A case of mosaic deletion of paternally-inherited PLAGL1 and two cases of upd(6)mat add to evidence for PLAGL1 under-expression as a cause of growth restriction.

PLAGL1 is one of a group of imprinted genes, whose altered expression causes imprinting disorders impacting growth, development, metabolism, and behavior. PLAGL1 over-expression causes transient neonatal diabetes mellitus (TNDM type 1) and, based on murine models, under-expression would be expected to cause growth restriction. However, only some reported individuals with upd(6)mat have growth restriction, giving rise to uncertainty about the role of PLAGL1 in human growth. Here we report three individuals investigated for growth restriction, two with upd(6)mat and one with a mosaic deletion of the paternally-inherited allele of PLAGL1. These cases add to evidence of its involvement in pre- and early post-natal human growth.

Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study.

BACKGROUND: Silver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis. METHODS: To determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS. RESULTS: In 20 participants (27% of the cohort) we identified genetic variants plausibly accounting for SRS. Coding SNVs were identified in genes including CDKN1C, IGF2, IGF1R and ORC1. Maternal-effect variants were found in mothers of five participants, including two participants with imprinting disturbance and one with multilocus imprinting disorder. Two regions of homozygosity were suggestive of UPD involving imprinted regions implicated in SRS and Temple syndrome, and three plausibly pathogenic CNVs were found, including a paternal deletion of PLAGL1. In 48 participants with no plausible pathogenic variant, unbiased analysis of SNVs detected a potential association with STX4. CONCLUSION: WGS analysis can detect UPD, CNV and SNV and is potentially a valuable addition to diagnosis of SRS and related growth-restricting disorders.

Lrig1 expression identifies airway basal cells with high proliferative capacity and restricts lung squamous cell carcinoma growth.

BACKGROUND: Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of cancer deaths worldwide, and is preceded by the appearance of progressively disorganised pre-invasive lesions in the airway epithelium. Yet the biological mechanisms underlying progression of pre-invasive lesions into invasive LUSC are not fully understood. LRIG1 (leucine-rich repeats and immunoglobulin-like domains 1) is downregulated in pre-invasive airway lesions and invasive LUSC tumours and this correlates with decreased lung cancer patient survival. METHODS AND RESULTS: Using an Lrig1 knock-in reporter mouse and human airway epithelial cells collected at bronchoscopy, we show that during homeostasis LRIG1 is heterogeneously expressed in the airway epithelium. In basal airway epithelial cells, the suspected cell of origin of LUSC, LRIG1 identifies a subpopulation of progenitor cells with higher in vitro proliferative and self-renewal potential in both the mouse and human. Using the N-nitroso-tris-chloroethylurea (NTCU)-induced murine model of LUSC, we find that Lrig1 loss-of-function leads to abnormally high cell proliferation during the earliest stages of pre-invasive disease and to the formation of significantly larger invasive tumours, suggesting accelerated disease progression. CONCLUSION: Together, our findings identify LRIG1 as a marker of basal airway progenitor cells with high proliferative potential and as a regulator of pre-invasive lung cancer progression. This work highlights the clinical relevance of LRIG1 and the potential of the NTCU-induced LUSC model for functional assessment of candidate tumour suppressors and oncogenes.

Multicenter Cohort Study to Evaluate the Relationship between Radiological Findings and Disability in Moderate and Severe Head Injury Patients.

This was a multicenter cohort study to evaluate the relationship between radiological findings and disability in moderate and severe head injury patients. The study places were the Neurosurgery department of Sylhet M A G Osmani Medical College Hospital, Sylhet Women's Medical College Hospital (SWMCH) and King Faisal Hospital (KFH), Taif, KSA. Sample size was 104 and the study period was 36 months (July 2021 to December 2022). On the basis of radiological findings the participants were divided into three arms. The different arms were diffused traumatic brain injury (arm-1), focal traumatic brain injury (arm-2) and both (diffused and traumatic) types traumatic brain injury (arm-3). Outcome was assessed by modified Rankin Score (mRS). Mean age was significantly higher in female. Overall mean age was 40.28 year. Highest number was in the below 20-year age group followed by the 41-50-year age group. Lowest number of participants was in the above 60-year group. Improved group was significantly higher than 'not improved' and the 'died' group (p<0.00001). Improved participants were significantly higher in the arm-1 and arm-2. Mortality was significantly higher (p<0.00001) in the arm-3 group.

