Bone abnormalities affect all individuals with Down syndrome (DS) and are linked to abnormal expression of DYRK1A, a gene found in three copies in people with DS and Ts65Dn DS model mice. Previous ...work in Ts65Dn male mice demonstrated that both genetic normalization of Dyrk1a and treatment with ~9 mg/kg/day Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea and putative DYRK1A inhibitor, improved some skeletal deficits. Because EGCG treatment improved mostly trabecular skeletal deficits, we hypothesized that increasing EGCG treatment dosage and length of administration would positively affect both trabecular and cortical bone in Ts65Dn mice. Treatment of individuals with DS with green tea extract (GTE) containing EGCG also showed some weight loss in individuals with DS, and we hypothesized that weights would be affected in Ts65Dn mice after EGCG treatment. Treatment with ~20 mg/kg/day EGCG for seven weeks showed no improvements in male Ts65Dn trabecular bone and only limited improvements in cortical measures. Comparing skeletal analyses after ~20mg/kg/day EGCG treatment with previously published treatments with ~9, 50, and 200 mg/kg/day EGCG showed that increased dosage and treatment time increased cortical structural deficits leading to weaker appendicular bones in male mice. Weight was not affected by treatment in mice, except for those given a high dose of EGCG by oral gavage. These data indicate that high doses of EGCG, similar to those reported in some treatment studies of DS and other disorders, may impair long bone structure and strength. Skeletal phenotypes should be monitored when high doses of EGCG are administered therapeutically.
X-linked adrenoleukodystrophy (X-ALD) is a rare neurodegenerative disease characterized by genetic mutation of the ABCD1 gene. This gene encodes for transmembrane adrenoleukodystrophy protein (ALDP). ...Defective ALDP protein results in the accumulation of a very long chain fatty acid (VLCFA) within certain tissues and plasma. X-ALD can initially present as Addison's disease (primary adrenal insufficiency) as the accumulation of VLCFA most importantly occurs in the adrenal gland. Our 20-year-old male patient, a known case of Addison's disease, presented with vision loss, neurologic symptoms, and psychiatric issues. Neurologic symptoms included poor concentration and memory, while psychiatric problems included primarily depressive disorder and mild psychotic behavior. His Addison's disease was secondary to X-ALD. Still, he was diagnosed late due to a lack of awareness of X-ALD and a lack of resources for genetic testing in Pakistan. Therefore, the purpose of this case report is to spread knowledge and understanding of X-ALD, so that it can be ruled out as the potential cause of adrenal insufficiency in young patients, particularly males diagnosed with Addison's disease. Moreover, if the patient presents with Addison's disease and psychiatric issues, they should be tested to rule out X-ALD.
Dysfunction of the endoplasmic reticulum (ER) in insulin‐producing beta cells results in cell loss and diabetes mellitus. Here we report on five individuals from three different consanguineous ...families with infancy‐onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD. The FICD gene encodes a bifunctional Fic domain‐containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock‐in of the mutation at the FICD locus of stressed CHO cells results in inappropriately elevated levels of AMPylated BiP and compromised secretion. These findings, guided by human genetics, highlight the destructive consequences of de‐regulated BiP AMPylation and raise the prospect of tuning FICD's antagonistic activities towards therapeutic ends.
Synopsis
Modification of the endoplasmic reticulum (ER) chaperone BiP by FICD, an enzyme that adds or removes an adenosine monophosphate (AMP), regulates protein folding homeostasis. Secretory cells that produce the hormone insulin or promote neurodevelopment depend on intact ER function.
Homozygosity of an Arg371Ser mutation in FICD causes infancy‐onset diabetes mellitus and neurodevelopmental delay.
The Arg371Ser corrupts FICD by inactivating its ability to remove AMP from BiP.
Inappropriately, elevated levels of AMPylated BiP interfere with secretion, suggesting a molecular mechanism for this genetic disorder.
Modification of the endoplasmic reticulum (ER) chaperone BiP by FICD, an enzyme that adds or removes an adenosine monophosphate (AMP), regulates protein folding homeostasis. Secretory cells that produce the hormone insulin or promote neurodevelopment depend on intact ER function.
