A randomized crossover trial of tamoxifen versus ovarian ablation for metastatic breast cancer in premenopausal women: A report of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial MA.1

Background: The outcome of breast cancer is usuallydetermined by multiple factors. Serum tumor necrosis factoralpha concentration has been found to be increasedin the circulation of patients with malignancy. Thisstudy was designed with the aim to investigateany correlation between the serum tumor necrosis factoralpha and the clinicopathological fetures and furthermore evaluatethe prognostic significance of serum tumor necrosis factoralpha concentration in breast cancer. Methods: Forty consecutivepatients with invasive breast cancer undergoing modified radicalmastectomy were prospectively included and evaluated. Venous bloodsamples were collected before the surgery. Sera wereobtained by centrifugation, and stored at – 70°C until assayed. The control group consisted 30healthy, age-matched subjects. Serum concentrations of tumor necrosisfactor alpha were measured by the quantitative sandwichenzyme immunoassay technique. The data on tumor size,age, estrogen receptor status, lymph node status andTNM staging were reviewed and recorded.Results: The mean value of serum tumor necrosis factor alphain patients with invasive breast cancer was 1.47± 0.58 pg/ml and that of the controlgroup was 0.98 ± 0.37 pg/ml, and thedifference was significant (P < 0.01). With univariableanalysis, patients with maximum tumor size of 5cm or larger (P=0.03), more advancedTNM staging (P < 0.01); and more advancedlymph node status (P < 0.01) were shownto have significantly higher serum concentrations of tumornecrosis factor alpha. However, with multivariable analysis, TNMstaging appeared as the only independent factor (P< 0.01) predicting the significant, higher serum concentrationsof tumor necrosis factor alpha. Conclusion: Preoperative evaluationof serum tumor necrosis factor alpha concentrations maybe a valuable parameter for reflecting the severityof staging for invasive breast cancer.     

A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)¹, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c_min), the maximum plasma concentration (c_max), the time to reach that concentration (t_max), the time interval during which the plasma concentration exceeds 50% of c_max (t₅₀), the area under the plasma concentration-time curve (AUC_72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC_72–96 (AUC_NDM and AUC_DAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL^-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.     

Donor hyperglycemia as a minor risk factor and immunologic variables as major risk factors for pancreas allograft loss in a multivariate analysis of a single institution''s experience.

The impact of multiple donor and recipient variables on functional survival of 307 cadaveric pancreas allografts transplanted in 253 recipients at the authors' institution between July 25, 1978 and September 4, 1990 was determined using the Cox proportional hazards regression model. Relative risk of graft loss was calculated for all cases as well as for technically successful (TS) ones. Factors with an impact in descending order of significance for TS cases were immunosuppression (RR = 3.9 for double-drug versus triple-drug maintenance, p less than 0.0001); recipient category (RR = 2.4 for pancreas alone versus simultaneous pancreas/kidney, p = 0.009); retransplantation (RR = 1.8 for retransplants versus primary grafts, p = 0.007); donor hyperglycemia (RR = 1.7 for blood glucose greater than or equal to 200 versus less than 200 mg/dL, p = 0.02); human leukocyte antigen (HLA) matching (RR = 2.1 for poor versus a good match, p = 0.04). A logistic regression analysis also was performed to determine which factors predisposed to technical failure; none were identified. To make the model as relevant as possible to their current program, the authors analyzed only the bladder-drained cases (n = 221; 1984 to 1990). All patients received triple therapy. Recipient category, retransplantation, donor hyperglycemia, and degree of HLA matching remained as significant risk factors. Construction of estimated survival curves showed that the results of retransplantation were significantly improved, and the penalty incurred by using hyperglycemic donors was partially ameliorated by using well-matched donors. Because preservation times up to 30 hours did not exert an adverse effect on outcome, an argument is made to share pancreata between centers to achieve good matches.     

An unusual rotational fracture-dislocation of the thoracic spine without neurologic sequelae internally fixed with a combined anterior and posterior approach

A rare complete lateral dislocation of the thoracic spine with preservation of neurologic function is reported. Anatomic reduction was obtained using an anterior approach and Harrington distraction rods for reduction followed by a broad plate and subsequent posterior segmental fixation and fusion. Long-term followup showed an excellent result.     

Large-scale identification of mammalian proteins localized to nuclear sub-compartments

Many nuclear components participating in related pathways appear concentrated in specific areas of the mammalian nucleus. The importance of this organization is attested to by the dysfunction that correlates with mis-localization of nuclear proteins in human disease and cancer. Determining the sub-nuclear localization of proteins is therefore important for understanding genome regulation and function, and it also provides clues to function for novel proteins. However, the complexity of proteins in the mammalian nucleus is too large to tackle this on a protein by protein basis. Large-scale approaches to determining protein function and sub-cellular localization are required. We have used a visual gene trap screen to identify more than 100 proteins, many of which are normal, located within compartments of the mouse nucleus. The most common discrete localizations detected are at the nucleolus and the splicing speckles and on chromosomes. Proteins at the nuclear periphery, or in other nuclear foci, have also been identified. Several of the proteins have been implicated in human disease or cancer, e.g. ATRX, HMGI-C, NBS1 and EWS, and the gene-trapped proteins provide a route into further understanding their function. We find that sequence motifs are often shared amongst proteins co-localized within the same sub-nuclear compartment. Conversely, some generally abundant motifs are lacking from the proteins concentrated in specific areas of the nucleus. This suggests that we may be able to predict sub-nuclear localization for proteins in databases based on their sequence.     

