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1.
J Pharm Pharmacol ; 71(12): 1809-1821, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31579948

RESUMO

OBJECTIVES: Endoplasmic reticulum stress (ERS) has been shown to play a crucial role in the pathogenesis of hypertension. However, the role and mechanisms of ERS on hypertension-induced cardiac functional and morphological changes remain unclear. In this study, the effect of ERS inhibition with tauroursodeoxycholic acid (TUDCA) on hypertension-induced cardiac remodelling was examined. METHODS: Hypertension was induced by deoxycorticosterone-acetate (DOCA) and salt administration in uni-nephrectomized rats for 12 weeks. TUDCA was administered for the last four weeks. Rhythmic activity and contractions of the right atrium and left papillary muscle (LPM) were recorded. In the left ventricle, the expression of various proteins was examined and histopathological evaluation was performed. KEY FINDINGS: Hypertension-induced increments in systolic blood pressure and ventricular contractions were reversed by TUDCA. In the hypertensive heart, while expressions of glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated protein kinase-like ER kinase (p-PERK), sarcoplasmic reticulum Ca-ATPase-2 (SERCA2), matrix metalloproteinase-2 (MMP-2) and nuclear NF-κB p65 increased; Bcl-2 (B-cell lymphoma-2) expression decreased and the altered levels of all these markers were restored by TUDCA. In the microscopic examination, TUDCA treatment attenuated hypertension-stimulated cardiac inflammation and fibrosis. CONCLUSIONS: These results suggest that ERS inhibition may ameliorate cardiac contractility through improving ERS-associated calcium mishandling, apoptosis, inflammation and fibrosis, thereby offering therapeutic potential in hypertension-induced cardiac dysfunction.

2.
J Cardiovasc Pharmacol ; 74(2): 105-117, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31397742

RESUMO

In this study, the effect of liver X receptor (LXR) activation on hypertension-induced cardiac structural and functional alterations was investigated. Hypertension was induced by deoxycorticosterone acetate (DOCA)-salt administration in uninephrectomized rats for 6 weeks. LXR agonist GW3965 (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-acetic acid was given for the past week. Rhythmic activity and contractions of the isolated heart tissues were recorded. Biochemical parameters were assessed in ventricular tissue and plasma samples. Cardiac expressions of various proteins were examined, and histopathological evaluation was performed in the left ventricle and liver. GW3965 reduced systolic blood pressure and enhanced noradrenaline-stimulated papillary muscle contraction induced by DOCA-salt + uninephrectomy. Plasma and tissue total antioxidant capacity (TAC) increased and tissue 4-hydroxynonenal (4-HNE) levels decreased in the DOCA-salt group. GW3965 elevated plasma and tissue TAC levels in both of groups. Glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated-protein kinase-like ER kinase (p-PERK), matrix metalloproteinase-2 (MMP-2), and nuclear factor-κB p65 (NF-κB p65) expression was augmented, and inhibitor-κB-α (IκB-α) expression was reduced in hypertensive hearts. The altered levels of all these markers were reversed by GW3965. Also, GW3965 ameliorated DOCA-salt + uninephrectomy-induced cardiac and hepatic inflammation and fibrosis. However, GW3965 unchanged the plasma lipid levels and hepatic balloon degeneration score. These results demonstrated that LXR activation may improve hypertension-induced cardiac changes without undesired effects.

