ABSTRACT
BACKGROUND: Substance use disorder is a growing problem worldwide, and the stigma associated with it remains a significant barrier to treatment and recovery. This study aimed to assess the perceived stigma among individuals with substance use disorders and its correlation with their socio-demographic characteristics and clinical history Parameters. METHODS: A cross-sectional study was conducted among 552 patients with substance use disorders admitted to the outpatient clinics of Mansoura University Hospital, Addiction Treatment Unit of the Psychiatry Department, and Port Said Mental Hospital, Addiction Department. Participants completed a self-administered questionnaire, which included demographic information, clinical history parameters, and the Perceived Stigma of Substance Abuse Scale (PSAS). RESULTS: The study found that almost half of the participants were aged 29 or younger, married, and had a median stigma score of 20. The vast majority of participants were male, had no previous legal problems, and had a median stigma score of 19. The most common type of substance used was opioids, and more than half of the participants were still using drugs. The highest mean stigma scores were for the items "Most people think less of a person who has been in treatment for substance use" and "Most employers will pass over the application of someone who has been treated for substance use in favor of another applicant." The perceived stigma score was significantly correlated with the severity of use but not with age or duration of use. CONCLUSION: Our study investigates self-stigma in substance use disorder (SUD), revealing its variance across demographics and clinical groups. We found that self-stigma correlates with use severity and possibly decreases with abstinence. Notably, societal bias contributes significantly to self-stigma, necessitating societal interventions. The impact of self-stigma on patient well-being highlights the need for personalized treatments and stigma reduction strategies.
Subject(s)
Hospitals, Psychiatric , Substance-Related Disorders , Humans , Male , Female , Cross-Sectional Studies , Egypt , Social Stigma , Substance-Related Disorders/psychologyABSTRACT
Sepsis is the leading cause of death of hospitalized children worldwide. Despite the established link between immune dysregulation and mortality in pediatric sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. Identifying modifiable pathobiology is an essential first step to successful translation of biologic insights into precision therapeutics. We designed a prospective, longitudinal cohort study of 88 critically ill pediatric patients with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define subphenotypes associated with targetable mechanisms of immune dysregulation. We first assessed plasma proteomic profiles and identified shared features of immune dysregulation in MODS patients with and without sepsis. We then employed consensus clustering to define three subphenotypes based on protein expression at disease onset and identified a strong association between subphenotype and clinical outcome. We next identified differences in immune cell frequency and activation state by MODS subphenotype and determined the association between hyperinflammatory pathway activation and cellular immunophenotype. Using single cell transcriptomics, we demonstrated STAT3 hyperactivation in lymphocytes from the sickest MODS subgroup and then identified an association between STAT3 hyperactivation and T cell immunometabolic dysregulation. Finally, we compared proteomics findings between patients with MODS and patients with inborn errors of immunity that amplify cytokine signaling pathways to further assess the impact of STAT3 hyperactivation in the most severe patients with MODS. Overall, these results identify a potentially pathologic and targetable role for STAT3 hyperactivation in a subset of pediatric patients with MODS who have high severity of illness and poor prognosis.
ABSTRACT
We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.
