Late intensification therapy for acute leukemia in remission. Chemotherapy and immunotherapy

Nineteen patients in continous complete remission of acute leukemia for at least one year received late intensification therapy, after which they received no further chemotherapy, but most received BCG immunotherapy. Five patients have relapsed. The 14 patients still in remission have been followed up for at least 60 weeks after late intensification, with a median time of 98 weeks. The length of complete remission subsequent to a comparable time was 44 weeks for a reference control group and 24 weeks for a matched control group. These results support this type of approach for long-term control of acute leukemia in adults.     

Nervous signs in bovine coccidiosis

In 2 outbreaks of coccidiosis due to E bovis and/or E zurnii infection in Canadian cattle, nervous signs included opisthotonos, medial strabismus, hypersensitivity, tetanic spasms, and convulsions. All of the affected animals died in convulsions after an illness of one to several days during which time they showed periodic nervous signs. Necropsy revealed a very severe enteritis with the most severe lesions in the spiral colon. Much of the intestinal mucosa in this area had been destroyed by the parasite. None of several suggested causes of such nervous signs was indicated by laboratory findings, but the possibility of toxins produced by the coccidia could not be ruled out.     

Reversible thrombocytosis and anemia due to miconazole therapy

Miconazole was administered intravenously in six consecutive patients with, active coccidioidal infection. Such treatment was associated with progressive anemia and thrombocytosis. The hematological abnormalities appeared to be dose related and potentially reversible. Bone marrow studies demonstrated erythroid hypoplasia and increased or active platelet production in three subjects. No hemorrhagic or thrombotic episodes were identified. It is suggested that careful hematological monitoring be performed in subjects undergoing systemic miconazole therapy.     

Gastritis duodenitis, and circulating levels of gastrin in duodenal ulcer before and after vagotomy

Biopsy specimens have been taken from five standard sites in the stomach and from the duodenal bulb in order to investigate the association of gastritis and duodenitis with duodenal ulcer. Twenty patients with chronic duodenal ulcer were investigated in this manner and in addition had gastric secretion tests and a radio-immune assay of serum gastrin under differing conditions. The patients were then treated either by a truncal vagotomy and pyloroplasty (TVP) or by a highly selective vagotomy without a drainage procedure (HSV). All the investigations were repeated three months postoperatively. Duodenal ulcer was usually associated with gastriitis, although this varied in extent and severity from patient to patient. In nearly all the patients, gastritis was present at the pyloric end of the stomach and along the lesser curve. In more than half of the patients, gastritis was also present in the body of the stomach but the fundus was usually spared. Chronic duodenitis was found in the duodenal bulb in all these patients. After vagotomy there was a marked increase in both the extent and severity of the proximal gastritis in both treatment groups but the distal gastritis remain almost unchanged. There was little change in the incidence of duodenitis after vagotomy but its severity was lessened. No correlation was found between the peak acid output (PAO) in response to Histalog and the severity of the gastritis or the duodenitis either before or after operation, with one exception. The postoperative PAO was significantly less in those patients who developed a severe proximal gastritis after vagotomy. No relationship was found between the severity of the distal gastritis and the levels of serum gastrin. No correlation was found between either the basal or peak acid output and the corresponding serum gastrin levels before or after vagotomy.     

Bile acid metabolism and plasma protein turnover in Crohn's disease

Postprandial duodenal bile acids, intestinal protein loss, and albumin and IgG turnover were studied in 19 non-operated patients with Crohn's disease. A lesion of the terminal ileum was present in 18 of 19 patients, either alone or associated with regional colitis. Identical bile acid studies were made in a control group of 20 patients with chronic diarrhoea of undetermined origin. Duodenal bile acid concentration was decreased in 9 of 19 patients with Crohn's disease, and in 5 of 20 patients with unexplained diarrhoea. The glycine/taurine-ratio was increased in 8 of 17 patients with Crohn's disease, but in only one of the 20 control patients. Abnormal intestinal protein loss was present in 13 of 14 patients with Crohn's disease. The fractional catabolic rate of albumin and IgG was increased in all 17 cases of Crohn's disease studied, except the patient with no protein loss. A statistically significant and positive correlation was observed between glycine/taurine-ratio and fractional catabolic rate of both albumin and IgG. No patient with Crohn's disease harboured an abnormal bacterial flora in the proximal small intestine. It is concluded that, in the absence of abnormal bacterial flora in the proximal jejunum, the glycine/taurine-ratio is more valuable as an indicator of terminal ileopathy than postprandial duodenal bile acid concentration in nonoperated patients with terminal ileitis. Abnormal intestinal protein loss and increased catabolic rate of albumin and IgG are practically always present in active Crohn's disease and are strong evidence of an organic gastrointestinal lesion in patients with normal radiographic findings.     

