TBX6 null variants and a common hypomorphic allele in congenital scoliosis.

BACKGROUND: Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis. METHODS: We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions. RESULTS: We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis. CONCLUSIONS: Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.).

Preoperative and intraoperative factors predictive of complications and stricture recurrence following multiple urethroplasty techniques.

Objectives: To investigate factors predictive of postoperative recurrence and complications in patients undergoing urethroplasty for stricture repair at a single center. Patients and methods: We retrospectively reviewed the records of 108 men who underwent urethroplasty for urethral stricture disease (USD) at a single center from 2016 to 2020. Demographic data, comorbidities, stricture history including etiology and prior treatments, patient-reported symptoms, and outcomes data were collected for analysis. Data were analyzed in aggregate, then, stratified by type of urethroplasty performed. Descriptive statistics, univariate analysis, multivariate logistic regression, and intergroup comparisons were completed using STATA, with an alpha value of 0.05 and a confidence interval of 95%. Results: The median age of our patients was 58 years (interquartile range: 42-69; range: 29-83), with a median stricture length of 2.0 cm (interquartile range: 1.0-4.5; range: 0.5-10). The most common stricture etiology was iatrogenic (n = 33, 31%) and the most common urethroplasty was anterior anastomotic urethroplasty (n = 38, 35%), followed by buccal mucosal graft (BMG) urethroplasty (n = 35, 32%). Twenty-four patients (22%) had stricture recurrence. Within the aggregate data, recurrence was significantly predicted by obesity (BMI > 30) (Odds Ratio [OR] 3.2, 95% Confidence Interval [CI]: 1.06-10), and the presence of postoperative complications (OR 6.3, CI: 1.9-21). The presence of any postoperative complications within 90 days was significantly predicted by stricture length ≥ 5 cm (OR 3.5, CI 1.09-12) and recurrence (OR 6.0, CI 1.7-21). Conclusion: Despite serving as the most definitive treatment for urethral stricture management, stricture recurrence and postoperative complications are not uncommon after urethroplasty. Obesity and stricture length negatively impact outcomes while a penile stricture location is associated with a lower recurrence rate, though this is not statistically significant.

Adipocyte fatty acid-binding protein as a novel prognostic factor in obese breast cancer patients.

Several adipocytokines, such as leptin or adiponectin, are associated with obesity and the risk for breast cancer. Adiopcyte fatty acid binding-protein(A-FABP) is another protein found in adipose tissue;therefore, we investigated the association of A-FABP with the occurrence and prognosis of breast cancer. In our study,200 women attending the University of Ulm for breast surgery between the years 2005 and 2007 were included;159 had histologically confirmed breast cancer; 41 had histologically confirmed benign lesions. Serum levels ofA-FABP, leptin, and adiponectin were measured, and their relationship to body-mass-index (BMI), breast cancer, and tumor characteristics were analyzed; logistic regression model was adjusted to age, BMI, menopausal status, use of Hormone Replacement Therapy (HRT), and family history of breast cancer. Serum A-FABP levels were found to be significantly higher in obese (BMI C 25) than in non-obese women (BMI B 24.9), 41.16 ng/ml and 24.95 ng/ml,respectively (P\0.0001). Independent of obesity, the serum A-FABP levels were significantly higher in breast cancer patients (34.65 ng/ml) than in healthy controls(24.47 ng/ml), P\0.0001; the odds ratio (1.038, P\0.05,95% confidence interval 1.001-1.72) showed a significant association of A-FABP with breast cancer risk. Serum leptin levels showed a strong correlation with BMI(rs = 0.78) and were significantly higher in breast cancer patients (20.87 ng/ml) than in controls (14.90 ng/ml),P\0.05. In contrast, adiponectin showed no significant association with breast cancer. Concerning tumor characteristics,A-FABP was positively connected with tumor size (T C 2 cm, P\0.05) and nodal-status (P\0.05).Our study reveals that high A-FABP serum levels are associated with obesity, breast cancer risk, and adverse tumor characteristics.

Preoperative anaemia and clinical outcomes in the South African Surgical Outcomes Study.

