Hereditary vitamin D resistant rickets (HVDRR) case series: phenotype, genotype, conventional treatment, and adjunctive cinacalcet therapy.

INTRODUCTION: Hereditary vitamin D resistant rickets (HVDRR) is a rare autosomal recessive disorder marked by end-organ resistance of 1,25-dihydroxyvitamin D secondary to various mutations in the vitamin D receptor gene. The currently accepted treatment modality involves bypassing the affected receptors in the gut with high-dose intravenous calcium. In a few limited case reports, cinacalcet, a calcimimetic, has been used as an adjunctive therapy. MATERIAL AND METHODS: Retrospective chart reviews were conducted to collect the clinical and biochemical data of 8 patients with HVDRR from 5 Saudi families. Four patients received only high-dose calcium, while the remaining 4 received adjuvant cinacalcet. Serum chemistry and PTH levels were measured before and during cinacalcet treatment. Gene sequencing was performed to identify the disease-causing mutation. RESULTS: All 8 patients exhibited alopecia and secondary hyperparathyroidism. Other clinical and biochemical features of rickets were present to varying degrees. Genetic analysis revealed 3 distinct mutations: a ligand-binding domain mutation in 3 unrelated patients, a ligand-binding domain mutation in 2 sisters, and a missense DNA-binding domain mutation in 3 brothers. While the overall response to therapy was variable, none of the 4 patients who received adjunctive cinacalcet developed hypocalcaemia, and there was some initial promise in improving serum PTH levels. CONCLUSIONS: This series provides new insight into the clinical and biochemical characteristics as well as treatment responses in Saudi children with HVDRR. The findings suggest that cinacalcet is a safe and potentially valuable adjuvant in this understudied population; however, further research is required to verify these results.

Synergistic enhancement of maize crop yield and nutrient assimilation via zinc oxide nanoparticles and phosphorus fertilization.

BACKGROUND: Low recovery of conventional fertilizers remains a significant bottleneck for maize production globally. In particular, with phosphate fertilization, zinc (Zn) is prone to precipitation in soil, reducing recovery of both phosphorus (P) and Zn by maize. RESULTS: The present study was designed to investigate the synergistic effect of zinc oxide (ZnO) nanoparticles (NPs) and P on maize crop growth, yield, and nutrient uptake under ZnO seed coating and foliar application in a randomized complete block design. However, plants were subjected to two ZnO NPs levels (0.5 and 12 kg ha-1) amended with two P levels (45 and 90 kg ha-1). ZnO NPs, especially in the form of foliar application, with a P dose of 90 Kg ha-1 significantly (P < 0.05) improved maize crop growth, yield, and nutrient uptake compared with control. In comparison with the control group, plants grown in these conditions absorbed higher levels of Zn and P. Zn uptake rose to 16.34 g ha-1, 137.88 g ha-1, and 166.89 g ha-1 in roots, grains, and stover respectively, and P uptake increased to 0.80 mg kg-1, 10.066 mg kg-1, and 12.17 mg kg-1 respectively. Additionally, seed emergence rate, plant height, and cob length increased by up to 2%, 1177 cm2, and 3.3 cm respectively compared with control. Furthermore, Zn use efficiency was increased up to 38.55% in ZnO NPs foliar application. CONCLUSIONS: Application of ZnO NPs at 0.5 kg ha-1 in the form of foliar application with 90 kg ha-1 P dose produced a more pronounced increment in the parameters studied than ZnO NPs seed coating did. © 2024 Society of Chemical Industry.

Formulation development of pharmaceutical nanoemulgel for transdermal delivery of feboxostat: Physical characterization and in vivo evaluation.

