ABSTRACT
Acral peeling skin syndrome (APSS) is a rare, autosomal, recessive genodermatosis characterized by painless spontaneous exfoliation of the skin of the hands and feet at a subcorneal or intracorneal level. It usually presents at birth or appears later in childhood or early adulthood. Some cases result from mutations in the TGM5 gene that encodes transglutaminase 5, which has an important role in cross-linking cornified cell envelope proteins. We report a new APSS pedigree from Jordan that contains at least 10 affected family members, although sequencing of the TGM5 gene failed to disclose any pathogenic mutation(s). On the basis of probable consanguinity, we performed homozygosity mapping and identified areas of homozygosity on chromosomes 1, 6, 10, 13, and 16, although none of the intervals contained genes of clear relevance to cornification. APSS is a clinically and genetically heterogeneous disorder, and this Jordanian pedigree underscores the likelihood of still further heterogeneity.
Subject(s)
Dermatitis, Exfoliative/genetics , Dermatitis, Exfoliative/pathology , Genetic Variation , Pigmentation Disorders/genetics , Pigmentation Disorders/pathology , Transglutaminases/genetics , Adolescent , Base Sequence , Chromosome Mapping , Consanguinity , Female , Homozygote , Humans , Jordan , Male , Molecular Sequence Data , Pedigree , Skin Diseases/congenital , Young AdultABSTRACT
AIM AND METHODS: We distributed 282 questionnaires to doctors to ascertain their opinions on obtaining the advance directives regarding the end-of-life treatment of patients at the terminal stage. We received 136 (48%) responses. RESULTS: A total of 62% of the respondents stated a desire for patients to indicate their advance directives "if at all possible". Only 36% stated that the need for advance directives "depended on the circumstances". A total of 80% of doctors aged under 40 wished patients to provide advanced directives "if at all possible", while 59% of doctors over 61 wanted advanced directives "depending on the circumstances" (p=0.008). A large number of doctors stated a desire for patients to indicate their preference in writing, particularly directives regarding the "use of a ventilator to prolong life" (76%) or the "use of artificial nourishment through a gastric fistula etc. as part of a proactive approach to sustaining life" (67%). Regarding the optimal timing of this declaration, 59% chose "at the first diagnosis of a terminal illness", and 47% chose "at the diagnosis of a chronic illness", regardless of whether it could become terminal. Of those respondents under 40, 32% believed that doctors should strictly follow the patients' advance directives, while only 11% of doctors over 61 years old believed the same. There was a statistically significant relationship between aging and dealing with advance directives of patients in the terminal stages of illness (p=0.002). CONCLUSION: These results suggest that doctors under 40 years of age should focus on how to correctly interpret the wishes of the patients expressed in the directives, while doctors over 61 should concentrate on the importance of the clinical application of advance directives, and how to balance the need to make qualified medical decisions on treatment in compliance with the wishes of end-stage terminal patients.
Subject(s)
Advance Directives , Attitude of Health Personnel , Physicians , Adult , Age Factors , Humans , Informed Consent , Middle Aged , Surveys and Questionnaires , Terminal CareABSTRACT
Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.
Subject(s)
Amyloidosis, Familial/genetics , Oncostatin M Receptor beta Subunit/genetics , Amino Acid Sequence , Amyloidosis, Familial/pathology , Brazil , Cell Culture Techniques , Chromosomes, Human, Pair 5 , DNA Mutational Analysis , Female , Genes, Dominant , Humans , Keratinocytes , Male , Molecular Sequence Data , Mutation, Missense , Oncostatin M Receptor beta Subunit/chemistry , Pedigree , Sequence Homology , South Africa , United KingdomABSTRACT
Junctional epidermolysis bullosa associated with pyloric atresia (JEB-PA) is one of the most severe inherited skin diseases, characterized by generalized blister formation and occlusion of the pylorus at birth. Most JEB-PA patients have mutations in the gene encoding ß4 integrin (ITGB4). No recurrent mutations in ITGB4 have been described as having founder effects. We collected three JEB-PA families with c.1938delC in ITGB4. Haplotype analysis using single nucleotide polymorphism markers throughout ITGB4 suggested one rare haplotype (2.8% of the Han Chinese and ethnic Japanese populations) in all alleles with c.1938delC. The parents of one of the three families sought prenatal diagnosis for a subsequent pregnancy. We succeeded in performing prenatal exclusion of JEB-PA using the foetal genomic DNA. Our study clearly demonstrated that recurrent c.1938delC in ITGB4 is a founder mutation in JEB-PA patients, and that genotyping of the mutation can be utilized for prenatal diagnosis of JEB-PA.
