Impairments in Physiological Reactivity to Emotive Stimuli After Traumatic Brain Injury: A Systematic Review of Skin Conductance and Heart Rate Variability Evidence.

OBJECTIVE: To examine evidence of impairments in physiological reactivity to emotive stimuli following traumatic brain injury (TBI). METHODS: A search of PsychINFO, CINAHL (Cumulative Index to Allied Health Literature), Web of Science, EMBASE (Excerpta Medica dataBASE), and Scopus databases was conducted from 1991 to June 24, 2021, for studies comparing changes in skin conductance or heart rate variability to emotive stimuli between adults with TBI and controls. Two reviewers independently assessed eligibility and rated methodological quality. RESULTS: Twelve eligible studies examined physiological reactivity to laboratory-based emotive stimuli, which included nonpersonal pictures/videos, posed emotion, stressful events, and personal event recall. Overall, 9 reported evidence that individuals with TBI experience lower physiological reactivity to emotive stimuli compared with healthy controls, although the findings varied according to the type and valence of emotional stimuli and physiological parameter. Most studies using nonpersonal pictures or videos found evidence of lower physiological reactivity in TBI participants compared with controls. CONCLUSIONS: Based on laboratory-based studies, individuals with TBI may experience lower physiological reactivity to emotive stimuli. Further research is needed to investigate physiological responses to personally relevant emotional stimuli in real-world settings and to understand the interplay between physiological reactivity, subjective experiences, and behavior.

STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis.

BACKGROUND: Lymphocyte differentiation is regulated by coordinated actions of cytokines and signaling pathways. IL-21 activates STAT1, STAT3, and STAT5 and is fundamental for the differentiation of human B cells into memory cells and antibody-secreting cells. While STAT1 is largely nonessential and STAT3 is critical for this process, the role of STAT5 is unknown. OBJECTIVES: This study sought to delineate unique roles of STAT5 in activation and differentiation of human naive and memory B cells. METHODS: STAT activation was assessed by phospho-flow cytometry cell sorting. Differential gene expression was determined by RNA-sequencing and quantitative PCR. The requirement for STAT5B in B-cell and CD4+ T-cell differentiation was assessed using CRISPR-mediated STAT5B deletion from B-cell lines and investigating primary lymphocytes from individuals with germline STAT5B mutations. RESULTS: IL-21 activated STAT5 and strongly induced SOCS3 in human naive, but not memory, B cells. Deletion of STAT5B in B-cell lines diminished IL-21-mediated SOCS3 induction. PBMCs from STAT5B-null individuals contained expanded populations of immunoglobulin class-switched B cells, CD21loTbet+ B cells, and follicular T helper cells. IL-21 induced greater differentiation of STAT5B-deficient B cells into plasmablasts in vitro than B cells from healthy donors, correlating with higher expression levels of transcription factors promoting plasma cell formation. CONCLUSIONS: These findings reveal novel roles for STAT5B in regulating IL-21-induced human B-cell differentiation. This is achieved by inducing SOCS3 to attenuate IL-21 signaling, and BCL6 to repress class switching and plasma cell generation. Thus, STAT5B is critical for restraining IL-21-mediated B-cell differentiation. These findings provide insights into mechanisms underpinning B-cell responses during primary and subsequent antigen encounter and explain autoimmunity and dysfunctional humoral immunity in STAT5B deficiency.

How the physical appearance of companions affects females with high or low social physique anxiety: a virtual reality exercise study.

Technologies such as virtual reality (VR), an immersive computer-based environment that induces a feeling of mental and physical presence, are becoming increasingly popular for promoting participation in exercise. The purpose of this study was to explore changes in motivation and other psychological states when the physique of an exercise companion was altered during a VR-based exercise task, and whether trait social physique anxiety (SPA) altered these effects. Using a mixed experimental design, female participants (N = 43) categorised as high or low in SPA participated in two counterbalanced 10-min running tasks within a VR environment where the exercise companion was either overweight or in-shape. Across both running tasks, individuals with high SPA reported higher negative affect, pressure and tension, and lower perceived competencies, than those with low SPA. Pressure and tension were also higher when exercising with an in-shape companion than with an overweight companion for all participants. In addition, participants with high SPA reported a stronger preference to exercise with an overweight companion than those with low SPA in a real exercise setting, but not in a VR setting. The findings suggest that the physique of an exercise companion and the SPA of an exerciser have important, but independent, psychosocial effects during exercise. That an in-shape physique of a virtual exercise companion was not a deterrent among those with high SPA has provided preliminary evidence that VR-based exercise may be helpful among females who worry about their appearance or feel self-conscious while exercising.

