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Kabuki syndrome (KS) is a rare genetic disorder characterized by distinct facial features, intellectual disability, and multiple congenital anomalies. We conducted a comprehensive analysis of the genetic and phenotypic spectrum of KS in a Taiwanese patient group of 23 patients. KMT2D variants were found in 22 individuals, with missense (26.1%), nonsense (21.7%), and frameshift (17.4%) variants being the most prevalent. One patient had a KMT2D variant of uncertain significance. The most common clinical characteristics included distinct facial features (100%), intellectual disability (100%), developmental delay (95.7%), speech delay (78.3%), hypotonia (69.6%), congenital heart abnormalities (69.6%), and recurrent infections (65.2%). Other abnormalities included hearing loss (39.1%), seizures (26.1%), cleft palate (26.1%), and renal anomalies (21.7%). This study broadens the mutational and phenotypic spectrum of KS in the Taiwanese population, highlighting the importance of comprehensive genetic testing and multidisciplinary clinical evaluations for diagnosis and treatment.
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Background: Muscular dystrophies and congenital myopathies encompass various inherited muscular disorders that present diagnostic challenges due to clinical complexity and genetic heterogeneity. Methods: This study aimed to investigate the use of whole exome sequencing (WES) in diagnosing muscular disorders in pediatric patients in Taiwan. Out of 161 pediatric patients suspected to have genetic/inherited myopathies, 115 received a molecular diagnosis through conventional tests, single gene testing, and gene panels. The remaining 46 patients were divided into three groups: Group 1 (multiplex ligation-dependent probe amplification-negative Duchenne muscular dystrophy) with three patients (6.5%), Group 2 (various forms of muscular dystrophies) with 21 patients (45.7%), and Group 3 (congenital myopathies) with 22 patients (47.8%). Results: WES analysis of these groups found pathogenic variants in 100.0% (3/3), 57.1% (12/21), and 68.2% (15/22) of patients in Groups 1 to 3, respectively. WES had a diagnostic yield of 65.2% (30 patients out of 46), detecting 30 pathogenic or potentially pathogenic variants across 28 genes. Conclusion: WES enables the diagnosis of rare diseases with symptoms and characteristics similar to congenital myopathies and muscular dystrophies, such as muscle weakness. Consequently, this approach facilitates targeted therapy implementation and appropriate genetic counseling.
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Congenital heart defects (CHDs) affect a substantial proportion of patients with Kabuki syndrome. However, the prevalence and type of CHD and the genotype-phenotype correlations in Asian populations are not fully elucidated. This study performed a retrospective analysis of 23 Taiwanese patients with molecularly confirmed Kabuki syndrome. Twenty-two patients presented with pathogenic variants in the KMT2D gene. Comprehensive clinical assessments were performed. A literature review was conducted to summarize the spectrum of CHDs in patients with Kabuki syndrome. In total, 16 (73.9%) of 22 patients with pathogenic KMT2D variants had CHDs. The most common types of CHD were atrial septal defects (37.5%), ventricular septal defects (18.8%), coarctation of the aorta (18.8%), bicuspid aortic valve (12.5%), persistent left superior vena cava (12.5%), mitral valve prolapse (12.5%), mitral regurgitation (12.5%), and patent ductus arteriosus (12.5%). Other cardiac abnormalities were less common. Further, there were no clear genotype-phenotype correlations found. A literature review revealed similar patterns of CHDs, with a predominance of left-sided obstructive lesions and septal defects. In conclusion, the most common types of CHDs in Taiwanese patients with Kabuki syndrome who presented with KMT2D mutations are left-sided obstructive lesions and septal defects.
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Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.
