Human alloreactive CTL interactions with gliomas and with those having upregulated HLA expression from exogenous IFN-gamma or IFN-gamma gene modification.

By flow cytometry, a panel of 18 primary glioma cell explants exhibited high expression of class I HLA-A, B, C, but class II HLA-DR expression was absent. Freshly isolated normal brain cells displayed little or no HLA antigens. Alloreactive cytotoxic T lymphocytes (aCTL), sensitized to the HLA of the patient, were generated in a one-way mixed lymphocyte response (MLR). The specificity of aCTL was confirmed to be to target cells (patient glioma cells or lymphoblasts) expressing the relevant HLA antigens. However, nontumor patient-specific aCTL did not lyse normal brain cells. Titration of antibodies to HLA class I into cytotoxicity assays blocked lysis of gliomas by aCTL, confirming aCTL T cell receptor (TCR) interactions with the class I antigen on gliomas. Furthermore, aCTL interactions with glioma cells caused their apoptosis. Coincubations of aCTL with gliomas resulted in upregulated cytokine secretion. Importantly, dexamethasone, an immunosuppressive steroid used for brain edema, did not affect aCTL lytic function against tumor, indicating that steroid-dependent patients may benefit from the immunotherapy. We also explored the use of interferon-gamma (IFN-gamma) to increase aCTL tumor recognition. Coincubation of gliomas with exogenous IFN-gamma (500 U/ml, 48 h) caused a 3-fold upregulation of HLA class I and a slight induction of class II antigen expression. Gene-modified glioma cells producing IFN-gamma similarly displayed upregulated HLA expression. Glioma cells incubated with exogenous IFN-gamma or IFN-gamma-transduced glioma cells were more susceptible to lysis by aCTL than their parental counterparts, thus supporting the concept of combining IFN-gamma cytokine gene therapy with adoptive aCTL immunotherapy for brain tumor treatment.     

Investigation of the phenylalanine hydroxylase gene and tardive dyskinesia.

Phenylketonuria (PKU), an inborn error of phenylalanine metabolism, has been shown to be a risk factor for tardive dyskinesia (TD). In male psychiatric patients there was a significant relationship between TD and measures of plasma phenylalanine following ingestion of a standardized phenylalanine dose that was indicative of higher brain availability of phenylalanine in patients with TD. In addition, a medical food formulation consisting of branched chain amino acids, which compete with phenylalanine for transport across the blood-brain barrier, has been demonstrated to be an efficacious treatment for TD. Cumulatively these findings suggested that TD was related to phenylalanine metabolism and thus that sequence variants in the gene for phenylalanine hydroxylase (PAH), the rate-limiting enzyme in the catabolism of phenylalanine, could be associated with TD susceptibility. Genetic screening of PAH in a group of 123 psychiatric patients revealed ten sequence polymorphisms and two mutations, but none appeared to be a significant risk factor for TD.     

Recombination or heterogeneity: is there a second locus for adult polycystic kidney disease?

Twenty-four families with adult onset polycystic kidney disease were typed for markers flanking the PKD1 locus on chromosome 16. The aggregated results gave a significant lod score in favour of linkage to PKD1. Within this group of families two showed unusual features: recombinations, including double recombinations, and, in one family, an unexpectedly high proportion of affected people. We consider the evidence that in these families the disease might result from a mutation at a different locus, PKD2, not linked to PKD1. We suggest that a useful test is to compare the relative numbers of meioses apparently non-recombinant and doubly recombinant for markers flanking the normal disease locus, ignoring meioses recombinant for only a single marker. Using this test, neither our two families nor the data published so far on other families provide compelling evidence for the existence of a second locus for adult polycystic kidney disease. For genetic counselling in families too small to give internal evidence for or against linkage, the extra uncertainty can be handled by using a higher recombination rate.     

Acute rheumatic fever: Findings of a hospital-based study and an overview of reported outbreaks

To review the characteristics of reported outbreaks of acute rheumatic fever in the United States, and to determine if there is an increase in the incidence of acute rheumatic fever in the population served by the Hospital for Sick Children, Toronto, Ontario, the authors conducted a literature search and a retrospective review of inpatients and outpatients, satisfying the revised Jones criteria for the diagnosis of acute rheumatic fever, from 1972 to 1988. Patients satisfying the revised Jones criteria for the time period 1972-88 were included in the study. There have been eight articles reporting an increase in acute rheumatic fever in the United States. In three, the majority of children were white and from middle class suburban/rural communities in different geographic locations. Mucoid strains of group A streptococci were implicated but not confirmed as being associated with the outbreaks in three. The results of the chart review at the Hospital for Sick Children revealed that 83 cases satisfied the revised Jones criteria. The number of cases per 100,000 children (aged 18 years or less) per year, decreased progressively over the study period. Polyarthritis was the most frequently seen major criterion occurring in 73% of patients (61 of 83). The most frequently affected ethnic groups were Italians 23%, Afro-Canadians 19% and Orientals 8%. The reported outbreaks in the United States are multifocal and predominantly confined to white middle class children residing in suburban/rural communities. There was no evidence of an increase in the number of cases of acute rheumatic fever seen in the population served by the Hospital for Sick Children; there was a progressive decline in number of cases over the study period. The results facilitate the characterization of acute rheumatic fever within North America into three different patterns of occurrence.     