This study aimed to fabricate and characterize feboxostat (FXT) loaded nanoemulgel (NEG) for transdermal delivery. NEG was prepared by high sheared homogenization technique and characterized for thermodynamic stability, pH analysis, drug content, zeta analysis, viscosity, spreadability, FTIR, in-vitro drug release and ex-vivo permeation. In vivo anti-inflammatory activity was evaluated in albino rats by inducing edema in hind paws using carrageenan. The formulations showed optimum thermodynamic stability, having no phase separation and color change. The pH was in the range of human skin range i.e. 5.5-6.5. The drug content of F3 and F4 formulations were 97.56 ± 3.45 % and 83.88 ± 3.12 % respectively which were in official limit of USP i.e. 90 ± 10 %. No interaction was found between the FXT and various components after FTIR analysis. The viscosity of NEG was 4587 cp at 6 rpm and 2681 cp at 12 rpm. The droplet sizes of F1 (Blank NE), F2 (Blank NEG), F3 (Drug loaded NE) and F4 (Drug loaded NEG) were 148.6 nm, 153.4 nm, 402.1 nm and 498.3 nm respectively. The percent drug release of F3 was 82 ± 0.97 %, while F4 released 78 ± 0.91 % after 24 h. The drug permeation was 77 ± 1.28 % and 74 ± 1.10 % for F3 and F4 respectively. The optimized formulation significantly (p < 0.05; ANOVA) inhibited the paw edema in albino rats as compared to the control and standard group. It has been concluded that FXT loaded NEG can be a safe and effective alternative to the oral therapy of FXT.

Environmental implications of phosphate-based fertilizer industrial waste and its management practices.

During the green revolution in the mid-twentieth century, the consumption of inorganic phosphorous and phosphate-based fertilizers (P-fertilizers) in the developing world skyrocketed, resulting in a proliferation of P-fertilizer industries. Phosphate-based fertilizer industries are ranked among the most environment-polluting industries. The worldwide phosphorus market, which was 68.5 million metric tons in 2020, is expected to increase at a compound annual growth rate (CAGR) of 2.5% to 81 million metric tons by 2027. The release of untreated hazardous pollutants from these fertilizer industries into the soil, water, and atmosphere has resulted in severe environmental health issues. Excessive surface runoff of phosphorus from agricultural fields and its deposition in water promote the growth of algae and macrophytes and lower dissolved oxygen concentration through eutrophication, which is detrimental to aquatic life. Fluorides (F-) and sulfur dioxide (SO2) and/or heavy metals (potentially toxic elements, PTEs) are also detected in the emissions from these fertilizer industries. The main solid waste generated from the phospho-gypsum plant produced up to 5 tons of di-hydrogen phosphate (H2PO4), including PTEs and radioactive substances. Phosphates and fluorenes from these industries are usually disposed of as sludge in storage ponds or trash piles. Humans inhaling poisonous gases released from the P-fertilizer industries can develop hepatic failure, autoimmune diseases, pulmonary disorders, and other health problems. The objectives of this review are to provide guidelines for eliminating the bottleneck pollutions that occur from the phosphate-based fertilizer industries and explore the management practices for its green development.

Impact of biochar on the yield and nutritional quality of tomatoes (Solanum lycopersicum) under drought stress.

BACKGROUND: Undeviating climatic instabilities have increased the incidents of drought. Crop performance and yield attributes of tomatoes are negatively affected by drought stress. Biochar is an organic amendment that can increase crop yield and nutritional value under water-deficient conditions by retaining water and providing nutrients (nitrogen, phosphorus, potassium, and other trace elements). RESULTS: The present study was designed to investigate the effects of biochar on tomato plant physiology, yield, and nutritional quality under deficit moisture regimes. Plants were subjected to two biochar levels (0.1% and 0.2%) and four moisture levels [100%, 70%, 60%, and 50% field capacities (FCs)]. Drought stress, especially 50D (50% FC), severely affected the plant morphology, physiology, yield, and fruit quality attributes. However, plants grown in biochar-amended soil showed significant increase in the studied attributes. Plant height, root length, fresh and dry weight of root, the number of fruits per plant, fruit fresh and dry weight, ash percent, crude fat, crude fiber, crude protein, and lycopene contents were increased in plants grown in biochar-amended soil under control and drought stress. CONCLUSION: Biochar at 0.2% application rate depicted a more pronounced increment in the studied parameters than 0.1% and can save 30% water without compromising tomato crop yield and nutritional value. © 2023 Society of Chemical Industry.

Study protocol of DIVERGE, the first genetic epidemiological study of major depressive disorder in Pakistan.