3.
Pediatr Neurol ; 99: 7-15, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31421914

RESUMO

Craniosynostosis is a pathologic craniofacial disorder and is defined as the premature fusion of one or more cranial (calvarial) sutures. Cranial sutures are fibrous joints consisting of nonossified mesenchymal cells that play an important role in the development of healthy craniofacial skeletons. Early fusion of these sutures results in incomplete brain development that may lead to complications of several severe medical conditions including seizures, brain damage, mental delay, complex deformities, strabismus, and visual and breathing problems. As a congenital disease, craniosynostosis has a heterogeneous origin that can be affected by genetic and epigenetic alterations, teratogens, and environmental factors and make the syndrome highly complex. To date, approximately 200 syndromes have been linked to craniosynostosis. In addition to being part of a syndrome, craniosynostosis can be nonsyndromic, formed without any additional anomalies. More than 50 nuclear genes that relate to craniosynostosis have been identified. Besides genetic factors, epigenetic factors like microRNAs and mechanical forces also play important roles in suture fusion. As craniosynostosis is a multifactorial disorder, evaluating the craniosynostosis syndrome requires and depends on all the information obtained from clinical findings, genetic analysis, epigenetic or environmental factors, or gene modulators. In this review, we will focus on embryologic and genetic studies, as well as epigenetic and environmental studies. We will discuss published studies and correlate the findings with unknown aspects of craniofacial disorders.

4.
Am J Med Genet A ; 179(11): 2241-2245, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31353793

RESUMO

Craniosynostosis consists of premature fusion of one or more cranial sutures and can be seen as part of a syndrome or diagnosed as nonsyndromic (isolated). Although more than 180 craniosynostosis syndromes have been identified, 70% of the cases are diagnosed as nonsyndromic. On the other hand, genetic causes of the cases are mostly unknown and the overall frequency of the genetic diagnosis is around 25%. In this study, we used targeted Next Generation Sequencing (NGS) analysis to identify the genetic variations of two craniosynostosis cases. We have identified two different truncating mutations, a known NM_207036.1:c.778_779delAT;p.(Met260Valfs*5) and a novel NM_207036.1:c.1102_1108delTCACCTC;p.(Pro369Glnfs*26) TCF12 variants. Additionally, upon physical examination of these two cases, we have observed some shared clinical similarities as well as differences such as bilateral simian crease and hidden cleft palate. This is the first study that reports the TCF12 mutations in Turkish patients with coronal suture synostosis.

5.
Genet Med ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31316167

RESUMO

PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31356548

RESUMO

In the present study, the effect of LXR (Liver X Receptor) activation on hypertension-induced cardiac structural and functional alterations was investigated.Hypertension was induced by deoxycorticosterone acetate (DOCA)-salt administration in uni-nephrectomized rats for 6 weeks. LXR agonist GW3965 (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propoxy}-phenyl)-aceticacid) was given for last week. Rhythmic activity and contractions of the isolated heart tissues were recorded. Biochemical parameters were assessed in ventricular tissue and plasma samples. Cardiac expressions of various proteins were examined and histopathological evaluation was performed in left ventricle and liver.GW3965 reduced systolic blood pressure and enhanced noradrenaline-stimulated papillary muscle contraction induced by DOCA-salt+uni-nephrectomy. Plasma and tissue total antioxidant capacity (TAC) increased and tissue 4-hydroxynonenal (4-HNE) levels decreased in DOCA-salt group. GW3965 elevated plasma and tissue TAC levels in both of groups. Glucose-regulated protein-78 (GRP78), phospho-dsRNA-activated-protein kinase-like ER kinase (p-PERK), matrix metalloproteinase-2 (MMP-2) and nuclear factor-κB p65 (NF-κB p65) expression was augmented and inhibitor-κB-α (IκB-α) expression was reduced in hypertensive hearts. The altered levels of all these markers were reversed by GW3965. Also, GW3965 ameliorated DOCA-salt+uni-nephrectomy-induced cardiac and hepatic inflammation and fibrosis. However, GW3965 unchanged the plasma lipid levels and hepatic balloon degeneration score.These results demonstrated that LXR activation may improve hypertension-induced cardiac changes without undesired effects.

