Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates

OBJECTIVES: We investigated the role of P-selectin in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates. BACKGROUND: Plaque rupture followed by thrombus formation is a fundamental pathophysiology of acute coronary syndromes. Although the adhesive interaction between platelets and leukocytes via P-selectin is known to mediate platelet-rich thrombi, the true function of P-selectin in thrombus formation in vivo is unknown. METHODS: In wild-type (P(+/+)) and P-selectin-deficient (P(-/-)) mice with ferric chloride (FeCl(3))-induced carotid arterial thrombosis model, we measured in vivo platelet P-selectin expression and adenosine diphosphate (ADP)-induced ex vivo platelet aggregation. We also measured ex vivo ADP-induced whole blood aggregations and their size distribution by flow cytometry. RESULTS: Time to thrombotic occlusion was longer in P(-/-) mice than in P(+/+) mice. Spontaneous reflow after total thrombotic occlusion was observed in 8 of 10 P(-/-) mice but not in any P(+/+) mice. ADP-induced ex vivo platelet aggregation was not different between the two groups. However, ADP-induced ex vivo whole blood aggregation was inhibited in P(-/-) mice compared to P(+/+) mice. FeCl(3) application increased in vivo expressions of platelet P-selectin in P(+/+) mice but not in P(-/-) mice. The number of leukocytes within thrombi was less in P(-/-) mice than in P(+/+) mice. In flow cytometric analysis of size distribution of ADP-induced whole blood aggregates, the number of large aggregates was less in P(-/-) mice than in P(+/+) mice. Using platelet and leukocyte fluorescence makers, the large aggregates were confirmed as platelet-leukocyte aggregates. CONCLUSIONS: Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates.     

Endoscopic submucosal dissection for cancers of the remnant stomach after distal gastrectomy

BACKGROUND: Endoscopic submucosal dissection (ESD) of early gastric cancer is less invasive than surgical resection, and if technically feasible, it may result in less long-term morbidity than does incisional surgery. However, ESD is technically difficult in patients who have had a previous distal gastrectomy. OBJECTIVE: Our purpose was to retrospectively assess the results of ESD of early gastric cancer in the remnant stomach. DESIGN: Case series. SETTING AND PATIENTS: A total of 31 lesions in 30 patients with early remnant gastric cancer were treated with ESD at Okayama University Hospital, Tsuyama Central Hospital, Hiroshima City Hospital, Kagawa Prefectural Central Hospital, and Mitoyo General Hospital from March 2001 to January 2007. INTERVENTION: ESD. MAIN OUTCOME MEASUREMENTS: En bloc resection rate, complete resection rate, operation time, and complications. RESULTS: En bloc resection and complete resection were achieved in 30 (97%) and in 23 (74%) lesions, respectively. The median operation time required for ESD in the remnant stomach was 113 minutes (range 45-450 minutes). Perforation occurred in 4 (13%). The incidence of delayed bleeding requiring blood transfusion was 0%. LIMITATION: Short duration of follow-up. CONCLUSIONS: ESD is feasible in the remnant stomach but has a relatively high complication rate and should only be performed by experienced endoscopists.     

A case of non-tuberculous mycobacteriosis with pleurisy with a past history of dense exposure to environmental asbestos

We report a case of non-tuberculous mycobacteriosis (NTM) with pleurisy in a 75-year-old man. The patient was admitted with a diagnosis of pneumonia. Chest radiography and CT scans revealed a tumorous shadow that increased rapidly in size despite treatment with antibiotics. Bronchoalveolar lavage fluid (BALF) disclosed numerous asbestos bodies, suggesting dense exposure and pulmonary silicosis. The tumorous chest shadow remained undiagnosed. Repeated microscopic examination of sputum and BALF revealed no acidophilic-bacilli. Diagnostic pneumonectomy was performed to further explore the nature of the tumorous shadow on chest radiography. Ziehl-Neelsen staining of excised lung tissue disclosed no acid-bacilli; however, the washed fluid of the tissue specimen showed acid-fast bacilli that were subsequently verified as M. avium by in vitro culture. The X-ray findings in our case were not consistent with NTM or specific for disease due to asbestos inhalation. A final diagnosis of NTM was confirmed via open biopsy of the lung. Our case suggests that in addition to tuberculosis, NTM should be taken into consideration as a complication of silicosis.     

Nonclinical Safety Profile of Tolvaptan

Purpose

In the present study, the nonclinical safety profile of tolvaptan was evaluated.

Methods

A series of safety pharmacology and toxicology studies were performed in vitro and in mice, rats, dogs, rabbits and guinea pigs.

Results

In safety pharmacological studies, tolvaptan had no adverse effects on the central nervous, somatic nervous, autonomic nervous, smooth muscle, respiratory and cardiovascular, or digestive systems. In general toxicity studies, a single dose of tolvaptan up to 2,000 mg/kg was not lethal in rats and dogs. Tolvaptan did not cause any target organ toxicity in rats after treatment for 26 weeks or in dogs after treatment for 52 weeks at oral doses of up to 1,000 mg/kg/day. The toxicities observed in the present studies were generally attributable to the exaggerated pharmacological action of tolvaptan. In reproductive and developmental toxicity studies in rats, fertility was not affected. Suppressed viability or growth observed in the prenatal and postnatal progeny occurred at the maternally toxic dose of 1,000 mg/kg/day. In rabbits, tolvaptan showed teratogenicity at 1,000 mg/kg/day, a dose that was maternally toxic causing abortion. Tolvaptan was not genotoxic or carcinogenic, and did not induce phototoxicity, antigenicity or immunotoxicity.