Subject(s)
Autoimmunity , Intraepithelial Lymphocytes , Membrane Glycoproteins , Receptors, Antigen, T-Cell, alpha-beta , Humans , Autoimmunity/genetics , Cell Differentiation , Homozygote , Intraepithelial Lymphocytes/immunology , Receptors, Antigen, T-Cell, alpha-beta/genetics , Membrane Glycoproteins/genetics , Loss of Function Mutation , Lymphocyte Count , Alleles , Infections/immunology , Lymphoproliferative Disorders/immunology , Pedigree , Male , Female , Middle Aged , Aged , Aged, 80 and overABSTRACT
1st episode drug naïve patients with psychosis might be at higher risk for cardiometabolic disturbances which could affect the different cognitive, and executive functions and domains of social cognition. This study aimed to study the metabolic parameters in 1st episode drug naïve patients with psychosis, to evaluate the relation of these cardiometabolic domains to the cognitive, executive functions, and social cognition. Socio-demographic characteristics of 150 first episode drug naïve patients with psychosis and 120 matched healthy control groups were collected. The current study also assessed the cardiometabolic profile and cognitive functions in both groups. Social cognition was examined by Edinburgh Social Cognition Test. The study revealed a statistically significant difference in parameters of metabolic profile among the studied groups (p < 0.001*), the scores of cognitive and executive tests were statistically significantly different (p < 0.001*). In addition, the patient's group has lowered scores of domains of social cognition (p < 0.001*). Also, the mean affective theory of mind was negatively correlated with the conflict cost of the Flanker test (r = -.185* p value = .023). The total cholesterol level (r = - 0.241**, p value = .003) and level of triglycerides (r = - 0.241**, p value = 0.003) were negatively correlated with the interpersonal domain of social cognition, the total cholesterol level is positively correlated to the total score of social cognition (r = 0.202*, p value = 0.013). Patients with 1st episode drug naïve psychosis showed disturbed cardiometabolic parameters which have deleterious effects on cognitive functions and social cognition.
Subject(s)
Cardiovascular Diseases , Cognition Disorders , Psychotic Disorders , Humans , Neuropsychological Tests , Social Cognition , Case-Control Studies , Psychiatric Status Rating Scales , Cognition Disorders/psychology , Psychotic Disorders/psychology , Cognition , Metabolome , CholesterolABSTRACT
The COVID-19 pandemic hit Afghanistan at a time when the country was most vulnerable, with a fragile healthcare system and unable to contain the disease, and meet the needs of the vulnerable people. The country has gone through four waves of the disease thus far. An analysis of the COVID-19 cases reported by the District Health Information Software-2 shows that the fourth wave has just passed in March 2022. With the resurgence of the COVID-19 cases in other countries, it is likely that the next wave might not be too far. Challenges such as the lack or insufficiency of donor funds, unstable political situation, inadequate healthcare services, insufficient healthcare workers and diagnostic capacity, illiteracy of people, poor economy and shortage of the COVID-19 vaccine are greatly threatening the nation. The de facto authority does not seem to have a clear plan to fight against the pandemic. Therefore, the international community, civil societies, healthcare workers and other stakeholders should stay alert and combine their efforts to rescue an already plagued nation. Fortunately, many COVID-19 hospitals and laboratories have resumed their activities with the funds coming from international donors. However, to combat the infection in the long term, there seems to be a great need to integrate the COVID-19 services in the existing package of healthcare services, ie the Sehatmandi project. Moreover, awareness campaigns should be continued to keep the most vulnerable groups safe and protected. Vaccination services also need to be speeded up to have a significant portion of people immunized. Public willingness towards getting the vaccine should be increased through awareness campaigns mostly conducted by social media volunteers and healthcare workers.
ABSTRACT
BACKGROUND: Respiratory viruses, air pollutants, and aeroallergens are all implicated in worsening pediatric asthma symptoms, but their relative contributions to asthma exacerbations are poorly understood. A significant decrease in asthma exacerbations has been observed during the coronavirus disease 2019 pandemic, providing a unique opportunity to study how major asthma triggers correlate with asthma activity. OBJECTIVE: To determine whether changes in respiratory viruses, air pollutants, and/or aeroallergens during the coronavirus disease 2019 pandemic were concomitant with decreased asthma exacerbations. METHODS: Health care utilization and respiratory viral testing data between January 1, 2015, and December 31, 2020, were extracted from the Children's Hospital of Philadelphia Care Network's electronic health record. Air pollution and allergen data were extracted from US Environmental Protection Agency public databases and a National Allergy Bureau-certified station, respectively. Pandemic data (2020) were compared with historical data. RESULTS: Recovery of in-person asthma encounters during phased reopening (June 6 to November 15, 2020) was uneven: primary care well and specialty encounters reached 94% and 74% of prepandemic levels, respectively, whereas primary care sick and hospital encounters reached 21% and 40% of prepandemic levels, respectively. During the pandemic, influenza A and influenza B decreased to negligible frequency when compared with prepandemic cases, whereas respiratory syncytial virus and rhinovirus infections decreased to low (though nonnegligible) prepandemic levels, as well. No changes in air pollution or aeroallergen levels relative to historical observations were noted. CONCLUSIONS: Our results suggest that viral respiratory infections are a primary driver of pediatric asthma exacerbations. These findings have broad relevance to both clinical practice and the development of health policies aimed at reducing asthma morbidity.