7.
Turk J Med Sci ; 49(1): 429-434, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30761835

RESUMO

Background/aim: Based on our previous in vitro study with multilamellar liposomal bupivacaine (MLB) versus bupivacaine alone in artificial cerebrospinal fluid, we aimed to investigate in vivo antinociceptive effect of intrathecal MLB by determining tail flick latency (TFL) time after thermal stimulation in rats. Materials and methods: After preparing MLB and high-yield drug entrapment in liposome (HYDEL) bupivacaine, 18 female Wistar rats were assigned to 3 groups as control (bupivacaine) and study groups (MLB and HYDEL bupivacaine) including 6 rats in each group to administer these drugs intrathecally. Antinociceptive activity was determined in terms of TFL time after thermal stimulation. Maximum possible effect (MPE) calculated from TFL times and rats with motor block were documented. Results: TFL times after intrathecal injection of HYDEL bupivacaine were significantly longer than that of the control and MLB groups (P < 0.05) and returned to baseline 180 min after intrathecal injection. MPE (100%) with intrathecal HYDEL bupivacaine occurred between 10 to 45 min. Afterwards, MPEs were 70% and 50% for the control and MLB groups, respectively. Motor block disappeared after 20 min in the study groups while it lasted 75 min in the control. Conclusion: Intrathecal administration of MLB and HYDEL bupivacaine in rats resulted in longer duration of antinociceptive activity with shorter motor block duration.


Assuntos
Analgésicos/farmacologia , Bupivacaína/farmacologia , Lipossomos/farmacologia , Analgésicos/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Bupivacaína/administração & dosagem , Preparações de Ação Retardada , Feminino , Humanos , Injeções Espinhais , Lipossomos/administração & dosagem , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar
8.
Vascul Pharmacol ; 2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30458302

RESUMO

Hypertension has complex vascular pathogenesis and therefore the molecular etiology remains poorly elucidated. Endoplasmic reticulum stress (ERS), which is a condition of the unfolded/misfolded protein accumulation in the endoplasmic reticulum, has been defined as a potential target for cardiovascular disease. In the present study, the effects of ERS inhibition on hypertension-induced alterations in the vessels were investigated. In male Wistar albino rats, hypertension was induced through unilateral nephrectomy, deoxycorticosterone-acetate (DOCA) injection (20 mg/kg, twice a week) and 1% NaCl with 0.2% KCI added to drinking water for 12 weeks. An ERS inhibitor, tauroursodeoxycolic acid (TUDCA) (150 mg/kg/day, i.p.), was administered for the final four weeks. ERS inhibition in DOCA-salt induced hypertension was observed to have reduced systolic blood pressure, improved endothelial dysfunction, enhanced plasma nitric oxide (NO) level, reduced protein expressions of phosphorylated-double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (pPERK), 78 kDa glucose-regulated protein (GRP78), Inositol trisphosphate receptor1 (IP3R1) and Epidermal growth factor receptor (EGFR), increased expressions of endoplasmic reticulum Ca2+-ATPase2 (SERCA2) and B cell lymphoma2 (Bcl2) in vessels. These findings suggest that the beneficial effects of ERS inhibition on hypertension may be related to protection of vessel functions through restoration of endoplasmic reticulum calcium homeostasis, and apoptotic and mitotic pathways.