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Trastornos de Impronta , Síndrome de Silver-Russell , Recién Nacido , Femenino , Embarazo , Humanos , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patología , Metilación de ADN/genética , Fenotipo , Disomía Uniparental/genéticaRESUMEN
Background: 22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome exhibiting significant clinical phenotype variability. This study aimed to investigate the clinical features, immune profiles, and cognitive abilities of 22q11.2DS patients receiving treatment at MacKay Memorial Hospital in Taipei, Taiwan. Methods: This is a cross-sectional analysis between January 2001 and December 2022. We recruited 27 patients with 22q11.2DS using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). Our evaluation included patient history, physical examination, laboratory analysis, and cardiac and cognitive assessment. Results: We included 27 patients with 22q11.2DS, 7 (25.9%) of whom were female. The median age of the patients was 17.9 yr. Ninety-three percent of the patients exhibited the characteristic facial features associated with the syndrome. A family history of 22q11.2DS was found in 11.1% of the patients. Furthermore, 74.1% of the patients had a congenital heart defect, the most common of which was tetralogy of Fallot (40.7%). Hypocalcemia was observed in 40.7% of the patients. A low T-cell count was observed in 66.7% of the patients, whereas 18.5% had low immunoglobulin levels. Cognitive assessments revealed that four out of six evaluated patients (66.7%) had an intellectual disability, as evidenced by intellectual quotient scores less than 70. The remaining two patients (33.3%) had a borderline intellectual function. Conclusion: Tetralogy of Fallot, hypocalcemia, immunologic defects, and cognitive impairment were common among our patients. To address the potential multisystem involvement, we recommend that all affected individuals undergo a comprehensive evaluation by a multidisciplinary care team.
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Síndrome de DiGeorge , Cardiopatías Congénitas , Hipocalcemia , Tetralogía de Fallot , Humanos , Femenino , Masculino , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/diagnóstico , Tetralogía de Fallot/genética , Hipocalcemia/genética , Hibridación Fluorescente in Situ , Taiwán/epidemiología , Estudios Transversales , Hibridación Genómica Comparativa , Cardiopatías Congénitas/genética , Sistema Inmunológico , Deleción CromosómicaRESUMEN
Mucopolysaccharidosis (MPS) is a lysosomal storage disease caused by genetic defects that result in deficiency of one specific enzyme activity, consequently impairing the stepwise degradation of glycosaminoglycans (GAGs). Except for MPS II, the other types of MPS have autosomal recessive inheritance in which two copies of an abnormal allele must be present in order for the disease to develop. In this study, we present the status of variant alleles and biochemistry results found in infants suspected of having MPS I, II, IVA, and VI. A total of 324 suspected infants, including 12 for MPS I, 223 for MPS II, 72 for MPS IVA, and 17 for MPS VI, who were referred for MPS confirmation from newborn screening centers in Taiwan, were enrolled. In all of these infants, one specific enzyme activity in dried blood spot filter paper was lower than the cut-off value in the first blood sample, as well asin a second follow-up sample. The confirmatory methods used in this study included Sanger sequencing, next-generation sequencing, leukocyte enzyme fluorometric assay, and GAG-derived disaccharides in urine using tandem mass spectrometry assays. The results showed that five, nine, and six infants had MPS I, II, and IVA, respectively, and all of them were asymptomatic. Thus, a laboratory diagnosis is extremely important to confirm the diagnosis of MPS. The other infants with identified nucleotide variations and reductions in leukocyte enzyme activities were categorized as being highly suspected cases requiring long-term and intensive follow-up examinations. In summary, the final confirmation of MPS depends on the most powerful biomarkers found in urine, i.e., the quantification of GAG-derived disaccharides including dermatan sulfate, heparan sulfate, and keratan sulfate, and analysis of genetic variants can help predict outcomes and guide treatment.