INTRODUCTION: Globally, 80% of the burdenof major depressive disorder (MDD) pertains to low- and middle-income countries. Research into genetic and environmental risk factors has the potential to uncover disease mechanisms that may contribute to better diagnosis and treatment of mental illness, yet has so far been largely limited to participants with European ancestry from high-income countries. The DIVERGE study was established to help overcome this gap and investigate genetic and environmental risk factors for MDD in Pakistan. METHODS: DIVERGE aims to enrol 9000 cases and 4000 controls in hospitals across the country. Here, we provide the rationale for DIVERGE, describe the study protocol and characterise the sample using data from the first 500 cases. Exploratory data analysis is performed to describe demographics, socioeconomic status, environmental risk factors, family history of mental illness and psychopathology. RESULTS AND DISCUSSION: Many participants had severe depression with 74% of patients who experienced multiple depressive episodes. It was a common practice to seek help for mental health struggles from faith healers and religious leaders. Socioeconomic variables reflected the local context with a large proportion of women not having access to any education and the majority of participants reporting no savings. CONCLUSION: DIVERGE is a carefully designed case-control study of MDD in Pakistan that captures diverse risk factors. As the largest genetic study in Pakistan, DIVERGE helps address the severe underrepresentation of people from South Asian countries in genetic as well as psychiatric research.

Clinicohematological, Mutagenic, and Oxidative Stress Induced by Pendimethalin in Freshwater Fish Bighead Carp (Hypophthalmichthys nobilis).

Currently, aquatic and terrestrial ecosystems are continuously and chronically polluted by cocktails of countless chemical compounds. The susceptibility to infections is tremendously increasing in a variety of organisms due to exposure to environmental pollutants. Pendimethalin, an herbicide, is continuously used in agriculture to remove unwanted broadleaf weeds across the globe. Therefore, this study investigates the mechanisms of toxicity of pendimethalin in freshwater fish bighead carp upon exposure to low and environmentally relevant concentrations. For this purpose, 48 fish without any clinical abnormalities were kept in a glass aquarium in different experimental groups (T0, T1, T2, and T3). These groups were treated with pendimethalin at 0.00, 0.25, 0.50, and 0.75 mg/L, respectively. Four fish were randomly picked from each experimental group and killed at 72, 96, and 120 hours of the trial to study hematobiochemical parameters and visceral tissues including the brain, liver, heart, gills, and kidneys for histopathology. Herbicide-treated fish indicated various physical and behavioral abnormalities including hypersecretion of mucus, erratic swimming, operculum movement, air gulping, tremors of fins, loss of equilibrium, and increased surface breathing. Histopathologically, gills tissues of treated fish indicated atrophied lamellae, uplifting of secondary lamellae, necrosis of primary and secondary lamellar epithelial cells, telogenesis, congestion, and lamellar fusion. Histopathological examination of liver tissues of treated fish showed mild to moderate congestion, necrosis of hepatocytes, and atrophy of hepatocytes while kidneys revealed degeneration of renal tubules, glomerular atrophy, ceroid, and necrosis of renal tubules. The erythrocyte counts, monocyte and lymphocyte counts, and hemoglobin values were significantly (P < 0.05) reduced in pendimethalin-treated fish. Results on serum biochemistry showed that the biomarkers of kidneys, heart, and liver were significantly higher in fish of treated groups. In addition, values of different biochemical reactions like reactive oxygen species (ROS), thiobarbituric acid reactive species (TBARS), total proteins, and quantity of different antioxidant enzymes including reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were significantly different when compared to untreated fish. Moreover, the percentile of different nuclear abnormalities in red blood cells and frequency of DNA damage increased significantly in treated fish. It can be concluded from the findings that pendimethalin causes its toxic effects via disruption of physiological and hematobiochemical reactions of fish.

A single-centre study of genetic mutations, audiology, echocardiogram and pulmonary function in Saudi children with osteogenesis imperfecta.

