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Summary: Symptoms of depression are common among patients before surgery. Depression may be associated with worse postoperative pain and other pain‐related outcomes. This review aimed to characterise the impact of pre‐operative depression on postoperative pain outcomes. We conducted a systematic review of observational studies that reported an association between pre‐operative depression and pain outcomes after major surgery. Multilevel random effects meta‐analyses were conducted to pool standardised mean differences and 95%CI for postoperative pain scores in patients with depression compared with those without depression, at different time intervals. A meta‐analysis was performed for studies reporting change in pain scores from the pre‐operative period to any time‐point after surgery. Sixty studies (n = 501,962) were included in the overall review, of which 18 were eligible for meta‐analysis. Pre‐operative depression was associated with greater pain scores at < 72 h (standardised mean difference 0.97 (95%CI 0.37–1.56), p = 0.009, I2 = 41%; moderate certainty) and > 6 months (standardised mean difference 0.45 (95%CI 0.23–0.68), p < 0.001, I2 = 78%; low certainty) after surgery, but not at 3–6 months after surgery (standardised mean difference 0.54 (95%CI ‐0.06–1.15), p = 0.07, I2 = 83%; very low certainty). The change in pain scores from pre‐operative baseline to 1–2 years after surgery was similar between patients with and without pre‐operative depression (standardised mean difference 0.13 (95%CI ‐0.06–0.32), p = 0.15, I2 = 54%; very low certainty). Overall, pre‐existing depression before surgery was associated with worse pain severity postoperatively. Our findings highlight the importance of incorporating psychological care into current postoperative pain management approaches in patients with depression. [ABSTRACT FROM AUTHOR]

Background: Monosomy 1p36 is the most common terminal deletion syndrome with an autosomal dominant pattern of inheritance. This syndrome is defined by an extremely wide spectrum of characteristics; however, developmental delay and intellectual disability of various degree are present in all patients and about the 90% of patients have a severe intellectual disability. Dental agenesis or other dental anomalies have not been described in previous reports.Case Presentation: We report the case of two little sisters born from healthy and non-consanguineous parents, presenting with dental anomalies and one of them with epilepsy, dilated cardiomyopathy with left-ventricular non-compaction, strabismus, history of poor growth, hypotonia and mild language delay. Patients were evaluated in several departments (genetic, child neuropsychiatric, cardiology, odontostomatology, ophthalmology, otorhinolaryngology) of Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy. They underwent investigations such as electrocardiogram, echocardiogram, dental orthopantomography X-Ray and Computed Tomography, electroencephalograms, abdomen ultrasound, blood tests, IQ tests, genetic analysis. They both have an Intelligence Quotient greater than 70 and a negative neurologic exam. Each sister carries the same 1p36 deletion of about 2.3 Mb. Genetic analysis of the parents' blood samples (Single Nucleotide Polymorphism- array, karyotype and Fluorescent In Situ Hybridization) did not reveal any deletion, translocation or inversion and confirmed the paternity. A third sib of the probands does not carry the 1p36 deletion or other quantitative alterations.Conclusion: This report describes a new trait linked to monosomy 1p36, namely a mild intellectual outcome associated with significant dental anomalies. Our finding suggests that 1p36 deletion syndrome may present with a mild cognitive impairment or even with a normal intellectual development: this is very important for the genetic counselling, especially in a prenatal setting. Moreover, we report the third study with recurrent 1p36 deletion syndrome in two siblings, likely due to germline mosaicism. Finally, we believe that the dental anomalies should be investigated in 1p36 deletion syndrome and that the spectrum of the condition could be broader than we assume. [ABSTRACT FROM AUTHOR]

Background: Delirium is a common and potentially serious complication after major surgery. A previous history of depression is a known risk factor for experiencing delirium in patients admitted to the hospital, but the generalised risk has not been estimated in surgical patients., Methods: We conducted a systematic review and meta-analysis of studies reporting the incidence or relative risk (or relative odds) of delirium in the immediate postoperative period for adults with pre-operative depression. We included studies that defined depression as either a formal pre-existing diagnosis or having clinically important depressive symptoms measured using a patient-reported instrument before surgery. Multilevel random effects meta-analyses were used to estimate the pooled incidences and pooled relative risks. We also conducted subgroup analyses by various study-level characteristics to identify