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Congenital hearing loss is a common disorder worldwide. Heterogeneous gene variation accounts for approximately 20-25% of such patients. We investigated a five-generation Chinese family with autosomal-dominant nonsyndromic sensorineural hearing loss (SNHL). No wave was detected in the pure-tone audiometry, and the auditory brainstem response was absent in all patients. Computed tomography of the patients, as well as of two sporadic SNHL cases, showed bilateral inner ear anomaly, cochlear maldevelopment, absence of the osseous spiral lamina, and an enlarged vestibular aqueduct. Such findings were absent in nonaffected persons. We used linkage analysis and exome sequencing and uncovered a heterozygous missense mutation in the PI4KB gene (p.Gln121Arg) encoding phosphatidylinositol 4-kinase β (PI4KB) from the patients in this family. In addition, 3 missense PI4KB (p.Val434Gly, p.Glu667Lys, and p.Met739Arg) mutations were identified in five patients with nonsyndromic SNHL from 57 sporadic cases. No such mutations were present within 600 Chinese controls, the 1000 genome project, gnomAD, or similar databases. Depleting pi4kb mRNA expression in zebrafish caused inner ear abnormalities and audiosensory impairment, mimicking the patient phenotypes. Moreover, overexpression of 4 human missense PI4KB mutant mRNAs in zebrafish embryos resulted in impaired hearing function, suggesting dominant-negative effects. Taken together, our results reveal that PI4KB mutations can cause SNHL and inner ear malformation. PI4KB should be included in neonatal deafness screening.

Hyperinsulinemic hypoglycemia (HH) is characterized by unregulated insulin release, leading to persistently low blood glucose concentrations with lack of alternative fuels, which increases the risk of neurological damage in these patients. It is the most common cause of persistent and recurrent hypoglycemia in the neonatal period. HH may be primary, Congenital HH (CHH), when it is associated with variants in a number of genes implicated in pancreatic development and function. Alterations in fifteen genes have been recognized to date, being some of the most recently identified mutations in genes HK1, PGM1, PMM2, CACNA1D, FOXA2 and EIF2S3. Alternatively, HH can be secondary when associated with syndromes, intra-uterine growth restriction, maternal diabetes, birth asphyxia, following gastrointestinal surgery, amongst other causes. CHH can be histologically characterized into three groups: diffuse, focal or atypical. Diffuse and focal forms can be determined by scanning using fluorine-18 dihydroxyphenylalanine-positron emission tomography. Newer and improved isotopes are currently in development to provide increased diagnostic accuracy in identifying lesions and performing successful surgical resection with the ultimate aim of curing the condition. Rapid diagnostics and innovative methods of management, including a wider range of treatment options, have resulted in a reduction in co-morbidities associated with HH with improved quality of life and long-term outcomes. Potential future developments in the management of this condition as well as pathways to transition of the care of these highly vulnerable children into adulthood will also be discussed.

Selective estrogen receptor downregulators (SERDs) are a novel class of compounds capable of reducing the ERα protein level and blocking ER activity. Therefore, SERDs are considered as a significant therapeutic approach to treat ER+ breast cancer in both early stage and more advanced drug-resistant cases. After the FDA approval of a steroidal drug, fulvestrant, as a SERD for the treatment of breast cancer in patients who have progressed on antihormonal agents, several molecules with diverse chemical structures have been rapidly developed, studied and evaluated for selective estrogen receptor downregulation activity. Here we compile the promising SERDs reported in recent years and discuss the chemical structure and pharmacological profile of the most potent compound of the considered series. Because of the availability of only a limited number of effective drugs for the treatment of breast cancer, the quest for a potent SERD with respectable activity and bioavailability is still ongoing. The goal of this article is to make available to the reader an overview of the current progress in SERDs and provide clues for the future discovery and development of novel pharmacological potent SERDs for the treatment of breast cancer.

