Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.

PURPOSE: CDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1 mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT). METHODS: During genetic screening for familial hyperparathyroidism, three novel CDKIs germline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples. RESULTS: DNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1B in cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3. CONCLUSION: Germline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.

Glucagon stimulation test to assess growth hormone status in Prader-Willi syndrome.

PURPOSE: Growth hormone deficiency (GHD) must be confirmed before starting treatment in adults with Prader-Willi syndrome (PWS). Most studies use the growth-hormone-releasing hormone plus arginine (GHRH-arginine) test. No data are available on the glucagon stimulation test (GST) in PWS. We compared the utility of fixed-dose (1 mg) GST versus GHRH-arginine test in diagnosing GHD. METHODS: Adults and late adolescents with PWS underwent both tests on separate days. In the GHRH-arginine test, GHD was defined according to body mass index. In the GST, two cutoffs were analyzed: peak GH concentration < 3 ng/mL and < 1 ng/mL. For analyses, patients were divided into two groups according to body weight (≤ 90 kg and > 90 kg). RESULTS: We analyzed 34 patients: 22 weighing ≤ 90 kg and 12 weighing > 90 kg. In patients weighing ≤ 90 kg, the two tests were concordant in 16 (72.72%) patients (k = 0.476, p = 0.009 with GST cutoff < 3 ng/mL, and k = 0.450, p = 0.035 with GST cutoff < 1 ng/mL). In patients weighing > 90 kg, the two tests were not concordant with GST cutoff < 3 ng/mL, but were concordant in 11 (91.6%) patients (k = 0.833, p = 0.003) with GST cutoff < 1 ng/mL. GH peaks on the two tests correlated (r = 0.725, p = 0.008). CONCLUSION: Fixed-dose (1 mg) GST using a peak GH cutoff of < 3 ng/mL or < 1 ng/mL promises to be useful for screening for GHD in adults and late adolescents with PWS. However, in those weighing > 90 kg, the < 1 ng/mL cutoff seems better. Larger studies are necessary to establish definitive glucagon doses and cutoffs, especially in extremely obese patients.

Low frequency of positive antithyroid antibodies is observed in patients with thyroid dysfunction related to immune check point inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICI), such as programmed death-1 inhibitors (anti-PD1), have become a cornerstone for the treatment of different advanced cancers. These antibodies act as modulators of immune checkpoint proteins. However, ICI can lead to the breaking of immune self-tolerance, inducing autoimmune side effects (irAEs), including endocrinopathies. One of the most frequent endocrine irAE of anti-PD1 is thyroid dysfunction, but the exact mechanism of this disease still remains unknown. MATERIALS AND METHODS: We conducted a descriptive retrospective study, analyzing 11 patients who received at least one dose of anti-PD1 (nivolumab or pembrolizumab) and presented thyroid irAEs. Data were collected between September 2015 and May 2018 in our hospital. The aim was to analyze the clinically relevant features of thyroid irAEs and the frequency of antithyroid antibodies (ATA) positivity observed on them. RESULTS AND DISCUSSION: 8 of the 11 patients were treated with nivolumab and the other three patients received pembrolizumab. Six patients presented silent thyroiditis with a thyrotoxicosis phase; three patients developed directly primary/subclinical hypothyroidism and two patients showed primary hyperthyroidism. Thyroid autoantibodies (anti-Thyroglobulin and anti-Thyroid Peroxidase) were assessed in all the 11 patients, and only in two of them (18%) a positive titer was displayed. Anti-TSH receptor antibodies (TRAbs) were examined in five patients, three with painless thyroiditis at the time of thyrotoxicosis and two with primary hyperthyroidism, and they all had undetectable levels. CONCLUSIONS: In our sample of 11 Caucasian patients with thyroid dysfunction related with anti-PD1, we found low frequency of ATA positive titers, comparable to other recent reports in others ethnicities, which could suggest that silent thyroiditis due to pembrolizumab or nivolumab has a different pathogenesis from the classical autoimmune spontaneous thyroiditis. Further investigations are required to completely understand the immune mechanisms involved.

