Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans.

The scavenger receptor class B, member 1 (SR-BI), is a key cellular receptor for high-density lipoprotein (HDL) in mice, but its relevance to human physiology has not been well established. Recently a family was reported with a mutation in the gene encoding SR-BI and high HDL cholesterol (HDL-C). Here we report two additional individuals with extremely high HDL-C (greater than the 90th percentile for age and gender) with rare mutations in the gene encoding SR-BI. These mutations segregate with high HDL-C in family members of each proband and are associated with a 37% increase in plasma HDL-C in heterozygous individuals carrying them. Both mutations occur at highly conserved positions in the large extracellular loop region of SR-BI and are predicted to impair the function of the SR-BI protein. Our findings, combined with the prior report of a single mutation in the gene encoding SR-BI, further validate that mutations in SR-BI are a rare but recurring cause of elevated HDL-C in humans.

Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial.

Fluconazole is recommended in the prophylaxis of oropharyngeal candidiasis (OPC) in patients undergoing radiotherapy for head-neck tumours; however, the actual effectiveness of fluconazole in this setting remains unclear. Adult patients with cervico-cephalic carcinoma submitted to radical or adjuvant radiotherapy were randomized to 100 mg fluconazole (n = 138) or matched placebo (n = 132) oral suspension once daily from the sixth session of radiotherapy up to the end of treatment. The final analysis of the investigation showed a higher rate of the OPC outbreak-free survival in the fluconazole compared with placebo (P = 0.008 in the log-rank test). The mean time (95% CI) to OPC outbreak was 56 (53-59) days in the fluconazole group and 47 (43-51) days with placebo. The mean duration of radiotherapy was 43.5 and 39.9 days, respectively in the two groups (P = 0.027). Adverse effects were reported in 70.3% of patients in the fluconazole group and in 67.4% with placebo. The results showed prophylaxis with fluconazole given in irradiated patients with head-neck tumours significantly reduces the rate and the time to development of OPC compared with placebo.

Reproductive isolation between chromosomal races of the house mouse Mus musculus domesticus in a parapatric contact area revealed by an analysis of multiple unlinked loci.

The house mouse, Mus musculus domesticus, exhibits a high level of chromosomal polymorphism because of the occurrence and fast fixation of Robertsonian fusions between telocentric chromosomes. For this reason, it has been considered a classical speciation model to analyse the role of the chromosomal changes in reproductive isolation. In this study, we analysed a parapatric contact area between two metacentric races in central Italy, the Cittaducale race (CD: 2n = 22) and the Ancarano race (ACR: 2n = 24), to estimate gene flow at the boundary. Hybrids between these two races show high levels of structural heterozygosity and are expected to be highly infertile. A sample of 88 mice from 14 sites was used. The mice were genotyped by means of eight microsatellite loci mapped in four different autosomal arms. The results show clear genetic differentiation between the CD and ACR races, as revealed by differences in allele frequencies, factorial correspondence analysis and indexes of genetic population (e.g. F(ST) and R(ST)) along the contact zone. The genetic differentiation between the races was further highlighted by assignation and clustering analyses, in which all the individuals were correctly assigned by their genotypes to the source chromosomal race. This result is particularly interesting in view of the absence of any geographical or ecological barrier in the parapatric contact zone, which occurs within a village. In these conditions, the observed genetic separation suggests an absence of gene flow between the races. The CD-ACR contact area is a rare example of a final stage of speciation between chromosomal races of rodents because of their chromosomal incompatibility.

Treatment of early-stage Hodgkin's disease with four cycles of ABVD followed by adjuvant radio-therapy: analysis of efficacy and long-term toxicity.

