A new X-linked mental retardation (XLMR) syndrome with late-onset primary testicular failure, short stature and microcephaly maps to Xq25-q26

X-linked mental retardation (XLMR) is a heterogeneous disorder with both syndromic and non-syndromic forms. Here we describe the clinical and molecular characterisation of a family with a syndromic form of XLMR with hypogonadism and short stature. We investigated a family in which four male members in two generations presented with hypergonadotrophic hypogonadism associated with development of small and abnormal testes. In two of the males, late-onset testicular ascent was noted. In addition, all affected males had short stature (<0.4th centile) and mild learning difficulties and three out of the four had microcephaly. Karyotypes were normal and endocrine investigations confirmed primary testicular failure. The phenotype segregated as an X-linked trait. Haplotype and genetic two-point linkage analysis with 22 microsatellites excluded the whole X chromosome except for a region on Xq25-Xq27 encompassing 13.7Mb with a maximum LOD score of 1.1 for marker DXS8038 at theta=0.05. One family previously described as having XLMR with hypogonadism and short stature maps to the same X chromosome region implicated in our family. However, the more severe mental retardation, muscle wasting and tremor described in this other family would suggest that our family is affected by a novel XLMR syndrome.     

Unintentional injury mortality in the European Union: how many more lives could be saved?

AIMS: The wide variation of unintentional (accidental) injury mortality rates in the European Union (EU) member states suggests that there is high potential for prevention. This paper attempts to quantify the potential for saving lives in this part of the world if all 25 member states were to learn from the experience of countries with advanced injury prevention records. METHODS: Unintentional injury mortality data (latest three available years), including denominator population estimates, were obtained from the World Health Organization (WHO) mortality database for all 22 EU countries with a population of more than one million. Annual average age-adjusted injury mortality rates were used to derive the potential for saving of lives under two scenarios: (a) if all EU member states matched the country with the lowest unintentional rate for all causes of injury combined; (b) if the benchmark was alternatively the country with the lowest unintentional injury cause-specific rate. Separate calculations were performed for children (0-14), adults (15-64), and the elderly (65 and over). RESULTS: Under the first scenario, over 73,000 lives could have been saved in the EU 25 in a single year, notably nearly half (47.4%) fewer unintentional injury deaths could be observed in children, over half in adult (54%), and two-fifths (38%) in the elderly. Under the second, more optimistic, scenario 59% of childhood and adult and 75% of unintentional injury deaths among the elderly would have been avoided. CONCLUSIONS: A substantial proportion of lives lost due to unintentional injury might be saved if all countries were to achieve the lowest unintentional injury mortality rates in the EU. The above calculations are based on a simple theoretical model but there is increasing evidence on the array of existing effective preventive interventions and improved trauma care calls for public health action in each member state that could in practice halt, to the extent possible, the unintentional injury epidemic.     

Metformin increases degradation of phospholamban via autophagy in cardiomyocytes

Phospholamban (PLN) is an effective inhibitor of the sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA). Here, we examined PLN stability and degradation in primary cultured mouse neonatal cardiomyocytes (CMNCs) and mouse hearts using immunoblotting, molecular imaging, and [³⁵S]methionine pulse-chase experiments, together with lysosome (chloroquine and bafilomycin A1) and autophagic (3-methyladenine and Atg5 siRNA) antagonists. Inhibiting lysosomal and autophagic activities promoted endogenous PLN accumulation, whereas accelerating autophagy with metformin enhanced PLN degradation in CMNCs. This reduction in PLN levels was functionally correlated with an increased rate of SERCA2a activity, accounting for an inotropic effect of metformin. Metabolic labeling reaffirmed that metformin promoted wild-type and R9C PLN degradation. Immunofluorescence showed that PLN and the autophagy marker, microtubule light chain 3, became increasingly colocalized in response to chloroquine and bafilomycin treatments. Mechanistically, pentameric PLN was polyubiquitinylated at the K3 residue and this modification was required for p62-mediated selective autophagy trafficking. Consistently, attenuated autophagic flux in HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1-null mouse hearts was associated with increased PLN levels determined by immunoblots and immunofluorescence. Our study identifies a biological mechanism that traffics PLN to the lysosomes for degradation in mouse hearts.Phospholamban (PLN) is a 52-amino acid peptide located in the sarcoplasmic reticulum (SR) membrane in cardiac, slow-twitch skeletal, and smooth muscle, where it exists as a monomer or pentamer. Whereas monomeric PLN physically interacts with sarco(endo)plasmic reticulum Ca²⁺ ATPase type 2a (SERCA2a) to antagonize its function, pentameric PLN complexes are thought to be a reservoir of inactive PLN (1–3). The physical interaction between SERCA2a and PLN reduces the apparent affinity of SERCA2a for Ca²⁺, thereby making SERCA2a less active in transporting Ca²⁺ from the cytoplasm to the lumen of the SR at the same concentration of cytoplasmic Ca²⁺. The physical interaction between the two proteins is regulated by phosphorylation of PLN at Ser16 by protein kinase A or at Thr17 by Ca²⁺/calmodulin-dependent protein kinase II (2). Phosphorylation of PLN reduces its affinity for SERCA2a, thereby increasing SERCA2a activity (2). Evidence from transgenic mice also supports the inhibitory function of PLN. Although targeted PLN deletion enhances baseline cardiac performance, cardiac-specific overexpression of superinhibitory forms of PLN leads to decreases in the affinity of SERCA2a for Ca²⁺ (2). These observations underscore the primary role of PLN as a regulator of SERCA2a activity and, therefore, as a crucial regulator of cardiac contractility. PLN inhibition of SERCA2a can be reversed by either external (i.e., activation of β-adrenergic receptors) or internal (i.e., increased intracellular Ca²⁺ concentration) stimuli.Previous studies identified three PLN mutations in families of patients with hereditary dilated cardiomyopathy. These mutations, the substitution of Cys for Arg9 (R9C) (4), Arg14 deletion (RΔ14) (5), and the substitution of TGA for TAA in the Leu39 codon, creating a stop codon (L39stop) (6), also lead to dilated cardiomyopathy in transgenic mice. At the cellular level, ectopically expressed RΔ14 and L39stop PLN mutants localize at the plasma membrane in HEK-293T cells, cultured mouse neonatal cardiomyocytes, and cardiac fibroblasts, whereas wild-type and the R9C mutant reside within the endoplasmic reticulum (ER)/SR (6, 7). These data, together with a recent study by Sharma et al. (8), suggest a highly ordered trafficking of PLN, ultimately ensuring correct localization, and thus function, within the SR. However, PLN trafficking and degradation mechanisms in mammalian cardiomyocytes have not been clearly established.Protein degradation and clearance of damaged organelles are critical for cellular physiology, and failure in proper clearance has been shown to have pathological repercussions (9). Autophagy is a major mechanism that mediates protein and organelle degradation in response to external and internal signals. External stimulation through pharmacological agonists, such as metformin and rapamycin, promotes autophagy via AMP-activated protein kinase (AMPK) and mammalian target of rapamycin signal pathways, whereas amino acid starvation and an increased intracellular AMP/ATP ratio serve as internal signals to promote autophagy via the Ca²⁺/Calmodulin-dependent kinase kinase-β (10). Steps in the autophagy pathway involve nucleation of targeted macromolecules on the ER membrane, trafficking of autophagosomes to lysosomes and, finally, fusion of the autophagosome-lysosome, resulting in targeted protein degradation (11). In the heart, autophagy plays a crucial role in response to insults, in part by relieving ER stress (12) and removing damaged mitochondria (13). Loss of autophagy could result in irreversible apoptosis and reduced cardiac functioning (14).To characterize PLN degradation, we conducted a series of assays in cultured mouse neonatal cardiomyocytes (CMNCs) and the hearts of HECT domain and ankyrin repeat-containing E3 ubiquitin protein ligase 1 (Hace1)-null mice. Our results show that PLN degradation required both polyubiquitinylation and p62-mediated selective autophagy in CMNCs. Loss of HACE1 was associated with increased PLN levels, supporting the notion that selective autophagy modulates PLN degradation in vivo. Metformin promoted wild-type and R9C PLN degradation through autophagic pathways, resulting in metformin-induced inotropic enhancement.     

Obesity, periodontal and general health: Relationship and management

Obesity is a multifaceted subject. It has increased at an alarming rate in recent years. Being overweight increases the likelihood of a patient having associated health and social problems which may affect dental services and dental management. A review of the literature on obesity and periodontal disease suggested that they both confound each other and obesity itself has been recognized as a major risk factor for periodontal disease. It has been found that adverse effects of obesity on the periodontium may be mediated through pro-inflammatory cytokines and various other bioactive substances. This article tries to focus on the possible role of obesity and obesity-related diseases like diabetes and coronary heart diseases (CHD), as a potential contributor to periodontal disease and vice versa. The meanings of these associations can be useful for various diagnostic and treatment planning purposes.     