Differential involvement of synovial adipokines in pain and physical function in female patients with knee osteoarthritis. A cross-sectional study.

OBJECTIVE: Adipokines have been reported to play a role in the development, progression and severity of knee osteoarthritis but the influence of the different adipokines are not well known. The aim of this study was to evaluate the association between different synovial fluid adipokines with pain and disability knee osteoarthritis patients. METHODS: Cross-sectional study with systematic inclusion of 115 symptomatic primary knee osteoarthritis female patients with ultrasound-confirmed joint effusion. Age, physical exercise, symptoms duration and different anthropometric measurements were collected. Radiographic severity was evaluated according to Kellgren-Lawrence scale. Pain and disability were assessed by WOMAC-total, -pain, -function subscales and Knee injury and Osteoarthritis Outcome Score (KOOS) pain and function scales. Seven adipokines and three inflammatory markers were measured by ELISA in synovial fluid. Partial Correlation Coefficient (PCC) and corresponding 95% confidence interval were used as a measure of association. RESULTS: Leptin, osteopontin and inflammatory factors, especially TNF-alpha, were associated to pain and function. After adjustment for potential confounders including inflammatory factors and all adipokines, an association was found for adiponectin with pain (PCC 0.240 [0.012, 0.444]) and for resistin and visfatin with function (PCC 0.336 [0.117, 0.524] and -0.262 [-0.463, -0.036]). No other adipokines or inflammatory markers were statistically and independently associated. An association between physical exercise and pain and disability remained after adjustment, whereas an attenuation of the influence of anthropometric measurements was observed. CONCLUSIONS: Different patterns of association between synovial fluid adipokines were observed regarding pain and disability in knee osteoarthritis patients. Specifically, adiponectin was associated to pain while resistin and visfatin were mainly related to function.

[Barcelona Test for Intellectual Disability: a new instrument for the neuropsychological assessment of adults with intellectual disability]. / Test Barcelona para discapacidad intelectual: un nuevo instrumento para la valoracion neuropsicologica clinica de adultos con discapacidad intelectual.

INTRODUCTION: Neuropsychological assessment in individuals with intellectual disability is of utmost importance in order to determine the cognitive deficits underlying brain dysfunction and limiting intellectual functioning and adaptive behavior. However, no neuropsychological batteries in Spanish language have been created and validated for this population. AIM: To adapt the 'programa integrado de exploracion neuropsicologica-test Barcelona' and to validate the new version, the Barcelona Test for Intellectual Disability (TB-DI). To create normative data for its clinical use. SUBJECTS AND METHODS: The original test was modified based on data from a pilot sample of 65 individuals with intellectual disability. In order to study the psychometric properties of the TB-DI, it was administered to a sample of 170 individuals with intellectual disability and to a group of 60 individuals without it. The relevant variables for stratification of normative data were determined by means of regression models. RESULTS: The TB-DI was finally composed by 67 subtests grouped in eight cognitive domains and it showed good psychometric properties. Normative data were created for five groups taking into account intellectual disability level, age and acquired curricular competence. These data were organized in percentiles in a way that allows the creation of cognitive profiles in the clinical and experimental fields. CONCLUSION: The TB-DI constitutes a tool of high applicability in the population with intellectual disability. It shows adequate validity and reliability, and it has good psychometric properties. The cognitive profiles obtained by the TB-DI will provide valuable information for the treatment of adult adults with mild and moderate intellectual disability.

