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Purpose: In some Huntington disease (HD) patients, the "loss of interruption" (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI's effect on AOO., Methods: We developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO., Results: Mean onset for LOI carriers (n = 49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36-39 CAGs)., Conclusion: The LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36-39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range.

Purpose: We aimed to determine the origin and genetic characteristics of Huntington disease (HD) in the Middle East., Methods: We performed genetic and genealogical analyses to establish the ancestral origin of the HTT pathgenic variant from a large kindred from Oman (hereafter called the OM-HD-01 pedigree) by single-nucleotide polymorphism and dense haplotype analysis genotyping., Results: We traced the oldest ancestry of the largest, eight-generation, OM-HD-01 pedigree (n = 302 subjects, with 54 showing manifest HD) back to sub-Saharan Africa and identified a unique HD haplotype carried by all pedigree members, which consisted of portions of the C6 and C9 haplotypes and was carried by all affected members. Such a unique HD haplotype was of African origin and appeared to be associated with large CAG repeat expansions on average and high frequency of juvenile-onset HD. Three other families from the same area were also identified and found carrying a Caucasian HD haplotype A, also shared by most families of Arab ancestry., Conclusion: Mutated HTT spread into Middle East with a unique haplotype of African origin, appeared to be associated with juvenile-onset, a HD condition frequently occurring in Black Africans, and may have a significant impact on further development of novel targeted genetic therapies.

Major surgery is associated with a systemic inflammatory cascade that is thought, in some cases, to contribute to transient and/or sustained cognitive decline, possibly through neuroinflammatory mechanisms. However, the relationship between surgery, peripheral and central nervous system inflammation, and post-operative cognitive outcomes remains unclear in humans, primarily owing to limitations of in vivo biomarkers of neuroinflammation which vary in sensitivity, specificity, validity, and reliability. In the present study, [ 11 C]PBR28 positron emission tomography, cerebrospinal fluid (CSF), and blood plasma biomarkers of inflammation were assessed pre-operatively and 1-month post-operatively in a cohort of patients (N = 36; 30 females; ≥70 years old) undergoing major orthopedic surgery under spinal anesthesia. Delirium incidence and severity were evaluated daily during hospitalization. Whole-brain voxel-wise and regions-of-interest analyses were performed to determine the magnitude and spatial extent of changes in [ 11 C]PBR28 uptake following surgery. Results demonstrated that, compared with pre-operative baseline, [ 11 C]PBR28 binding in the brain was globally downregulated at 1 month following major orthopedic surgery, possibly suggesting downregulation of the immune system of the brain. No significant relationship was identified between post-operative delirium and [ 11 C]PBR28 binding, possibly due to a small number (n = 6) of delirium cases in the sample. Additionally, no significant relationships were identified between [ 11 C]PBR28 binding and CSF/plasma biomarkers of inflammation. Collectively, these results contribute to the literature by demonstrating in a sizeable sample the effect of major surgery on neuroimmune activation and preliminary evidence identifying no apparent associations between [ 11 C]PBR28 binding and fluid inflammatory markers or post-operative delirium., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