BACKGROUND AND OBJECTIVES: The use of combined modality therapy in early-stage Hodgkin's disease can spare staging laparotomy and reduces the risk of relapse compared to radiation alone. This paper reports on the efficacy and long-term events of a combined modality approach consisting of a brief course of chemotherapy followed by adjuvant radiotherapy, without laparotomy, in early-stage Hodgkin's disease. DESIGN AND METHODS: This study included 78 patients with Hodgkin's disease (20 in stage I and 58 in stage II); 60% had mediastinal enlargement (12% had bulky disease) and 5% had subdiaphragmatic disease. Their median age was 33 years (range: 15-64) and median follow-up 60 months. The treatment program consisted of four cycles of ABVD followed by adjuvant radiation to involved sites (43 patients) or involved and contiguous sites of disease (35 patients); radiation doses ranged from 30 to 36 Gy to uninvolved and involved sites, respectively; bulky disease received up to 44 Gy. Gonadal function in women was assessed by hormonal tests and evaluation of menses; young men were given the opportunity to have their semen cryopreserved. RESULTS: The treatment program was completed in a median of 6.2 months (range: 5-10). The complete remission rate was 88% after 4 courses of ABVD and 98.7% after adjunctive RT. The 5-year relapse-free survival was 97% and overall survival 98%; three patients died, one of disease progression and two of small cell lung carcinoma. Long-term events included three cases of pulmonary fibrosis with symptomatic interstitial disease, one case of dilated cardiomyopathy with cardiac failure (all had received mediastinal radiation) and four cases of dysthyroidism. Fertility was preserved in young women, with three subsequent normal pregnancies. Second neoplasms included two small cell lung carcinomas and one breast carcinoma. INTERPRETATION AND CONCLUSIONS: In early-stage Hodgkin's disease, four cycles of ABVD followed by adjuvant radiotherapy produced a 5-year overall survival of 98%. Prolonged monitoring for therapy-related long term complications is mandatory in these potentially curable patients.

Investigating site-specific effects of the -X glutamate in a parvalbumin CD site model peptide.

The -X glutamate in a 33-residue model peptide comprising the CD site of carp parvalbumin 4.25 (ParvCD) was replaced with aspartate (ParvCD-XD) and the effect on calcium-dependent dimerization and calcium affinity assessed. The peptide ParvCD demonstrates a 10(5)-fold lower calcium affinity than the same site in the native protein. Both the ParvCD and ParvCD-XD model peptides fail to bind magnesium. The low calcium affinity and failure of the model ParvCD site to bind magnesium may be due to higher enthalpic costs of chelation by the -X glutamate. Replacement of the -X glutamate with an aspartate resulted in a twofold increase in the calcium affinity of both the monomer and dimer forms and a twofold increase in the calcium dependent dimerization of the peptide. A -X glutamate to aspartate replacement in 33-residue model peptides corresponding to bovine brain calmodulin site 3 (R. M. Procyshyn and R. E. Reid, Arch. Biochem. Biophys. 311, 425-429, 1994) and in Escherichia coli d-galactose-binding protein (S. K. Drake, K. L. Lee, and J. J. Falke, Biochemistry 35, 6697-6705, 1996) agree with results in the ParvCD site. However, in rat oncomodulin a -X glutamate to aspartate replacement increases calcium affinity (R. C. Hapak, P. J. Lammers, W. A. Palmisano, E. R. Birnbaum, and M. T. Henzl, J. Biol. Chem. 264, 18751-18760, 1989). The different effect of a -X glutamate to aspartate substitution in the different sites suggests site-specific factors dictating the thermodynamic contribution of the -X glutamate to calcium affinity.

A model for circular dichroism monitored dimerization and calcium binding in an EF-hand synthetic peptide.

