Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy

PURPOSE: We investigated the ability of In-111-capromab pendetide to separate patients who have failed radical prostatectomy into categories of those who would versus those who would not respond to salvage radiotherapy. METHODS: Prostate-specific antigen (PSA) levels in 32 men with prostate cancer who had failed radical prostatectomy and had undergone a whole-body In-111-capromab pendetide scan were followed-up for 13 months (median) after salvage radiotherapy to the pelvis. A logistic regression model was used to determine whether the scan findings, as well as other clinical variables, were associated with a durable complete response (DCR), a nondurable response (NDR), or no response (NR). RESULTS: Sixteen of 23 (70%) men with a normal scan outside the prostatic fossa achieved a DCR after salvage radiotherapy versus two of nine (22%) who had a positive scan outside the prostate fossa and pelvis (P = .0225, Fisher's exact test). Predicted probability (95% confidence interval [CI]) that a DCR would be obtained with a normal scan was 0.88 (0.55 to 0.98); for men with a positive scan limited to the prostatic fossa it was 0.62 (0.42 to 0.79); and for men with a positive scan outside the pelvis it was 0.27 (0.09 to 0.58). No other variables before radiotherapy showed a significant association with the DCR rate. CONCLUSION: Salvage radiotherapy is statistically more likely to lead to a durable complete PSA response in men with prostate cancer who have failed radical prostatectomy and have a negative In-111-capromab pendetide scan outside the pelvis as compared with those who have a positive scan.     

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival

The EMS1 and CCND1 genes at chromosome 11q13 are amplified in about 15% of primary breast cancers but appear to confer different phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene amplification (P = 0.0061), whereas cyclin D1 mRNA overexpression was not (P = 0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P = 0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P = 0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically significant (P = 0.0951). In marked contrast there was a significant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P = 0.030). A potential explanation for this difference was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without effect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age > 50 years (P = 0.0001), postmenopausal status (P = 0.0008), lymph node negativity (P = 0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene amplification, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer different phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene amplification.     

Clinical effects of longitudinal division of the corpus callosum in normal dogs

Longitudinal division of the corpus callosum was performed in six normal beagles to determine surgical morbidity. The corpus callosum was divided sagittally on the midline and the effect on neurological function was determined. Five of six dogs were clinically normal within 14 days or less after surgery. One dog had persistent but improving clinical signs consistent with a forebrain disturbance at 30 days after surgery. Overall, minimal morbidity and no mortality was associated with this surgical procedure. Further study is indicated to determine the efficacy of this surgical treatment for seizure control in dogs with idiopathic epilepsy.     

Atlantoaxial instability complicating radiation therapy for recurrent nasopharyngeal carcinoma. A case report

STUDY DESIGN: A case report of a patient in whom atlantoaxial instability developed secondary to repeat radiation therapy for recurrent nasopharyngeal carcinoma. OBJECTIVES: To illustrate a dramatic and previously unreported complication of local radiation to the posterior nasopharynx. SUMMARY OF BACKGROUND DATA: Nasopharyngeal carcinoma is an unusual tumor that usually is managed with local, external-beam radiation. It is not thought to involve the cervical spine directly, although local invasion of the skull base is common. METHODS: A review of the medical records and radiographs of the only patient known to develop this complication of radiation used to manage nasopharyngeal carcinoma. RESULTS: Atlantoaxial instability developed in a patient as a result of repeat radiation for a locally recurrent tumor. The instability was associated with intrusion of the anterior arch of C1 into the posterior nasopharynx and was managed successfully with a posterior stabilization using transarticular screws and supplemental wiring. CONCLUSIONS: Patients who have undergone local irradiation for nasopharyngeal carcinoma may be at risk for developing atlantoaxial instability.     

Analysis of regulated exocytosis in adrenal chromaffin cells: insights into NSF/SNAP/SNARE function

In a duplicate study during 1987-1991, 478 24-h duplicate samples from 14 homes for elderly people and 10 homes for youth were investigated for their contents of selected harmful substances. The analyses covered 45 active substances of pesticides, 17 PCB-congeners as well as lead, cadmium, and nitrate contents. Pesticides could be detected only in 15% of the investigated samples. The pesticide contents reached max. 8% of the respective FAO/WHO-limits. As the mean intake of the three most important PCB-congeners (sum of the congeners 138, 153, and 180) values of 0.9 and 1.1 micrograms per day and ration or person, respectively, were found. Also in the worst case the daily PCB intake was below the recommended ADI value of the FDA of 1 microgram/kg of body weight. The daily nutritional intake of lead and cadmium via the investigated daily rations reached about 5.6% and 20% of the Provisionally Tolerably Weekly Intake values of the FAO/WHO. The mean nitrate content of the duplicate portions was 101 mg per day and person (median: 79 mg per day and person). Referred to the median value the WHO limit (3.65 mg/kg body weight and day) was exhausted to about 36%.     

