Pretreatment of low dose radiation reduces radiation-induced apoptosis in mouse lymphoma (EL4) cells

Induction of an adaptive response to ionizing radiation in mouse lymphoma (EL4) cells was studied by using cell survival fraction and apoptotic nucleosomal DNA fragmentation as biological end points. Cells in early log phase were pre-exposed to low dose of γ-rays (0.01 Gy) 4 or 20 hrs prior to high dose γ-ray (4, 8 and 12 Gy for cell survival fraction analysis; 8 Gy for DNA fragmentation analysis) irradiation. Then cell survival fractions and the extent of DNA fragmentation were measured. Significant adaptive response, increase in cell survival fraction and decrease in the extent of DNA fragmentation were induced when low and high dose γ-ray irradiation time interval was 4 hr. Addition of protein or RNA synthesis inhibitor, cycloheximide or 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRFB), respectively during adaptation period, the period from low dose γ-ray irradiation to high dose γ-ray irradiation, was able to inhibit the induction of adaptive response, which is the reduction of the extent DNA fragmentation in irradiated EL4 cells. These data suggest that the induction of adaptive response to ionizing radiation in EL4 cells required both protein and RNA synthesis.     

Hypothermia does not result in more complications after colon surgery

Our objective was to determine the incidence of complications in postoperative patients who were either normothermic or hypothermic. A recent, widely publicized paper concluded that the maintenance of normothermia could reduce the incidence of infectious complications and shorten hospitalization in patients undergoing colorectal surgery. However, some controversy arose regarding the methods of this paper. Patients were deliberately rendered hypothermic, were given more than 3.5 days of prophylactic antibiotics and were transfused significantly more units of blood. We reviewed the charts of 150 consecutive patients who underwent elective partial or subtotal colectomy with primary anastomosis. Among the key items analyzed were intraoperative and postoperative temperature, use of warming devices, duration of surgery, transfusions, interval to oral intake and bowel function, length of stay, complications, infections, and laboratory values. Hypothermia was defined as intraoperative temperature <95.5 degrees F. There were 101 normothermic patients and 49 hypothermic patients. Hypothermic patients had a mean age of 68.7 years versus 66.8 for the normothermic patients (P = 0.472). Comorbidities were similar in both groups. Warming devices were used in >90 per cent of the patients in both groups. The rates of postoperative infections and complications were similar in both groups. Postoperative lengths of stay were also not different. Despite finding that one-third of our patients were hypothermic during elective colon resection, hypothermia had no effect on outcome variables. In contrast to the previous study, the incidence of infectious complications was identical in our patients. Before ascribing postoperative complications and increased resource utilization as adverse effects of hypothermia, further studies are indicated.     

Pseudolesion in segments II and III of the liver on CT during arterial portography caused by aberrant right gastric venous drainage

We report three cases of pseudolesions caused by aberrant right gastric venous drainage (AGVD) in segment II/III of the liver as demonstrated on CT during arterial portography (CTAP). On CTAP, the lesions were seen as wedge-shaped perfusion defects, and on hepatic arteriography, AGVD directed to the area with the perfusion defect was visible in all three cases. When a perfusion defect is detected at the edge of segments II/III at CTAP, a pseudolesion caused by AGVD should be suspected.     

Differentiation and expansion of beta cell mass in porcine neonatal pancreatic cell clusters transplanted into nude mice

Neonatal porcine pancreas has considerable capacity for growth and differentiation, making it an attractive potential source of islet tissue for xenotransplantation. Pancreases from 1-3-day-old newborn pigs were digested with collagenase and cultured for 8 days. The resulting cellular aggregates are called porcine neonatal pancreatic cell clusters (NPCCs). The mean yield of NPCCs from a newborn pig was 28,200 +/- 1700 islet equivalents. Cytokeratin 7 (CK7) was used as a marker for the immunostaining of pancreatic duct cells. In neonatal pancreas, 18% of the insulin-positive cells co-stained for CK7, thus being protodifferentiated. NPCCs also contained protodifferentiated cells; insulin/PP and insulin/somatostatin co-stained cells were more common than insulin/glucagon cells. Between 1 and 8 days of culture, the DNA content of the NPCCs fell to 16% and the insulin content to 33% of the starting value, mainly due to the preferential loss of exocrine cells. Transplantation of 2000 or 4000 NPCCs into diabetic nude mice typically normalized glucose values in 10-20 weeks. Mice with successful grafts had lower fasting blood glucose levels than normal mice and accelerated glucose clearance after an i.p. glucose load. The starting NPCCs consisted of 17% insulin-staining cells, but the grafts of mice with reversed diabetes consisted of 94% beta cells, with some co-stained for CK7, indicating that the grafts still contained immature cells. The mass of insulin-producing cells rose from 0.22 +/- 0.08 mg 1 week after transplantation to 4.34 +/- 0.27 mg in mice sacrificed at 27-35 weeks. In summary, NPCCs contain mostly islet precursor cells, which when transplanted into nude mice undergo striking differentiation and beta cell expansion.     

Mouse-to-rat testicle transplantation

This report details mouse-to-rat testicular transplantation with immediate revascularization. Donor preparation involved grafting a long segment of aorta and inferior vena cava (IVC) containing the testicular artery and vein. The graft aorta and IVC were anastomosed to the rat aorta and IVC, respectively. Vasovasostomy was completed and the scrotal epithelia were anastomosed to draw the graft toward the host scrotal sac. Twenty-nine of 53 transplants were determined to be viable. Histologically, 6- to 18-hr-old grafts displayed moderate to minimal polymorphonuclear neutrophil (PMN) infiltrates. Ischemia set in somewhere between 18-24 hr postoperatively. Beyond 24 hr the grafts displayed progressive infiltration of PMN and perivascular and intertubular lymphocytes, disorganization of the germinal epithelium, and cessation of spermatogenesis.     