Mucormycosis is a cause of fulminant necrotising fungal infection in children with underlying immunocompromising conditions. Rhino-orbito-cerebral infection is its most common form in the paediatric ...group with uncontrolled diabetes mellitus or diabetic ketoacidosis. The initial presentation can mimic a bacterial infection; thus a high index of suspicion is needed for timely intervention to reduce morbidity and mortality. We have presented a case of rhino-orbito-cerebral mucormycosis (ROCM) in two patients with diabetic ketoacidosis for the first time from Pakistan. Both the patients couldnot survive due to extensive disease on late presentation.
Precise enteric fever disease burden data are needed to inform prevention and control measures, including the use of newly available typhoid vaccines. We established the Surveillance for Enteric ...Fever in Asia Project (SEAP) to inform these strategies.
From September, 2016, to September, 2019, we conducted prospective clinical surveillance for Salmonella enterica serotype Typhi (S Typhi) and Paratyphi (S Paratyphi) A, B, and C at health facilities in predetermined catchment areas in Dhaka, Bangladesh; Kathmandu and Kavrepalanchok, Nepal; and Karachi, Pakistan. Patients eligible for inclusion were outpatients with 3 or more consecutive days of fever in the last 7 days; inpatients with suspected or confirmed enteric fever; patients with blood culture-confirmed enteric fever from the hospital laboratories not captured by inpatient or outpatient enrolment and cases from the laboratory network; and patients with non-traumatic ileal perforation under surgical care. We used a hybrid surveillance model, pairing facility-based blood culture surveillance with community surveys of health-care use. Blood cultures were performed for enrolled patients. We calculated overall and age-specific typhoid and paratyphoid incidence estimates for each study site. Adjusted estimates accounted for the sensitivity of blood culture, the proportion of eligible individuals who consented and provided blood, the probability of care-seeking at a study facility, and the influence of wealth and education on care-seeking. We additionally calculated incidence of hospitalisation due to typhoid and paratyphoid.
A total of 34 747 patients were enrolled across 23 facilitates (six tertiary hospitals, surgical wards of two additional hospitals, and 15 laboratory network sites) during the study period. Of the 34 303 blood cultures performed on enrolled patients, 8705 (26%) were positive for typhoidal Salmonella. Adjusted incidence rates of enteric fever considered patients in the six tertiary hospitals. Adjusted incidence of S Typhi, expressed per 100 000 person-years, was 913 (95% CI 765-1095) in Dhaka. In Nepal, the adjusted typhoid incidence rates were 330 (230-480) in Kathmandu and 268 (202-362) in Kavrepalanchok. In Pakistan, the adjusted incidence rates per hospital site were 176 (144-216) and 103 (85-126). The adjusted incidence rates of paratyphoid (of which all included cases were due to S Paratyphi A) were 128 (107-154) in Bangladesh, 46 (34-62) and 81 (56-118) in the Nepal sites, and 23 (19-29) and 1 (1-1) in the Pakistan sites. Adjusted incidence of hospitalisation was high across sites, and overall, 2804 (32%) of 8705 patients with blood culture-confirmed enteric fever were hospitalised.
Across diverse communities in three south Asian countries, adjusted incidence exceeded the threshold for "high burden" of enteric fever (100 per 100 000 person-years). Incidence was highest among children, although age patterns differed across sites. The substantial disease burden identified highlights the need for control measures, including improvements to water and sanitation infrastructure and the implementation of typhoid vaccines.
Bill & Melinda Gates Foundation.
Recently, the minimal invasive tissue sampling (MITS) procedure has been developed to support determination of the cause of death as an alternate to conventional autopsy, especially in countries ...where complete diagnostic autopsy is not routine. To assess the feasibility of implementation of the MITS procedure for a study to determine cause of death in premature births and stillbirths in south Asia, we explored the views and perceptions of parents and religious leaders on the acceptability of MITS.
A qualitative study was conducted at the National Institute of Child Health (NICH) hospital of Karachi, Pakistan. Focus group discussions (FGDs) were conducted with parents of newborns who visited well-baby clinics of the NICH hospital for post-natal check-ups. Key-informant interviews (KIIs) were conducted with religious leaders. Data were analyzed using NVivo 10 software.