Recognition of psychogenic nonepileptic seizures diminishes acute care utilization.

Patients with psychogenic nonepileptic seizures (PNES) frequently use acute health care resources including emergency departments (EDs), resulting in redundant efforts. We asked whether establishing the diagnosis of PNES via video/EEG telemetry reduces subsequent ED use. Twenty-three patients with PNES were studied over a 48-month period surrounding the diagnosis using a provincewide database. There was a 39% reduction in total ED visits and a 51% reduction in ED visits for neurological causes during the 24 months following the diagnosis, and decreased ED use persisted throughout the follow-up period. There was no significant change in ED utilization for psychiatric causes. The proportion of patients with PNES who used ED services once or not at all per year increased from 26% in the 2 years prior to the diagnosis to 57% following the diagnosis. These findings suggest that a definitive, telemetry-based diagnosis relieves diagnostic uncertainties for the patient and physician, but also has quantifiable economic benefits.

Scleral-fixated intraocular lens implants-evolution of surgical techniques and future developments.

Varied options are available for the implantation of secondary intraocular lens implants in the absence of zonular or capsular support. Loss of the capsule can occur in the context of complicated cataract surgery, trauma or inherited conditions such as Marfan syndrome or pseudoexfoliation. Approaches to overcome this include optical measures such as the use of spectacles or contact lenses, and surgical therapy incorporating the use of anterior chamber, iris-fixated or scleral-fixated lenses. Surgical techniques to implant scleral-fixated lenses have undergone various modifications, since the first publication of sutured intrascleral fixation described in the 1980s. However, despite the advances in surgical techniques, studies are limited either by their retrospective nature, small sample size and most importantly small duration of follow-up. This comprehensive review aims to amalgamate the evolution of various surgical techniques with regards to intrascleral lens fixation and suggests areas for future development.

A precision measurement of the mass of the top quark.

The standard model of particle physics contains parameters--such as particle masses--whose origins are still unknown and which cannot be predicted, but whose values are constrained through their interactions. In particular, the masses of the top quark (M(t)) and W boson (M(W)) constrain the mass of the long-hypothesized, but thus far not observed, Higgs boson. A precise measurement of M(t) can therefore indicate where to look for the Higgs, and indeed whether the hypothesis of a standard model Higgs is consistent with experimental data. As top quarks are produced in pairs and decay in only about 10(-24) s into various final states, reconstructing their masses from their decay products is very challenging. Here we report a technique that extracts more information from each top-quark event and yields a greatly improved precision (of +/- 5.3 GeV/c2) when compared to previous measurements. When our new result is combined with our published measurement in a complementary decay mode and with the only other measurements available, the new world average for M(t) becomes 178.0 +/- 4.3 GeV/c2. As a result, the most likely Higgs mass increases from the experimentally excluded value of 96 to 117 GeV/c2, which is beyond current experimental sensitivity. The upper limit on the Higgs mass at the 95% confidence level is raised from 219 to 251 GeV/c2.

[HBsAg quantification: virological significance]. / Quantification de l'antigène HBs: signification virologique.

HBsAg is a classic marker of hepatitis B virus infection. Since the levels of serum HBsAg are correlated to those of intrahepatic cccDNA, HBsAg quantification indirectly reflects the number of infected hepatocytes. The kinetics of serum HBsAg decline seems to be a predictive marker for sustained virological response, and clearance of HBsAg. This new tool may be clinically relevant for the monitoring and optimization of hepatitis B treatments. To fulfill this objective, prospective studies are still warranted for the the spread of sensitive and standardized techniques standardization of the quantification assays and to define cut off values with clinical predictive values.

The absence of (TCAGGG)n repeats in some telomeres, combined with variable responses to NR2F2 depletion, suggest that this nuclear receptor plays an indirect role in the alternative lengthening of telomeres.