TITLE: Test Barcelona para discapacidad intelectual: un nuevo instrumento para la valoracion neuropsicologica clinica de adultos con discapacidad intelectual.Introduccion. La evaluacion neuropsicologica en las personas con discapacidad intelectual es importante para determinar los deficits cognitivos especificos que subyacen a la afectacion cerebral, limitan el funcionamiento intelectual y afectan al comportamiento adaptativo. A pesar de ello, no existen baterias neuropsicologicas en castellano adaptadas y validadas para esta poblacion. Objetivo. Adaptar el programa integrado de exploracion neuropsicologica-test Barcelona y validar la nueva version, el test Barcelona para discapacidad intelectual (TB-DI), estableciendo datos normativos para el empleo clinico. Sujetos y metodos. A partir de los datos obtenidos en una muestra piloto de 65 personas con discapacidad intelectual, se realizaron cambios en el test original. Para estudiar las propiedades psicometricas del TB-DI, se administro a una muestra de 170 personas con discapacidad intelectual y a un grupo de 60 personas sin ella. Mediante modelos de regresion, se determino que variables eran importantes para la estratificacion de los datos normativos. Resultados. El TB-DI, compuesto de 67 subtests agrupados en ocho dominios cognitivos, muestra unas buenas propiedades psicometricas. Se crean datos normativos para cinco grupos en funcion del nivel de discapacidad intelectual, la edad y la competencia curricular. Estos datos se organizan en percentiles, lo que permite trazar perfiles cognitivos en el ambito clinico y experimental. Conclusion. El TB-DI es un instrumento de alta aplicabilidad para la poblacion con discapacidad intelectual, y muestra una validez y una fiabilidad adecuadas, y con buenas propiedades psicometricas. Los perfiles cognitivos determinados mediante el TB-DI proporcionaran informacion valiosa para el tratamiento integral de las personas adultas con discapacidad intelectual leve y moderada.

Sleep biosignature of Type 2 diabetes: a case-control study.

AIM: To determine whether or not the sleep disturbances associated with Type 2 diabetes affect the structure of sleep. METHODS: We designed a case-control study in 76 patients with Type 2 diabetes and 76 control subjects without Type 2 diabetes, matched by age, gender, BMI and waist and neck circumferences. A subgroup of 32 patients with Type 2 diabetes was also matched with 64 control subjects without Type 2 diabetes according to apnoea-hypopnoea index score. Examination included an overnight full polysomnography. RESULTS: No differences in the percentage of time spent in either rapid eye movement or non-rapid eye movement sleep were observed between groups; however, patients with Type 2 diabetes had more microarousal events during sleep than control subjects [41.4 (total range 4.0-104.4) vs 20.7 (total range 1.3-94.5) events/h; P < 0.001]. These differences were mainly observed during the non-rapid eye movement sleep [7.4 (total range 0-107.2) vs 0.2 (total range 0-65.2) events/h; P < 0.001]. In addition, sleep variables related to oxygen saturation measures, such as the percentage of time spent with oxygen saturation ≤90%, were significantly greater during the rapid eye movement sleep in patients with Type 2 diabetes [20.3 (total range 0-99.2) vs. 10.5 (total range 0-94.0)%; P = 0.047]. This pattern was maintained in the subgroup of patients matched by apnoea-hypopnaea index. Finally, stepwise regression analyses showed that apnoea-hypopnoea index, the presence of Type 2 diabetes and fasting plasma glucose value were independently associated with the number of microarousals (R2 =0.667). CONCLUSIONS: Type 2 diabetes is associated with an altered sleep structure, with different effects according to rapid eye movement (increase in nocturnal hypoxia) or non-rapid eye movement (increase in sleep fragmentation) sleep.

Lipopolysaccharide-binding protein is increased in patients with psoriasis with metabolic syndrome, and correlates with C-reactive protein.

Lipopolysaccharide-binding protein (LBP) is a reliable indicator of serum lipopolysaccharide (LPS) concentration. Raised levels of circulating LPS can trigger an increase in chronic pro-inflammatory cytokines, which may mediate the development of insulin resistance and obesity. Psoriasis is a chronic inflammatory skin disease that has been associated with metabolic syndrome. We aimed to study the expression of LBP in patients with psoriasis treated with narrowband ultraviolet B phototherapy, and controls matched by age, gender and body mass index (BMI). We did not find any differences in serum LBP concentration between patients and controls, and serum LBP did not correlate with the Psoriasis Area and Severity Index. However, patients with psoriasis and metabolic syndrome had higher serum concentration of LBP than controls. Furthermore, correlation with BMI and apolipoprotein B was present in controls, but not in patients with psoriasis. Serum LBP level did not change significantly after treatment with phototherapy.

