MAFA missense mutation causes familial insulinomatosis and diabetes mellitus.

The ß-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in ß-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in ß-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet ß-cell activity.

Impact of Substance Use Disorder on Quality of Inpatient Mental Health Services for People With Anxiety and Depression.

Objective: Substance use disorders are commonly comorbid with anxiety and depressive disorders and are associated with poor treatment outcomes. The mechanisms underlying this association remain unclear-one possibility is that patients with anxiety/depressive disorders and substance use disorders receive poorer treatment. Concerns have been raised about the quality of inpatient care received by patients with substance use disorders. The purspose of this research was to examine the quality of care received by inpatients with an anxiety or depressive disorder, comparing subgroups with or without a comorbid substance use disorder. Methods: This was a retrospective case-note review of 3,795 patients admitted to inpatient psychiatric wards in England. Data were gathered on all acute admissions with anxiety/depressive illness over a 6-month period, for a number of measures of quality of care derived from national standards. Association of coexisting substance use disorders with a variety of quality of care outcomes (relating to assessment, care planning, medication management, psychological therapies, discharge, crisis planning, and follow-up) was investigated using multivariable regression analyses. Results: In all, 543 (14.3%) patients in the study had a secondary diagnosis of a substance use disorder. Patients with substance use disorders were less likely to have had care plans that were developed jointly (i.e., with input from both patient and clinician; odds ratio [OR] = 0.76, 95% confidence interval [CI] [0.55, 0.93], p = .034) and less likely to have had their medication reviewed either during the admission (OR = 0.83, 95% CI [0.69, 0.94], p = .030) or at follow-up after discharge (OR = 0.58, 95% CI [0.39, 0.86], p = .007). Carers of patients with substance use disorders were less likely to have been provided with information about available support services (OR = 0.79, 95% CI [0.57, 0.98], p = .047). Patients with substance use disorders were less likely to have received adequate (at least 24 hours) notice in advance of their discharge (OR = 0.72, 95% CI [0.54, 0.96], p = .033), as were their carers (OR = 0.63, 95% CI [0.41, 0.85], p = .007). They were less likely to have a crisis plan in place at the point of discharge (OR = 0.85, 95% CI [0.74, 0.98], p = .044). There was also strong evidence that patients with substance use disorders were less likely to have been referred for psychological therapy (OR = 0.69, 95% CI [0.55, 0.87], p = .002). Conclusions: We found evidence of poorer quality of care for inpatients with anxiety and depressive disorders with comorbid substance use disorders, highlighting the need for more to be done to support these patients. Discrepancies in care quality may be contributed to the poor treatment outcomes experienced by patients with substance use disorders, and strategies to reduce this inequality are necessary to improve the well-being of this substantial patient group.

Risk category system to identify pituitary adenoma patients with AIP mutations.

BACKGROUND: Predictive tools to identify patients at risk for gene mutations related to pituitary adenomas are very helpful in clinical practice. We therefore aimed to develop and validate a reliable risk category system for aryl hydrocarbon receptor-interacting protein (AIP) mutations in patients with pituitary adenomas. METHODS: An international cohort of 2227 subjects were consecutively recruited between 2007 and 2016, including patients with pituitary adenomas (familial and sporadic) and their relatives. All probands (n=1429) were screened for AIP mutations, and those diagnosed with a pituitary adenoma prospectively, as part of their clinical screening (n=24), were excluded from the analysis. Univariate analysis was performed comparing patients with and without AIP mutations. Based on a multivariate logistic regression model, six potential factors were identified for the development of a risk category system, classifying the individual risk into low-risk, moderate-risk and high-risk categories. An internal cross-validation test was used to validate the system. RESULTS: 1405 patients had a pituitary tumour, of which 43% had a positive family history, 55.5% had somatotrophinomas and 81.5% presented with macroadenoma. Overall, 134 patients had an AIP mutation (9.5%). We identified four independent predictors for the presence of an AIP mutation: age of onset providing an odds ratio (OR) of 14.34 for age 0-18 years, family history (OR 10.85), growth hormone excess (OR 9.74) and large tumour size (OR 4.49). In our cohort, 71% of patients were identified as low risk (<5% risk of AIP mutation), 9.2% as moderate risk and 20% as high risk (≥20% risk). Excellent discrimination (c-statistic=0.87) and internal validation were achieved. CONCLUSION: We propose a user-friendly risk categorisation system that can reliably group patients into high-risk, moderate-risk and low-risk groups for the presence of AIP mutations, thus providing guidance in identifying patients at high risk of carrying an AIP mutation. This risk score is based on a cohort with high prevalence of AIP mutations and should be applied cautiously in other populations.