Subject(s)
Asthma , COVID-19 , Respiratory Tract Infections , Virus Diseases , Asthma/epidemiology , Child , Humans , Pandemics , Respiratory Tract Infections/epidemiology , SARS-CoV-2 , Virus Diseases/epidemiologyABSTRACT
The mechanism of insulin dysregulation in children with hyperinsulinism associated with inactivating mutations of short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) was examined in mice with a knock-out of the hadh gene (hadh(-/-)). The hadh(-/-) mice had reduced levels of plasma glucose and elevated plasma insulin levels, similar to children with SCHAD deficiency. hadh(-/-) mice were hypersensitive to oral amino acid with decrease of glucose level and elevation of insulin. Hypersensitivity to oral amino acid in hadh(-/-) mice can be explained by abnormal insulin responses to a physiological mixture of amino acids and increased sensitivity to leucine stimulation in isolated perifused islets. Measurement of cytosolic calcium showed normal basal levels and abnormal responses to amino acids in hadh(-/-) islets. Leucine, glutamine, and alanine are responsible for amino acid hypersensitivity in islets. hadh(-/-) islets have lower intracellular glutamate and aspartate levels, and this decrease can be prevented by high glucose. hadh(-/-) islets also have increased [U-(14)C]glutamine oxidation. In contrast, hadh(-/-) mice have similar glucose tolerance and insulin sensitivity compared with controls. Perifused hadh(-/-) islets showed no differences from controls in response to glucose-stimulated insulin secretion, even with addition of either a medium-chain fatty acid (octanoate) or a long-chain fatty acid (palmitate). Pull-down experiments with SCHAD, anti-SCHAD, or anti-GDH antibodies showed protein-protein interactions between SCHAD and GDH. GDH enzyme kinetics of hadh(-/-) islets showed an increase in GDH affinity for its substrate, α-ketoglutarate. These studies indicate that SCHAD deficiency causes hyperinsulinism by activation of GDH via loss of inhibitory regulation of GDH by SCHAD.
Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/deficiency , Carbohydrate Metabolism, Inborn Errors/enzymology , Glutamate Dehydrogenase/metabolism , Hyperinsulinism/enzymology , Insulin-Secreting Cells/enzymology , Amino Acids/metabolism , Amino Acids/pharmacology , Animals , Blood Glucose/genetics , Blood Glucose/metabolism , Carbohydrate Metabolism, Inborn Errors/genetics , Enzyme Activation/drug effects , Enzyme Activation/genetics , Glutamate Dehydrogenase/genetics , Hyperinsulinism/genetics , Insulin/blood , Ketoglutaric Acids/metabolism , Mice , Mice, KnockoutABSTRACT
BACKGROUND: Individuals infected by the novel coronavirus (SARS-CoV-2) have experienced different psychiatric manifestations during the period of infectivity and post-COVID-19 infection. Fatigue and anhedonia are among the frequently reported manifestations after recovery from this novel viral pandemic, leading to early evaluation of those patients and proper management of their complaints which have a drastic burden on different domains of life. Also, the period after recovery might have an effect on the severity of these two psychiatric presentations. AIM OF THE WORK: This cross-sectional observational study aimed to investigate the occurrence of post-COVID-19 fatigue and anhedonia and whether the duration after 2 consecutive PCR-negative tests has an implication on the severity of the above-mentioned psychiatric manifestations. METHODS: Socio-demographic characteristics of 200 post-COVID-19 patients were collected, and also, the self-assessment anhedonia scale was used to evaluate the degree of anhedonia. Fatigue assessment scale used to investigate this domain. The study targeted to find a possible correlation between the period after recovery and the other variables including anhedonia and fatigue. RESULTS: The study revealed high scores of different subtypes of self-assessment anhedonia scale (including total intensity, total frequency, and total changes scores) in the studied group, also high score of fatigue assessment scale in those patients. Positive statistically significant correlation between anhedonia and fatigue in post-COVID-19 group, also negative statistically significant correlation between duration after recovery and the other 2 variables(anhedonia and fatigue) in the examined patients. CONCLUSION: Post-COVID-19 fatigue and anhedonia were prevalent and commonly reported in the post-COVID-19 period, also the duration after 2 consecutive negative PCR tests has an implication on the severity rating scale of both anhedonia and fatigue. These findings directed our attention to those reported manifestations which affected the socio-occupational functioning of the individuals during this whole world pandemic.
