysis evaluated the relationship between predictor variables and operative time. Multivariate logistic regression characterized the influence of potential predictor variables and operative time on post-operative outcomes. Subgroup analysis evaluated the association between MIE >4 h vs. ≤4 h and complications, readmissions and survival.ResultsFor the 297 esophageal cancer patients who underwent MIE between 2010 and 2021, the median operative duration was 4.8 h [IQR: 3.7–6.3]. For patients with anastomotic leak (5.1%) and 1-year mortality, operative duration was elevated above the median at 6.3 h [IQR: 4.8–8.6], p = 0.008) and 5.3 h [IQR: 4.4–6.8], p = 0.04), respectively. In multivariate logistic regression, each additional hour of operative time increased the odds of anastomotic leak and 1-year mortality by 39% and 19%, respectively.ConclusionsEsophageal cancer is a poor prognosis disease, even with optimal treatment. Operative efficiency, a modifiable surgical variable, may be an important target to improve MIE patient outcomes

Bringing the real world into the fMRI scanner: Repetition effects for pictures versus real objects

Our understanding of the neural underpinnings of perception is largely built upon studies employing 2-dimensional (2D) planar images. Here we used slow event-related functional imaging in humans to examine whether neural populations show a characteristic repetition-related change in haemodynamic response for real-world 3-dimensional (3D) objects, an effect commonly observed using 2D images. As expected, trials involving 2D pictures of objects produced robust repetition effects within classic object-selective cortical regions along the ventral and dorsal visual processing streams. Surprisingly, however, repetition effects were weak, if not absent on trials involving the 3D objects. These results suggest that the neural mechanisms involved in processing real objects may therefore be distinct from those that arise when we encounter a 2D representation of the same items. These preliminary results suggest the need for further research with ecologically valid stimuli in other imaging designs to broaden our understanding of the neural mechanisms underlying human vision

Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.

PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease