Endemic and emerging acute virus infections in Indonesia: an overview of the past decade and implications for the future

Being the largest archipelago country in the world, with a tropical climate and a unique flora and fauna, Indonesia habitats one of the most diverse biome in the world. These characteristics make Indonesia a popular travel destination, with tourism numbers increasing yearly. These characteristics also facilitate the transmission of zoonosis and provide ideal living and breading circumstances for arthropods, known vectors for viral diseases. A review of the past 10 years of literature, reports of the Ministry of Health, Republic of Indonesia and ProMED-mail shows a significant increase in dengue infection incidence. Furthermore, chikungunya, Japanese encephalitis and rabies are proven to be endemic in Indonesia. The combination of cohort studies, governmental data and ProMED-mail reveals an integrated overview for those working in travel medicine and public health, focusing on both endemic and emerging acute virus infections. This review summarizes the epidemiology of acute virus infections in Indonesia, including outbreak reports, as well as public health response measurements and their potential or efficacy. Knowledge about human behaviour, animal reservoirs, climate factors, environment and their role in emerging virus infection are discussed. We aim to support public health authorities and health care policy makers in a One Health approach.     

Value of tissue Doppler myocardial velocities of tricuspid lateral annulus for the diagnosis of right heart failure in patients with COPD

OBJECTIVE: Aim of this study was to investigate the value of systolic indices of tricuspid valve annular motion measured by tissue Doppler imaging for the diagnosis right ventricular failure in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients with COPD with right heart failure symptoms and/or right ventricular dilatation were enrolled for the study. The control group consisted of age and sex matched patients referred to the echocardiography laboratory who had normal echocardiographic examination. Tricuspid valve annulus peak systolic velocity and myocardial acceleration during isovolumic contraction were recorded by tissue Doppler imaging. RESULTS: IVA and Sa wave velocities were found to be significantly decreased in patients with right ventricular failure. For the prediction of right heart failure IVA <3.8 m/sec2 had 91% sensitivity, 80% specificity, 90% positive predictive value (PPV), and 82% negative predictive value (NPV) and Sa wave velocity <9.2 cm/sec had 80% sensitivity, 62% specificity, 75% PPV, and 68% NPV. CONCLUSION: Tricuspid valve annular velocities measured by tissue Doppler imaging especially IVA, offer potential diagnostic value for the diagnosis of right heart failure in patients with COPD.     

GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum?

We report four patients with GLI2 mutations together with their associated phenotypes: (1) holoprosencephaly-like phenotype, (2) anophthalmia, branchial arch anomalies, and CNS abnormalities, (3) heminasal aplasia and orbital anomalies, and (4) lobar holoprosencephaly. This diversity of phenotypes expands our understanding. Findings include not only (1) holoprosencephaly or a holoprosencephaly-like phenotype, but also (2) heminasal aplasia with orbital anomalies, and (3) branchial arch anomalies of the type seen in hemifacial microsomia with anophthalmia and in oculoauriculofrontonasal syndrome. Finally, this is the first report of a double mutation involving GLI2 and PTCH in the same patient.     

Naproxen treatment prevents periprocedural inflammatory response but not myocardial injury after percutaneous coronary intervention

BACKGROUND AND AIM: Recent studies have documented that elevation of C-reactive protein (CRP) levels after percutaneous coronary intervention (PCI) have been predictive of adverse outcome. This study was performed to test the hypothesis that preprocedural use of naproxen sodium is associated with a reduction in the extent of inflammatory response and myocardial injury after PCI. METHODS: Ninety-seven patients who were scheduled for elective PCI were randomized either for naproxen sodium (500 mg bid) (n:39, 75% male, 59+/-10 years) or control (n:58, 76% male, 60+/-10 years). All patients were troponin negative before the procedure. Blood samples for CRP, Troponin I and CK-MB were collected at baseline and after the procedure. RESULTS: The characteristics were similar between the two groups. After coronary stenting, the rise in CRP levels was significantly higher in controls than those treated with naproxen (DeltaCRP=6.4 mg/L in the controls and 0.43 mg/L in the naproxen group, p<0.0001). The incidence of any troponin I elevation or CK-MB elevation above upper limit of normal was not statistically different between groups. During follow up (12+/-2 months), major cardiac adverse events (death, myocardial infarction, and revascularization of target lesion) was similar between groups. CONCLUSION: Our data show that naproxen pretreatment leads to significant suppression in PCI related CRP elevation. However this improvement in CRP levels was not associated with any significant reduction in post-PCI myonecrosis.     

Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder caused by contractions of repetitive elements within the macrosatellite D4Z4 on chromosome 4q35. The pathophysiology of FSHD is unknown and, as a result, there is currently no effective treatment available for this disease. To better understand the pathophysiology of FSHD and develop mRNA-based biomarkers of affected muscles, we compared global analysis of gene expression in two distinct muscles obtained from a large number of FSHD subjects and their unaffected first-degree relatives. Gene expression in two muscle types was analyzed using GeneChip Gene 1.0 ST arrays: biceps, which typically shows an early and severe disease involvement; and deltoid, which is relatively uninvolved. For both muscle types, the expression differences were mild: using relaxed cutoffs for differential expression (fold change ≥1.2; nominal P value <0.01), we identified 191 and 110 genes differentially expressed between affected and control samples of biceps and deltoid muscle tissues, respectively, with 29 genes in common. Controlling for a false-discovery rate of <0.25 reduced the number of differentially expressed genes in biceps to 188 and in deltoid to 7. Expression levels of 15 genes altered in this study were used as a “molecular signature” in a validation study of an additional 26 subjects and predicted them as FSHD or control with 90% accuracy based on biceps and 80% accuracy based on deltoids.     

A unique library of myogenic cells from facioscapulohumeral muscular dystrophy subjects and unaffected relatives: family, disease and cell function

To explore possible mechanisms of pathology in facioscapulohumeral muscular dystrophy (FSHD), we generated a novel library of myogenic cells composed of paired cultures derived from FSHD subjects and unaffected first-degree relatives. We prepared cells from biopsies of both biceps and deltoid muscles obtained from each of 10 FSHD and 9 unaffected donors. We used this new collection to determine how family background and disease affected patterns of growth and differentiation, expression of a panel of candidate, and muscle-specific genes, and responses to exogenous stressors. We found that FSHD and unaffected cells had, on average, indistinguishable patterns of differentiation, gene expression, and dose-response curves to staurosporine, paraquat, hydrogen peroxide, and glutathione depletion. Differentiated FSHD and unaffected cultures were both more sensitive to glutathione depletion than proliferating cultures, but showed similar responses to paraquat, staurosporine, and peroxide. For stress responses, the sample size was sufficient to detect a 10% change in effect at the observed variability with a power of >99%. In contrast, for each of these properties, we found significant differences among cells from different cohorts, and these differences were independent of disease status, gender, or muscle biopsied. Thus, though none of the properties we examined could be used to reliably distinguish between FSHD and unaffected cells, family of origin was an important contributor to gene-expression patterns and stressor responses in cultures of both FSHD and unaffected myogenic cells.     

Genetic variants in IRF6 and the risk of facial clefts: single-marker and haplotype-based analyses in a population-based case-control study of facial clefts in Norway

Mutations in the gene encoding interferon regulatory factor 6 (IRF6) underlie a common form of syndromic clefting known as Van der Woude syndrome. Lip pits and missing teeth are the only additional features distinguishing the syndrome from isolated clefts. Van der Woude syndrome, therefore, provides an excellent model for studying the isolated forms of clefting. From a population-based case-control study of facial clefts in Norway (1996-2001), we selected 377 cleft lip with or without cleft palate (CL/P), 196 cleft palate only (CPO), and 763 control infant-parent triads for analysis. We genotyped six single nucleotide polymorphisms within the IRF6 locus and estimated the relative risks (RR) conferred on the child by alleles and haplotypes of the child and of the mother. On the whole, there were strong statistical associations with CL/P but not CPO in our data. In single-marker analyses, mothers with a double-dose of the 'a'-allele at rs4844880 had an increased risk of having a child with CL/P (RR=1.85, 95% confidence interval: 1.04-3.25; P=0.036). An RR of 0.38 (95% confidence interval: 0.16-0.92; P=0.031) was obtained when the child carried a single-dose of the 'a'-allele at rs2235371 (the p.V274I polymorphism). The P-value for the overall test was <0.001. In haplotype analyses, several of the fetal and maternal haplotype relative risks were statistically significant individually but were not strong enough to show up on the overall test (P=0.113). Taken together, these findings further support a role for IRF6 variants in clefting of the lip and provide specific risk estimates in a Norwegian population.     

Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2

FSHD2 is a rare form of facioscapulohumeral muscular dystrophy (FSHD) characterized by the absence of a contraction in the D4Z4 macrosatellite repeat region on chromosome 4q35 that is the hallmark of FSHD1. However, hypomethylation of this region is common to both subtypes. Recently, mutations in SMCHD1 combined with a permissive 4q35 allele were reported to cause FSHD2. We identified a novel p.Lys275del SMCHD1 mutation in a family affected with FSHD2 using whole-exome sequencing and linkage analysis. This mutation alters a highly conserved amino acid in the ATPase domain of SMCHD1. Subject III-11 is a male who developed asymmetrical muscle weakness characteristic of FSHD at 13 years. Physical examination revealed marked bilateral atrophy at biceps brachii, bilateral scapular winging, some asymmetrical weakness at tibialis anterior and peroneal muscles, and mild lower facial weakness. Biopsy of biceps brachii in subject II-5, the father of III-11, demonstrated lobulated fibers and dystrophic changes. Endomysial and perivascular inflammation was found, which has been reported in FSHD1 but not FSHD2. Given the previous report of SMCHD1 mutations in FSHD2 and the clinical presentations consistent with the FSHD phenotype, we conclude that the SMCHD1 mutation is the likely cause of the disease in this family.     

Intravascular volume dependency of left ventricular mass calculation by two-dimensional guided M-mode echocardiography

BACKGROUND: Increased left ventricular mass (LVM) is an independent risk factor for cardiovascular morbidity and mortality, and may be used for risk stratification. Two-dimensional echocardiography, the most commonly used technique for estimation of LVM, uses the third power of the left ventricular internal diameter (LVID) for the calculation. OBJECTIVES: To determine whether a decrease in intravascular volume after dialysis may cause inaccurate estimation of LVM by echocardiography. METHODS: Thirty-eight patients undergoing hemodialysis due to chronic renal failure constituted the study group (14 women [37%] and 24 men [63%], mean age +/- SD 38.7+/-10.9 years). LVID, and interventricular and posterior wall thicknesses were measured by two-dimensionally guided M-mode echocardiography. Stroke volume and cardiac output were calculated using left ventricular outflow tract diameter and the pulsed-wave Doppler time-velocity integral obtained from left ventricular outflow tract. LVM was calculated by using Devereux's formula, and was indexed for body surface area and height. All echocardiographic parameters were measured or calculated before and after dialysis (on the same day), and then compared. RESULTS: There were no significant changes in wall thickness; however, LVID, LVM, the LVM/body surface index and the LVM/height index significantly decreased after dialysis (P<0.001 for each parameter). There was a significant correlation between the change in LVID and the change in LVM (P<0.001, r=0.59). Stroke volume and cardiac output also decreased significantly after hemodialysis (P<0.001 for each parameter). CONCLUSIONS: Intravascular volume-dependent change in LVID causes inaccurate estimation of LVM, so volume status should be kept in mind, especially in serial assessment of LVM.