Subject(s)
Anhedonia , COVID-19/complications , COVID-19/epidemiology , Fatigue/epidemiology , Adult , COVID-19/physiopathology , Cross-Sectional Studies , Fatigue/etiology , Fatigue/physiopathology , Female , Humans , Male , Middle Aged , SARS-CoV-2 , Time Factors , Post-Acute COVID-19 SyndromeABSTRACT
BACKGROUND: COVID-19 pandemic became a global health problem affecting the life of millions of people all over the world. The effects of this pandemic were not only on the physical and medical aspects but also on the psychological issues including anxiety disorders, depressive manifestations, sleep problems and others. Sleep disorders were very commonly reported during the novel Coronavirus-19 pandemic either in the acute phase of COVID-19 infection or after recovery. These sleep problems might have a drastic burden on the recovered patients' life. This study aimed to investigate the sleep in the post-Coronavirus-19 period and if has an impact on the different items of patients' quality of life. This cross-sectional observational study investigated the sleep problems in 500 patients in the post recovery period using Insomnia Severity Index and Pittsburgh sleep quality index (PSQI), their relation to this critical period and their impact on different domains of Quality of Life which was assessed by the SF36 Health Survey. RESULTS: Socio-demographic characteristics of 500 post-Coronavirus-19 patients were collected; the insomnia severity index and Pittsburgh sleep quality index evaluated the sleep pattern. The quality of life was investigated using Short Form 36 scale. The study revealed high scores of insomnia severity index (13.01 ± 4.9), Pittsburgh sleep quality index (15.37 ± 4.43), also high scores of different items of scale of quality of life in the studied group. CONCLUSION: Post-COVID-19 sleep disturbances were commonly reported in the recovery period, also these sleep deficits had an impact on the physical and mental aspects of quality of life, so these sleep problems must be managed properly especially in this critical pandemic era.
ABSTRACT
Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.
Subject(s)
COVID-19/immunology , Lymphocyte Activation , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Aging/immunology , Child , Child, Preschool , Female , Flow Cytometry , Humans , Leukopenia/immunology , Male , Young AdultABSTRACT
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic caused dramatic changes in daily routines and health care utilization and delivery patterns in the United States. Understanding the influence of these changes and associated public health interventions on asthma care is important to determine effects on patient outcomes and identify measures that will ensure optimal future health care delivery. OBJECTIVE: We sought to identify changes in pediatric asthma-related health care utilization, respiratory viral testing, and air pollution during the COVID-19 pandemic. METHODS: For the time period January 17 to May 17, 2015 to 2020, asthma-related encounters and weekly summaries of respiratory viral testing data were extracted from Children's Hospital of Philadelphia electronic health records, and pollution data for 4 criteria air pollutants were extracted from AirNow. Changes in encounter characteristics, viral testing patterns, and air pollution before and after Mar 17, 2020, the date public health interventions to limit viral transmission were enacted in Philadelphia, were assessed and compared with data from 2015 to 2019 as a historical reference. RESULTS: After March 17, 2020, in-person asthma encounters decreased by 87% (outpatient) and 84% (emergency + inpatient). Video telemedicine, which was not previously available, became the most highly used asthma encounter modality (61% of all visits), and telephone encounters increased by 19%. Concurrently, asthma-related systemic steroid prescriptions and frequency of rhinovirus test positivity decreased, although air pollution levels did not substantially change, compared with historical trends. CONCLUSIONS: The COVID-19 pandemic in Philadelphia was accompanied by changes in pediatric asthma health care delivery patterns, including reduced admissions and systemic steroid prescriptions. Reduced rhinovirus infections may have contributed to these patterns.
