Consequences of interaction of a lipophilic endotoxin antagonist with plasma lipoproteins

E5531, a novel synthetic lipid A analogue, antagonizes the toxic effects of lipopolysaccharide, making it a potential intravenously administered therapeutic agent for the treatment of sepsis. This report describes the distribution of E5531 in human blood and its activity when it is associated with different lipoprotein subclasses. After in vitro incubation of [(14)C]E5531 with blood, the great majority (>92%) of material was found in the plasma fraction. Analysis by size-exclusion and affinity chromatographies and density gradient centrifugation indicates that [(14)C]E5531 binds to lipoproteins, primarily high-density lipoproteins (HDLs), with distribution into low-density lipoproteins (LDLs) and very low density lipoproteins (VLDLs) being dependent on the plasma LDL or VLDL cholesterol concentration. Similar results were also seen in a limited study of [(14)C]E5531 administration to human volunteers. The potency of E5531 in freshly drawn human blood directly correlates to increasing LDL cholesterol levels. Finally, preincubation of E5531 with plasma or purified lipoproteins indicated that binding to HDL resulted in a time-dependent loss of drug activity. This loss in activity was not observed with drug binding to LDLs or to VLDLs or chylomicrons. Taken together, these results indicate that E5531 binds to plasma lipoproteins, making its long-term antagonistic potency dependent on the plasma lipoprotein composition.     

<Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> mutations in a population-based study of male breast cancer

Background

The contribution of BRCA1 and BRCA2 to the incidence of male breast cancer (MBC) in the United Kingdom is not known, and the importance of these genes in the increased risk of female breast cancer associated with a family history of breast cancer in a male first-degree relative is unclear.

Methods

We have carried out a population-based study of 94 MBC cases collected in the UK. We screened genomic DNA for mutations in BRCA1 and BRCA2 and used family history data from these cases to calculate the risk of breast cancer to female relatives of MBC cases. We also estimated the contribution of BRCA1 and BRCA2 to this risk.

Results

Nineteen cases (20%) reported a first-degree relative with breast cancer, of whom seven also had an affected second-degree relative. The breast cancer risk in female first-degree relatives was 2.4 times (95% confidence interval [CI] = 1.4–4.0) the risk in the general population. No BRCA1 mutation carriers were identified and five cases were found to carry a mutation in BRCA2. Allowing for a mutation detection sensitivity frequency of 70%, the carrier frequency for BRCA2 mutations was 8% (95% CI = 3–19). All the mutation carriers had a family history of breast, ovarian, prostate or pancreatic cancer. However, BRCA2 accounted for only 15% of the excess familial risk of breast cancer in female first-degree relatives.

Conclusion

These data suggest that other genes that confer an increased risk for both female and male breast cancer have yet to be found.

     

Accelerated transplant coronary artery disease and massive silent acute myocardial infarction in a heart transplant patient--a case report and brief review of literature

This case report describes an aggressive form of accelerated atherosclerosis predicted early after transplant by dobutamine stress echocardiography in a patient who died of massive myocardial infarction 32 months after transplantation. The main objective finding of this event was markedly increased cardiac filling pressures during an elective cardiac catheterization and coronary angiography. The literature is briefly reviewed.     

Prolonged QT interval and cardiac arrhythmias in two neonates: sudden infant death syndrome in one case

Two neonates with arrhythmias and the long QT syndrome are described. The arrhythmias were detected in utero and both infants were apparently well after birth. The first infant, although well, had a bradycardia for the first 9 days of life. A normal heart rate was documented at 10 days but a prolonged QT interval was not appreciated on the ECG. He was discharged from hospital but died suddenly and unexpectedly 3 days later. A post-mortem examination failed to find a cause for his death which therefore fell into the category of the sudden infant death syndrome (SIDS). A retrospective analysis of the perinatal electrocardiogram showed a probable junctional rhythm with 2:1 conduction to the ventricle; the QT interval was prolonged at 0.52 seconds (QTC = 0.63). The second infant had a QT interval of 0.52 seconds (QTC = 0.54) and frequent ventricular premature beats on a 24-hour electrocardiogram. She was treated with propranolol and remains well 2 years later. Sudden infant death has often been described in the siblings of children with the long QT syndrome and one other report described a case of SIDS which was said to have had a prolonged QT interval on the perinatal ECG. This report, however, provides unquestionable evidence, in one case, of an association between the long QT syndrome and SIDS.     

Macroglobulinémie de Waldenström

Waldenström's macroglobulinemia (WM) is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with the presence of an IgM monoclonal gammopathy in the blood. WM remains incurable with a median of 8-year of overall survival for patients with symptomatic WM. Treatment is postponed for asymptomatic patients and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab, either alone or in combination. Studies involving new combination chemotherapy are ongoing and preliminary results are encouraging. However, there are several limitations to these approaches. The complete response rate is low and the treatment free survival is short in many patients, no specific agent or regimen has been shown to be superior to another, and no treatment has been specifically approved for WM. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of proteasome inhibitors as bortezomib, several Akt/mTor inhibitors, such as perifosine and Rad001. Many other agents and monoclonal antibodies are currently being tested in clinical trials and seem promising. This article provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.     