OBJECTIVES: Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders, characterised by skeletal fragility. Patients with OI may also exhibit extra-skeletal features like blue or grey scleral colour, fragile skin, easy bruising, joint laxity, short stature, deafness, cardiac valve abnormalities and abnormal pulmonary function. The objective of this study is to describe genetic mutations, prevalence of hearing issues, cardiac complications and impaired pulmonary function in children with OI. METHODS: This is a cross-sectional study of 23 Saudi children aged 6 months to 18 years who were diagnosed with OI. The revised Sillence classification (2,105) was used to classify the OI type. Whole exome sequencing was performed for genetic mutations. The hearing was assessed by either pure-tone audiometry and/or otoacoustic emission testing. Cardiac defects were screened by echocardiograms. Spirometry was performed to assess pulmonary function. Data were analysed with descriptive statistics. RESULTS: Based on the Sillence classification, 16 patients had OI type III, 6 had type IV and 1 had type I. Of the18 patients who had genetic sequencing, 66.6% had autosomal dominant and 33.3% had autosomal recessive mutations. Among children who had screening, hearing loss was diagnosed in 53% (9/17), congenital cardiac malformations in 26% (5/19) and restrictive lung disease in 70% (7/10). CONCLUSIONS: We found significant extra-skeletal features and a high yield of genetic mutations associated with OI. We suggest further studies to develop a screening protocol for extra-skeletal features in children with OI.

Use of ultrasonic aspirator for CNS tumour resection.

Ultrasonic aspirator (UA), or the Cavitron Ultrasonic Aspirator (CUSA) as it is commonly referred to, utilizes ultrasonic waves of variable range of frequencies to disintegrate and excise tumours. It is developed as a substitute of bipolar diathermy; a tool commonly employed for coagulation that uses focussed electric current and may damage tissues by virtue of contact, or by the heat that it produces. Over the last 30 years, CUSA has become increasingly popular in several soft tissue surgeries, especially brain and spine tumour resection, as it allows reduction in the use of bipolar diathermy. It is assumed that CUSA improves both surgical safety and clinical outcomes, and also reduces surgical time. Herein the authors have reviewed the available literature on the advantages of CUSA.

Management of Intracranial Haemangiopericytomas.

Haemangiopericytomas are rare tumours, commonly mistaken as meningiomas on radiology. These tumours are considered malignant and treatment involves aggressive surgery, followed by adjuvant radiation therapy, and close radiological and clinical follow ups. Herein the authors have reviewed the recent literature on the management of these tumours.

A blessing in disguise?: Assessing the impact of 2010-2011 floods on trust in Pakistan.

The existing literature concludes that natural disasters have cataclysmic effects on the economic well-being of people. But how natural disasters shape psychological behavior is still ambiguous. In this paper, we study the effects of a natural disaster on individuals' interpersonal trust in Pakistan. By exploiting a nationally representative cross-sectional survey and combining it with the district-level geospatial data on floods, we observe the positive and statistically significant impact of 2010-2011 flooding on the reported levels of trust, after 23-36 months of the exposure. Quantitatively, a 1% increase in district's exposure to flooding increases interpersonal trust by 5%, after controlling for individual and district level characteristics. Our empirical strategy enables us to control for various geographical characteristics to counter the concerns regarding the otherwise exogenous natural experiment. Next, our results suggest that flooding heterogeneously affects individuals who are male, live in urban areas, and have higher educational attainment. These findings remain robust to different sensitivity and robustness checks.

Adrenal function following acute discontinuation of glucocorticoids in children with acute lymphocytic leukemia: A prospective study.

Background: Children with acute lymphocytic leukemia (ALL) are enrolled in advanced treatment protocols involving high doses of glucocorticoids (GCs). Current protocols do not advocate tapering of GCs doses postinduction phase. Prolonged administration of supra-physiologic doses of GCs can induce transient suppression of the hypothalamic pituitary adrenal axis (HPA). Timely recognition of adrenal insufficiency is important in order to ensure that children at risk receive the necessary treatment and follow-up including stress coverage during illness and surgical procedures. Methods: 21 newly diagnosed patients with ALL aged 3-10 years old were prospectively enrolled in the study over a 2-year period. All enrolled patients received high doses of GCs as part of a chemotherapy treatment protocol. The HPA axis was assessed prior to the induction phase of chemotherapy and 1-2 weeks after un-tapered discontinuation of GCs. Results: All children had normal HPA axis at baseline. Postinduction 1 mcg ACTH stimulation test result was normal (cortisol > 500 nmol/L) in 75% of children and partially responsive in 25% (cortisol 300-500 nmol/L). None of the participants demonstrated clinically significant adrenal insufficiency following abrupt cessation of GCs. Conclusion: All children in our cohort had either normal or subnormal cortisol response during a low dose ACTH stimulation test 1 to 2 weeks following abrupt discontinuation of GCs, suggesting that any inhibition of the HPA axis is of short duration. We suggest that future studies investigate the timing of adrenal function recovery following GC discontinuation as well as whether tapering of the GC should be recommended.