A total of 13 interviews (FGDs = 8; KIIs = 5) were conducted. Three overarching themes were identified: (I) acceptability of MITS; (II) concerns affecting the implementation of MITS; and (III) religious and cultural perspectives. Participants' acceptance of MITS was based on personal, religious, cultural and social beliefs. Parents widely recognized the need for this procedure in cases where the couple had experienced multiple stillbirths, neonatal deaths and miscarriages. Counseling of parents was considered vital to address emotional concerns of the parents and the family. Religious leaders indicated acceptability of the MITS procedure from a religious perspective and advised that respect for the deceased and consent of the guardians is mandatory when performing MITS.
This qualitative study provided a unique opportunity to understand the views of parents and religious leaders towards the use of MITS. Generally, MITS appears to be an acceptable method for identifying the cause of death in neonates and stillbirths, provided that the deceased is respected and buried as soon as possible without any delays and parents are counseled appropriately. Findings from this research are essential in approaching families for consent for MITS.
In South Asia, where most stillbirths and neonatal deaths occur, much remains unknown about the causes of these deaths. About one-third of neonatal deaths are attributed to prematurity, yet the ...specific conditions which cause these deaths are often unclear as is the etiology of stillbirths. In low-resource settings, most women are not routinely tested for infections and autopsy is rare.
This prospective, cohort study will be conducted in hospitals in Davengere, India and Karachi, Pakistan. All women who deliver either a stillbirth or a preterm birth at one of the hospitals will be eligible for enrollment. With consent, the participant and, when applicable, her offspring, will be followed to 28-days post-delivery. A series of research tests will be conducted to determine infection and presence of other conditions which may contribute to the death. In addition, all routine clinical investigations will be documented. For both stillbirths and preterm neonates who die ≤ 28 days, with consent, a standard autopsy as well as minimally invasive tissue sampling will be conducted. Finally, an expert panel will review all available data for stillbirths and neonatal deaths to determine the primary and contributing causes of death using pre-specified guidance.
This will be among the first studies to prospectively obtain detailed information on causes of stillbirth and preterm neonatal death in low-resource settings in Asia. Determining the primary causes of death will be important to inform strategies most likely to reduce the high mortality rates in South Asia.
Clinicaltrials.gov ( NCT03438110 ) Clinical Trial Registry of India ( CTRI/2018/03/012281 ).
Abstract Autosomal Recessive Osteopetrosis is a genetic disorder characterized by increased bone density due to lack of resorption by the osteoclasts. Genetic studies have widely unraveled the ...molecular basis of the most severe forms, while cases of intermediate severity are more difficult to characterize, probably because of a large heterogeneity. Here, we describe the use of exome sequencing in the molecular diagnosis of 2 siblings initially thought to be affected by “intermediate osteopetrosis”, which identified a homozygous mutation in the CTSK gene. Prompted by this finding, we tested by Sanger sequencing 25 additional patients addressed to us for recessive osteopetrosis and found CTSK mutations in 4 of them. In retrospect, their clinical and radiographic features were found to be compatible with, but not typical for, Pycnodysostosis. We sought to identify modifier genes that might have played a role in the clinical manifestation of the disease in these patients, but our results were not informative. In conclusion, we underline the difficulties of differential diagnosis in some patients whose clinical appearance does not fit the classical malignant or benign picture and recommend that CTSK gene be included in the molecular diagnosis of high bone density conditions.
To create a prediction model for preterm neonatal mortality.
A secondary analysis was conducted using data from a prospective cohort study, the Project to Understand and Research Preterm Pregnancy ...Outcome South Asia. The Cox proportional hazard model was used and adjusted hazard ratios (AHR) with 95% confidence intervals (95% CI) were reported.
Overall, 3446 preterm neonates were included. The mean age of preterm neonates was 0.65 (1.25) hours and 52% were female. The preterm neonatal mortality rate was 23.3%. The maternal factors predicting preterm neonatal death was any antepartum hemorrhage, AHR 1.99 (1.60-2.47), while neonatal predictors were preterm who received positive pressure ventilation AHR 1.30 (1.08-1.57), temperature <35.5°C AHR 1.18 (1.00-1.39), and congenital malformations AHR 3.31 (2.64-4.16).
This study identified key maternal and neonatal predictors of preterm neonatal mortality, emphasizing the need for targeted interventions and collaborative public health efforts to address disparities and regional variations.
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