As their illness progresses, patients with the semantic variant of Primary Progressive Aphasia (svPPA) frequently exhibit peculiar behaviors indicative of altered visual attention or an increased interest in artistic endeavors. In the present study, we examined changes within and between large-scale functional brain networks that may explain this altered visual behavior. We first examined the connectivity of the visual association network, the dorsal attention network, and the default mode network in healthy young adults (n = 89) to understand the typical architecture of these networks in the healthy brain. We then compared the large-scale functional connectivity of these networks in a group of svPPA patients (n = 12) to a group of age-matched cognitively normal controls (n = 30). Our results showed that the between-network connectivity of the dorsal attention and visual association networks was elevated in svPPA patients relative to controls. We further showed that this heightened between-network connectivity was associated with a decrease in the within-network connectivity of the default mode network, possibly due to progressive degeneration of the anterior temporal lobes in svPPA. These results suggest that focal neurodegeneration can lead to the reorganization of large-scale cognitive networks beyond the primarily affected network(s), possibly contributing to cognitive or behavioral changes that are commonly present as part of the clinical phenotype of svPPA., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Heterogeneity within the Alzheimer's disease (AD) syndromic spectrum is typically classified in a domain-specific manner (e.g., language vs. visual cognitive function). The central aim of this study was to investigate whether impairment in visual cognitive tasks thought to be subserved by posterior cortical dysfunction in non-amnestic AD presentations is associated with tau, amyloid, or neurodegeneration in those regions using 18 F-AV-1451 and 11 C-PiB positron emission tomography (PET) and magnetic resonance imaging (MRI). Sixteen amyloid-positive patients who met criteria for either Posterior Cortical Atrophy (PCA; n = 10) or logopenic variant Primary Progressive Aphasia (lvPPA; n = 6) were studied. All participants underwent a structured clinical assessment, neuropsychological battery, structural MRI, amyloid PET, and tau PET. The neuropsychological battery included two visual cognitive tests: VOSP Number Location and Benton Facial Recognition. Surface-based whole-cortical general linear models were used to first explore the similarities and differences between these biomarkers in the two patient groups, and then to assess their regional associations with visual cognitive test performance. The results show that these two variants of AD have both dissociable and overlapping areas of tau and atrophy, but amyloid is distributed with a stereotyped localization in both variants. Performance on both visual cognitive tests were associated with tau and atrophy in the right lateral and medial occipital association cortex, superior parietal cortex, and posterior ventral occipitotemporal cortex. No cortical associations were observed with amyloid PET. We further demonstrate that cortical atrophy has a partially mediating effect on the association between tau pathology and visual cognitive task performance. Our findings show that non-amnestic variants of AD have partially dissociable spatial patterns of tau and atrophy that localize as expected based on symptoms, but similar patterns of amyloid. Further, we demonstrate that impairments of visual cognitive dysfunction are strongly associated with tau in visual cortical regions and mediated in part by atrophy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Pancreatic cytopathology, particularly through the use of endoscopic ultrasound-guided fine-needle aspiration (FNA), has excellent specificity and sensitivity for the diagnosis of pancreatic lesions. Such diagnoses can help guide preoperative management of patients, provide prognostic information, and confirm diagnoses in patients who are not surgical candidates. Furthermore, FNA can be used to obtain cyst fluid for ancillary tests that can improve the diagnosis of cystic lesions. In this article, we describe the cytomorphological features and differential diagnoses of the most commonly encountered pancreatic lesions on FNA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A low level of HDL cholesterol (HDL-C) is a common clinical scenario and an important marker for increased cardiovascular risk. Many patients with very low or very high HDL-C have a rare mutation in one of several genes, but identification of the molecular abnormality in patients with extreme HDL-C is rarely performed in clinical practice. We investigated the accuracy and diagnostic yield of a targeted next-generation sequencing (NGS) assay for extreme levels of HDL-C. We developed a targeted NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with highly penetrant effects on plasma lipid levels. We sequenced 141 patients with extreme HDL-C levels and prioritized variants in accordance with medical genetics guidelines. We identified 35 pathogenic and probably pathogenic variants in HDL genes, including 21 novel variants, and performed functional validation on a subset of these. Overall, a molecular diagnosis was established in 35.9% of patients with low HDL-C and 5.2% with high HDL-C, and all prioritized variants identified by NGS were confirmed by Sanger sequencing. Our results suggest that a molecular diagnosis can be identified in a substantial proportion of patients with low HDL-C using targeted NGS., (Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.)