Type 1 diabetes incidence increased during the COVID-19 pandemic years 2020-2021 in Czechia: Results from a large population-based pediatric register.

BACKGROUND: To explore type 1 diabetes incidence patterns during the pandemic years 2020 and 2021 in Czechia, to compare them to the trends from the previous decade, and to test its association with indicators of containment measures and of pandemic severity (school closing and the all-cause excess mortality). METHODS: The Czech Childhood Diabetes Register is a population-based incidence register recording patients age 0-14.99 years at diabetes onset. Type 1 diabetes incidence in the pandemic period (April 2020-end of observation Dec 2021) was compared by Poisson regression models to the incidence patterns over the past decade 2010-2019. RESULTS: During the pandemic years 2020-2021, 956 children 0-14.99 years old manifested with type 1 diabetes in Czechia. The observed incidence (27.2/100,000/year) was significantly higher than what was expected from the trends over 2010-2019 (incidence rate ratio, IRR = 1.16, 95%CI 1.06-1.28, p = 0.0022). The incidence had a trough during the first lockdown (March-May 2020), then it rose above expected values with no usual summer decrease. The assessed pandemic indicators (school closing and all-cause excess mortality) were not associated with the incidence levels. CONCLUSIONS: The COVID-19 pandemic was associated with a notable upward inflection of the type 1 diabetes incidence curve; the early months of the first lockdown were however hallmarked by a significant dip in new diabetes diagnoses. Long-term observation will show whether the increased incidence originated only from accelerating an advanced preclinical Stage 2 to overt diabetes, or whether the pandemic triggered new cases of islet autoimmunity.

Use of continuous glucose monitoring and its association with type 1 diabetes control in children over the first 3 years of reimbursement approval: Population data from the CENDA registry.

OBJECTIVE: Increased access to modern technologies is not always accompanied by a decrease in HbA1c. The aim of this study was to identify changes in the proportion of continuous glucose monitoring (CGM) users since 2017, when general reimbursement for CGM became effective in Czechia, and to test whether HbA1c is associated with the percentage of time spent on CGM. RESEARCH DESIGN AND METHODS: All T1D children in the Czech national CENDA registry (3197 children) were categorized according to their time spent on CGM and associations with age, sex, center size, and HbA1c were tested with calendar year as a stratification factor. RESULTS: The proportion of children with any CGM use increased from 37.9% in 2017 to 50.3% in 2018 and 74.8% in 2019. Of the CGM users, 16%, 28%, and 41% of the children spent >70% of their time on CGM over the 3 years of the study period, with an overrepresentation of children in the <10 years age group versus the older age groups (p < 0.001). The proportion of CGM users differed among centers and was positively associated with a large center size (>100 patients) (p < 0.001). HbA1c was negatively associated with the time spent on CGM (p < 0.001). CONCLUSIONS: A rapid increase in CGM use was reported over the 3 years after general reimbursement. HbA1c was associated with time spent on CGM, a continuing decrease was observed in the >70% category. Reimbursement for CGM likely contributes to the improvement of T1D control at the population level.

Iodine status in premature newborns.

Iodine is a micronutrient essential for normal thyroid function, growth and development of a child. Iodine deficiency remains an unresolved problem worldwide, where even in countries with adequate iodine supply certain population groups remain particularly at risk. Premature newborns comprise one such group as several factors including organic and functional developmental immaturity, a lower iodine reserve pool and insufficient postnatal iodine intake may contribute to iodine deficiency. However, such newborns are also more susceptible to autoregulatory thyroid inhibition upon excessive iodine supply. Several guidelines on the optimal daily iodine intake for preterm newborns exist in different parts of the world. Our article presents an overview of these guidelines and current data about iodine content in parenteral nutrition, breast milk and milk formulas.

Five years of improving diabetes control in Czech children after the establishment of the population-based childhood diabetes register CENDA.

