Maternal arsenic exposure modifies associations between arsenic, folate and arsenic metabolism gene variants, and spina bifida risk: A case‒control study in Bangladesh.

BACKGROUND: Spina bifida is a type of neural tube defect (NTD); NTDs are developmental malformations of the spinal cord that result from failure of neural tube closure during embryogenesis and are likely caused by interactions between genetic and environmental factors. Arsenic induces NTDs in animal models, and studies demonstrate that mice with genetic defects related to folate metabolism are more susceptible to arsenic's effects. We sought to determine whether 25 single-nucleotide polymorphisms (SNPs) in genes involved in folate and arsenic metabolism modified the associations between maternal arsenic exposure and risk of spina bifida (a common NTD) among a hospital-based case-control study population in Bangladesh. METHODS: We used data from 262 mothers and 220 infants who participated in a case‒control study at the National Institutes of Neurosciences & Hospital and Dhaka Shishu Hospital in Dhaka, Bangladesh. Neurosurgeons assessed infants using physical examinations, review of imaging, and we collected histories using questionnaires. We assessed arsenic from mothers' toenails using inductively coupled plasma mass spectrometry (ICP-MS), and we genotyped participants using the Illumina Global Screening Array v1.0. We chose candidate genes and SNPs through a review of the literature. We assessed SNP-environment interactions using interaction terms and stratified models, and we assessed gene-environment interactions using interaction sequence/SNP-set kernel association tests (iSKAT). RESULTS: The median toenail arsenic concentration was 0.42 µg/g (interquartile range [IQR]: 0.27-0.86) among mothers of cases and 0.47 µg/g (IQR: 0.30-0.97) among mothers of controls. We found an two SNPs in the infants' AS3MT gene (rs11191454 and rs7085104) and one SNP in mothers' DNMT1 gene (rs2228611) were associated with increased odds of spina bifida in the setting of high arsenic exposure (rs11191454, OR 3.01, 95% CI: 1.28-7.09; rs7085104, OR 2.33, 95% CI: 1.20-4.and rs2228611, OR 2.11, 95% CI: 1.11-4.01), along with significant SNP-arsenic interactions. iSKAT analyses revealed significant interactions between mothers' toenail concentrations and infants' AS3MT and MTR genes (p = 0.02), and mothers' CBS gene (p = 0.05). CONCLUSIONS: Our results support the hypothesis that arsenic increases spina bifida risk via interactions with folate and arsenic metabolic pathways and suggests that individuals in the population who have certain genetic polymorphisms in genes involved with arsenic and folate metabolism may be more susceptible than others to the arsenic teratogenicity.

Arsenic modifies the effect of folic acid in spina bifida prevention, a large hospital-based case-control study in Bangladesh.

BACKGROUND: Spina bifida, a developmental malformation of the spinal cord, is associated with high rates of mortality and disability. Although folic acid-based preventive strategies have been successful in reducing rates of spina bifida, some areas continue to be at higher risk because of chemical exposures. Bangladesh has high arsenic exposures through contaminated drinking water and high rates of spina bifida. This study examines the relationships between mother's arsenic exposure, folic acid, and spina bifida risk in Bangladesh. METHODS: We conducted a hospital-based case-control study at the National Institute of Neurosciences & Hospital (NINS&H) in Dhaka, Bangladesh, between December 2016 and December 2022. Cases were infants under age one year with spina bifida and further classified by a neurosurgeon and imaging. Controls were drawn from children seen at NINS&H and nearby Dhaka Shishu Hospital. Mothers reported folic acid use during pregnancy, and we assessed folate status with serum assays. Arsenic exposure was estimated in drinking water using graphite furnace atomic absorption spectrophotometry (GF-AAS) and in toenails using inductively coupled plasma mass spectrometry (ICP-MS). We used logistic regression to examine the associations between arsenic and spina bifida. We used stratified models to examine the associations between folic acid and spina bifida at different levels of arsenic exposure. RESULTS: We evaluated data from 294 cases of spina bifida and 163 controls. We did not find a main effect of mother's arsenic exposure on spina bifida risk. However, in stratified analyses, folic acid use was associated with lower odds of spina bifida (adjusted odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.25-1.00, p = 0.05) among women with toenail arsenic concentrations below the median value of 0.46 µg/g, and no association was seen among mothers with toenail arsenic concentrations higher than 0.46 µg/g (adjusted OR: 1.09, 95% CI: 0.52-2.29, p = 0.82). CONCLUSIONS: Mother's arsenic exposure modified the protective association of folic acid with spina bifida. Increased surveillance and additional preventive strategies, such as folic acid fortification and reduction of arsenic, are needed in areas of high arsenic exposure.