EF-hand peptides have been shown to bind calcium and dimerize to form an intact protein domain [Shaw, G.S., Hodges, R.S. & Sykes, B.D. (1990). Science, 249, 280-283]. A synthetic 33-residue EF-hand peptide with the sequence of carp parvalbumin CD site demonstrated a seven-fold increase in the apparent calcium dissociation constant with a eight-fold decrease in peptide concentration when fit to a single-site calcium-binding model. This observation is consistent with EF-hand dimerization. This paper describes a method to determine the dimerization dissociation constant and the calcium dissociation constants for both the monomer and dimer forms of this EF-hand peptide using circular dichroism techniques. By monitoring the increase in negative molar ellipticity at 222 nm with increasing peptide concentration under calcium-saturating conditions the dimerization dissociation constant for the synthetic parvalbumin CD site was determined to be 55.68+/-10.76 microM. Using the dimerization constant, the calcium dissociation constants for both the monomer and dimer forms of this peptide were determined by monitoring the change in ellipticity of peptide solutions on addition of increasing amounts of calcium. A fit of this data to a mathematical model that takes into account dimerization results in calcium dissociation constants of 421.3+/-21.56 and 47.06+/-6.72 microM for the monomer and dimer forms, respectively.

[The relationships between the general practitioner and the oncological radiotherapist. A preliminary study by telephone interviews]. / I rapporti tra medico generico e radioterapista oncologo. Studio preliminare attraverso interviste telefoniche.

PURPOSE: We addressed the issue of the relationship between the general practitioner (GP) and the radiotherapist to improve the quality of care of cancer patients. MATERIAL AND METHODS: The study consisted in evaluating medical requests and phone interviews, with a questionnaire with yes/no and multiple choice answers to the following 5 questions: 1) Do you think a cancer diagnosis is always a hopeless death sentence? 2) Is it professionally rewarding to cure a cancer patient? 3) Are you satisfied with your relationship, as a general practitioner, with oncologic reference centers? 4) Is it more wearing for a general practitioner to manage a cancer than a noncancer patient? 5) Would you answer a questionnaire about the relationship between the general practitioner, the cancer patient and the oncologist? We evaluated 1590 medical requests and made 401 phone interviews; 255 colleagues (70%) answered the questionnaire. RESULTS: Medical requests were correctly and completely formulated by GPs in 45% of cases. A cancer diagnosis was not considered a hopeless death sentence in 90.9% of cases and 76% of GPs considered it professionally rewarding to cure a cancer patient. 75.6% of GPs considered it more wearing to manage a cancer than a noncancer patient, and female GPs felt this more strongly than their male counterparts. Irrespective of gender, GPs over 50 years of age tend to consider cancer a hopeless and fatal disease. The relationship with oncologic centers was considered satisfactory in 86.2% of cases. However, since cancer patients need greater medical care, GPs would like a closer cooperation with oncologists. DISCUSSION AND CONCLUSIONS: The great interest GPs took in this study encourages further investigation through a more in depth questionnaire designed with the help of GPs themselves and interested statisticians.

[Electron beam radiotherapy for loco-regional recurrence of breast cancer]. / Radioterapia con fascio di elettroni delle recidive loco-regionali del cancro della mammella.

125 cases of recurrent breast carcinoma (skin nodules or regional lymphnodes) after the primary radical treatment have been treated from 1975 to 1980. Most of these patients were irradiated with 6 MeV electron beams at 50-65 Gy; some of them with 20 MeV electrons. A complete response followed in 68% of lesions, a partial response in 23.2%. The survival at 5 and 10 years was respectively 25.6% and 8.8%. Low energy electron beam therapy is therefore an efficient way of treating loco-regional recurrences of breast carcinoma, after the failure of a radical primary treatment.

[Vocal cords carcinoma. Results of radiotherapy (author's transl)]. / Il cancro delle corde vocali: risultati della radioterapia.

The results of larynx carcinoma radiotherapy with electron beams are reported: 67 cases of glottic carcinoma (vocal cords) Tis, T1a, T1b, T2, treated between 1965 and 1978 are studied. Survival cumulative and not evidence disease rates are reported 84.7% at three years, 80.2% at five years, 77.1% at ten years, 77.1% at fourteen years. To conclude we underline the importance of radiotherapy in the treatment of carcinoma of the vocal cords.