Effect of narrowband ultraviolet B therapy on inflammatory markers and body fat composition in moderate to severe psoriasis.

BACKGROUND: Previous studies have shown increased prevalence of metabolic syndrome in patients with psoriasis. OBJECTIVES: To characterize the anthropometric and metabolic profile of Spanish patients with moderate to severe psoriasis compared with controls without psoriasis matched for gender, age and body mass index (BMI), and to evaluate the impact of narrowband ultraviolet B (NB-UVB) therapy on patient profiles. METHODS: Baseline waist circumference, body fat composition, lipid, carbohydrate and calcium metabolism profile, inflammation markers, homocysteine, vitamins D, B(6) and B(12) and folic acid of 50 patients with psoriasis and 50 matched controls were recorded then evaluated after NB-UVB in patients with psoriasis and correlated with clinical outcome. RESULTS: Despite very similar BMIs, 54% of patients met International Diabetes Foundation criteria for metabolic syndrome compared with 42% of controls (P = 0·01); body fat was 29·9% in patients and 28·0% in controls (P = 0·037), correlating with waist circumference; while patient atherogenic profiles were less favourable, with higher apolipoprotein B and low density lipoprotein cholesterol than controls, and both patients and controls showed insufficient vitamin D serum levels (< 20 ng mL(-1)). Mean improvement of Psoriasis Area and Severity Index (PASI) after NB-UVB was 78·2%. Ferritin, B(12) and C-reactive protein decreased significantly after NB-UVB therapy. Vitamin D levels reached adequate levels after phototherapy; however, no relationship with PASI improvement was observed. CONCLUSIONS: We characterized inflammatory and atherogenic profiles of Spanish patients with psoriasis compared with matched controls. After NB-UVB therapy we demonstrated improvement in psoriasis and some systemic inflammation markers, which were not mediated by enhancement of vitamin D synthesis.

Insulin resistance, low-grade inflammation and type 1 diabetes mellitus.

To assess the relationships between insulin resistance and low-grade inflammation in subjects with type 1 diabetes mellitus (T1DM) who do not have clinical macrovascular complications. A total of 120 subjects diagnosed with T1DM 14 years before were evaluated for the following: (1) sex, age, body mass index, waist-to-hip ratio (WHR), blood pressure, smoking, alcohol intake, insulin dose, HbA1c and lipid profile; (2) microvascular complications; (3) plasma concentrations of soluble fractions of tumour necrosis factor-α receptors type 1 and 2, interleukin-6, adiponectin, leptin and high-sensitivity C-reactive protein (hs-CRP); and (4) insulin resistance (estimation of the glucose disposal rate-eGDR). Those subjects with an eGDR below the median of the same sex group were classified as insulin resistant and the others as insulin sensitive. Insulin-resistant men, compared to the insulin-sensitive, had higher WHR (0.89 ± 0.08 vs. 0.83 ± 0.05; P < 0.01), higher systolic [121 (118-125) vs. 114 (108-120) mmHg; P = 0.01] and diastolic [73 (66-80) vs. 67 (70-73) mmHg; P = 0.02] blood pressures, higher HbA1c values [8.7 (8.1-9.9) vs. 7.5 (7.2-8.0) %; P < 0.01] and higher hs-CRP concentrations [1.16 (0.61-3.20) vs. 0.49 (0.31-0.82) mg/dl; P = 0.01], but no other significant differences between groups were found. Insulin-resistant women had higher WHR and HbA1c values, compared to the insulin-sensitive, but they did not have any other differences. In men, hs-CRP correlated significantly with WHR and HbA1c (r = 0.363; P = 0.016 and r = 0.317; P = 0.036, respectively), after adjusting for age, alcohol intake, smoking and microvascular complications. Insulin-resistant men with T1DM have an increase in plasma concentrations of hs-CRP. Central obesity and HbA1c are its main determinants.