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Mucopolisacaridosis , Mucopolisacaridosis II , Mucopolisacaridosis I , Disacáridos , Glicosaminoglicanos/genética , Humanos , Lactante , Recién Nacido , Mucopolisacaridosis/diagnóstico , Mucopolisacaridosis/genética , Espectrometría de Masas en Tándem/métodosRESUMEN
Mucopolysaccharidosis type IVA (MPS IVA or Morquio A), a lysosomal storage disease with an autosomal recessive inherited pattern, is induced by GALNS gene mutations causing deficiency in N-acetylgalactosamine-6-sulfatase activity (GALNS; EC 3.1.6.4). Currently, intravenous (IV) enzyme replacement therapy (ERT) with elosulfase alfa is employed for treating MPS IVA patients. A systematic literature review was conducted to evaluate the efficacy and safety of IV elosulfase alfa for MPS IVA by searching the National Center for Biotechnology Information, U.S. National Library of Medicine National Institutes of Health (PubMed), Excerpta Medica dataBASE, and Cochrane Library databases, limited to clinical trials. Four cohort studies and two randomized controlled trials, with a total of 550 participants (327 on ERT treatment versus 223 on placebo treatment), satisfied the inclusion criteria. Pooled analysis of proportions and confidence intervals were also utilized to systematically review clinical cohort studies and trials. Per the pooled proportions analysis, the difference in means of urinary keratan sulfate (uKS), 6-min walk test, 3-min stair climb test, self-care MPS-Health Assessment Questionnaire, caregiver assistance and mobility, forced vital capacity, the first second of forced expiration, and maximal voluntary ventilation between the ERT and placebo treatment groups were -0.260, -0.102, -0.182, -0.360, -0.408, -0.587, -0.293, -0.311, and -0.213, respectively. Based on the currently available data, our meta-analysis showed that there is uKS, physical performance, quality of life, and respiratory function improvements with ERT in MPS IVA patients. It is optimal to start ERT after diagnosis.
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BACKGROUND: Mucopolysaccharidosis II (MPS II) is an X-linked disorder resulting from a deficiency in lysosomal enzyme iduronate-2-sulfatase (IDS), which causes the accumulation of glycosaminoglycans (GAGs) in the lysosomes of many tissues and organs, leading to progressive cellular dysfunction. An MPS II newborn screening program has been available in Taiwan since 2015. The aim of the current study was to collect and analyze the long-term follow-up data of the screen-positive subjects in this program. METHODS: From August 2015 to April 2022, 548,624 newborns were screened for MPS II by dried blood spots using tandem mass spectrometry, of which 202 suspected infants were referred to our hospital for confirmation. The diagnosis of MPS II was confirmed by IDS enzyme activity assay in leukocytes, quantitative determination of urinary GAGs by mass spectrometry, and identification of the IDS gene variant. RESULTS: Among the 202 referred infants, 10 (5%) with seven IDS gene variants were diagnosed with confirmed MPS II (Group 1), 151 (75%) with nine IDS gene variants were classified as having suspected MPS II or pseudodeficiency (Group 2), and 41 (20%) with five IDS gene variants were classified as not having MPS II (Group 3). Long-term follow-up every 6 months was arranged for the infants in Group 1 and Group 2. Intravenous enzyme replacement therapy (ERT) was started in four patients at 1, 0.5, 0.4, and 0.5 years of age, respectively. Three patients also received hematopoietic stem cell transplantation (HSCT) at 1.5, 0.9, and 0.6 years of age, respectively. After ERT and/or HSCT, IDS enzyme activity and the quantity of urinary GAGs significantly improved in all of these patients compared with the baseline data. CONCLUSIONS: Because of the progressive nature of MPS II, early diagnosis via a newborn screening program and timely initiation of ERT and/or HSCT before the occurrence of irreversible organ damage may lead to better clinical outcomes. The findings of the current study could serve as baseline data for the analysis of the long-term effects of ERT and HSCT in these patients.