The Role of Epigenetics in Type 1 Diabetes.

PURPOSE OF REVIEW: Epigenetics is defined as mitotically heritable changes in gene expression that do not directly alter the DNA sequence. By implication, such epigenetic changes are non-genetically determined, although they can be affected by inherited genetic variation. Extensive evidence indicates that autoimmune diseases including type 1 diabetes are determined by the interaction of genetic and non-genetic factors. Much is known of the genetic causes of these diseases, but the non-genetic effects are less clear-cut. Further, it remains unclear how they interact to cause the destructive autoimmune process. This review identifies the key issues in the genetic/non-genetic interaction, examining the most recent evidence of the role of non-genetic effects in the disease process, including the impact of epigenetic effects on key pathways. RECENT FINDINGS: Recent research indicates that these pathways likely involve immune effector cells both of the innate and adaptive immune response. Specifically, there is evidence of cell type-specific enrichment in altered DNA methylation, changes which were temporally stable and enriched at gene regulatory elements. Epigenomics remains in its infancy, and we anticipate further studies will define how the interaction of genetic and non-genetic effects induces tissue-specific destruction and enhances our ability to predict, and possibly even modify that process.

Near-miss transcription errors: a comparison of reporting rates between a novel error-reporting mechanism and a current formal reporting system.

PURPOSE: The medication use process comprises several steps. In institutions without full implementation of computerized prescriber order entry (CPOE), transcription is a critical step in this process. As focus is increasingly placed on identifying near-miss errors, this study aimed to compare near-miss transcription error (NMTE) reporting rates between an institution's formal reporting system and an NMTE reporting mechanism. METHODS: Two NMTE reporting mechanisms were assessed for 3 months. These mechanisms included the institution's formal error-reporting system and a specific transcription error queue within the institution's order imaging software. Date, patient-care unit, and type of transcription error were recorded for each order image in the transcription error queue and for each transcription error reported formally. Following data collection, reporting rates for both systems were compared. RESULTS: Data collection spanned 92 days and an estimated 460,000 medication orders. In total, 1,563 NMTEs were reported using the transcription error queue and 12 errors were reported via the formal reporting mechanism. Of the 1,563 errors identified via the transcription error queue, 325 (20.79%) were of an unknown type. Reporting rates (with unknown errors removed) were 0.27% and 0.0026% for the novel system and formal reporting system, respectively (P < .001). CONCLUSION: Significantly more NMTEs were reported utilizing the novel system compared with the formal reporting system.

Epigenetics in autoimmune diseases with focus on type 1 diabetes.

Autoimmune diseases arise when the body mounts an immune response against 'self' cells and tissues causing inflammation and damage. It is commonly accepted that these diseases develop because of the interplay of genetic and environmental factors. Evidence for genetic factors includes the higher concordance of disease in monozygotic twins than in dizygotic twins. However, monozygotic twins may remain discordant for disease indicating a role for environmental factors. Environmental factors may alter gene expression via epigenetic mechanisms. This is particularly pertinent in type 1 diabetes in which DNA methylation and histone modifications have been associated with altered gene expression. The low disease concordance rate in adult-onset type 1 diabetes (<20%) suggests that environmental and epigenetic changes may play a predominant role. Defining the role of epigenetic changes could identify specific gene pathways and dysregulated expression of gene products that contribute to the pathogenesis of type 1 diabetes. This article reviews how epigenetic mechanisms may contribute to the development of autoimmune diseases with a focus on type 1 diabetes.

A Child with COVID-19 and Immunoglobulin A Vasculitis.