The Importance of Neurosurgical Intervention and Surgical Timing for Management of Pediatric Patients with Myelomeningoceles in Bangladesh.

OBJECTIVE: Reports on the management and survival of children with myelomeningocele defects in Bangladesh are limited. This study describes the characteristics and outcomes of these children, focusing on the timing of surgical repair and factors affecting survival. METHODS: We enrolled patients with myelomeningoceles in a case-control study on arsenic exposure and spina bifida in Bangladesh. Cases were subsequently followed at regular intervals to assess survival. Demographic, clinical, and surgical characteristics were reviewed. Univariate tests identified factors affecting survival. RESULTS: Between 2016 and 2022, we enrolled 272 patients with myelomeningocele. Postnatal surgical repair was performed in 63% of cases. However, surgery within 5 days after birth was infrequent (<10%) due to delayed presentation, and there was a high rate (29%) of preoperative deaths. Surgical repair significantly improved patient survival (P < 0.0001). Older age at time of surgery was also associated with improved survival rates, which most likely represents that those who survived to older ages prior to surgery accommodated better with their lesions. Patients who presented with ruptured lesions had lower survival rates. CONCLUSIONS: Timely neurosurgical repair of myelomeningoceles in Bangladesh is hindered by late patient presentation, resulting in a high preoperative patient death rate. Neurosurgical intervention remains a significant predictor of survival. Increased access to neurosurgical care and education of families and non-neurosurgical providers on the need for timely surgical intervention are important for improving the survival of infants with myelomeningoceles.

Arsenic modifies the effect of folic acid in spina bifida prevention, a large hospital-based case-control study in Bangladesh.

Background: Spina bifida, a developmental malformation of the spinal cord, is associated with high rates of mortality and disability. Although folic acid-based preventive strategies have been successful in reducing rates of spina bifida, some areas continue to be at higher risk because of chemical exposures. Bangladesh has high arsenic exposures through contaminated drinking water and high rates of spina bifida. Methods: We conducted a hospital-based case-control study at the National Institute of Neurosciences & Hospital (NINS&H) in Dhaka, Bangladesh, between December 2016 and December 2022. Cases were infants under age one year with spina bifida and further classified using data from observations by neurosurgeons and available imaging. Controls were drawn from children who presented to NINS&H or Dhaka Shishu Hospital (DSH) during the same study period. Mothers reported folic acid use during pregnancy, and we assessed folate status with serum assays. Arsenic exposure was estimated in drinking water using graphite furnace atomic absorption spectrophotometry (GF-AAS) and in toenails using inductively coupled plasma mass spectrometry (ICP-MS). Results: We evaluated data from 294 cases of spina bifida and 163 controls. We did not find a main effect of mother's arsenic exposure on spina bifida risk. However, in stratified analyses, folic acid use was associated with lower odds of spina bifida (adjusted odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.25-1.00, p = 0.05) among women with toenail arsenic concentrations below the median, and no association was seen among mothers with toenail arsenic concentrations higher than median (adjusted OR: 1.09, 95% CI: 0.52-2.29, p = 0.82). Conclusions: Mother's arsenic exposure modified the protective association of folic acid with spina bifida. Increased surveillance and additional preventive strategies, such as folic acid fortification and reduction of arsenic, are needed in areas of high arsenic exposure.

Genome-wide analysis of spina bifida risk variants in a case-control study from Bangladesh.

