Genomewide association studies have implicated allelic variation at 9p21.3 in multiple forms of vascular disease, including atherosclerotic coronary heart disease and abdominal aortic aneurysm. As ...for other genes at 9p21.3, human expression quantitative trait locus studies have associated expression of the tumor suppressor gene CDKN2B with the risk haplotype, but its potential role in vascular pathobiology remains unclear.
Here we used vascular injury models and found that Cdkn2b knockout mice displayed the expected increase in proliferation after injury, but developed reduced neointimal lesions and larger aortic aneurysms. In situ and in vitro studies suggested that these effects were attributable to increased smooth muscle cell apoptosis. Adoptive bone marrow transplant studies confirmed that the observed effects of Cdkn2b were mediated through intrinsic vascular cells and were not dependent on bone marrow-derived inflammatory cells. Mechanistic studies suggested that the observed increase in apoptosis was attributable to a reduction in MDM2 and an increase in p53 signaling, possibly due in part to compensation by other genes at the 9p21.3 locus. Dual inhibition of both Cdkn2b and p53 led to a reversal of the vascular phenotype in each model.
These results suggest that reduced CDKN2B expression and increased smooth muscle cell apoptosis may be one mechanism underlying the 9p21.3 association with aneurysmal disease.
Objective The purpose of this study was to assess the prevalence of endometriosis in women with premenstrual spotting and to determine the predictive value of this symptom in the diagnosis of ...endometriosis. Study Design We conducted a retrospective cohort study of 80 consecutive women who presented to the infertility clinic for evaluation and who subsequently underwent laparoscopic assessment for infertility with or without pelvic pain. Our main outcome measure was the presence or absence of histologically confirmed endometriosis in women with and without premenstrual spotting. Results Endometriosis was significantly more prevalent in subfertile women who reported premenstrual spotting for ≥2 days relative to women without this symptom (89% 34/38 women vs 26% 11/42 women; P < .0001). Multinomial logistic regression analysis demonstrated the presence of premenstrual spotting for ≥2 days to be associated significantly with the presence of endometriosis (odds ratio, 16; 95% confidence interval, 3.9–65.4; P < .01) and red vesicular lesion type (odds ratio, 52.6; 95% confidence interval, 8.6–323.1; P < .001). Conclusion In this cohort of women with infertility, premenstrual spotting of ≥2 days was associated strongly with histologically confirmed endometriosis and a better predictor than dysmenorrhea or dyspareunia of finding endometriosis at laparoscopy. Premenstrual spotting of at least 2 days was also associated strongly with both higher stage disease and the red vesicular peritoneal endometriosis phenotype.
Category:
Trauma; Ankle
Introduction/Purpose:
Ankle fractures are among the most common orthopaedic injuries treated surgically, with indications well- established. However, post-operative care ...protocols remain controversial and vary widely between surgeons. This prospective controlled trial compared functional outcomes of the local institutional standard (control group) of nonweightbearing (NWB) for two weeks in a short leg splint followed by weightbearing as-tolerated (WBAT) in a boot with range of motion (ROM), versus immediate unprotected weightbearing (IMWB).
Methods:
40 consecutive patients undergoing ankle fracture open reduction internal fixation (ORIF) at a single level-1 trauma center meeting inclusion and exclusion criteria were enrolled into the control group, and the next 40 consecutive patients were enrolled in the IMWB group. The study sample size was powered to detect a statistically significant difference in the Olerud- Molander score (OMAS), the primary study outcome. Secondary outcome measures included the Euroquol-5D (EQ5D) self reported patient score and Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) scores, ankle ROM, wound complications, time to return to work, radiograph measurements and loss of fracture reduction. Patients underwent ankle ORIF with surgical technique and implant choice left to the surgeon’s discretion. Postoperative follow-ups were done at 2, 6, and 12 weeks.
Results:
Demographics of the two groups were similar except for the control group having 4 patients with type II diabetes and the IMWB group having none. There was no statistically significant difference in OMAS at any time point. There were also no statistically significant differences in the EQ5D or WPAI:SHP scores, ROM, time to return to work, or radiographic measurements at any time point. The IMWB group had 5 superficial wound complications versus 1 in the control group. There were 2 cases of loss of reduction in the IMWB group versus none in the control group. Both loss of reductions were determined to not be related to the post operative protocol.
Conclusion:
Immediate unprotected weightbearing after ORIF of ankle fractures results in equivocal functional outcomes compared with 2 weeks of NWB followed by protected weightbearing and ROM over the first 3 postoperative months. An increased number of wound healing complications was seen in the IMWB group which requires further investigation.
The HELLP syndrome (haemolysis, elevated liver blood tests and low platelets) is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count ...occurring in 0.5 to 0.9% of all pregnancies and in 10-20% of cases with severe preeclampsia. Hepatic capsular rupture is a rare yet dramatic complication of HELLP syndrome. The majority of cases occur in multiparous women over the age of 30. Classically it presents with acute onset right upper quadrant pain in the presence of constitutional symptoms such as vomiting and pyrexia. However, symptoms and signs are usually non specific. Spontaneous hepatic rupture can be preceded by signs of hypovolaemic shock; yet the diagnosis is infrequently made prior to emergent laparotomy. We present the case of a 35 year old nulliparous woman with a second trimester gestational hepatic rupture associated with HELLP syndrome. We briefly discuss the aetiology, diagnostic difficulties and treatment options associated with this rare presentation.
Background
The current standard of care in locally advanced rectal cancer (LARC) is neoadjuvant long‐course chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). Surgery is ...conventionally performed approximately 6–8 weeks after nCRT. This study aimed to determine the effect on outcomes of extending this interval.
Methods
A systematic search was performed for studies reporting oncological results that compared the classical interval (less than 8 weeks) from the end of nCRT to TME with a minimum 8‐week interval in patients with LARC. The primary endpoint was the rate of pathological complete response (pCR). Secondary endpoints were recurrence‐free survival, local recurrence and distant metastasis rates, R0 resection rates, completeness of TME, margin positivity, sphincter preservation, stoma formation, anastomotic leak and other complications. A meta‐analysis was performed using the Mantel–Haenszel method.
Results
Twenty‐six publications, including four RCTs, with 25 445 patients were identified. A minimum 8‐week interval was associated with increased odds of pCR (odds ratio (OR) 1·41, 95 per cent c.i. 1·30 to 1·52; P < 0·001) and tumour downstaging (OR 1·18, 1·05 to 1·32; P = 0·004). R0 resection rates, TME completeness, lymph node yield, sphincter preservation, stoma formation and complication rates were similar between the two groups. The increased rate of pCR translated to reduced distant metastasis (OR 0·71, 0·54 to 0·93; P = 0·01) and overall recurrence (OR 0·76, 0·58 to 0·98; P = 0·04), but not local recurrence (OR 0·83, 0·49 to 1·42; P = 0·50).
Conclusion
A minimum 8‐week interval from the end of nCRT to TME increases pCR and downstaging rates, and improves recurrence‐free survival without compromising surgical morbidity.
Antecedentes
El tratamiento estándar actual del cáncer de recto localmente avanzado (locally advanced rectal cancer, LARC) consiste en quimiorradioterapia neoadyuvante de ciclo largo (neoadjuvant, long‐course chemoradiation, nCRT) seguida de exéresis total del mesorrecto (total mesorectal excision, TME). De forma convencional, la cirugía se realiza a las 6‐8 semanas después de la nCRT. Este estudio tuvo como objetivo determinar el efecto sobre los resultados de ampliar este intervalo.
Métodos
Se realizó una búsqueda sistemática de los estudios que analizaban los resultados oncológicos, comparando el intervalo clásico (< 8 semanas) desde el final de la nCRT hasta la TME con un intervalo mínimo de 8 semanas, en pacientes con LARC. El criterio de valoración principal fue la tasa de respuesta patológica completa (pathologic complete response, pCR). Los criterios de valoración secundarios fueron las tasas de supervivencia sin recidiva (recurrence‐free survival, RFS), recidiva local (local recurrence, LR) y metástasis a distancia (distant metastasis, DM), tasas de resección R0, integridad (completeness) del mesorrecto, afectación del margen de resección, preservación esfinteriana, formación de estoma, fuga anastomótica y otras complicaciones. Se realizó un metaanálisis utilizando el método de Mantel‐Haenszel.