After three different outbreaks were linked to the consumption of nonintact meat products contaminated with Escherichia coli O157:H7, the U.S. Food Safety and Inspection Service published notice requiring establishments producing mechanically tenderized and moisture-enhanced beef products to reassess their respective hazard analysis and critical control point systems, due to potential risk to the consumers. The objective of this study was to validate the use of lactic acid bacteria (LAB), acidified sodium chlorite (ASC), and lactic acid (LA) sprays when applied under a simulated purveyor setting as effective interventions to control and reduce E. coli O157:H7 and Salmonella Typhimurium DT 104 in inoculated U.S. Department of Agriculture (USDA) Choice strip loins (longissimus lumborum muscles) pieces intended for either mechanical blade tenderization or injection enhancement with a brine solution after an aging period of 14 or 21 days at 4.4°C under vacuum. After the mechanical process, translocation of E. coli O157:H7 and Salmonella Typhimurium DT 104 from the surface into the internal muscles occurred at levels between 1.00 and 5.72 log CFU/g, compared with controls. LAB and LA reduced internal E. coli O157:H7 loads up to 3.0 log, while ASC reduced the pathogen 1.4 to 2.3 log more than the control (P < 0.05), respectively. Salmonella Typhimurium DT 104 was also reduced internally 1.3 to 2.8, 1.0 to 2.3, and 1.4 to 1.8 log after application of LAB, LA, and ASC, respectively. The application of antimicrobials by purveyors prior to mechanical tenderization or enhancement of steaks should increase the safety of these types of products.

After three different outbreaks were linked to the consumption of nonintact meat products contaminated with Escherichia coli O157:H7, the U.S. Department of Agriculture, Food Safety and Inspection Service published notice requiring establishments producing mechanically tenderized and moisture-enhanced beef products to reassess their respective hazard analysis and critical control point system, due to potential risk to the consumers. The purpose of this study was to determine the effectiveness of different intervention strategies (lactic acid, lactic acid bacteria, and acidified sodium chlorite) to control E. coli O157:H7 and Salmonella enterica serotype Typhimurium definitive phage type 104 in mechanically tenderized and brine-enhanced beef strip loins when applied to the steaks prior to packaging and shipment for processing. After the mechanical process, translocation of E. coli O157:H7 and Salmonella Typhimurium DT 104 from the surface into the internal muscles occurred at levels between 2.0 and 4.0 log CFU/g (from an initial inoculation level of 5.0 log) after mechanical tenderization, and at levels of 1.0 to 3.0 log CFU/g after injection, with all the interventions consistently presenting lower microbial counts (P < 0.05) than did the controls. Lactic acid bacteria reduced internal E. coli O157:H7 loads 1.2 to > 2.2 log cycles, while the acidified sodium chlorite and lactic acid reduced them between 0.8 and 3.0 log, respectively. Salmonella Typhimurium DT 104 was also reduced internally after application of all interventions between 0.9 and 2.2 log. The application of antimicrobials to the steaks prior to packaging and shipment on day 0 was effective in reducing internalization of both pathogens in nonintact beef products stored for both 14 and 21 days.

Background: Varicocele repair is a widely used treatment for subfertility. Our aim was to identify and combine the results from randomised controlled trials published to ascertain whether the pregnancy rates after varicocele repair are higher than those with no treatment., Methods: We did a systematic review of seven studies identified by searching Medline and a register of controlled trials. We also searched the contents of specialist journals and the annual meeting programmes of relevant societies by hand. Inclusion criteria were treatment of varicocele in subfertile couples, random allocation to treatment and control groups, and pregnancy or livebirth rates as an outcome measure. We pooled data by use of fixed and random effects models., Findings: None of seven eligible studies published between 1979 and 2002 described a strategy for concealment of the allocation sequence. There were 61 pregnancies among 281 treated couples and 50 pregnancies among 259 controls. The overall relative benefit of treatment was 1.01 (95% CI 0.73-1.40) by the fixed effects model and 1.04 (0.62-1.75) by the random effects model. The overall risk difference was 0.2% (-7 to 7) and 3% (-7 to 14), respectively. In subgroup analyses, varicocele treatment was not effective in trials restricted to male subfertility with clinical varicocele, or in those that included men with subclinical varicocele or normal semen analysis. However, this systematic review, done with a meta-analytical method, might have had insufficient power to detect small effects because of the small number of patients in some subgroups., Interpretation: Varicocele repair does not seem to be an effective treatment for male or unexplained subfertility.

