Recovery from gastric mucus depletion in the intact guinea pig mucosa

BACKGROUND: In developed countries one-third of the population is infected with the gastric pathogen Helicobacter pylori. In the early stages of H. pylori-induced gastritis, typical symptoms include gastric erosions and mucus depletions. Artificial mucus depletion was generated, demonstrating both consequent irritation and recovery processes in the mucosa. METHODS: The mucus depletion was examined by removing a small cylinder of mucus from the surface of the explanted guinea pig corpus mucosa, leaving the epithelial surface intact. pH microelectrodes were inserted into the mucosa in vitro, measuring the epicellular mucus pH, the pH(i) of the underlying epithelial cells and the pH inside the gastric glands during mucus regeneration. Using infrared microscopy, the same process of mucus layer renewal was followed in anaesthetized animals. RESULTS: The depletion exposed the tissue surface to low luminal pH levels. At a luminal pH of 2.5, a decrease was observed in the crypt outlet pH and surface cell pH(i), while deeper cells were less affected. However, a subsequent neutralization in the deep gland lumen was found. During the repair process, a quarter of the mucus layer was regenerated within the first 5 min. This newly secreted mucus formed a structure similar to that before depletion. Within 45 min, pH(i) and tissue-near pH values had fully recovered. CONCLUSION: Following mucus depletion, there is a decrease in surface cell pH(i) and crypt outlet pH values. The repair process is then characterized by extensive mucus secretion and local cessation of acid secretion.     

Influence of hydration on dihydroxyacetone-induced pigmentation of stratum corneum

Dihydroxyacetone, the browning ingredient in sunless tanning formulations, reacts with amino acids in the outer stratum corneum to form a mixture of high molecular weight pigments. Our initial observations indicated that high hydration of dihydroxyacetone-treated skin completely inhibited development of pigmentation. To investigate the mechanism underlying this effect, studies were carried out in isolated murine epidermis, polyvinyl alcohol/lysine films, and lysine in glycerol/water solvent. Murine epidermis treated with dihydroxyacetone showed a biphasic dependence on relative humidity: maximum pigmentation developed at 84% relative humidity and minimum pigmentation at 0% and 100% relative humidity. Filaggrin proteolysis, which shows a similar dependence on relative humidity and provides free amino acids in the outer stratum corneum, did not account for the relative humidity dependence of dihydroxyacetone pigmentation. A similar biphasic pigmentation response was obtained when polyvinyl alcohol film containing lysine was treated with dihydroxyacetone and incubated at various relative humidities, indicating that the structure of the stratum corneum was not a major factor. To remove the influence of the matrix, the reaction of dihydroxyacetone with lysine was followed at varying concentrations of water in mixed glycerol/buffer solvent. Again, greater pigment formation was found at an intermediate level of water (6% vol/vol) and little pigmentation at 0% and 100% water content. These results are consistent with a requirement for water at low relative humidity, which facilitates formation of free amine groups needed for the initial reaction with dihydroxyacetone, and with inhibition of the dehydration reactions by water through the law of mass action at high relative humidity.     

Subcutaneous T-cell lymphoma

A 70-year-old woman presents with a 2-year history of intermittent, subcutaneous nodules. The patient was otherwise asymptomatic. A biopsy specimen was consistent with a subcutaneous T-cell lymphoma, a rare subset of peripheral T-cell lymphoma; when accompanied by the hemocphagocytic syndrome, it can be rapidly fatal. The histopathologic characteristics and nature of the disease are discussed.     

Meta-analysis of the effects of endothelin receptor blockade on survival in experimental heart failure

BACKGROUND: Although an initial study of endothelin receptor blockade reported positive findings, subsequent experiments and clinical trials in humans found little or no benefit. METHODS: We applied meta-analytic methods to assess the methodologic rigor of preclinical studies of endothelin blockade and to quantitatively evaluate the totality of evidence regarding the effect of endothelin receptor blockers in experimental heart failure. A total of 396 animals were assigned to control and 594 were assigned to experimental therapy in the pooled analysis. Of the 9 studies identified, no study reported a priori sample size justification. Although there was a tendency to increased mortality with early administration (relative risk 1.39, P=.15) and decreased mortality with late administration (relative risk 0.85, P=.6), in the overall analysis, there was no significant evidence of benefit or harm (relative risk 1.03, P=.9). Studies with a small sample size had estimated effects that tended to deviate further from the pooled estimate of all studies. CONCLUSIONS: Consideration of mortality effects in the totality of studies revealed no significant effect of endothelin antagonists in animal models of experimental heart failure. Given the potential for between-study variability, reliance on studies with small sample size may lead to unrealistic expectations when extrapolating preclinical experimental results to future research.     

