Fate of TR-2, the hepatic metabolite of the tremorgenic mycotoxin verruculogen, in sheep

1. Verruculogen is eliminated in bile after transformation to TR-2, only a trace of which was excreted as such in faeces of sheep given verruculogen per os. Negligible TR-2 was present free in urine; no glucuronide was found. 2. An isomer of TR-2, a minor component of the bile of sheep given verruculogen, has been defined by 1H-n.m.r. spectroscopy and the isomerism involves the disposition of the two adjacent hydroxyl groups with a concomitant change in the conformation of the ring adjacent to the indole. 3. 14C-TR-2, added to the perfusate of isolated rat liver, was excreted unchanged in the bile, implying no significant loss of any biliary TR-2 subject to enterohepatic recycling in vivo. 4. 14C-TR-2 incubated anaerobically in sheep ileum contents was 95% transformed into more polar metabolites, the majority of the radiolabelled metabolites isolated being water soluble. 5. The principal fate of biliary TR-2 is as a metabolic substrate for the intestinal microflora.     

The essential fatty acid deficient chicken as a model for cystic fibrosis

The essential fatty acid deficient (EFAD) chicken was evaluated as a model for cystic fibrosis (CF). Three semipurified diets--(I) 1% hydrogenated coconut oil (HCO), (II) 10% soybean oil + 1% HCO, and (III) 11% HCO--were fed to chickens from hatching to 5, 8, or 11 wk. Groups I and III exhibited poor weight gain and abnormal serum fatty acid patterns characteristic of EFAD. Production of prostaglandin F2 alpha, thromboxane B2, 6-keto-prostaglandin F1 alpha, and prostaglandin E in lung was significantly reduced at 5, 8, and 11 wk in both EFAD groups. Histopathologic examination revealed increased peribronchiolitis in group I compared with II. Incidence of pulmonary lesions in group III was intermediate. These data support the theory that essential fatty acids are necessary to maintain proper lung function. In this respect, the chicken is a good model for studying the relationship between EFAD and pulmonary disease in CF patients.     

Subfractionation of human peripheral blood lymphocytes by partitioning in two-polymer aqueous phase systems. Characteristics of a small subpopulation of cells with high partition coefficient

Mixtures of aqueous solutions of dextran and poly(ethylene glycol) form immiscible 2-phase systems that are suitable for the separation of viable, functionally-competent cells on the basis of their surface properties. With the appropriate choice of ionic composition, these systems will separate cells on the basis of charge-related surface characteristics. We have previously shown that in charge-sensitive phase systems, human B lymphocytes have a low partition coefficient (K) and T cells have an intermediate K. The cell subpopulation with the highest K values contains large null lymphocytes that have most of the antibody-dependent and natural killer activities. The present study further characterizes this latter cell subpopulation. 8-33% of peripheral blood lymphocytes in normal persons had high K values. About 50% of these cells had typical Giemsa-staining granules characteristic of killer cells and one third had Fc receptors, but lacked complement receptors. Although 15-30% of the cells with high K values formed rosettes with sheep erythrocytes, there was virtually no response to T-cell mitogens such as PHA and Con A. Mixing cells having high K values with mitogen-responsive T cells from intermediate cell fractions revealed no evidence of suppressor-cell activity to explain the poor mitogen response. The studies indicate that a heterogeneous population of cells share charge-related surface properties resulting in a high partition coefficient. These cells comprise a significant proportion of human peripheral blood lymphocytes and include virtually all of the large granular lymphocytes as well as a large population without this morphology that shares the feature of unresponsiveness to T-cell mitogens.     

Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations

We analyzed 11 consecutive unrelated cases of polyneuropathy due to transthyretin amyloidosis. Direct sequencing of the promoter region, exons, and splice junctions revealed that each patient was heterozygous for a mutation: six patients had valine 30 substituted by methionine (V30----M; Portuguese-Japanese type), one had threonine 60 substituted by alanine (T60----A; Appalachian type), and two had serine 77 substituted by tyrosine (S77----Y; Illinois type). In addition, two patients had previously undescribed mutation: phenylalanine 33 substituted by leucine (F33----L) and phenylalanine 64 substituted by leucine (F64----L). From present information, the probands of these novel mutations do not exhibit any pathology that clearly distinguishes them from individuals with the other mutations. The mutations extend the range of mutations associated with amyloidotic polyneuropathy. In our 11 patients, the different mutations did not seem to correlate with distinct clinical phenotypes. We developed PASA assays (PCR amplification of specific alleles) for each of the five mutations. PASA can be used by any diagnostic laboratory that can perform PCR to rapidly detect any of the known mutations. The minority of samples with an undescribed mutation can be sent to a specialty laboratory for delineation of the mutation by direct genomic sequencing. The presently described combination of methods may have widespread utility in the diagnosis of genetic disease.     

Cyclosporin in the management of polymyositis and dermatomyositis.

Three patients with polymyositis refractory to conventional steroid and immunosuppressive treatment, but responsive to cyclosporin A, are described. In a fourth patient cyclosporin A was used as a first line drug in combination with steroids in the treatment of life-threatening dermatomyositis. Cyclosporin A in the management of polymyositis/dermatomyositis requires formal assessment of its costs and benefits compared with conventional treatments.     

Physical exercise and voluntary hyperventilation in childhood absence epilepsy.

The aim of this study was to compare the effects of a physical exercise test and of voluntary hyperventilation between controls and children with absence epilepsy. Eighteen children (6 controls and 12 epileptics) were studied during rest (R), a maximal physical exercise test (15 min; PE), recovery (REC) and voluntary hyperventilation (3 min; VHPV). EEG and ECG were recorded during the experiment; respiratory parameters were measured to quantify PE; plasma levels of pH, lactate, pyruvate, glucose and antiepileptic drugs were determined. A decrease in the number of absences was observed during PE whereas an increase was observed during VHPV. We found significant positive correlations between the number of children with absences, the total number of absences for each state, frequency of absences per minute and the corresponding mean plasma pH, which demonstrate that the lower the pH is, the fewer absences occur. On the other hand, there was no relationship between the number of absences and the values of other parameters. Relations between variations of the plasma value of the pH, and thus the probable cerebral value of pH, and neuronal excitability are discussed. Our results indicate that children who suffer absence epilepsy should not be discouraged from sport practice.