BACKGROUND: In high-income countries, preoperative anaemia has been associated with poor postoperative outcomes. To date, no large study has investigated this association in South Africa (SA). The demographics of SA surgical patients differ from those of surgical patients in the European and Northern American settings from which the preoperative anaemia data were derived. These associations between preoperative anaemia and postoperative outcomes are therefore not necessarily transferable to SA surgical patients. OBJECTIVES: The primary objective was to determine the association between preoperative anaemia and in-hospital mortality in SA adult non-cardiac, non-obstetric patients. The secondary objectives were to describe the association between preoperative anaemia and (i) critical care admission and (ii) length of hospital stay, and the prevalence of preoperative anaemia in adult SA surgical patients. METHODS: We performed a secondary analysis of the South African Surgical Outcomes Study (SASOS), a large prospective observational study of patients undergoing inpatient non-cardiac, non-obstetric surgery at 50 hospitals across SA over a 1-week period. To determine whether preoperative anaemia is independently associated with mortality or admission to critical care following surgery, we conducted a multivariate logistic regression analysis that included all the independent predictors of mortality and admission to critical care identified in the original SASOS model. RESULTS: The prevalence of preoperative anaemia was 1 727/3 610 (47.8%). Preoperative anaemia was independently associated with in-hospital mortality (odds ratio (OR) 1.657, 95% confidence interval (CI) 1.055 - 2.602; p=0.028) and admission to critical care (OR 1.487, 95% CI 1.081 - 2.046; p=0.015). CONCLUSIONS: Almost 50% of patients undergoing surgery at government-funded hospitals in SA had preoperative anaemia, which was independently associated with postoperative mortality and critical care admission. These numbers indicate a significant perioperative risk, with a clear need for quality improvement programmes that may improve surgical outcomes. Long waiting lists for elective surgery allow time for assessment and correction of anaemia preoperatively. With a high proportion of patients presenting for urgent or emergency surgery, perioperative clinicians in all specialties should educate themselves in the principles of patient blood management.

Normal skeletal development of mice lacking matrilin 1: redundant function of matrilins in cartilage?

Matrilin 1, or cartilage matrix protein, is a member of a novel family of extracellular matrix proteins. To date, four members of the family have been identified, but their biological role is unknown. Matrilin 1 and matrilin 3 are expressed in cartilage, while matrilin 2 and matrilin 4 are present in many tissues. Here we describe the generation and analysis of mice carrying a null mutation in the Crtm gene encoding matrilin 1. Anatomical and histological studies demonstrated normal development of homozygous mutant mice. Northern blot and biochemical analyses show no compensatory up-regulation of matrilin 2 or 3 in the cartilage of knockout mice. Although matrilin 1 interacts with the collagen II and aggrecan networks of cartilage, suggesting that it may play a role in cartilage tissue organization, studies of collagen extractability indicated that collagen fibril maturation and covalent cross-linking were unaffected by the absence of matrilin 1. Ultrastructural analysis did not reveal any abnormalities of matrix organization. These data suggest that matrilin 1 is not critically required for cartilage structure and function and that matrilin 1 and matrilin 3 may have functionally redundant roles.

MRI characteristics of globus pallidus infarcts in isolated methylmalonic acidemia.

