Upper Range Of Normal Research Articles

Adolescent Gynecomastia due to Minimal Androgen Resistance Syndrome: A Case Report and Literature Review

A 14-year-old boy with a 46,XY karyotype and persistent breast-3-stage gynecomastia is reported. The reproductive axis was investigated by standard laboratory methods and the androgen receptor (AR) gene was sequenced. Also, a literature review of phenotypes associated with the AR genetic variant p.Pro392Ser was performed. The boy presented with height in the upper normal range (+1.9 SDS) and normal body mass index (−0,3 SDS); pubertal development was PH5/G4 (mean testicular volume 15 mL; 0 SDS). Laboratory findings were normal for age and sex, except aromatization index (0.09; reference range 0.03–0.07). Analysis of the AR gene showed the single nucleotide variant c.1174C>T (p.Pro392Ser) in exon 1, leading to the diagnosis of minimal androgen insensitivity syndrome (AIS). This genetic variant is reported in other 8 patients with AIS and is associated with variable clinical phenotypes ranging from complete to partial and minimal AIS. To the best of our knowledge, this is the first adolescent in whom the p.Pro392Ser mutation is associated with isolated persistent gynecomastia. The underlying reason of phenotypic variability due to this AR mutation remains unknown. Persistent gynecomastia due to minimal AIS has been reported in few additional males with variable AR mutations. Since fertility troubles may occur in adult men with minimal AIS, early diagnosis can allow optimizing the clinical management.

Higher thyroid hormone levels and cancer.

This narrative review aims to summarize the relationship between hyperthyroidism, upper reference range thyroid hormone (TH) levels, and cancer, and to address the clinical management of hyperthyroidism in cancer patients. A comprehensive search was performed by an independent reviewer through Google Scholar and PubMed Electronic databases. All searches were restricted to English language manuscripts published between 2000 and 2020. Numerous in vitro, in vivo, and population-based studies suggest cancer-stimulating effect of triiodothyronine and thyroxin. THs are presented as mediators for tumor growth, proliferation, and progression. Many population and case-control studies suggest an increased risk of several solid but also hematologic malignancies in relation to hyperthyroidism and upper normal range TH levels. However, results are not unambiguous. In this review, we will summarize population and case-control studies that investigated the relationship between hyperthyroidism, upper reference range TH levels, lower thyrotropin (TSH) levels, lower reference range TSH levels with cancer risk, cancer prognosis, and cancer outcome. The vast majority of evidence suggests an association between clinical and subclinical hyperthyroidism with the risk of developing several types of cancer. Furthermore, hyperthyroidism is also linked with a poorer cancer prognosis. In this review, we will also discuss the diagnosis of hyperthyroidism in patients with pre-existing cancer and cover the management of hyperthyroidism in cancer patients, with special attention on the role of nuclear medicine. It is crucial to emphasize the importance of the rapid establishment of euthyroidism, and consequently, the importance of radioiodine therapy, as the therapy of choice in most cancer patients. We want to show that in this day and age there still is a high relevance for I-131 to achieve a permanent solution and thus likely reduce the risk of adverse influence of hyperthyroidism on the occurrence of new and course of existing cancer cases.

A Novel Long-Term Graves’ Disease Animal Model Confirmed by Functional Thyrotropin Receptor Antibodies