Berries are natural sources of anthocyanins, especially cyanidin-3-glucoside (C3G), and exhibit significant antioxidant, antidiabetic, anti-inflammatory, and cytoprotective effects against various oxidative stress-induced disorders. C3G and its metabolites possess higher absorption and bioavailability, and interaction with gut microbiota may enhance their health benefits. Various in vitro studies have shown the reactive oxygen species (ROS)-mitigating potential of C3G. However, in in vivo models, C3G exerts its cytoprotective properties by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant-responsive element (ARE) pathway. Despite existing reports stating various health benefits of C3G, its antioxidant potential by modulating the Nrf2 pathway remains less identified. This review discusses the Nrf2-mediated antioxidant response of C3G in modulating oxidative stress against DNA damage, apoptosis, carcinogen toxicity, and inflammatory conditions. Furthermore, we have reviewed the recent clinical trial data to establish cross talk between a berry-rich diet and disease prevention.

The p53 protein plays a central role in mediating immune functioning and determines the fate of the cells. Its role as a tumor suppressor, and in transcriptional regulation and cytokine activity under stress conditions, is well defined. The wild type (WT) p53 functions as a guardian for the genome, while the mutant p53 has oncogenic roles. One of the ways that p53 combats carcinogenesis is by reducing inflammation. WT p53 functions as an anti-inflammatory molecule via cross-talk activity with multiple immunological pathways, such as the major histocompatibility complex I (MHCI) associated pathway, toll-like receptors (TLRs), and immune checkpoints. Due to the multifarious roles of p53 in cancer, it is a potent target for cancer immunotherapy. Plant flavonoids have been gaining recognition over the last two decades to use as a potential therapeutic regimen in ameliorating diseases. Recent studies have shown the ability of flavonoids to suppress chronic inflammation, specifically by modulating p53 responses. Further, the anti-oxidant Keap1/Nrf2/ARE pathway could play a crucial role in mitigating oxidative stress, leading to a reduction of chronic inflammation linked to the prevention of cancer. This review aims to discuss the pharmacological properties of plant flavonoids in response to various oxidative stresses and immune dysfunctions and analyzes the cross-talk between flavonoid-rich dietary intake for potential disease prevention.

Objective Bone loss in anorexia nervosa and following bariatric surgery is associated with an elevated circulating concentration of the gastrointestinal, anorexigenic hormone, peptide YY (PYY). Selective deletion of the PYY receptor Y1R in osteoblasts or Y2R in the hypothalamus results in high bone mass, but deletion of PYY in mice has resulted in conflicting skeletal phenotypes leading to uncertainty regarding its role in the regulation of bone mass. As PYY analogs are under development for treatment of obesity, we aimed to clarify the relationship between PYY and bone mass. Methods The skeletal phenotype of Pyy knockout (KO) mice was investigated during growth (postnatal day P14) and adulthood (P70 and P186) using X-ray microradiography, micro-CT, back-scattered electron scanning electron microscopy (BSE-SEM), histomorphometry and biomechanical testing. Results Bones from juvenile and Pyy KO mice were longer (P, Highlights • Juvenile Pyy KO mice have accelerated growth and reduced bone mass. • Adult Pyy KO mice have increased bone mass and mineralisation. • Adult Pyy KO mice have increased osteoblastic bone formation and mineral apposition. • Adult Pyy KO mice have increased bone strength despite increased porosity. • Elevated PYY implicated in the pathogenesis of weight loss related osteoporosis.

Introduction: Congenital hyperinsulinism (CHI) is a rare condition which leads to unregulated insulin secretion causing hyperinsulinemic hypoglycemia. At present, genetic abnormalities in nine different genes have been described which lead to unregulated insulin secretion. Typically CHI presents in the newborn period but it can present in infancy and childhood. The hypoglycemia is usually severe and can lead to brain damage if not managed appropriately. At a histological level, there are two major subtypes of CHI, namely focal and diffuse. The management of diffuse CHI (DCHI) remains a real challenge.Areas covered: This review provides an overview of the clinical characteristics of CHI, the known genetic causes, pancreatic histology, medical management and pharmacology of the medications currently in use.Expert opinion: Until recently, most patients with DCHI required a near total pancreatectomy and nearly all of these patients then develop life-long diabetes mellitus. There is now intensive research focu...