Increased bioavailability of clomipramine after sublingual administration in rats

This study examined the absorption and disposition of clomipramine in rats after sublingual (5 and 50 mg/kg), oral (50 mg/kg), and iv (5 mg/kg) administration. The mean oral bioavailability of clomipramine was 24.8% and 29.7%, respectively, in conscious rats and in rats anesthetized with ketamine/xylazine (30/3 mg/kg). When given sublingually in isotonic saline at a dose of 50 mg/kg, clomipramine was rapidly absorbed, and the mean absolute bioavailability (36.2%) was increased over oral dosing. The mean AUC values of clomipramine were 2258 +/- 1762 ng.h/mL and 1891 +/- 867 ng.h/mL after oral administration to conscious and anesthetized rats, respectively, and 3303 +/- 1576 ng.h/mL after sublingual administration to anesthetized rats. Sublingual administration (5 mg/kg doses) of clomipramine formulated with a permeation enhancer, 2-hydroxypropyl beta-cyclodextrin, further increased the sublingual bioavailability to 57.1%. The sublingual route may be an alternative route of administration of clomipramine, providing enhanced bioavailability.     

Cytotoxic constituents from the roots ofAnthriscus sylvestris

Activity-guided fractionation of the roots of Anthriscus sylvestris resulted in the isolation and characterization of five cytotoxic compounds, deoxypodophyllotoxin (1), falcarindiol (2), and angeloyl podophyllotoxin (5) from the hexane soluble fraction and morelensin (3), bursehernin (4) from the chloroform soluble fraction. It is the first report of the occurrence of compound 5 in nature.     

Effect of DW2282 on the induction of methemoglobinemia, hypoglycemia or WBC count and hematological changes

DW2282,(S)-(+)-4-phenyl-1-[1-(4-aminobenzoyl)-indoline-5-sulfonyl] -4,5-dihydro-2-imidazolone hydrochloride, is a new anticancer agent which is thought to exhibit a characteristic mechanism of action in the inhibition of tumor growth. In this study, we estimated the toxicities of DW2282 in mice. When mice were orally dosed for five consecutive days at the dosages of 50, 100 and 150 mg/kg, DW2282 did not induce methemoglobinemia and hypoglycemia at any of these doses. However, increased ALT and AST values were observed in the 150 mg/kg dosing group, and white blood cells (WBC) were significantly decreased at all doses. However, the changes in WBC count, ALT and AST immediately reversed after the cessation of drug administration. In addition, we found that DW2282 did not cause an increase in hemolysis in human blood. Taken together, these data suggested that DW2282 may have a relatively low level of toxicity, and that there may be a quick recovery from any toxicity it does produce.     

Multidisciplinary management of metastatic colorectal cancer

When colorectal cancer metastasizes to distant organs, usually multiple sites are involved and treatment consists primarily of systemic chemotherapy and supportive care. Chemotherapeutic agents effective against metastatic colorectal cancer include 5-fluorouracil, often used in combination with leucovorin or methotrexate, and irinotecan (CPT-11). Median survival with optimal chemotherapy regimens ranges from 10 to 15 months. Less frequently, colorectal cancer metastasizes only to the liver or lung. In a minority of these cases, surgical resection can be performed and results in a median survival of 28-46 months for hepatic resections and 24-25 months for pulmonary resections. Five-year survival rates range from 24 to 38% and 21 to 44% for hepatic and pulmonary resections, respectively. For isolated liver metastases that are not surgically resectable, other regional therapies that can be considered are hepatic cryosurgery, radiofrequency ablation, and hepatic arterial infusion chemotherapy. Median survival following cryosurgery is between 26 and 30 months, while median survival following radiofrequency ablation has not been established in large series. Hepatic arterial infusion chemotherapy, especially with newer combination drug regimens, may increase survival in patients with isolated liver metastases compared to systemic chemotherapy, but this must be confirmed in randomized, prospective trials. Colorectal cancer metastases to the brain can be treated with radiation therapy or surgical resection, but median survival with treatment is less than one year.     

Biological response modifiers in the management of rheumatoid arthritis.

The management of rheumatoid arthritis (RA) with biological response modifiers (BRMs) is reviewed. RA, an autoimmune disorder affecting 1-2% of the world's population, is characterized by inflammation of synovial tissues, joint swelling, stiffness, and pain that may progress to joint erosion. There is strong evidence that inflammatory mediators, such as tissue necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1), play a critical role in the pathogenesis of this disorder. IL-1-receptor antagonist (IL-1Ra) is produced in healthy subjects and helps to protect against the adverse effects associated with IL-1 overexpression. Administration of IL-1Ra or similar agents may reduce the effects of IL-1 and ameliorate inflammatory conditions. Traditional treatment of RA has been based on symptomatic management with non-steroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, and corticosteroids, each of which has substantial drawbacks in terms of effectiveness or adverse effects. Newer therapeutic strategies for blocking the biological effects of inflammatory cytokines include antibodies directed against TNF (e.g., infliximab), soluble receptors (e.g., etanercept) and receptor antagonists to IL-1 (anakinra) [corrected]. Clinical trials indicate that these BRMs may be more effective than traditional agents because they are able to alter joint remodeling in addition to attenuating symptoms. Anti-TNF therapies may be associated with increased risk for infections, sepsis, tuberculosis reactivation, demyelination disorders, and blood dyscrasias; anakinra appears to be safer. Combination therapy with BRMs may be more appropriate for RA than monotherapy. The role of BRMs in the treatment of RA will evolve as investigators learn more about the drugs and the disorder.