Subject(s)
Epidermolysis Bullosa, Junctional/diagnosis , Epidermolysis Bullosa, Junctional/genetics , Integrin beta4/genetics , Asian People/genetics , Base Sequence , DNA Mutational Analysis , Female , Founder Effect , Haplotypes , Humans , Japan , Male , Pregnancy , Prenatal Diagnosis , Sequence DeletionABSTRACT
Plectin is a cytoskeletal linker protein which has a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC) cause two distinct autosomal recessive subtypes of epidermolysis bullosa: EB simplex (EBS) with muscular dystrophy (EBS-MD), and EBS with pyloric atresia (EBS-PA). Previous studies have demonstrated that loss of full-length plectin with residual expression of the rodless isoform leads to EBS-MD, whereas complete loss or marked attenuation of expression of full-length and rodless plectin underlies the more severe EBS-PA phenotype. However, muscular dystrophy has never been identified in EBS-PA, not even in the severe form of the disease. Here, we report the first case of EBS associated with both pyloric atresia and muscular dystrophy. Both of the premature termination codon-causing mutations of the proband are located within exon 32, the last exon of PLEC. Immunofluorescence and immunoblot analysis of skin samples and cultured fibroblasts from the proband revealed truncated plectin protein expression in low amounts. This study demonstrates that plectin deficiency can indeed lead to both muscular dystrophy and pyloric atresia in an individual EBS patient.
Subject(s)
Digestive System Abnormalities/genetics , Epidermolysis Bullosa Simplex/complications , Epidermolysis Bullosa Simplex/genetics , Muscular Dystrophies/genetics , Mutation , Plectin/deficiency , Pylorus/abnormalities , Base Sequence , Cells, Cultured , Digestive System Abnormalities/complications , Epidermolysis Bullosa Simplex/physiopathology , Exons/genetics , Fatal Outcome , Female , Fibroblasts/metabolism , Fluorescent Antibody Technique , Genotype , Humans , Immunoblotting , Infant, Newborn , Male , Molecular Sequence Data , Muscular Dystrophies/complications , Phenotype , Plectin/chemistry , Plectin/genetics , Plectin/metabolism , Skin/metabolismABSTRACT
Autosomal recessive hypotrichosis (ARH) is characterized by sparse hair on the scalp without other abnormalities. Three genes, DSG4, LIPH, and LPAR6 (P2RY5), have been reported to underlie ARH. We performed a mutation search for the three candidate genes in five independent Japanese ARH families and identified two LIPH mutations: c.736T>A (p.Cys246Ser) in all five families, and c.742C>A (p.His248Asn) in four of the five families. Out of 200 unrelated control alleles, we detected c.736T>A in three alleles and c.742C>A in one allele. Haplotype analysis revealed each of the two mutant alleles is derived from a respective founder. These results suggest the LIPH mutations are prevalent founder mutations for ARH in the Japanese population. LIPH encodes PA-PLA(1)alpha (LIPH), a membrane-associated phosphatidic acid-preferring phospholipase A(1)alpha. Two residues, altered by these mutations, are conserved among PA-PLA(1)alpha of diverse species. Cys(246) forms intramolecular disulfide bonds on the lid domain, a crucial structure for substrate recognition, and His(248) is one amino acid of the catalytic triad. Both p.Cys246Ser- and p.His248Asn-PA-PLA(1)alpha mutants showed complete abolition of hydrolytic activity and had no P2Y5 activation ability. These results suggest defective activation of P2Y5 due to reduced 2-acyl lysophosphatidic acid production by the mutant PA-PLA(1)alpha is involved in the pathogenesis of ARH.