Incorporation and integration of implanted myogenic and stem cells into native myocardial fibers: anatomic basis for functional improvements

BACKGROUND: Myoblasts and stem cells implanted into myocardium can differentiate into myocytes and may functionally improve impaired ventricles. For implanted cells to actually contribute to the synchronous contractions of the heart, however, they must be anatomically integrated with the existing native myocardial fibers. METHODS: Isogenic Lewis rats were used as donors and recipients to simulate clinical autotransplantation. Either skeletal myoblasts or marrow stromal stem cells were isolated from donors, culture expanded, and labeled with 4',6-diamidino-2-phenylindole (4',6-diamidino-2-phenylindole). Labeled cells were then injected into the myocardium of recipients. At intervals specimens were obtained, sectioned, and stained with hematoxylin and eosin and immunohistochemically against connexin-43 to demonstrate gap junctions (intercalated discs). RESULTS: At 1 week the labeled cells were still undifferentiated, but early expression of connexin-43 could be detected at contact points between the implanted cells and the native myocytes. By 4 to 6 weeks, labeled, fully differentiated myocytes could be seen to interconnect among themselves and with native cardiomyocytes by means of intercalated discs. In sections parallel to the myofibers, full integration of new labeled myocytes with the native myofiber cells could be observed. Furthermore, the labeled myofibers were in parallel with the native, unlabeled fibers. We postulate that such supracellular structural integration was enhanced by fiber stretching during cardiac contractions, sending signals for cellular reorientation and incorporation, in which the cytoskeletal system may play an important role. CONCLUSION: We conclude that implanted precursor cells can be integrated into native myocardial structure so as to contribute to myocardial function. Direct cell-to-cell contact seems to be an important signaling mechanism, which has implications for cellular implantation strategies.     

RET proto-oncogene mutations affecting codon 790/791: A mild form of multiple endocrine neoplasia type 2A syndrome?

BACKGROUND: In patients with multiple endocrine neoplasia type 2A syndrome, prophylactic thyroidectomy is generally recommended at the age of 5 to 6 years. Whether this recommendation is justified for exon 13 mutations is unknown. METHODS: We analyzed the clinical data from 40 patients harboring RET codon 790/791 mutations (exon 13) who had been treated in 4 specialized centers. RESULTS: Mean age was 35.2 +/- 21.6 years (range, 5.1-69.0 years). Thirteen patients were index patients (mean age, 57.7 +/- 11.3 years), 27 patients were screening patients (mean age, 24.4 +/- 16.5 years). In the index group, pT-category was: T0, n = 2; T1, n = 6; T2, n = 2; T3, n = 1; and T4, n = 2. Lymph node metastases were found in 5 patients and distant metastases in 1 patient. Postoperatively, 69% of index patients were biochemically cured. In the screening group, pT-category was: T0, n = 19; T1, n = 7; and T2, n = 1. Lymph node metastases were found in 2 patients. Postoperatively, 93% of screening patients were biochemically cured. The youngest patient with medullary thyroid carcinoma was 13.8 years, the youngest patient with lymph node metastases was 46.4 years. CONCLUSIONS: Patients with RET codon 790/791 mutations seemed to have a less aggressive clinical course compared with patients with classic multiple endocrine neoplasia type 2A syndrome. Still, index patients had a lower biochemic cure rate in comparison with screening patients. Timely total thyroidectomy including lymph node dissection is warranted.     

The effects of advanced age on the incidence of supraventricular arrhythmias after pneumonectomy in dogs

Because advanced age is the strongest independent risk factor for the development of supraventricular arrhythmias after lung resection, we compared the incidence and premorbid events of supraventricular arrhythmias after pneumonectomy in young and elderly dogs with the aim of better understanding potential age-related arrhythmogenic mechanisms. Right pneumonectomy was performed in 15 male mongrel dogs ("old" > or =8 yr [n = 8], "young" <4 yr [n = 7]) and the electrocardiogram continuously recorded by an implantable telemetry system for 1 wk before euthanizing. After surgery, 7 of 8 older animals (88%) developed a total of 23 episodes of sustained (>30 s) paroxysmal supraventricular tachycardia (SVT), compared with 0 of 7 (0%) young dogs, P = 0.0014. Analysis of heart rate over the 60 min preceding the onset of SVT revealed a progressive increase in sinus rhythm beginning 15 min before the arrhythmia. Comparison of the heart rate and rhythm obtained in younger animals from the corresponding postoperative hour demonstrated that although older animals developed more atrial (P = 0.03) and ventricular premature contractions (P = 0.056) and episodes of nonsustained ventricular tachycardia (P = 0.01), heart rate was similar for both groups until the increase in elderly dogs preceding the onset of SVT. Histologic examination of the atria showed interstitial fibrosis in old but not young animals. In addition, 4 of 8 (50%) elderly animals exhibited an inflammatory response within the atria consistent with acute myo- and epicarditis. We conclude that elderly dogs have an increased supraventricular arrhythmogenic potential within the first week after pneumonectomy than younger animals, perhaps because of increased atrial fibrosis and inflammation. Heart rate analysis before SVT onset suggests that adrenergic predominance was a probable responsible trigger. IMPLICATIONS: In this canine pneumonectomy model, advanced age was associated with an increased incidence of supraventricular arrhythmias, perhaps because of increased atrial fibrosis and inflammation.     

Recklinghausen's disease and gastrointestinal stromal tumors

Gastro-intestinal stromal tumors associated with Recklinghausen's disease should be considered in the current concept of the stromal tumors with reference to recent advances in immuno-chemistry. In this setting, there is an high potential of maluignancy. For the treatment of these lesions, surgery is the main tool. Frequency of malignant digestive diseases associated with Recklinghausen disease should be kept in mind.