Congenital hyperinsulinism (CHI) is a common cause of hypoglycaemia due to unregulated insulin secretion from pancreatic β cells. Medical management includes use of oral diazoxide (a KATP channel agonist) and daily injectable octreotide (somatostatin analogue) therapy. However, diazoxide is associated with severe sideeffects such as coarse facies, hypertrichosis and psychosocial/compliance issues in adolescents. Lanreotide (a long-acting somatostatin analogue) is used in adults with neuroendocrine tumours; however, its role in patients with CHI has not been well described. A 15-year-old girl with diazoxide-responsive CHI had severe hypertrichosis secondary to diazoxide and subsequent compliance/psychosocial issues. She was commenced on 30 mg of lanreotide every 4 weeks as a deep subcutaneous injection, in an attempt to address these issues. She was able to come off diazoxide treatment 2 months after starting lanreotide. Presently, after 2.5 years of lanreotide treatment, her blood glucose control is stable with complete resolution of hypertrichosis. Clinically significant improvements in the self-reported Paediatric Quality of Life (PedsQL) questionnaire and Strengths and Difficulties Questionnaire (SDQ) were reported after 1 year on lanreotide. No side effects were found, and her liver/thyroid function and abdominal ultrasound have been normal. We report the first case on the use of lanreotide in an adolescent girl with diazoxide-responsive CHI with significant improvement of quality of life.

Penelitian ini membahas tentang Kualitas Pelayanan Izin Mendirikan Bangunan (IMB) di Dinas Penanaman Modal Pelayanan Terpadu Satu Pintu (DPMPTSP) Kabupaten Ciamis, dengan menggunakan teori servqual dari Zeithaml mengukur 5 dimensi, yaitu Tangible, Reliabillity, Assurance, responsiveness dan Empathy. Penelitian ini merupakan penelitian jenis kualitatif dengan tekhnik pengumpulan data dengan menggunakan studi kepustakaan, dan studi lapangan berupa observasi dan wawancara dengan 6 informan yaitu, Kepala DPMPTSP, Kabid Perizinan, Kabid Pengaduan dan Advokasi, Petugas Frontliner, Kabid Kepegawaian dan Pemohon Perzinan IMB.Berdasarkan hasil penelitian, Kualitas Pelayanan di DPMPTSP Kabupaten Ciamis masih belum berjalan secara efektif dan efisien dikarenakan kurang nya SDM si bagian pelayanan perizinan DPMPTSP Kabupaten Ciamis, kurangnya kemampuan petugas dan sarana untuk menunjang online service. Kata kunci : Kualitas Pelayanan, Izin Mendirikan Bangunan, Servqual.AbstractThis study discusses the Quality of Building Construction Permits (IMB) at the Ciamis District One-Stop Integrated Services Investment Office (DPMPTSP), using the servqual theory from Zeithaml to measure 5 dimensions, namely Tangible, Reliabillity, Assurance, Responsiveness and Empathy. This research is a qualitative type of research with data collection techniques using library studies, and field studies in the form of observation and interviews with 6 informants namely, Head of DPMPTSP, Head of Licensing, Head of Complaints and Advocacy, Frontliner Officers, Head of Personnel and IMB Licensing Applicants. research, Service Quality in DPMPTSP Ciamis Regency still has not run effectively and efficiently because of the lack of human resources in the licensing service section of DPMPTSP in Ciamis Regency, lack of staff ability and means to support online services.Keywords: Service Quality, Building Construction Permit, Servqual.

