Polymorphic forms of prostate specific antigen and their interaction with androgen receptor trinucleotide repeats in prostate cancer

BACKGROUND: Recent data has suggested that polymorphisms in the prostate specific antigen (PSA) may increase prostate cancer (PC) risk. The PSA gene contains a G/A substitution in the androgen response element (ARE) 1 region. The androgen receptor (AR) gene has polymorphic regions containing variable length glutamine and glycine repeats and these are believed to be associated with PC risk. The effect on PC risks from PSA polymorphisms alone and synergistically with the AR gene was examined in this report. METHODS: One hundred PC patients and an age matched cohort of 79 benign prostate hyperplasia and 67 population controls were entered in this study. DNA was extracted from blood and PSA/ARE promoter region amplified by PCR. PCR products were cut with Nhe 1 restriction enzyme to distinguish G/A alleles. AR/CAG and GGC repeat length was detected by automated fluorescence from PCR products. RESULTS: We found a significantly higher PSA/GG distribution in PC (30%) than either benign prostatic hyperplasia (BPH) (18%) or population controls (16%) (P = 0.025). Furthermore the GG distribution within cases was even greater in younger men (< 65 years; 42%; P = 0.012). Additionally, when PSA genotype was cross classified with CAG repeat, significantly more cases than both BPH and population controls were observed to have a short (< 22) CAG/GG genotype (P = 0.006). CONCLUSIONS: Our results indicate that the PSA/ARE GG genotype confers an increased risk of PC especially among younger men. Moreover, we confirm previous results that a short glutamine repeat in conjunction with GG genotype significantly increases the risk of malignant disease.     

Auditory evoked potential patterns to voiced and voiceless speech sounds in adult developmental dyslexics with persistent deficits

Auditory evoked potentials (AEPs) were recorded from eight developmental dyslexic adults with persistent reading, spelling and phonological deficits, and 10 non-dyslexic controls to voiced (/ba/) and voiceless (/pa/) consonant-vowel syllables. Consistent with previous data, non-dyslexics coded these stimuli differentially according to the temporal cues that form the basis of the voiced/voiceless contrast: AEPs had time-locked components with latencies that were determined by the temporal structure of the stimuli. Dyslexics were characterized by one of two electrophysiological patterns: AEP pattern I dyslexics demonstrated a differential coding of stimuli on the basis of some temporal cues, but with an atypically large number of components and a considerable delay in AEP termination time; AEP pattern II dyslexics demonstrated no clear differential coding of stimuli on the basis of temporal cues. These data reveal the presence of anomalies in cortical auditory processing which could underlie persistent perceptual and linguistic impairments in some developmental dyslexics. Furthermore, scalp AEP distribution maps showing the difference observed between /ba/ and /pa/ activity over time suggest that the regions implicated in the processing of crucial time-related acoustic cues were not systematically lateralized to the left hemisphere like they were for non-dyslexics. These findings may be conducive to a better understanding and treatment of perceptual dysfunctions in developmental language disorders.     

Liver resection in a patient with concomitant thoraco-abdominal and cerebral aneurysms

Background. Surgical resection remains the only curative procedure for liver metastases but even in expert hands it has appreciable morbidity and mortality rates. The presence of a concomitant aortic aneurysm greatly increases these risks. Case outline. A 66-year-old woman who was known to have large aneurysms of the thoraco-abdominal aorta and middle cerebral artery presented with colorectal liver metastases. After detailed preoperative assessment, she underwent resection of segments V and VI of the liver. The surgical procedure was uneventful. She made a good initial recovery, but on day 7 she suddenly became hypotensive and died from a cardiorespiratory arrest. Post-mortem examination revealed a ruptured thoracic portion of the thoraco-abdominal aortic aneurysm. Conclusion. Despite careful control of perioperative blood pressure and the lack of abdominal complication, intrathoracic aneurysmal rupture on day 7 highlights the risk of major unrelated operations in patients with aneurysmal disease.     

The production and characterization of novel heavy-chain antibodies against the tandem repeat region of MUC1 mucin

Camelidae are known to produce immunoglobulins (Igs) devoid of light chains and constant heavy-chain domains (CH1). Antigen-specific fragments of these heavy-chain IgGs (VHH) are of great interest in biotechnology applications. This paper describes the first example of successfully raised heavy-chain antibodies in Camelus dromedarius (single-humped camel) and Camelus bactrianus (two-humped camel) against a MUC1 related peptide that is found to be an important epitope expressed in cancerous tissue. Camels were immunized against a synthetic peptide corresponding to the tandem repeat region of MUC1 mucin and cancerous tissue preparation obtained from patients suffering from breast carcinoma. Three IgG subclasses with different binding properties to protein A and G were purified by affinity chromatography. Both conventional and heavy-chain IgG antibodies were produced in response to MUC1-related peptide. The elicited antibodies could react specifically with the tandem repeat region of MUC1 mucin in an enzyme linked immunosorbant assay (ELISA). Anti-peptide antibodies were purified after passing antiserum over two affinity chromatography columns. Using ELISA, immunocytochemistry and Western blotting, the interaction of purified antibodies with different antigens was evaluated. The antibodies were observed to be selectively bound to antigens namely: MUC1 peptide (tandem repeat region), human milk fat globule membrane (HMFG), deglycosylated human milk fat globule membrane (D-HMFG), homogenized cancerous breast tissue and a native MUC1 purified from ascitic fluid. Ka values of specific polyclonal antipeptide antibodies were estimated in C. dromedarius and C. bactrianus, as 7 x 10(10) M(-1) and 1.4 x 10(10) M(-1) respectively.     