BACKGROUND: Bilateral infarcts confined to the globus pallidus are unusual and occur in conjunction with only a few disorders, including isolated methylmalonic acidemia, a heterogeneous inborn error of metabolism. On the basis of neuroradiographic features of metabolic strokes observed in a large cohort of patients with methylmalonic acidemia, we have devised a staging system for methylmalonic acidemia-related globus pallidus infarcts. MATERIALS AND METHODS: Forty patients with isolated methylmalonic acidemia and neurologic symptoms underwent clinical brain MR imaging studies, which included 3D-T1WI. Infarcted globus pallidus segments were neuroanatomically characterized, and infarct volumes were measured. RESULTS: Globus pallidus infarcts were present in 19 patients; all were bilateral, and most were left-dominant. A neuroanatomic scoring system based on the infarct patterns was devised; this revealed a 5-stage hierarchical susceptibility to metabolic infarct, with the posterior portion of the globus pallidus externa being the most vulnerable. Globus pallidus infarct prevalence by methylmalonic acidemia class was the following: cblA (5/7, 71%), cblB (3/7, 43%), mut(o) (10/22, 45%), and mut- (1/4, 25%). Tiny lacunar infarcts in the pars reticulata of the substantia nigra, previously unrecognized in methylmalonic acidemia, were found in 17 patients, 13 of whom also had a globus pallidus infarct. CONCLUSIONS: The staged pattern of globus pallidus infarcts in isolated methylmalonic acidemia suggests a nonuniform, regionally specific cellular susceptibility to metabolic injury, even for patients having milder biochemical phenotypes. In support of this hypothesis, the delineation of lacunar infarcts in the pars reticulata of the substantia nigra, a tissue functionally and histologically identical to the globus pallidus interna, supports the concept of cell-specific pathology.

Risk of port-site metastases in pelvic cancers after robotic surgery.

OBJECTIVE: To assess the risk of occurrence of port-site metastases after robotic surgery for pelvic cancer. METHODS: Retrospective study from June 2007 to March 2013 of patients with gynecologic cancer who underwent robot-assisted surgery. We collected preoperative data, including characteristics of patients and FIGO stage, intraoperative data (surgery performed, number of ports), and postoperative data (occurrence of metastases, occurrence of port-site metastases). RESULTS: 115 patients were included in the study: 61 with endometrial cancer, 50 with cervical cancer and 4 with ovarian cancer. The surgical procedures performed were: hysterectomy with bilateral salpingo-oophorectomy, radical hysterectomy, pelvic lymphadenectomy, para-aortic lymphadenectomy and omentectomy. All surgical procedures required the introduction of 4 ports, 3 for the robot and 1 for the assistant. With a mean follow-up of 504.4 days (507.7 days for endometrial cancer, 479.5 days for cervical cancer, and 511.3 for ovarian cancer), we observed 9 recurrences but no port-site metastasis. CONCLUSION: No port-site metastasis has occurred in our series. However, larger, prospective and randomized works are needed to formally conclude.

Genome-wide analysis of yeast transcription upon calcium shortage.

Several regulatory circuits related to important functions, like membrane excitation, immunoresponse, replication, control of the cell cycle and differentiation, among others, cause an increase in intracellular calcium level that finally has a consequence upon transcription of specific genes. The sequencing of the whole genome of eukaryotic cells enables genome-wide analysis of gene expression under many conditions not yet assessed by conventional methods. Using the array technology, the effect of calcium shortage in yeast cells was studied. Correspondence analysis of data showed that there is a response in transcription that is correlated to calcium shortage. The distribution of up-regulated-genes in functional categories suggests a regulatory connection between the cell-cycle progression and the energetic metabolic requirements for growth and division. In silico analysis of promoters reveals the frequent appearance of the Mlu I cell cycle box (MCB) cis element that binds the transcriptional regulatory factor Mcm1.

Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon.

An abundant matrix protein was purified under native conditions from adult bovine tendon and identified as cartilage oligomeric matrix protein (COMP) by immunochemical crossreaction, amino acid sequence identity of tryptic peptides derived from both N- and C-terminal regions, and structure revealed by electron microscopy. Immunohistochemistry showed age-dependent differences in distribution of COMP in tendon.

Tendon extracellular matrix contains pentameric thrombospondin-4 (TSP-4).

In preparations of cartilage oligomeric matrix protein (COMP) from bovine tendon two contaminating polypeptides of 120 and 135 kDa were detected. N-terminal protein sequencing of these polypeptides showed homology to the N-terminus and to an internal sequence in TSP-4, respectively. TSP-4 was further enriched by heparin affinity chromatography. Electron microscopy of this sample shows primarily five armed particles with globular domains at the periphery connected to a central assembly domain in which smaller N-terminal globular domains can be resolved tightly packed at the center of the particle. We can thereby confirm the pentameric model for TSP-4 proposed by Lawler et al. [(1995) J. Biol. Chem. 270, 2809-2814], on the basis of recombinantly expressed protein. We further show that TSP-4 is abundant in tendon.