Outcomes of lower extremity amputations

In an effort to identify variables that could be used to predict outcomes of amputation, a cohort of 97 veteran amputees with a median age of 64 years who underwent 155 lower extremity procedures during 1984 was followed for 15 months. A high incidence of postoperative complication, revision, and mortality with poor quality of life confirm the serious prognosis of these individuals. Regression analyses indicated that peripheral vascular disease and prolonged preoperative hospitalization were associated with complications. Preoperative gangrene and peripheral vascular disease were associated with the need for revision. Complications, a low body mass index, and multiple diseases were related to death. Those with multiple diseases and extensive atherosclerosis were less likely to walk. Ability to perform activities of daily living was the most important predictor of quality of life. Patients at higher risk for these adverse outcomes need to be identified early in their hospital stay. The involvement of the patient or his or her surrogate in decisions regarding the course of treatment and the level of amputation is essential.     

Effect of ingestion of fat on ileostomy effluent.

Infusion of fat into the ileum slows small bowel transit and increases absorption of a carbohydrate meal. Paired studies were undertaken to investigate the effect of adding fat to the diet on gastrointestinal transit and absorption in eight people with terminal ileostomies. Each subject ate a daily diet that contained either low or high levels of fat but equivalent amounts of carbohydrate, protein, and fibre. Solid and liquid markers were added to the food to measure transit times. The ileostomy outputs after the meals were analysed for protein, fat, carbohydrate, polyethylene glycol, and the delivery of solid markers. All subjects produced more ileal effluent while taking the high fat diet compared with the low fat diet. Fat and protein outputs were significantly higher on the high fat days, but a greater proportion of the fat was absorbed during the high fat diet compared with the low fat diet. The output of carbohydrate on the two diets was not significantly different. The incorporation of fat in the diet produced no significant differences in the transit times of the first marker, but a slight prolongation of the transit time of the second marker. Increasing the fat content of the diet did not slow small bowel transit or increase nutrient absorption. The increase in protein and water output could be explained by an increased secretion of pancreatic enzymes.     

Enhanced potency of truncated insulin-like growth factor-I (des(1-3)IGF-I) relative to IGF-I in lit/lit mice

The relative potencies of insulin-like growth factor (IGF-I) and the N-terminal truncated derivative, des(1-3)IGF-I, have been compared in lit/lit mice. Injection of 30 micrograms IGF-I, 30 micrograms des(1-3)IGF-I or 3 micrograms des(1-3)IGF-I daily for 3 weeks increased total length and nose-rump length of the animals substantially more than in controls or animals treated with 3 micrograms IGF-I daily. Body weight changes were not statistically significant. The lower dose of des(1-3)IGF-I, but not that of IGF-I, led to increases in kidney and heart weights relative to controls, while the higher dose of either IGF-I or des(1-3)IGF-I also increased the weights of liver, lungs and stomach. These results indicate that the higher potency of des(1-3)IGF-I demonstrated in cultured cells also applies in vivo to at least one strain of GH-deficient animals.     

Neurological disorders and adult coeliac disease

An investigation into the incidence of neurological disorder in 30 patients with adult coeliac disease has shown that three patients had severe depression, two had epileptiform convulsions, and one patient only had signs of involvement of the peripheral nervous system. Motor nerve conduction velocity was low in only one patient. When the nerve conduction velocities of the group on a gluten-free diet were compared with the group who were not on a gluten-free diet, there was no statistically significant difference. Similarly, nerve conduction velocities in patients with a low serum pyridoxal level were not significantly different from those with normal serum pyridoxal levels.Measurements of the serum level of pyridoxal in 30 patients confirmed that pyridoxine deficiency occurs in adult coeliac disease and that the restriction of gluten from the diet appeared to affect pyridoxal levels favourably.     

Supralevator abscess: Diagnosis and Treatment

Anorectal suppurations are quite common. Supralevator abscesses, previously regarded as a rare subgroup, were seen in 9.1 per cent of 506 patients admitted to Cook County Hospital in a two-year period. Aggressive supportive management was followed by early, adequate drainage through single or multiple radial perianal incisions or through the rectum whenever indicated. When fistulas were identified, either a primary fistulotomy or a two-stage fistulotomy using a seton was performed in the majority of cases. Important factors in the prevention of morbidity and mortality included debridement of all necrotic tissue, careful bacteriologic studies and judicious use of antibiotics, close postoperative observation, and long-term follow-up of the patients. Read at the meeting of the American Society of Colon and Rectal Surgeons, Hollywood, Florida, May 11 to 16, 1980.