Quality assessment of clinical practice guidelines for the management of wheezing disorders in children.

BACKGROUND: The quality of available clinical practice guidelines (CPGs) for childhood wheezing disorders have not been systematically evaluated.METHODS: CPGs were systematically evaluated by four independent reviewers using Appraisal of Guidelines Research and Evaluation (AGREE) II instrument and the Reporting Items for Practice Guidelines in HealTHcare (RIGHT) checklist. We calculated the overall agreement among reviewers with the intraclass correlation coefficient (ICC).RESULTS: A total of 35 CPGs published between January 2000 and December 2020 were evaluated. The overall agreement among reviewers was good (ICC 0.85, 95% CI 0.83-0.87). The average CPGs score was 42% (range: 25-79). The mean scores of four domains were low: 37% for Stakeholder Involvement (range: 10-85), 28% for Rigour of Development (range: 42-81), 35% for Applicability (range: 11-73) and 24% for Editorial Independence (range: 0-83). The mean reporting rate of the RIGHT checklist was 31%. The Basic Information domain had the highest reporting rate (65%); the Review and Quality Assurance domain had the lowest rate (3%).CONCLUSIONS: The quality of the CPGs was poor. Greater efforts are needed to improve quality in domains to provide high-quality guidelines that can be used as reliable tools for clinical decision-making.

HSP20-mediated cardiomyocyte exosomes improve cardiac function in mice with myocardial infarction by activating Akt signaling pathway.

OBJECTIVE: To explore the role of heat shock protein 20 (HSP20)-mediated cardiomyocyte exosomes in the cardiac function in mice with myocardial infarction via the activation of the protein kinase B (Akt) signaling pathway. MATERIALS AND METHODS: A total of 30 mice were enrolled to establish the model of myocardial infarction. Next, these mice were divided into three groups, namely Blank group (healthy mice), Model group (mouse models of myocardial infarction), and HSP20 group (mouse models of myocardial infarction transfected with lentivirus to overexpress HSP20). After that, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining assay was performed to detect myocardial apoptosis. Reactive oxygen species (ROS) accumulation in myocardial tissues was determined via dihydroethidium (DHE) staining assay. Western blotting was employed to analyze the expression level of Akt. The expression levels of inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1ß) in HSP20-mediated cardiomyocyte exosomes were measured through quantitative real time polymerase chain reaction (qRT-PCR). RESULTS: Compared with that in Blank group, the number of cardiomyocyte exosomes was increased in Model group and HSP20 group under anoxic conditions (p<0.05). The results of quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) proved that the HSP20 messenger ribonucleic acid (mRNA) expression in mediated cardiomyocyte exosomes was significantly lower in Model group than that in Blank group (p<0.05), while in HSP20 group, it was overtly higher than that in Model group but clearly lowered compared with that in Blank group (p<0.05). The protein expression of Akt in cardiomyocyte exosomes was evidently decreased in Model group compared with that in Blank group (p<0.05), while it was notably increased in HSP20 group compared with that in Model group (p<0.05). In comparison with Blank group, Model group had significantly elevated mRNA expression levels of TNF-α and IL-1ß. The mRNA expression levels of TNF-α and IL-1ß in HSP20 group were remarkably lower than those in Model group (p<0.05). The results of TUNEL assay revealed that the overexpression of HSP20 affected myocardial apoptosis. The myocardial apoptosis index in Model group [(38.42±2.52) %] was higher than that in Blank group [(9.74±1.21) %], HSP20 group had a significantly decreased myocardial apoptosis index [(22.36±2.13) %] in comparison with Model group (p<0.05). In accordance with DHE staining comparison, the accumulation of ROS in myocardial tissues in Model group was significantly higher than that in Blank group (p<0.05) and HSP20 group (p<0.05). CONCLUSIONS: We demonstrated that HSP20-mediated cardiomyocyte exosomes activate the AKT signaling pathway, repress TNF-α and IL-1ß factors, and alleviate myocardial infarction.

Altered oesophageal mechanosensitivity of secondary peristalsis as a pathophysiological marker in patients with globus sensation.

