Molecular pathologic analysis enhances the diagnosis and management of Muir-Torre syndrome and gives insight into its underlying molecular pathogenesis.

The Muir-Torre syndrome (MTS) is an autosomal dominantly inherited disorder, characterized by visceral malignancies and sebaceous skin lesions. In a subset of MTS families the disease is due to an underlying DNA mismatch-repair defect. We have identified a MTS family whose spectrum of reported neoplasia included adenocarcinomas of numerous gastrointestinal sites, carcinomas of the endometrium, ovary and breast, papillary transitional cell carcinoma of the ureter, a range of cutaneous tumors, as well as keratoacanthomas. All tumors were tested for microsatellite instability and immunohistochemically stained for expression of MLH1 and MSH2 proteins. All tumors were found to be microsatellite unstable and lacking in MSH2 protein expression. The subsequent mutation detection focused on hMSH2, and a germline mutation was identified (CAA-->TAA, Gln-->STOP, codon 337). This mutation was subsequently found in a family member with a single skin lesion only. We propose that the combination of immunohistologic and microsatellite instability analysis can be exploited to screen individuals with characteristic skin lesions even before development of visceral tumors and to direct the subsequent germline mutation search. The profile of microsatellite instability and the genes rendered dysfunctional differed between tumor samples, suggesting that the molecular pathogenesis varied between lesions, despite a common germline mutation.     

Tissue distribution of terbinafine in rats.

Terbinafine is an allylamine antifungal agent that is highly lipophilic and keratophilic. The aim of this study was to investigate terbinafine distribution in peripheral and visceral tissues after intravenous administration to rats. Terbinafine, 6 mg/kg, was administered to 33 male Sprague-Dawley rats via a jugular vein cannula over 30 s. Groups of 3 rats were sacrificed at each of 11 time points (up to 24 h), and plasma and tissues were dissected, sampled, and analyzed by high-performance liquid chromatography. Terbinafine plasma concentrations declined in a triexponential fashion, with an estimated elimination half-life of 10 h. The estimated clearance of terbinafine in rats was 2 L/h/kg and the volume of distribution at steady state was 6 L/kg. The tissue-to-plasma partition coefficient (K(p)) of terbinafine for different tissues was calculated using the ratio of the area under the curve of concentration-time for tissues (AUC(tissue)) to that for plasma (AUC(plasma)), by parametric and semiparametric approaches. There was good agreement between K(p) estimates determined by different approaches. The preferential distribution of terbinafine to adipose and skin (K(p) = 49 and 45, respectively) was consistent with the lipophilicity of the drug. Uptake of terbinafine into brain (K(p) = 1.3) and muscle (K(p) = 1.0) was significantly lower. In conclusion, terbinafine displays extensive uptake to peripheral tissues, which contributes to the long elimination half-life of this drug.     

Modification of the atrophic effects of tenotomy on mouse soleus muscles by various hind limb nerve lesions and different levels of voluntary motor activity

The response of mouse soleus muscles to transection of the proximal tendon was examined at both gross and microscopic levels. Changes in length and mass of the muscle, and in the dimensions, number, and ATPase staining characteristics of the muscle fibers, were determined at various times to 4 to 6 weeks after tenotomy. Muscles shortened by more than 50% and lost about 60% of their mass. Fiber cross-sectional area increased, and then decreased and stabilized below control after 7 days, and degenerative lesions appeared in some fibers. Fiber numbers decreased by nearly 20% and then remained constant, apparently by regeneration of new fibers replacing atrophied ones. The proportion of muscle fibers of the slow-twitch type was reduced. No structural or functional changes in motor nerve terminals could be detected, except for detachment from severely atrophied fibers. Concurrent denervation decreased both shortening and the loss of mass after tenotomy. Fiber diameter decreased but no significant degenerative lesions or loss of fibers could be detected. Fiber-type composition was unchanged. These experiments provide quantitative information about the degenerative changes in tenotomized muscles without the variable complications arising from tendon reattachment. Comparison of the responses with those that follow transection of the Achilles tendon shows that the degree of atrophy is independent of the extent of active muscle shortening after tenotomy.     