9.
Life Sci ; 213: 287-293, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30366037

RESUMO

AIMS: Liver X receptors (LXRs) play an important role in the regulation of cholesterol, fatty acid and glucose metabolisms together with inflammatory processes. In the present study, the effects of LXR agonist GW3965 on vascular reactivity and expression of functional proteins in DOCA-Salt induced hypertension were examined. MAIN METHODS: Hypertension was induced through unilateral nephrectomy and deoxycorticosterone-acetate (DOCA) injection (20 mg/kg, twice a week) for 6 weeks in male Wistar albino rats (8 weeks old). An LXR agonist GW3965 (10 mg/kg/day, i.p.) was administered to animals for last seven days. KEY FINDINGS: GW3965 treatment reduced systolic blood pressures in hypertensive rats. Acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent vasorelaxations were decreased in hypertensive rats but not affected by GW3965. GW3965 treatment enhanced plasma nitrite levels in normotensive rats. KCl and phenylephrine (Phe)-induced vasocontractions were reduced in hypertensive groups and increased with GW3965 treatment. Decreased sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) expression in the hypertensive aorta was not changed by GW3965 treatment. Expression of inositoltrisphosphate receptor1 (IP3R1) was increased by GW3965 in normotensive animals. The nuclear factor kappaB (NF-κB) and tumor necrosis factor alpha (TNF-α) expressions were increased in hypertensive rats and reduced by GW3965 treatment. SIGNIFICANCE: The results of study indicate that the LXR agonist, GW3965, exhibited a beneficial effect on increased blood pressure and improved hypertension-induced impairment in contractile activity of vessel and inflammatory markers in vascular tissue. Therefore, these effects of LXR agonists on vessel should be taken into account in experimental or therapeutic approaches to hypertension.

10.
Nat Commun ; 9(1): 3087, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082715

RESUMO

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.

11.
Am J Med Genet A ; 176(9): 1976-1980, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30088857

RESUMO

The bones of the skull are held together by fibrous joints called sutures. Premature fusion of these sutures leads to a pathologic condition called as craniosynostosis. Although at least 50 nuclear genes including FGFR2, TWIST1, TCF12, and SMAD6 were identified as causative of craniosynostosis; only 25% of the patients can be genetically diagnosed. Here, we report a 3-year-old Turkish Caucasian boy with sagittal craniosynostosis with a de novo loss-of-function mutation in exon 4 of the AXIN2 gene for the first time. The patient has frontal bossing, high anterior hair line, depressed nasal bridge, bilateral epicanthus and low set ears which are correlated with his scaphocephaly. As a negative regulator of the Wnt signaling pathway which is one of the key modulators of craniosynostosis syndrome, it has been shown in model organisms that Axin2 orchestrates the regulation of beta-catenin especially in the intramembranous ossification process. This clinical report adds value to the literature that AXIN2 gene mutations could be a potential cause in human calvarial malformations, especially for the sagittal synostosis.

12.
Hum Genet ; 137(6-7): 479-486, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29982980

RESUMO

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.

13.
Turk J Med Sci ; 48(3): 584-591, 2018 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-29914256

RESUMO

Background/aim: Declined morbidity rates after craniosynostosis surgery indicate bypassing the pediatric intensive care unit (PICU) course to minimize treatment costs and bed usage. The aim of this study is to examine the incident rates of PICU admission and assess its necessity. Materials and methods: A retrospective analysis of 41 patients (operated on by open surgical techniques) between July 2011 and December 2015 was carried out. Intraoperative/postoperative vital signs, hemodynamic and metabolic parameters, estimated blood loss (EBVloss), blood transfusions, length of PICU, and hospitalizations were recorded. Results: Major and minor events reached 51.2% and 82.9%, respectively. EBVloss within 24 h was calculated as 39.58 ± 8.19 (median: 38.44, 25.68-66.34) with 75.6% blood transfusion rate. Hypotension and hypothermia were associated with prolonged surgery (P = 0.001 and P = 0.007, respectively), but were not related to age (P = 0.054, P = 0.162) or procedure types (P = 0.558, P = 0.663). Prolonged surgery and younger age had an impact on the complications. One patient died of persistent hemorrhage at 96 h. Conclusion: Monitoring cardiovascular and metabolic dynamics at PICU during the first 24 h after surgery is crucial. Additional studies are needed to define the threshold values of several metabolic and hemodynamic markers in risk assessment after cranial vault surgery.