Subject(s)
Hypotrichosis/genetics , Hypotrichosis/metabolism , Lipase/genetics , Phospholipases A1/metabolism , Receptors, Purinergic P2/metabolism , Alleles , Cell Line , Child , Genes, Recessive , Haplotypes , Humans , Linkage Disequilibrium , Mutation , Pedigree , PrevalenceABSTRACT
OBJECTIVE: To perform a retrospective analysis of carboplatin (CBDCA) and weekly paclitaxel (PTX) combination chemotherapy for elderly patients with unresectable non-small cell lung cancer (NSCLC) in order to evaluate both treatment efficacy and toxicity. SUBJECTS: 48 patients aged more than 70 years with non-resectable NSCLC who received CBDCA+weekly PTX from January 2001 to March 2008. RESULTS: The median age of the patients (32 male, 16 female) was 74 years. Patients received 1-6 courses of this chemotherapy (median 4 courses). The overall response rate, time to progression, median survival time and 1-year survival rate was 51%, 183 days, 411 days and 52%, respectively. With regard to toxicity, grade 3-4 neutropenia was observed in 38% of patients and anemia in 25% of the patients, and 29% of the patients had grade 2 and above periferal nerve disorder. CONCLUSION: This regimen showed a good response and was safe for elderly patients with advanced NSCLC, but a high incidence of neuropathy was observed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Paclitaxel/therapeutic use , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/pathology , Male , Neoplasm Staging , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Retrospective StudiesSubject(s)
Amyloidosis/complications , Mycosis Fungoides/complications , Skin Diseases/complications , Skin Neoplasms/complications , Aged , Amyloidosis/diagnosis , Amyloidosis/drug therapy , Glucocorticoids/therapeutic use , Humans , Male , Mycosis Fungoides/diagnosis , PUVA Therapy , Skin Diseases/diagnosis , Skin Diseases/drug therapy , Skin Neoplasms/diagnosisABSTRACT
PURPOSE: The aim of this study was to evaluate retrospectively chemotherapy of weekly carboplatin and paclitaxel with concurrent radiation therapy for patients with locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Between January 2000 and March 2008, 38 patients were treated by chemotherapy with carboplatin and paclitaxel once a week, repeated for 6 weeks, with thoracic radiation therapy of 1 or 2 times a day on weekdays. After concurrent chemoradiotherapy, we planned consolidation chemotherapy of carboplatin(AUC 5-6)and weekly paclitaxel(70- 80 mg/m(2)) on day 1, 8 and 15, when possible. RESULTS: The enrolled patients were 31 men and 7 women, with the median age of 59 years (39-76 years), stage III A/III B: 10/28, Ad/Sq/AdSq/Un: 17/17/2/2. The response rate of this chemoradiotherapy was 78. 9%. The median survival time and time to progression were 24. 7 months and 8. 1 months, respectively. Grade 3 or 4 hematological toxicities during concomitant chemoradiotherapy were leukocytopenia(5. 2%)and neutropenia(5. 2%). Grade 3 or 4 non-hematological toxicities were esophagitis(2. 6%)and pneumonitis (5. 2%). There was a therapy-associated death by radiation pneumonitis. CONCLUSION: Carboplatin and paclitaxel with concurrent radiation therapy for a patient with stage III NSCLC showed a good response with relatively mild side effects. We reached the conclusion that concurrent chemoradiotherapy would be a useful choice for locally advanced non-small cell lung cancer on the practical clinic.
Subject(s)
Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Paclitaxel/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Combined Modality Therapy/adverse effects , Disease Progression , Dose-Response Relationship, Drug , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Retrospective Studies , Survival RateABSTRACT
Harlequin ichthyosis (HI) is a devastating skin disorder with an unknown underlying cause. Abnormal keratinocyte lamellar granules (LGs) are a hallmark of HI skin. ABCA12 is a member of the ATP-binding cassette transporter family, and members of the ABCA subfamily are known to have closely related functions as lipid transporters. ABCA3 is involved in lipid secretion via LGs from alveolar type II cells, and missense mutations in ABCA12 have been reported to cause lamellar ichthyosis type 2, a milder form of ichthyosis. Therefore, we hypothesized that HI might be caused by mutations that lead to serious ABCA12 defects. We identify 5 distinct ABCA12 mutations, either in a compound heterozygous or homozygous state, in patients from 4 HI families. All the mutations resulted in truncation or deletion of highly conserved regions of ABCA12. Immunoelectron microscopy revealed that ABCA12 localized to LGs in normal epidermal keratinocytes. We confirmed that ABCA12 defects cause congested lipid secretion in cultured HI keratinocytes and succeeded in obtaining the recovery of LG lipid secretion after corrective gene transfer of ABCA12. We concluded that ABCA12 works as an epidermal keratinocyte lipid transporter and that defective ABCA12 results in a loss of the skin lipid barrier, leading to HI. Our findings not only allow DNA-based early prenatal diagnosis but also suggest the possibility of gene therapy for HI.