Confirmation of a prognostic index for patients with metastatic breast cancer treated by endocrine therapy

Summary We have previously reported a retrospectively constructed index which can accurately predict survival at the time of diagnosis of symptomatic metastatic breast cancer. The index, derived from a Cox model, is scored: Index score = (4 × Grade) – (6 × ER) + (4 × SIMD) – (0.1 × DFI), where histological grade is scored 1–3 (good, moderate, or poor), oestrogen receptor (ER) is scored 0 (negative) or 1 (positive), site of initial metastasis (SIMD) is scored 1–4 for bone only, lung only, bone and lung, or visceral metastases, respectively, and disease-free interval (DFI) is measured in months. Patients were divided into three prognostic groups on the basis of index score.In the present study we have tested this index prospectively on a new group of 147 patients with metastatic breast cancer. The percentage of patients in each of the three groups was similar between the retrospective and prospective studies. In the prospective study the difference in survival between the 3 groups was highly significant (p<0.001), confirming our retrospective analysis. No single one of the four factors was as powerful in predicting survival as the index itself. We now use this index in our patient management.     

Age-associated chromosome 21 loss in Down syndrome: Possible relevance to mosaicism and Alzheimer disease

We previously observed low level mosaicism (2–4% normal cells) in phytohemagglutinin-stimulated peripheral blood lymphocytes (PBL) in 29% of a small group of elderly persons with Down syndrome (DS). An analysis of cytogenetic data on 154 trisomy 21 cases (age 1 day to 68 years) showed that the proportion of diploid cells in such cultures significantly increased (P < 0.005) with advancing age. Thus, the “;occult”; mosaicism in PBL of the elderly persons with DS is likely due to the accumulation of cells that have lost a chromosome 21. A consequence of chromosome 21 loss could be uniparental disomy of the 2n cells, a factor that might have significant biological consequences if some chromosome 21 genes are imprinted. Loss of a chromosome 21 from trisomic cells might result in tissue-specific mosaicism and “;classical”; mosaicism in different age groups. Chromosome 21 loss might also be relevant to the development of Alzheimer-type dementia in DS and in the general population. © 1993 Wiley-Liss, Inc.     

Nuclear Magnetic Resonance Relaxometry in a Penicillin Model of Focal Epilepsy

Magnetic resonance imaging (MRI) is effective in demonstrating pathologic lesions in patients with epilepsy. It has been suggested that MRI might also reveal functional abnormalities at an interictal epileptic focus when no gross structural change such as gliosis or tumor is present. Experimental epileptic foci were produced by topical application of penicillin to the cortex of rats. In vitro proton nuclear magnetic resonance (NMR) relaxometry of tissue excised from the experimental foci revealed an increase in spin-echo relaxation time as compared to that in control tissue. The elevated relaxation times occurred in tissue samples from areas of active electroencephalographic (EEG) spiking. This is the first direct demonstration of an alteration in proton magnetic resonance parameters by functional abnormalities (focal interictal spike activity) in the brain, supporting the concept that MRI might be similarly affected.     

The effects of polychlorinated biphenyls given prenatally on the neurobehavioral development of mice.

When tested at adulthood, albino mice exposed in utero to 3,4,3′,4′-tetrachlorobiphenyl (TCB) demonstrated signs of neurotoxicity. The most severely affected subjects (TCB-spinners) displayed a neurobehavioral syndrome consisting of intermittent stereotypic circling, head bobbing, and hyperactivity. TCB-spinners were found to be markedly hyperactive during the dark phase of the diurnal phase and showed impaired forelimb grip strength, ability to traverse a wire rod, visual placement responding, and acquisition of one-way avoidance. Some mice did not display the spinning syndrome (TCB-nonspinners), but were found to be deficient in traversing a wire rod and avoidance acquisition. None of the TCB-exposed mice were found to have depressed neuromuscular reflexes in response to a variety of stimuli. Tissue distribution studies demonstrated that TCB levels were not detectable in adult mice following prenatal exposures. The results of these experiments demonstrate that prenatal exposure to TCB can influence neurobehavioral functioning of mice during adulthood and, in some cases, such effects can be observed in the absence of clinical signs of toxicity.