OBJECTIVE: Secondary peristalsis is important for clearance of retained food bolus and refluxate from the oesophagus. We aimed to investigate whether patients with globus sensation have altered physiological characteristics of secondary peristalsis. DESIGN: Prospective case-controlled study SETTING: Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan. PARTICIPANTS: Seventeen globus patients and 18 healthy controls. MAIN OUTCOME MEASURES: After a baseline recording of primary peristalsis, secondary peristalsis was stimulated with slow and rapid mid-oesophageal injections of air. Distension thresholds and peristaltic activities of secondary peristalsis were analysed and compared between the patients and healthy controls. RESULTS: The threshold volume for generating secondary peristalsis during slow air distension did not differ between the patient and control groups (P = .55). The threshold volume for generating secondary peristalsis during rapid air distension was significantly greater in patients with globus than healthy controls (7.0 ± 0.9 vs 5.0 ± 0.3 mL, P = .04). Secondary peristalsis was triggered less frequently in globus patients as compared with healthy control after rapid air distension (40% [30%-65%] vs 60% [60%-83%], P = .001). There was no difference in any of peristaltic parameters for primary and secondary peristalsis between the groups. CONCLUSIONS: Our work identifies functional defects of oesophageal secondary peristalsis in patients with globus sensation and such defects are characterised with defective triggering of secondary peristalsis during rapid air distension. Whether current findings have therapeutic implication in the management of patients with globus sensation warrants further investigation.

Risk factors for early-onset ventilator-associated pneumonia in aneurysmal subarachnoid hemorrhage patients

This study aimed to investigate the risk factors related to ventilator-acquired pneumonia (VAP) in aneurysmal subarachnoid hemorrhage (SAH) patients. From January 2011 to December 2015, a single-center retrospective study including 200 SAH patients requiring mechanical ventilation (MV) ≥48 h was performed. The clinical data of these patients were collected and analyzed. The age range of the patients were 41-63 and 72 (36%) were male. The Glasgow coma scale score range was 5-15 and the Simplified Acute Physiology Score II range was 31-52. One hundred and forty-eight (74%) patients had a World Federation of Neurosurgeons (WNFS) score ≥III. Aneurysm was secured with an endovascular coiling procedure in 168 (84%) patients and 94 (47%) patients presented VAP. Male gender (OR=2.25, 95%CI=1.15-4.45), use of mannitol (OR=3.02, 95%CI=1.53-5.94) and enteral feeding above 20 kcal·kg−1·day−1 (OR=2.90, 95%CI=1.26-6.67) after day 7 were independent factors for VAP. Patients with early-onset VAP had a longer duration of sedation (P=0.03), MV (P=0.001) and ICU length of stay (P=0.003) and a worse Glasgow Outcome Scale score (P<0.001), but did not have a higher death rate.

Urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as early biomarkers for predicting vancomycin-associated acute kidney injury: a prospective study.

OBJECTIVE: Previous studies have demonstrated that urinary kidney injury molecule-1 (uKIM-1) and neutrophil gelatinase-associated lipocalin (uNGAL) were superior to serum creatinine (Scr) in detecting acute kidney injury (AKI), but their ability to predict clinical vancomycin-associated AKI has not been investigated. This study aimed to investigate the abilities of uKIM-1 and uNGAL individually and in combination to predict vancomycin-associated AKI. PATIENTS AND METHODS: Scr, uKIM-1, and uNGAL were measured on the day before and days 1, 2, and 3 of vancomycin therapy in a generalized adult population. Levels of these biomarkers between AKI and non-AKI groups were comparatively analyzed. Predictive performances were evaluated by receiver operating characteristic curve (ROC) analysis. RESULTS: A total of 87 patients were enrolled, and among them, 11 (12.6%) patients developed AKI. Urinary KIM-1 and NGAL levels in the AKI group were higher than in the non-AKI group at all time points (p < 0.05), and the areas under the receiver operating characteristic curves (AUC) were 0.849 (95% confidence interval [CI] 0.750-0.948) for uKIM-1 and 0.824 (95% CI 0.726-0.922) for uNGAL, with cut-off values of 1.72 ng/mL and 9.07 ng/mL respectively. The AUC of uKIM-1 and uNGAL combined was 0.852 (95% CI 0.754-0.949), and the sensitivity and specificity were 90.9% and 75.0%, respectively. CONCLUSIONS: Urinary KIM-1 and NGAL could efficiently discriminate patients with or without vancomycin-associated AKI earlier than Scr, and the combined urinary biomarkers showed fair discrimination compared with the individual biomarkers.

Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer's disease: a meta-analysis study (N=7277).

Studies suggest that dysfunction of brain-derived neurotrophic factor (BDNF) is a possible contributor to the pathology and symptoms of Alzheimer's disease (AD). Several studies report reduced peripheral blood levels of BDNF in AD, but findings are inconsistent. This study sought to quantitatively summarize the clinical BDNF data in patients with AD and mild cognitive impairment (MCI, a prodromal stage of AD) with a meta-analytical technique. A systematic search of Pubmed, PsycINFO and the Cochrane Library identified 29 articles for inclusion in the meta-analysis. Random-effects meta-analysis showed that patients with AD had significantly decreased baseline peripheral blood levels of BDNF compared with healthy control (HC) subjects (24 studies, Hedges' g=-0.339, 95% confidence interval (CI)=-0.572 to -0.106, P=0.004). MCI subjects showed a trend for decreased BDNF levels compared with HC subjects (14 studies, Hedges' g=-0.201, 95% CI=-0.413 to 0.010, P=0.062). No differences were found between AD and MCI subjects in BDNF levels (11 studies, Hedges' g=0.058, 95% CI=-0.120 to 0.236, P=0.522). Interestingly, the effective sizes and statistical significance improved after excluding studies with reported medication in patients (between AD and HC: 18 studies, Hedges' g=-0.492, P<0.001; between MCI and HC: 11 studies, Hedges' g=-0.339, P=0.003). These results strengthen the clinical evidence that AD or MCI is accompanied by reduced peripheral blood BDNF levels, supporting an association between the decreasing levels of BDNF and the progression of AD.

Retrospective analysis of vancomycin treatment outcomes in Chinese paediatric patients with suspected Gram-positive infection.

WHAT IS KNOWN AND OBJECTIVE: Vancomycin is one of the most widely used antibiotics for treating serious Gram-positive infections in children. Few clinical studies have examined the potential risk factors for treatment failure in children receiving vancomycin. The objectives of this study were to evaluate the relationships between vancomycin trough concentration and treatment outcomes in Chinese paediatric patients with suspected Gram-positive infections and to identify baseline characteristics that may affect treatment failure associated with vancomycin use. METHODS: A retrospective cohort study was conducted from April 2007 to October 2015. Patients were included in this study if they were <18 years old, had received vancomycin for at least 72 h and had at least one bacterial culture and one serum steady-state vancomycin trough concentration. Treatment outcomes were defined as success or failure. Nephrotoxicity was defined as a serum creatinine (Scr) increase ≥44·2 µmol/L or a ≥50% increase in baseline Scr for at least two consecutive days. Univariate and multivariate logistic regression analyses were performed to identify risk factors for treatment failure with vancomycin. RESULTS AND DISCUSSION: One hundred and eighty-two patients were included. Vancomycin treatment failure occurred in 52 patients (28·6%), and the incidence of nephrotoxicity was low. No significant difference was observed in the vancomycin trough concentrations between the treatment success and failure groups. Multivariate logistic regression analyses showed that the vancomycin trough concentration [odds ratio (OR), 1·046; 95% confidence interval (CI), 0·979-1·118; P = 0·179, statistical power: 62·04%)] was not associated with treatment outcome, and only intensive care unit (ICU) admission (OR, 3·808; 95% CI, 1·714-8·465; P = 0·001, statistical power: 90·40%) was found to be independently associated with vancomycin treatment failure. WHAT IS NEW AND CONCLUSION: Our findings suggest that the vancomycin trough concentration is not associated with treatment outcome. ICU admission is an independent predictor of treatment failure.

Hyperhomocysteinemia Is Associated with Vitamin B-12 Deficiency: A Cross-sectional Study in a Rural, Elderly Population of Shanxi China.