BACKGROUND: Human studies of genetic risk factors for neural tube defects, severe birth defects associated with long-term health consequences in surviving children, have predominantly been restricted to a subset of candidate genes in specific biological pathways including folate metabolism. METHODS: In this study, we investigated the association of genetic variants spanning the genome with risk of spina bifida (i.e., myelomeningocele and meningocele) in a subset of families enrolled from December 2016 through December 2022 in a case-control study in Bangladesh, a population often underrepresented in genetic studies. Saliva DNA samples were analyzed using the Illumina Global Screening Array. We performed genetic association analyses to compare allele frequencies between 112 case and 121 control children, 272 mothers, and 128 trios. RESULTS: In the transmission disequilibrium test analyses with trios only, we identified three novel exonic spina bifida risk loci, including rs140199800 (SULT1C2, p = 1.9 × 10-7), rs45580033 (ASB2, p = 4.2 × 10-10), and rs75426652 (LHPP, p = 7.2 × 10-14), after adjusting for multiple hypothesis testing. Association analyses comparing cases and controls, as well as models that included their mothers, did not identify genome-wide significant variants. CONCLUSIONS: This study identified three novel single nucleotide polymorphisms involved in biological pathways not previously associated with neural tube defects. The study warrants replication in larger groups to validate findings and to inform targeted prevention strategies.

EMR adoption in Dhaka, Bangladesh: a template to index pediatric central nervous system tumor care and a review of preliminary neuro-oncologic observations.

PURPOSE: To describe the design, implementation, and adoption of a simplified electronic medical record (EMR) and its use in documenting pediatric central nervous system (CNS) tumors at a tertiary care referral hospital in South-East Asia. METHODS: A novel EMR, cataloguing pediatric CNS tumors was used to collect data from August 2017 to March 2020 at National Institute of Neurosciences and Hospital (NINS&H) in Dhaka, Bangladesh. RESULTS: Two hundred forty-nine pediatric patients with a CNS tumor were admitted to NINS&H. Fifty-eight percent of patients were male, and the median age was 8 years. A total of 188/249 patients (76%) underwent surgery during their index admission. Radiographic locations were known for 212/249 (85%) of cases; the most common radiographic locations were infratentorial (81/212; 38%), suprasellar (45/212; 21%), and supratentorial (29/212; 14%). A histopathological classification was reported on 156/249 (63%) of patients' cytology. The most common infratentorial pathologies were medulloblastoma (22/47; 47%) and pilocytic astrocytoma (14/47; 30%). The median time between admission and surgery was 36 days, while the median post-operation stay was 19.5 days. CONCLUSIONS: The feasibility of a basic EMR platform for a busy pediatric neurosurgery department in a lower-middle income country is demonstrated, and preliminary clinical data is reviewed. A wide variety of pediatric CNS tumors were observed, spanning the spectrum of anatomic locations and histopathologic subtypes. Surgical intervention was performed for the majority of patients. Barriers to care include limited molecular diagnostics and unavailable data on adjuvant therapy. Future targets include improvement of clinical documentation in the pre-operative and post-operative period.

Arsenic exposure during pregnancy and postpartum maternal glucose tolerance: evidence from Bangladesh.

BACKGROUND: Arsenic exposure has been associated with gestational diabetes mellitus. However, the extent to which arsenic exposure during pregnancy is associated with postpartum glucose intolerance is unknown. METHODS: We studied 323 women in Bangladesh. We assessed arsenic exposure in early pregnancy via toenail and water samples. We measured fasting glucose and insulin in serum at a mean (SD) of 4.0 (3.5) weeks post-delivery. We ran covariate-adjusted, linear regression models to examine associations of arsenic concentrations with HOMA-IR, a marker of insulin resistance, and HOMA-ß, a marker of beta cell function. RESULTS: Median (IQR) arsenic concentration was 0.45 (0.67) µg/g in toenails and 2.0 (6.5) µg/L in drinking water. Arsenic concentrations during pregnancy were not associated with insulin resistance or beta cell function postpartum. HOMA-IR was 0.07% (- 3.13, 3.37) higher and HOMA-ß was 0.96% (- 3.83, 1.99) lower per IQR increment in toenail arsenic, but effect estimates were small and confidence intervals crossed the null. CONCLUSIONS: Although arsenic exposure during pregnancy has been consistently associated with gestational diabetes mellitus, we found no clear evidence for an adverse effect on postpartum insulin resistance or beta cell function.

Parental metal exposures as potential risk factors for spina bifida in Bangladesh.