Resultados
Se identificaron 26 publicaciones, incluidos cuatro ensayos clínicos aleatorizados, con 17.220 pacientes. Un intervalo mínimo de 8 semanas se asoció con un aumento de la razón de oportunidades (odds ratio, OR) de pCR (OR, 1,68, i.c. del 95% 1,37‐2,06, P < 0,001) y de disminución del estadio tumoral (OR 1,18, i.c. del 95% 1,05‐1,32, P = 0,004). Los porcentajes de resección R0, integridad del mesorrecto, ganglios linfáticos identificados, preservación esfinteriana, formación de estoma y complicaciones fueron similares entre los dos grupos. El aumento del porcentaje de pCR se tradujo en una disminución de las DM (OR 0,71, i.c. del 95% 0,54‐0,93, P = 0,01) y de la recidiva global (OR 0,76, i.c. del 95% 0,58‐0,98, P = 0,04), pero no de la LR (OR 0,83, i.c. del 95% 0,49‐1,42, P = 0,50).
Conclusión
Un intervalo mínimo de 8 semanas entre el final de la nCRT y la TME aumenta las tasas de pCR y la reducción del estadio tumoral, así como mejora la RFS sin comprometer la morbilidad quirúrgica.
This meta‐analysis of 26 publications, including four RCTs, of 17 221 patients with rectal cancer found an enhanced rate of pathological complete response with a minimum 8‐week wait interval from the end of neoadjuvant long‐course chemoradiotherapy to total mesorectal excision, with improved recurrence‐free survival and similar morbidity compared with the classical interval of less than 8 weeks.
Longer better
Fibrosis is a common pathological response to inflammation in many peripheral tissues and can prevent tissue regeneration and repair. Here, we identified persistent fibrotic scarring in the CNS ...following immune cell infiltration in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Using lineage tracing and single-cell sequencing in EAE, we determined that the majority of the fibrotic scar is derived from proliferative CNS fibroblasts, not pericytes or infiltrating bone marrow-derived cells. Ablating proliferating fibrotic cells using cell-specific expression of herpes thymidine kinase led to an increase in oligodendrocyte lineage cells within the inflammatory lesions and a reduction in motor disability. We further identified that interferon-gamma pathway genes are enriched in CNS fibrotic cells, and the fibrotic cell-specific deletion of Ifngr1 resulted in reduced fibrotic scarring in EAE. These data delineate a framework for understanding the CNS fibrotic response.
Mass-spectrometry based omics technologies - namely proteomics, metabolomics and lipidomics - have enabled the molecular level systems biology investigation of organisms in unprecedented detail. ...There has been increasing interest for gaining a thorough, functional understanding of the biological consequences associated with cellular heterogeneity in a wide variety of research areas such as developmental biology, precision medicine, cancer research and microbiome science. Recent advances in mass spectrometry (MS) instrumentation and sample handling strategies are quickly making comprehensive omics analyses of single cells feasible, but key breakthroughs are still required to push through remaining bottlenecks. In this review, we discuss the challenges faced by single cell MS-based omics analyses and highlight recent technological advances that collectively can contribute to comprehensive and high throughput omics analyses in single cells. We provide a vision of the potential of integrating pioneering technologies such as Structures for Lossless Ion Manipulations (SLIM) for improved sensitivity and resolution, novel peptide identification tactics and standards free metabolomics approaches for future applications in single cell analysis.
We report 3 patients with coronavirus disease who had a decline in respiratory status during their hospital course that responded well to intravenous steroids and interleukin-6 receptor antagonist ...therapy. These patients later showed development of persistent hypoxia with increased levels of d-dimer levels and were given a diagnosis of pulmonary embolisms.
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