An analysis of eccentric photo refraction

The optics of eccentric photo refraction are analysed. The variation of photo refractive lunula area with refractive error, pupil size, flash eccentricity and camera aperture were calculated using a model eye. Measurements from photographs of paraxial (eccentric) photo refraction of model eyes show that a good agreement exists between theory and experiment over a range of refractive errors from — 10 D to +10 D. Calculations were also made for a standard reduced eye. The optimal set-up for measuring refractive error accurately over a wide range of refractive states is discussed, as are the problems which arise from non-central fixation.     

Protective effects of vitamin A against the genotoxicity of NNK, a nicotine-derived N-nitrosamine

In this investigation, the effect of vitamin A on 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced genotoxic damage in rat liver was studied and correlated with NNK metabolism and DNA single strand breaks (DNA-SSBs). Male adult Fischer rats were fed a vitamin A deficient diet for 8 weeks and then divided into two sub-groups. Rats in group Ia and group Ib were fed vitamin A supplemented and vitamin A deficient diets respectively for an additional 4 weeks. Rats were then treated with a single i.p. injection of NNK (25-100 mg/kg) and subjected to partial hepatectomy 1 week later. After 72 h, liver perfusions were performed for cell preparation. Non-hepatectomized rats were used as controls (group IIa and IIb, consisting of rats fed vitamin A supplemented and deficient diets respectively). In non-hepatectomized rats (groups IIa and IIb), micronucleus (MN) frequencies were not significantly increased. This confirms the importance of cell proliferation for MN formation. In rats fed a vitamin A deficient diet and subjected to partial hepatectomy (group Ib), a significant increase of MN was observed (2.2 +/- 0.3, 5.7 +/- 0.9, 12.8 +/- 3.8 and 21.2 +/- 4.3% for control, 25, 50 and 100 mg NNK/kg body wt respectively). In rats fed a vitamin A supplemented diet (group Ia) we have observed a significant decrease of MN induction, as compared to rats fed a vitamin A deficient diet (group Ib) (2.7 +/- 1.0, 2.9 +/- 0.9, 9.7 +/- 2.7, 14.8 +/- 3.2% for control, 25, 50 and 100 mg NNK/kg body wt respectively). Freshly isolated hepatocytes from rats fed vitamin A deficient and supplemented diets but without NNK treatment in vivo were used to study NNK metabolism and DNA-SSBs. Results showed that hepatocytes isolated from rats fed a vitamin A supplemented diet (group C) metabolized NNK less effectively than hepatocytes isolated from rats fed a vitamin A deficient diet (group B) (NNK metabolism was decreased by 0.5-fold in group C as compared to group B). This inhibition was observed only with the NNK activation pathway, alpha-carbon hydroxylation, but not with a deactivation pathway: pyridine-N-oxidation. DNA-SSBs induced by NNK were also reduced in hepatocytes isolated from rats fed a vitamin A supplemented diet as compared to hepatocytes isolated from rats fed a deficient diet. These reductions were 7.8, 12.4 and 4.5% after 6 h of elution and 9.1, 8.5 and 3.0% after 9 h of elution for 1, 5 and 10 mM NNK respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pineal germinoma: MR imaging

Magnetic resonance (MR) imaging characteristics of pineal germinomas are described in seven patients imaged with MR and computed tomography (CT). In patients with symptoms of an enlarging process in the quadrigeminal plate cistern, MR imaging was as sensitive as CT scanning in detecting the mass. MR imaging did not detect a normal-sized, calcified neoplastic gland. Germinoma, germinoma with embryonal cell carcinoma elements, and pineoblastoma demonstrated different MR signal characteristics. Although direct coronal and sagittal MR images were useful in defining the relationship of the tumor to the posterior third ventricle, Sylvian aqueduct, and vein of Galen, the ease, rapidity, and sensitivity of CT scanning suggest that CT should remain the modality of choice for initial evaluation and screening of the pineal region, especially in the younger pediatric population, in whom detection of calcification may provide the only clue of an abnormality.     

Pharmacologic study of nicergoline in the pathology of the cervico-prostatic sphincter

An urodynamic survey and an E.M.G. of the striated sphincters were performed in 20 patients presenting with prostatism, before and after infusion of either nicergoline or placebo, under double-blind conditions. Statistical analysis was performed and demonstrated a significant decrease in the tone of the bladder neck, the prostate, the striated sphincter and the bladder; impoverished electromyographic activity of the striated sphincters; increased maximal and mean urine flow and decreased post-voiding residue. The authors stress the efficacy of nicergoline in cervico-prostato-sphincteric syndromes.     

Radical retropubic prostatectomy: complications and quality of life (429 cases, 1983-1989).

From March 1983 to December 1989 we have performed radical prostatectomy on 429 patients with prostate cancer. With 117 of the cases we performed the sparing nerve procedure. Follow-up was 6-72 months. Early postoperative complications concerned 36 patients (8.4%). We have not had any total incontinence. After a 6-month postoperative period we had a rate of 13.8 +/- 3% of stress incontinence with a confidence level of 95%. This percentage changed to 6.2 +/- 3% after a 12-month period. 33% of the patients after 6 months and 68.5% after 1 year reported full potency with similar pre- and postoperative quality of sexual intercourse. To manage localized prostate cancer it is important to know that with radical prostatectomy we can obtain an excellent quality of life with low morbidity even if the best management of localized prostate cancer is not resolved.