important moderators of pooled estimates., Results: Forty-two studies (n = 4,664,051) from five continents were included. The pooled incidence of postoperative delirium for patients with pre-operative depression was 29% (95%CI 17-43%, I 2  = 99.0%), compared with 15% (95%CI 6-28%, I 2  = 99.8%) in patients without pre-operative depression and 21% (95% CI 11-33%, I 2  = 99.8%) in the cohorts overall. For patients with pre-operative depression, the risk of delirium was 1.91 times greater (95%CI 1.68-2.17, I 2  = 42.0%) compared with patients without pre-operative depression., Conclusions: Patients with a previous diagnosis of depression or clinically important depressive symptoms before surgery have substantially greater risk of experiencing delirium after surgery. Clinicians and patients should be informed of these increased risks. Robust screening and other risk mitigation strategies for postoperative delirium are warranted, especially for patients with pre-operative depression., (© 2024 The Author(s). Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Background: The suitability of ambulatory surgery for patients with obstructive sleep apnea (OSA) remains controversial. This systematic review and meta-analysis aimed to evaluate the odds of perioperative adverse events in patients with OSA undergoing ambulatory surgery, compared to patients without OSA., Methods: Four electronic databases were searched for studies published between January 1, 2011 and July 11, 2023. The inclusion criteria were: adult patients with diagnosed or high-risk of OSA undergoing ambulatory surgery; perioperative adverse events; control group included; general and/or regional anesthesia; and publication on/after February 1, 2011. We calculated effect sizes as odds ratios using a random effects model, and additional sensitivity analyses were conducted., Results: Seventeen studies (375,389 patients) were included. OSA was associated with an increased odds of same-day admission amongst all surgery types (OR 1.94, 95% CI 1.46-2.59, I 2 :79%, P < 0.00001, 11 studies, n = 347,342), as well as when only orthopedic surgery was considered (OR 2.68, 95% CI 2.05-3.48, I 2 :41%, P < 0.00001, 6 studies, n = 132,473). Three studies reported that OSA was strongly associated with prolonged post anesthesia care unit (PACU) length of stay (LOS), while one study reported that the association was not statistically significant. In addition, four studies reported that OSA was associated with postoperative respiratory depression/hypoxia, with one large study on shoulder arthroscopy reporting an almost 5-fold increased odds of pulmonary compromise, 5-fold of myocardial infarction, 3-fold of acute renal failure, and 5-fold of intensive care unit (ICU) admission., Conclusions: Ambulatory surgical patients with OSA had almost two-fold higher odds of same-day admission compared to non-OSA patients. Multiple large studies also reported an association of OSA with prolonged PACU LOS, respiratory complications, and/or ICU admission. Clinicians should screen preoperatively for OSA, optimize comorbidities, adhere to clinical algorithm-based management perioperatively, and maintain a high degree of vigilance in the postoperative period., Competing Interests: Declaration of competing interest This research did not receive any grants or funding., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Preoperative depression is prevalent among patients undergoing metabolic and bariatric surgery (MBS) and is a potentially modifiable risk factor. However, the impact of preoperative depression on MBS outcomes has not been systematically reviewed. A search of MEDLINE, Embase, Cochrane, and PsychINFO (inception to June 2023) was conducted for studies reporting associations between preoperative depression and any clinical or patient-reported outcomes after MBS. Eighteen studies (5 prospective and 13 retrospective) reporting on 5933 participants were included. Most participants underwent gastric bypass or sleeve gastrectomy. Meta-analyses were not conducted due to heterogeneity in reported outcomes; findings were instead synthesized using a narrative and tabular approach. Across 13 studies (n = 3390) the associations between preoperative depression and weight loss outcomes at 6-72 months were mixed overall. This may be related to differences in cohort characteristics, outcome definitions, and instruments used to measure depression. A small number of studies reported that preoperative depression was associated with lower quality of life, worse acute pain, and more perioperative complications after surgery. Most of the included studies were deemed to be at high risk of bias, resulting in low or very low certainty of evidence according to the Risk of Bias In Non-randomized Studies - of Exposure (ROBINS-E) tool. While the impact of preoperative depression on weight loss after MBS remains unclear, there is early evidence that depression has negative consequences on other patient-important outcomes. Adequately powered studies using more sophisticated statistical methods are needed to accurately estimate these associations., (© 2024 