EMC10 homozygous variant identified in a family with global developmental delay,mild intellectual disability,and speech delay

In recent years, several genes have been implicated in the variable disease presentation of global developmental delay (GDD) and intellectual disability (ID). The endoplasmic reticulum membrane protein complex (EMC) family is known to be involved in GDD and ID. Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders. EMC10 is a bone marrow-derived angiogenic growth factor that plays an important role in infarct vascularization and promoting tissue repair. However, this gene has not been previously associated with human disease. Herein, we describe a Saudi family with two individuals segregating a recessive neurodevelopmental disorder. Both of the affected individuals showed mild ID, speech delay, and GDD. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify candidate genes. Further, to elucidate the functional effects of the variant, quantitative real-time PCR (RT-qPCR)-based expression analysis was performed. WES revealed a homozygous splice acceptor site variant (c.679-1G>A) in EMC10 (chromosome 19q13.33) that segregated perfectly within the family. RT-qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients, indicating the pathogenicity of the identified variant. For the first time in the literature, the EMC10 gene variant was associated with mild ID, speech delay, and GDD. Thus, this gene plays a key role in developmental milestones, with the potential to cause neurodevelopmental disorders in humans.     

The significance of 'anti-HBc only' in the clinical virology laboratory.

BACKGROUND: Isolated detection of hepatitis B core antibody (anti-HBc) in the absence of surface antigen (HBsAg) or antibody (anti-HBs) has been reported, particularly among individuals infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The significance of this phenomenon is unknown and it is unclear whether all individuals with such serological pattern need further molecular investigations. OBJECTIVES: To determine the prevalence of 'anti-HBc only' in samples referred to a clinical virology laboratory and to evaluate its significance and possible mechanisms. STUDY DESIGN: Samples identified as anti-HBc positive (389/4359, 8.9%) during an 11-month period were investigated for HBsAg, anti-HBs, anti-HCV and anti-HIV. 'Anti-HBc only' samples were tested for HBV DNA using a nested qualitative PCR. Viral loads were measured in samples with detectable HBV DNA and the DNA sequences were analysed. RESULTS: Of 379 samples with detectable anti-HBc, 155 (40.9%) were 'anti-HBc only'. HBV DNA was detected in 6/151 (4%), all of which had a viral load <400 copies per ml. Anti-HIV was found in 50/151 (33.1%) and anti-HCV in 14/151 (9.3%). Of these, only one of the HIV infected patients had detectable HBV DNA. Phylogenetic analysis of the HBV surface gene from three patients showed a variety of genotypes (A, E and G). One sequence had a mutation in codon 144, which has previously been reported to give false negative HBsAg results. CONCLUSIONS: 'Anti-HBc only' is a common phenomenon in the clinical virology laboratory but only a small proportion of samples had detectable HBV DNA. The presence of HBsAg mutants with possible false negative HBsAg test result is of concern. Samples with 'anti-HBc only' could be used to monitor the emergence of these mutants.     