We describe the case of a child with progressive abdominal pain and rash admitted to a large tertiary children's hospital in the Chicago metropolitan area and subsequently found to have immunoglobulin A (IgA) vasculitis and coronavirus disease 2019 (COVID-19). This patient presented with abdominal pain, purpuric lesions, hematochezia, increasingly elevated D-dimer, and abnormal inflammatory markers on laboratory evaluation. To the best of our knowledge, this article describes the only reported pediatric case of COVID-19 associated with IgA vasculitis. [Pediatr Ann. 2021;50(1):e44-e48.].

Variation in clinical care associated with weekend admission and discharge in psychiatric in-patient units: retrospective case-note review.

BACKGROUND: Questions have been raised regarding differences in the standards of care that patients receive when they are admitted to or discharged from in-patient units at weekends. AIMS: To compare the quality of care received by patients with anxiety and depressive disorders who were admitted to or discharged from psychiatric hospital at weekends with those admitted or discharged during the 'working week'. METHOD: Retrospective case-note review of 3795 admissions to in-patient psychiatric wards in England. Quality of care received by people with depressive or anxiety disorders was compared using multivariable regression analyses. RESULTS: In total, 795 (20.9%) patients were admitted at weekends and 157 (4.8%) were discharged at weekends. There were minimal differences in quality of care between those admitted at weekends and those admitted during the week. Patients discharged at weekends were less likely to be given sufficient notification (48 h) in advance of being discharged (OR = 0.55, 95% CI 0.39-0.78), to have a crisis plan in place (OR = 0.65, 95% CI 0.46-0.92) or to be given medication to take home (OR = 0.45, 95% CI 0.30-0.66). They were also less likely to have been assessed using a validated outcome measure (OR = 0.70, 95% CI 0.50-0.97). CONCLUSIONS: There is no evidence of a 'weekend effect' for patients admitted to psychiatric hospital at weekends, but the quality of care offered to those who were discharged at weekends was relatively poor, highlighting the need for improvement in this area.

Impact of co-morbid personality disorder on quality of inpatient mental health services for people with anxiety and depression.

INTRODUCTION: Concerns have been raised about the quality of inpatient care received by patients with a diagnosis of personality disorder. OBJECTIVES: The aim of this study was to examine the quality of care received by inpatients with an anxiety or depressive disorder, comparing subgroups with or without a co-morbid personality disorder. METHOD: We used a retrospective case-note review of 3 795 patients admitted to inpatient psychiatric wards in England, utilizing data from the National Clinical Audit of Anxiety and Depression. Data were gathered on all acute admissions with an anxiety or depressive disorder over a 6-month period, for a number of measures reflecting quality of care derived from national standards. Association of coexisting personality disorder with quality of care was investigated using multivariable regression analyses. RESULTS: Four hundred sixteen (11.0%) of the patients had a co-co-morbid diagnosis of personality disorder. Patients with personality disorder were less likely to have been asked about prior responses to treatment in their initial assessment (odds ratio (OR) = 0.67, 95% confidence interval (CI) 0.50 to 0.89, p = 0.007). They were less likely to receive adequate notice in advance of their discharge (OR = 0.87, 95% CI 0.65 to 0.98, p = 0.046). They were more likely to be prescribed medication at the point of discharge (OR = 1.52, 95% CI 1.02 to 2.09, p = 0.012) and less likely to have been provided with information about the medicines they were taking (OR = 0.86, 95% CI 0.69 to 0.94, p = 0.048). In addition, the carers of patients with co-morbid personality disorder were less likely to have been provided with information about available support services (OR = 0.73, 95% CI 0.51 to 0.93, p = 0.045). CONCLUSION: We found evidence of poorer quality of care for patients with co-morbid personality disorder who were admitted to psychiatric hospital for treatment of anxiety or depressive disorders, highlighting the need for improved clinical care in this patient group.

Cantú syndrome with coexisting familial pituitary adenoma.

