Is abdominal adiposity in healthy Sri Lankan neonates different from the rest of the world?

BACKGROUND AND OBJECTIVES: Adiposity at birth is a predictor of childhood obesity. Abdominal circumference (AC) at birth has been shown to correlate well with visceral adipose tissue and abdominal subcutaneous adipose tissue. Adiposity differs according to ethnicity and geography. The aim of this study was to describe the anthropometry derived adiposity phenotype in neonates from Colombo, Sri Lanka and compare it with global data. METHODS AND STUDY DESIGN: Birth anthropometry was performed within 12-24 hours by the same investigator as part of a prospective cohort study on healthy term babies, at a tertiary care hospital in Colombo, Sri Lanka, 2015-2019. The anthropometry derived adiposity phenotype was indicated by skinfold thickness, AC and upper arm fat area (UFA) derived from the mid-upper arm circumference (MUAC). RESULTS: Sri Lankan neonates had a significantly lower weight with significantly higher AC (n=337, 2.9±0.4 kg, 30.6±2.3 cm) compared to Canadian (n=389, 3.5±0.02 kg, 29.9±2.1 cm; p<0.001) and Australian (n=1270, 3.4±0.4 kg, 28.5±1.9 cm; p<0.001) neonates. Anthropometry derived adiposity at birth showed a significant correlation with weight and BMI of both mother and father (p<0.05) as opposed to their income or education (p>0.05). CONCLUSIONS: Healthy neonates from Colombo, Sri Lanka demonstrated significantly higher AC despite significantly lower weight, indicating increased abdominal adiposity compared to neonates from high-income countries as well as Indian neonates with the thin-fat phenotype.

Birth anthropometry from a tertiary care hospital in Sri Lanka: Differs from the WHO growth standards.

BACKGROUND AND OBJECTIVES: The nutritional status of infants is assessed using the WHO growth references, based on the Multicenter Growth Reference Study (MGRS) in many countries including Sri Lanka. Birth parameters define infant growth curves. The aim of this study was to compare the birth anthropometric data of a healthy population of babies born in Colombo, Sri Lanka with the WHO MGRS birth data and determine its suitability for assessment of growth in this population. METHODS AND STUDY DESIGN: Birth data were obtained as part of a study on longitudinal infant body composition from birth to 2 years from 2015-2019. Healthy babies, born to non-smoking mothers, >18 years old, with a singleton pregnancy at term, living in the study area and intending to breastfeed, were recruited. The Ethical Review Committee of the Faculty of Medicine, University of Colombo, approved the study. RESULTS: Compared to WHO data, the mean birth weight (2.9±0.4 kg), length (48.2±2.7 cm) and head circumference (33.6±1.2 cm) of our study population (n=337) was significantly lower with a left shift in the z score distribution. This was despite similar background characteristics except for significantly lower income (USD 200) and lower maternal (154.2±9.0 cm) and paternal height (165±11.6 cm) in our study population. A significant change in birth parameters was only seen with maternal height when disaggregated. CONCLUSIONS: WHO birth parameters were significantly higher and underestimated the growth of healthy babies in Sri Lanka.

Obstetric outcomes and effects on babies born to women treated for epilepsy during pregnancy in a resource limited setting: a comparative cohort study.

BACKGROUND: Management of epilepsy during pregnancy in a resource-limited setting (RLS) is challenging. This study aimed to assess obstetric outcomes and effects on babies of women with epilepsy (WWE) exposed to Anti-epileptic drugs (AEDs) compared to non-exposed controls in a RLS. METHODS: Pregnant WWE were recruited from antenatal and neurology clinics of a tertiary care hospitals in Sri Lanka. Patients were reviewed in each trimester and post-partum. Medication adherence, adverse effects, seizure control and carbamazepine blood levels were monitored. Post-partum, measurements for anthropometric and dysmorphic features of the babies and congenital abnormalities were recorded. Age and sex matched babies not exposed to AED recruited as controls were also examined. RESULTS: Ninety-six pregnant WWE were recruited (mean period of gestation 22.9 weeks). Mean age was 28 years and 48(50%) were primigravidae. Fifty percent (48) were on monotherapy, while 23.8, 15.9 and 4.1% were on two, three and four AEDs respectively. AEDs in first trimester (TM1) were carbamazepine (71%), valproate (25.8%) clobazam (29.5%), lamotrigine (7%) topiramate (5%) and others (3.4%). Sodium valproate use reduced significantly from T1 to T2(p < 0.05). Sub-therapeutic carbamazepine levels correlated positively (r = 0.547) with poor medication adherence (p = 0.009) and negatively (r = 0.306) with adverse effects (p = 0.002). Seventy-six WWE completed follow-up reporting w 75 (98.6%) live births and one T1 miscarriage (1.3%). Three (4.3%) were preterm. Majority (73.33%) were normal vaginal deliveries. Cesarean sections were not increased in WWE. Fifty-nine (61.45%) babies were examined. For those examined during infancy, 53 age and sex matched controls were recruited and examined.. Congenital abnormalities occurred in 5 (9.43%) babies of WWE [atrio-ventricular septal defect (2), renal hypoplasia (1), cryptorchidism (1), microcephaly (1)] compared to 2 (3.77%) in controls (2 microcephaly; p = 0.24). Fetal exposure to AEDs increased a risk of low birth weight (RR 2.8; p = 0.049). Anthropometric parameters of AED exposed babies were lower at birth but not statistically significant between the two groups (weight p = 0.263, length p = 0.363, occipito-frontal circumference (OFC) p = 0.307). However, weight (p = 0.009), length (p = 0.016) and OFC (p = 0.002) were significantly lower compared to controls at an average of 3.52 months. CONCLUSION: Most pregnancies are unplanned in the RLS studied, and AEDs were altered during pregnancy. Congenital anomalies occurred at rates comparable to previous reports. Fetal exposure to AED had growth retardation in infancy compared to non-exposed babies.