The recent Women's Health Initiative study report evaluated the long-term benefits and risks of hormone replacement therapy among healthy postmenopausal women. The report showed that the risk-benefit profile of continuous combined hormone replacement therapy was not consistent with the primary prevention of coronary heart disease. The Women's Health Initiative study of continuous combined hormone replacement therapy is a landmark study and the results provide valuable information for patients and clinicians. However, the most common indication for hormone replacement therapy is menopausal symptoms, for which it is effective, not prevention of disease, and the most common use is for less than three years. Nevertheless, even short-term use has small effects on some outcomes. This statement discusses how the findings of the Women's Health Initiative study can be applied to reach appropriate clinical decisions.

Oral contraceptives are one of the most highly effective forms of contraception and provide many short- and long-term noncontraceptive health benefits. They control menstrual cycle irregularities, such as breakthrough bleeding and amenorrhea, and are effective in treating dysfunctional uterine bleeding. In addition, for decades after oral contraceptive use is discontinued they are associated with substantial decreases in the risk of ovarian cancer (up to 80%) and of endometrial cancer (40%-50%), and nearly eliminate benign functional ovarian cysts. Long-term oral contraceptive use confers protection against benign breast disease and colorectal cancer, may help prevent rheumatoid arthritis, decreases ectopic pregnancy and hospitalizations for pelvic inflammatory disease, and helps preserve bone mineral density to reduce risk of fractures. Large bodies of evidence from extensive research have clarified the perceived association of oral contraceptive use with cardiovascular disease and with breast cancer. Findings indicate that there is no increased risk of myocardial infarction or stroke associated with oral contraceptive use in healthy, nonsmoking, normotensive women. Although there is a 3- to 4-fold increased risk of venous thromboembolism with current oral contraceptive use, the absolute risk is very small and is half that associated with pregnancy. Women of all reproductive ages, including perimenopausal women, can realize many health benefits through oral contraceptive use, including improved health status later in life.

Hormone replacement therapy with estrogen alone or with added progestin relieves menopausal symptoms and physical changes associated with depleted endogenous estrogen levels. Estrogen replacement has also demonstrated a clear benefit in the prevention of osteoporosis. Hormone replacement therapy with added progestin maintains spinal bone density, protects against postmenopausal hip fractures, and provides these benefits even when therapy is started after age 60. More recently, additional benefits have emerged. Current estrogen and hormone replacement therapy users have a 34% reduction in the risk of colorectal cancer and a 20% to 60% reduction in the risk of Alzheimer's disease. Until recently, the body of evidence indicated that hormone replacement therapy with estrogen only reduced cardiovascular disease risk by 40% to 50% in healthy patients; whether the findings of 3 ongoing trials will change this conclusion is pending availability of the final results. The many benefits of estrogen and hormone replacement therapy must be weighed against a slight increase in the risk of breast cancer diagnosis with use for 5 or more years, but which disappears following cessation of therapy. Overall, estrogen and hormone replacement therapy improves the quality of life and increases life expectancy for most menopausal women.