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Objective: The objective of this scoping review is to map the evidence on clinical tools to assess functional capacity prior to elective non-cardiac surgery., Introduction: Functional capacity is a strong prognostic indicator before surgery, which can be used to identify patients at elevated risk of postoperative complications, yet, there is no consensus on which clinical tools should be used to assess functional capacity in patients prior to non-cardiac surgery., Inclusion Criteria: This review will consider any randomized or non-randomized studies that evaluate the performance of a functional capacity assessment tool in adults (≥18 years) prior to non-cardiac surgery. For studies to be included, the tool must be used clinically for risk stratification. We will exclude studies on lung and liver transplant surgery, as well as ambulatory procedures performed under local anesthesia., Methods: The review will be conducted in line with the JBI methodology for scoping reviews. A peer-reviewed search strategy will be used to query relevant databases (ie, MEDLINE, Embase, EBM Reviews). Additional sources of evidence will include databases of non-peer-reviewed literature and the reference lists of included studies. Two independent reviewers will identify eligible studies in 2 stages: stage 1, based on titles and abstracts; and stage 2, based on full texts. Information on study details, measurement properties, pragmatic qualities, and/or clinical utility metrics will be charted in duplicate onto standardized data collection forms. The results will be presented using descriptive summaries, frequency tables, and visual plots that highlight the extent of evidence and remaining gaps in the validation process of each tool., Review Registration: Open Science Framework https://osf.io/6nfht., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 JBI.)

Determining the prevalence and risk factors related to sleep disturbance in surgical patients would be beneficial for risk stratification and perioperative care planning. The objectives of this systematic review and meta-analysis are to determine the prevalence and risk factors of sleep disturbances and their associated postoperative complications in surgical patients. The inclusion criteria were: (1) patients ≥18 years old undergoing a surgical procedure, (2) in-patient population, and (3) report of sleep disturbances using a validated sleep assessment tool. The systematic search resulted in 21,951 articles. Twelve patient cohorts involving 1497 patients were included. The pooled prevalence of sleep disturbances at preoperative assessment was 60% (95% Confidence Interval (CI): 50%, 69%) and the risk factors for postoperative sleep disturbances were a high preoperative Pittsburgh sleep quality index (PSQI) score indicating preexisting disturbed sleep and anxiety. Notably, patients with postoperative delirium had a higher prevalence of pre- and postoperative sleep disturbances and high preoperative wake after sleep onset percentage (WASO%). The high prevalence of preoperative sleep disturbances in surgical patients has a negative impact on postoperative outcomes and well-being. Further work in this area is warranted., Competing Interests: Declaration of competing interest FC reports research support from the University Health NetworkFoundation, ResMed Foundation, consultant to Takeda Pharma, and Up-to-Date royalties, STOP-Bang proprietary to University Health Network. Outside of the submitted work, Dr. M.I. Boulos reports in-kind support for his research program from Braebon Medical Corporation and Interaxon. Dr. M.I. Boulos also reports financial support for his research program from the Mahaffy Family Research Fund, and grant funding from the Canadian Institutes of Health Research, the Division of Neurology at the University of Toronto, the Sunnybrook Education Advisory Council and Education Research Unit, and the Alternative Funding Plan from the Academic Health Sciences Centres of Ontario. Dr. M.I. Boulos has also received consultancy and speaker fees from Jazz Pharmaceuticals, Paladin Labs, and Eisai. All other authors have no conflicts to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To assess the efficacy and safety of N-acetylcysteine in the treatment of chronic pain., Methods: A systematic search was carried out until April 2020 for clinical studies of N-acetylcysteine in the management of any persistent or recurrent chronic pain condition for adults ≥ 18 years old. Risk of bias was assessed using the validated risk of bias tools. When appropriate, a meta-analysis using a random-effects model was performed, with a fixed-effect model for sensitivity analysis., Results: Nine studies (n = 863) were included (five randomized controlled trials [RCTs], two open-label non-comparative studies and two comparative studies), that evaluated patients with sickle cell disease (3), complex regional pain syndrome (1), pelvic pain/endometriosis (2), rheumatoid arthritis (1), diabetic neuropathy (1), and chronic neuropathic pain (1). In the pooled analysis of three RCTs, N-acetylcysteine did