The engagement of activating FcgammaRs inhibits primate lentivirus replication in human macrophages.

We previously reported that the stimulation of monocyte-derived macrophages (MDM) by plate-bound i.v. Igs inhibits HIV-1 replication. In this study, we show that IgG immune complexes also suppress HIV-1 replication in MDMs and that activating receptors for the Fc portion of IgG-FcgammaRI, FcgammaRIIA, and FcgammaRIII-are responsible for the inhibition. MDM stimulation through FcgammaRs induces activation signals and the secretion of HIV-1 modulatory cytokines, such as M-CSF, TNF-alpha, and macrophage-derived chemokine. However, none of these cytokines contribute to HIV-1 suppression. HIV-1 entry and postintegration steps of viral replication are not affected, whereas reduced levels of reverse transcription products and of integrated proviruses, as determined by real-time PCR analysis, account for the suppression of HIV-1 gene expression in FcgammaR-activated MDMs. We found that FcgammaR-dependent activation of MDMs also inhibits the replication of HIV-2, SIVmac, and SIVagm, suggesting a common control mechanism for primate immunodeficiency lentiviruses in activated macrophages.

The 2',5'-oligoadenylate synthetase 1b is a potent inhibitor of West Nile virus replication inside infected cells.

The 2',5'-oligoadenylate synthetase (OAS) proteins associated with endoribonuclease RNase L are components of the interferon-regulated OAS/RNase L system, which is an RNA decay pathway known to play an important role in the innate antiviral immunity. A large body of evidence suggests a critical role for the 1b isoform of the mouse Oas gene (Oas1b) in resistance to West Nile virus (WNV) infection in vivo. WNV is a positive, single-stranded RNA virus responsible for severe encephalitis in a large range of animal species and humans. To investigate the molecular basis for the sensitivity of WNV to the Oas1b antiviral pathway, we established a stable mouse fibroblastic cell clone that up-regulates Oas1b protein expression under the control of the Tet-Off expression system. We showed that murine cells respond to Oas1b expression by efficiently inhibiting WNV replication. The antiviral action of Oas1b was essentially restricted to the early stages in virus life cycle. We found that the inability of WNV to productively infect the Oas1b-expressing cells was attributable to a dramatic reduction in positive-stranded viral RNA level. Thus, Oas1b represents an antiviral pathway that exerts its inhibitory effect on WNV replication by preventing viral RNA accumulation inside infected cells.

The Israeli strain IS-98-ST1 of West Nile virus as viral model for West Nile encephalitis in the Old World.

West Nile virus (WNV) recently became a major public health concern in North America, the Middle East, and Europe. In contrast with the investigations of the North-American isolates, the neurovirulence properties of Middle-Eastern strains of WNV have not been extensively characterized. Israeli WNV strain IS-98-ST1 that has been isolated from a white stork in 1998, was found to be highly neuroinvasive in adult C57BL/6 mice. Strain IS-98-ST1 infects primary neuronal cells from mouse cortex, causing neuronal death. These results demonstrate that Israeli strain IS-98-ST1 provides a suitable viral model for WNV-induced disease associated with recent WNV outbreaks in the Old World.

New insights on the neuropathology of West Nile virus.