Induction of mosquitocidal activity in mice immunized with Anopheles gambiae midgut cDNA

Vaccines that induce mosquito-killing (mosquitocidal) activity could substantially reduce the transmission of certain mosquito-borne diseases, especially vaccines against African malaria vectors, such as the mosquito Anopheles gambiae. To generate and characterize antimosquito immunity we immunized groups of mice with two individual A. gambiae midgut cDNAs, Ag-Aper1 (a secreted peritrophic matrix protein) and AgMuc1 (a midgut-bound mucin), and an A. gambiae midgut cDNA library from blood-fed mosquitoes. We observed significantly increased mortality among mosquitoes that fed on either the AgMuc1- or the cDNA library-immunized mice compared to that of controls, but no differences were observed among those fed on Ag-Aper1-immunized mice. Analysis of the humoral and cellular immune responses from mice showed that the induced mosquitocidal effect was associated with immune profiles characterized by elevated tumor necrosis factor alpha and gamma interferon cytokine levels and very low antibody titers. Furthermore, an additional immunization of cDNA library-immunized mice with midgut protein shifted immunity toward a Th2-type immune response, characterized by elevated antibody titers and high interleukin-5 and interleukin-10 cytokine levels; importantly, mosquitoes feeding on these mice exhibited no undue mortality. Finally, when immune sera was ingested by mosquitoes through a membrane feeder, no effect on mosquito mortality was observed, indicating that serum factors alone were not responsible for the mosquitocidal effect. Our results demonstrate that mosquitocidal immunity in mice can be consistently generated by midgut cDNA immunization and suggest this cDNA-induced mosquitocidal immunity is cell mediated.     

Hippocampal granule cells are necessary for normal spatial learning but not for spatially-selective pyramidal cell discharge

Summary The effects of massive destruction of granule cells of the fascia dentata on the spatial and temporal firing characteristics of pyramidal cells in the CA1 and CA3 subfields of the hippocampus were examined in freely moving rats. Microinjections of the neurotoxin colchicine were made at a number of levels along the septo-temporal axis of the dentate gyri of both hemispheres, resulting in destruction of over 75% of the granule cells. By contrast there was relatively little damage to the pyramidal cell fields. As assessed by three different behavioral tests, the colchicine treatment resulted in severe spatial learning deficits. Single units were recorded from the CA1 and CA3 subfields using the stereotrode recording method while the animals performed a forced choice behavioral task on the radial 8-arm maze. Considering the extent of damage to the dentate gyrus, which has hitherto been considered to be the main source of afferent information to the CA fields, there was remarkably little effect on the spatial selectivity of place cell discharge on the maze, as compared to recordings from control animals. There was, however, a change in the temporal firing characteristics of these cells, which was manifested primarily as an increase in the likelihood of burst discharge. The main conclusion derived from these findings is that most of the spatial information exhibited by hippocampal pyramidal cells is likely to be transmitted from the cortex by routes other than the traditional trisynaptic circuit. These routes may include the direct projections from entorhinal layers II and III to CA3 and CA1, respectively.     

Physical training plasma lipoproteins and faecal steroid excretion in sedentary men

Thirty sedentary men aged 25-52 participated in a 4-month randomized and controlled study of the effects of exercise on plasma lipoproteins and faecal steroid excretion. After 4 months the aerobic training group showed a significant (P = 0.047) increase in physical work capacity (+38 watts) and a significant (P = 0.025) decrease in faecal total steroid excretion (-257 mg/day) compared to corresponding changes in the control group. The drop in faecal total steroid excretion in the men who trained was mainly due to a significant (P less than 0.05) fall in faecal neutral sterol excretion (-240 mg/day). Plasma lipoprotein lipid concentrations did not change significantly during the study although plasma levels of very low density lipoprotein (VLDL) cholesterol and low density lipoprotein (LDL) cholesterol tended to fall in the men who trained. In the aerobic training group individual changes in plasma LDL cholesterol levels were significantly correlated with decreases in faecal total steroid excretion (p = 0.615, P less than 0.05) and faecal neutral sterol excretion (p = 0.627, P less than 0.05). The results of this study show that regular exercise is associated with a drop in faecal neutral sterol excretion which, if sufficiently large, may be associated with a decrease in plasma LDL cholesterol concentration.