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Mucopolysaccharidosis type I (MPS I) is an inherited autosomal recessive disease resulting from mutation of the α-l-Iduronidase (IDUA) gene. New unknown mutated nucleotides of idua have increasingly been discovered in newborn screening, and remain to be elucidated. In this study, we found that the z-Idua enzymatic activity of zebrafish idua-knockdown embryos was reduced, resulting in the accumulation of undegradable metabolite of heparin sulfate, as well as increased mortality and defective phenotypes similar to some symptoms of human MPS I. After microinjecting mutated z-idua-L346R, -T364M, -E398-deleted, and -E540-frameshifted mRNAs, corresponding to mutated human IDUA associated with MPS I, into zebrafish embryos, no increase in z-Idua enzymatic activity, except of z-idua-E540-frameshift-injected embryos, was noted compared with endogenous z-Idua of untreated embryos. Defective phenotypes were observed in the z-idua-L346R-injected embryos, suggesting that failed enzymatic activity of mutated z-Idua-L346R might have a dominant negative effect on endogenous z-Idua function. However, defective phenotypes were not observed in the z-idua-E540-frameshifted-mRNA-injected embryos, which provided partial enzymatic activity. Based on these results, we suggest that the z-Idua enzyme activity assay combined with phenotypic observation of mutated-idua-injected zebrafish embryos could serve as an alternative platform for a preliminary assessment of mutated idua not yet characterized for their role in MPS I.
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The pathogenesis of primary focal hyperhidrosis (PFH) is still not clear. PFH is thought to be a genetic disease. Whether activin A receptor type 1 (ACVR1) is involved in the pathogenesis of PFH is unknown. In this study, the expression of ACVR1 in sweat glands of patients with PAH was detected by western blot and immunofluorescence. The primary sweat gland cells obtained from primary axillary hyperhidrosis (PAH) patients were transfected with acvr1 vector. Cell proliferation, apoptosis and cell cycling of gland cells were measured after transfection with acvr1 vector. The mRNA and protein expression of aquaporin 5 (AQP5) and Na:K:2Cl Cotransporter 1 (NKCC1/SLC12A2) were detected. Our data showed that ACVR1 expression in axillary sweat gland tissue of PAH patients was significantly higher than that of normal control group. The function of ACVR1 was further investigated in the gland cells obtained from PAH patients. Compared with NC group, ACVR1 overexpression significantly promoted the proliferation of sweat gland cells and inhibited the apoptosis of sweat gland cells. Meanwhile, ACVR1 overexpression significantly reduced the percentage of cells in G0/G1 and G2/M phases, and increased the percentage of cells in S phase. In addition, ACVR1 overexpression significantly promoted the expression of AQP5 and NKCC1 at both mRNA and protein levels. Together, ACVR1 expression is related to PFH and ACVR1 overexpression can promote the proliferation of sweat gland cells and inhibit apoptosis by promoting the expression of AQP5 and NKCC1.
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Receptores de Activinas Tipo I/metabolismo , Hiperhidrosis/metabolismo , Hiperhidrosis/patología , Apoptosis , Acuaporina 5/genética , Acuaporina 5/metabolismo , Proliferación Celular , Regulación de la Expresión Génica , Humanos , Hiperhidrosis/genética , Miembro 2 de la Familia de Transportadores de Soluto 12/genética , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Glándulas Sudoríparas/metabolismo , Glándulas Sudoríparas/patologíaRESUMEN
BACKGROUND: Transareolar single-port endoscopic thoracic sympathectomy (ETS) with a flexible endoscope has rarely been reported. This study assessed the performance of this novel minimally invasive technique for primary palmar hyperhidrosis (PPH). METHODS: From January 2019 to September 2019, 118 males with severe PPH requiring single-port and bilateral ETS were randomly allocated to undergo transareolar ETS using a flexible endoscope (group A, n=58) or transaxillary ETS using a 5 mm thoracoscope (group B, n=60). RESULTS: Both groups had similar patient characteristics. All procedures were performed successfully, with no mortality or conversion to open surgery. All patients had dry and warm palms immediately after surgery. Compared with group B, group A had a significantly shorter median incision length [5.1 (5.0-5.2) vs. 10.9 (10.8-11.9) mm; P<0.001], and significantly lower median postoperative pain score [1 (1.0-2.0) vs. 3 (3.0-4.0); P<0.001]. There were no differences between the two groups in operative time, palmar temperature increase, and transient postoperative sweating. After complete follow-up, group A had a significantly higher median cosmetic score than group B [4.0 (3.0-4.0) vs. 3.0 (3.0-3.0); P<0.001]. There were no differences between the two groups regarding symptom resolution, compensatory hyperhidrosis, and satisfaction score. No patient reported residual pain or symptom recurrence. CONCLUSIONS: Transareolar single-port ETS with a flexible endoscope is safe, effective, and minimally invasive with a small incision, minimal pain, and excellent cosmetic results. This novel procedure is suitable for routine treatment of PPH in males.
