Characterization of spontaneous dermatitis in beige rats with IgE hyperproduction

BACKGROUND: Atopic dermatitis (AD) is a common skin disease characterized by chronic recurrent eczematous lesions, but its exact etiology and mechanism are unclear. We found that beige rats (DAbg/bg), a mutant model of Chediak-Higashi syndrome, develop skin lesions characterized by pruritus, excoriation, erosion and alopecia. We describe the beige rat and examine its possible usefulness as an AD model. METHODS: Beige rats of 4, 8, 13, 16, 26 and 52 weeks were used. Histological analysis of the skin was performed. Plasma IgE and cytokines were measured. Th1 and Th2 cytokines and RANTES mRNA expression of skin and lymph nodes were evaluated. Passive cutaneous anaphylaxis (PCA) reactions were examined, and maximization tests were conducted. RESULTS: Skin lesions begin to develop with increases in serum IgE levels and the expression of IL-4 mRNA in the lymph node and skin. Histologically, skin lesions are characterized by acanthosis, ulceration and inflammatory cell infiltration in the dermis. Inflammatory cells consist of CD3+, CD4+, ED1+, ED2+ and I-A+ mononuclear cells, eosinophils, degranulated mast cells and neutrophils accompanying interleukin (IL)-4, interferon (IFN)-gamma and RANTES mRNA expressions of the skin. Inflammatory cells are reduced during chronification with decreased expressions of IL-4, IFN-gamma and RANTES mRNA. In addition, the rats show a high sensitivity to PCA reactions and maximization tests. CONCLUSIONS: Our results show that some of the skin lesions of beige rats are morphologically similar to human AD, being characterized by inflammatory cell composition in the acute phase, and increased IgE and RANTES levels. However, the inflammatory process and cytokine expression pattern are different from those in human AD.     

REACTIVE LYMPHOID HYPERPLASIA OF THE STOMACH

The surgically excised stomachs were re-examined histopathologically, and eighteen cases were placed in the category of reactive lymphoid hyperplasia (RLH). The distribution and the classes of infiltrating immunoglobulin (Ig) bearing cells were examined on lesions of RLH cases together with ten histopathologically determined malignant lymphomas (ML) of the stomach and the control stomachs. It was found that in eleven cases of RLH and one case of ML, many lymphoid cells bearing different classes of Ig were present in those lesions in an intermingled way (polyspecific group). Meanwhile, lymphoid cells in three RLH cases and two ML cases bore only a single mono-specific Ig (monospecific group). In other cases, the number of Ig bearing cells were not sufficient to reach any clear conclusions (undetermined group). It was speculated that regardless of the histopathological diagnosis, the mono-specific group might belong to the category of neoplasm of B cell type and the polyspecific group in the category of true reactive process. The possible histopathological criteria for differentiation of the reactive process and lymphoid neoplasm of the stomach were re-checked, and the importance of immunohistochemical study on these cases were stressed.     

Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.     

Involvement of opioid receptors in phencyclidine-induced enhancement of brain histamine turnover in mice

Summary When the histamine (HA) turnover in the brain of mice was estimated on the basis of the pargyline-induced accumulation of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, the enhancing effect of phencyclidine (PCP) on the HA turnover was antagonized by a large dose of naloxone. However, a dopamine receptor antagonist haloperidol, which is also a potent receptor antagonist, did not inhibit the effect of PCP on the HA turnover. [abetd-Ala², abetd-Leu⁵]enkephalin, a prototypic opioid agonist, markedly enhanced the HA turnover. The effect of this peptide was demonstrated not only when the HA turnover was determined by the pargyline-induced t-MH accumulation but when it was estimated by the HA depletion induced by -fluoromethylhistidine, a specific inhibitor of histidine decarboxylase. A agonist, SKF-10047, and a agonist, ethylketazocine, had no PCP-like enhancing effect on the HA turnover. These results suggest that PCP enhances the brain HA turnover in mice by stimulating, probably indireclty, endogenous opioid systems. Send offprint requests to K. Saeki at the above address     

Effects of pentagastrin and carbachol on the gastric histamine level in α-fluoromethylhistidine-treated mice and rats

