A genetic study in hypertrophic cardiomyopathies (Czech population).

In order to verify the type of heredity and to identify other genealogical characteristics in the Czech population, the authors examined 105 families with incidence of hypertrophic cardiomyopathy (HCM). The probands' siblings presented a 24-percent empiric risk of the disease; in male probands the risk for brothers was four times that for sisters, in female probands it was three times higher for sisters than brothers. Sex ratio of affected siblings was 20:4 in male and 3:14 in female probands. Disease risk for children was substantially higher in younger probands (under 30 yrs. of age: 40%, above 51 yrs.: 6.7%). Reproduction fitness was decreased in the whole group more so in women. Gene penetration was estimated using the "safe carriers" method, as 50 p.c. Anticipation and more severe course were recorded in all families with HCM incidence in more than two generations. The HCM heredity does not resemble that of the autosomal dominant type. The heterogeneity, phenocopy and sexual modulation could not be excluded. Genetic counselling and, possibly, DNA diagnostics would be necessary to elucidate the hereditary nature of hypertrophic cardiomyopathy.     

Regulation of idiotype expression. II. The phenotypic diversity of T15 idiotype-bearing antibody to phosphorylcholine in response to T-dependent and T-independent antigens.

The idiotypic (Id) diversity of the immune response to phosphorylcholine (PC) was studied by immunization of mice with thymus-dependent (PC-keyhole limpet haemocyanin; PC-KLH) and thymus-independent (S. pneumoniae R36a; Pn) forms of the antigen. Mice with the BALB/c genetic background (BALB/c, C.B20, and BALB.B) were used because their response to PC is dominated by immunoglobulins encoded in VH-1 and V kappa 22 genes, which uniformly express the T15 idiotype. The actual repertoire of the antibody was determined by idiotypic markers (Id) defined with monoclonal antibodies designated AB1-2, B36-82, MaId5-4, and B24-44. Previous studies from our laboratory have shown that these Id are present on T15 (VS107-1/V kappa 22) immunoglobulins only, but that they differentiate between somatic variants of the antibody molecules. We have measured the serum concentrations of these four Id after primary (1 degree), secondary (2 degree), and tertiary (3 degree) immunization; all of the Id activity was associated with the PC-binding antibody, as shown by specific immunoadsorbents. However, the levels of the Id-bearing (Id+) antibody did not correlate with each other. After immunization with PC-KLH, the AB1-2+ antibody declined precipitously, whereas the levels of B24-44 and B36-82 remained steady. A similar pattern of Id heterogeneity was seen at the level of direct antibody-plaque-forming cells from the spleen, suggesting that the idiotopic (clonal) diversification occurred already during the early IgM response. A significant portion of anti-PC antibody after the 3 degrees PC-KLH immunization was negative for all four Id, implying that the late response to the antigen involved distinct, T15-negative clones.     

Idiopathic congenital central hypoventilation syndrome: the next generation

In the present study, we sought to identify genetic variation in the metabotropic glutamate receptor 3 (GRM3) gene, which has been mapped to chromosome 7q21.1-q21.2 [Scherer et al., 1996] and might contribute to genetic predisposition to schizophrenia and/or bipolar affective disorder. Using single-strand conformation analysis (SSCA), we screened the complete coding sequence as well as adjacent splice sites of the GRM3 gene in a sample of 46 bipolar affective and 46 schizophrenic patients. We detected three sequence variants: a rare C/T substitution at nucleotide position +885 (T209T), a C/T substitution at nucleotide position +2130 (Y624Y), and a more common C/T substitution at nucleotide position +1131 (A291A). The occurrence of the +1131C/T variant was investigated in a sample of bipolar affective patients (n=283), schizophrenic patients (n=265), and ethnically matched controls (n=227). We observed a significant overrepresentation of the +1131T allele in schizophrenic patients when compared to controls (P=0.0022). This finding was followed up in an independent sample of schizophrenic patients (n=288) and controls (n=162) and 128 schizophrenic trios but could not be confirmed. It is therefore unlikely that this variant plays a major role in predisposing to schizophrenia and/or bipolar affective disorder at least in the German population.     

