High frequency of BRCA1/2 germline mutations in 42 Belgian families with a small number of symptomatic subjects

AIM: The initial risk assessments for BRCA1/2 mutation carriers and estimates of carrier frequencies were based on extended pedigrees with a large number of symptomatic subjects. When counselling based on BRCA gene mutation analysis was initiated, we faced requests for counselling mostly from members of small families with only two or three affected members. We report on the likelihood of finding a BRCA mutation in such small families. METHODS: In the first 100 families that came for oncogenetic counselling since September 1994, a BRCA1/2 gene mutation screen was initiated if there were two or more symptomatic first degree relatives, if one of them had ovarian cancer, or if one breast cancer was diagnosed before the age of 50 years. RESULTS: BRCA gene mutations were found and confirmed by sequencing in 14 out of 42 families (33%); 10 mutations were in the BRCA1 gene and four in the BRCA2 gene. Our findings indicate an increased probability of detecting a BRCA gene mutation when ovarian cancer occurred in the family. There is no increased probability of detecting a mutation with increasing numbers of breast cancers. Only 22% of the eligible presymptomatic family members opted for testing. The presymptomatic female carriers currently prefer breast surveillance rather than prophylactic surgery. CONCLUSION: BRCA1/2 gene mutation testing can be done with reasonable efficiency in the Belgian population when there are two symptomatic family members. The availability of testing does not lead to a high frequency of requests for testing by presymptomatic family members.     

Plasminogen activator inhibitor-1 as a measure of vascular remodelling in breast cancer

The generation of urokinase plasminogen activator (uPA) by tumours is an important pathway for neoplastic cell invasion and metastasis. Indeed in several tumour types, elevated levels of uPA, its receptor (uPAR) or its inhibitor plasminogen activator inhibitor-1 (PAI-1) is associated with a poorer prognosis. Since endothelial cells also use this proteolytic system to remodel the extracellular matrix during angiogenesis and since angiogenesis, as assessed by microvessel density, is also a predictor of patient survival, this study was designed to investigate the relationship between angiogenesis and the urokinase system in breast tumours. The aims were to assess whether the uPA, uPAR and/or PAI-1 correlates with angiogenic activity and could therefore be a useful objective clinical measure of tumour neovascularization; and to clarify whether the poor outcome associated with high levels of the urokinase system is due to its association with angiogenesis. The study also sought to examine the relationship between the uPA system and vessel remodelling using loss of a basement membrane epitope (LH39) normally associated with established capillaries. The cytosolic levels of uPA, PAI-1 and uPAR were therefore measured by enzyme linked immunoabsorbent assay, together with tumour vascularity, in 136 well-characterized invasive breast carcinomas. There were significant relationships between uPA and uPAR (Spearman r=0.37, p<0.0001), uPA and PAI-1 (Spearman r=0.19, p=0.03) and between uPAR and PAI-1 (Spearman r=0.23 p=0.01). A significant correlation was also observed between PAI-1 and vessel remodelling (Spearman r=0.34, p=0.04), patient age (p=0.01), nodal status (p=0.047) and tumour grade (p=0.04), but no association between tumour vascularity and PAI (p=0.96), uPA (p=0.69) or uPAR (p=0.81) was present. No significant association was seen between any of the urokinase variables and expression of the angiogenic factor thymidine phosphorylase. Furthermore, no significant associations were found between any of the studied parameters and overall survival in a univariate analysis of the cancer patients. A multivariate Cox proportional hazard model of overall survival showed that uPA (p=0.15), but not uPAR (p=0.52) or PAI-1 (p=0.61), gave no additional prognostic information. These findings show that uPA may work via an independent pathway to angiogenesis and therefore combined blockade of uPA and angiogenesis may have additional therapeutic benefits. It also shows, as recently demonstrated in animal models, that PAI-1 may be a key regulator of vascular remodelling in human cancer.     

The homogeneous photopolymerization of methyl methacrylate by colloidal cadmium sulfide

A completely new method of initiating the homogeneous radical polymerization of methyl methacrylate in bulk or in solution via the photogeneration of an electron hole pair in colloidal cadmium sulfide is presented. A polymerization mechanism involving an excited cadmium sulfide particle in both the initiation and termination steps is proposed. In the initiation a methyl methacrylate molecule is oxidized by a positive hole photogenerated in a CdS particle, which results in a novel chain-end structure of the poly(methyl methacrylate) (PMMA). Degradative chain transfer to reduced excited cadmium sulfide particles is responsible for chain termination. Thus, for the first time, a detailed polymerization mechanism in which all states of the polymerization, i.e., initiation, propagation, chain transfer and termination, is presented for the polymerization of vinyl monomers initiated by semiconductors. Thermogravimetry (TG) showed that the newly synthesized PMMA has greatly enhanced thermal stability when compared to normal radically prepared PMMA. In fact, the thermal stability approaches that of anionically prepared PMMA but is experimentally much easier to prepare. This technique enables the homogeneous embedding of CdS particles in a polymer matrix.     