Conclusion

Nonclinical toxicity that precludes the safe administration of tolvaptan to humans was not observed. However, appropriate cautions should be taken in women of childbearing potential.

     

Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study

Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 ± 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 ± 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies.     

Na/H exchange isoform 1 is involved in mineralocorticoid/salt-induced cardiac injury

Long-term exposure of uninephrectomized rats to desoxycorticosterone acetate (DOCA)/salt induces cardiac fibrosis and hypertrophy through mineralocorticoid receptors (MRs). However, the underlying cellular mechanisms remain unclear. To determine whether Na/H exchange isoform 1 (NHE1) is involved in the cellular mechanisms, we examined the effects of a specific NHE1 inhibitor, cariporide, and an MR antagonist, spironolactone, on DOCA/salt-induced cardiac fibrosis and hypertrophy. Uninephrectomized rats were given 20 mg of DOCA (single subcutaneous injection) plus 0.9% NaCl/0.3% KCl to drink and were killed at 8 days. Two groups of rats given DOCA/salt were treated with either spironolactone (50 mg/kg per day SC) or cariporide (30 mg/kg per day PO) for 8 days. Control rats were treated with only high salt after the operation. The DOCA/salt-induced perivascular collagen deposition was completely abolished by cariporide and spironolactone. DOCA/salt-induced interstitial collagen deposition was partially and completely suppressed by spironolactone and cariporide, respectively. The rats exposed to DOCA/salt had cardiocyte hypertrophy in the subendocardial and subepicardial regions, a finding that was completely inhibited by cariporide but not by spironolactone. In rats given DOCA/salt, NHE1 protein expression was markedly increased. This was partially and completely reversed by spironolactone and cariporide, respectively. We concluded that cardiac NHE1 contributes to DOCA/salt-induced cardiac fibrosis and hypertrophy and that the NHE1 inhibitor cariporide completely prevents the detrimental effects of DOCA/salt on the heart. We also demonstrated that DOCA/salt-induced cardiac injury through the MRs partly occurs through NHE1 activation.     

Primary cutaneous diffuse large B‐cell lymphoma,leg type,with features simulating POEMS syndrome

A 91‐year‐old woman presented with a rapidly proliferative cutaneous lesion on the left lower limb, which was identified as a primary cutaneous diffuse large B‐cell lymphoma (PCLBCL), leg type, on biopsy. The patient also showed complications of hepatomegaly, endocrinopathy, edema, skin change, and polyneuropathy without monoclonal plasma cell proliferative disorder, and was therefore diagnosed with POEMS‐like syndrome owing to the lack of monoclonal plasma cell proliferative disorder. Levels of serum vascular endothelial growth factor (VEGF) and interleukin‐6 (IL‐6) were high with the lymphoma cells immunostained positively for VEGF and IL‐6. To the best of our knowledge, this is the first case report of PCLBCL, leg type, with POEMS‐like syndrome. The findings in this case suggest that the symptoms of POEMS‐like syndrome might be caused by the cytokines produced by the lymphoma cells. Furthermore, a wider range of diagnostic criteria associated with the result of abnormal secretion of cytokine may have to be considered for the diagnosis and evaluation of patients with possible POEMS syndrome, as against the present criteria specifying monoclonal plasma cell proliferative disorder as the essential criterion.     

The combination of dulaglutide and biguanide reduced bodyweight in Japanese patients with type 2 diabetes

The efficacy and safety of once‐weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D) were evaluated according to subgroups defined by concomitant oral hypoglycaemic agents. This exploratory analysis included data from a randomized, open‐label, phase III study that compared dulaglutide with insulin glargine (glargine) (n = 361). The three subgroups were dulaglutide or glargine in combination with sulphonylurea (SU) alone, biguanide (BG) alone or SU and BG combined. There were no clinically relevant differences in glycated haemoglobin (HbA1c) changes among the three subgroups in the dulaglutide group; in the glargine group, a numerically greater reduction was observed in combination with BG alone compared to the other two groups (SU alone and SU + BG). Weight loss was observed with dulaglutide in combination with BG alone or with SU + BG. The incidence of adverse events among subgroups was significantly different in the glargine group but not in the dulaglutide group. Incidence of hypoglycaemia was highest in combination with SU for both treatments. For patients with T2D, dulaglutide added to concomitant BG may be more likely to result in weight loss than dulaglutide added to concomitant SU.     

Novel and safer endoscopic cholecystectomy using only a flexible endoscope via single port

AIM: To apply the laparoscopic and endoscopic cooperative surgery concept, we investigated whether endoscopic cholecystectomy could be performed more safely and rapidly via only 1 port or not.METHODS: Two dogs(11 and 13-mo-old female Beagle) were used in this study. Only 1 blunt port was created, and a flexible endoscope with a tip attachment was inserted between the fundus of gallbladder and liver. After local injection of saline to the gallbladder bed, resection of the gallbladder bed from the liver was performed. After complete resection of the gallbladder bed, the gallbladder was pulled up to resect its neck using the Ring-shaped thread technique. The neck of the gallbladder was cut using scissor forceps. Resected gallbladder was retrieved using endoscopic net forceps via a port. RESULTS: The operation times from general anesthetizing with sevoflurane to finishing the closure of the blunt port site were about 50 min and 60 min respectively. The resection times of gallbladder bed were about 15 min and 13 min respectively without liver injury and bleeding at all. Feed were given just after next day of operation, and they had a good appetite. Two dogs are in good health now and no complications for 1 mo after endoscopic cholecystectomy using only a flexible endoscope via one port.CONCLUSION: We are sure of great feasibility of endoscopic cholecystectomy via single port for human.