OBJECTIVES: The Czech National Childhood Diabetes Register (CENDA) is a web-based nationwide database that collects treatment and outcome data in children and adolescents with diabetes. Here, we present data from the first 5 years of CENDA (2013-2017). METHODS: Data include characteristics of disease onset and annual summaries of key clinical care parameters from every patient treated by participating pediatric diabetes outpatient clinics. RESULTS: The database contains data of 4361 children (aged 0-19 years) from 52 centers (85% of all Czech pediatric patients). Of these, 94% had type 1 diabetes (T1D), 4.5% had genetically proven monogenic or secondary, and 1.5% had type 2 diabetes. In children with T1D, median glycated hemoglobin (HbA1c) decreased throughout the observed period from 66.3 to 61.0 mmol/mol (P < .0001, 95% confidence interval [CI] for change -5.6 to -4 mmol/mol). Consequently, the proportion of children reaching the target therapeutic goal of 58.5 mmol/mol increased from 28% in 2013 to 40% in 2017. The proportion of children treated with insulin pumps (CSII) remained stable over the observed period (25%). In a subanalysis of 1602 patients (long-standing T1D diagnosed before 2011), the main predictors associated with lower HbA1c were treatment with CSII, male sex and care provided at a large diabetes center (>100 patients). CONCLUSIONS: A significant continuous decrease in HbA1c was observed in Czech children over the past 5 years. As this improvement was not accompanied by appreciable changes in the mode of therapy, we assume that the establishment of our nationwide register has itself constituted a stimulus towards improvement in the care process.

The sensitivity of 38 heart rate variability measures to the addition of artifact in human and artificial 24-hr cardiac recordings.

BACKGROUND: Artifact is common in cardiac RR interval data derived from 24-hr recordings and has a significant impact on heart rate variability (HRV) measures. However, the relative impact of progressively added artifact on a large group of commonly used HRV measures has not been assessed. This study compared the relative sensitivity of 38 commonly used HRV measures to artifact to determine which measures show the most change with increasing increments of artifact. A secondary aim was to ascertain whether short-term and long-term HRV measures, as groups, share similarities in their sensitivity to artifact. METHODS: Up to 10% of artifact was added to 20 artificial RR (ARR) files and 20 human cardiac recordings, which had been assessed for artifact by a cardiac technician. The added artifact simulated deletion of RR intervals and insertion of individual short RR intervals. Thirty-eight HRV measures were calculated for each file. Regression analysis was used to rank the HRV measures according to their sensitivity to artifact as determined by the magnitude of slope. RESULTS: RMSSD, SDANN, SDNN, RR triangular index and TINN, normalized power and relative power linear measures, and most nonlinear methods examined are most robust to artifact. CONCLUSION: Short-term time domain HRV measures are more sensitive to added artifact than long-term measures. Absolute power frequency domain measures across all frequency bands are more sensitive than normalized and relative frequency domain measures. Most nonlinear HRV measures assessed were relatively robust to added artifact, with Poincare plot SD1 being most sensitive.

The general facilitation effect of implementation intentions on prospective memory performance in patients with schizophrenia.

INTRODUCTION: Prospective memory (PM) refers to remembering to execute a planned intention in the future. It can be divided into event- and time-based, according to the nature of the PM cue. Event-based PM cues can be classified as focal or non-focal. Patients with schizophrenia (SCZ) have been found to be impaired in both event- and time-based PM. PM has been found to be improved by implementation intentions, which is an encoding strategy in the format of "if X then Y". This study examined the effect of implementation intentions on a non-focal event-based and a time-based PM task in patients with SCZ. METHODS: Forty-two patients with SCZ and 42 healthy controls were allocated to either an implementation intention or a control PM instruction condition and were asked to complete two PM tasks. RESULTS: Implementation intentions was found to improve performance in both the non-focal event-based and time-based PM tasks in patients with SCZ and healthy controls, with no costs to the ongoing task. The improvement in time-based PM performance in the implementation intentions condition was partially mediated by the frequency of clock checking behaviour. CONCLUSIONS: Implementation intentions can facilitate PM performance in patients with SCZ and has the potential to be used as a clinical intervention tool.

Validation of the Empathy Quotient in Mainland China.

This research aimed to validate a simplified Chinese version of the Empathy Quotient (EQ; 60 items) for use with Mainland Chinese people. The original English version of the EQ was translated into simplified Chinese. Through an online survey, 588 Mainland Chinese participants completed the EQ and 3 other questionnaires: the Interpersonal Reactivity Index (IRI), the Autism-Spectrum Quotient (AQ), and the 20-item Toronto Alexithymia Scale (TAS-20). Thirty-five participants completed retesting of the EQ 3 to 4 weeks later. Sex differences on the EQ scores and psychometric properties of the EQ items were examined. Confirmatory factor analysis suggested that an EQ 15-item structural model fitted the data quite well. Self-report empathy, as assessed by the current simplified Chinese version of the EQ, appeared to relate to participants' autistic and alexithymic traits but not sex.