OBJECTIVES: To report the association of lifestyle factors and plasma vitamin B-12 with hyperhomocysteinemia in a large sample of men and women living in a region of China where there is an increased risk of NTDs. DESIGN: Community-based, cross-sectional study of Lvliang City, Shanxi Province, China. SETTING: Hyperhomocysteinemia is an independent risk factor for cardiovascular disease (CVD) and a sensitive marker of vitamin B-12 and folate deficiency. PARTICIPANTS: A total of 2355 (1044 men and 1311 women) participants born before 1 January 1958 (≥55 years of age) and living in Lvliang City for at least 2 months a year were included. MEASUREMENTS: The participants were assessed regarding demographic characteristics, height, weight, as well as having a physical examination and blood sampling for serum cholesterol, total homocysteine (tHcy), folate, and vitamin B12 levels. RESULTS: The median (25th-75th percentile) tHcy concentration was 21.5 (15.8-33.6) µmol/L in men and 18.0 (13.4-24.8) µmol/L in women. The overall prevalence of hyperhomocysteinemia (tHcy ≥15 µmol/L) was 72.6% (84.3% in men and 63.2% in women), inversely correlated with folate (r=-0.230, P=0.006) and vitamin B-12 (r=-0.540, P<0.001), and positively correlated with uric acid (r=0.054, P<0.001). Vitamin B-12 and folate deficiency, older age, and male gender were associated with elevated tHcy; with vitamin B-12 deficiency being the strongest. CONCLUSIONS: Plasma tHcy concentration and hyperhomocysteinemia were significantly higher in this population than in previously studied populations. Vitamin B-12 and folate supplementation, concomitant lifestyle changes such as smoking cessation, and lipid-lowering treatments may help to decrease plasma tHcy concentrations and reduce the CVD risk in this population.

The roles of MAPKs in rabbit nucleus pulposus cell apoptosis induced by high osmolality.

BACKGROUND: Earlier work has suggested that the p38 MAPK, JNK1/2 and ERK1/2 signal pathway existed in nucleus pulposus cells and the cell growth, differentiation and apoptosis were regulated by them. Because osmotic fluctuations are inevitable in the physicochemical environment of intervertebral disc cells, high osmolality could activate p38 MAPK, JNK1/2 and ERK1/2 signal pathway. The effects of high osmolality on the catabolic program and proliferation of nucleus pulposus cells are still not clear. AIM: To explore the possible roles of MAPKs in rabbit nucleus pulposus cell apoptosis induced by high osmolality. MATERIALS AND METHODS: Rabbit nucleus pulposus cells were cultured and divided into different group at random. The cells were pretreated with inhibitor for p38 MAPK, JNK1/2 and ERK1/2 signal pathway respectively. In next step, the cells were cultured in different osmolality environment for different time at 37°C in 5% carbon dioxide incubator. After treatments, ratio of apoptosis was measured by flow cytometry, and western blotting was performed to quantify the expression of the activated forms of p38 MAPK, JNK1/2 and ERK1/2. Furthermore, immunofluorescence analysis with confocal microscopy was performed to confirm the hyperosmolality effects on activation of p38 MAPK, JNK1/2 and ERK1/2 signal pathways in nucleus pulposus cells. RESULTS: Our results show that in 500 and 600 mOsm/kg medium, rabbit nucleus pulposus cell apoptosis increased, and a persistent phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 proteins were observed. In the same condition, the apoptotic cells death remarkably decreased when the p38 MAPK and JNK1/2 signal pathways were blocked by their inhibitors SB203580, SP600125 repectively. On the other side, the apoptotic cells death rate reraised greatly when the ERK1/2 signal pathways were blocked by its inhibitor PD98059. CONCLUSIONS: High osmolality activated p38MAPK, JNK1/2 and ERK1/2 in rabbit nucleus pulposus cell, and the activated p38 MAPK and JNK1/2 induced cell apoptosis, on the contrary, the activated ERK1/2 made the cell survived.

Evidence for up-regulation of purinergic receptor genes associating with TRPV1 receptors and neurotrophic factors in the inflamed human esophagus.