Inhibition of plaque-forming cells with anti-idiotope or hapten: variation due to hapten density on indicator red cells

Phosphorylcholine (PC)-specific antibody plaque-forming cells (PFC) were enumerated in the spleen of BALB/c mice immunized with S. pneumoniae R36a bacterial vaccine. Two indicator red blood cells were compared: RBC coupled with the hapten, PC-RBC, and cells coupled with PC-bearing polysaccharide from the pneumococcus, PnC-RBC. Equal numbers of direct (IgM) PFC were detected with both types of indicator cells. However, a significant difference appeared in the attempt to inhibit the respective PFC either with hapten (monovalent PC chloride, PCCl) or with monoclonal antibodies against T15 idiotopes (anti-Id). At optimal coupling concentrations, inhibition of anti-PnC-RBC plaques required a 10-fold higher concentration of the hapten when compared to anti-PC-SRBC plaques. Also, the inhibition of anti-PnC-SRBC plaques with anti-Id required much higher concentration of the antibody. The phenomenon may be explained by a higher epitope density on PnC-RBC than on PC-RBC. Heavily coupled PC-RBC were more difficult to inhibit (much like the PnC-RBC) by either the hapten or the anti-Id than lightly coupled PC-RBC. A mathematical analysis of the experimental curves supports the notion that under the assay conditions used, inhibition by either the hapten or the anti-Id is influenced primarily by antibody secretion rate and epitope density on indicator cells. If the 2 variables are too high, a significant inhibition of PFC with a low affinity anti-Id may not be possible. The theory also predicted that addition of a small amount of hapten into the assay would be roughly equivalent to secretion rate reduction and would facilitate the plaque inhibition by anti-Id. Indeed, we show a synergism between a minute (non-inhibitory) amount of PCCl and anti-Id in the inhibition of PC-specific PFC. These results point out that the detection of an idiotype-bearing PFC by plaque-inhibition assay is greatly influenced by technical variation in the assay, in particular, the preparation of the indicator red cells.     

Bioavailability of ifosfamide in patients with bronchial carcinoma

Summary The pharmacokinetics of ifosfamide (I) were determined in ten patients with bronchogenic carcinoma. In seven patients, doses of 1 and 2 g (I) were given both as a bolus orally and later intravenously and were well tolerated. A further three patients received 5 g (I) as a single oral dose but in two this produced reversible CNS toxicity and severe vomiting. The area under the curve (AUC, g.h.l^-1) for the 1-g dose was the same following oral and i. v. treatment and this was also true for the 2-g doses. There was a proportionate increase in the AUC for the 5-g oral dose, indicating 100% bioavailability at all three dose levels. We conclude that doses up to 2 g by mouth represent a well-tolerated alternative route of administration.T. Cerny is the recipient of an EORTC Research Fellowship     

Breast cancer: Pretreatment drug resistance parameters (GSH-system, ATase, P-glycoprotein) in tumor tissue and their correlation with clinical and prognostic characteristics