The heartbreak of depression: 'Psycho-cardiac' coupling in myocardial infarction.

Ample evidence identifies strong links between major depressive disorder (MDD) and both risk of ischemic or coronary heart disease (CHD) and resultant morbidity and mortality. The molecular mechanistic bases of these linkages are poorly defined. Systemic factors linked to MDD, including vascular dysfunction, atherosclerosis, obesity and diabetes, together with associated behavioral changes, all elevate CHD risk. Nonetheless, experimental evidence indicates the myocardium is also directly modified in depression, independently of these factors, impairing infarct tolerance and cardioprotection. It may be that MDD effectively breaks the heart's intrinsic defense mechanisms. Four extrinsic processes are implicated in this psycho-cardiac coupling, presenting potential targets for therapeutic intervention if causally involved: sympathetic over-activity vs. vagal under-activity, together with hypothalamic-pituitary-adrenal (HPA) axis and immuno-inflammatory dysfunctions. However, direct evidence of their involvement remains limited, and whether targeting these upstream mediators is effective (or practical) in limiting the cardiac consequences of MDD is unknown. Detailing myocardial phenotype in MDD can also inform approaches to cardioprotection, yet cardiac molecular changes are similarly ill defined. Studies support myocardial sensitization to ischemic insult in models of MDD, including worsened oxidative and nitrosative damage, apoptosis (with altered Bcl-2 family expression) and infarction. Moreover, depression may de-sensitize hearts to protective conditioning stimuli. The mechanistic underpinnings of these changes await delineation. Such information not only advances our fundamental understanding of psychological determinants of health, but also better informs management of the cardiac consequences of MDD and implementing cardioprotection in this cohort.

Developmental differences in aversive conditioning, extinction, and reinstatement: A study with children, adolescents, and adults.

This study investigated developmental differences in aversive conditioning, extinction, and reinstatement (i.e., the recovery of conditioned aversive associations following reexposure to the unconditioned stimulus [US] post-extinction). This study examined these mechanisms in children (Mage=8.8years), adolescents (Mage=16.1years), and adults (Mage=32.3years) using differential aversive conditioning with a geometric shape conditional stimulus (CS+) paired with an aversive sound US and another shape (CS-) presented alone. Following an extinction phase in which both CSs were presented alone, half of the participants in each age group received three US exposures (reinstatement condition) and the other half did not (control condition), followed by all participants completing an extinction retest phase on the same day. Findings indicated (a) significant differences in generalizing aversive expectancies to safe stimuli during conditioning and extinction that persisted during retest in children relative to adults and adolescents, (b) significantly less positive CS reevaluations during extinction that persisted during retest in adolescents relative to adults and children, and (c) reinstatement of US expectancies to the CS+ relative to the CS- in all age groups. Results suggest important differences in stimulus safety learning in children and stimulus valence reevaluation in adolescents relative to adults.

Clinical assessment of the lag-time and tmax of pellets with controlled release of glucose: in vitro/in vivo comparison using 13 C-breath test.

Maintaining a stable glycaemia in diabetes mellitus type 1 requires flexible insulin administration and carbohydrate intake to affected individuals. In real life, there might be some situations limiting the insulin-sugar balance control, e.g. night sleep or prolonged sporting activities. Glucose pellets with a pre-determined time lag between the pellet administration and glucose release were developed to mimic a 'snack eaten in advance'. In this article, a 13 C-glucose breath test was introduced to translate laboratory dissolution testing to clinical confirmation of the glucose release pattern using 5% δ abundance to differentiate the appearance of in 13 C exhaled breath. An independent two-sample t-test (p = 0.20) confirmed an average clinical lag time of 300 min and an in vitro time of 338 min to be identical at a level of significance of α = 0.05. Moreover, using the same statistical method, the clinical tmax (564 min) and the in vitro t50 (594 min) were also considered identical (p = 0.34). It was concluded that dissolution testing is a relevant method to determine the time lags of dosage forms with controlled release of glucose and that the 13 C-glucose breath test is a suitable clinical tool for lag time verification in clinical studies.

Evaluation of a newly developed measure of theory of mind: The virtual assessment of mentalising ability.