Introduction: A novel long-term murine model for Graves’ disease (GD) using repeated, long-term immunizations with recombinant adenovirus expressing the extracellular A-subunit of the human thyrotropin receptor (Ad-TSHR) was applied to evaluate the functional anti-TSHR-antibody (TSHR-Ab) profile. Methods: BALB/c mice received 7 immunizations with either 10¹⁰ plaque-forming units of Ad-TSHR or control Ad-GFP. Naïve (nonimmuized native) mice were also studied. Three 3-weekly immunizations were followed by 4-weekly boosts until the 7th immunization. Blocking (TBAb) and stimulating (TSAb) TSHR-Ab were measured with bioassays. Assay cut-offs for TBAb/TSAb were at 34% inhibition and a specimen-to-reference ratio (SRR) of 140%. Results: Nineteen (8 Ad-TSHR-, 4 Ad-GFP-immunized, and 7 native) mice were investigated. All native mice were negative for TSHR-binding inhibitory immunoglobulins (TBII) prior to immunization. Native and Ad-GFP mice were negative in weeks 17 and 27 for TBII and TBAb/TSAb. In native mice, the free thyroxine (fT4) levels (median [25th percentile; 75th percentile]) were in the upper normal range (1.2 ng/mL [1.1; 1.6]) prior to immunization, at weeks 17 (2.2 ng/mL [2.1; 2.4]) and 27 (1.4 ng/mL [1.1; 1.7]), respectively. In contrast, in Ad-TSHR-immunized mice, fT4 values were markedly increased at weeks 17 (4.4 ng/mL [3.9; 6]) and 27 (4.5 ng/mL [4.2; 6]) compared to those in Ad-GFP mice (2 ng/mL [1.8; 2.1] and 1.4 ng/mL [1.1; 1.6]), respectively (p = 0.0008, p = 0.001). In contrast, at week 17, in Ad-TSHR mice, the mean TBII, TBAb, and TSAb levels were 40 IU/L (40; 40); 62% inhibition (38; 69), and 116% SRR (97; 185), respectively; at week 27, they were 40 IU/L (39; 40); 65% inhibition (34; 80) and 95% SRR (63; 187), respectively. Three serum samples from Ad-TSHR mice (38%) demonstrated dual TBAb/TSAb positivity. Conclusions: TBAb/TSAb were highly prevalent in Ad-TSHR-immunized mice, thus confirming the successful establishment of a novel, long-term murine model for GD. All TBAb- and TSAb-positive Ad-TSHR-immunized mice were TBII-positive. Thus, the binding immunoassay did not differentiate between TSHR-Ab functionality.

Assessment of nutritional status of students of medical institute according to the blood biochemical parameters

The biochemical blood parameters characterizing the students ’nutritional status were evaluated: protein, lipid, carbohydrate metabolism, a number of minerals. The mean values, errors of the mean, median (Me), boundary (Q) and the range of 25–75 percentiles were determined. In 9.1 % of students and 28.6 % of students, the total protein was increased. Creatinine in men was in the upper normal range, in women — at the upper limit of normal, of which 46.2 % was higher than normal. The interval Q25–75 of uric acid in students is determined in the lower normal zone. In 40.0 % of men, decreased high-density lipoprotein cholesterol (Q25–75 corresponded to 1.15–1.79), in women — below normal, Q25–75 5 was 1.3–1.5, decreased in 73.3 %. Me and Q25–75 iron were in the lower normal range; 14.1 % of men and 13.2 % of women are below normal. Me sodium and potassium at the level of the lower boundary of the norm, Q25–75 in the lower zone of the norm: in 16.0 % and 15.4 % of students the levels are reduced. Calcium is slightly above the lower limit of the norm, Q25–75–2.1–2.24, indicating an insufficient intake in the whole group; 25.0 % are below normal. The border of the 25th percentile of magnesium is at the level of the lower border of the norm, in 19.2 % it is reduced. 7.2 % lack of chlorine. Phosphorus is normal, but Q25–75 is in the upper zone; 17.9 % increased. Biochemical markers can identify individuals with metabolic disorders of nutrients. Statistical indicators — the median, the boundaries of 25–75 quartiles and their scope characterize the metabolism of macronutrients and minerals in the group and subgroups of students. Laboratory and mathematical methods can provide a basis for identifying the specific causes of these changes. For this, you can use the questionnaire method of studying the nutrition of students, possibly using the developed questionnaires for a specific situation.

Phenotype and risk factors of venom-induced anaphylaxis: A case-control study of the European Anaphylaxis Registry

Venom-induced anaphylaxis (VIA) is a common, potentially life-threatening hypersensitivity reaction associated with (1) a specific symptom profile, 2) specific cofactors, and 3) specific management. Identifying the differences in phenotypes of anaphylaxis is crucial for future management guidelines and development of a personalized medicine approach. This study aimed to evaluate the phenotype and risk factors of VIA. Using data from the European Anaphylaxis Registry (12,874 cases), we identified 3,612 patients with VIA and analyzed their cases in comparison with sex- and age-matched anaphylaxis cases triggered by other elicitors (non-VIA cases [n= 3,605]). VIA more frequently involved more than 3 organ systems and was associated with cardiovascular symptoms. The absence of skin symptoms during anaphylaxis was correlated with baseline serum tryptase level and was associated with an increased risk of a severe reaction. Intramuscular or intravenous epinephrine was administered significantly less often in VIA, in particular, in patients without a history of anaphylaxis. Abaseline serum tryptase level within the upper normal range (8-11.5 ng/mL) was more frequently associated with severe anaphylaxis. Using a large cohort of VIA cases, we have validated that patients with intermediate baseline serum tryptase levels (8-11 ng/mL) and without skin involvement have a higher risk of severe VIA. Patients receiving β-blockers or angiotensin-converting enzyme inhibitors had a higher risk of developing severe cardiovascular symptoms (including cardiac arrest) in VIA and non-VIA cases. Patients experiencing VIA received epinephrine less frequently than did cases with non-VIA.