Effect of aging on the morphology of epididymal adipose tissue in the rat.

Quantitative morphometrical parameters were compared in epididymal adipose tissue of adult (6 months old) and old (24 months old) Wistar rats, using light and electron microscopy of embedded material and freeze-etch replicas, and taking into account the functional unit of adipose tissue: the capillary-adipocyte. Despite an insignificant reduction of the adipocyte number and size in old rats when the whole population was sampled, the confounding factor of size of adipocytes could be excluded from morphometric computations in adult and old rats. Morphometric measures were performed on the whole transit from capillaries to adipocytes. They revealed that the plasma membranes, as seen in freeze etching, and the thicknesses of endothelial and adipocyte cytoplasms, as seen in ultra-thin sections, remained unaltered with aging. By contrast, the basement membranes were changed but differently around capillaries and adipocytes. The capillary-adipocyte distances were shorter and the vascularization density was higher in old rats.

Increased degradation and altered tissue distribution of cartilage oligomeric matrix protein in human rheumatoid and osteoarthritic cartilage.

We investigated the degradation and tissue distribution of cartilage oligomeric matrix protein in normal, osteoarthritic, and rheumatoid arthritic articular cartilage of the human knee. Cartilage was subjected to sequential extractions with buffers containing neutral salt, with EDTA, and finally with guanidine/HCl and then was analyzed by Western blotting with a polyclonal antiserum to human cartilage oligomeric matrix protein. Western blots of the nine neutral salt extracts from normal cartilage revealed mostly intact pentameric molecules of cartilage oligomeric matrix protein, in contrast to the 13 osteoarthritic and five rheumatoid arthritic cartilage samples that demonstrated marked degradation of cartilage oligomeric matrix protein as noted by a predominance of reduction-sensitive bands at approximately 150 kDa and nonreduction-sensitive bands in the 67-94 kDa range. The EDTA and guanidine/HCl extracts from all groups were similar and showed mostly intact molecules of cartilage oligomeric matrix protein, with smaller amounts of degraded cartilage oligomeric matrix protein identical to those resolved by the Western blots of the neutral salt extracts. Western blots of matched pairs of synovial fluid and cartilage extracts demonstrated cartilage oligomeric matrix protein fragments of the same molecular mass. Competitive enzyme-linked immunosorbent assay revealed significantly less cartilage oligomeric matrix protein in rheumatoid articular cartilage than in either normal or osteoarthritic cartilage. In contrast to normal cartilage, where cartilage oligomeric matrix protein was predominantly localized to the interterritorial matrix throughout all zones of the matrix, with increased staining in the deeper cartilaginous zones, the most intense staining in osteoarthritic cartilage was in the superficial zones of fibrillated cartilage, with little to no immunostaining in the midzones and relatively poor staining in the deeper cartilaginous zones. This distribution was the inverse of that for proteoglycans, as demonstrated by toluidine blue staining, where proteoglycans were depleted primarily from the superficial fibrillated cartilage. In mild to moderately affected rheumatoid cartilage, the tissue distribution of cartilage oligomeric matrix protein was similar to the distribution of proteoglycans, with relatively uniform staining of the interterritorial and territorial matrics. In more severely affected rheumatoid cartilage, the superficial zones demonstrated punctate immunostaining for cartilage oligomeric matrix protein in the interterritorial and territorial matrics, and staining was restricted to the territorial matrix in the deep cartilaginous zones. It is evident from this study that (a) noncollagenous proteins such as cartilage oligomeric matrix protein are greatly affected in arthritis, (b) degradation fragments released from the matrix into the synovial fluid reflect the processes occurring within the matrix, and (c) different zones of the articular cartilage are susceptible to degradation of cartilage oligomeric matrix protein in the different disease processes.

Competency assessment and proficiency testing.

