The heterogeneity of autoimmune polyendocrine syndrome type 1: Clinical features, new mutations and cytokine autoantibodies in a Brazilian cohort from tertiary care centers.

Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by multiorgan autoimmunity. We aim at characterizing a multi-center Brazilian cohort of APS1 patients by clinical evaluation, searching mutation in the AIRE gene, measuring serum autoantibodies, and investigating correlations between findings. We recruited patients based on the clinical criteria and tested them for AIRE mutations, antibodies against interferon type I and interleukins 17A, 17F and 22. We identified 12 unrelated families (13 patients) with typical signs of APS1 in the proband, and the screening of relatives recognized an asymptomatic child. Candidiasis was present in all cases, and 19 other manifestations were observed. All patients carried one of 10 different mutations in AIRE, being 3 new ones, and were positive for anti-interferon type I serum antibody. Anti-interleukin-17A levels inversely correlated with the number of manifestations in each patient. This negative correlation may suggest a protective effect of anti-interleukin-17A with a potential therapeutic application.

Update on trabecular bone score.

Trabecular bone score (TBS) is an indirect and noninvasive measure of bone quality. A low TBS indicates degraded bone microarchitecture, predicts osteoporotic fracture, and is partially independent of clinical risk factors and bone mineral density (BMD). There is substantial evidence supporting the use of TBS to assess vertebral, hip, and major osteoporotic fracture risk in postmenopausal women, as well as to assess hip and major osteoporotic fracture risk in men aged > 50 years. TBS complements BMD information and can be used to adjust the FRAX (Fracture Risk Assessment) score to improve risk stratification. While TBS should not be used to monitor antiresorptive therapy, it may be potentially useful for monitoring anabolic therapy. There is also a growing body of evidence indicating that TBS is particularly useful as an adjunct to BMD for fracture risk assessment in conditions associated with increased fracture risk, such as type-2 diabetes, chronic corticosteroid excess, and other conditions wherein BMD readings are often misleading. The interference of abdominal soft tissue thickness (STT) on TBS should also be considered when interpreting these findings because image noise can impact TBS evaluation. A new TBS software version based on an algorithm that accounts for STT rather than BMI seems to correct this technical limitation and is under development. In this paper, we review the current state of TBS, its technical aspects, and its evolving role in the assessment and management of several clinical conditions.

Effect of soft tissue noise on trabecular bone score in postmenopausal women with diabetes: A cross sectional study.

BACKGROUND: Type 2 diabetes (T2D) is associated with increased fracture risk, despite similar or greater BMD compared to nondiabetics. TBS predicts fracture risk in T2D and nondiabetics. However, increased abdominal thickness, a common feature in T2D, may reduce TBS values. AIM: To study the relationship among glycemic status, BMD and TBS, considering abdominal soft tissue thickness (STT) interference. METHODS: Cross-sectional analysis of 493 women ≥65 years, with simultaneous DXA scans and HbA1c measures. STT and TBS (iNsight Software, v3.0) were derived from lumbar spine (LS) scans. Subjects were divided according to HbA1c levels: 1 (≥6.5%; n = 116), 2 (5.7-6.4%; n = 217) and 3 (≤5.6%; n = 160). Group 1 was further divided based on HbA1c and/or disease duration: 1a (HbA1c ≥ 7.5%; n = 42), 1b (HbA1c ≥ 6.5% and disease duration ≥5 years; n = 63) and 1c (HbA1c ≥ 7.5% and disease duration ≥5 years; n = 30). FINDINGS: For the entire cohort, mean age, TBS, BMI and STT were 71.8 ± 6.0 years, 1.299 ± 0.101, 26.9 ± 4.1 kg/m2, and 21.4 ± 2.9 cm, respectively. LS-BMD was similar among groups. BMD in hip sites and STT were higher in group 1. TBS was lower in patients with higher HbA1c (P = 0.020), with a mean TBS in groups 1, 2, and 3 of 1.280, 1.299 and 1.314, respectively. This difference remained after adjusting for age, LS-BMD and BMI (P = 0.010). After replacing BMI with STT, TBS differences were no longer significant (P = 0.270). The same was observed when subgroups 1a and 1b were compared to group 3. However, for subgroup 1c, TBS remained lower compared to group 3, even after adjusting for age, LS-BMD and STT, with a borderline P-value (1.275 vs. 1.308; P = 0.047). CONCLUSION: Higher HbA1c levels were associated with greater BMD in hip sites, higher abdominal STT and lower TBS values. However, after including the STT in the adjustment, TBS differences among groups disappeared, except in women with higher HbA1c levels and longer disease duration.