Cardiac autonomic dysfunction in survivors of acute lymphoblastic leukemia in childhood

Lower levels of baseline ventilatory function have consistently been associated with increased risk of cardiovascular mortality in prospective studies, but the underlying mechanisms are not known. Increased risk of coronary heart disease is associated with higher serum insulin levels. This report examines the relationship between ventilatory function and indirect measures of insulin resistance. Cross-sectional data from 922 nondiabetic participants in the Normative Aging Study were analysed using multiple linear regression models with adjustment for potential confounders. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were examined in relation to indicators of insulin resistance, i.e. fasting insulin and the fasting insulin resistance index (FIRI). Diabetics were excluded because impaired insulin secretion interferes with the validity of these as measures of insulin resistance. Fasting insulin and FIRI were negatively correlated with FVC and FEV1 (all p< 0.001). These associations persisted after adjusting for potential confounders including age, height, body mass index, waist to hip circumference ratio, physical activity, alcohol intake and smoking in separate multiple linear regression models, for both insulin (all p< or =0.0008) and FIRI (all p< or =0.0001). Negative cross-sectional associations between ventilatory function and indirect measures of insulin resistance were found in nondiabetic males. Insulin resistance may contribute to the previously unexplained association between ventilatory function impairment and cardiovascular mortality. Mechanisms underlying the relationship between insulin resistance and decreased ventilatory function remain to be elucidated.     

Age-related changes in sympathetic modulation of sensory nerve activity in rat skin

OBJECTIVES: Sensory nerves play an important role in mediating neurogenic inflammation and subsequent tissue healing. A decrease in sensory nerve function with increasing age has been reported to correlate with poor tissue healing. Sympathetic nerves are known to modulate sensory nerve function, and changes in this modulation could also have important implications with ageing. The aims of this study were to examine the effect of different frequency electrical stimulation (ES) on the microvascular responses obtained to sensory nerve activation in young, aged and capsaicin-pretreated rats and modulation of these responses by sympathetic efferents. METHODS: Using laser Doppler flowmetry, vascular responses to antidromic ES of the sciatic nerve were monitored in the base of vacuum-induced blisters in the hind footpad. The non-selective alpha-adrenoceptor antagonist phentolamine (3 mg/kg, i.v.) was administered 20 min prior to ES. RESULTS: At high frequency ES (20V, 2ms, 15Hz for 1 min), the vascular response in old rats was significantly reduced (46 percent decrease, p < 0.05) compared to young control. At low frequency ES (20 V, 2 ms, 5 Hz for 1 min) however, older rats produced similar vascular responses to the young. Capsaicin-pretreated rats showed significantly reduced vascular responses to both high and low frequency ES, regardless of age. Pretreatment with phentolamine significantly increased the microvascular response in young rats at high (87 percent) and low (36 percent) frequency ES. In contrast, phentolamine significantly increased the ES-induced response in old rats at high frequency only (147 percent increase). CONCLUSIONS: The results suggest that the aged sensory nerve responds preferentially to low frequency ES and that sympathetic efferents exert an inhibitory modulatory effect on the vascular response evoked by sensory nerve stimulation. There are age-related changes in sympathetic modulation of sensory nerve-mediated responses which is dependent on stimulation frequency.     

Physiological phosphorylation of protein kinase A at Thr-197 is by a protein kinase A kinase

Phosphorylation of the catalytic subunit of cyclic AMP-dependent protein kinase, or protein kinase A, on Thr-197 is required for optimal enzyme activity, and enzyme isolated from either animal sources or bacterial expression strains is found phosphorylated at this site. Autophosphorylation of Thr-197 occurs in Escherichia coli and in vitro but is an inefficient intermolecular reaction catalyzed primarily by active, previously phosphorylated molecules. In contrast, the Thr-197 phosphorylation of newly synthesized protein kinase A in intact S49 mouse lymphoma cells is both efficient and insensitive to activators or inhibitors of intracellular protein kinase A. Using [35S]methionine-labeled, nonphosphorylated, recombinant catalytic subunit as the substrate in a gel mobility shift assay, we have identified an activity in extracts of protein kinase A-deficient S49 cells that phosphorylates catalytic subunit on Thr-197. The protein kinase A kinase activity partially purified by anion-exchange and hydroxylapatite chromatography is an efficient catalyst of protein kinase A phosphorylation in terms of both a low Km for ATP and a rapid time course. Phosphorylation of wild-type catalytic subunit by the kinase kinase activates the subunit for binding to a pseudosubstrate peptide inhibitor of protein kinase A. By both the gel shift assay and a [gamma-32P]ATP incorporation assay, the enzyme is active on wild-type catalytic subunit and on an inactive mutant with Met substituted for Lys-72 but inactive on a mutant with Ala substituted for Thr-197. Combined with the results from mutant subunits, phosphoamino acid analysis suggests that the enzyme is specific for phosphorylation of Thr-197.     

Solving applied general equilibrium models represented as a mixture of linearized and levels equations

General equilibrium moels are usually represented as a system of levels equations (e.g., in North America) or a system of linearized equations (e.g., in Australia). Either representation can be used to obtain accurate solutions. General-purpose software is available in both cases-GAMS or MPS/GE is typically used by levels modellers and GEMPACK by linearizers. Some equations (notably accounting identities) are naturally expressed in the levels while others (especially behavioural equations) are naturally expressed in a linearized form. This paper describes the new GEMPACK facility for solving models represented as a mixture of levels and linearized equations and discusses the advantages to modellers of using such a representation.