Summary The gastric mucosal histamine level in mice increased by about 80% and 100% after fasting for 24 and 48 h, respectively. In non-fasted mice, -fluoromethylhistidine (-FMH), a specific histidine decarboxylase inhibitor, significantly decreased the histamine level, the reduction amounting to 35% and 49%, 2 h and 4 h after treatment, respectively. In mice fasted for 24 h, a significant decrease of 42% was observed 4 h after treatment. However, in mice fasted for 48 h, no significant decrease was seen even 4 h after -FMH treatment. Therefore, the histamine-releasing effect of re-feeding and drugs on the gastric mucosa was examined in vivo, using animals fasted for 48 h and subsequently treated with -FMH. Food given simultaneously with -FMH to 48-h fasted mice significantly decreased the histamine level 4 h later. Pentagastrin and carbachol administered alone (0.25–2.0 mg/kg, i.p.) had no significant effect on the histamine level. However, the combined treatment with these drugs significantly decreased the histamine level. In rats fasted for 48 h and treated with -FMH, pentagastrin (0.25 and 0.5 mg/kg, i.p.) but not carbachol (0.125 – 0.5 mg/kg, i. p.) caused a significant decrease in the mucosal histamine level. In contrast to mice, the effect of the combined treatment with pentagastrin and carbachol was not synergistic in rats. These findings suggest that gastrin acts synergistically with acetylcholine in the histamine release from the gastric mucosa in mice, whereas such synergism may not occur in rats. Send offprint requests to K. Saeki     

Successful Single-Lung Transplant for the Dominant Side: A Case Report

Although single-lung transplant on the side with better lung function is challenging in patients with significantly asymmetrical lung function between the right and left sides, it sometimes can be a realistic option because of the recipient's condition and from the viewpoint of organ sharing. We report our experience with a successful case of single-lung transplant on the side with a pulmonary perfusion ratio of 89%. The transplant was performed with the patient under central venoarterial extracorporeal membrane oxygenation through a clamshell incision, and the patient had an acceptable short- and long-term outcome with a remarkable improvement of lung function.     

Nondomain biopolymers: Flexible molecular strategies to acquire biological functions

A long-standing assumption in molecular biology posits that the conservation of protein and nucleic acid sequences emphasizes the functional significance of biomolecules. These conserved sequences fold into distinct secondary and tertiary structures, enable highly specific molecular interactions, and regulate complex yet organized molecular processes within living cells. However, recent evidence suggests that biomolecules can also function through primary sequence regions that lack conservation across species or gene families. These regions typically do not form rigid structures, and their inherent flexibility is critical for their functional roles. This review examines the emerging roles and molecular mechanisms of “nondomain biomolecules,” whose functions are not easily predicted due to the absence of conserved functional domains. We propose the hypothesis that both domain- and nondomain-type molecules work together to enable flexible and efficient molecular processes within the highly crowded intracellular environment.     

Breast-Conserving therapy: Experience of the breast cancer research group of Tokyo women’s medical college

Conclusion  We are morally obligated to select therapies which are maximally beneficial for patients. Promoting or discouraging the use of a particular treatment modality, such as BCT, should never be a consideration. To meet this goal, our society must establish guidelines as a part of comprehensive policy. The specialist system, launched under the auspices of the specialist system committee, will hopefully lead to further development of the Japanese Breast Cancer Society.     

A new paradigm for alcohol use in older persons

BACKGROUND: Current paradigms for conceptualizing alcohol-related problems typically focus on persons who are abusing or dependent on alcohol. These paradigms may not apply to older drinkers whose alcohol use, regardless of consumption-level, can cause problems because of age-related changes in physiology and interactions with increased morbidity, medication use, and functional limitations. OBJECTIVE: We convened an expert panel# to develop clinical indications of harmful, hazardous, and nonhazardous drinking in persons 65 years of age and older. RESEARCH DESIGN AND SUBJECTS: Nine panelists with expertise in psychiatry, geriatrics, internal medicine, and alcohol research were provided with epidemiological data and a published explicit literature review of alcohol use in the elderly. The RAND/UCLA two-round panel method was used to develop the indications. After the second round, the authors wrote a draft statement that was circulated to the panelists whose comments were incorporated into a final document. RESULTS: Panelists agreed on 215 scenarios in which older peoples' use of alcohol either alone or in the presence of chronic medical conditions, medication use, symptoms, smoking, and functional limitations are hazardous or harmful. Panelists' ratings of risk did not differ significantly between persons aged 65 to 74 years and those aged 75 years and older. CONCLUSION: Alcohol use may be hazardous or harmful for older persons, particularly in conjunction with physical or emotional illnesses, medication use, functional limitations, smoking, and driving after drinking. When asking about alcohol use in older persons, clinicians need to be aware of these factors to assist in identifying and managing potential or actual alcohol-related problems.