[Diabetes insipidus in a pacient with multiple sclerosis]. / Diabetes insípido em paciente com esclerose múltipla.

Multiple Sclerosis (ME) is a chronic progressive disease characterized by relapses of demyelination that can occur anywhere in the brain stem, spinal cord and optic nerve. Since central diabetes insipidus (DI) is mainly caused by central nervous system damage (such as trauma, surgery, tumor, infection, sarcoidosis), ME is included among its possible etiologies. However, this association is not commonly described. The clinical suspicion must be made in the presence of polyuria and polydipsia or refractory hypernatremia (in patients without free access to water) during the evolution of ME. We will describe a clinical report in which this association occurred and, after the beginning of desmopressin therapy, the clinical findings were reverted.

The Role of AIRE in the Immunity Against Candida Albicans in a Model of Human Macrophages.

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a primary immunodeficiency caused by mutations in the autoimmune regulator gene (AIRE). Patients with AIRE mutations are susceptible to Candida albicans infection and present with autoimmune disorders. We previously demonstrated that cytoplasmic AIRE regulates the Syk-dependent Dectin-1 pathway. In this study, we further evaluated direct contact with fungal elements, synapse formation, and the response of macrophage-like THP-1 cells to C. albicans hyphae to determine the role of AIRE upon Dectin receptors function and signaling. We examined the fungal synapse (FS) formation in wild-type and AIRE-knockdown THP-1 cells differentiated to macrophages, as well as monocyte-derived macrophages from APECED patients. We evaluated Dectin-2 receptor signaling, phagocytosis, and cytokine secretion upon hyphal stimulation. AIRE co-localized with Dectin-2 and Syk at the FS upon hyphal stimulation of macrophage-like THP-1 cells. AIRE-knockdown macrophage-like THP-1 cells exhibited less Dectin-1 and Dectin-2 receptors accumulation, decreased signaling pathway activity at the FS, lower C. albicans phagocytosis, and less lysosome formation. Furthermore, IL-1ß, IL-6, or TNF-α secretion by AIRE-knockdown macrophage-like THP-1 cells and AIRE-deficient patient macrophages was decreased compared to control cells. Our results suggest that AIRE modulates the FS formation and hyphal recognition and help to orchestrate an effective immune response against C. albicans.

Relief of primary cervical dystonia symptoms by low frequency transcranial magnetic stimulation of the premotor cortex: case report.

OBJECTIVE: To evaluate the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on the symptoms of a patient with primary segmental dystonia (PSD). METHOD: 1200 TMS pulses at a frequency of 1Hz, over the premotor cortex, with an intensity of 90% of the motor threshold (MT), using an eight-shaped coil; a total of 5 sessions were carried out. RESULTS: A reduction of 50 percent in the neck subset of the Burke, Fahn and Marsden torsion dystonia scale (BFM) was observed in our patient. CONCLUSION: The reduction in the BFM scale supports the concept that rTMS of the premotor cortex may reduce specific motor symptoms in PSD.

Update on trabecular bone score

ABSTRACT Trabecular bone score (TBS) is an indirect and noninvasive measure of bone quality. A low TBS indicates degraded bone microarchitecture, predicts osteoporotic fracture, and is partially independent of clinical risk factors and bone mineral density (BMD). There is substantial evidence supporting the use of TBS to assess vertebral, hip, and major osteoporotic fracture risk in postmenopausal women, as well as to assess hip and major osteoporotic fracture risk in men aged > 50 years. TBS complements BMD information and can be used to adjust the FRAX (Fracture Risk Assessment) score to improve risk stratification. While TBS should not be used to monitor antiresorptive therapy, it may be potentially useful for monitoring anabolic therapy. There is also a growing body of evidence indicating that TBS is particularly useful as an adjunct to BMD for fracture risk assessment in conditions associated with increased fracture risk, such as type-2 diabetes, chronic corticosteroid excess, and other conditions wherein BMD readings are often misleading. The interference of abdominal soft tissue thickness (STT) on TBS should also be considered when interpreting these findings because image noise can impact TBS evaluation. A new TBS software version based on an algorithm that accounts for STT rather than BMI seems to correct this technical limitation and is under development. In this paper, we review the current state of TBS, its technical aspects, and its evolving role in the assessment and management of several clinical conditions.