210-LB: Combined Use of Oral Standard Cookie Meal (OSC) and the Newly Revised Insulin Suppression Test for the Evaluation of Whole Body (WB), Muscle, and Hepatic Glucose Clearance (GC) Under Endogenous or Exogenous Insulin and Its Clinical Usefulness

Adequate insulin action (sensitivity: IS) in muscle, liver and WB is the most important metabolic factor in diabetes, especially in S-GLUT-2 user. Oral intake of hypoglycemic agents followed by the standard 75g starch including 15% maltose (OSC, Saraya Co.), which is digested and absorbed into blood glucose at a constant rate for 2 hours, minus urinary glucose loss, divided by the steady state PG at 2h equals the GC in WB under the endogenous insulin secretion. In SGLUT-2 user(HbA1c, 6.8%, BMI, 25.3), this was significantly low(4.2±0.5,SE ml/kg/min, n=6 vs. normal, 8.7,n=10). Average of 1 and 2h insulin was low,10.5 vs. normal,30μU/ml. They are recommended to keep BMI below 23, upper normal range of IS, and use GLP-1 analog or insulin to compensate insufficient IS. This approximation is further evaluated using the revised half dose of glucose and insulin infusion, 3mg, 0.39mU/kg/min, with octreotide 50μg SC for muscle, 100μg for whole body, 30min before the test. Under this exogenous insulin(19.1μU/ml, at 2-4h), 2h GC is confirmed significantly low (2.3±0.1,n=6 vs. control, 3.7±1.0, n=10) reflecting impaired muscle GC in SGLUT-2 user. Additional intake of OSC under continued subcutaneous insulin(1.5 rate over iv), gives the 2h decreased GC (5.84, vs. normal, 9.5,) of WB, and the difference corresponding to hepatic GC, which was significantly low. Better GC was obtained for non-SGLUT groups on oral agents with or without insulin secretagogues. Conclusion Combined use of OSC and simplified IS test enables to evaluate muscle, hepatic and WB glucose utilization under endogenous or exogenous insulin. The method is useful to detect and clarify the various mechanisms of insulin resistance in diabetes, metabolic syndrome, heart failure, Alzheimer disease or fatty liver, etc. Disclosure Y. Harano: None.

Could Serum TSH Levels Predict Malignancy in Euthyroid Patients Affected by Thyroid Nodules with Indeterminate Cytology?

Background Serum TSH levels in the upper-normal range were reported to be associated with increased risk of thyroid malignancy. However, measurement of TSH levels is currently not recommended for assessing the risk of malignancy in patients with newly diagnosed thyroid nodules. Objective To evaluate a possible relationship between the serum levels of TSH and the histological outcome of patients undergoing thyroidectomy for thyroid nodules with indeterminate cytology. Materials and Methods We collected the clinical data of all patients who had performed ultrasound-guided FNA of thyroid nodules with cytological diagnosis of indeterminate lesions (TIR3A and TIR3B) and serum TSH levels within the normal range. All patients had been submitted to thyroid surgery (hemi or thyroidectomy, as appropriate), and histological diagnosis had been performed. Results A histological diagnosis of thyroid malignancy was rendered in 74/378 (19.6%) nodules. Patients with histologically proven thyroid malignancy were characterized by higher serum levels of TSH as compared to patients with histologically proven benign nodules (3.03 ± 1.16 vs. 2.37 ± 1.19 mIU/L, p < 0.001). To further analyze the role of serum TSH in predicting thyroid cancer, patients were stratified in 4 groups according to quartiles of TSH concentrations. The prevalence of malignancy was 12.2% for the first quartile and 50.0% for the last quartile. ROC curve analysis identified that a serum TSH level of ≥2.7 mIU/L predicted thyroid malignancy with a sensitivity of 61% and a specificity of 65%. Conclusions TSH levels in the upper-normal range are associated with an increased risk of thyroid malignancy in patients affected by thyroid nodules with indeterminate cytology at FNA. The measurement of serum TSH levels represents an easily performed additional tool for decision-making in patients with indeterminate cytological findings.