Subject(s)
Air Pollution/statistics & numerical data , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Child Health Services/statistics & numerical data , Coronavirus Infections/epidemiology , Pneumonia, Viral/epidemiology , Adenovirus Infections, Human/diagnosis , Adenovirus Infections, Human/epidemiology , Adolescent , Adrenal Cortex Hormones/therapeutic use , Ambulatory Care/statistics & numerical data , Asthma/physiopathology , Betacoronavirus , COVID-19 , COVID-19 Testing , Child , Child, Preschool , Clinical Laboratory Techniques , Coronaviridae Infections/diagnosis , Coronaviridae Infections/epidemiology , Coronavirus Infections/diagnosis , Coronavirus Infections/prevention & control , Emergency Service, Hospital/statistics & numerical data , Female , Hospitalization/statistics & numerical data , Hospitals, Pediatric , Humans , Influenza, Human/diagnosis , Influenza, Human/epidemiology , Male , Nitrogen Dioxide , Ozone , Pandemics/prevention & control , Paramyxoviridae Infections/diagnosis , Paramyxoviridae Infections/epidemiology , Particulate Matter , Philadelphia/epidemiology , Picornaviridae Infections/diagnosis , Picornaviridae Infections/epidemiology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/prevention & control , Respiratory Syncytial Virus Infections/diagnosis , Respiratory Syncytial Virus Infections/epidemiology , SARS-CoV-2 , Telemedicine/statistics & numerical data , Telephone , VideoconferencingABSTRACT
CONTEXT: Postprandial hypoglycemia (PPH) is a frequent complication of Nissen fundoplication in children. The mechanism responsible for the PPH is poorly understood, but involves an exaggerated insulin response to a meal and subsequent hypoglycemia. We hypothesize that increased glucagon-like peptide-1 (GLP-1) secretion contributes to the exaggerated insulin surge and plays a role in the pathophysiology of this disorder. OBJECTIVE: The aim of the study was to characterize glucose, insulin, and GLP-1 response to an oral glucose load in children with symptoms of PPH after Nissen fundoplication. DESIGN: Ten patients with suspected PPH and a history of Nissen fundoplication and eight control subjects underwent a standard oral glucose tolerance test at The Children's Hospital of Philadelphia. Blood glucose (BG), insulin, and intact GLP-1 levels were obtained at various time points. PARTICIPANTS: Children ages 4 months to 13 years old were studied. MAIN OUTCOME MEASURES: Change scores for glucose, insulin, and intact GLP-1 were recorded after an oral glucose tolerance test. RESULTS: All cases had hypoglycemia after the glucose load. Mean BG at nadir (+/- sd) was 46.7 +/- 11 mg/dl for cases (vs. 85.9 +/- 21.3 mg/dl; P < 0.0005). Mean change in BG from baseline to peak (+/- sd) was 179.3 +/- 87.4 mg/dl for cases (vs. 57.8 +/- 39.5 mg/dl; P = 0.003). Mean change in BG (+/- sd) from peak to nadir was 214.4 +/- 85.9 mg/dl for cases (vs. 55.9 +/- 41.1 mg/dl, P < 0.0005). Mean change in insulin (+/- sd) from baseline to peak was 224.3 +/- 313.7 microIU/ml for cases (vs. 35.5 +/- 22.2 microIU/ml; P = 0.012). Mean change in GLP-1 (+/- sd) from baseline to peak was 31.2 +/- 24 pm (vs. 6.2 +/- 9.5 pm; P = 0.014). CONCLUSIONS: Children with PPH after Nissen fundoplication have abnormally exaggerated secretion of GLP-1, which may contribute to the exaggerated insulin surge and resultant hypoglycemia.