BACKGROUND: Neural tube defects are a pressing public health concern despite advances in prevention from folic acid-based strategies. Numerous chemicals, in particular arsenic, have been associated with neural tube defects in animal models and could influence risk in humans. OBJECTIVES: We investigated the relationship between parental exposure to arsenic and 17 metals and risk of neural tube defects (myelomeningocele and meningocele) in a case control study in Bangladesh. METHODS: Exposure assessment included analysis of maternal and paternal toenail samples using inductively coupled plasma mass spectrometry (ICP-MS). A total of 278 participants (155 cases and 123 controls) with data collected from 2016 to 2020 were included in the analysis. RESULTS: In the paternal models, a one-unit increase in the natural logarithm of paternal toenail arsenic was associated with a 74% (odds ratio: 1.74, 95% confidence interval: 1.26-2.42) greater odds of having a child with spina bifida, after adjusting for relevant covariates. Additionally, paternal exposure to aluminum, cobalt, chromium, iron, selenium, and vanadium was associated with increased odds of having a child with spina bifida in the adjusted models. In the maternal models, a one-unit increase in the natural logarithm of maternal toenail selenium and zinc levels was related to a 382% greater (odds ratio: 4.82, 95% confidence interval: 1.32-17.60) and 89% lower (odds ratio: 0.11, 95% confidence interval: 0.03-0.42) odds of having a child with spina bifida in the adjusted models, respectively. Results did not suggest an interaction between parental toenail metals and maternal serum folate. DISCUSSION: Parental toenail levels of numerous metals were associated with increased risk of spina bifida in Bangladeshi infants. Paternal arsenic exposure was positively associated with neural tube defects in children and is of particular concern given the widespread arsenic poisoning of groundwater resources in Bangladesh and the lack of nutritional interventions aimed to mitigate paternal arsenic exposure. The findings add to the growing body of literature of the impact of metals, especially paternal environmental factors, on child health.

Therapeutic efficacy of arginine-rich exenatide on diabetic neuropathy in rats.

Diabetes mellitus is characterized by metabolic dysregulation associated with a number of health complications. More than 50% of patients with diabetes mellitus suffer from diabetic polyneuropathy, which involves the presence of peripheral nerve dysfunction symptoms. The aim of this study was to evaluate the potential of a new synthetic arginine-rich exendin-4 (Peptide D) in the treatment of complications caused by diabetes, including peripheral neuropathy, in rats. Diabetes was induced by administering streptozotocin (STZ). Three groups of diabetic rats were treated with Peptide D (0.1, 1, and 10 µg/kg). One group of diabetic rats was treated with Byetta® (1 µg/kg) for 80 days. Neuropathic pain development was assessed by tactile allodynia. STZ-treated rats showed an increased level of tactile allodynia unlike naïve animals. A histological study revealed that the diameter of the sciatic nerve fibers in STZ-treated rats was smaller than that of the naïve animals. An IHC study demonstrated decreased expression of myelin basic protein (MBP) in the sciatic nerve of diabetic rats compared to that in the naïve animals. Peptide D reduced the severity of tactile allodynia. This effect was more pronounced in the Peptide D treated groups than in the group treated with Byetta®. Peptide D and Byetta® treatment resulted in increased MBP expression in the sciatic nerve and increased diameter of myelinated nerve fibers. These findings suggest that poly-arginine peptides are promising agents for the treatment of peripheral polyneuropathies.

Characterisation of porcine epidemic diarrhea virus isolates during the 2014-2015 outbreak in the Philippines.

The viral agent of the porcine epidemic diarrhea (PED) was investigated during the reported 2014-2015 outbreaks in commercial farms in Central Luzon, Philippines. The study covered detection of PED virus (PEDV) in fecal and intestinal samples through reverse transcription PCR and sequence analysis of the nucleocapsid (N) gene. Results showed that 10 out of 34 fecal and intestinal samples examined were positive for PEDV. The partial nucleotide sequence of the N gene of the field samples showed 98-99% homologous to PEDV sequences registered in the GenBank. It was also noted that N gene sequences between field samples were 98% homologous. Interestingly, the partial sequences of the N genes of the field samples were genetically similar to the PEDV isolates from USA, China, Mexico, Canada and Japan. The phylogenetic tree analysis revealed that the Philippine samples clustered in group 2-1 of the PEDV, wherein the isolates of this group were responsible for the outbreaks in Asia and the USA. Analysis of the partial nucleotide and amino acid sequences revealed polymorphisms, deletions and insertions in the N-gene of the PEDV. Amino acid sequence alignment also showed deletions and insertion in the PEDV detected in the Philippines.