Escherichia coli endocarditis: seven new cases in adults and review of the literature

Described here are seven new cases of infective endocarditis due to Escherichia coli, including four involving prosthetic valves, followed by a review of similar cases in the literature. The review identified cases according to the modified Dukes criteria and revealed 16 cases reported before 1960, 5 between 1960 and 1980, and 11 after 1980. Currently, patients diagnosed with E. coli endocarditis are older than the patients diagnosed before 1960 (p<0.05), and they are often diabetic with underlying heart disease. Prosthetic valves are frequently involved (p<0.05), and the principal source of infection is the urinary tract. Surgery is often necessary. The mortality rate associated with this type of infection has decreased since 1960, but it remains high, with 17% calculated for the present series of seven new cases. The data presented here suggest that elderly patients with prior valve disease or prosthetic valve and E. coli urinary tract infection should be examined for endocarditis.     

Mortality rates among nuclear industry workers at Lucas Heights Science and Technology Centre

OBJECTIVES: To assess whether workers at Lucas Heights Science and Technology Centre (LHSTC) have different levels of mortality from the New South Wales (NSW) and Australian populations. METHODS: A retrospective cohort study was undertaken at LHSTC. Data on 7,076 workers employed between 1957-98 were abstracted from personnel, dosimetry, and medical files. Deaths registrations in the cohort were identified to 1998 through electronic linkage of records with NSW and national registers of cancer incidence and mortality. Two inception cohorts were defined as including 4,717 and 3,543 workers in employment between 1972-98 and 1980-98, to examine cancer mortality and all-cause mortality respectively. RESULTS: All-cause mortality was 31% lower than the national rates; all-cancer mortality was 19% below the NSW rate. Of 37 specific cancers and groups of cancers examined, statistically significant excesses relative to NSW rates were observed only for pleural cancer mortality (SMR = 21.11; 95% Cl 8.79-50.72). CONCLUSIONS: The observed increase in the risk of cancer of the pleura was probably due to unmeasured exposures, given the lack of an established association with radiation exposure and the strong link to asbestos exposure.     

Cyclooxygenase involvement in thromboxane-dependent contraction in rat mesenteric resistance arteries

The influence of cyclooxygenase pathway activation following thromboxane-endoperoxide (TP) receptor stimulation was studied in rat mesenteric resistance arteries (n=6 to 10 per group). We studied isolated, perfused, and pressurized mesenteric resistance arteries (mean internal diameter 214 microm) using an arteriograph, enabling us to study arteries in physiological conditions of flow and pressure. Changes in diameter were continuously recorded, and contractions measured as internal diameter reduction. Release of cyclooxygenase pathway metabolites was also assessed by enzyme immunoassay (EIA) analysis of mesenteric bed perfusions. The thromboxane A2 (TxA2) analog U-46619 (1 micromol/L) induced a significant contraction (108 microm maximal diameter reduction). Inhibition by 3 chemically different cyclooxygenase inhibitors (ie, flurbiprofen, indomethacin, and aspirin) potently reduced the contraction to 27%, 25%, and 6% of control, respectively. The selective cyclooxygenase-1 inhibitor SC-58560 inhibited U-46619 contraction, whereas selective cyclooxygenase-2 inhibition (SC-58236) had no effect. Thromboxane synthase inhibition (furegrelate) did not affect U-46619-induced contraction, but it was reduced by cytosolic phospholipase A2 inhibition. Measurement of cyclooxygenase derivatives produced by the isolated mesenteric bed showed that PGE2 was produced after TxA2-receptor stimulation with U-46619. Exogenous prostaglandin E2 (in the presence of the TxA2 receptor antagonist SQ 29 548) and U-46619 contracted mesenteric arteries with a similar potency (EC50: 0.30 and 0.48 micromol/L, respectively). This study provides the first evidence that TxA2-receptor-dependent contraction in a resistant artery involved cyclooxygenase stimulation and, at least in part, a PGE2 formation. This mechanism of TxA2-dependent contraction in resistant arteries might be of importance in the understanding of diseases affecting resistant arteries and involving TxA2, such as hypertension.     

Pulmonary neutrophil infiltration in murine sepsis: role of inducible nitric oxide synthase

Nitric oxide (NO) derived from inducible NO synthase (iNOS) contributes to the pathophysiology of acute lung injury (ALI). The effect of iNOS on pulmonary neutrophil infiltration in ALI is not known. Thus, we assessed pulmonary microvascular neutrophil sequestration through intravital videomicroscopy and pulmonary neutrophil infiltration, reflected by myeloperoxidase activity and lavage neutrophil counts, after induction of sepsis by cecal ligation/perforation in wild-type (iNOS+/+) versus iNOS-/- mice. Pulmonary microvascular neutrophil sequestration was attenuated in septic iNOS-/- versus iNOS+/+ mice (15 +/- 1 vs. 20 +/- 1 leukocytes per field, p < 0.05), but lavage neutrophil counts were greater in iNOS-/- mice (5.7 +/- 1.5% vs. 0.7 +/- 0.1%, p < 0.05) between 6 and 18 hours after cecal ligation and perforation. When iNOS+/+ bone marrow was transplanted into bone marrow-depleted iNOS-/- mice (+ to - chimeras; iNOS limited to marrow-derived inflammatory cells), septic pulmonary microvascular neutrophil sequestration and lavage neutrophil counts were restored to levels seen in septic iNOS+/+ mice. In contrast, in - to + chimeras, pulmonary neutrophil trafficking was similar to iNOS-/- mice. In vitro cytokine-stimulated neutrophil transendothelial migration was significantly greater for iNOS-/- versus iNOS+/+ neutrophils (7.9 +/- 0.7% vs. 3.8 +/- 0.6%, p < 0.05) but was independent of endothelial iNOS. Thus, neutrophil iNOS-derived NO is an important autocrine modulator of pulmonary neutrophil infiltration in murine sepsis.