Possible pro‐inflammatory role of heparin‐binding epidermal growth factor‐like growth factor in the active phase of systemic sclerosis

Heparin‐binding epidermal growth factor (EGF)‐like growth factor (HB‐EGF) is a member of the EGF family growth factors, which affects multiple aspects of the wound healing process such as epithelialization, wound contraction and angiogenesis. In our study, we measured the serum HB‐EGF levels of 51 systemic sclerosis (SSc) patients, which showed a significant increase compared with those of 20 normal subjects. Further analysis revealed a positive correlation between the HB‐EGF level and pulmonary ground‐glass score but no correlation between the former and pulmonary fibrosis score. Other findings include: a significant increase of serum sialylated carbohydrate antigen KL‐6 levels and significant shortness of disease duration in the diffuse cutaneous SSc patients with elevated HB‐EGF levels; and significantly higher HB‐EGF levels in the presence of Raynaud's phenomenon, in that of telangiectasia, and in the absence of contracture of phalanges in all SSc patients. We then evaluated HB‐EGF mRNA levels of fibroblasts harvested from skin samples of the SSc patients and those of foreskin‐derived fibroblasts treated with transforming growth factor‐β, both of which were significantly higher than each control. In conclusion, we speculate that HB‐EGF plays a pro‐inflammatory role in the active skin and lung lesions of SSc.     

Impact of next generation sequencing on diagnostics in a genetic skin disease clinic

Individuals with inherited skin diseases often pose one of the most difficult diagnostic challenges in dermatology. The hunt for the underlying molecular pathology may involve candidate gene screening or linkage analysis, which is usually determined by the initial history, the physical findings and laboratory tests. Recent technical advances in DNA sequencing, however, are shifting the diagnostic paradigm. Notably, next‐generation sequencing allows a more comprehensive approach to diagnosing inherited diseases, with potential savings of both time and money. In the setting of a paediatric dermatology genetics clinic in Kuwait, we therefore performed whole‐exome sequencing on seven individuals without a priori detailed knowledge of the patients’ disorders: from these sequencing data, we diagnosed X‐linked hypohidrotic ectodermal dysplasia (two cases), acrodermatitis enteropathica, recessive erythropoietic protoporphyria (two siblings) and localized recessive dystrophic epidermolysis bullosa (two siblings). All these groups of disorders are clinically and genetically heterogeneous, but the sequencing data proved inherently useful in improving patient care and avoiding unnecessary investigations. Our observations highlight the value of whole‐exome sequencing, in combination with robust bioinformatics analysis, in determining the precise molecular pathology and clinical diagnosis in patients with genetic skin disorders, notably at an early stage in the clinical evaluation of these often complex disorders and thereby support a new paradigm for future diagnostics.     

Cholesterol crystal embolization (CCE) after cardiac catheterization: a case report and a review of 36 cases in the Japanese literature

Cholesterol crystal embolization (CCE) is a complication of atherosclerosis. A 67-year-old Japanese man underwent coronary artery bypass grafting. After the surgery, he underwent coronary angiography via the right femoral artery. Twelve days later, he suddenly developed acalculous cholecystitis and was treated with antibiotics. Gradual deterioration in renal function, purplish discoloration of the distal portion of his toes, and eosinophilia were noted. We performed a skin biopsy and made a diagnosis of CCE. Cilostazol and intravenous heparin improved the symptoms and decreased the creatinine level. We retrospectively studied the clinical features of 36 cases registered with a diagnosis of CCE in the Japanese literature.     

Change in Colonic Motility After Extrinsic Autonomic Denervation in Dogs

Changes in colonic motility were compared indogs undergoing autonomic denervation of the paraaorticand presacral (group A), paraaortic (group B), ormesocolonic region (group C), and sham operation (group D). Five bipolar recording electrodes wereplaced into the seromuscular layer of the colon andrectum. The numbers of continuous electrical responseactivity and contractile electrical complex after an intragastric olive oil injection were smallerin group A than in the other groups (P < 0.05) fromthree weeks through six months after denervation. Thisdifference was significant even in the proximal colon. These data suggest that the pelvic plexus mayplay an important role in colonic motility including theproximal colon. The damage to the plexus did not recoverfor at least six months after denevation. Pelvic plexus injury may thus be one ofpossible explanations for the prolonged change in bowelhabit after anterior resection of the rectum.     

A novel videoendoscopy system by using autofluorescence and reflectance imaging for diagnosis of esophagogastric cancers

BACKGROUND: Image quality of the prior autofluorescence (AF) imaging systems, including the fiber-optic endoscope, was not feasible for general clinical use. The use of AF image alone resulted in low specificity. The objective of the study was to evaluate the resolution and the sensitivity of the novel videoendoscopy system by using AF and reflectance imaging (AFI) in the diagnosis of early esophagogastric cancers. METHODS: This was a case series study. The setting was a pretreatment examination at a cancer center. Five patients with superficial esophageal cancers (SEC) and 21 patients with 22 early gastric cancers (EGC) were included in the study. The extent of the tumors was diagnosed by white light (WL), AF and chromoendoscopic observations. The main outcome measurement was the diagnostic accuracy of each observation in relation to the histologic mapping as a criterion standard. RESULTS: Two of 5 SECs (40%) were correctly diagnosed in the WL image and all (100%) in the AF image as purple or magenta color in a green background. EGCs in atrophic mucosa were observed as purple or magenta areas in a green background, while diffuse-type EGCs in fundic mucosa were observed as green areas in a purple background. Of the 22 EGCs, diagnostic accuracy of WL, AF, and chromoendoscopic observations were 36%: 95% CI [16%, 56%], 68%: 95% CI [49%, 88%], and 91%: 95% CI [79%, 100%], respectively. AFI could reveal flat or isochromatic extensions that were not detected in the WL images. The limitations of the study were ulcerations or inflammation that caused overdiagnosis in the AF observation. CONCLUSIONS: The resolution of the AFI at present is limited, but the image quality was acceptable. The current system of AFI does not equal to chromoendoscopy in sensitivity but has an advantage over standard WL videoendoscopy.     