The abnormal lipid profile in obesity and coronary heart disease (CHD) in Pakistani subjects

BackgroundObesity has become global epidemic in the last three decades, whereas Coronary Heart Disease (CHD) still remains the most important cause of mortality in the world. The study was aimed at determining the pattern of lipid profile for the obese and CHD population in Pakistan. As obesity is a strong predisposing risk factor for CHD, we aimed to analyze the lipid parameters in both conditions and compare them with the healthy controls of the same ethnicity.MethodsBlood samples were collected from one thousand individuals (500 with CHD, 250 with obesity, 250 healthy controls). The lipid profile (total Cholesterol, triglycerides, HDL-C, LDL-C and VLDL) was measured using commercially available kits. The pattern of dyslipidemia was then studied by comparing the results in both groups with controls as well as population cutoffs. The quantitative variables were checked for normality and log transformation was done for variables where appropriate. Analysis of variance and logistic regression were done to check the association of lipid parameters with obesity and CHD.ResultsThe obese and CHD groups showed a dyslipidemic profile than the healthy controls. CHD group had a higher proportion of CHD in any of the first degree blood relatives (36.0% vs. 1.8%), a similar trend was observed in the obese group, where 63.9% cases had positive family history. Among cases, 50.7% had combined lipid abnormalities, i.e., the values of TC, LDL-C, TG and HDL-C, all were deranged. Whereas 49.52% had TC more than normal cut off (> 200 mg/dl), 51.6% had LDL-C > 100 mg/dl. Similarly, 80.4% of patients had TG levels more than upper normal range (> 150 mg/dl) and 64% had HDL values in moderate CHD risk group (< 50 mg/dl). The results show that Pakistani cases are hyperlipidemic for lipid traits except for HDL which is lowered. Patients with comorbidities also had lipid profiles deviated from the normal range.ConclusionThe study provides information regarding the aberration of lipid profile in the metabolic disorders that can increase the predisposition to complications.

C-Peptide levels as a screening marker for initiating insulin therapy in type 2 diabetics.

Objectives: Serum C-peptide is identified as an indicator of insulin secretion and a useful marker of beta-cell function. Clinically C-peptide is a good indicator in differentiating between type 1 and type 2 diabetes. It is the more reliable indicator of insulin secretion and beta cell function than insulin itself. In liver during first pass metabolism half of the insulin is metabolized however the hepatic clearance of C-peptide is negligible. The purpose of this study was to explore the probability of C-peptide level as an indicator or screening for initiating insulin therapy in type 2 diabetics. Study Design: Cross sectional descriptive study. Setting: The study was conducted in attached teaching hospitals Peshawar Medical College. Period: From February 2017 to July 2017. Material and Method: In the present study 45 type 2 diabetic patients were selected from the admitted patients and patients visiting outpatient departments of Mercy and Kuwait teaching Hospitals as per the inclusion and exclusion criteria and were compared with 45 non diabetic controls. Results: A total of ninety subjects who fulfilled the inclusion criteria participated in this study. Out of them 45 were diabetics (cases) and 45 were non diabetics (controls). The mean HbA1c levels of controls was 5.351±0.57% and mean among type 2 diabetics was 8.6± 1.7%. The mean of C-peptide among type 2 diabetics is 2.349± 0.73 and the mean value of C-peptide among controls is 2.529±1.060. Patients with HbA1c of 5.5-6.8 % (Good Control), 8 patients have C-peptide in lower normal range 0.1-2 ng/mL, among patients with HbA1c of 6.9-7.6% (Fair Control), 5 patients had C-peptide in the lower normal range 0.1-2 ng/ mL and among patients with HbA1c › 7.6 (Uncontrolled), 2 had C peptide in lower normal range and 30 patients had C-peptide in the upper normal range 2.1-4 ng/ mL. In our study population the type 2 diabetics have C-peptide levels in normal range. Most of the type 2 diabetics have uncontrolled diabetes as evident from their high HbA1c levels but their C-peptide levels are in upper normal ranges. This shows that these patients have intact beta cell function and the cause of their uncontrolled diabetes may be insulin resistance, poor drug compliance and lack of awareness about the disease management. To explore the probability of C-peptide level as an indicator or screening for initiating insulin therapy in type 2 diabetics. Conclusion: It is concluded that C-peptide is not a useful marker for starting insulin therapy in type 2 diabetics. However it can be used for the clinical monitoring and management of the disease.