Competency assessment is an ongoing, continuous process of monitoring individuals' abilities to perform their specific job functions. A variety of methods are useful in monitoring cytology competency, including rescreening studies, descriptive monitors (abnormality rates), discrepancy rates, workload patterns, competency-based educational programs and programs using unknown slide challenges. The goal of proficiency testing (PT) is to ascertain and assess the ability of individuals beyond the particular items or challenges presented. However, cytology PT faces many challenges for implementation as it cannot duplicate normal working conditions, and there is often no gold standard to define the truth. PT is just one measure of performance and should be considered in conjunction with other quality assessment monitors. There is no consensus on the value or validity of a large-scale regulatory PT program. Any regulatory PT program should be field tested prior to implementation, and the grading system should be scientifically defensible. Scoring of performance on PT should occur in a timely fashion, and there should be an opportunity for educational feedback. The ultimate aim of both competency assessment and PT is to positively affect laboratory procedures and improve the cervical cancer screening process.

[Polypharmacy is an indicator for a poor prognosis, which is not altered by deprescribing in nursing home]. / Polypharmazie ist ein Indikator für kurze Überlebensdauer im Pflegeheim - Daran ändert das Absetzen von Medikamenten nichts.

AIM: To examine the influence of polypharmacy ordered by the pretreating site and deprescribing (i.e. the appropriate withdrawal of prescribed drugs) by the nursing home physician on survival time. METHODS: Retrospective Analysis of medical databasis from 1,249 patients, thereof 611 in a nursing home with practice of deprescribing. RESULTS: 70% of the patients with excessive polypharmacy (>9 drugs), 57% of those with polypharmacy (6 to 9 drugs) and 43% of the remaining patients (<6 drugs) deceased within 286 days after admission (chi-squared 2 DF = 43.72; p <0.001). Deprescribing by the nursing home physician at admission revealed no influence on survival time. CONCLUSION: Polypharmacy is not the reason, but an indicator for a poor prognosis, which is not altered by deprescribing.

Hyperlipidemia resulting in abnormal density and signal intensity of blood in a neonate with lipoprotein lipase deficiency.

We present the imaging findings in an 8-week-old infant with LPL deficiency. Due to markedly increased lipoproteins in the serum, abnormal hypodensity and abnormal T1-weighted hyperintensity were identified in the dural venous sinuses and medullary veins.

Preoperative anaemia and clinical outcomes in the South African surgical outcomes study

Background.In high-income countries, preoperative anaemia has been associated with poor postoperative outcomes. To date, no large study has investigated this association in South Africa (SA). The demographics of SA surgical patients differ from those of surgical patients in the European and Northern American settings from which the preoperative anaemia data were derived. These associations between preoperative anaemia and postoperative outcomes are therefore not necessarily transferable to SA surgical patients.Objectives. The primary objective was to determine the association between preoperative anaemia and in-hospital mortality in SA adult non-cardiac, non-obstetric patients. The secondary objectives were to describe the association between preoperative anaemia and (i) critical care admission and (ii) length of hospital stay, and the prevalence of preoperative anaemia in adult SA surgical patients.Methods. We performed a secondary analysis of the South African Surgical Outcomes Study (SASOS), a large prospective observational study of patients undergoing inpatient non-cardiac, non-obstetric surgery at 50 hospitals across SA over a 1-week period. To determine whether preoperative anaemia is independently associated with mortality or admission to critical care following surgery, we conducted a multivariate logistic regression analysis that included all the independent predictors of mortality and admission to critical care identified in the original SASOS model.Results. The prevalence of preoperative anaemia was 1 727/3 610 (47.8%). Preoperative anaemia was independently associated with in-hospital mortality (odds ratio (OR) 1.657, 95% confidence interval (CI) 1.055 - 2.602; p=0.028) and admission to critical care (OR 1.487, 95% CI 1.081 - 2.046; p=0.015).Conclusions. Almost 50% of patients undergoing surgery at government-funded hospitals in SA had preoperative anaemia, which was independently associated with postoperative mortality and critical care admission. These numbers indicate a significant perioperative risk, with a clear need for quality improvement programmes that may improve surgical outcomes. Long waiting lists for elective surgery allow time for assessment and correction of anaemia preoperatively. With a high proportion of patients presenting for urgent or emergency surgery, perioperative clinicians in all specialties should educate themselves in the principles of patient blood management