not reduce pain intensities (SMD -0.21, 95% confidence interval [CI]: -0.33 to 0.75, random-effects), improve functional outcomes (SMD 0.21, 95% CI -0.33 to 0.75) or quality of life (SMD 0.60, 95% CI: -4.44 to 5.64); however, sensitivity analysis with a fixed effect model demonstrated an effect for pain intensities and function. Due to adverse events being inconsistently reported, no conclusion could be made regarding safety of N-acetylcysteine in chronic pain., Conclusions: While there is some evidence to indicate N-acetylcysteine may provide analgesic efficacy for certain pain conditions, there is insufficient evidence to provide definitive evidence on NAC in chronic pain management. Larger-size RCTs spanning a variety of chronic pain conditions are needed to determine N-acetylcysteine's role, if any, in pain medicine., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Obstructive sleep apnea (OSA) is a critical occupational health concern, but is often undiagnosed in the general population and commercial drivers. The STOP-Bang questionnaire is a simple, reliable tool to screen for OSA, which could improve public health in a cost-effective manner. The objective of this systematic review and meta-analysis is to assess the validity of the STOP-Bang questionnaire to detect OSA in these key populations., Methods: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO, Journals @ Ovid, Web of Science, Scopus, and CINAHL for relevant articles from 2008 to March 2020. The quality of studies was appraised using Cochrane Methods criteria. To calculate pooled predictive parameters, we created 2 × 2 contingency tables and performed random-effects meta-analyses., Results: Of 3871 citations, five studies that evaluated STOP-Bang in the general population (n = 8585) and two in commercial drivers (n = 185) were included. In the general population, prevalence of all OSA (AHI ≥ 5), moderate-to-severe OSA (AHI ≥ 15), and severe OSA (AHI ≥ 30) was 57.6%, 21.3%, and 7.8% respectively. In commercial drivers, the prevalence of moderate-to-severe OSA was 37.3%. The trends of high sensitivity and negative predictive value of a STOP-Bang score ≥ 3 illustrates that the questionnaire helps detect and rule out clinically significant OSA in the general population and commercial drivers., Conclusion: This meta-analysis demonstrates that the STOP-Bang questionnaire is a valid and effective screening tool for OSA in the general population and commercial drivers., Trial Registration: PROSPERO No. CRD42020200379; 08/22/2020., (© 2021. The Author(s).)

Importance: Obstructive sleep apnea (OSA) is a highly prevalent global health concern and is associated with many adverse outcomes for patients., Objective: To evaluate the utility of the STOP-Bang (snoring, tiredness, observed apnea, blood pressure, body mass index, age, neck size, gender) questionnaire in the sleep clinic setting to screen for and stratify the risk of OSA among populations from different geographical regions., Data Sources and Study Selection: MEDLINE, MEDLINE In-process, Embase, EmCare Nursing, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO, Journals@Ovid, Web of Science, Scopus, and CINAHL electronic databases were systematically searched from January 2008 to March 2020. This was done to identify studies that used the STOP-Bang questionnaire and polysomnography testing in adults referred to sleep clinics., Data Extraction and Synthesis: Clinical and demographic data were extracted from each article independently by 2 reviewers. The combined test characteristics were calculated using 2 × 2 contingency tables. Random-effects meta-analyses and metaregression with sensitivity analyses were performed. The Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guideline was followed., Main Outcomes and Measures: The combined test characteristics and area under summary receiver operating characteristic curves (AUCs) were used to compare STOP-Bang questionnaire accuracy with polysomnography testing., Results: A total of 47 studies with 26 547 participants (mean [SD] age, 50 [5] years; mean [SD] body mass index, 32 [3]; 16 780 [65%] men) met the criteria for the systematic review. Studies were organized in different geographic regional groups: North America, South America, Europe, Middle East, East Asia, and South or Southeast Asia. The prevalence rates for all OSA, moderate to severe OSA, and severe OSA were 80% (95% CI, 80%-81%), 58% (95% CI, 58%-59%), and 39% (95% CI, 38%-39%), respectively. A STOP-Bang score of at least 3 had excellent sensitivity (>90%) and high discriminative power to exclude moderate to severe and severe OSA, with negative predictive values of 77% (95% CI, 75%-78%) and 91% (95% CI, 90%-92%), respectively. The diagnostic accuracy of a STOP-Bang score of at least 3 to detect moderate to severe OSA was high (>0.80) in all regions except East Asia (0.52; 95% CI, 0.48-0.56)., Conclusions and Relevance: The results of this meta-analysis suggest that the STOP-Bang questionnaire can be used as a screening tool to assist in triaging patients with suspected OSA referred to sleep clinics in different global regions.