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With the advent of molecularly targeted therapy, it is necessary to reconsider the strategy for malignant pleural effusion in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The aim of this study was to evaluate the efficacy of a two-line sequential treatment strategy in this patient subgroup. First-line treatment was gefitinib (250 mg/day) until disease progression. Second-line treatment was thoracoscopic talc pleurodesis followed by chemotherapy. Primary endpoints were the overall response and progression-free survival rates after first-line treatment, and the overall survival rate after first- and second-line treatment. Secondary endpoints were the success rate of thoracoscopic talc pleurodesis and gefitinib toxicity. Among the 76 patients enrolled, 61 (80%) were female and the median age was 62 years. The overall response rate after first-line treatment was 92.1% and median progression-free survival was 15 months. The success rate for thoracoscopic talc pleurodesis in 33 patients was 94%. Median follow-up was 35 months. Median overall survival was 39 months. The 1- and 3-year overall survival rates were 86.4% and 46.1%, respectively. The two-line sequential treatment strategy enhanced survival. These preliminary findings provide an insight into novel therapeutic models for malignant pleural effusion in NSCLC harbouring EGFR mutations.
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Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Receptores ErbB/genética , Derrame Pleural Maligno/tratamiento farmacológico , Quinazolinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Femenino , Gefitinib , Humanos , Masculino , Persona de Mediana Edad , Mutación , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Derrame Pleural Maligno/etiologíaRESUMEN
BACKGROUND: Conventional endoscopic thoracic sympathectomy (ETS) is usually performed with 5-mm thoracoscope under general anesthesia with endotracheal intubation. Needlescopic thoracic sympathectomy under total intravenous anesthesia without intubation has rarely been attempted. This randomized controlled trial assesses the feasibility and safety of this minimally invasive therapeutic procedure in managing primary palmar hyperhidrosis. METHODS: From July 2012 to July 2014, 221 patients with severe primary palmar hyperhidrosis underwent bilateral ETS and were randomly allocated to group A or group B. Patients in group A (n=108) underwent nonintubated ETS using a needle endoscope, whereas those in group B (n=113) underwent traditional transaxillary single-port ETS using a 5-mm thoracoscope. RESULTS: ETS was successfully performed in all patients. The palms of all patients became dry and warm immediately after surgery. The mean resuscitation time was significantly shorter in nonintubated patients than in intubated patients (P<0.01). Postoperative sore throat occurred in 37 patients in group B, whereas none of the patients in group A complained about sore throat after surgery (P<0.01). The mean incision length was 5.1±0.1 mm with needle endoscope and 11.0±0.8 mm with traditional thoracoscope (P<0.01). The mean postoperative pain score was 1.1±0.8 in group A and 3.2±0.8 in group B (P<0.01). The mean cost of anesthesia was considerably lower in nonintubated patients than in intubated patients (P<0.01). Follow-up was 100% completed. The mean cosmetic scores were higher in group A than in group B (P<0.01). Residual pain occurred in 2 patients in group A and in 18 patients in group B (P<0.01). CONCLUSIONS: Nonintubated needlescopic thoracic sympathectomy is a safe, effective, and minimally invasive therapeutic procedure, which has the advantages of a smaller incision with less pain, shorter resuscitation time, and better cosmetic results.