CONTEXT: Pseudoacromegaly describes conditions with an acromegaly related physical appearance without abnormalities in the growth hormone (GH) axis. Acromegaloid facies, together with hypertrichosis, are typical manifestations of Cantú syndrome. CASE DESCRIPTION: We present a three-generation family with 5 affected members, with marked acromegaloid facies and prominent hypertrichosis, due to a novel missense variant in the ABCC9 gene. The proband, a 2-year-old girl, was referred due to marked hypertrichosis, noticed soon after birth, associated with coarsening of her facial appearance. Her endocrine assessment, including of the GH axis, was normal. The proband's father, paternal aunt, and half-sibling were referred to the Endocrine department for exclusion of acromegaly. Although the GH axis was normal in all, two subjects had clinically non-functioning pituitary macroadenomas, a feature which has not previously been associated with Cantú syndrome. CONCLUSIONS: Activating mutations in the ABCC9 and, less commonly, KCNJ8 genes-representing the two subunits of the ATP-sensitive potassium channel-have been linked with Cantú syndrome. Interestingly, minoxidil, a well-known ATP-sensitive potassium channel agonist, can cause a similar phenotype. There is no clear explanation why activating this channel would lead to acromegaloid features or hypertrichosis. This report raises awareness for this complex condition, especially for adult or pediatric endocrinologists who might see these patients referred for evaluation of acromegaloid features or hirsutism. The link between Cantú syndrome and pituitary adenomas is currently unclear.

Reduced protein expression of the phosphodiesterases PDE4A4 and PDE4A8 in AIP mutation positive somatotroph adenomas.

Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.

Emergence of Pituitary Adenoma in a Child during Surveillance: Clinical Challenges and the Family Members' View in an AIP Mutation-Positive Family.

INTRODUCTION: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations are responsible for 15-30% of familial isolated pituitary adenomas (FIPAs). We report a FIPA kindred with a heterozygous deletion in AIP, aiming to highlight the indications and benefits of genetic screening, variability in clinical presentations, and management challenges in this setting. PATIENTS: An 18-year-old male was diagnosed with a clinically nonfunctioning pituitary adenoma (NFPA). Two years later, his brother was diagnosed with a somatolactotrophinoma, and a small Rathke's cleft cyst and a microadenoma were detected on screening in their 17-year-old sister. Following amenorrhoea, their maternal cousin was diagnosed with hyperprolactinaemia and two distinct pituitary microadenomas. A 12-year-old niece developed headache and her MRI showed a microadenoma, not seen on a pituitary MRI scan 3 years earlier. DISCUSSION: Out of the 14 members harbouring germline AIP mutations in this kindred, 5 have pituitary adenoma. Affected members had different features and courses of disease. Bulky pituitary and not fully suppressed GH on OGTT can be challenging in the evaluation of females in teenage years. Multiple pituitary adenomas with different secretory profiles may arise in the pituitary of these patients. Small, stable NFPAs can be present in mutation carriers, similar to incidentalomas in the general population. Genetic screening and baseline review, with follow-up of younger subjects, are recommended in AIP mutation-positive families.

Diagnostic challenges and management of a patient with acromegaly due to ectopic growth hormone-releasing hormone secretion from a bronchial carcinoid tumour.

A male patient presented at the age of 30 with classic clinical features of acromegaly and was found to have elevated growth hormone levels, not suppressing during an oral glucose tolerance test. His acromegaly was originally considered to be of pituitary origin, based on a CT scan, which was interpreted as showing a pituitary macroadenoma. Despite two trans-sphenoidal surgeries, cranial radiotherapy and periods of treatment with bromocriptine and octreotide, his acromegaly remained active clinically and biochemically. A lung mass was discovered incidentally on a chest X-ray performed as part of a routine pre-assessment for spinal surgery 5 years following the initial presentation. This was confirmed to be a bronchial carcinoid tumour, which was strongly positive for growth hormone-releasing hormone (GHRH) and somatostatin receptor type 2 by immunohistochemistry. The re-examination of the pituitary specimens asserted the diagnosis of pituitary GH hyperplasia. Complete resolution of the patient's acromegaly was achieved following right lower and middle lobectomy. Seventeen years following the successful resection of the bronchial carcinoid tumour the patient remains under annual endocrine follow-up for monitoring of the hypopituitarism he developed after the original interventions to his pituitary gland, while there has been no evidence of active acromegaly or recurrence of the carcinoid tumour. Ectopic acromegaly is extremely rare, accounting for <1% of all cases of acromegaly. Our case highlights the diagnostic challenges differentiating between ectopic acromegaly and acromegaly of pituitary origin and emphasises the importance of avoiding unnecessary pituitary surgery and radiotherapy. The role of laboratory investigations, imaging and histology as diagnostic tools is discussed. LEARNING POINTS: Ectopic acromegaly is rare, accounting for less than 1% of all cases of acromegaly.Ectopic acromegaly is almost always due to extra-pituitary GHRH secretion, mainly from neuroendocrine tumours of pancreatic or bronchial origin.Differentiating between acromegaly of pituitary origin and ectopic acromegaly can cause diagnostic challenges due to similarities in clinical presentation and biochemistry.Serum GHRH can be a useful diagnostic tool to diagnose ectopic acromegaly.Pituitary imaging is crucial to differentiate between a pituitary adenoma and pituitary hyperplasia, which is a common finding in ectopic acromegaly.Diagnosing ectopic acromegaly is pivotal to avoid unnecessary interventions to the pituitary and preserve normal pituitary function.