Autoimmune polyendocrine syndrome type 1: case report and review of literature.

Autoimmune polyendocrine syndrome type 1 (APECED) is a rare autosomal recessive disorder characterized by autoimmune multiorgan attack. The disease is caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein, which is essential for selftolerance. Clinical manifestations are widely variable. Although the classic triad is composed by mucocutaneous candidiasis, hypoparathyroidism and adrenal failure, many other components may develop. Treatment is based on supplementation of the various deficiencies, and patients require regular follow-up throughout their lifespan. This article describes the case of a patient with the disease, and reviews literature data on the epidemiology, clinical course, immunogenetic aspects, diagnosis and treatment of the syndrome.

Low frequency (0.5Hz) rTMS over the right (non-dominant) motor cortex does not affect ipsilateral hand performance in healthy humans.

Reduction of excitability of the dominant primary motor cortex (M1) improves ipsilateral hand function in healthy subjects. In analogy, inhibition of non-dominant M1 should also improve ipsilateral performance. In order to investigate this hypothesis, we have used slow repetitive transcranial magnetic stimulation (rTMS) and the Purdue Pegboard test. Twenty-eight volunteers underwent 10 minutes of either 0.5Hz rTMS over right M1 or sham rTMS (coil perpendicular to scalp). The motor task was performed before, immediately after, and 20 minutes after rTMS. In both groups, motor performance improved significantly throughout the sessions. rTMS inhibition of the non-dominant M1 had no significant influence over ipsilateral or contralateral manual dexterity, even though the results were limited by unequal performance between groups at baseline. This is in contrast to an improvement in left hand function previously described following slow rTMS over left M1, and suggests a less prominent physiological transcallosal inhibition from right to left M1.

Autoimmune polyendocrine syndrome type 1: case report and review of literature / Síndrome poliglandular autoimune tipo 1: descrição de caso e revisão da literatura

Autoimmune polyendocrine syndrome type 1 (APECED) is a rare autosomal recessive disorder characterized by autoimmune multiorgan attack. The disease is caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein, which is essential for selftolerance. Clinical manifestations are widely variable. Although the classic triad is composed by mucocutaneous candidiasis, hypoparathyroidism and adrenal failure, many other components may develop. Treatment is based on supplementation of the various deficiencies, and patients require regular follow-up throughout their lifespan. This article describes the case of a patient with the disease, and reviews literature data on the epidemiology, clinical course, immunogenetic aspects, diagnosis and treatment of the syndrome.

Síndrome poliglandular autoimune tipo 1 é uma rara desordem autossômica recessiva caracterizada por ataque autoimune a diversos órgãos. A doença é causada por mutações no gene AIRE (autoimmune regulator), resultando em uma proteína AIRE defeituosa, proteína esta essencial para a manutenção da autotolerância. As manifestações clínicas são extremamente variáveis. A tríade clássica é composta por candidíase mucocutânea crônica, hipoparatiroidismo e insuficiência adrenal, porém diversos outros componentes podem estar presentes. A base do tratamento é a reposição das diversas deficiências, e os pacientes devem ser acompanhados por toda a vida. Este artigo descreve o caso de uma paciente com a síndrome e apresenta uma revisão sobre a epidemiologia, quadro clínico, aspectos imunogenéticos, diagnóstico e tratamento da desordem, de acordo com a literatura publicada.

Diabetes insípido em paciente com esclerose múltipla / Diabetes insipidus in a pacient with multiple sclerosis

A esclerose múltipla (EM) é uma doença crônica e progressiva que se caracteriza por surtos de desmielinização que podem atingir qualquer topografia do cérebro, medula espinhal e nervo óptico. Sendo o diabetes insípido (DI) central causado, principalmente, em virtude de danos do sistema nervoso central (tais como trauma, cirurgia, tumor, infecção, sarcoidose), a EM está inclusa entre suas possíveis etiologias. Entretanto, a ocorrência dessa associação não é comumente descrita. A suspeita clínica deve ser feita na presença de poliúria e polidipsia ou hipernatremia refratária (em pacientes privados do acesso à água) durante a evolução da EM. Descreveremos um caso em que essa associação ocorreu e, após o início da terapêutica com desmopressina, a paciente reverteu o quadro clínico.