Purinergic receptors are implicated in nociceptive signaling in small primary afferents via activation of adenosine triphosphate (ATP). ATP appears to mediate HCl-induced transient receptor potential vanilloid receptor 1 (TRPV1) activation in esophageal mucosa. Up-regulation of TRPV1 expression in gastroesophageal reflux disease (GERD) is associated with increased nerve growth factor (NGF) and glial derived neurotrophic factor (GDNF). This study aims to genetically determine the expression of purinergic receptors in severe inflamed human esophagus. Distal esophageal biopsies from the subjects with erosive GERD, asymptomatic patients (AP) and healthy ones were examined. Using real-time qPCR for detecting purinergic receptors (P2X2, P2X3, P2X7, P2Y1, P2Y2, P2Y4, P2Y6 and P2Y12), TRPV1, TRPV4, NGF, and GDNF was done in this study. Both P2X3 and P2X7 mRNA expressions in GERD patients significantly increased than those in healthy controls (P < 0.001) and AP (P < 0.001), but P2X2, P2Y1, P2Y2, P2Y4, P2Y6, P2Y12 or P2Y12 had no difference within the control, AP or GERD subjects. The well correlated expression in P2X3 gene with TRPV1 (r = 0.46, P = 0.002), NGF (r = 0.54, P = 0.0002), and GDNF (r = 0.64, P = 0.0001) was found. The P2X7 gene expressions also well correlated with TRPV1 (r = 0.47, P = 0.002), NGF (r = 0.32, P = 0.037), and GDNF (r = 0.42, P = 0.005). These results suggest that chronic esophagitis increases mRNA expressions of P2X3 and P2X7 receptors accompanied by up-regulation of TRPV1 and neurotrophic factors (NGF and GDNF). These genetical alterations in esophageal mucosa might mediate sensitization of inflamed human esophagus.

The visual diagnosis of tuberculous pleuritis under medical thoracoscopy: a retrospective series of 91 cases.

BACKGROUND: Despite progress of medical, the fast and accurate diagnosis of tuberculous pleuritis (TP) continues to be a challenge, mainly because of the lack of specific clinical features and the difficulty in isolating the Mycobacterium tuberculosis. OBJECTIVES: To investigate the role of medical thoracoscopy in definite diagnosis of tuberculous pleuritis, especially the feature of visual diagnosis in tuberculous pleuritis via medical thoracoscopy. We performed a retrospective review of the utility of medical thoracoscopy in tuberculous pleuritis. PATIENTS AND METHODS: A retrospective chart review was performed of 91 patients who had medical thoracoscopy for suspected TP at the Second Xiangya Hospital from October 1, 2006 to July 30, 2012. RESULTS: In ninety one cases, 76 patients were diagnosed with TP by pathologic diagnosis. The visual findings via thoracoscopy of 76 TP patients included the following: (1) necrosis (76.32%, n=58), (2) diffuse miliary nodules (64.67%, n=49), (3) single or multiple pleural nodules (14.47%, n=11), (4) hyperemic, edematous and thickened pleura (56.58%, n=43), and (5) pleural adhesions or fibrotic septa (78.95%, n=60), and all of these samples had hydrothorax or loculated effusion. The diagnostic efficiency of visual diagnosis via medical thoracoscopy about tuberculous pleuritis was 93.41%. In the non-invasive test, ADA > 40 u/l with LDH > 200 u/l for TP showed relatively high sensitivity and specificity (73.68%, 80.00%, respectively). CONCLUSIONS: TP presents a variety of scopic phenotypes under medical thoracoscopy. The experienced pulmonologists visually diagnose TP efficiently and directly via medical thoracoscopy. Medical thoracoscopy with combined biopsy is an accurate and safe method for diagnosing TP.

Novel mutation affecting the pterin-binding site of PTS gene and review of PTS mutations in Thai patients with 6-pyruvoyltetrahydropterin synthase deficiency.

Tetrahydrobiopterin (BH(4)) deficiency comprises heterogeneous disorders resulting in hyperphenylalaninaemia (HPA) and lack of monoamine neurotransmitters. Among these, 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is the most common disorder. We report a female Thai patient with PTPS deficiency who was initially detected by newborn screening for HPA, and later treated by supplements of BH(4), L-dopa/carbidopa, and 5-hydroxytryptophan. Monitoring of serum prolactin representing dopamine sufficiency is used for optimizing the dosage of L-dopa. She showed a remarkable progress of development despite delayed treatment at 5 months of age. Mutation analysis revealed two heterozygous missense mutations of the PTS gene: c.259C>T (p.P87S) inherited from the father; and c.147T>G (p.H49Q) inherited from the mother. The latter is a novel mutation that affects the pterin-binding site of the PTPS enzyme. This novel mutation expands the mutation spectrum of PTPS deficiency. Notably, some PTS mutations have been reported in both Thai and Chinese patients. Whether these common mutations are the result of a founder effect with common ancestors of Thai and Chinese people or intermarriage between Thai and Chinese descents in Thailand remain unclear. In conclusion, severe neurological impairment from BH(4) deficiency could be prevented by newborn screening for HPA and proper metabolic management. However, pterin analysis for early diagnosis of BH(4) deficiency is still not available in most developing countries.