Pseudoacromegaly: A Differential Diagnostic Problem for Acromegaly With a Genetic Solution.

Acromegaly is usually not a difficult condition to diagnose once the possibility of this disease has been raised. However, a few conditions present with some aspects of acromegaly or gigantism but without growth hormone (GH) excess. Such cases are described as "pseudoacromegaly" or "acromegaloidism". Here we describe a female patient investigated for GH excess at 10 years of age for tall stature since infancy (height and weight > +3 standard deviations) and typical acromegalic features, including large hands/feet, large jaw, tongue, hoarse deep voice, and headache. Results of radiography of the sella turcica and GH response at an oral glucose tolerance test and insulin-arginine- thyrotrophin-luteinizing hormone-releasing hormone test were normal. Ethinylestradiol and medroxyprogesterone were given for 2 years; this successfully stopped further height increase. Although the patient's growth rate plateaued, coarsening of the facial features and acral enlargement also led to investigations for suspicion of acromegaly at 23 and 36 years of age, both with negative results. On referral at the age of 49 years, she had weight gain, sweating, sleep apnea, headaches, joint pain, and enlarged tongue. Endocrine assessment again showing normal GH axis was followed by genetic testing with a macrocephaly/overgrowth syndrome panel. A denovo mutation in the NSD1 gene (c.6605G>C; p.Cys2202Ser) was demonstrated. Mutations affecting the same cysteine residue have been identified in patients with Sotos syndrome. In summary, Sotos syndrome and other overgrowth syndromes can mimic the clinical manifestations of acromegaly or gigantism. Genetic assessment could be helpful in these cases.

Pituitary Carcinoma in a Patient with an SDHB Mutation.

We present the first case of pituitary carcinoma occurring in a patient with a succinate dehydrogenase subunit B (SDHB) mutation and history of paraganglioma. She was initially treated for a glomus tumour with external beam radiotherapy. Twenty-five years later, she was diagnosed with a non-functioning pituitary adenoma, having developed bitemporal hemianopia. Recurrence of the pituitary lesion (Ki-67 10% and p53 overexpressed) occurred 5 years after her transsphenoidal surgery, for which she underwent two further operations followed by radiotherapy. Histology showed large cells with vacuolated clear cytoplasm with positive immunostaining for steroidogenic factor 1 (SF1) and negative staining for pituitary hormones. Four years after the pituitary radiotherapy, two metastatic deposits were identified: a foramen magnum lesion and an intradural extra-medullary cervical lesion at the level of C3/C4. There was also significant growth of the primary pituitary lesion with associated visual deterioration. A biopsy of the foramen magnum lesion, demonstrating cells with vacuolated, clear cytoplasm and positive SF1 staining confirmed a pituitary carcinoma, for which she was commenced on temozolomide chemotherapy. There was dramatic clinical improvement after three cycles and reduction in the size of the lesions was observed following six cycles of temozolomide, and further shrinkage after 10 cycles. The plan is for a total of 12 cycles of temozolomide chemotherapy. SDH mutation-related pituitary tumours have an aggressive phenotype which, in this case, led to metastatic disease. SF1 immunostaining was helpful to identify the tissue origin of the metastatic deposit and to confirm the pituitary carcinoma.