The alternative lengthening of telomeres (ALT) facilitates telomere lengthening by a DNA strand invasion and copying mechanism. The nuclear receptors (NRs), NR2F2 and NR2C2, can bind to (TCAGGG)n variant repeats within telomeres and it has been proposed that this facilitates telomere interactions in ALT+ cells. Here we show that the frequency of cells with detectable NR2F2 and NR2C2 nuclear foci varies considerably between ALT+ cell lines and does not correlate with the level of protein expression. In addition, four of five ALT+ cell lines lack (TCAGGG)n repeats in some telomeres, indicating that direct NR binding does not play a role in ALT at these telomeres. NR2F2-depletion altered the abundance of C-circles and APBs but the direction of the response was inconsistent between three ALT+ cell lines. Moreover, transcriptome analysis following NR2F2-depletion in the ALT+ cell lines revealed different very responses. For example, NR2F2-depletion down-regulated many genes in U2OS cells, consistent with the cell cycle arrest and changes to ALT markers, but these features were not shared by the other two ALT+ cell lines. Among 86 ALT-associated genes, only MND1 showed consistent down-regulation across three NR2F2-depleted ALT+ cell lines. Altogether our data suggest that NR2F2 does not play a direct role in ALT and we speculate about an alternative role for this NR in a DNA damage response at telomeres.

Selective amygdalohippocampectomy: surgical outcome in children versus adults.

INTRODUCTION: The objective of the study was to review our experience with selective amygdalohippocampectomy (SAH) in children and adults with intractable temporal lobe epilepsy. METHODS: A retrospective case series was used in the setting of a tertiary care hospital which provides epilepsy care to both children and adults. All patients underwent a selective amygdalohippocampectomy procedure and had at least one year of follow-up. Adults and children were divided into two groups and the data was compared between children and adults. RESULTS: Twenty three patients, 9 children and 14 adults were studied. Age of surgery varied from 6 to 58 years. Surgical outcome was variable between the two groups. Amongst the children, three patients (33%) were seizure-free (Engel Class I), two patients (22%) had rare seizures (Engel Class II), one patient (11%) had a worthwhile decrease in seizures (Engel class III) and three patients (32%) had refractory seizures that required re-operation with an anterior temporal lobectomy. This differed from the adults, who all had a good outcome. Ten patients (71%) were seizure-free (Engel Class I) and the remainder (29%) had rare seizures (Engel Class II). CONCLUSION: Selective amygdalohippocampectomy can lead to excellent seizure surgical outcome in adults with refractory temporal lobe epilepsy. However, preliminary results show less favorable results in children. The difference is probably related to the different pathology between the two groups. Anterior temporal lobe resection may prove to be a more successful operation than SAH in children with intractable temporal lobe epilepsy.

Sanitizing effect of salts on experimentally inoculated organisms on pork carcasses.

Pork forequarters procured from freshly slaughtered animals were decontaminated with hot water and inoculated with Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, Yersinia enterocolitica, Listeria monocytogenes, Serratia marcescens, Pseudomonas aeruginosa and Proteusvulgaris. The forequarters were individually spray washed with 5% potassium sorbate and a combination of 5% sodium chloride and 2.5% each of sodium acetate, sodium citrate, sodium lactate and potassium sorbate solutions. The total viable count (TVC) of the treated meat samples was reduced by 0.96 and 1.31 log units by spraying with salt and salt combination respectively with marginal changes in colour and odour scores. Inoculated organisms were found to be highly sensitive to salt combination treatment as compared to potassium sorbate alone. Shelf-life of salt and salt combination treated samples was increased to 8 and 11days as against 4days in untreated samples. Carcass washing with salt and salt combination was found to be suitable for extension of shelf-life and improvement in the sensory and microbiological quality of meat.

Anaes practice guidelines for vaccination against hepatitis B virus: impact on general practitioners.

INTRODUCTION: In September 2003, Agency for Accreditation and Evaluation in Health (ANAES) published its consensus recommendations for vaccination practices against hepatitis B virus (HBV), one objective of which was to decrease the risk of HBV transmission to those in the environments of patients who are carriers of the HBs antigen. The aim of our survey was to measure the awareness and application of these recommendations among general practitioners (GPs) in the Loiret region. PATIENTS AND METHODS: This retrospective survey analysed the decisions, using a semi-directed interview, made by all consenting GPs who, in 2004, had referred newly diagnosed HBs antigen-positive patients to the liver unit of the hospital of Orleans. RESULTS: Of the contacted GPs, 83% agreed to participate. Although only one-third of them were familiar with the recommendations, all identified the sexual partners and people living under the same roof as the patient targets for screening and/or vaccination. Also, 75% of the GPs had a consultation with some or all of the identified at-risk individuals in their patient's environment, but only 58% succeeded in vaccinating these at-risk people. Among the interviewed GPs, 71% were in favour of mass vaccination practices against HBV and all were in favour of vaccination targeting the at-risk individuals. CONCLUSION: Dissemination of the ANAES recommendations needs to be improved, even though the majority of the GPs included in the present study were in favour of mass vaccination against HBV and all were in favour of vaccination of at-risk individuals. However, one-third of the identified at-risk individuals eluded screening and/or vaccination, indicating the need for a specific organized program to make contact with these prone populations.