Acute respiratory failure and generalized hypotonia secondary to vitamin D dependent rickets type 1A.

Vitamin D dependent rickets is a rare autosomal recessive disorder secondary to mutation in 1 α hydroxylase enzyme gene. We are presenting a case of a two-year-old boy with vitamin D dependent rickets type 1A whose diagnosis was missed for a long period and he was treated as nutritional rickets. He suffered with severe hypotonia and regressing milestones. Severe hypotonia with proximal muscle weakness caused respiratory failure which required intensive care admission and mechanical ventilation. DNA analysis revealed previously reported homozygous mutation in CYP27B1 gene (p.Arg429Pro (R429P) at exon c.1286 G > C). Rare genetic disorders of rickets are not considered in early course of disease in regions with high prevalence of vitamin D deficiency. This severe presentation of rickets highlights the need of close monitoring of treatment response and consideration of other differential diagnosis in children who are not responding to vitamin D supplements. There is a high prevalence of genetic disorders particularly autosomal recessive conditions in societies having high rate of inter-family and consanguineous marriages.

Recurrent insulinoma in a 10-year-old boy with Down's syndrome.

An insulinoma is a rare tumour with an incidence of four cases per million per year in adults. The incidence in children is not established. There is limited literature available in children with insulinoma, and only one case is reported in association with Down's syndrome in adults. Insulinoma diagnosis is frequently missed in adults as well as in children. The Whipple triad is the most striking feature although it has limited application in young children. Hypoglycaemia with elevated insulin, C-peptide and absent ketones is highly suggestive of hyperinsulinism. We present a case of 10-year-old boy with Down's syndrome with recurrent insulinoma. He was initially misdiagnosed as having an adrenal insufficiency and developed cushingoid features and obesity secondary to hydrocortisone treatment and excessive sugar intake. The tumour was successfully localised in the head of the pancreas with an MRI and octreotide scan on first presentation. Medical treatment with diazoxide and octreotide could not achieve normal blood glucose levels. The insulinoma was laparoscopically enucleated and pathological examination confirmed a neuroendocrine tumour. Subsequently, he had complete resolution of symptoms. He had a recurrence after 2 years with frequent episodes of hypoglycaemia. The biochemical workup was suggestive of hyperinsulinism. MRI and PET scan confirmed the recurrence at the same site (head of the pancreas). He had an open laparotomy for insulinoma resection. The pathology was consistent with benign insulinoma, and subsequently, he had complete resolution of symptoms. LEARNING POINTS: Insulinoma is a very rare tumour in children; it should be considered in the differential diagnosis of hypoglycaemia with absent ketones.Refractory neurological symptoms like seizure, migraine, mood changes and regression of learning abilities should suggest evaluation for hypoglycaemia.MRI with contrast and PET scan would localise the majority of pancreatic beta islet cell lesions.Medical treatment with diazoxide, octreotide and the addition of corn starch in feeds is not curative but can be supportive to maintain normoglycemia until the surgical resection.Surgical resection is the only curative treatment. The surgical procedure of choice (laparoscopic/open laparotomy) depends on local expertise, preoperative localisation, tumour size and number.Surgical treatment results in complete resolution of symptoms, but all cases should be closely followed up to monitor for recurrence. The recurrence rate is four times higher in MEN1 cases.

Neonatal severe hyperparathyroidism secondary to a novel homozygous CASR gene mutation.