Summary Pancreatic β cells are functionally programmed to release insulin in response to changes in plasma glucose concentration. Insulin secretion is precisely regulated so that, under normal physiological conditions, fasting plasma glucose concentrations are kept within a narrow range of 3·5–5·5 mmol/L. In hyperinsulinaemic hypoglycaemia, insulin secretion becomes dysregulated (ie, uncoupled from glucose metabolism) so that insulin secretion persists in the presence of low plasma glucose concentrations. Hyperinsulinaemic hypoglycaemia is the most common cause of severe and persistent hypoglycaemia in neonates and children. At a molecular level, mutations in nine different genes can lead to the dysregulation of insulin secretion and cause this disorder. In adults, hyperinsulinaemic hypoglycaemia accounts for 0·5–5·0% of cases of hypoglycaemia and can be due either to β-cell tumours (insulinomas) or β-cell hyperplasia. Rapid diagnosis and prompt management of hyperinsulinaemic hypoglycaemia is essential to avoid hypoglycaemic brain injury, especially in the vulnerable neonatal and childhood periods. Advances in the field of hyperinsulinaemic hypoglycaemia include use of rapid molecular genetic testing for the disease, application of novel imaging techniques (6-[fluoride-18]fluoro-levodopa [ 18 F-DOPA] PET-CT and glucagon-like peptide 1 (GLP-1) receptor imaging), and development of novel medical treatments (eg, long-acting octreotide formulations, mTOR inhibitors, and GLP-1 receptor antagonists) and surgical therapies (eg, laparoscopic surgery).

Glucose is the key metabolic substrate for tissue energy production. In the perinatal period the mother supplies glucose to the fetus and for most of the gestational period the normal lower limit of fetal glucose concentration is around 3 mmol/L. Just after birth, for the first few hours of life in a normal term neonate appropriate for gestational age, blood glucose levels can range between 1.4 mmol/L and 6.2 mmol/L but by about 72 h of age fasting blood glucose levels reach normal infant, child and adult values (3.5–5.5 mmol/L). Normal blood glucose levels are maintained within this narrow range by factors which control glucose production and glucose utilisation. The key hormones which regulate glucose homoeostasis include insulin, glucagon, epinephrine, norepinephrine, cortisol and growth hormone. Pathological states that affect either glucose production or utilisation will lead to hypoglycaemia. Although hypoglycaemia is a common biochemical finding in children (especially in the newborn) it is not possible to define by a single (or a range of) blood glucose value/s. It can be defined as the concentration of glucose in the blood or plasma at which the individual demonstrates a unique response to the abnormal milieu caused by the inadequate delivery of glucose to a target organ (eg, the brain). Hypoglycaemia should therefore be considered as a continuum and the blood glucose level should be interpreted within the clinical scenario and with respect to the counter-regulatory hormonal responses and intermediate metabolites.

Background Alstrom syndrome (AS) is an extremely rare, autosomal recessive disorder characterised by multi-organ features that typically manifest within the first two decades of life. AS is caused by mutations in the Alstrom syndrome 1 (ALMS1) gene located at 2p13.1. Methods In the current study, two brothers from a first-cousin consanguineous family presented with a complex phenotype and were suspected of having AS. Results Both brothers were found to be homozygous for a novel nonsense c.7310C>A (p.S2437X) mutation in exon-8 of ALMS1 gene. The consanguineous parents were sequenced and both were heterozygous for the same mutation. Conclusions This particular mutation has never been reported before and confirmed the diagnosis of AS in the patients. Our work identifies a novel mutation in ALMS1 gene responsible for the complex phenotype of AS in these patients.

Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic β-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8,KCNJ11,GLUD1,GCK,HNF4A,HNF1A,SLC16A1,UCP2andHADH) have been identified which cause CHI. Autosomal recessive and dominant mutations inABCC8/KCNJ11are the commonest cause of medically unresponsive CHI. Mutations inGLUD1andHADHlead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities inHNF4AandHNF1Alead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.

Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N 6 -methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO “obesity-risk” rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N 6 -methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N 6 -methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans.