Chronic kidney disease of uncertain aetiology: adding vital piece of information to the national project team report of Sri Lanka

In a recent study published by the National Project Team on chronic kidney diseases of unknown origin in Sri Lanka, identified cadmium as a major risk factor but strong conclusions were not made as the identified environmental toxins were within the permissible levels.Sri Lankan food consumption pattern is different so that approach of total exposure of cadmium by food and water been calculated. Such calculation point out that total exposure of cadmium exceed the provisional tolerable weekly intake determined by international agencies.     

Duane's retraction syndrome: a retrospective review from Kathmandu, Nepal

Purpose: The aim was to study the clinical characteristics of Duane's retraction syndrome (DRS) in Nepalese patients. Method: Medical records from 52 cases of DRS from May 2003 to April 2010 were retrospectively reviewed for age, gender, laterality and clinical characteristics. Forty‐one case records (78.8 per cent) that had complete clinical findings were considered for further evaluation. Examination included visual acuity by Snellen chart, refraction, associated horizontal and vertical strabismus in primary gaze, upshoot and downshoot on attempted adduction, binocular vision assessed with the Worth four‐dot test on adopted gaze and stereopsis examined with the Titmus stereo test. Results: DRS type I was the most common type observed in 73.2 per cent of cases, followed by DRS type II (14.6 per cent) and DRS type III (12.2 per cent). It was more common in female patients (58.5 per cent) than male patients (χ²= 4.6, df = 1, p = 0.03). DRS was more common in the left eye (68.3 per cent) than the right eye and unilaterally present in 95.1 per cent of subjects. In primary gaze, orthotropia (41.5 per cent) was more common than exotropia (34.1 per cent) and esotropia (24.4 per cent) and vertical strabismus was present in 24.4 per cent of subjects. Upshoot and downshoot on attempted adduction was seen in 14.6 and 9.8 per cent, respectively. Binocular single vision was present in 68.3 per cent of subjects by Worth four‐dot test at near. Stereopsis of 3,000 seconds of arc was present in 9.8 per cent, 100 to 200 seconds of arc in 14.6 per cent and 40 to 60 seconds of arc in 43.9 per cent with the Titmus stereo test. Conclusion: DRS is more common in female patients and the left eye. DRS type I is the most common type.     

Dengue in the Middle East: a neglected, emerging disease of importance

Dengue transmission has increased worldwide, particularly in Asia and Latin America since the 1970s, but limited information on the disease is available from the Middle East. Saudi Arabia and Yemen have reported a few epidemics of dengue. Three of the four dengue virus serotypes (DENV-1-3) have been reported in the region. Climate conditions in the Middle East are not favourable for the disease vector, but all other risk factors for dengue are potentially increasing. The existence of a large immigrant work force from dengue-endemic countries, increased travel from and to dengue-endemic countries and increased urbanization are expected to increase the likelihood of the emergence of dengue in the Middle East.     

Serotype-specific dengue virus circulation and dengue disease in Bangkok,Thailand from 1973 to 1999

Dengue virus circulation and association with epidemics and severe dengue disease were studied in hospitalized children with suspected dengue at the Queen Sirikit National Institute of Child Health in Bangkok, Thailand, from 1973 to 1999. Dengue serology was performed on all patients and viral isolation attempted on laboratory-confirmed patients. Acute dengue was diagnosed in 15,569 children and virus isolated from 4,846. DEN-3 was the most frequent serotype in primary dengue (49% of all isolates), DEN-2 in secondary and in dengue hemorrhagic fever (37% and 35%, respectively). The predominant dengue serotype varied by year: DEN-1 from 1990-92, DEN-2 from 1973-86 and 1988-89; DEN-3 in 1987 and 1995-99; and DEN-4 from 1993-94. Only DEN-3 was associated with severe outbreak years. Our findings illustrate the uniqueness of each serotype in producing epidemics and severe disease and underscore the importance of long-term surveillance of dengue serotypes in understanding the epidemiology of these viruses.     