[Exocrin pancreatic deficiency revealing an alpha-1-antitrypsin deficiency]. / Insuffisance pancréatique exocrine révélant un déficit en alpha-1-antitrypsine.

There are genetic mutations taking part in the physiopathology of pancreatitis. The role of alpha-1-antitrypsin (AAT) deficiency in this pathology is debated. We report the case of a 60-year-old man with a pancreatic exocrine insufficiency. He was diagnosed with AAT deficiency. The phenotype was Pi SZ, with genotyping confirmation. The place of AAT deficiency in the midst of pancreatic diseases should be further studied.

Effect of Resin-modified Glass Ionomer Cement Dispensing/Mixing Methods on Mechanical Properties.

STATEMENT OF THE PROBLEM: Resin-modified glass ionomer cements (RMGIs) are often used for luting indirect restorations. Hand-mixing traditional cements demands significant time and may be technique sensitive. Efforts have been made by manufacturers to introduce the same cement using different dispensing/mixing methods. It is not known what effects these changes may have on the mechanical properties of the dental cement. PURPOSE: The purpose of this study was to evaluate the mechanical properties (diametral tensile strength [DTS], compressive strength [CS], and fracture toughness [FT]) of RMGIs with different dispensing/mixing systems. METHODS AND MATERIALS: The RMGI specimens (n=14)-RelyX Luting (hand mix), RelyX Luting Plus (clicker-hand mix), RelyX Luting Plus (automix) (3M ESPE), GC Fuji PLUS (capsule-automix), and GC FujiCEM 2 (automix) (GC)-were prepared for each mechanical test and examined after thermocycling (n=7/subgroup) for 20,000 cycles to the following: DTS, CS (ISO 9917-1) and FT (ISO standard 6872; Single-edge V-notched beam method). Specimens were mounted and loaded with a universal testing machine until failure occurred. Two-/one-way analysis of variance followed by Tukey honestly significantly different post hoc test was used to analyze data for statistical significance ( p<0.05). RESULTS: The interaction effect of both dispensing/mixing method and thermocycling was significant only for the CS test of the GC group ( p<0.05). The different dispensing/mixing methods had no effect on the DTS of the tested cements. The CS of GC Fuji PLUS was significantly higher than that of the automix version ( p<0.05). The FT decreased significantly when switching from RelyX (hand mix) to RelyX Luting Plus (clicker-hand mix) and to RelyX Luting Plus (automix) ( p<0.05). Except in the case of the DTS of the GC group and the CS of GC Fuji PLUS, thermocycling had a significant effect reducing the mechanical properties of the RMGI cements ( p<0.05). CONCLUSIONS: Introducing alternative dispensing/mixing methods for mixing RMGIs to reduce time and technique sensitivity may affect mechanical properties and is brand dependent.

Epidemiology of chronic hepatitis B infection in France: risk factors for significant fibrosis--results of a nationwide survey.

BACKGROUND: Epidemiological data concerning hepatitis B are scarce in France. AIM: To describe epidemiological, clinical, virological and histological features of HBsAg-positive patients followed at non-academic hospitals in France. METHODS: Clinical, biological, virological and histological data of all HBsAg-positive consecutive patients observed from April 1, 2001 to May 31, 2002 in participating centres were recorded prospectively. Multivariate analyses of factors associated with significant fibrosis and cirrhosis were performed. RESULTS: Nearly 1166 HBsAg-positive patients were seen in the 58 centres: 671 males and 495 females from metropolitan France (32%) and from outside metropolitan France (68%); mean age 41 +/- 15 years. Twenty-nine percent of patients were probable HBsAg inactive carriers, while 50% had chronic hepatitis; 43% of these were HBeAg-positive and 57% HBeAg-negative. Liver biopsy had been performed in 558 (51%) patients; 205 (17.6%) patients had cirrhosis. By multivariate analysis, factors associated with significant fibrosis were: age >40 years (P < 0.05), HBeAg-negative status (P < 0.02) and histological activity (P < 0.0001). Factors associated with cirrhosis: age (P < 0.0001), platelet count <150 000/mm(3) (P < 0.0001) and viral co-infection (P < 0.03). CONCLUSION: HBV infection represents a significant workload for hepatogastroenterologists at non-academic hospitals in France.