West Nile virus (WNV) is a mosquito-borne disease that emerged in North America where it caused in 2002 te largest arboviral meningoencephalitis outbreak ever recorded in this area. The viral variant responsible for this outbreak has been found to share 99.7% identity over the entire genome with the viral variant that caused the epizootic in Israel in 1998 and has been referred as "Isr98/NY99". It has been shown to exhibit an increased neurovirulence in humans, as well as in experimental infections in different animal models. Mouse model has allowed to demonstrate the preferential infection of neurons within the central nervous system and to point out the genetic determinism of host susceptibility to WNV. In murine neural cell cultures, the selective infection of neurons was accompanied by physiopathological changes and a cytopathic effect, showing the direct effect of infection of neurons as one of the causes of WNV neuropathogenicity.

Structural and functional genomics and evolutionary relationships in the cluster of genes encoding murine 2',5'-oligoadenylate synthetases.

2',5'-Oligoadenylate synthetases (2',5'-OASs) are interferon-inducible enzymes. Some of these proteins play an important role in cellular physiology, in particular, in the innate defense mechanisms against RNA virus infections. In the present publication we report the complete genomic structure of the cluster of genes encoding mouse 2',5'-OAS, with all its transcription units, their predicted functions, and their evolutionary relationships. We found that mouse Oas2/Oas3 genes have a genomic structure similar to that of human OAS2/OAS3, while the mouse equivalent of human OAS1 is composed of eight (Oas1a to Oas1h) tandemly arranged transcription units. For all these eight genes a specific inducible promoter controls transcription. The possible functions of this family of proteins are discussed.

Infection of mouse neurones by West Nile virus is modulated by the interferon-inducible 2'-5' oligoadenylate synthetase 1b protein.

Over the past 7 years, West Nile zoonosis has been an emerging concern for public health in Europe, Middle East and more recently in North America. West Nile virus causes epidemic outbreaks in humans and infected patients may exhibit severe neurological symptoms. Because susceptibility and sensitivity to West Nile virus infections may depend on host genetic factors, a mouse model has been established to investigate the genetic determinism of host susceptibility to West Nile virus. A nonsense mutation in gene encoding the 1b isoform of the 2'-5'oligoadenylate synthetase (OAS1b) was constantly associated with the susceptibility of mouse strains to experimental West Nile virus infection. Oligoadenylate synthetase are interferon-inducible proteins playing a role in the endogeneous antiviral pathway. It was of interest to establish whether interferon-alpha and OAS 1B were sufficient to mediate resistance to West Nile virus infection. In the present study, we showed that interferon-alpha had the ability to modulate West Nile virus infection in mouse. In vitro, interferon-alpha protected mouse neuroblastoma cells against West Nile virus infection if cells have been pretreated with the cytokine for several hours. As a consequence of the presence of a stop codon, the Oas1b gene of the susceptible mice encodes a truncated and presumably inactive form, while resistant mice have a normal copy of the gene. Stable mouse neuroblastoma cell clones overexpressing mutant or wild-type OAS 1B were established. Replication of West Nile virus was less efficient in cells that produce the normal copy of OAS 1B as compared to those expressing the truncated form. Our data illustrate the notion that interferon-alpha and Oas genes may be critical for West Nile virus pathogenesis.

A nonsense mutation in the gene encoding 2'-5'-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice.

A mouse model has been established to investigate the genetic determinism of host susceptibility to West Nile (WN) virus, a member of the genus flavivirus and family Flaviviridae. Whereas WN virus causes encephalitis and death in most laboratory inbred mouse strains after peripheral inoculation, most strains derived from recently trapped wild mice are completely resistant. The phenotype of resistance/susceptibility is determined by a major locus, Wnv, mapping to chromosome 5 within the 0.4-cM-wide interval defined by markers D5Mit408 and D5Mit242. We constructed a high resolution composite/consensus map of the interval by merging the data from the mouse T31 Radiation Hybrid map and those from the homologous region of human chromosome 12q, and found the cluster of genes encoding 2'-5'-oligoadenylate synthetases (2'-5'-OAS) to be the most prominent candidate. This cluster encodes a multimember family of IFN-inducible proteins that is known to play an important role in the established endogenous antiviral pathway. Comparing the cDNA sequences of 2'-5'-OAS L1, L2, and L3 isoforms, between susceptible and resistant strains, we identified a STOP codon in exon 4 of the gene encoding the L1 isoform in susceptible strains that can lead to a truncated form with amputation of one domain, whereas all resistant mice tested so far have a normal copy of this gene. The observation that WN virus sensitivity of susceptible mice was completely correlated with the occurrence of a point mutation in 2'-5'-OAS L1 suggests that this isoform may play a critical role in WN pathogenesis.