Third-Generation Cephalosporin-Resistant Vibrio cholerae, India

Vibrio cholerae resistance to third-generation cephalosporins is rarely reported. We detected a strain that was negative for extended-spectrum β-lactamase and positive for the AmpC disk test, modified Hodge test, and EDTA disk synergy test and harbored the blaDHA-1 and blaNDM-1 genes. The antimicrobial drug susceptibility profile of V. cholerae should be monitored.     

Knowledge, attitudes, beliefs and practices regarding measles in a rural area of Delhi

387 mothers in Mehrauli block of Delhi were interviewed regarding their knowledge, attitudes, beliefs and practices regarding measles. 98.4% enumerated one or the other symptoms, fever being the commonest. 77.5% were aware of the infectious nature and 97% had favourable attitude regarding feeding the child during measles. The commonest foodstuff given was cowmilk and khichdi. 95.1% of the respondents intended to apply local herbs on eruptions. There was a variety of local medicines for home treatment and Laung, Tulsi leaves and Kishmish being the practice in descending order of preference. 98.4% respondents favoured giving special nutritional care during the attack of measles to their children.     

Benign fibrous tumor of the tunica vaginalis testis. Report of a case with light, electron microscopic, and immunocytochemical study, and review of the literature.

Benign fibrous tumor of the tunica vaginalis testis is an uncommon lesion of unknown pathogenesis and histogenesis, frequently described as fibrous pseudotumor. We describe a case of a fibrous tumor of the tunica vaginalis testis studied with light, immunocytochemical, and electron microscopy in a 64-year-old man who also developed a metachronous renal cell carcinoma. To our knowledge, this is the first such case to be presented. We describe the cell of origin of this rare entity and its similarity to fibrous tumors of pleura and extrapleural sites, with a review of the English-language literature and emphasize that not all intrascrotal tumors are malignant.     

West Nile virus in Pakistan. II. Entomological studies at Changa Manga National Forest, Punjab Province

During 1978–1979, 43,729 adult mosquitoes comprising six genera and 30 species were collected during weekly resting and biting collections at the Changa Manga National Forest, Kasur District, Punjab Province. Emphasis was placed on studying the bionomics of Culex tritaeniorhynchus and other culicine mosquitoes to assess their potential role in the transmission of West Nile virus. Cx tritaeniorhynchus (57 · 7% of the total specimens collected), Cx quinquefasciatus (21 · 2%) and Aedes lineatopennis (8 · 2%) were the most abundant mosquito species. Based on comparisons between different collection methods and supported by microprecipitin tests on blood meals from resting females, the abundant mosquitoes were categorized into five groups: (i) resting in houses and feeding on man at night—Cx quinquefasciatus, (ii) resting indoors and feeding on bovids at night—five species of Anopheles, (iii) resting in the forest and feeding on man during day—Ae. yusafi and Ae. w-albus, (iv) resting in the forest and feeding on man during the day and night—Ae. indicus, (v) resting in agricultural fields or forest and feeding on bovids at night—Ae. caspius, Ae. culicinus, Ae. lineatopennis, Cx fuscocephala, Cx pseudovishnui, Cx tritaeniorhynchus and Mansonia uniformis. Few blood smears were positive for birds, with the exception of Cx quinquefasciatus collecting resting outdoors. No species other than Cx quinquefasciatus frequently fed on man.Cx tritaeniorhynchus populations were most abundant during the hot-dry pre-monsoon season when the forest was irrigated, decreasing during the monsoon and post-monsoon seasons and absent in collections during winter. Vertical estimates of survivorship using dissection age-grading methods were highest during the pre-monsoon season. Cx quinquefasciatus was most abundant in spring when females could also be collected resting in the forest, decreasing during the hot, summer months, but recovering after the monsoon when temperatures in houses were once again below 30 °C. Overwintering eggs of Ae. lineatopennis synchronously hatched in the spring after forest irrigation, with succeeding generations appearing in response to irrigation and/or rainfall. The present findings were discussed in the context of West Nile virus ecology.