Selective COX2 inhibition improves whole body and muscular insulin resistance in fructose-fed rats.

BACKGROUND: The effects of cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2) inhibition on insulin resistance in subjects with the metabolic syndrome remain elusive. Aims of this study were to examine the effects of COX1 and COX2 inhibitors on whole body and muscular insulin resistance in fructose-fed rats, an animal model of the metabolic syndrome. MATERIALS AND METHODS: The rats on regular or 60% fructose-enriched diets for 6 weeks were further divided into rats combined with or without piroxicam (a selective COX1 inhibitor) or celecoxib (a selective COX2 inhibitor) treatment for an additional 2 weeks. Euglycaemic hyperinsulinaemic clamp (EHC) with a tracer dilution method was performed at the end of the study. RESULTS: The present result showed that fructose-induced increases in systolic blood pressure and fasting plasma insulin levels were significantly suppressed in rats treated with celecoxib but not piroxicam. In the EHC period, celecoxib significantly reversed fructose-induced decreases in whole body glucose uptake, mainly by glucose storage. Hepatic glucose production and whole body glycolysis were not significantly changed among groups. Celecoxib but not piroxicam significantly reversed fructose-induced decreases in glycogen synthase activities in red and white quadriceps muscles and insulin-stimulated membrane GLUT4 recruitment in soleus muscles. Celecoxib and piroxicam both significantly diminished fructose-induced increases in plasma thromboxane B2 and 6-keto prostaglandin (PG) F1alpha; but only celecoxib treatment significantly attenuated a fructose-induced increase in 8-isoprostane levels. Plasma PGE metabolites were not different among groups. CONCLUSIONS: This study demonstrates that a therapeutic dose of celecoxib, but not piroxicam, could significantly attenuate fructose-induced whole body and muscular insulin resistance in rats.

Effects of water-soluble natural antioxidants on photosensitized oxidation of conjugated linoleic acid in an oil-in-water emulsion system.

The effect of photosensitized oxidation of conjugated linoleic acid in an oil-in-water (o/w) emulsion system was studied. Water-soluble natural antioxidants, including apple polyphenols from apple extract, green tea extract, 4-hydroxy-2(or 5)-ethyl-5(or2)-methyl-3(2H)-furanone(HEMF), 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF), and ascorbic acid, were tested for antioxidant activity in this system. The green tea extract showed the highest antioxidant activity followed by ascorbic acid. Apple polyphenols did not give significant antioxidant activity. HEMF and HDMF exhibited a prooxidant effect. The antioxidant activity of tea catechins was also investigated. Of them, EGCG and ECG exhibited antioxidant activity at 50 ppm, but the antioxidant activity between them was not significantly different (P < 0.05). Comparatively, EC, EGC, and GCG showed no significant antioxidative effect at 50 ppm. When the concentration increased to 100 ppm, the antioxidant activity of ECG and EGCG significantly increased compared with that at 50 ppm, and EGCG had higher antioxidant activity than ECG. GCG also showed significant antioxidant activity at 100 ppm. EGCG exhibited the highest antioxidant activity among the tea catechins in the emulsion system at 100 ppm.

Genome-wide scan identifies a susceptibility locus for familial primary cutaneous amyloidosis on chromosome 5p13.1-q11.2.