Use of serum insulin-like growth factor-I levels to predict psychiatric non-response to donepezil in patients with Alzheimer's disease.

OBJECTIVE: Insulin-like growth factor-I (IGF-I) deficiency may be involved in cognitive deficits seen with aging and in neurodegenerative diseases such as Alzheimer's disease (AD). This study was aimed at investigating whether non-responder to donepezil could be predicted using decreased serum levels of IGF-I in AD patients. DESIGN: This study involved 106 elderly subjects: 50 patients with AD and 56 age-matched controls without dementia. In patients with AD, donepezil was given orally 3 mg/day for 4 weeks and 5 mg/day for another 12 weeks. AD patients were divided into responders and non-responders based on the changes in mini-mental state examination (MMSE) scores before and 16 weeks after treatment with donepezil. Serum levels of IGF-I and atherogenic biomarkers were determined. RESULTS: Before treatment with donepezil, there was a significant positive correlation between serum IGF-I levels and the MMSE scores in all subjects. Serum IGF-I levels and the MMSE scores were significantly lower in AD patients than in non-demented controls and were the lowest in non-responders to donepezil. Atherogenic biomarkers (LDL cholesterol, triglycerides, lipoprotein(a), lipid peroxide, apolipoprotein E, and glucose levels) did not differ significantly among these groups. On multiple logistic regression, non-responders to donepezil showed decreased serum IGF-I levels <110 ng/ml and MMSE scores <15 points before treatment. CONCLUSIONS: These findings suggest that decreased levels of serum IGF-I combined with MMSE scores before treatment could predict non-responders to donepezil among AD patients, which may be a simple and practical method for selecting patients expected to show a response to treatment.     

High-resolution computed tomography patterns and immunopathogenetic findings in drug-induced pneumonitis

We tried to determine whether high-resolution computed tomography (HRCT) patterns correlate with the immunopathogenetic findings and whether they could provide helpful information for predicting the outcomes in non-neoplastic drug-induced pneumonitis. The HRCT images were classified as most suggestive of pneumonitis, diffuse alveolar damage (DAD), non-specific interstitial pneumonia, organizing pneumonia (OP), hypersensitivity pneumonitis, and acute eosinophilic pneumonia (AEP) in 34 patients with non-neoplastic drug-induced pneumonitis. The patients were analyzed for the bronchoalveolar lavage (BAL) cell findings and for the circulating levels of interferon-inducible protein 10 (IP-10) and macrophage-derived chemokine (MDC), which were measured by an enzyme-linked immunosorbent assay. The cumulative dose of corticosteroids received by the patients and the day when they required supplemental oxygen were calculated as outcome markers. There were no differences in the circulating chemokine levels and the BAL cell profiles except for the eosinophil percentages among the HRCT patterns. Most of the cases with pulmonary eosinophilia belonged to the OP and AEP groups, and the circulating MDC levels correlated with BAL eosinophil percentages. We could not find any relationship between the BAL cell profiles or the chemokine levels and the outcome markers. In contrast, the HRCT patterns rather predicted the outcomes because larger cumulative dose of steroids and longer oxygen supply were required for the patients in the DAD and OP groups. In contrast, all patients with AEP recovered without steroid administration. The present study suggests that HRCT does not predict cellular pathophysiology but it may predict the corticosteroid use in non-neoplastic drug-induced pneumonitis.     

Infarct Size Limitation by Bradykinin Receptor Activation Is Mediated by the Mitochondrial But Not by the Sarcolemmal KATP Channel

Earlier studies have shown that activation of bradykinin B₂ receptor triggers protein kinase C (PKC)-mediated cardioprotective mechanism in ischemic preconditioning (PC). In the present study, we examined whether the effector in this B₂-receptor triggered pathway of PC is the ATP sensitive potassium (K_ATP) channel in the mitochondria (mito-K_ATP channel) or K_ATP channel in the sarcolemma (sarc-K_ATP channel). Isolated rabbit hearts were perfused with modified Krebs-Henseleit buffer in a Langendorff mode, and regional myocardial ischemia was induced by occluding a left coronary artery for 30 min and then reperfusing for 2 hours. Infarct size was determined by triphenyltetrazolium chloride staining and expressed as a percentage of area at risk (% IS/AR). Infusion of bradykinin (500 nmol/L) for 15 min prior to ischemia significantly reduced % IS/AR from 37.4 ± 2.9 (SE) of the untreated controls to 12.0 ± 3.3%. This protective effect of bradykinin was completely abolished by coinfusion of 5-hydroxydecanoate (5-HD, 50 mol/L), a selective mito-K_ATP channel blocker (% IS/AR = 44.2 ± 6.4). In contrast, a high dose of HMR1098 (20 mol/L), which is a newly developed sarc-K_ATP channel selective blocker with IC₅₀ of 0.6 mol/L, failed to modify the infarct size limitation by preischemic infusion of bradykinin (% IS/AR = 11.7 ± 3.4). Neither 5-HD nor HMR1098 alone modified infarct size (% IS/AR = 37.8 ± 3.8 and 35.1 ± 6.2, respectively). These results suggest that opening of the mito-K_ATP channel but not the sarc-K_ATP channel is involved in infarct size limitation by a mechanism triggered by bradykinin B₂ receptor activation.