Do Prior Driveline Infections Increase the Risk of Infection in Heart Transplant Patients Treated With Rabbit Antithymocyte Globulin Induction Therapy?

BACKGROUND: The use of mechanical circulatory support devices (MCSDs) has been increasing over the past several years. Driveline infections (DLIs) are one of the most common complications seen in these patients; reportedly, up to 50% of patients with MCSDs can develop this complication. It is believed that the removal of the driveline results in treatment of the localized infection area. MCSD patients are also known to develop circulating antibodies. These circulating antibodies have been associated with poor outcomes after heart transplantation. The use of rabbit antithymocyte globulin (ATG) as induction therapy reportedly decreases the development of circulating antibodies; it is now commonly used in sensitized patients undergoing heart transplantation. It is unknown whether ATG induction therapy immediate posttransplant will increase the risk of infection of those MCSD patients with DLIs. METHODS: Between 2003 and 2013, we evaluated 57 MCSD patients who subsequently underwent heart transplantation and received ATG induction therapy. Patients were divided into those with previous MCSD DLI and those without, and they were assessed for 1-year freedom from infection (specifically, sternal wound infections). One-year survival and freedom from treated rejection, both cellular and antibody mediated, were also assessed. RESULTS: MCSD patients with DLIs who received ATG induction did not have a lower freedom from any treated infection and from sternal wound infection posttransplant compared with those MCSD patients without DLIs and not treated with ATG induction. There were also no significant differences between the 2 groups in terms of 1-year posttransplant survival and freedom from treated rejection. CONCLUSIONS: The use of ATG induction in patients with prior DLIs did not seem to increase the risk for posttransplant infection (eg, sternal wound infection). ATG induction can therefore be safely used in this population.

Colistin and tigecycline susceptibility among multidrug-resistant Acinetobacter baumannii isolated from ventilator-associated pneumonia.

Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most important pathogens in intensive care units related to morbidity and mortality, especially in ventilator-associated pneumonia (VAP). In this study, 80.5% of isolates were MDR. The antimicrobial susceptibilities for 12 different antibiotics of MDR A. baumannii isolated from VAP were tested. Among the MDR A. baumannii isolates, resistance rates were found to be 95.5%, 72.7%, 80.3%, 71.2% and 68.2% for ciprofloxacin, cefepime, imipenem, meropenem and cefoperazone/sulbactam, respectively. Netilmicin resistance was detected in 30.3% of the isolates. Resistance rates for colistin and tigecycline were 0% and 25.8%, respectively. It is obvious that new alternative drugs are needed for the treatment of MDR A. baumannii-related VAP owing to high resistance to carbapenems, quinolones, aminoglycosides and cefoperazone/sulbactam. Although colistin appears to be a good choice, adverse reactions and unavailability of colistin limit its wide usage in Turkey. Tigecycline, which will shortly be introduced commercially in Turkey, is very effective against MDR A. baumannii isolates and shows promising results to solve the problem, however resistance rates should be monitored closely.

Age and duration of disease as factors affecting clinical findings and sacroiliitis in brucellosis.

OBJECTIVE: Brucellosis may be seen in any age group, but it still involves young and middle aged adults more frequently. Our aim was to investigate the relationship between age and the duration of disease on clinical findings of brucellosis in adults in this study. PATIENTS AND METHOD: One hundred and sixty-three patients with brucellosis, treated in our hospital, between 1997 and 2003, were evaluated retrospectively. RESULTS: Fever was found in 60.7% of the patients, and it was significantly higher when the duration of disease was less than one month (p = 0.03). Fever was significantly lower in the > or = 65 age group (p = 0.01). Sacroiliitis was detected in 44.1% of patients. Sacroiliitis was significantly higher in the 15-35 age group (p = 0.03). There were no differences between age groups and other clinical and laboratory findings. CONCLUSIONS: Sacroiliac involvement was noted particularly in young adults who manifested lumbar pain and fever, but this might not be a major symptom of brucellosis in the elderly, or in patients showing symptoms for more than a month.