519P - Carcinoid heart disease (CHD): the CRUSOE-NETs, a prospective cohort study from the French group of endocrine tumours (GTE)

BackgroundNeuroendocrine tumors (NET) represent a heterogeneous group of rare tumors, some of them secreting serotonin resulting in the carcinoid syndrome (CS). CHD is an integral part of this syndrome but remains poorly understood. The GTE is conducting a national survey of patients at risk for CHD aiming at evaluating the occurrence & progression rates of CHD, the frequency & results of cardiac surgery, and patient outcomes as well as the role of clinical characteristics and biomarkers as predictive markers; 600 patients are expected over a 5-year period with a 10-year follow-up. We herein present the study status at one year. MethodsPatients with a metastatic ileum or bronchial NET, or any NET with a CS or 5HIAA levels greater than at least twice the upper normal range, seen by a NET specialist and a referee cardiologist are eligible. Clinical, pathological, biological parameters and previous treatments are collected. A transthoracic echocardiography is realised at inclusion and at least every year. ResultsFrom March 2018 to March 2019, 167 patients from 8 centers were included. Median [range] time from NET diagnosis to study inclusion was 56 months [0-501]. Median age was 66 years [34-86] with a male preponderance (53%); 85% had ileum NETs, 8% lung NETs, and 7% other NETs with CS or elevated 5HIAA; 100% had metastatic disease. Most of them have been pretreated: somatostatin analogs 96%, surgery of primary tumor 81% or metastasis 34%, liver embolization 24%, peptide receptor radionuclide therapy 19%, chemotherapy 16%, targeted therapy 12%, radiofrequency ablation 6%, interferon 2%. At inclusion, 81 patients (49%) had a CS, 67% with flushing, 68% with diarrhea. CHD was documented in 22 (13%) patients, all of them had tricuspid disease and simultaneous pulmonary, mitral and/or aortic disease for respectively 13, 3 and 1 of them; 14 patients with CHD had a CS. Seven patients underwent cardiac surgery for CHD. ConclusionsThe first large prospective multicentric study about CHD is ongoing. Preliminary results confirm the feasibility of the study with nearly 170 patients included in one year and 13% of CHD. The inclusion of new patients and 10-year follow-up will allow a better knowledge of the current incidence, progression and prognosis of CHD. Clinical trial identificationNCT03498040. Legal entity responsible for the studyFrench Group of Endocrine Tumors (GTE). FundingIPSEN. DisclosureG. Cadiot: Advisory / Consultancy: Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: AAA; Advisory / Consultancy: Keocyt. P. Nazeyrollas: Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Novartis; Honoraria (self), Non-remunerated activity/ies: MSD; Honoraria (institution): Sanofi; Honoraria (institution): novo-nordisk; Travel / Accommodation / Expenses, Non-remunerated activity/ies: actelion; Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Servier; Non-remunerated activity/ies: bms. P. Afchain: Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Ipsen. F. Delelis: Honoraria (self): Novartis; Honoraria (self): boehringer. J. Forestier: Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Honoraria (self): Servier. C. Lombard Bohas: Advisory / Consultancy: Ipsen; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AAA. All other authors have declared no conflicts of interest.

SUN-532 Interferon Gamma-1b Does Not Increase Markers of Bone Resorption in Autosomal Dominant Osteopetrosis

In autosomal dominant osteopetrosis type 2 (ADO2) CLCN7 mutations cause impaired osteoclast function. Severe consequences include skeletal fragility despite high bone mass, osteomyelitis, osteonecrosis, bone marrow failure, and severe cranial nerve impingement. There is no effective medical treatment for ADO2. We recruited subjects with ADO2 into a 14-week, open-label, pilot clinical trial of interferon gamma-1b. Doses were titrated based on tolerability and if fasting serum C-telopeptide (CTX) was <25% above baseline at week 8, targeting doses of 100 mcg/m2 three times a week. The primary outcomes were change from baseline in CTX and N-telopeptide/creatinine ratio (NTX/Cr) at week 14. Secondary outcomes included changes in urine calcium/creatinine ratio, bone formation markers and tolerability. Nine adults and 3 children were recruited. Severe manifestations of ADO2 included histories of fractures (100%), osteomyelitis (16.7%), vision loss attributable to ADO2 (50%), and anemia (58.3%). Baseline CTX and NTX/Cr were in the normal range, though frequently in the lower half of the normal range. Procollagen type I N-terminal propeptide (P1NP) was elevated or in the upper normal range in 11/12 (91.6%) subjects. Elevations of AST, and LDH were common (each 75%). One subject withdrew due to rash. Five subjects achieved doses of 50 ug/m2 three days a week, while 6 reached the full dose of 100 ug/m2 three days a week. Only 3/11 (27.3%) completing subjects achieved the primary outcome of increasing CTX ≥25% above baseline at week 14. The mean change from baseline in CTX at week 14 was +2.2% (SD 43.2%, p=0.86). Likewise, there was no significant change in NTX/Cr (mean change -2.1%, p=0.81). Interferon gamma-1b was poorly tolerated. Most subjects had adverse events, and the Mental Health and Mental Component Scales of the SF-36v2 declined slightly, but significantly (p<0.05). Over 14 weeks, interferon gamma-1b failed to significantly increase bone turnover markers in ADO2 and was poorly tolerated. Consequently, effects to decrease bone mass by increasing osteoclastic bone resorption in ADO2 are unlikely.