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Hiperhidrosis/cirugía , Simpatectomía/métodos , Toracoscopía/métodos , Adolescente , Adulto , Periodo de Recuperación de la Anestesia , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Faringitis/etiología , Complicaciones Posoperatorias/etiología , Cirugía Torácica Asistida por Video/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The expression of aquaporin 5 (AQP5) in human axillary sweat glands has never been studied so far. OBJECTIVE: To detect the expression of AQP5 in axillary sweat glands of patients with primary focal hyperhidrosis (PFH) relative to control subjects. METHODS: The morphological characteristics and the number of sweat coils in axillary sweat glands were compared between two groups by using transmission electron microscopy. The expression of AQP5 was detected by immunohistochemistry, Western blot analysis, and real-time transcription polymerase chain reaction. RESULTS: There were no significant differences between the two groups in terms of morphological characteristics and the number of sweat coils in axillary sweat glands. The expressions of AQP5 protein and AQP5 mRNA were significantly higher in the patient group than in the control group. CONCLUSION: AQP5 is involved in the secretion of human axillary sweat glands. The overexpression of AQP5 in sweat glands is probably one pathogenetic mechanism underlying PFH.
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Acuaporina 5/análisis , Hiperhidrosis/metabolismo , ARN Mensajero/análisis , Glándulas Sudoríparas/química , Adolescente , Adulto , Acuaporina 5/genética , Axila , Estudios de Casos y Controles , Femenino , Humanos , Hiperhidrosis/genética , Hiperhidrosis/patología , Masculino , Microscopía Electrónica de Transmisión , Glándulas Sudoríparas/ultraestructura , Adulto JovenRESUMEN
BACKGROUND: Traditional endoscopic thoracic sympathicotomy is usually performed through an axillary incision with 5-mm thoracoscope under general anesthesia with endotrachea intubation. Nonintubated transareolar single-port thoracic sympathicotomy with a needle scope has rarely been attempted. The objective of this study is to evaluate the feasibility and safety of this minimally invasive technique in managing primary palmar hyperhidrosis (PPH). METHODS: From May 2012 to May 2014, a total of 85 male patients with severe PPH underwent transareolar single-port thoracic sympathicotomy by use of a 2-mm needle scope under total intravenous anesthesia without endotrachea intubation. RESULTS: All procedures were successfully performed with a mean operating time of 13.5 min. The palms of all patients became dry and warm as soon as the sympathetic chain was cut off. There were no sore throat, and all the patients regained consciousness rapidly after surgery. Eighty-two patients (96.5 %) were discharged from the hospital on the first postoperative day. The postoperative complications were minor, and no patients developed Horner's syndrome. At 6 months postoperatively, there is no obvious surgical scar on the chest wall, and none of the patients complained about postoperative pain. Compensatory sweating appeared in 31 patients. No recurrent symptoms were observed in our study. One-year follow-up revealed an excellent cosmetic result and degree of satisfaction. CONCLUSIONS: Nonintubated transareolar single-port needlescopic thoracic sympathicotomy is a safe, effective and minimally invasive therapeutic procedure, which can be performed in routine clinical practice for male PPH patients.