Methylation Analysis in Distinct Immune Cell Subsets in Type 1 Diabetes.

Epigenetics provides a mechanism in which the environment can interact with the genotype to produce a variety of phenotypes. These epigenetic modifications have been associated with altered gene expression and silencing of repetitive elements, and these modifications can be inherited mitotically. DNA methylation is the best characterized epigenetic mark and earlier studies have examined DNA methylation profiles in peripheral blood mononuclear cells in disease. However, any disease-related signatures identified would just display differences in the relative abundance of individual cell types as each cell subset generates a unique methylation profile. Therefore is it important to identify cell- or tissue-specific changes in DNA methylation, particularly in autoimmune diseases such as type 1 diabetes.

AIP mutations in young patients with acromegaly and the Tampico Giant: the Mexican experience.

Although aryl hydrocarbon receptor-interacting protein (AIP) mutations are rare in sporadic acromegaly, their prevalence among young patients is nonnegligible. The objectives of this study were to evaluate the frequency of AIP mutations in a cohort of Mexican patients with acromegaly with disease onset before the age of 30 and to search for molecular abnormalities in the AIP gene in teeth obtained from the "Tampico Giant". Peripheral blood DNA from 71 patients with acromegaly (51 females) with disease onset <30 years was analysed (median age of disease onset of 23 years) and correlated with clinical, biochemical and imaging characteristics. Sequencing was also carried out in DNA extracted from teeth of the Tampico Giant. Five patients (7 %) harboured heterozygous, germline mutations of the AIP gene. In two of them (a 9-year-old girl with gigantism and a young man with symptoms of GH excess since age 14) the c.910C>T (p.Arg304Ter), well-known truncating mutation was identified; in one of these two cases and her identical twin sister, the mutation proved to be a de novo event, since neither of their parents were found to be carriers. In the remaining three patients, new mutations were identified: a frameshift mutation (c.976_977insC, p.Gly326AfsTer), an in-frame deletion (c.872_877del, p.Val291_Leu292del) and a nonsense mutation (c.868A > T, p.Lys290Ter), which are predicted to be pathogenic based on in silico analysis. Patients with AIP mutations tended to have an earlier onset of acromegaly and harboured larger and more invasive tumours. A previously described genetic variant of unknown significance (c.869C > T, p.Ala299Val) was identified in DNA from the Tampico Giant. The prevalence of AIP mutations in young Mexican patients with acromegaly is similar to that of European cohorts. Our results support the need for genetic evaluation of patients with early onset acromegaly.

Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.

Increased DNA methylation variability in type 1 diabetes across three immune effector cell types.

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.

Transformation of a pharmacy department: impact on pharmacist interventions, error prevention, and cost.

BACKGROUND: Current medical literature supports the unit-based (UB) pharmacy concept as a best practice. In an effort to determine its feasibility, Huntsville Hospital (Huntsville, Alabama) conducted a pilot study to compare the central-based (CB) model with the UB model and then implemented the new model. IMPLEMENTING THE PILOT STUDY: Data were collected for two high-volume nursing units for 10 days for each model. Pharmacists practicing in the UB setting documented more interventions than the CB pharmacist by a factor of three to one, resulting in an 85% increase in cost avoidance. IMPLEMENTING THE UB MODEL: Converting the pharmacy services to a UB model entailed creating 16 new pharmacist positions. Extrapolation of the savings for the UB model ($520 per day) and the CB model ($280) for 1 year suggested that adoption of the UB model would generate an additional $87,600 in cost avoidance for these two nursing units. Each new pharmacist was trained for at least 3 months before being scheduled to work independently as a UB pharmacist. Clinical interventions by pharmacists greatly increased after implementation of the UB model. The baseline monthly average of interventions for the 6 months before implementation was 239, and the monthly cost avoidance was $21,300. In October 2001, the first full month of implementation, there were 1,315 interventions and a monthly cost avoidance of $130,192. SUMMARY: Converting to the UB model has required a considerable increase in the number of pharmacist positions, yet there has been a dramatic increase in clinical pharmacy interventions, with a corresponding decrease in drug expenditures.