Fasting plasma peptide YY concentrations are increased in patients with major depression who associate weight loss.

BACKGROUND: Many patients with major depression refer a decreased appetite and weight loss among their symptoms. Peptide YY (PYY) and ghrelin belong to the family of peptides of the gut-brain axis implicated in the regulation of appetite and energy metabolism. PYY stimulates a powerful central satiety response and ghrelin increases food intake and weight gain. Brain-derived neurotrophic factor (BDNF) also contributes to the central control of food intake as an anorexigenic factor. AIM: To study fasting plasma total and acylated ghrelin, plasma PYY and serum BDNF levels in patients with major depression with weight loss as one of their symptoms and compare them with matched healthy controls. SUBJECTS AND METHODS: Fifteen adult patients, 9 male and 6 female, with recent diagnosis of major depression, and 16 healthy adult subjects, matched by age and anthropometric parameters were studied. All depressed patients referred weight loss and were not under antidepressant therapy. Fasting total PYY, total ghrelin and acylated ghrelin and BDNF were determined. RESULTS: Fasting total PYY was higher in patients than controls (2.01±0.09 vs 1.29±0.16 pmol/l). There were no differences in fasting total ghrelin, acylated ghrelin or BDNF levels. CONCLUSIONS: Major depressed patients, with weight loss at diagnosis, showed higher fasting plasma PYY levels that could contribute to their reduced appetite.

Comparativa entre los diversos tratamientos de la hiperglucemia: estrategias para minimizar la ganancia ponderal en la diabetes tipo 2 / Comparison between several antihyperglycemic treatments: strategies to minimize weight gain in type 2 diabetes

La pérdida de peso es fundamental para el tratamiento de los pacientes condiabetes tipo 2, dado que se asocia a disminución de la resistencia a la insulinay a mejoría del control metabólico. Sin embargo, los fármacos disponibles parael tratamiento de la hiperglucemia tienen un efecto variable sobre el peso: losanálogos del GLP-1 lo disminuyen; el tratamiento con sulfonilureas, meglitinidas,tiazolidindionas e insulina se asocia a ganancia ponderal, mientras que lametformina, los inhibidores de la enzima dipeptidilpeptidasa IV y los inhibidoresde la alfaglucosidasa tienen un efecto neutral en el peso. Al mismo tiempo, lamayoría de guías de práctica clínica para el tratamiento de la hiperglucemiaproponen escaladas terapéuticas sin tener en cuenta la ganancia ponderal. Elobjetivo de este seminario es revisar el efecto sobre el peso de los diversostratamientos para la hiperglucemia y proponer estrategias terapéuticas paraminimizar la ganancia ponderal asociada al tratamiento de la diabetes tipo 2(AU)

Weight loss is important for treatment of type 2 diabetic patients, because it isassociated with a decrease in insulinresistance and with the improvement ofmetabolic control. However, the available antihyperglycemic treatments mayhave variable effects on body weight. GLP-1 analogues induce weight loss.Sulfonylureas, meglitinides, thiazolidinediones and insulin are associated withweight gain, whereas metformin, dipeptidyl peptidase 4 inhibitors and alphaglucosidaseinhibitors are weight neutral. Concomitantly, most of the clinicalpractice guidelines for diabetes treatment propose therapeutical steps independentlyof their effect on weight. The aim of this seminary is to review theeffect of different antihyperglycemic treatments on weight and propose strategiesto minimize weight gain in type 2 diabetes(AU)

Plasma visfatin concentrations increase in both hyper and hypothyroid subjects after normalization of thyroid function and are not related to insulin resistance, anthropometric or inflammatory parameters.