Background: Financial conflicts of interest (FCOIs) are widespread in inflammatory bowel disease (IBD) and may be particularly important in point-of-care (POC) resources, such as UpToDate, that are used to aid clinical decision making. In this study, we determined the prevalence of industry payments from companies making biologic medications for IBD to contributors of UpToDate articles on IBD., Methods: This cross-sectional analysis included UpToDate articles that mention the use of biologic medications for IBD. We collected the names of the contributors (authors and editors) and their disclosures on UpToDate. We then searched for their names on the Center for Medicare and Medicaid Open Payments database and compared the payment information from 2013 to 2018 with UpToDate's disclosures. We presented data per episode , which describes one instance of participation by one person in one article, regardless of whether that person contributed to multiple articles., Results: We identified 23 articles on the treatment of Crohn's disease and ulcerative colitis that mentioned the use of biologic medications, with 86 total episodes. Sixty-two (72%) episodes involved FCOIs. The median payment associated with each episode was $$55 (interquartile range = $44 to $145,241). Contributors did not fully disclose FCOIs in 41 (48%) episodes. Deputy editors, who are required to be free of FCOIs, in general did not have substantial episodes involving FCOI., Conclusions: We found that UpToDate articles on inflammatory bowel disease involve substantial FCOI, many of which are not disclosed. The presence of these FCOIs may hamper trust in the objectivity of treatment recommendations., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Microduplications involving 1q32.1 chromosomal region have been rarely reported in literature. Patients with these microduplications suffer from intellectual disability, developmental delay and a number of dysmorphic features, although no clear karyotype/phenotype correlation has yet been determined. In this case report we describe two monochorionic-diamniotic twins with intellectual disability, abnormality of coordination and dysmorphic features associated with a de novo 280 kb mosaic microduplication of 1q32.1 chromosomal region, identified using a Chromosome Microarray Analysis (CMA) and confirmed by quantitative PCR analysis. The duplicated region encompassed entirely three OMIM genes KDM5B (*605393), KLHL12 (*614522), RABIF (*603417) and involved partially SYT2 (*600104). This unique case report allows to redefine the critical 1q32.1 microduplicated region implicated in the ethiopathogenesis of intellectual disability and developmental delay. Furthermore, it suggests that KDM5B gene can have a pivotal role in the development of neurodevelopmental disorders through its demethylase activity., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objective: FMF is an inherited autoinflammatory syndrome, characterized by attacks of painful periodic fever caused by diffuse serositis and risk of secondary amyloidosis due to IL-1β-mediated inflammation. The disease appears to be transmitted through autosomal recessive mutations in the MEFV gene encoding the pyrin protein Although more than 300 variants have been reported worldwide so far, their association with symptom severity, the relative frequencies in different populations and the disease penetrance are far from being completely understood. We investigated genotype-phenotype correlations in two large nuclear families and verified whether commonly used web-based tools can usefully predict variant pathogenicity in FMF., Methods: Peripheral blood samples were obtained from 15 patients of two families who had been diagnosed with FMF according to international criteria. The entire MEFV coding region was sequenced in all subjects, and 179 MEFV variants were surveyed with five different pathogenicity predictors., Results: The inheritance of FMF could not be explained by traditional autosomal recessivity in both families. In silico tools demonstrated a significant association of variants' pathogenicity with their position along the coding sequence but not with variants' frequency., Conclusion: By describing two large families with paradigmatic complexity of FMF genetics, we conclude that established concepts in assessing the causative role of variants identified in mutation screening cannot be easily translated into appropriate genetic counselling in FMF. Furthermore, we demonstrate that variants frequently associated with severe disease are not predicted to significantly impact protein function using in silico algorithms., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The stromal vascular fraction (SVF) derived from adipose tissue contains adipose-derived stromal/stem cells (ASC) and can be used for regenerative applications. Thus, a validated protocol for SVF isolation, freezing, and thawing is required to manage product administration. To comply with Good Manufacturing Practice (GMP), fetal bovine serum (FBS), used to expand ASC in vitro, could be replaced by growth factors from platelet concentrates., Methods: Throughout each protocol, GMP-compliant reagents and devices