Congenital esophageal stenosis associated with esophageal atresia: new concepts

Congenital esophageal stenosis (CES) is suspected by a fixed intrinsic narrowing of the esophagus that affects the normal swallowing mechanism. The diagnosis is only confirmed by histopathologic picture, which may show fibromuscular disease (FMD) or tracheobronchial remnants (TBR). The latter involves ciliated pseudo stratified columnar epithelium, seromucous glands or cartilage each alone or in combination. The aim of this study is to document the usefulness of histologic picture of surgical specimens obtained from the lower esophageal pouch (LEP) during primary repair in detecting cases of CES associated with esophageal atresia (EA) with or without tracheoesophageal fistula (TEF). Over an 8-year period, 57 consecutive cases operated upon for EA with or without TEF were subjected for histologic examination of surgical specimens obtained from the tip of the LEP. Cases that histologically showed FMD or TBR were included. The usefulness of this histologic picture as a diagnostic and therapeutic aid is assessed. Methods of treatment and outcome were also reviewed. Eight patients out of 57 (14%) had a histologic picture suggestive of CES, two with FMD, four with TBR without cartilage and two with cartilage. Out of 57 patients, 23 developed strictures, six of them had positive biopsies suggestive of CES. One patient with TBR without cartilage did not have stricture. Another case of pure atresia had LEP resection and gastric pull up showed cartilage involving the whole lower esophagus. Excluding the case of pure EA with gastric pull up, all patients suffered from feeding problems and recurrent aspiration. Fluoroscopic barium studies showed late onset minor dysmotility in five patients and late onset major dysmotility in two. All cases studied showed significant gastro-esophageal reflux (GER). Stricture was seen at the anastomotic site extending distally in the two fibromuscular cases and one case with cartilage, at the anastomotic site in three cases with TBR without cartilage. Anti reflux surgical procedures were performed in four patients without benefit in two patients with major dysmotility. Dilatation was successful in the three patients with TBR without cartilage. One patient with cartilage had resection of the anastomotic site and required frequent dilatations and is now doing well. A case of FMD did not improve after frequent dilatations and myotomy together with Nissen’s fundoplication and required resection while the other case of FMD responded partially to dilatations. Cartilage in cases of CES requires surgical resection. Those with TBR without cartilage may not develop stricture. If stricture develops, it responds well to dilatation and patients have good clinical outcomes. Unlike isolated CES, GER is a significant feature in CES with EA. Anti reflux procedures should be avoided before definitive surgery for the stricture and if necessary a partial wrap with gastrostomy is recommended. CES should be considered in the etiology of anastomotic stricture. Taking a surgical specimen routinely from the tip of the LEP during primary esophageal repair for histologic studies is highly recommended.     

Contribution of microdissection for the detection of microsatellite instability in colorectal cancer

The determination ofmicrosatellite instability (MSI) is an important step in the identification of familial colorectal cancer such as hereditary nonpolyposis colon cancer. It could also be of interest in the therapeutic management of sporadic cancer. International criteria for the determination of MSI have been published, recommending the use of microdissection. The aim of this work was to evaluate the impact of contaminant normal DNA in tumor samples for MSI assessment in colorectal cancer using a microdissection technique. We performed a comparative analysis of the microsatellite status between total DNA (DNA extracted from whole tumor samples) and microdissected DNA in 3 different regions from 23 cases of colorectal cancer. Six microsatellites were amplified using fluorescent polymerase chain reaction. We analyzed 9 cases with MSI and 14 cases without instability, with similar results between total DNA and microdissected DNA. Moreover, within a same tumor, the MSI phenotype was observed regardless of the region analyzed. Thus, this work shows the reproducibility of the MSI phenotype throughout a tumor. However, we observed a regional heterogeneity of the MSI profile, consisting of variations in the number and the size of unstable alleles within different regions. This result reflects the genetic heterogeneity of colorectal cancer with MSI. In the 14 cases without instability, we observed an increase of more than 60% in the loss of heterozygosity detection rate after microdissection. Thus, this work confirms the contribution of microdissection for loss of heterozygosity assessment.     

Absorption and release of protein from hydroxyapatite-polylactic acid (HA-PLA) membranes

Objectives

The aim of this study was to investigate the kinetics of protein interactions with a novel hydroxyapatite-polylactide (HA-PLA) composite membrane material.

Methods

Trilayer PLA and HA-PLA composite membranes reinforced with PLA fibres were used to absorb and release protein which was measured by a BioRad assay. The proteins used were fetal calf serum and bovine serum albumin. PLA and HA-PLA composite films were manufactured to test permeability.

Results

Maximal protein absorption was seen within 5 min of treating materials; a nearly 8-fold increase in total absorption was seen with HA-containing composites compared to those without HA. These also exhibited a more gradual and sustained release of protein for periods of up to 96 h, for example at 24 h protein concentrations released were 2.20 ± 2.80 and 0.49 ± 5.38 μg/ml for membranes with and without HA respectively. In addition low pressure and temperature used during production of membranes also allowed greater and more sustained protein release. HA-PLA composite films also showed marked increased permeability compared to plain PLA films, for example after 24 h PLA only films 3.64 ± 1.01 μg/ml, PLA film with 25% HA: 44.99 ± 35.61 μg/ml, PLA film with 75% HA: 153.12 ± 65.57 μg/ml.