In vitro activity of eight antibiotics against Salmonella and Shigella species.

The minimum inhibitory concentrations (MICs) of ampicillin, chloramphenicol, trimetoprimsulfamethoxazole (TMP-SMX), ofloxacin, ciprofloxacin, pefloxacin, enoxacin and fleroxacin for Salmonella spp. (n = 72) and Shigella spp. (n = 52) were established. S. typhi isolates were all susceptible to all of the antibiotics tested. In non-typhi salmonellae and Shigella spp., resistance to ampicillin, chloramphenicol and TMP-SMX with various rates were encountered, but all isolates were susceptible to fluoroquinolones.

[Ofloxacin treatment of salmonella infections]. / Salmonella enfeksiyonlarinda ofloksasin tedavisi.

In the present study, 33 adult patients with salmonella infections consisting of 13 typhoid fever, 9 paratyphoid fever, 8 enterocolitis, 2 carriers, 1 acute gastroenteritis have been treated with ofloxacin. The duration of treatment was 10 days for typhoid fever, 7 days for paratyphoid fever, 5 days for enterocolitis, 3 days for acute gastroenteritis and 7 days for asymptomatic carriers. All the patients recovered without any complication and fever declined to normal levels within a mean of 3.0 +/- 1.34 days. Two carriers of S. enteritidis became salmonella free after 7 days of ofloxacin treatment. One of the patients who had severe S. paratyphi B bacteremia remained carrier for about 6 months. None of the patients have relapsed. The antibiotic therapy proposals on salmonella in adults were discussed in the light of our results and the other studies.

Contamination in contact lens care systems.

We studied the rate of contamination in the contact lens care systems and conjunctivas of 30 asymptomatic cosmetic soft contact lens wearers. In caring for their lenses, 23 patients used chemical disinfection systems (quaternary ammonium solutions), six patients used hydrogen peroxide, and one used heat. Eighteen patients used unpreserved intravenous saline solution, and only seven patients used commercially prepared preserved saline solutions. Cultures were obtained from lens cases, lens care solutions, and conjunctivas. Contamination was found in 70% of the lens care systems. Fifty-seven percent of the patients had lens case contamination, and 17% had conjunctival contamination. The most frequently isolated bacteria in the lens care systems were Pseudomonas, Staphylococcus epidermidis, and Escherichia coli. We suggest the development of more effective systems for disinfection.

[In vitro activity of various antibiotics against Shigella strains]. / Cesitli antibiyotiklerin Shigella suslarina in-vitro etkinlikleri.

The in-vitro activity of ampicillin, chloramphenicol, oxytetracycline, trimethoprim-sulfamethaxazole (TMP-SMX), cefoperazone, ceftriaxone, cefotaxime, ceftizoxime, ofloxacin, pefloxacin, ciprofloxacin and fleroxacin against clinically isolated strains of Shigella spp. (n 42) have been determined in this study. The minimum inhibitory concentrations (MICs) were established using the microtube dilution technique. In shigella strains relatively high percentage of resistance was found against ampicillin (% 36.5), chloramphenicol (% 34), oxytetracycline (% 35), and TMP-SMX (% 25.6). The antibiotic therapy proposals reviewed according to these results.

[Susceptibility of Vibrio cholerae El-Tor strains to various antibiotics]. / Vibrio cholerae El-Tor suslarinin çesitli antibiyotiklere duyarliliklarinin arastirilmasi.

In this study, the in-vitro activity of ampicillin, chloramphenicol, oxytetracycline, trimethoprim-sulfamethoxazole (TMP-SMX), cefoperazone, ceftriaxone, cefotaxime, ceftizoxime, ofloxacin, pefloxacin, ciprofloxacin, and fleroxacin against clinically isolated strains of V. cholerae biotype El-Tor have been investigated. The minimum inhibitory concentrations (MICs) were determined using the microtube dilution technique except for TMP-SMX which was tested by agar dilution technique. All of El-Tor strains tested have been found to be susceptible to all the antibiotics used in this study. The antimicrobial therapy proposals on cholera in adults reviewed.