This study examined the reliability and validity of the Virtual Assessment of Mentalising Ability (VAMA). The VAMA consists of 12 video clips depicting a social drama imposed within an interactive virtual environment with questions assessing the mental states of virtual friends. Response options capture the continuum of ability (i.e., impaired, reduced, accurate, and hypermentalising) within first- and second-order cognitive and affective theory of mind (ToM). Sixty-two healthy participants were administered the VAMA, three other ToM measures, and additional measures of neurocognitive abilities and social functioning. The VAMA had sound internal consistency and high test-retest reliability. Significant correlations between performance on the VAMA and other ToM measures provided preliminary evidence of convergent validity. Small to moderate correlations were observed between performance on the VAMA and neurocognitive tasks. Further, the VAMA was found to correlate significantly with indices of social functioning and was rated as more immersive, more reflective of everyday ToM processes, and was afforded a higher recommendation than an existing computer-based ToM task. These results provide potential evidence that the VAMA is an ecologically valid tool that is sensitive to the spread of ability that can occur in ToM subprocesses and may be a valuable addition to existing ToM measures. Future research should explore the validity and utility of the VAMA in larger, more diverse samples of healthy adult and clinical populations.

Interdiction of hypoglycemia in diabetic children by multiparticulate dosage form with controlled glucose release.

Patients tend to evade the occurrence of hypoglycemic episodes by excessive carbohydrate intake. Glucose pellets with delayed release in the time of the maximum effect of insulin can not only prevent hypoglycemia but also eliminate the preventive carbohydrate intake. The pellets can be administered in a mixture with semisolid food. The cores containing glucose in combination with osmotically active agents (croscarmellose sodium, carmellose sodium, polyethylene glycol, or carboxymethyl starch) were prepared by extrusion-spheronization and coated with 15% water ethylcellulose dispersion (Surelease® B NF) in Wurster column (Medipo, Havlíckuv Brod, Czech Republic) into four coating levels (12.5, 25, 35, and 50%). Mean particle size is 0.63-0.73 for cores and 0.82-0.98 for coated pellets. Cores and coated pellets have excellent or good flow properties according to Hausner ratio and Carr index. Aspect ratio ranges from 1.78 to 2.17 for cores and from 1.73 to 2.31 for coated pellets. Dissolution was performed using pH-independent method and method with continual change of pH. The suitable pH-independent release was achieved in the samples containing carboxymethyl starch or polyethylene glycol. Glucose release is enabled by a membrane rupture caused by core swelling. It can be, therefore, assumed that the glucose release profile will not be affected by food or transit time.

[Influence of the mesh of extrusion dies on the properties of cores intended for the preparation of pellets with controlled glucose release]. / Vliv velikosti oka extruzní prepázky na vlastnosti jader urcených k príprave pelet s rízeným uvolnováním glukosy.

UNLABELLED: Diabetes mellitus and its compensation are accompanied by serious complications. One of them is hypoglycaemia, which occurs in patients treated with insulin and/or certain peroral antidiabetics. Hypoglycaemic episodes can be prevented by a dosage form with controlled release of glucose. The pellet cores of four compositions and three different sizes corresponding to the diameter of extrusion screen mesh (0.6, 0.8, and 1.0 mm) were prepared for this purpose. The cores contain 75-80% of glucose combined with one of the following osmotically or swellable active agents: croscarmellose sodium (ADS), a mixture of microcrystalline cellulose and carmellose sodium Avicel RC 591 (RC), polyethylene glycol 6000 (PEG), and carboxymethyl starch (CMS). The cores were prepared by extrusion-spheronization and are intended for subsequent coating by a semipermeable membrane based on ethylcellulose. The aim of the work was to statistically evaluate the results of the physical evaluation of the pellets which were prepared and evaluated in previously published papers. The results are processed in the form of a meta-analysis using principle component analysis. The physical characteristics of the individual pellet sizes were different among themselves. Although the same compositions and manufacturing methods were used for all the pellets sizes, the cores produced through a 0.6 and 0.8 mm mesh screens showed similar properties while the properties of cores produced through a 1.0 mm mesh screen were rather different. KEY WORDS: hypoglycemia delayed release glucose principal component analysis PCA meta-analysis of data.

[Iodine supply of pregnant women in the Czech Republic]. / Zásobení jodem u tehotných zen v Ceské republice.