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Hiperhidrosis/cirugía , Simpatectomía/métodos , Toracoscopios , Toracoscopía , Adolescente , Adulto , Estudios de Factibilidad , Humanos , Masculino , Persona de Mediana Edad , Tempo Operativo , Satisfacción del Paciente , Simpatectomía/instrumentación , Adulto JovenRESUMEN
OBJECTIVES: Transient receptor potential vanilloid 4 (TRPV4) calcium channels are known to promote endothelium-dependent relaxation of mouse mesenteric arteries but TRPV4's role in the pulmonary vasculature is uncertain. Thus, we characterized TRPV4 channel vascular tone regulation in mouse main pulmonary artery rings and in the isolated perfused pulmonary circulation and studied possible mechanisms behind these characterizations. METHODS AND RESULTS: Using myography and a TRPV4 specific agonist GSK1016790A in a C57BL/6 WT mouse model of isolated constant-flow lung perfusion, we studied vascular tone regulation in arterial rings from the main left and right pulmonary arteries and vascular resistance of the intra-pulmonary circulation beyond the second branches of the pulmonary arteries. Removal of the endothelium confirmed endothelial dependence. GSK1016790A relaxed the main pulmonary artery (EC50 4 × 10(-8)mol/L), which was inhibited by removal of the endothelium from main pulmonary artery rings. GSK1016790A significantly increased vascular resistance of the pulmonary circulation in isolated perfused lungs, but these effects were inhibited by a TRPV4 antagonist AB159908. A nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and K(+) channel blockers apamin plus charybdotoxin (ChTx) significantly inhibited GSK1016790A in the main pulmonary artery and in an isolated perfused lung in vitro. CONCLUSIONS: Activated TRPV4 channels increase pulmonary vascular resistance and vasodilate the main pulmonary artery.
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Pulmón/irrigación sanguínea , Pulmón/fisiología , Arteria Pulmonar/fisiología , Canales Catiónicos TRPV/metabolismo , Animales , Apamina/farmacología , Fármacos Cardiovasculares/farmacología , Caribdotoxina/farmacología , Inhibidores Enzimáticos/farmacología , Leucina/análogos & derivados , Leucina/farmacología , Pulmón/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Modelos Cardiovasculares , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/metabolismo , Arteria Pulmonar/efectos de los fármacos , Circulación Pulmonar/efectos de los fármacos , Circulación Pulmonar/fisiología , Sulfonamidas/farmacología , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/antagonistas & inhibidores , Técnicas de Cultivo de Tejidos , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiología , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
OBJECTIVE: To investigate the prevalence and epidemiological characteristics of primary palmar hyperhidrosis (PPH) among adolescents in PR China. METHODS: A nationwide survey was performed, including all seven geological areas of Mainland China. Stratified cluster sampling was performed, and a cross-sectional epidemiological survey was applied via questionnaire among 10,000 college students in each geological area. RESULTS: The prevalence rate of PPH was 2.08%. The prevalence in female adolescents was slightly higher than the prevalence in male adolescents (2.29 vs. 1.94%). The prevalence of PPH in coastal areas was higher than the prevalence of PPH in inland areas (2.81 vs. 1.53%). The peak age of onset is 7-15 years, accounting for 97.3% of the PPH population. Positive family history was found in 25.40% of PPH cases. In addition to palms, axillae and soles can also be affected. CONCLUSIONS: PPH affects a larger group of individuals than previously reported. More measures should be taken to enhance the recognition, diagnosis, and treatment of PPH.