Subject(s)
Fundoplication/adverse effects , Glucagon-Like Peptide 1/metabolism , Hypoglycemia/etiology , Adolescent , Blood Glucose/analysis , Child , Child, Preschool , Female , Glucose Tolerance Test , Humans , Infant , Insulin/blood , MaleABSTRACT
Studies using vitamin D-binding protein (DBP) concentrations to estimate free and bioavailable vitamin D have increased dramatically in recent years. Combinations of two single-nucleotide polymorphisms (SNPs) produce three major DBP isoforms (Gc1f, Gc1s, and Gc2). A recent study showed that DBP concentrations quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) did not differ by race, whereas a widely used monoclonal enzyme-linked immunosorbent assay (ELISA) quantified DBP differentially by isoform, yielding significantly lower DBP concentrations in black versus white individuals. We compared measurements of serum DBP using a monoclonal ELISA, a polyclonal ELISA, and LC-MS/MS in 125 participants in the Chronic Renal Insufficiency Cohort (CRIC). Serum free and bioavailable 25OHD were calculated based on DBP concentrations from these three assays in homozygous participants, and race differences were compared. We confirmed that the monoclonal ELISA quantifies DBP differentially by isoform and showed that the polyclonal ELISA is not subject to this bias. Whereas ≤9% of the variability in DBP concentrations quantified using either LC-MS/MS or the polyclonal ELISA was explained by genotype, 85% of the variability in the monoclonal ELISA-based measures was explained by genotype. DBP concentrations measured by the monoclonal ELISA were disproportionately lower than LC-MS/MS-based results for Gc1f homozygotes (median difference -67%; interquartile range [IQR] -71%, -64%), 95% of whom were black. In contrast, the polyclonal ELISA yielded consistently and similarly higher measurements of DBP than LC-MS/MS, irrespective of genotype, with a median percent difference of +50% (IQR +33%, +65%). Contrary to findings using the monoclonal ELISA, DBP concentrations did not differ by race, and free and bioavailable 25OHD were significantly lower in black versus white participants based on both the polyclonal ELISA and LC-MS/MS, consistent with their lower total 25OHD. Future studies of DBP and free or bioavailable vitamin D metabolites should employ DBP assays that are not biased by DBP genotype. © 2016 American Society for Bone and Mineral Research.
Subject(s)
Homozygote , Mass Spectrometry/methods , Polymorphism, Single Nucleotide , Renal Insufficiency, Chronic/blood , Vitamin D-Binding Protein , Vitamin D/blood , Adult , Aged , Enzyme-Linked Immunosorbent Assay/methods , Female , Humans , Male , Middle Aged , Protein Isoforms/blood , Vitamin D-Binding Protein/blood , Vitamin D-Binding Protein/geneticsABSTRACT
OBJECTIVE: Heterozygous activating mutations of glucokinase have been reported to cause hypoglycemia attributable to hyperinsulinism in a limited number of families. We report three children with de novo glucokinase hyperinsulinism mutations who displayed a spectrum of clinical phenotypes corresponding to marked differences in enzyme kinetics. RESEARCH DESIGN AND METHODS: Mutations were directly sequenced, and mutants were expressed as glutathionyl S-transferase-glucokinase fusion proteins. Kinetic analysis of the enzymes included determinations of stability, activity index, the response to glucokinase activator drug, and the effect of glucokinase regulatory protein. RESULTS: Child 1 had an ins454A mutation, child 2 a W99L mutation, and child 3 an M197I mutation. Diazoxide treatment was effective in child 3 but ineffective in child 1 and only partially effective in child 2. Expression of the mutant glucokinase ins454A, W99L, and M197I enzymes revealed a continuum of high relative activity indexes in the three children (26, 8.9, and 3.1, respectively; wild type = 1.0). Allosteric responses to inhibition by glucokinase regulatory protein and activation by the drug RO0281675 were impaired by the ins454A but unaffected by the M197I mutation. Estimated thresholds for glucose-stimulated insulin release were more severely reduced by the ins454A than the M197I mutation and intermediate in the W99L mutation (1.1, 3.5, and 2.2 mmol/l, respectively; wild type = 5.0 mmol/l). CONCLUSIONS: These results confirm the potency of glucokinase as the pancreatic beta-cell glucose sensor, and they demonstrate that responsiveness to diazoxide varies with genotype in glucokinase hyperinsulinism resulting in hypoglycemia, which can be more difficult to control than previously believed.