14.
Exp Gerontol ; 110: 191-201, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29908346

RESUMO

The purpose of this study was to determine the effects of resveratrol and regular aerobic exercise on vascular functions and biomarkers related to vessel responsiveness in an age and gender-dependent manner. The study used young (3 months) and old (12 months) male and female Wistar albino rats. Resveratrol was given in the drinking water (0.05 mg/ml; approximately 7.5 mg/kg) for 6 weeks. In the exercise group, all rats performed treadmill running at 20 m/min on a 0° incline, 40 min/day, 3 times a week, for 6 weeks. Acetylcholine-induced, endothelium-dependent and sodium nitroprusside-mediated, endothelium-independent relaxations of rat thoracic aorta and blood levels of biomarkers were separately changed by resveratrol intake and exercise-training in an age and gender-dependent manner. Antioxidant enzymes and eNOS expressions in vessels were elevated by resveratrol and exercise. Resveratrol and exercise enhanced gene expressions of non-selective PDE1, 2, 3 and cAMP selective PDE4 but not cGMP selective PDE5 in the aorta. In addition, the aortic mRNA expression of inflammation markers were altered by resveratrol and exercise-training. The results of the study demonstrated that vessel responsiveness and biomarkers related to vascular functions were altered by resveratrol consumption and exercise-training in an age and gender-dependent manner.

15.
Rheumatol Int ; 38(8): 1557-1564, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29869009

RESUMO

OBJECTIVE: To create a new multidimensional questionnaire for the assessment of juvenile idiopathic arthritis (JIA) patients in standard clinical practice and study the validity and reliability of this questionnaire. METHODS: The Juvenile Arthritis Biopsychosocial and Clinical Questionnaire (JAB-Q) was created using the Delphi technique and consensus conference following an initial literature search. The questionnaire has three parts including a clinician form, child form and parent form. This is a patient/parent-centered outcome tool, which helps us to evaluate the biopsychosocial aspects of the patient, including disease activity, posture, functional and psychosocial status, fatigue, and performance in school. From January 2015 to January 2018, 6-18 years old children with JIA were enrolled in the study. The previously validated questionnaires were also applied to each participant to validate the JAB-Q: Juvenile Idiopathic Disease Arthritis Score (JADAS) and Childhood Health Assessment Questionnaire (CHAQ), and the Family Impact Questionnaire (FIS). The same questionnaire was re-administered after one week to assess the test-retest reliability in randomly selected 50 children and their parents. RESULTS: A group of experts were invited to the Delphi survey. After the Delphi tours, the final form of the questionnaire containing three parts as clinician form, child form and parent form was created. This tool was applied to 310 JIA patients and their parents. The children and parents easily handled the JAB-Q and filled the forms in around 10-15 min. The validity of the clinician, child and parents' forms were assessed by the JADAS, CHAQ, and FIS, respectively. The validity of these three scales were determined as moderate. In addition, the test-retest reliability of the clinician, child and parents' forms were considerably high. CONCLUSION: JAB-Q is a valid and reliable multidimensional biopsychosocial outcome tool that can be used routinely in clinical practice of pediatric rheumatology. The main advantage of this tool is incorporation of patients' and parents' perspectives separately while providing a practical and standard setting for the clinician's evaluation. However, further validation of this tool in an independent cohort is needed to improve its applicability.

16.
Clin Endocrinol (Oxf) ; 89(1): 65-75, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29722904

RESUMO

OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naïve patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease.

