TNF receptors differentially signal and are differentially expressed and regulated in the human heart.

Tumor necrosis factor (TNF) utilizes two receptors, TNFR1 and 2, to initiate target cell responses. We assessed expression of TNF, TNFRs and downstream kinases in cardiac allografts, and compared TNF responses in heart organ cultures from wild-type ((WT)C57BL/6), TNFR1-knockout ((KO)), TNFR2(KO), TNFR1/2(KO) mice. In nonrejecting human heart TNFR1 was strongly expressed coincidentally with inactive apoptosis signal-regulating kinase-1 (ASK1) in cardiomyocytes (CM) and vascular endothelial cells (VEC). TNFR2 was expressed only in VEC. Low levels of TNF localized to microvessels. Rejecting cardiac allografts showed increased TNF in microvessels, diminished TNFR1, activation of ASK1, upregulated TNFR2 co-expressed with activated endothelial/epithelial tyrosine kinase (Etk), increased apoptosis and cell cycle entry in CM. Neither TNFR was expressed significantly by cardiac fibroblasts. In (WT)C57BL/6 myocardium, TNF activated both ASK1 and Etk, and increased both apoptosis and cell cycle entry. TNF-treated TNFR1(KO) myocardium showed little ASK1 activation and apoptosis but increased Etk activation and cell cycle entry, while TNFR2(KO) myocardium showed little Etk activation and cell cycle entry but increased ASK1 activation and apoptosis. These observations demonstrate independent regulation and differential functions of TNFRs in myocardium, consistent with TNFR1-mediated cell death and TNFR2-mediated repair.

DC-SIGN association with the Th2 environment of lepromatous lesions: cause or effect?

The clinical spectrum of leprosy is related to patients' immune responses. Non-responsiveness towards Mycobacterium leprae (ML) seems to correlate with a Th2 cytokine profile. The reason for such a polarized immune response remains unclear. The C-type lectin, DC-SIGN, expressed by subsets of dendritic cells (DCs) and macrophages, has previously been associated with Th2 responses. Here we show abundant DC-SIGN expression in lepromatous but not borderline tuberculoid leprosy, in both HIV-positive and HIV-negative patients. Moreover, we demonstrate that DC-SIGN can act as an entry receptor for ML, as it does for M. tuberculosis, through the cell wall component lipoarabinomannan. DC-SIGN is expressed on virtually all ML-containing cells, providing further evidence for its role as a receptor. DC-SIGN may therefore be induced on macrophages in lepromatous leprosy and may then contribute to mycobacterial entry into these cells.

Cardiac metastasis from a bronchial carcinoid: report of a case presenting with diffuse thickening of the left ventricular wall.

Bronchial carcinoids are low grade malignancies with an excellent prognosis and a low incidence of metastases. This report describes a case of a typical carcinoid tumour with metastases to the spine after four years and to the heart after eight years. Carcinoid tumours rarely metastasise to the heart and previous reports have identified gastrointestinal primaries as the source in most cases. This is the first published case of typical carcinoid tumour that metastasised to the heart from a bronchial primary.

The evaluation of liquid-based 'Cyto-SED' cytology of bronchioalveolar lavage specimens in the diagnosis of pulmonary neoplasia against conventional direct smears.

Historically, bronchioalveolar lavage (BAL) samples have been prepared by a direct smear (DS) technique. Recent advances in liquid-based cytology have led to a revolution in cytological specimen preparation. Cyto-SED system (CS) is a manual liquid-based cytology system, designed for small-scale use. A total of 137 samples from patients with radiographically detectable lesions underwent BAL procedures at Papworth Hospital NHS Trust over a 4-month period. After preparation for diagnostic purposes with the DS method, the remaining sample was prepared using the CS system. The slides produced were allocated a blind study number and screened by three independent screeners. The cellular morphology was well preserved and comparable between both techniques. Of the 137 patients, 38% were confirmed as malignant by cytology or histology; 71% of these malignant diagnosis were confirmed by the DS technique and 91% confirmed by the CS. The results demonstrate that the CS is a viable alternative to the DS technique. The cytological detail is clearly defined without a loss of three-dimensional information, thus aiding the differential diagnosis of malignancy. Cyto-SED cytology system yields a higher diagnostic accuracy than the conventional direct smear technique without compromising on cytological detail.

Context modulation of US signal value.

Context modulation of unconditioned stimulus (US) signal value was examined in two experiments. In Experiment 1, rats showed significantly more magazine entries after a single food pellet US in Context A (in which three additional pellets shortly followed) than in Context B (in which the delivery of three additional pellets was delayed). Experiment 2 replicated this effect and showed that any differences in contextual associative strength at the time the single food pellet was delivered did not importantly contribute to context modulation. Implications for theories of occasion setting and context modulation are considered.

Peripheral neuropathy in workers exposed to nitromethane.

BACKGROUND: Two workers from a headlight subassembly plant developed severe peripheral neuropathy. These workers had extensive, but brief (1-2 months) dermal and inhalational exposure to nitromethane, a solvent. METHODS: Environmental sampling was performed for nitromethane and ethyl cyanoacrylate. Medical records, including electrodiagnostic studies, were reviewed. Literature on nitromethane, ethyl cyanoacrylate, and other exposures in the workplace was reviewed. RESULTS: Electromyography and nerve conduction studies performed on these patients were consistent with a severe, axonal neuropathy. No etiology was discovered despite an extensive medical evaluation. Environmental sampling revealed exposure to nitromethane at the threshold limit value. CONCLUSIONS: The history of acute onset of severe peripheral neuropathy temporally associated with exposure to nitromethane is suggestive of a toxic neuropathy. While it cannot be definitively concluded that these two workers developed peripheral neuropathy secondary to exposures at work, occupational exposure to nitromethane appears to be the most likely etiology.

Two stage model for carcinogenesis: number and size distributions of premalignant clones in longitudinal studies.

The two stage clonal expansion model of carcinogenesis provides a convenient biologically based framework for the description of toxicologic and epidemiologic data on carcinogenesis. