Effect of age and breast density on screening mammograms with false-positive findings

OBJECTIVE: The objective of this study was to examine the effect of breast density and age on screening mammograms with false-positive findings. MATERIALS AND METHODS: The study sample was taken from the Washington State Mammography Tumor Registry, which links data from participating radiologists with the Puget Sound Cancer Surveillance System and the Washington State Cancer Registry. Participants (n = 73,247) were women 35 years old and older who underwent screening mammography for which an assessment and a four-category density rating were coded. A total of 46,340 mammograms were sampled to avoid interpreter bias. In this study of false-positive mammograms, only women with no diagnosis of breast cancer within 12 months of the index mammogram were included. Logistic regression was used to estimate the odds ratios of a false-positive mammogram being associated with each category of breast density or age, adjusting for the other factor as a covariate. RESULTS: After controlling for breast density, we found that the risk of a false-positive mammogram was not affected by age (p = 27). However, the trend of increasing risk of a false-positive mammogram with increasing breast density was highly significant (p < .001). Women with extremely dense breast tissue were almost two times more likely to have a false-positive mammogram than were women with fatty breast tissue. This effect persisted after controlling for age. CONCLUSION: Breast density, not age, is an important factor when predicting risk of a false-positive mammogram. Breast density should be considered when educating individual women on the risks and benefits of screening mammography.     

New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects

Rationale: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy [“therapeutic index” (TI)] has fit well with clinical results. Objectives: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D₁ antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT₂ serotonergic/DA D₁ and D₂ antagonist) and DOD 647 (DA D₁ and D₂ antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine’s neuropharmacology. Methods: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI. Results: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2–4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3–5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses. Received: 31 October 1997/Final version: 9 November 1998     

Risk factors in calcium stone disease of the urinary tract.

The concept that calcium stone formation may be explained on the basis of a number of risk factors is developed. The main risk factors involved are shown to be calcium, oxalate, pH, acid mucopolysaccharides and uric acid. A method is described for calculating and combining the individual risk factors into a measure of the "relative probability" of forming stones (PSF). PSF values are generally lower in normal subjects than in stone-formers. Amongst the normals, PSF values are lower in children and women than in men. Recurrent stone-formers have the highest PSF values and these correlate well with the severity of the diseases as defined by the stone episode rate of the patient. Single stone-formers have PSF values intermediate between those of normal men and those of recurrent stone-formers.     

Lower Limb Swelling Due to Femoral Aneurysms

A man of 53 presented with left lower limb swelling, which was found to be caused by compression of the femoral vein by a common femoral artery aneurysm. Seven years later a similar situation developed in the opposite limb. On each occasion the diagnosis was confirmed radiologically and the symptoms resolved rapidly following surgery.

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Enhanced cell killing in lewis lung carcinoma and a human pancreatic-carcinoma xenograft by the combination of cytotoxic drugs and misonidazole.

The "chemosensitizing" properties of the radiosensitizer misonidazole (MISO) were examined in 2 tumour systems, murine Lewis lung carcinoma and human pancreatic adenocarcinoma xenografted into immune-suppressed mice, using a soft-agar colony assay to measure tumour-cell survival. In mice bearing Lewis lung tumour, the administration of MISO simultaneously with melphalan, cyclophosphamide. CCNU, FU or vincristine gave substantial enhancement of cytotoxicity (DEFs from 1.5 to 3.5). However, no enhancement was seen with bleomycin, VP 16-213 or cis-Pt. The same level of enhancement of cyclophosphamide effect (DEF = 2.0) was seen with both cell survival and growth delay end-points effect (DEF = 2.0) was seen with both cell survival and growth delay end-points of tumour response. Enhancement was also seen in the human tumour xenograft with melphalan, cyclophosphamide and MeCCNU, using a cell survival assay, but cis-Pt was again not enhanced.     

The muscarinic M1/M4 receptor agonist xanomeline exhibits antipsychotic-like activity in Cebus apella monkeys.

Xanomeline is a muscarinic M(1)/M(4) preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (-)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits D-amphetamine- and (-)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis.     

Comparison of total alkaline phosphatase and three assays for bone-specific alkaline phosphatase in childhood and adolescence

We compared serum levels of total alkaline phosphatase (TAP) and bone-specific alkaline phosphatase (BAP) as determined by three different assays (lectin affinity electrophoresis, immunoradiometric assay, enzyme-linked immunosorbent assay) in subjects aged 5–20 years suffering from X-linked hypophosphatemic rickets ( n = 14), chronic renal failure ( n = 10) and chronic cholestatic liver disease ( n = 16). Results were compared to controls of the same age and were expressed as standard deviation scores (SDS). TAP correlated significantly with BAP ( r > 0.9 for each assay; p <0.001) in controls. In children with cholestatic diseases, TAP (median SDS + 2.0) was elevated, but BAP, as measured by the electrophoretic assay, was within the reference range for most patients (median SDS: -0.4; p = 0.003 for the difference between the median SDS of TAP and BAP). In contrast, results for BAP as determined by the two immunoassays were not significantly different from TAP in any of the three patient groups ( p > 0.05 in each group for both assays). In this study, the two immunoassays did not have a detectable advantage over lectin affinity electrophoresis in the determination of BAP.     

Isolation and characterization of propagable cell lines (HUNC) from the androgen-sensitive Dunning R3327H rat prostatic adenocarcinoma

The Dunning H rat prostate tumor (R3327H) is a widely used experimental model of human prostatic adenocarcinoma (CaP). The Dunning H tumor has been characterized as androgen-sensitive, androgen-receptor (AR) positive, prostate-specific antigen and prostatic acid phosphatase (PAP) positive. To date, the tumor has been maintained by serial passage in vivo because of the lack of an in vitro cell line that retains the characteristics of the in vivo tumor. The objective of the present study was to establish a propagable cell line from R3327H adenocarcinoma that maintained androgen sensitivity and expression of AR, PSA and PAP. Tissue harvested from an in vivo R3327H tumor was dissociated with collagenase and placed into Richter's improved media (with supplements). A cytokeratin-positive epithelial cell line (HUNC- E) and a vimentin-positive stromal cell line (HUNC-S) were generated from the primary culture, subcultured continuously for >300 days, and passaged >50 times. Survival of the HUNC-E cell line in vitro depended on several media supplements, including nicotinamide, insulin, transferrin, selenium and epidermal growth factor (EGF). HUNC-E cells expressed AR and produced PSA and PAP throughout the culture period, as confirmed by immunocytochemistry and Western blot analyses. Addition of 14 nM testosterone (T) or dihydrotestosterone (DHT) to HUNC-E cells, stimulated DNA synthesis as well as anchorage-independent growth and PSA production, which demonstrated the androgen-sensitive nature of the cells in vitro. When HUNC-E and HUNC-S cells were combined in a 3:1 ratio and introduced subcutaneously into syngeneic male hosts, tumors formed in 2/3 animals with an average latency of 7 months. RT-PCR and immunocytochemical characterization of the HUNC cell lines revealed that the cells expressed several growth factors and their cognate receptors, including HGF, TGF-alpha and the TGF-betas, indicating the establishment of potential autocrine loops in the neoplastic cells. The HUNC-E and HUNC-S CaP cell lines, which retain the characteristics of the epithelial and stromal components of the in vivo R3327H tumor, will allow a more thorough and informative molecular and biological analysis of prostatic adenocarcinoma.