Conformational changes in the 20S proteasome upon macromolecular ligand binding analyzed with monoclonal antibodies

Proteasomes interact with a variety of macromolecular ligands that modulate their ability to degrade peptide and protein substrates. The effector PA28 increases the peptidase activities of proteasomes whereas HSP90 and alpha-crystallin inhibit a peptide-hydrolyzing activity. Four monoclonal antibodies were used as probes to detect conformational changes of proteasome subunits. Conformational changes in alpha- or beta-subunits were found upon binding PA28, HSP90, alpha-crystallin, and the substrate casein but not with the peptide substrate analogs calpain inhibitor 1 (Ac-Leu-Leu-norleucinal), calpain inhibitor 2 (Ac-Leu-Leu-methioninal), or MG 132 (N-Cbz-Leu-Leu-leucinal).     

The requirement for molecular chaperones during endoplasmic reticulum-associated protein degradation demonstrates that protein export and import are mechanistically distinct

Polypeptide import into the yeast endoplasmic reticulum (ER) requires two hsp70s, Ssa1p in the cytosol and BiP (Kar2p) in the ER lumen. After import, aberrant polypeptides may be exported to the cytoplasm for degradation by the proteasome, and defects in the ER chaperone calnexin (Cne1p) compromise their degradation. Both import and export require BiP and the Sec61p translocation complex, suggesting that import and export may be mechanistically related. We now show that the cne1Delta and two kar2 mutant alleles exhibit a synthetic interaction and that the export and degradation of pro-alpha factor is defective in kar2 mutant microsomes. Pulse-chase analysis indicates that A1PiZ, another substrate for degradation, is stabilized in the kar2 strains at the restrictive temperature. Because two of the kar2 mutants examined are proficient for polypeptide import, the roles of BiP during ER protein export and import differ, indicating that these processes must be mechanistically distinct. To examine whether Ssa1p drives polypeptides from the ER and is also required for degradation, we assembled reactions using strains either containing a mutation in SSA1 or in which the level of Ssa1p could be regulated. We found that pro-alpha factor and A1PiZ were degraded normally, indicating further that import and export are distinct and that other cytosolic factors may pull polypeptides from the ER.     

Immunohistochemical detection of infected neurons as a rapid diagnosis of enterovirus 71 encephalomyelitis

Dementia due to cerebral ischemic lesions is relatively common in the elderly. Since many of these lesions are probably caused by emboli, studying emboli-induced cerebral lesions in rabbits should, hopefully, provide information that is useful when searching for a means of preventing and treating vascular dementia in humans. Using magnetic resonance imaging we have found that N-tert-butyl-alpha-phenyl-nitrone (a free radical scavenger) reduced the number of emboli-induced cerebral microinfarctions in the rabbit cortex but did not have any impact on the number of infarctions found in the subcortical structures. The results suggest that significant amount of free radicals are produced in the ischemic foci located in the cortex, but not in the ischemic foci located in the subcortical structures. This finding may be of importance when considering treatments for cerebral ischemia in humans.     

High degree of occult tumor contamination in bone marrow and peripheral blood stem cells of patients undergoing autologous transplantation for non-Hodgkin''s lymphoma

Treatment of cultured bovine adrenal chromaffin cells with dbcAMP increased [3H]STX binding with an EC50 of 126 microM and a half-effective time of 12 h; dbcAMP (1 mM x 18 h) raised the Bmax approximately 1.5-fold without altering the Kd value. Forskolin (0.1 mM) or IBMX (0.3 mM) also increased [3H]STX binding, while dbcGMP had no effect. Effects of dbcAMP and forskolin were abolished by H-89, an inhibitor of cAMP-dependent protein kinase. Cycloheximide (10 microgram/ml) and actinomycin D (10 microgram/ml), inhibitors of protein synthesis, nullified the stimulatory effect of dbcAMP, whereas tunicamycin, an inhibitor of protein glycosylation, had no effect. Treatment with dbcAMP augmented veratridine-induced 22Na influx, 45Ca influx via voltage-dependent Ca channels and catecholamine secretion, while the same treatment did not alter 45Ca influx and catecholamine secretion caused by high K (a direct activation of voltage-dependent Ca channels) [25]. Na influx via single Na channel calculated from 22Na influx and [3H]STX binding was quantitatively similar between non-treated and dbcAMP-treated cells. Brevetoxin allosterically enhanced veratridine-induced 22Na influx approximately 3-fold in dbcAMP-treated cells as in non-treated cells. These results suggest that cAMP-dependent protein kinase is involved in the modulation of Na channel expression in adrenal medulla.