Androgens in Cushing's Syndrome.

Although polycystic ovary syndrome (PCOS) is the most common androgen excess disorder, screening for Cushing's Syndrome (CS) should be considered in women with PCOS phenotype, particularly if they are also affected by other disturbances that increase their pretest probability (e.g., osteoporosis/bone fractures). Approximately 70-80% of women with CS present menstrual abnormalities, and PCOS findings are found in 46% of these patients. Diagnostic efforts should strengthen if the clinical picture is severe or of rapid onset in order to ensure the earliest and most appropriate treatment. If the diagnosis of CS is challenging, its differentiation from PCOS is not outdone: isolated PCOS may be associated to hypothalamic-pituitary-adrenal axis disruption, leading to false-positive results in screening tests. Because of this overlap, the diagnosis of CS is initially missed or delayed. Diagnostic utility of serum androgen assessment is controversial, but the widespread use of high-performance liquid chromatography and gas chromatography-mass spectrometry for urinary steroid profiling is showing promising results. According to the role of adrenocorticotropic hormone (ACTH) in adrenal androgen secretion, it is not surprising that the levels of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and androstenedione (A4) are generally elevated or in the upper normal range in patients with ACTH-dependent CS. Conversely, adrenal androgens are generally low in patients with cortisol-secreting adrenocortical adenoma. However, androgen-secreting adrenal tumors (adenoma and carcinoma) can be also associated with severe hyperandrogenism. Regression of hypercortisolism after treatment causes disappearance of hyperandrogenism. However, signs of androgen excess may be detectable in well-controlled CS as a result of ACTH compensatory response to certain adrenal steroidogenesis inhibitors.

Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism

Neurodevelopmental disorders (NDD) are genetically and phenotypically heterogeneous conditions due to defects in genes involved in development and function of the nervous system. Individuals with NDD, in addition to their primary neurodevelopmental phenotype, may also have accompanying syndromic features that can be very helpful diagnostically especially those with recognizable facial appearance. In this study, we describe ten similarly affected individuals from six unrelated families of different ethnic origins having bi-allelic truncating variants in TMEM94, which encodes for an uncharacterized transmembrane nuclear protein that is highly conserved across mammals. The affected individuals manifested with global developmental delay/intellectual disability, and dysmorphic facial features including triangular face, deep set eyes, broad nasal root and tip and anteverted nostrils, thick arched eye brows, hypertrichosis, pointed chin, and hypertelorism. Birthweight in the upper normal range was observed in most, and all but one had congenital heart defects (CHD). Gene expression analysis in available cells from affected individuals showed reduced expression of TMEM94. Global transcriptome profiling using microarray and RNA sequencing revealed several dysregulated genes essential for cell growth, proliferation and survival that are predicted to have an impact on cardiotoxicity hematological system and neurodevelopment. Loss of Tmem94 in mousemodel generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, suggesting that this gene is important in craniofacial, cardiovascular, and nervous system development. Our study suggests the genetic etiology of a recognizable dysmorphic syndrome with NDD and CHD and highlights the role of TMEM94 in early development.

Breath test using 13C methacetin does not seem to be useful in the assessment of liver function in girls with anorexia nervosa: a case control study

