Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed 'retinal vasculopathy with cerebral leukodystrophy'. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud's phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (AE standard deviation) age at diagnosis was 42.9 AE 8.3 years and at death 53.1 AE 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 AE 10.6 years). Of them, 54% had mild Raynaud's phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud's phenomenon appear to be part of the clinical spectrum as well. Penetrance

The gene encoding fimA, a 36 kDa fimbrial adhesion of Streptococcus parasanguis FW213, is highly conserved in all four genetic groups of sanguis streptococci. FimA-like peptides were produced by all strains tested. The nucleotide sequence directly upstream of fimA contains two open reading frames, ORF5 and ORF1, whose deduced protein products are homologous to members of a superfamily of ATP-binding cassette membrane transport proteins, including both prokaryotic and eukaryotic uptake and export systems. The amino acid sequence of FimA contains the consensus prolipoprotein cleavage site (LxxC) common to the 'periplasmic' binding proteins of Gram-positive transport systems. The deduced product of ORF5 is a 28.6 kDa membrane-associated protein that has the consensus binding site for ATP (GxxGxGKS). It shares significant homology with AmiE of Streptococcus pneumoniae as well as with Escherichia coli proteins involved in iron(III) uptake. Allelic-replacement mutagenesis of ORF5 resulted in greatly increased resistance to aminopterin. These data demonstrate functionality with the amiE locus as well. The deduced product of ORF1 is an extremely hydrophobic integral membrane protein of 30.8 kDa with a pattern of six potential membrane-spanning regions, typical of a component of these types of transport system. The nucleotide sequence downstream of fimA, ORF3, encodes a 20 kDa protein having 78% identity with the 20 kDa protein encoded downstream of ssaB, a fimA homologue in S. sanguis 12. It also exhibits significant homology with bacterioferritin co-migratory protein (Bcp) of E. coli K-12. Allelic-replacement mutagenesis in the fimA locus of FW213 showed that (i) expression of fimA was initiated at a site far upstream of the fimA start codon, and (ii) expression of fimA was not linked to expression of ORF3. Northern blots probed with internal fragments of ORF5, ORF1, fimA or ORF3 hybridized to the same transcript of 3.3 kb, which suggested that these loci were transcribed as a polycistronic message. The ORF3 probe also hybridized to a 540 bp transcript consistent with the size of ORF3 alone and supportive of the mutagenesis data of non-linkage. Strains mutated in fimA continued to produce fimbriae, indicating that FimA was not the fimbrial structural subunit. Immunoelectron microscopy revealed FimA was localized at the tips of the fimbriae of FW213. This is the first study that demonstrates that an adhesin which binds a bacterial cell to a substrate is associated with an ATP-binding cassette.

Aicardi-Goutières syndrome (AGS), Systemic Lupus Erythematosus (SLE), Familial Chilblain Lupus (FCL) and Retinal Vasculopathy and Cerebral Leukodystrophy (RVCL) {a new term encompassing three independently described conditions with a common etiology--Cerebroretinal Vasculopathy (CRV), Hereditary Vascular Retinopathy (HVR) and Hereditary Endotheliopathy, Retinopathy and Nephropathy (HERNS)}--have previously been regarded as distinct entities. However, recent genetic analysis has demonstrated that each of these diseases maps to chromosome 3p21 and can be caused by mutations in TREX1, the major human 3'-5' exonuclease. In this review, we discuss the putative functions of TREX1 in relationship to the clinical, genetic and functional characteristics of each of these conditions.

Introduction: Prolonged rupture of membrane (PROM) is an important risk factor for early onset neonatal sepsis (EONS), which is associated with increased neonatal morbidity and mortality. We reported the incidence and associated risk factors of PROM for culture-proven EONS. Methodology:The medical records of all neonates born at Aga Khan University, Karachi over a period of five years (2007)(2008)(2009)(2010)(2011) with PROM (> 18 hours) were reviewed. Data about maternal and neonatal risk factors for EONS was collected and adjusted logistic regression (AOR) analysis was applied. Results:Incidence of PROM in this neonatal birth cohort was 27/1,000 live births. A total of 17 (4%) cases with blood-culture proven bacterial sepsis were identified within 72 hours of birth. Klebsiella pneumonia (n = 5; 29%) and Pseudomonas aeruginosa (n = 4; 24%) were the commonest isolates followed by group B Streptococcus (n = 3; 18%) and Escherichia coli (n = 2; 12%). Maternal fever (p = <0.001; AOR, 36.6), chorioamnionitis (p < 0.001; AOR, 4.1), PROM > 48 hr. (p < 0.001; AOR, 8.2), neonatal prematurity < 34 weeks (p < 0.001; AOR, 4.1) and low birth weight < 1,500 grams (p 0.001; AOR, 9.8) along with neonatal thrombocytopenia and raised CRP were found to be independent risk factors associated with culture-proven EONS in PROM. Conclusions: Preventive measures should focus on recognition of these high-risk infants with prompt laboratory screening for sepsis and early institution of empirical antibiotic based on local data. Such approaches would be a safe and cost-effective strategy, especially in developing countries.