INTRODUCTION: Iodine deficiency is a global public health problem which is particularly noticeable in pregnant or breastfeeding women and their children. Even mild iodine deficiency during pregnancy can lead to damage to the developing brain and thus affecting the fetus intelligence, his cognitive and neurological function, embryogenesis and growth. PATIENTS: In the period 2010-2015 was determined by spectrophotometry at the Institute of Endocrinology the basal urinary iodine in 532 pregnant women at the age of 32 ± 5 (18-44) years, which came from Prague, Hradec Kralove and Mlada Boleslav. It was located 349 women in the first trimester, 112 in the second trimester, and 71 women in the third trimester. In the monitoring of pregnant women in the first trimester 218 basal urine samples of women were determined by mass spectrometry with inductively coupled plasma (ICP MS) in The National Institute of Public Health (NIPH). Women came from the 6 areas in the Czech Republic. Development of urinary iodine in the general population in the period 1994-2015 was observed in patients who underwent Institute of Endocrinology and from population studies conducted in 7 regions of the Czech Republic. It performed 52 648 spectrophotometric analysis of urinary iodine in the general population. METHODS: Urinary iodine was determined by alkali melting of urine samples, followed by spectrophotometric determination of iodine in the form of iodide using the Sandell-Kolthoff reaction in the Institute of Endocrinology or determination was performed by ICP-MS in the laboratory of NIPH. RESULTS: On average, only 21.8 % of pregnant women had urinary iodine values determined by spectrophotometry higher than 150 µg/L. The results of iodine nutrition of pregnant women in the first trimester analyzed using ICP-MS are better, but even so, only 50.5 % of pregnant women have urinary iodine higher than 150 µg/L. CONCLUSION: The results of iodine nutrition of pregnant women are alarming, on average, only 30 % of the total of 750 examined women have urinary iodine values greater than 150 µg/L and therefore meet the requirements of the WHO for pregnant women. Our results, however, show that iodine deficiency is not major public health problem in the general population.Key words: ICP-MS - pregnant women - Sandell-Kolthoff reaction - urinary iodine.

Applying the Theory of Planned Behavior to Physical Activity: The Moderating Role of Mental Toughness.

This study explored whether mental toughness, the capacity to maintain performance under pressure, moderated the relation between physical activity intentions and subsequent behavior. Participants (N = 117) completed the Mental Toughness Index and a theory of planned behavior questionnaire. Seven days later, physical activity was assessed using the International Physical Activity Questionnaire. Attitudes, subjective norms, and perceived behavioral control explained substantial variance (63.1%) in physical activity intentions. Intentions also significantly predicted physical activity behavior. The simple slopes analyses for the moderation effect revealed a nonsignificant intention-behavior relation at low levels of mental toughness. However, intentions were significantly and positively related to physical activity when mental toughness was moderate or high, suggesting that the development of a mentally tough mindset may reduce the gap between behavior and physical activity intention. Future research is needed to confirm these findings and apply them in the design of mental toughness interventions to facilitate physical activity engagement.

Diagnostic and predictive value of ultrasound and isotope thyroid scanning, alone and in combination, in infants referred with thyroid-stimulating hormone elevation on newborn screening.

OBJECTIVE: To determine the diagnostic and predictive value of ultrasound and radioisotope scans of the thyroid, alone and in combination, during a single visit after initial referral by the screening laboratory with thyroid-stimulating hormone (TSH) elevation. STUDY DESIGN: Retrospective blind review of ultrasound and radioisotope images followed by final diagnosis based on clinical features, biochemistry, imaging, and molecular genetic study. RESULTS: Infants (n = 97; 61 female) with median birthweight 3.38 kg (range 2.04-4.86) and gestation 40 weeks (range 33-42), underwent successful dual thyroid ultrasound and technetium-99m pertechnetate radioisotope scan in a single center. Combined scanning at the initial visit resulted in a correct final diagnosis in 79 of 97 (81%) cases. One patient was misdiagnosed initially as having athyreosis as the result of delayed radioisotope scan and the diagnosis of ectopia made later on diagnostic challenge. The specificity/sensitivity for radioisotope scan and for ultrasound was as follows: 100%/97% and 100%/55% for ectopia (n = 39); 81%/100% and 54%/100% for athyreosis (n = 18); and 89%/90% and 80%/95% for dyshormonogenesis (n = 20). Neither modality, alone or in combination, predicted final diagnosis in eutopic glands due to hypoplasia (n = 4), transient TSH elevation (n = 12), and status still uncertain (n = 4). CONCLUSION: More than 80% of newborn infants with TSH elevation can be diagnosed correctly on initial imaging with combined radioisotope scan and ultrasound. Ultrasound cannot reliably detect thyroid ectopia. Radioisotope scan, especially if performed late, may show no uptake despite the presence of a eutopic gland.

New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe.

BACKGROUND: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. OBJECTIVE: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. RESULTS: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. CONCLUSIONS: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.