18.
Neuromuscul Disord ; 27(10): 923-930, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28754454

RESUMO

Lipodystrophy is a heterogeneous group of disorders characterized by loss of adipose tissue. Here, we report on clinical spectra of neuromuscular manifestations of Turkish patients with lipodystrophy. Seventy-four patients with lipodystrophy and 20 healthy controls were included. Peripheral sensorimotor neuropathy was a common finding (67.4%) in lipodystrophic patients with diabetes. Neuropathic foot ulcers were observed in 4 patients. Drop foot developed in 1 patient with congenital generalized lipodystrophy type 1. Muscle symptoms and hypertrophy were consistent findings in congenital generalized lipodystrophy (21/21) and familial partial lipodystrophy (25/34); on the other hand, overt myopathy with elevated creatine kinase activity was a distinctive characteristic of congenital generalized lipodystrophy type 4. Muscle biopsies revealed myopathic changes at different levels. Accumulation of triglycerides was observed which contributes to insulin resistance. All patients with congenital generalized lipodystrophy suffered from tight Achilles tendons at various levels. Scoliosis was observed in congenital generalized lipodystrophy type 4 (2/2) and familial partial lipodystrophy type 2 (2/17). Atlantoaxial instability was unique to congenital generalized lipodystrophy type 4 (2/2). Bone cysts were detected in congenital generalized lipodystrophy type 1 (7/10) and congenital generalized lipodystrophy type 2 (2/8). Our study suggests that lipodystrophies are associated with a wide spectrum of neuromuscular abnormalities.


Assuntos
Tecido Adiposo/patologia , Lipodistrofia Generalizada Congênita/patologia , Lipodistrofia Parcial Familiar/patologia , Doenças Musculares/patologia , Adolescente , Adulto , Feminino , Humanos , Resistência à Insulina/fisiologia , Lipodistrofia Generalizada Congênita/diagnóstico , Lipodistrofia Generalizada Congênita/terapia , Lipodistrofia Parcial Familiar/diagnóstico , Lipodistrofia Parcial Familiar/terapia , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Triglicerídeos/metabolismo , Adulto Jovem
19.
PLoS Genet ; 13(3): e1006683, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28346496

RESUMO

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Predisposição Genética para Doença/genética , Deformidades Congênitas da Mão/genética , Neoplasias Hematológicas/genética , Deficiência Intelectual/genética , Mutação , Unhas Malformadas/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Western Blotting , Proteínas de Transporte/metabolismo , Linhagem Celular , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Células HEK293 , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Unhas Malformadas/metabolismo , Unhas Malformadas/patologia , Proteínas Nucleares/metabolismo , Fenótipo
20.
J Bone Miner Metab ; 35(3): 338-343, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27193466

RESUMO

Mucopolysaccharidosis type III (MPS III) is a neurodegenerative disorder. In MPS III patients, heparan sulfate accumulates in many tissues especially the central nervous system. There are limited data regarding bone involvement in MPS III compared to other MPS types. The aim of this study was to evaluate bone mineral density (BMD) and the prevalence of low bone mass, and to explore the association between BMD, vitamin D levels, bone fracture, and patient characteristics in MPS III. A clinical assessment and interview was held to obtain data about family history, height, weight, body mass index (BMI), nutrition, walking capacity, bone fracture, epilepsy, and medical therapy of 15 patients with MPS III. Height, weight, and BMI z scores were calculated. Laboratory tests including 25-hydroxyvitamin D (25-OH-D) were measured. BMD measurements for the lumbar spine were obtained using dual-energy X-ray absorptiometry (DXA). BMD z scores were adjusted for height-for-age z score (HAZ) to provide correction for height deficits. Lumbar spine BMD z score was low (<-1) in five patients for chronological age and normalized in two of five patients after adjustment for HAZ. Three patients continued to have low BMD; these were older than the other patients and one had a history of long bone fracture. Two of these patients were observed to have lost walking capacity at 10 and 14 years, and the other was walking with support. Six patients had deficient, and three patients had insufficient levels of 25-OH-D. Two osteoporotic patients had significantly lower levels of 25-OH-D. We found that older patients with immobility are at high risk of osteoporosis and bone fracture, and vitamin D deficiencies/insufficiencies are widely seen. We recommend monitoring BMD by DXA and checking vitamin D metabolism to assess low bone mass and fracture risk in older MPS III patients with immobility.


Assuntos
Densidade Óssea , Mucopolissacaridose III/fisiopatologia , Absorciometria de Fóton , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Adulto Jovem
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