Segmenting the human genome based on states of neutral genetic divergence

Many studies have demonstrated that divergence levels generated by different mutation types vary and covary across the human genome. To improve our still-incomplete understanding of the mechanistic basis of this phenomenon, we analyze several mutation types simultaneously, anchoring their variation to specific regions of the genome. Using hidden Markov models on insertion, deletion, nucleotide substitution, and microsatellite divergence estimates inferred from human–orangutan alignments of neutrally evolving genomic sequences, we segment the human genome into regions corresponding to different divergence states—each uniquely characterized by specific combinations of divergence levels. We then parsed the mutagenic contributions of various biochemical processes associating divergence states with a broad range of genomic landscape features. We find that high divergence states inhabit guanine- and cytosine (GC)-rich, highly recombining subtelomeric regions; low divergence states cover inner parts of autosomes; chromosome X forms its own state with lowest divergence; and a state of elevated microsatellite mutability is interspersed across the genome. These general trends are mirrored in human diversity data from the 1000 Genomes Project, and departures from them highlight the evolutionary history of primate chromosomes. We also find that genes and noncoding functional marks [annotations from the Encyclopedia of DNA Elements (ENCODE)] are concentrated in high divergence states. Our results provide a powerful tool for biomedical data analysis: segmentations can be used to screen personal genome variants—including those associated with cancer and other diseases—and to improve computational predictions of noncoding functional elements.Whole-genome sequencing studies have demonstrated that divergence estimates for several mutation types (e.g., nucleotide substitutions, insertions, and deletions) vary substantially across the human genome. This phenomenon has been studied at various genomic scales and evolutionary distances (reviewed in ref. 1), and—whereas initially of interest solely to evolutionary biologists—is now entering the purview of main biomedical research. Specifically, human population (e.g., ref. 2) and cancer (3, 4) genome resequencing projects have revealed that incidences of single nucleotide polymorphisms (SNPs), insertions and deletions (indels), and copy number variants (CNVs) vary across the genome. Divergence estimates for different mutation types also covary across the genome (5, 6)—e.g., substitution rates increase in regions with high indel rates (7)—suggesting that regional variation is an important and general characteristic of mutations.Variation in divergence is often linked to genomic landscape features such as base composition, replication timing, and recombination rates (1). For instance, nucleotide substitution rates are elevated in late-replicating regions because of an accumulation of single-stranded DNA susceptible to endogenous damage (8) and are affected by chromatin structure (9) and recombination as a result of either biased gene conversion (BGC) (10) or the mutagenicity of recombination (2). Moreover, nucleotide substitution rates depend nonlinearly on guanine and cytosine (GC) content (11) and are affected by methylation levels and GC content at cytosine—phosphate—guanine (CpG) sites (12) and by replication timing and distance to telomeres at non-CpG sites (13). Covariation in divergence among rates of different mutation types can also be at least partly attributed to the influence of a common genomic landscape (5). Importantly, we note that, whereas selection may indeed operate in noncoding regions, it is unlikely to explain the large degree of variation and covariation in divergence estimates computed from putatively neutral sequences (1, and references therein). Divergence computed for neutral DNA ought to reflect mutation, BGC, and—for relatively distant species—only a minimal amount of diversity.Anchoring variation and covariation of divergence estimates for different mutation types to specific regions of the genome is crucial for elucidating how biochemical processes—e.g., replication and recombination—drive mutagenesis (8, 10) and for understanding genome evolution. Such a “geographic” characterization may correlate with the spatial distribution of genes; for instance, cellular receptor and housekeeping genes tend to locate, respectively, in high and low nucleotide substitution rate regions (14). It may also aid prediction of noncoding functional elements (15, 16) and studies of the genetic basis of disease. For instance, it could assist in (i) discerning whether a locus exhibits an excess of mutations because it resides in a hotspot, thus preventing false positive associations with a disease; and (ii) identifying loci with mutational signatures typical of a disease, e.g., explaining frequent coincidence in tumors of sites prone to DNA damage and chromosomal instability (17).With this motivation, we used hidden Markov models (HMMs) (18), a well-established statistical tool, to analyze human divergence for different mutation types. An HMM models a sequence of observations as governed by underlying states that are not directly observable (hidden) but can be inferred based on the data. These states alternate along the sequence following a Markovian structure, i.e., the state governing a given observation may depend on the state governing the preceding observation. Maximum likelihood techniques are used to select an appropriate number of states, characterize them, and partition the sequence into contiguous segments governed by each state.In genomics, HMMs have been used to model stretches of DNA—the sequences of observations—in a variety of applications ranging from gene finders (19) to epigenomic segmentations (20, 21). In our study, we compute divergence estimates for four mutation types—substitutions, insertions, deletions, and microsatellite repeat number alterations—in nonoverlapping windows of neutrally evolving sequences present in human–orangutan genomic alignments. Modeling the resulting observations with HMMs, we identify distinct divergence states characterized by biologically meaningful combinations of elevated, average, or depressed divergence levels for the four mutation types, e.g., a state where only microsatellite mutations are elevated, whereas the other divergence types are average; one where substitutions, insertions, and deletions are all elevated, whereas microsatellite divergence is average, etc. Correspondingly, we partition the genome into chromosomal segments governed by these states. Our analysis departs from previous applications in considering several mutation types simultaneously—thus accounting for their interdependencies—and in generating segmentations not on a small 100-bp scale (22), but on a larger 1-Mb scale that robustly captures variation in divergence for mammalian genomes (11, 23). Additionally, we investigate whether divergence states differ in genomic landscape features that proxy underlying mutagenic processes, correlate with the spatial organization of functional elements, and persist when assessed from human diversity estimates or for varying genomic scales.     

Therapeutic rationale for low dose doxepin in insomnia patients

Histamine is an excitatory neurotransmitter in central nervous system. It plays an important role in the regulation of the sleep-wake cycle. Antidepressant with sleep-promoting effects, for example, doxepin, promotes sleep not through a sedative action but through resynchronisation of circadian cycle. The stimulation of the H1 receptor is thought to play an important role in mediating arousal. Doxepin has a high affinity for the H1 receptor, making it a selective H1 antagonist at low dose and it has been shown to display sedating properties. Compared to other sedative antidepressant, low dose doxepin is the only tricyclic drug which has been evaluated by well-designed, randomised, double blind, placebo controlled studies in both adult and elderly patients. Doxepin is not designated as controlled substance/unscheduled drugs and thus may be of special advantage to use in patients with a history of substance abuse. Hence, well-documented therapeutic efficacy, tolerability and lack of important adverse effects make the low dose doxepin as a unique, rational drug for the treatment of insomnia in adult and elderly patients.