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Hiperhidrosis/epidemiología , Adolescente , China/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Prevalencia , Adulto JovenRESUMEN
ß-elemene (ß-ELE) is a new anticancer drug extracted from Curcuma zedoaria Roscoe and has been widely used to treat malignant tumors. Recent studies have demonstrated that ß-ELE reverses the drug resistance of tumor cells. To explore the possible mechanisms of action of ß-ELE, we investigated its effects on cisplatin-resistant human lung adenocarcinoma A549/DDP cells. The effects of ß-ELE on the growth of A549/DDP cells in vitro were determined by MTT assay. Apoptosis was assessed by fluorescence microscopy with Hoechst 33258 staining and flow cytometry with Annexin V-FITC/PI double staining. Mitochondrial membrane potential was assessed using JC-1 fluorescence probe and laser confocal scanning microscopy, and intracellular reactive oxygen species levels were measured by 2',7'-dichlorofluorescein-diacetate staining and flow cytometry. Cytosolic glutathione content was determined using GSH kits. The expression of cytochrome c, caspase-3, procaspase-3 and the Bcl-2 family proteins was assessed by western blotting. The results demonstrated that ß-ELE inhibited the proliferation of A549/DDP cells in a time- and dose-dependent manner. Furthermore, ß-ELE enhanced the sensitivity of A549/DDP cells to cisplatin and reversed the drug resistance of A549/DDP cells. Consistent with a role in activating apoptosis, ß-ELE decreased mitochondrial membrane potential, increased intracellular reactive oxygen species concentration and decreased the cytoplasmic glutathione levels in a time- and dose-dependent manner. The combination of ß-ELE and cisplatin enhanced the protein expression of cytochrome c, caspase-3 and Bad, and reduced protein levels of Bcl-2 and procaspase-3 in the A549/DDP lung cancer cells. These results define a pathway of procaspase3-ß-ELE function that involves decreased mitochondrial membrane potential, leading to apoptosis triggered by the release of cytochrome c into the cytoplasm and the modulation of apoptosis-related genes. The reversal of drug resistance of the A549/DDP cell line by ß-ELE may be derived from its effect in inducing apoptosis.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Sesquiterpenos/farmacología , Apoptosis/efectos de los fármacos , Caspasa 3/biosíntesis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Ciclosporina/farmacología , Citocromos c/biosíntesis , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Especies Reactivas de Oxígeno/metabolismo , Proteína Letal Asociada a bcl/biosíntesisRESUMEN
BACKGROUND: : Phase II-III trials in patients with untreated and previously treated locally advanced or non-small cell lung cancer (NSCLC) suggested that Endostar was able to enhance the effect of platinum-based chemotherapy (NP regimen) with tolerable adverse effects. METHODS: Four hundred and eighty six patients were randomized into two arms: study arm A: NP plus Endostar (n = 322; vinorelbine, cisplatin, Endostar), and study arm B: NP plus placebo (n = 164; vinorelbine, cisplatin, 0.9% sodium chloride). Patients were treated every third week for two to six cycles. RESULTS: : Overall response rates were 35.4% in arm A and 19.5% in arm B (P = 0.0003). The median time to progression was 6.3 months for arm A and 3.6 months for B, respectively (P < 0.001). The clinical benefit rates were 73.3% in arm A and 64.0% in arm B (P = 0.035). Grade 3/4 neutropenia, anemia, and nausea/vomiting were 28.5%, 3.4%, and 8.0%, respectively, in Arm A compared with 28.2%, 3.0%, and 6.6%, respectively, in Arm B (P > 0.05). There were two treatment related deaths in arm A and one in arm B (P > 0.05). The median overall survival was longer in arm A than in arm B (P < 0.0001). CONCLUSION: : Long-term follow-up revealed that the addition of Endostar to an NP regimen can result in a significant clinical and survival benefit in advanced NSCLC patients, compared with NP alone.
RESUMEN
OBJECTIVE: To evaluate the cosmetic effect and safety of transaxillary concealing single incision endoscopic thoracic sympathectomy in the treatment of palmar hyperhidrosis (PH). METHODS: Retrospective study was conducted for 326 PH cases undergoing transaxillary concealing single incision endoscopic thoracic bilateral sympathectomy during January 2009 and March 2011. RESULTS: All operations were successfully performed without severe complication and mortality. No conversion into open technique was necessary. The mean unilateral operative duration was 5.8 (5-8) min. It was calculated from the time of skin incision to the application of dressing over wound. The mean follow-up period was 25 (8-38) months. All patients achieved excellent cosmetic effects with undetectable incision. CONCLUSION: Transaxillary concealing single incision endoscopic thoracic sympathectomy is a safe and effective procedure for treating primary PH. Incision is undetectable with excellent cosmetic effect. It is worthy of wider popularization.