Conclusions

The results demonstrate that these composite membranes rapidly absorb protein and that the absorbed protein is released slowly for periods of up to 96 h, dependent on constituents of the material and the manufacturing conditions. Incorporation of HA into these membranes was the key factor for improved protein kinetics and membrane permeability.     

Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging for Differentiation Between Parotid Neoplasms

PurposeThis study was designed to evaluate the role of multiparametric magnetic resonance imaging (MRI) for differentiation of parotid gland neoplasms.MethodsProspective study was conducted upon 52 consecutive patients (30 men, 22 women; aged 24–78 years; mean, 51 years) with parotid tumours that underwent multiparametric MRI using combined static MRI, dynamic contrast enhanced (DCE) MRI, and diffusion-weighted imaging (DWI). The static MRI parameter, time signal intensity curves (TIC) derived from DCE-MRI, and apparent diffusion coefficient (ADC) values of parotid tumours were correlated with histopathological findings.ResultsStatic MRI revealed a significant difference between both benign and malignant lesions in regards to margin definition (P < .001) and T2 hypointensity (P < .013), with a diagnostic accuracy 95% and 78.33% respectively. Study of the TIC type on DCE-MRI revealed statistically significant difference between benign and malignant lesions (P < .001) and diagnostic accuracy 96.55%. There was no statistically significant difference (P = .181) between the ADC values of benign and malignant lesions. ROC curve analysis revealed that by using ADC cut-off value of 1 × 10^?3 mm²/s had accuracy of 84.62% respectively for differentiating Warthin from malignant tumours that could be modified to higher value (94.28%) by excluding lymphoma from malignant lesions. By using cutoff value of 1.3 × 10^?3 mm²/s to differentiate pleomorphic adenoma from malignancy, ROC curve analysis had high accuracy of 97.06%.ConclusionMultiparametric MRI can be used for differentiation of malignant from benign parotid tumours and characterization of some benign parotid tumours.     

Treatment of NZB/NZW F1 hybrid mice with Mycobacterium bovis strain BCG or type II interferon preparations accelerates autoimmune disease

NZB/NZW F1 hybrid mice develop a spontaneous autoimmune disease characterized by the appearance of antinuclear antibodies and premature death due to immune complex glomerulonephritis. To investigate the possible effects of cellular immune stimulation on this disorder, groups of female NZB/NZW mice, aged 2, 5, and 7 months, were treated either with the nonspecific immunostimulatory agent Mycobacterium bovis strain BCG or with saline. Mice treated with BCG at ages 5 and 7 months died sooner than age-matched controls, and death was associated with severe glomerulonephritis, suggesting that BCG may have accelerated autoimmunity in these mice. Since BCG is known to stimulate the production of type II (or gamma) interferon, a substance with potent immunoregulatory effects, a second study was carried out to assess the effects of type II interferon on NZB/NZW disease. A greater number of type II interferon-treated mice died by 9 months of age when compared to controls, and the increased death rate was associated with a more rapid development of antinuclear antibodies and histologically confirmed glomerulonephritis. These data, together with a recent report of increases in the level of serum type II interferon in patients with active systemic lupus erythematosus, suggest that type II interferon may play a role in the pathogenesis of autoimmune disease.     

The effects of thyroid hormone abnormalities on periodontal disease status

Thyroid hormones play an important role in the regulation of physiologic processes. Thyroid disease can lead to imbalance in the homeostasis of the body and affect the healing capacity of tissues. However, limited data are available regarding the relationship between thyroid hormone imbalance (thyroid disease) and periodontal health. This review is carried out to summarize the relationship between thyroid disease and periodontal status. PUBMED and MEDLINE searches of both human and animal studies were performed to investigate the relationship between thyroid disease, periodontal status, and dental implants. Results suggest that thyroid diseases may affect the status of periodontal diseases, especially in hypothyroid conditions. The duration from disease onset to treatment of thyroid disorders may be critical, since uncontrolled thyroid disease may result in destruction of the periodontium. Further controlled studies are needed to explore the relationship between thyroid hormone imbalance and periodontal status. Periodontal therapies, including dental implant placement, appear to be safe with no increase in treatment failure, so long as the status of the thyroid gland is controlled.