Background: A low concentration of HDL cholesterol is the most common lipoprotein abnormality in patients with premature atherosclerosis. We have shown that Tangier disease, a rare and severe form of HDL deficiency characterised by a biochemical defect in cellular cholesterol efflux, is caused by mutations in the ATP-binding-cassette (ABC1) gene. This gene codes for the cholesterol-efflux regulatory protein (CERP). We investigated the presence of mutations in this gene in patients with familial HDL deficiency., Methods: Three French-Canadian families and one Dutch family with familial HDL deficiency were studied. Fibroblasts from the proband of each family were defective in cellular cholesterol efflux. Genomic DNA of each proband was used for mutation detection with primers flanking each exon of the ABC1 gene, and for sequencing of the entire coding region of the gene. PCR and restriction-fragment length polymorphism assays specific to each mutation were used to investigate segregation of the mutation in each family, and to test for absence of the mutation in DNA from normal controls., Findings: A different mutation was detected in ABC1 in each family studied. Each mutation either created a stop codon predicted to result in truncation of CERP, or altered a conserved aminoacid residue. Each mutation segregated with low concentrations of HDL-cholesterol in the family, and was not observed in more than 500 control chromosomes tested., Interpretation: These data show that mutations in ABC1 are the major cause of familial HDL deficiency associated with defective cholesterol efflux, and that CERP has an essential role in the formation of HDL. Our findings highlight the potential of modulation of ABC1 as a new route for increasing HDL concentrations.

In an attempt to evaluate the efficacy of salpingoovariolysis we studied 147 women who were found to have periadnexal adhesions on laparoscopic examination. Among these women, 69 were treated by laparotomy and salpingoovariolysis and 78 were not treated. There was no significant difference between the degree of adhesions in the treated group and in the nontreated group. With the use of life table analysis, the cumulative pregnancy rate at 12 and 24 months follow-up was 32% and 45% in the treated group and 11% and 16% in the nontreated group, respectively (p less than 10(-6)). We suggest that although pregnancy might occur in infertile women who have periadnexal adhesions, treatment with salpingoovariolysis is associated with a higher pregnancy rate.

The glycosaminoglycan distribution patterns of the cerebrospinal fluid (CSF) outflow pathway, dura mater and cerebral cortex of young New Zealand red rabbits and 1-, 3- and 12-week-old C-57 mice were identified by analyses of the glycosaminoglycan moieties and by the use of zone electrophoresis. The glycosaminoglycans were identified by specific degradation procedures, i.e., hyaluronate lyase, chondroitin ABC lyase, endo-beta-D-galactosidase and nitrous acid treatment. The CSF outflow pathway and dura mater glycosaminoglycan components were primarily hyaluronic acid and chondroitin sulfate-dermatan sulfate, whereas the cerebral cortex glycosaminoglycan components were hyaluronic acid, chondroitin sulfate-dermatan sulfate, keratan sulfate and heparan sulfate. The glycosaminoglycan components of the dura mater and cerebral cortex decreased and those of the CSF outflow pathway increased as a function of age. These results demonstrate the feasibility of analyses of the CSF outflow pathway glycosaminoglycan components and suggest that topographical changes in the glycosaminoglycan distribution profiles may contribute to the pattern of cerebrospinal fluid outflow.

Exogenous estrogen use was determined by interview in 206 endometrial cancer patients, 191 women with nonmalignant gynecologic disorders, and 199 women with other illnesses. Separate comparisons of these patients with gynecologic and other illness control subjects provided estimates of the risk of endometrial cancer among estrogen users, adjusted for the effects of confounding variables, of 1.5 (95% confidence limits 0.9 and 2.7) and 4.8 (2.7 and 8.4), respectively. In both comparisons, risk increased with increasing duration of use; regardless of duration of use, risks were higher among users of estrogen within 12 months of diagnosis than among past users. The effects of bias, including surveillance bias, on the results were considered and it was concluded that the true risk was not less than the case/gynecologic control estimate and was likely to approach the case/other control estimate.

Midtrimester abortions were induced in 295 patients with a combination of intra-amniotic urea and intravenous oxytocin. The mean injection-abortion interval was 26.4 hours. Abortion occurred spontaneously within 50 hours of amnioinfusion in 257 patients. The macerating effect of the hypertonic urea on fetal tissues allowed easy termination of the remaining 38 pregnancies by suction curettage at 50 hours after injection. Decreased urinary output occurred during the oxytocin infusions, but water intoxication was prevented by close monitoring of urinary output and serum electrolytes, and by the use of a concentrated solution of oxytocin in normal saline, allowing the administration of small volumes.