Neonatal severe hyperparathyroidism (NSHPT) is a rare autosomal recessive disease. Children present within the first 6 months of life and more commonly in the first few weeks. Common presentation is poor feeding, polyuria, dehydration, lethargy, failure to thrive, hypotonia, gastrointestinal dysmotility, osteopenia and symptoms of respiratory distress due to a poorly developed chest cage. We present a case of a 2-month old girl with severe hypercalcemia and hyperparathyroidism. She was found to have a novel homozygous mutation in the acceptor splicing site of intron 4 (c.1378 -2A>G) of the calcium sensing receptor gene (CASR). This mutation causes frame shift deletion of exon 5 and insensitivity of CASR to calcium. The patient was treated with intravenous fluids, fruosemide, calcitonin, intravenous pamidronate and oral cinacalcet. She did not respond to medical treatment. Parathyroid gland imaging including ultrasound, MRI and sestamibi nuclear scan were not helpful in localizing the glands. Her symptoms resolved following total parathyroidectomy. She is being treated with alfacalcidiol and calcium supplements to maintain normal serum calcium and phosphate. She achieved her normal developmental milestones.

Consanguineous Marriages and Endocrine Diseases in Arab Societies.

The Arab societies have the highest prevalence of consanguineous marriages; this results in an increased incidence of autosomal recessive conditions. There are different trends of family marriages across the globe and also the teachings of major religions differ from each other. The culture of family marriages is no more limited in any specific part of world due to rapid and mass migration of people secondary to wars or economic reasons. The endocrine conditions are relatively less discussed in the medical literature as well as in genetic counselling programs. The aim of this review is to highlight endocrine conditions associated with consanguineous marriages; it also discusses the cultural and religious trends of family marriages; the barriers and scarcity of good counselling programs.

Gastrointestinal dysmotility and pancreatic insufficiency in 2 siblings with Donohue syndrome.

Donohue syndrome is a rare congenital syndrome of insulin-resistance and abnormal glucose homeostasis, caused by mutations in the insulin receptor (INSR) gene. It is characterized by specific phenotypic and clinical features and the diagnosis is based on clinical, biochemical and genetic criteria. We report 2 siblings with Donohue syndrome (cases 1, 2) with multiple clinical and biochemical characteristics. Both patients shared the same mutation and presented with intra-uterine growth restriction, failure to thrive, fasting hyperinsulinaemic hypoglycaemia and episodic post-prandial hyperglycaemia. Less common clinical features were also present, such as atrial septal defect and biventricular hypertrophy, clotting disorders, abnormal liver function tests and nephrocalcinosis. Interestingly, 2 previously unrecognized manifestations of the syndrome were also identified: severe gastrointestinal dysmotility (case 1) and exocrine pancreatic insufficiency (case 2). The co-existence of all the above clinical features makes these cases extremely rare. Gastrointestinal dysmotility should always be considered as a potentially fatal feature in patients with the syndrome, due to the complexity of the possible co-morbidities. In addition, our clinical experience for the first time suggests that pancreatic exocrine insufficiency may offer a possible explanation for the growth retardation observed in some patients with this syndrome. Our finding that replacement treatment with pancreatic enzymes improved weight gain (case 2) implies that all patients with Donohue syndrome should be investigated for exocrine pancreatic insufficiency.

Assessment and preparation of obese adolescents for bariatric surgery.

Obesity is generally considered an adult disease, although there has been a constant increase in the prevalence of overweight and obese children in the last few decades. Childhood obesity is not limited to developed countries, with increasing numbers being reported from developing countries as well as from Saudi Arabia. Young populations with obesity suffer from similar comorbidities as obese adults, including type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea, polycystic ovarian syndrome, pseudotumor cerebri, and fatty liver disease. Recent advances in weight loss surgery have given hope to obese adolescents who are refractory to lifestyle changes and low-calorie diet plans. This review emphasizes a holistic approach for obese adolescents and describes in detail a multidisciplinary team and their role in adolescent bariatric surgery. There are unique medical, psychological, and nutritional requirements during the pre-operative, immediate post-operative, and long-term phases to achieve a desirable outcome. Identification of an appropriate candidate for bariatric surgery is critical and must balance the risks and benefits of weight loss surgery. Different surgical procedures are available and should be tailored to the needs of the patient and the expertise of the surgeon.