Background During the SARS‐CoV2 pandemic, there has been increase in hyperinflammatory presentation in previously healthy children with a variety of cardiac manifestations. Our objective is to describe the cardiac manifestations found in an international cohort of 55 pediatric cases with multi‐system inflammatory syndrome (MIS‐C) during the SARS‐CoV2 pandemic. Methods and Results We reviewed data on previously healthy pediatric patients (≤18 years) with structurally normal hearts who presented at hospitals in the United States, United Kingdom, Spain and Pakistan with MIS‐C and had consultation with a pediatric cardiologist. Data collected included demographics, clinical presentation, laboratory values, electrocardiographic abnormalities, echocardiographic findings and initial therapies. A total of 55 patients presented with MIS‐C. Thirty‐five patients (64%) had evidence of decreased left ventricular function, 17 (31%) had valvulitis, 12 (22%) with pericardial effusion and 11 (20%) with coronary abnormalities. Twenty‐seven (49%) required ICU admission and 24 (44%) had evidence of shock. Eleven patients (20%) fulfilled complete Kawasaki disease criteria and had lower NT pro‐BNP, D‐dimer and ferritin levels compared with those who did not fulfill criteria. Electrophysiologic abnormalities occurred in 6 patients and included complete atrioventricular (AV) block, transient AV block and ventricular tachycardia. Conclusions We describe the first international cohort of pediatric patients with MIS‐C during the SARS‐CoV2 pandemic with a range of cardiac manifestations. This paper brings awareness and alertness to the global medical community to recognize these children during the pandemic and understand the need for early cardiology evaluation and follow‐up.

Sella bridging is frequently found in patients with impacted canines. Hence, sella bridging can complement other diagnostic parameters in confirming the status of canine impaction.

Objectives: To evaluate the cephalometric changes in skeletal, dentoalveolar and soft tissue variables induced by Clark's Twin Block (CTB) in Class II, Division 1 malocclusion patients and to compare these changes in different cervical vertebral maturation stages.Methods: Pre- and post-treatment/observation lateral cephalograms of 53 Class II, Division 1 malocclusion patients and 60 controls were compared to evaluate skeletal, dentoalveolar and soft tissue changes. Skeletal maturity was assessed according to cervical vertebral maturation stages. Pre- and post-treatment/observation mean changes and differences (T2-T1) were compared by means of Wilcoxon sign rank and Mann-Whitney U-tests, respectively. Intergroup comparisons between different cervical stages were performed by means of Kruskal-Wallis test and Mann-Whitney U-test (p ≤ 0.05) .Results: When compared with controls, there was a significant reduction in ANB angle (p < 0.001), which was due to a change in SNB angle in CS-2 and CS-3 (p < 0.001), and in SNA (p < 0.001) and SNB (p = 0.016) angles in the CS-4 group. There was significant increase in the GoGn-SN angle in CS-2 (p = 0.007) and CS-4 (p = 0.024), and increase in Co-Gn and Go-Gn amongst all cervical stages (p < 0.05). There was significant decrease in U1-SN and increase in IMPA amongst all cervical stages (p < 0.05). There was significant retraction of the upper lip in CS-3 (p = 0.001), protrusion of the lower lip in CS-2 (p = 0.005), increase in nasolabial angle in CS-4 (p = 0.006) and Z-angle in CS-3 (p = 0.016), reduction in H-angle in CS-2 (p = 0.013) and CS-3 (p = 0.002) groups. When pre- and post-treatment mean differences were compared between different cervical stages, significant differences were found for SNA, SNB and UI-SN angles and overjet. .Conclusions: The Twin-Block along with the normal craniofacial growth improves facial esthetics in Class II, Division 1 malocclusion by changes in underlying skeletal and dentoalveolar structures. The favorable mandibular growth occurs during any of the cervical vertebral maturation stages, with more pronounced effect during CS-3 stage.

A variety of factors regulate the efficiency of phosphate absorption in the intestine and phosphate reabsorption in kidney. Apart from the well-known regulators of phosphate homeostasis, namely parathyroid hormone (PTH) and the vitamin D-endocrine system, a number of peptides collectively known as the "phosphatonins" have been recently identified as a result of the study of various diseases associated with hypophosphatemia. These factors, fibroblast growth factor 23 (FGF-23), secreted frizzled-related protein 4 (sFRP-4), fibroblast growth factor 7 (FGF-7) and matrix extracellular phosphoglycoprotein (MEPE), have been shown to play a role in the pathogenesis of various hypophosphatemic and hyperphosphatemic disorders, such as oncogenic osteomalacia, Xlinked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia and tumoral calcinosis. Whether these factors are true hormones, in the sense that they are regulated by the intake of dietary phosphorus and the needs of the organism for higher or lower amounts of phosphorus, remains to be firmly established in humans. Additionally, new information demonstrates that the intestine "senses" luminal concentrations of phosphate and regulates the excretion of phosphate in the kidney by elaborating novel factors that alter renal phosphate reabsorption.