BackgroundAnorexia nervosa (AN) concerns approximately up to 1.8% of the pediatric female population. One of the complications that can occur in the course of this disease is acute liver failure. This study’s objective was to assess the usefulness of the 13C labeled Methacetin Breath Test (MBT) in the diagnostics of the liver function in girls with eating disorders.MethodsFor the study 81 girls aged 12 to 17 years were recruited, including 41 patients with confirmed diagnosis of AN (mean age 14.7 ± 1.48 years) and 40 age-matched controls. The diagnosis was based on the present Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. Weight and height were measured in all study participants and the Body Mass Index (BMI) was calculated. In the study and control group laboratory tests assessing the liver function and the MBT were performed.ResultsIn all controls the anthropometric as well as laboratory liver function parameters were normal. In the study group 25 patients (61%) had BMI below the lower limit for age. The total percentage of 13CO2 recovery in the 120th minute of the test did not exceed the lower limit in patients and controls. A result of the 13CO2 cumulative recovery above the upper normal range was found in 18 girls with AN (44% of the study group) and 2 controls (5%). Patients with AN were characterized by significantly higher 13CO2 cumulative dose recovery after ingestion of the substrate in comparison to the control group in all time points of the test.ConclusionsThe obtained results confirm a significant stimulation of the liver metabolism of 13C labeled methacetin in female patients with AN. The increased cumulative dose recovery of the substrate in girls with AN impacts the credibility of this measurement and implies a risk of false negative results.

ANALYSIS OF THE EFFECTIVENESS OF SCLEROPLASTIC OPERATIONS IN CHILDREN WITH PROGRESSIVE MYOPIA WITH LONG-TERM FOLLOW-UP. NEW POSSIBILITIES OF DRUG TREATMENT OF PROGRESSIVE MYOPIA

There were performed a retrospective study of scleroplasty results in patients with progressive myopia (1282 eyes) and a prospective study of patients with myopia after scleroplasty (192 eyes). The age of patients is from 5 to 17 years, mean age is (12,5 ± 0,07) years. The observation period is from 1 to 7 years. The studies showed slowing rate of myopia progression after sclera operations in the majority of operated patients - in 92 % of cases. The maximum stabilizing effect of scleroplasty is observed one year after the operation. After 4 years and 7 years after operation the stabilizing effect is reduced. The combination of weakness of accommodation, constantly redundant tension of accommodation (CRTA) and finding intraocular pressure values in the upper normal range indicate the progression of myopia. The use of 0,005 % solution of Latanoprost (Prolatan) in the complex treatment of patients with myopia leads to normalization of intraocular pressure, increase of corneal hysteresis and rigidity index of corneoscleral membrane, as well as increase in the coefficient of accommodative response and decrease in the coefficient of the ciliary body microfluctuations.

Pregnancy outcome after first trimester use of angiotensin AT1 receptor blockers: an observational cohort study

Ongoing discussion about the safety of renin-angiotensin inhibitors in the first trimester and limited data on pregnancy outcomes after exposure to angiotensin AT1 receptor blockers (ARBs). Observational cohort study compares outcomes of 215 prospectively ascertained pregnancies with first trimester exposure to ARBs with 642 non-hypertensive pregnancies. The rate of major birth defects in the ARB cohort (9/168, 5.4%) was higher than in the comparison group (17/570, 3%), but not significantly increased (ORadj 1.9, 95% CI 0.7-4.9). There was no distinct pattern of anomalies among infants with birth defects. The risk of spontaneous abortions was not increased (HRadj 0.9, 95% CI 0.5-1.6), although the cumulative incidence was in the upper normal range (0.22, 95% CI 0.15-0.32). Higher rates of prematurity (ORadj 3.0; 95% CI 1.7-5.1) and a reduced birth weight after adjustment for sex and gestational age were observed. There was no evidence for an increased risk for major birth defects, spontaneous abortions, or preterm birth in a sensitivity analysis comparing ARB exposed hypertensive women to hypertensive women without ARB exposure during the first trimester. Our study supports the hypothesis that ARBs are not major teratogens. Patients inadvertently exposed to ARBs during the early pregnancy may be reassured. Nevertheless, women planning pregnancy should avoid ARBs. In selected cases, ARBs might be continued under careful monitoring of menstrual cycle and discontinued as soon as pregnancy is recognized.

Primary Adrenal Insufficiency: Managing Mineralocorticoid Replacement Therapy.

Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome. Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, aldosterone, cardiovascular disease, hypertension, and heart failure. The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement. The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed.

Low-grade albuminuria is associated with poor memory performance in the nondemented Chinese elderly with type 2 diabetes.