Purification and optimization of functional reconstitution on the surface of leukemic cell lines of GPI-anchored Fc gamma receptor III.

Purified glycosyl phosphatidyl inositol (GPI)-anchored cell surface proteins can be reincorporated spontaneously into the cell membrane by incubating the cells with these proteins. This unique property provides a novel way of introducing cell surface receptors on live cell membranes without the use of gene transfection. Since any classical transmembrane cell surface protein can be converted to a GPI anchored protein by recombinant techniques, this method provides a means of studying ectodomain associated receptor functions on various cell types. Moreover, in some circumstances, it can be used to correct deficient cellular functions resulting from lack of cell surface protein expression. Using GPI-anchored Fc gamma receptor III (CD16B), a low affinity Fc gamma receptor, we have systematically studied the optimal conditions for reconstitution of a functional receptor on nucleated cells. CD16B is purified to homogeneity from neutrophil lysates by single step immunoaffinity chromatography. The purified CD16B is functionally active as evidenced by its ability to bind IgG opsonized erythrocytes. CD16B incorporation on nucleated cells is temperature dependent with an optimum of 37 degrees C. The level of expression of incorporated CD16B is also depend on the concentration of CD16B available and the duration of incubation. The incorporated CD16B retains its ability to bind ligand and also mediates endocytosis of the bound ligand. In summary, our results demonstrate that purified, functionally active GPI-anchored receptors can be expressed on desired cells in a controlled manner and retain some functional properties.

Improved long-term survival following myocardial revascularization in patients with severe left ventricular dysfunction.

The natural history of patients with coronary artery disease associated with poor left ventricular (LV) function is dismal. This report analyzes the efficacy of myocardial revascularization in this subset of patients with coronary artery disease manifesting severe LV dysfunction on the basis of LV angiography, LV ejection fraction (LVEF), and left ventricular end-diastolic pressure (LVEDP). For the 2 1/2 year period ending November, 1977, 59 consecutive patients with coronary artery disease complicated by severe LV dysfunction underwent aorta-coronary bypass at the University of Western Ontario. All patients had angina refractory to medical therapy. Objective criteria for compromised LV function included the presence of three or more dysfunctional (hypokinetic of akinetic) segments on biplane LV angiography. Eighty-three percent (49/59) of patients had triple-vessel coronary artery disease. The mean LVEF for the series was 0.28 and the mean LVEDP was 18 mm Hg. The duration of follow-up was 24 to 60 months (mean 37 months), with follow-up survival data available on 100% of patients. The hospital mortality was 1.7% (1/59), and there were nine late deaths. The 5 year actuarial survival rate (+/- SEM) was 80% +/- 6%. Of the 44 long-term survivors available for direct assessment, 98% (43/44) report improvement with respect to angina and 66% (29/44) are totally asymptomatic. Eighty percent (28/35) of the long-term survivors under the age of 65 years are currently employed. These results indicate that myocardial revascularization can be performed in patients with severe ischemic LV dysfunction at very low risk and, further, that operation results in a dramatic improvement in survival expectations compared with optimal medical therapy.

Role of free radical scavenger in protection of spinal cord during ischemia.

Previous work in our laboratory established an experimental model for the production of paraplegia in the anesthetized normothermic adult mongrel dog. The current study involves 24 animals divided into two equal groups: Group 1 served as control, and Group 2 received treatment with scavenger agent. Vascular occlusive clamps were placed on the thoracic aorta proximal to the left subclavian artery, on the left subclavian artery at its origin, and on the distal thoracic aorta at the diaphragm for 30 minutes. In Group 1,200 ml of normal saline solution (37 degrees C) was perfused into the occluded aortic segment at the rate of 0.33 ml per kilogram of body weight per minute. In Group 2, 90% dimethyl sulfoxide (DMSO) in a dose of 0.1 gm/kg in normal saline solution (37 degrees C) for a total volume of 200 ml, was likewise injected into the occluded aortic segment at the same infusion rate. Animals were observed for evidence of paresis in the postoperative period. Microscopic analysis revealed evidence of ischemic myelopathy in the control group but none in the treated group. Under the conditions of this experiment, we conclude that the scavenger agent DMSO has a highly protective effect on the spinal cord during ischemic insult.