were used. SVF cells were isolated from lipoaspirates by a standardized enzymatic protocol. Cells were cryopreserved in solutions containing different albumin or serum and dimethylsulfoxide (DMSO) concentrations. Before and after cryopreservation, we analyzed: cell viability (by Trypan blue); immunophenotype (by flow cytometry); colony-forming unit-fibroblast (CFU-F) formation; and differentiation potential. ASC, seeded at different densities, were expanded in presence of 10% FBS or 5% supernatant rich in growth factors (SRGF) from platelets. The differentiation potential and cell transformation grade were tested in expanded ASC., Results: We demonstrated that SVF can be obtained with a consistent yield (about 185 × 10 3 cells/ml lipoaspirate) and viability (about 82%). Lipoaspirate manipulation after overnight storage at +4 °C reduced cell viability (-11.6%). The relative abundance of ASC (CD34 + CD45 - CD31 - ) and endothelial precursors (CD34 + CD45 - CD31 + ) in the SVF product was about 59% and 42%, respectively. A period of 2 months cryostorage in autologous serum with added DMSO minimally affected post-thaw SVF cell viability as well as clonogenic and differentiation potentials. Viability was negatively affected when SVF was frozen at a cell concentration below 1.3 × 10 6 cells/ml. Cell viability was not significantly affected after a freezing period of 1 year. Independent of seeding density, ASC cultured in 5% SRGF exhibited higher growth rates when compared with 10% FBS. ASC expanded in both media showed unaltered identity (by flow cytometry) and were exempt from genetic lesions. Both 5% SRGF- and 10% FBS-expanded ASC efficiently differentiated to adipocytes, osteocytes, and chondrocytes., Conclusions: This paper reports a GMP-compliant approach for freezing SVF cells isolated from adipose tissue by a standardized protocol. Moreover, an ASC expansion method in controlled culture conditions and without involvement of animal-derived additives was reported.

The co-occurrence of gonadal agenesis alongside hypoplastic derivatives of the paramesonephric ducts has rarely been observed., Patient(s): 16-year-old dizygotic twin sisters were referred to our department because of primary amenorrhea. X-ray, bone densitometry, ultrasonography, pelvic MRI and measurement of pituitary, ovary, and thyroid hormones were performed. Both twins showed hypergonadotropic hypogonadism, bilateral gonadal agenesis, fallopian tube, uterus, and vaginal hypoplasia but normal kidney and urinary tract structures and skeletal system. Analysis of Q-banded chromosomes in peripheral blood for the search for centromeric X-chromosome DNA and SRY gene was normal as well as the molecular analysis of FMR1, GDF9, and BMP15 genes. Estradiol gel was administered for one year followed by estroprogestin treatment. Both twins growth increased; breast development was stimulated and first menses occurred. Deregulation in the expression of the various HOX genes along the axis of the developing reproductive tract in a determinate time of development may be one of the mechanisms involved in the origin of this complex and rare association.

Context: Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare imprinting disorder characterized by end-organ resistance to PTH and, frequently, to thyroid-stimulating hormone. PHP-Ib familial form, with an autosomal dominant pattern of transmission (autosomal dominant pseudohypoparathyroidism type Ib [AD-PHP-Ib]), is typically characterized by an isolated loss of methylation at the guanine nucleotide-binding protein α-stimulating activity polypeptide 1 A/B differentially methylated region (DMR), secondary to genetic deletions disrupting the upstream imprinting control region in the syntaxin-16 (STX16) locus. However, deletions described up to now failed to account some cases of patients with a methylation defect limited to the A/B DMR; thus, it is expected the existence of other still unknown rearrangements, undetectable with conventional molecular diagnostic methods., Objective: We investigated a PHP-Ib patient with a methylation defect limited to the A/B DMR and no known STX16 deletions to find the underlying primary genetic defect., Patient and Methods: A PHP-Ib patient (hypocalcaemia, hyperphosphataemia, raised serum PTH levels, no vitamin D deficiency) and his unaffected relatives were investigated by methylation specific-multiplex ligand-dependent probe amplification to search for novel pathogenetic defects affecting the guanine nucleotide-binding protein α-stimulating activity polypeptide 1 and STX16 loci., Results: We report the clinical, biochemical, and molecular analysis of an AD-PHP-Ib patient with a novel STX16 deletion overlapping with previously identified STX16 deletions but that, unlike these genetic defects associated with AD-PHP-Ib, goes unnoticed with commonly used first-level diagnostic techniques., Conclusions: Our work highlights the importance of performing accurate investigations in PHP-Ib patients with methylation defects to allow precise genetic counseling because, in case of deletions, the segregation ratio is about 50% and the disease phenotype is transmitted in an autosomal dominant fashion via the mother.

Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53(MUT) ) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53(MUT) by DNA-PKCS , eventually modulating p53(MUT) stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53(MUT) -dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS , p53(MUT) overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells., (Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)

Objective: To explain the lack of genotype-phenotype correlation observed in a patient double heterozygous for the 852del22 and F508del mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene., Design: Case report., Setting: Medical laboratory department., Patient(s): A 42-year-old asymptomatic patient underwent genetic screening for in vitro fertilization (IVF)., Intervention(s): CFTR genetic screening (commercial kit aimed at detecting 57 mutations), segregation analysis, evaluation of the polymerase chain reaction (PCR) products using a denaturing high performance liquid chromatography (DHPLC), and sequence analysis., Main Outcome Measure(s): To avoid diagnostic errors and improve genetic counseling., Result(s): Segregation analysis allowed us to establish that the mutations were in trans. Analysis of the PCR products using a DHPLC apparatus showed a heteroduplex formation indicative of a heterozygous variant in exon 6A. Direct sequencing characterized the heterozygous variant as an A to T transversion at nucleotide position 875+11. Therefore, the change of one single nucleotide in a portion surrounding the 852del22 mutation facilitated the aspecific interaction between the commercial oligonucleotide probe and the amplified genomic DNA, which explains the 852del22 mutation false molecular positivity that was detected by the line probe assay., Conclusion(s): The individualization of 852del22 mutation by a standard genetic panel should be confirmed by more extensive analyses., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Genetic mosaicism is the presence of genetically different cell populations within an individual and can be associated with a milder disease phenotype. We describe a somatic mosaicism in a Lynch syndrome patient with a MLH1 gene mutation (c.1050delA). Since she was the sister of a heterozygous proposita, the mosaicism appeared to be caused by reversion of an inherited mutation and not a de novo mutation. In order to better understand her cancer risk, we tested different tissues to quantify the amount of mutated allele in several districts. The mosaicism was analyzed using DNA sequencing, primer extension, and dHPLC. The MLH1 mutation was present in somatic cells representative of the three embryonic layers and its percentage was > or =80% in both blood and tissues. Since this patient had a relevant quota of mutated cells, a significantly milder phenotype is not expected., ((c) 2009 Wiley-Liss, Inc.)

Analysis of the immunoglobulin receptor (IGR) variable heavy- and light-chain sequences on 17 hepatitis C virus (HCV)-associated non-Hodgkin lymphomas (NHLs) (9 patients also had type II mixed cryoglobulinemia [MC] syndrome and 8 had NHL unrelated to MC) and analysis of intraclonal diversity on 8 of them suggest that such malignant lymphoproliferations derive from an antigen-driven pathologic process, with a selective pressure for the maintenance of a functional IgR and a negative pressure for additional amino acid mutations in the framework regions (FRs). For almost all NHLs, both heavy- and light-chain complementarity-determining regions (CDR3) showed the highest similarity to antibodies with rheumatoid factor (RF) activity that have been found in the MC syndrome, thus suggesting that a common antigenic stimulus is involved in MC syndrome and in HCV-associated lymphomagenesis. Moreover, because HCV is the recognized pathologic agent of MC and the CDR3 amino acid sequences of some HCV-associated NHLs also present a high homology for antibody specific for the E2 protein of HCV, it may be reasonable to speculate that HCV E2 protein is one of the chronic antigenic stimuli involved in the lymphomagenetic process. Finally, the use of specific segments, in particular the D segment, in assembling the IgH chain of IgR seems to confer B-cell disorders with the property to produce antibody with RF activity, which may contribute to the manifestation of an overt MC syndrome.