Recent studies have correlated cognitive function with albuminuria. We investigated the association between low-grade albuminuria and cognitive performance in nondemented elderly with type 2 diabetes in Fuzhou, China. Between January, 2013 and December, 2014, a retrospective study was performed in 815 patients with type 2 diabetes (398 female and 417 male patients), ages ≥60years, with normal urinary albumin to creatinine ratios (UACR <30mg/g). Patients were stratified into tertiles based on UACR levels (lowest tertile, UACR <5.8mg/g; highest tertile, UACR ≥18.1mg/g). Cognitive function was measured using the Mini Mental State Examination. UACR tertiles correlated directly (p<0.05) with age, duration of diabetes, systolic blood pressure (SBP), and pulse wave velocity (PWV). Patients in the second and highest tertiles performed significantly worse on memory and language than those in the lowest UACR tertile (p<0.05). The association between UACR and memory loss was stronger in patients younger than 70years of age and in those with a history of diabetes for less than 10years. Low-grade albuminuria is associated with poor memory performance, especially in the youngest old (60-69years) and in those with shorter duration of diabetes (< 10years). Type 2 diabetics with urinary albumin excretion in the upper normal range were also at risk for declining memory performance.

A case report of severe calciphylaxis \u2013 suggested approach for diagnosis and treatment

BackgroundCalciphylaxis is a serious complication in patients with chronic kidney disease associated mineral and bone disorder. It can occur in conditions with low and high bone turnover. So far, there are no definite diagnostic and therapeutic guidelines which may prevent the devastating outcome in many calciphylaxis patients. We report a case which clearly illustrates that knowledge of the underlying bone disorder is essential for a directed treatment. Based on this experience we discuss a systematic diagnostic and therapeutic approach in patients with calciphylaxis.Case presentationWe report a patient with severe calciphylaxis. Initial evaluation showed an elevated serum parathormone concentration and a bone-specific alkaline phosphatase activity in the upper normal range; however, the bone biopsy clearly showed adynamic bone disease. Extended dialysis with low calcium dialysate concentration and citrate anticoagulation, and administration of teriparatide led to a further increase in bone-specific alkaline phosphatase activity and most importantly, resulted in an activated bone turnover as confirmed by a second bone biopsy 11 weeks later.ConclusionsThis case illustrates that laboratory tests cannot reliably differentiate between high and low bone turnover in calciphylaxis patients. More importantly, this case highlights the fact that specific therapies that alter bone metabolism cannot be applied without knowledge of the bone status. On this background, we suggest that bone biopsies should be an integral part in the diagnosis and therapeutic decision in these patients and should be evaluated in further studies.

Hypolipidaemic and renoprotective effects of Glycine max (Soy bean) against lipid profile and renal biochemical alterations in hypercholesterolemic rat

Background : Hyperlipidemia can be defined as concentration of lipids in the blood of a fasted (>12hrs) patient that exceeds the upper range of normal for that species. Studies have showed that rats with hypercholesterolemia are prompt to the development of cardiovascular diseases (CVD). Methods: Twenty-four (24) male albino Wister rats were used in this study. The rats weighed between 180-190g and were randomly divided into four (4) groups (A-D) with six (6) rats per group. For hypercholesterolemia induction, rats in group B, C and D were administered with HCD (2000mg/kg) once daily in the presence of carbimazole (1.35mg/kg) for 14days. Group B (test group) were treated with soymilk (2000mg/kg) and group C (positive control) with atorvastatin (20mg/kg) for 14 days. Group A (normal control) received water and vital feed only. At the end, fasting blood specimens were collected from all the animals in all the groups for estimation of lipid profile and renal biochemical parameters. The biochemical parameters of lipid profile: Total Cholesterol (TC), High density lipoprotein (HDL), Low density lipoprotein (LDL), Very low density lipoprotein (VLDL) and Triglycerides (TG) were assayed. Results : Results showed that the test group (soymilk) showed a non-significant decrease in TC, TG, LDL, VLDL and a non-significant increase in HDL concentrations but not as much as group C (Atorvastatin) which showed a significant decrease in TC and LDL (p<0.01), TG (p<0.05), VLDL and also a significant increase in HDL concentrations (p<0.05) when compared to the negative control group (HCD alone).Renal injury was assessed by measuring serum Na + , K + , Cl - , HCO 3 - , creatinine and urea levels. The HCD treatment resulted in marked elevation of: K + (8.670.77mmol/l); creatinine (2.070.23mg/dl); and urea (89.0014.42mg/dl) and caused deranged renal functions which were significantly improved by soymilk treatment: K + (6.510.34mmol/l); creatinine (1.030.24mg/dl); and urea (46.676.89mg/dl) with [P<0.05 or p<0.01]. Conclusion: Arguably, the phytochemicals in soy prevented dyslipidaemia and protected the kidney against the oxidative stress and the resultant renal dysfunction produced by hypercholesterolemia.