At present, there is no sensitive and specific test to confirm the clinical impression that a respiratory disorder is due to aspiration of gastric contents. Since intravenous technetium pertechnetate (99mTcO4-) has been shown to be safe, actively concentrated in the gastrointestinal tract, and secreted into gastric juice, we sought to determine whether 99mTcO4-, when given intravenously, is suitable to detect pulmonary aspiration of small amounts of gastric contents in rabbits. Biodistribution studies over 24 h revealed that 99mTcO4- persistently appeared in the stomach, thyroid, and salivary glands and did not appear in the lungs. Pharmacokinetic studies showed that 99mTcO4- was rapidly picked up by the stomach wall and secreted promptly into the stomach lumen and that the stomach wall persistently secreted 99mTcO4- into stomach contents for 24 h. By injecting 99mTcO4- through an intratracheal catheter in order to simulate aspiration, the radioactive threshold for imaging intrapulmonary 99mTcO4- was determined to range between less than 0.5 microCi and 2 microCi, depending on the amount of background activity in the blood pool. By measuring the radioactivity in stomach contents (microCi/g), over 24 h after intravenous injection of 2 mCi of 99mTcO4-, we were able to calculate the amount of aspirated stomach contents that our technique should reveal at various time points. We concluded from this preliminary feasibility study that 99mTcO4-, when given intravenously, is suitable to detect pulmonary aspiration of small amounts (less than or equal to 4 ml for 8 h after an intravenous dose of 2 mCi) of gastric contents in human patients. Since our biodistribution studies show that saliva as well as stomach contents are potential sources for any aspirated 99mTcO4-, how to distinguish aspiration of oropharyngeal from stomach contents remains to be determined. It also remains to be determined how long 99mTcO4- remains in the lungs after it has been instilled; clearance that is too rapid significantly decreases the ability of this agent to reveal aspiration.

Three hundred and fifty-two cases of carcinoma of the cervix which required some surgical procedure are reviewed. In Group I (primary treated), the lymph nodes were positive in 9% with Stage I and 45% with Staqe II disease. This group had an 88% five-year survival rate; patients with positive lymph nodes had a 60% two-year survival rate. One or more surgical complications occurred in 16.5% of patients treated for recurrent disease. The five-year survival rate in patients treated for recurrent disease was 35%. The Schauta-Amreich procedure is being used more commonly for poor-risk patients with recurrent disease confined to the cervix or with superficial vaginal involvement.

Evaluated were methods of ordering the many possible predictors of infertility outcome. The clinical characteristics of infertile couples were studied with respect to the occurrence of pregnancy during follow-up, by means of the methods of survival analysis. Among 1,297 couples who were infertile for 12 months or more, the cumulative pregnancy rate at 36 months with 95% confidence limits was 49% +/- 4%. The proportional hazards analysis identified three independent predictors of the occurrence of pregnancy from the couple's history (with P values in brackets): a history of pregnancy in the partnership (0.0001); shorter duration of infertility (0.0001); and shorter length of marriage (0.005). The predictors arising from the diagnostic process (with P values in brackets) were: fewer infertility diagnoses (0.0001); a favorable primary clinical diagnosis (0.001); and the presence of any tubal disease, regardless of the primary clinical diagnosis (0.001). The analysis selected an economical set of significant predictor variables and demonstrated that a longer period of contraception was associated with a lower pregnancy rate among infertile couples. Also, three simple questions from the history were nearly equivalent to the entire diagnostic process as predictors of the outcome.

The oviducts of seventy-three women undergoing sterilization by partial salpingectomy were submitted for microbiological and histologic studies. Twenty women were intrauterine device users, twenty-five women were oral contraceptive pill users and twenty-eight women used natural or barrier methods of contraception. Among intrauterine device users, there was an excess of mild and severe acute inflammatory histologic changes involving both the lumen and the tubal mucosa. Five of the eight intrauterine device users with acute inflammatory change had sterile tubal cultures.