Multiple Sclerosis (ME) is a chronic progressive disease characterized by relapses of demyelination that can occur anywhere in the brain stem, spinal cord and optic nerve. Since central diabetes insipidus (DI) is mainly caused by central nervous system damage (such as trauma, surgery, tumor, infection, sarcoidosis), ME is included among its possible etiologies. However, this association is not commonly described. The clinical suspicion must be made in the presence of polyuria and polydipsia or refractory hypernatremia (in patients without free access to water) during the evolution of ME. We will describe a clinical report in which this association occurred and, after the beginning of desmopressin therapy, the clinical findings were reverted.

Low frequency (0.5Hz) rTMS over the right (non-dominant) motor cortex does not affect ipsilateral hand performance in healthy humans / A inibição do córtex motor não-dominante por meio da estimulação magnética transcraniana a 0, 5Hz não interfere no desempenho manual ipsilateral de sujeitos hígidos

Reduction of excitability of the dominant primary motor cortex (M1) improves ipsilateral hand function in healthy subjects. In analogy, inhibition of non-dominant M1 should also improve ipsilateral performance. In order to investigate this hypothesis, we have used slow repetitive transcranial magnetic stimulation (rTMS) and the Purdue Pegboard test. Twenty-eight volunteers underwent 10 minutes of either 0.5Hz rTMS over right M1 or sham rTMS (coil perpendicular to scalp). The motor task was performed before, immediately after, and 20 minutes after rTMS. In both groups, motor performance improved significantly throughout the sessions. rTMS inhibition of the non-dominant M1 had no significant influence over ipsilateral or contralateral manual dexterity, even though the results were limited by unequal performance between groups at baseline. This is in contrast to an improvement in left hand function previously described following slow rTMS over left M1, and suggests a less prominent physiological transcallosal inhibition from right to left M1.

A redução da excitabilidade do córtex motor primário (M1) dominante melhora o desempenho manual ipsilateral: a inibição do M1 não-dominante poderia, analogamente, aprimorar a função manual direita. Para investigar esta hipótese, utilizou-se a estimulação magnética transcraniana repetitiva (EMTr) de baixa frequência e o teste Purdue Pegboard. Submetemos 28 voluntários a 10 minutos de EMTr sobre o M1 direito (0,5 Hz) ou a EMTr placebo (bobina perpendicular ao escalpo). O teste foi executado antes, imediatamente após e 20 minutos após a EMTr. Nos dois grupos, o desempenho manual mostrou significativa melhora entre as sessões. A inibição do M1 não-dominante não influenciou significativamente a destreza motora ipsi ou contralateral, apesar da conclusão limitada pelo desempenho discrepante dos grupos na primeira sessão. Este resultado contrasta com a melhora da função manual esquerda descrita após a EMTr sobre o M1 esquerdo e sugere uma inibição transcalosa fisiológica menos intensa do M1 direito para o esquerdo.

Relief of primary cervical dystonia symptoms by low frequency transcranial magnetic stimulation of the premotor cortex: case report

OBJECTIVE: To evaluate the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on the symptoms of a patient with primary segmental dystonia (PSD). METHOD: 1200 TMS pulses at a frequency of 1Hz, over the premotor cortex, with an intensity of 90 percent of the motor threshold (MT), using an eight-shaped coil; a total of 5 sessions were carried out. RESULTS: A reduction of 50 percent in the neck subset of the Burke, Fahn and Marsden torsion dystonia scale (BFM) was observed in our patient. CONCLUSION: The reduction in the BFM scale supports the concept that rTMS of the premotor cortex may reduce specific motor symptoms in PSD.

OBJETIVO: Investigar o efeito da estimulação magnética transcraniana repetitiva (EMTr) de baixa freqüência nos sintomas de um paciente com distonia segmentar primária (DSP). MÉTODO: 1200 pulsos a uma freqüência de 1Hz, sobre o córtex pré-motor, a uma intensidade de 90 por cento do limiar motor (LM), usando uma bobina em forma de 8. Foram realizadas 5 sessões. RESULTADOS: Uma redução de 50 por cento no sub-item "pescoço" na escala de distonia de torção de Burke, Fahn e Marsden (BFM) foi observada no paciente em questão. CONCLUSÃO: A redução na escala BFM corrobora a idéia de que a EMTr sobre o córtex pré-motor pode reduzir sintomas motores específicos na DSP.