Biochemical investigation with regard to infection and immunity of Eimeria acervulina in the fowl

Summary Biochemical investigation of the fluid surrounding the sporocysts in the oocysts (oocyst fluid) showed the presence of the common amino acids, -isoaminobutyric acid, glycerol, an unidentified carbohydrate and proteins.Incubation experiments with D-glucose-¹⁴C (U) revealed the presence of enzymes able to convert glucose into lactic acid and other acids. Inside the sporocysts the common amino acids, glycerol and the unidentified carbohydrate were also present, but -isoaminobutyric acid did not occur. The carbohydrate binding protein carboglutelin, carbohydrate phosphate and small amounts of glucose and fructose were mainly found inside the sporocysts.Incubation experiments of oocyst fluid mixed with sporocysts with D-glucose-C¹⁴ (U) demonstrated an interchange between the fluid and the sporocysts. In the oocyst fluid lactic acid was formed, but inside the sporocysts the conversion appeared to stop mainly with formation of carbohydrate phosphate.Incubation experiments of intestinal pieces both from immunized and not-immunized birds with oocyst fluid, sporocysts and labelled glucose showed that a stronger reaction took place in immunized birds than in not-immunized ones.Similar experiments were performed with not-immunized birds at different days after a primary infection. The reaction of the intestinal wall, which seemed quite normal again since day 19 after infection, was comparable with that observed in immunized birds.Finally the hypothesis is given, that in the first part of the intestine of immunized birds compounds are present originating from the first infection. These compounds might enhance the reaction between the oocyst fluid and the present feed to such an extent that the pH decreases and much epithelial cells are pushed off possibly together with the sporocysts. Then leakage of serum proteins might occur.     

Chronopharmacokinetics of beta-receptor blocking drugs of different lipophilicity (propranolol,metoprolol, sotalol,atenolol) in plasma and tissues after single and multiple dosing in the rat

Summary Comparative pharmacokinetic studies with the -receptor blocking drugs propranolol, metoprolol, sotalol and atenolol, differing greatly in lipophilicity, and their main route of elimination were performed in light-dark-synchronized rats after equimolar single (6 moles/kg) or multiple (6x6 moles/kg) drug application. Drug concentrations were determined in plasma and various target organs of the drugs, e.g. heart, muscle, lung and brain, after drug application in the light period (L) and dark period (D), respectively. After single drug administration pharmacokinetic parameters of all drugs depended on the L and D conditions. Elimination half-lives in plasma and organs were shorter during D than during L. No L-D-differences were found in initial drug concentrations of the hydrophilic drugs sotalol and atenolol. In contrast, C₀-values of the lipophilic propranolol in highly perfused organs (muscle, lung, brain) and of metoprolol in muscle tissue were significantly higher in D than in L. No obvious temporal dependency was found in other pharmacokinetic parameters (AUC, plasma clearance,V _d) with the exception inV _d of propranolol. Due to the different physico-chemical properties of the compounds inter-drug-differences in pharmacokinetic parameters including drug accumulation into lung and brain tissue were observed. Multiple drug dosing abolished the circadian-phase-dependency in the elimination half-lives of the drugs due to an increase in D. Only for the highly lipophilic propranolol half-lives in highly perfused organs were still shorter in D than in L. It is concluded that L-D-differences in drug half-lives after single dose application are mainly due to circadian variations in drug elimination with a higher hepatic (propranolol, metoprolol) or renal (sotalol, atenolol) elimination in the activity period of rats during D. Additional studies with propranolol on heart rate of conscious rats revealed that a maximum in -receptor blockade was achieved at 10 moles/kg in L but not in D. Thus, it is assumed that abolition of circadian-phase-dependency in half-lives after 6x6 moles/kg of the drugs may be due to the longer lasting and more pronounced -receptor blockade after multiple drug dosing over a period of several hours in D. Thereby, liver-flow-dependent elimination of propranolol and metoprolol and renal elimination of sotalol and atenolol is reduced to base-line levels found in L.Parts of this work were presented at the 22nd Spring Meeting (Lemmer 1981) and at the Joint Meeting (Lemmer et al. 1983a) of the German Pharmacological Society     

Styles of coping with handicap in mentally retarded adults

Based on a conceptual analysis how mentally retarded adults experience their intellectual impairment four different styles of coping with the handicap were postulated. They could be demonstrated empirically from data of a standardized interview. The groups with different styles of coping also show difference in personality traits, in their social history, the level of independence in daily living and in psychosomatic complaints. The variables "norm orientation", "stigmatization" and "attention getting behavior" were used in a prediction analysis to characterize the coping styles in the following way: (1) the positive-passive style is characterized by high norm orientation with little tendency to get attention, (2) the negative-passive style only by a high tendency to get attention, (3) the assertive style by low norm orientation together with high stigmatization and a low tendency to get attention, (4) the defensive style by low stigmatization and a low tendency to get attention. In addition to behavior-oriented intervention in rehabilitation those cognitive processes should be considered, which contribute to the development of a mentally retarded person's coping style.     

Biosynthesis of phenylalanine and tyrosine in claviceps

Some enzymes of the terminal steps of phenylalanine and tyrosine biosyntheses were investigated in various alkaloid-forming ergot strains. All strains studied utilize both arogenate and phenylpyruvate as an intermediate in L-phenylalanine synthesis. L-Tyrosine is preferentially or exclusively synthesized via the arogenate pathway. No feedback inhibition of arogenate pathway enzymes by aromatic amino acids was observed.     

Interventions to Increase Multivitamin Use Among Women in the Interconception Period: An IMPLICIT Network Study

Maternal and Child Health Journal - Each year, 3% of infants in the Unites States (US) are born with congenital anomalies, including 3000 with neural tube defects. Multivitamins (MVIs) including...     

“Putting Meat on the Bones”: Understanding the Implementation of a Community-Based Early Intervention and Prevention Programme—Contextual,Person, and Programme Influences

Prevention Science - The adoption and effective delivery of evidence-based interventions within “real-world” community-based, primary health care service settings are of crucial...