Background: The identification of new factors predicting relapse,outcome and response to systemic therapy in breast cancer is warranted. Themeasurement of biological markers such as drug resistance parameters (DRPs),which are part of the phenotype of malignant cells and contribute toresistance to anti-cancer drugs may be a possibility, which may ultimatelylead to improvement of therapeutic results.Patients and methods: The level of glutathione (GSH), activities ofglutathione-S-transferase (GST), glutathione-peroxidase (GPx),06-alkylguanine-DNA-alkyltransferase (ATase), and P-glycoprotein (PGP) weremeasured in tumor and adjacent tumor free tissue samples from 89 consecutive,untreated females with breast cancer and correlated with clinical andprognostic factors. Early breast cancer (EBC) was diagnosed in 56 patients,22 patients had locally advanced (LABC) and 11 patients metastatic breastcancer.Results: All DRPs showed significantly higher expression in tumorthan in tumor free tissues. GPx was positively correlated with GST (R = 0.3, P = 0.0048) and with GSH (R = 0.5, P = 0.0001) in tumor as wellas in normal tissue. GST activity was significantly higher in EBC than in LABCor metastatic breast cancer ( P = 0.02). GSH level was significantlyhigher in grade 1 than in grade 2 or grade 3 tumors ( P = 0.01). Whenclinical characteristics were related to the level of DRP, high GSH wasassociated with age >60 years ( P = 0.01) in EBC, and with grade1–2 tumors ( P = 0.05) in LABC. No differences in OS were apparentbetween groups of high and low DRP-expression. However, the four-yearestimated disease-free survival of EBC tended to be higher in patients withhigh GST ( P = 0.10) and of LABC in patients with high GPx levels( P = 0.06).Conclusion: We conclude that high levels of DRP in tumor tissue ofbreast cancer patients are part of the initial phenotype of the malignantcells. Due to its high prevalence (83% in EBC, 100% in primarilymetastatic breast cancer), PGP did not add to prognostic information. Highlevels of GSH, GST and and GPx were associated with favorable clinicalcharacteristics and good prognosis, whereas low levels of GSH and GST activitywere associated with more aggressive or more advanced disease.     

An organizational model of sports medicine facilities in the United States

Information on establishing the organizational structure of sports medicine clinics is useful to clinicians intending to start or expand a clinic. The purpose of this study was to identify an organizational model of existing sports medicine facilities in terms of: 1) administration and management, 2) staff qualifications and professional development, 3) location of facility, 4) range of services, 5) availability of services, 6) physician referral base, and 7) fee structure. A survey of 250 sports medicine clinics located in or near urban cities across the United States was conducted by mail. Results of this study indicate that the typical sports medicine facility is corporate-owned. A physical therapist and/or a physician establishes policy, and the physical therapist directs day-to-day operations. On average, the professional staff have four years of athletic team affiliation and seven years of clinical experience with athletes. The staff have attended less than an average of one continuing education course a year over the last five years. The typical facility is located within five miles of a major city, within 10 miles of its primary referral source and competition, and within 10 miles of its clients' homes. Most facilities employ combinations of full-time and part-time physicians, physical therapists, and athletic trainers. The typical sports medicine facility is open 12 hours each weekday. The physician referral base is composed primarily of orthopaedic and family practice physicians who refer an average of 14 new patients a week. J Orthop Sports Phys Ther 1992;15(2):80-86.     

Cadmium pathways during gestation and lactation in control versus metallothoinein 1,2-knockout mice.

Effects of metallothionein (MT) on cadmium absorption and transfer pathways during gestation and lactation in mice were investigated. Female 129/SvJ metallothionein-knockout (MT1,2KO) and metallothionein-normal (MTN) mice received drinking water containing trace amounts of (109)CdCl(2) (0.15 ng Cd/ml; 0.074 micro Ci (109)Cd/ml). (109)Cd and MT in maternal, fetal, and pup tissues were measured on gestation days 7, 14, and 17 and lactation day 11. In dams, MT influenced both the amount of (109)Cd transferred from intestine into body (two- to three-fold higher in MT1,2KO than MTN dams) and tissue-specific (109)Cd distribution (higher liver/kidney ratio in MT1,2KO dams). Placental (109)Cd concentrations in MT1,2KO dams were three- and seven-fold higher on gestation days 14 and 17, respectively, than in MTN dams. Fetal (109)Cd levels were low in both mouse types, but at least 10-fold lower in MTN fetuses. MT had no effect on the amount of (109)Cd transferred to pups via milk; furthermore, 85-90% of total pup (109)Cd was recovered in gastrointestinal tracts of both types, despite high duodenal MT only in MTN pups. A relatively large percentage of milk-derived intestinal (109)Cd was transferred to other pup tissues in both MT1,2KO and MTN pups (14 and 10%, respectively). These results demonstrate that specific sequestration of cadmium by both maternal and neonatal intestinal tract does not require MT. Although MT decreased oral cadmium transfer from intestine to body tissues at low cadmium exposure levels, MT did not play a major role in restricting transfer of cadmium from dam to fetus via placenta and to neonate via milk.