OBJECTIVE: The objective of this study was to evaluate plasma visfatin levels in thyroid dysfunction and its relationship with inflammatory, anthropometric and insulin resistance parameters. DESIGN AND PATIENTS: Twenty-four hyperthyroid and 27 hypothyroid patients were studied before and after treatment. Forty-five euthyroid subjects were used as control group. MEASUREMENTS: Fasting plasma visfatin, IL-6, C reactive protein, adiponectin, thyroid hormones, waist-to-hip ratio, BMI, percentage of body fat and homeostasis model insulin resistance index (HOMA-IR) were measured. RESULTS: Hyperthyroid patients showed increased insulin resistance, IL-6 and visfatin levels compared with controls (3.21 +/- 3.0 vs. 1.67 +/- 0.75, P = 0.022; 3.35 +/- 0.41 vs. 2.10 +/- 0.25 pg/ml, P = 0.016; and 37.4 +/- 5.81 vs. 23.79 +/- 4.2 ng/ml, P = 0.061 respectively). After normalization of thyroid function, IL-6 levels and HOMA-IR decreased (2.35 +/- 0.37 vs. 2.10 +/- 0.25 pg/ml, P = 0.045 and 3.21 +/- 0.60 vs. 2.28 +/- 0.38, P = 0.032 respectively), while body weight, adiposity and visfatin levels increased (26.1 +/- 1.2 vs. 26.7 +/- 1.2 kg/m(2), P = 0.049; 30.9 +/- 1.6 vs. 32.2 +/- 1.6%, P = 0.007; and 37.4 +/- 5.81 vs. 63.13 +/- 8.72 ng/ml, P = 0.047 respectively). C reactive protein and adiponectin levels were similar to those of the control group. Hypothyroid patients showed high visfatin levels (40.59 +/- 3.07 vs. 29.34 +/- 4.9 ng/ml, P = 0.049) that increased after treatment (81.4 +/- 9.2 ng/ml, P = 0.001) without changes in anthropometric or insulin resistance parameters. C reactive protein, IL-6 and adiponectin levels were similar to those of the control group. No correlations between visfatin and any analysed parameter were found in either hyper- or hypothyroidism. CONCLUSION: Visfatin exhibits a marked increase after normalization of thyroid function in both hyper and hypothyroid patients. We suggest that visfatin may play a role in the hormone stabilization process independent of anthropometric, inflammatory or insulin resistance variables.

Adult subjects with Prader-Willi syndrome show more low-grade systemic inflammation than matched obese subjects.

AIM: Adult subjects with Prader-Willi syndrome (PWS) may show several conditions that are associated with an activation of innate immunity such as obesity, deficient GH secretion or hypogonadism. Our aim was to study whether obese adult PWS subjects show an additional low-grade systemic inflammation (LGSI) in relation to obese adult non-PWS subjects and lean healthy control subjects before and after a standardized liquid meal. METHODS: Seven obese adult PWS subjects, 7 matched obese non-PWS subjects and 7 lean healthy control subjects were studied for 6 h from the administration of a standard liquid meal. RESULTS: Compared to non-PWS, PWS subjects showed higher plasma concentrations of C-reactive protein (CRP) (p=0.030), complement component C3 (p=0.018), interleukin(IL)-18 (p=0.048), and IL-6 (p=0.041) that persisted post-prandially elevated for CRP (p<0.0001), C3 (p=0.015), and IL-18 (p=0.003). Tumor necrosis factor(TNF)-alpha did not differ between the 3 groups. These results were independent from IGF-I levels, homeostasis model assessment index, and body mass index (BMI). In male subjects with PWS, testosterone levels correlated to IL-18 (r=-0,646, p=0.041). CONCLUSIONS: Compared to matched non-PWS subjects, the obese PWS subjects in this study showed an additional LGSI that persisted postprandially and was independent from BMI, insulin resistance, and deficient GH secretion. However, in PWS males, high IL-18 levels were related to low testosterone concentrations.

Introducción, definición y medida del exceso de peso en adolescentes / No disponible

No disponible

Comorbilidades del exceso ponderal en el adolescente / No disponible

No disponible