Short-term psychological impact of the BRCA1/2 test result in women with breast cancer according to their perceived probability of genetic predisposition to cancer.

BACKGROUND: The effect of BRCA1/2 gene test result on anxiety, depression, cancer-related thought intrusion or avoidance and perceived control over cancer risk was assessed in breast cancer (BC) patients, according to their perceived probability of genetic predisposition to cancer. METHODS: Two hundred and forty-three (89% response rate) women with BC completed questionnaires after an initial genetic counselling visit (T1), of which 180 (66%) completed questionnaires again after receiving the BRCA1/2 results (T2). The discrepancy between women's perceived probability of cancer genetic predisposition at T1 and the geneticist's computed estimates was assessed. RESULTS: In all, 74% of women received a negative uninformative (NU), 11% a positive BRCA1/2 and 15% an unclassified variant (UV) result. On hierarchical regression analysis, in women with a positive BRCA1/2 result (vs NU or UV), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted lower levels of anxiety at T2 (ß=-0.28; P<0.01), whereas in women receiving a UV result (vs NU or positive BRCA1/2), a lower perceived probability of cancer genetic predisposition than objective estimates at T1 predicted higher levels of anxiety (ß=0.20; P<0.01), depression (ß=0.19; P<0.05) and intrusion (ß=0.18; P<0.05) at T2. CONCLUSION: The type of BRCA1/2 test result differently affects distress according to women's perceived probability of genetic predisposition before testing.

Latrepirdine increases cerebral glucose utilization in aged mice as measured by [18F]-fluorodeoxyglucose positron emission tomography.

Latrepirdine is hypothesized to exert a unique mechanism of action involving stabilization of mitochondria that may have utility in treating Alzheimer's disease. However, the ability of latrepirdine to improve cognition in Alzheimer's disease (AD) is controversial due to a discrepancy between the positive signal reported in the multi-site phase II clinical trial where latrepirdine met all primary and secondary endpoints [Doody et al. (2008) Lancet 372:207-215], and the subsequent null effect observed in a multicenter, phase III trial. While dysfunction of mitochondria and abnormal energy metabolism has been linked to AD pathology, no studies have been reported that investigate latrepirdine's effect on cerebral glucose utilization (CGU). Glucose metabolism, following acute latrepirdine administration, can be used to help dose selection in Phase I dose-ranging studies. The aim of the current study was to assess changes in CGU in young and aged mice in vivo using [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) after acute treatment with latrepirdine. Two ages of B6SJLF2 mice (5 and 20 months old) were tested. Three test-retest FDG-PET baseline scans were assessed across all subjects. As CGU was heterogeneous in aged mice, compared to young mice, aged subjects were rank ordered and then counterbalanced into two CGU homogenous groups. In Studies 1 and 2, latrepirdine (1.0 mg/kg) significantly enhanced CGU in aged mice. In contrast, Study 3 revealed that latrepirdine did not modulate CGU in young mice. Monitoring changes in CGU in response to acute drug administration may represent an imaging biomarker for dose selection in AD. Further studies that would establish the translation from mice to non-human primates to humans need to be investigated to confirm the utility of FDG-PET in dose-selection for mitochondrial modulators.

Unit dose sampling and final product performance: an alternative approach.

This article documents a proposed plan for validation testing for the content uniformity for final blends and finished solid oral dosage forms (SODFs). The testing logic and statistical justification of the plan are presented. The plan provides good assurance that a passing lot will perforin well against the USP tablet content uniformity test. The operating characteristics of the test and the probability of needing to test for blend sampling bias are reported. A case study is presented.

Therapeutic percutaneous injections in the treatment of malignant acetabular osteolyses.

Percutaneous injection of methylmethacrylate or ethanol may provide marked pain relief or bone strengthening in patients with malignant acetabular osteolyses who are unable to tolerate surgery. Injection of methylmethacrylate is usually indicated when osteolysis involves the weight-bearing part of the acetabulum (ie, the acetabular roof); in all other cases, ethanol injection is preferred. Ethanol and methylmethacrylate injections may be performed together if both weight-bearing and nonweight-bearing parts of the acetabulum are involved or extensive soft-tissue involvement is present. Moreover, these injections may be performed prior to radiation therapy, which complements their action due to similar but delayed effects on pain, or after radiation therapy that failed to relieve pain or in cases of local recurrence. Radiography and computed tomography must be performed prior to therapeutic percutaneous injection to assess the location and extent of the lytic process, the presence of cortical destruction or fracture, and the presence of soft-tissue involvement. Fever and transitory worsening in pain may occur secondary to inflammatory reaction in the hours following injection; however, these side effects usually resolve spontaneously within 1-3 days. The decision to perform therapeutic percutaneous injections should be made by a multidisciplinary team because the choice between this option and alternative methods of treatment depends on several factors including the location of the lesion, the local and general extent of the disease, the pain and functional disability experienced by the patient, and the patient's state of health and life expectancy.

Respiratory involvement in relapsing polychondritis. Clinical, functional, endoscopic, and radiographic evaluations.

Although respiratory involvement occurs in 50% of patients with relapsing polychondritis (RP) and augurs a poor prognosis, few previous studies have provided complete descriptions of respiratory tract involvement. For this reason, we investigated the respective role of clinical, functional, endoscopic, and radiographic (computed tomography [CT]) examinations in 9 consecutive patients with RP and lower respiratory tract localization. All exhibited cough, dyspnea, and wheezing. Eight had a nonreversible obstructive pattern with a marked decrease of the maximal flow ratio at 75% and 25% of vital capacity. Rotman functional criteria were evaluated to differentiate upper from lower respiratory tract involvement; they were consistent with the results of other examinations in 4/9 cases. Endoscopic examination showed moderate to severe inflammation in 8/9 patients; tracheal stenosis was present in 6/9 patients, bronchial stenosis in 4/9 patients, and tracheal collapse in 7 cases. CT showed tracheal stenosis in 8/9 patients (diffuse, 7; localized, 1) and bronchial stenosis in 6/9 patients. Tracheobronchial wall thickening and/or calcifications were observed in 7 cases. Clinical symptoms are of poor specificity for defining respiratory involvement precisely, although degree of dyspnea is correlated to the decrease in forced expiratory volume in 1 second (FEV1). Functional criteria were helpful in evaluating the obstructive ventilatory defect but did not differentiate, in most cases, the respective part of lower and upper respiratory involvement when using Rotman criteria. Compared to CT findings, endoscopic examination failed to identify tracheal and bronchial stenosis and tracheal wall alterations at an early stage of the disease. In our series CT appears to be a reliable method to identify tracheal and bronchial involvement and can be repeated safely during the course of the disease.

Percutaneous vertebroplasty: state of the art.

Vertebroplasty is an effective new radiologic procedure consisting of the percutaneous injection of a biomaterial, usually methyl methacrylate, into a lesion of a vertebral body. This technique allows marked or complete pain relief and bone strengthening in most cases. The principal indications for vertebroplasty are osteolytic metastasis and myeloma, painful or aggressive hemangioma, and osteoporotic vertebral collapse with debilitating pain that persists despite correct medical treatment. Radiography and computed tomography must be performed in the days preceding vertebroplasty to assess the extent of vertebral collapse, the location and extent of the lytic process, the visibility and degree of involvement of the pedicles, the presence of cortical destruction or fracture, and the presence of epidural or foraminal stenosis caused by tumor extension or bone fragment retropulsion. Leakage of methyl methacrylate during vertebroplasty may cause compression of adjacent structures and necessitate emergency decompressive surgery; thus, the procedure should be performed only in a surgical center. The decision to perform vertebroplasty should be made by a multidisciplinary team because the choice between vertebroplasty, surgery, radiation therapy, medical treatment, or a combination thereof depends on a number of factors. Radiologists need to be aware of the various indications for vertebroplasty and of potential future developments and applications of the procedure.

Percutaneous vertebroplasty for osteolytic metastases and myeloma: effects of the percentage of lesion filling and the leakage of methyl methacrylate at clinical follow-up.

PURPOSE: To determine whether the percentage of vertebral lesion filling and the leakage of methyl methacrylate have any clinical significance at follow-up. MATERIALS AND METHODS: Forty percutaneous vertebroplasties were performed for metastases (30 cases) and myeloma (10 cases) in 37 patients. A computed tomographic scan was obtained 1-8 hours after methyl methacrylate injection and was used to assess the percentage of lesion filling by methyl methacrylate and the leakage of methyl methacrylate into the epidural tissues, neural foramina, intervertebral disks, venous plexus, and paravertebral tissue. The results were correlated with those obtained at clinical follow-up. RESULTS: Partial or complete pain relief was sustained in 36 of 37 patients. Pain relief was not proportional to the percentage of lesion filling. Clinical improvement was maintained in most patients. The 15 epidural leaks, eight intradiskal leaks, and two venous leaks of methyl methacrylate had no clinical importance. Two of eight foraminal leaks produced nerve root compression that required decompressive surgery. One of 21 paravertebral leaks produced transitory femoral neuropathy. CONCLUSION: Pain relief can occur despite insufficient lesion filling. In most patients, intradiskal and paravertebral leaks of cement had no clinical importance.

[Normal and pathological aspects of the glenoid labrum in opaque arthro-scanner]. / Aspects normaux et pathologiques du bourrelet glénoïdien en arthroscanner opaque.

The morphology of the glenoid labrum was studied by CT arthrography in 88 patients. These were divided in 2 groups. In the first group, the patients underwent CT arthrography for a clinical instability of the shoulder. The second group was the reference group to study the morphology of the glenoid labrum, it included patients with rotator cuff tears or other pathology of the shoulder, without clinical instability. We described the normal labrum which presents important morphologic variations. Its study may be difficult because of the proximity of capsular structures of the shoulder, mainly the gleno-humeral ligaments. The normal variants and the pathologic aspects of the labrum were studied: the clefts, tears and degenerative phenomenous. The cleft aspect was studied comparatively in the instable population and in the reference population.

Multianalyte assay system developed for drugs of abuse.

A simple, 10-min immunoassay system has been developed that simultaneously screens for five different classes of drugs of abuse in a urine sample. This system tests for amphetamines, cannabinoids, cocaine metabolites, opiates, and phencyclidine, and each assay has a specific preset cutoff concentration. Accuracy is > 99% for reporting positive or negative results for samples with 200% or 50%, respectively, of the cutoff concentrations of the drugs. Tests of a panel of 96 compounds yielded only three cases of nonspecific reactivity (at a drug concentration of 100 mg/L). Another panel of 12 compounds that could normally be found in urine samples was also evaluated and no interferences were observed. Concordance was > 95% between this system and the comparable automated immunoassays for detecting drugs of abuse. Greater than 98% of GC/MS-confirmed positive samples gave positive results with this assay system.

Activation and oligomerization of immobilized biodegradative L-threonine dehydrase.

Biodegradative L-threonine dehydrase of Escherichia coli (radio labeled with [3H]pyridoxine) was immobilized on CNBr-activated Cl-Sepharose. The specific catalytic activity and S0.5 values of the matrix-bound dehydrase in the presence of AMP were similar to those of the soluble oligomeric enzyme in the presence of AMP (matrix-bound, associated dehydrase). When the bound dehydrase was washed with AMP-free buffer, about 50% of the bound dehydrase was removed and about 50% remained attached, as measured by radioactivity. The resulting matrix-bound, dissociated dehydrase possessed activity in the absence of AMP as is characteristic of soluble, unactivated dehydrase. The bound, dissociated dehydrase was capable of binding nearly an equal amount of soluble dehydrase in the presence of AMP; this treatment raised the specific enzyme activity of the bound dehydrase to 83% of that of the original matrix-bound, associated dehydrase. These observations correlate with the effects of AMP on the activity and quaternary structure of soluble dehydrase. When AMP was added to the matrix-bound, dissociated dehydrase, the activation observed was only a small fraction of that obtained with soluble dehydrase plus AMP. The failure of AMP to activate the major fraction of immobilized dehydrase monomer strongly suggests that dimerization is required in the activation by AMP.

Secondary kinase reactions catalyzed by yeast pyruvate kinase.

1. Yeast pyruvate kinase (EC 2.7.1.40) catalyzes, in addition to the primary, physiologically important reaction, three secondary kinase reactions, the ATP-dependent phosphorylations of fluoride (fluorokinase), hydroxylamine (hydroxylamine kinase) and glycolate (glycolate kinase). 2. These reactions are accelerated by fructose-1,6-bisphosphate, the allosteric activator of the primary reaction. Wth Mg2+ as the required divalent cation, none of these reactions are observed in the absence of fructose-biphosphate. With Mn2+, fructose-bisphosphate is required for the glycolate kinase reaction, but merely stimulates the other reactions. 3. The effect of other divalent cations and pH on three secondary kinase reactions was also examined. 4. Results are compared with those obtained from muscle pyruvate kinase and the implications of the results for the mechanism of the yeast enzyme are discussed.