BACKGROUND: Primary cutaneous amyloidosis (PCA) is a relatively common skin disorder in South America and Southeast Asia. Most cases of PCA are sporadic but familial aggregation has been reported from South America and Taiwan. The different susceptibility among ethnic groups suggests that genetic factors may play an important role in its pathogenesis. OBJECTIVES: We aimed to perform a genome-wide scan by linkage analysis across 15 families with familial primary cutaneous amyloidosis (FPCA) to map the disease gene(s) for FPCA. PATIENTS AND METHODS: A total of 15 FPCA families including 50 individuals affected with PCA were recruited. Throughout the 22 autosomes, 369 polymorphic microsatellite markers were used initially. Regions showing a LOD score > 1 identified in the initial scan were further analysed with additional markers. Two-point and multipoint linkage analysis were performed by using the LINKAGE program. Nonparametric linkage (NPL) analysis and reconstruction of haplotypes were performed with the GENEHUNTER program. RESULTS: A maximum two-point LOD score of 4.76 for the marker D5S1490 (theta = 0.10, alpha = 0.60) and a multipoint LOD score of 4.50 between D5S822 and D5S623 (alpha = 0.60) were obtained under the assumption of heterogeneity. A peak NPL score of 5.23 (P value = 0.000007) was found from D5S1490 to D5S2076. Further analysis focusing on two major families identifies a common haplotype shared by all affected individuals between D5S1490 and D5S623. To our knowledge, this is the first report of genome-wide analysis of a large number of FPCA pedigrees. CONCLUSIONS: Our study provides evidence for significant linkage to chromosome 5p13.1-q11.2 in a subset of FPCA families.

Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency.

Tetrahydrobiopterin (BH(4)) deficiency is an autosomal recessive disorder caused by enzyme defects in the biosynthesis or recycling of BH(4). Patients with BH(4) deficiency present with severe neurological signs and symptoms and require a different treatment from classical phenylketonuria. During the last 12 years, 31 cases of BH(4) deficiency were identified in our department. They were all classified as 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency. They were diagnosed at the ages of 2.5-48 months and treated with BH(4), L-dopa and 5-hydroxytryptophan immediately after diagnosis. The average development quotients (DQ) at diagnosis and after treatment for more than 3 years were 53+/- 16, and 78+/- 15, respectively. A significant negative correlation was observed between the level of the DQ and the age at which treatment was commenced (r = -0.751, p = 0.002). Developmental profiles were uneven. Language, adaptability and at later age mathematics were particularly weak areas. Only two patients achieved a good performance in mathematics. Eleven patients who were treated with drugs from ages of 2.9-48 months had neuroradiological scanning. Computed tomography disclosed calcification in lentiform nuclei in one patient and magnetic resonance imaging disclosed delayed myelination and abnormal high intensity signal in cerebral white matter in all of them. Even though most of abnormalities were reversible, small patchy or spotted areas were still present on these regions after treatment for 10-46 months. In summary, our study supports the substantial efficacy of the current therapeutic approach in PTPS deficiency of normalizing amine neurotransmitters with three drugs as early as possible. For the first time, calcifications could be detected in patients with PTPS deficiency. Abnormalities in white matter on magnetic resonance imaging were not related to clinical manifestations and most were reversible.

DNA sequence and comparative analysis of chimpanzee chromosome 22.

Human-chimpanzee comparative genome research is essential for narrowing down genetic changes involved in the acquisition of unique human features, such as highly developed cognitive functions, bipedalism or the use of complex language. Here, we report the high-quality DNA sequence of 33.3 megabases of chimpanzee chromosome 22. By comparing the whole sequence with the human counterpart, chromosome 21, we found that 1.44% of the chromosome consists of single-base substitutions in addition to nearly 68,000 insertions or deletions. These differences are sufficient to generate changes in most of the proteins. Indeed, 83% of the 231 coding sequences, including functionally important genes, show differences at the amino acid sequence level. Furthermore, we demonstrate different expansion of particular subfamilies of retrotransposons between the lineages, suggesting different impacts of retrotranspositions on human and chimpanzee evolution. The genomic changes after speciation and their biological consequences seem more complex than originally hypothesized.

Fabrication and Characterization of a New Self-Assembled Monolayer of Fullerene Dicarboxylic Acid Derivative and Its Photoelectric Conversion Property.

A new fullerene self-assembled monolayer (SAM) which has the property of photoelectric conversion is reported here. The SAM was fabricated on hydrophilic substrates by an esterification reaction. The SAM is characterized by contact angle, AFM, UV spectrum, and cyclic voltammetry. A cathodic photocurrent of 226 nA/cm(2) was obtained. Copyright 2000 Academic Press.