Subject(s)
ATP-Binding Cassette Transporters/genetics , Ichthyosis, Lamellar/genetics , Ichthyosis, Lamellar/therapy , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/therapy , Mutation , ATP-Binding Cassette Transporters/chemistry , Amino Acid Sequence , Base Sequence , Biological Transport, Active , Cells, Cultured , DNA Mutational Analysis , Female , Gene Transfer Techniques , Humans , Ichthyosis, Lamellar/etiology , Ichthyosis, Lamellar/metabolism , Infant, Newborn , Keratinocytes/metabolism , Keratinocytes/ultrastructure , Lipid Metabolism, Inborn Errors/complications , Lipid Metabolism, Inborn Errors/metabolism , Male , Molecular Sequence Data , Pedigree , Phenotype , Pregnancy , Prenatal Diagnosis , Sequence Homology, Amino AcidABSTRACT
BACKGROUND: Focal dermal hypoplasia (FDH) (OMIM 305600) is an X-linked dominant disorder of ecto-mesodermal development. Also known as Goltz syndrome, FDH presents with characteristic linear streaks of hypoplastic dermis and variable abnormalities of bone, nails, hair, limbs, teeth and eyes. The molecular basis of FDH involves mutations in the PORCN gene, which encodes an enzyme that allows membrane targeting and secretion of several Wnt proteins critical for normal tissue development. OBJECTIVES: To investigate the molecular basis of FDH in a 2-year-old Thai girl who presented at birth with depressed, pale linear scars on the trunk and limbs, sparse brittle hair, syndactyly of the right middle and ring fingers, dental caries and radiological features of osteopathia striata. METHODS: Sequencing of genomic DNA from the affected individual and both parents to search for pathogenic mutations in PORCN gene. RESULTS: DNA sequencing disclosed a heterozygous G>T substitution at nucleotide c.898 within exon 10 (NM_203475.1), converting a glutamic acid residue (GAA) to a premature termination codon (TAA). This mutation, designated p.E300X, was not detected in DNA from either parent or in 100 control chromosomes. CONCLUSION: Identification of this new de novo nonsense mutation confirms the diagnosis of FDH in this child and highlights the clinical importance of PORCN and Wnt signalling pathways in embryogenesis.
Subject(s)
Codon, Nonsense , Focal Dermal Hypoplasia/genetics , Focal Dermal Hypoplasia/pathology , Membrane Proteins/genetics , Acyltransferases , Amino Acid Substitution , Child, Preschool , DNA Mutational Analysis , Female , Humans , PhenotypeSubject(s)
Erythema/pathology , Pseudolymphoma/pathology , Skin/pathology , T-Lymphocytes/pathology , Biopsy , Breast , Erythema/immunology , Erythema/therapy , Female , Humans , Middle Aged , Pseudolymphoma/immunology , Pseudolymphoma/therapy , Skin/immunology , T-Lymphocytes/immunology , Treatment OutcomeABSTRACT
We apply periodic orbit theory to a two-dimensional nonintegrable billiard system whose boundary is varied smoothly from a circular to an equilateral triangular shape. Although the classical dynamics becomes chaotic with increasing triangular deformation, it exhibits an astonishingly pronounced shell effect on its way through the shape transition. A semiclassical analysis reveals that this shell effect emerges from a codimension-2 bifurcation of the triangular periodic orbit. Gutzwiller's semiclassical trace formula, using a global uniform approximation for the bifurcation of the triangular orbit and including the contributions of the other isolated orbits, describes very well the coarse-grained quantum-mechanical level density of this system. We also discuss the role of discrete symmetry for the large shell effect obtained here.
ABSTRACT
A 80-year-old man who came from Korea a few days previously, had a high fever and dyspnea. Chest radiography and computed tomography showed various shadow suggesting tumors, small nodules and reticular shadows with effusion. We made a clinical diagnosis of lung cancer with pneumonia. Finally, however, the culture of bronchial lavage fluid and transbronchial biopsy revealed tuberculosis. It was obvious that there were delaying factors such as the patient's social and economical situation as well as the diagnostic difficulty concerning the chest image findings. Whenever we find a abnormal shadow on chest images, we should consider mycobacterium infection in the differential diagnosis disease.
Subject(s)
Tuberculosis, Pulmonary/diagnosis , Aged, 80 and over , Humans , Korea/ethnology , MaleSubject(s)
Erythema/drug therapy , Erythema/pathology , Neutrophil Infiltration , Potassium Iodide/therapeutic use , Aged , Humans , MaleABSTRACT
When we studied the clinical aspects of 37 pneumonia patients with underlying respiratory disease in whom MRSA 1 + was identified from sputum, 43.2% of these 37 pneumonia cases were diagnosed as MRSA colonization. The whole clinical course of these pneumonia patients with MRSA colonization was average 39.5 days, on the other hand, the whole clinical course of MRSA pneumonia group was 55.3 days. We should consider that MRSA must be a cause of pneumonia, in only such cases as follows; (1) patients with unstable diabetes mellitus, or with long-term administration of steroid, (2) patients with infiltrative shadows appeared not only in the lower lobe but also the upper lobe in the chest x-ray films, (3) patients with remarkable decrease of PaO2 or patients who failed to recover within one month from MRSA isolation, (4) patients with nosocomial pneumonia or patients with poor performance status or poor prognosis, (5) patients with purulent sputum containing MRSA or other bacteria such as K. pneumoniae etc and patients who failed to respond to general antibacterial agents.