Gastric motility in patients with recurrent gastric ulcers.

The existence of abnormal gastric motility in gastric ulcer disease remains controversial. The aim of this study was to characterize gastric motility in patients with recurrent gastric ulcers. Studies were performed in 10 control subjects and in 24 patients with recurrent active gastric ulcer disease as diagnosed by gastrointestinal endoscopy. Gastric motility was evaluated by cutaneous electrogastrography (EGG) and by gastric semi-liquid meal emptying. The EGG was recorded before and after ingestion of a test meal containing 20 mg/kg of acetaminophen. Patients with a dominant EGG frequency of greater than 0.06 Hz were defined as tachygastria, while those with a frequency of less than 0.04 Hz were defined as bradygastria. A transient frequency decrease, called postprandial dip (PD), was identified visually. The degree of gastric emptying was determined from the serum acetaminophen concentration 45 minutes after the meal. Control subjects showed no irregularity in their dominant EGG frequency in tither fasting or postprandial states. PD was observed in 8 control subjects. In patients presenting with active gastric ulcers, abnormal patterns in the dominant EGG frequency (either as tachygastria or bradygastria) were observed in 14 of the 24 patients when fasting and in 15 of them in the postprandial state. After successful treatment, the number of patients with abnormal patterns in their dominant EGG frequency remained unchanged, while PD was observed in 11 patients. No significant difference was observed in the EGG power ratio as a result of successful treatment. Gastric emptying was significantly delayed compared with controls in both the active and healed stages. These findings suggest that abnormal gastric motility, including gastric electrical abnormalities and delayed gastric emptying, plays an important role in the pathophysiology of recurrent gastric ulcers.     

Alcohol increases c-myc mRNA and protein in skeletal and cardiac muscle

The pathogenic mechanisms responsible for alcohol-induced muscle disease are unknown, although it is possible that increased proto-oncogene expression may be the causative process. Therefore, we investigated the responses of skeletal muscle c-myc protein and mRNA to a standard acute ethanol dosage regimen (75 mmol/kg/body weight [BW]) for 2.5 to 24 hours. Comparative studies were made on the heart. Acute ethanol administration in vivo led to an increase in c-myc proto-oncogene mRNA in rat skeletal and cardiac muscle. The changes in c-myc mRNA were mirrored by increases in the c-myc protein as demonstrated by immunohistochemistry. The changes in the c-myc protein were localized to the myonuclei, with no corresponding changes seen in the interstitial cell nuclei. This is the first report of altered proto-oncogene expression in muscle in response to ethanol. Increased c-myc mRNA and protein may reflect adaptive changes, a stress response, or another uncharacterized cellular adaptation.     

Upregulated Expression of AQP 7 in the Skeletal Muscles of Obese ob/ob Mice

Aquaporin (AQP) is suggested to be regulated by leptin through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway. AQP7 and AQP9 are membrane proteins with water and glycerol channels, the latter of which is essential for triglyceride synthesis. We conjectured that the expression of AQP7 and AQP9 would be altered in the skeletal myofibers in obese leptin deficient ob/ob mice as compared with that of wild mice. RNA and protein levels were studied in the quadriceps femoris muscles of ob/ob and wild mice. Real time quantitative RT-PCR analysis showed that mouse AQP7 mRNA levels in skeletal muscles were significantly higher in ob/ob mice than in wild mice (P<0.01), whereas mouse AQP9 mRNA level was not different between the two groups (P>0.05). Histologically the type 1 myofibers of ob/ob mice contained numerous lipid droplets in oil red O stain samples. Immunohistochemical staining of ob/ob mouse muscles revealed enhanced expression of AQP7 at myofiber surface membranes, while AQP9 expression appeared to be similar to that of wild mice. The findings suggest that the upregulated expression of AQP7 in ob/ob mouse muscles facilitates the secretion of glycerol from myocytes.     

Loss of interaction between plectin and type XVII collagen results in epidermolysis bullosa simplex

Plectin is a linker protein that interacts with intermediate filaments and β4 integrin in hemidesmosomes of the epidermal basement membrane zone (BMZ). Type XVII collagen (COL17) has been suggested as another candidate plectin binding partner in hemidesmosomes. Here, we demonstrate that plectin–COL17 binding helps to maintain epidermal BMZ organization. We identified an epidermolysis bullosa (EB) simplex patient as having markedly diminished expression of plectin and COL17 in skin. The patient is compound heterozygous for sequence variants in the plectin gene (PLEC); one is a truncation and the other is a small in‐frame deletion sequence variant. The in‐frame deletion is located in the putative COL17‐binding domain of plectin and abolishes the plectin–COL17 interaction in vitro. These results imply that disrupted interaction between plectin and COL17 is involved in the development of EB. Our study suggests that protein–protein binding defects may underlie EB in patients with unidentified disease‐causing sequence variants.     

Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex

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. © 2010 Wiley‐Liss, Inc.     

Integrin β4 is a major target antigen in pure ocular mucous membrane pemphigoid

Background

Previous studies of ocular mucous membrane pemphigoid (OMMP) have identified several components of the basement membrane zone to be autoantigens, including integrin β4. However, there are no extensive or definitive reported studies that address this, particularly in pure OMMP.

Objectives

To clarify the major autoantigens in pure OMMP.

Materials and methods

In this study, we examined sera from 43 pure OMMP patients for both IgG and IgA antibodies using newly developed immunoblotting analyses with a hemidesmosome-rich fraction and various recombinant proteins of integrin α6β4, in addition to our routine immune-serological tests.

Results

Using a hemidesmosome-rich fraction, sera from patients with pure OMMP demonstrated reactivity of IgG and/or IgA antibodies to integrin β4, BP180 and laminin-332. The reactivity of pure OMMP sera to integrin β4 was further confirmed by immunoblotting using integrin β4 recombinant proteins. Using concentrated supernatant of HaCaT cells, only one serum sample showed positive IgG and IgA reactivity to LAD-1, the ectodomain of BP180. None of the pure OMMP sera reacted with any autoantigens on immunoblotting using normal human epidermal or dermal extracts, or purified human laminin-332.

Conclusions

Integrin β4 was considered to be the major and specific autoantigen for pureOMMP. The new methods established in this study are useful for detection of various autoantigens, particularly integrin β4.

     

Anti‐p200‐Pemphigoid – Eine neue blasenbildende Autoimmundermatose

Anti‐p200 pemphigoid is an autoimmune skin disease characterized by tense blisters, subepidermal split formation, and mainly neutrophilic inflammatory infiltration of the dermal‐epidermal junction (DEJ). Direct immunofluorescence microscopy of perilesional skin biopsies demonstrates linear deposits of IgG and C3 along the DEJ, while by indirect immunofluorescence microscopy on NaCl‐split human skin, patients' IgG labels the dermal side. The antigenic target of the autoantibodies is a 200 kD protein (p200) of the lower lamina lucida that can be detected in human dermal extracts by immunoblotting. While p200 is thought to be important for cell‐matrix adhesion, its exact identity is unknown. To date, the p200 autoantigen has been demonstrated to be distinct from bullous pemphigoid antigens 180 und 230, laminin 1, 5, and 6, α6β4 integrin, and type VII collagen. Biochemical characterization of the p200 molecule revealed a noncollagenous N‐glycosylated acidic protein with an isoelectric point of approximately 5.5. We provide an overview on pathogenesis, clinical features, diagnosis, and treatment of this unique autoimmune dermatosis.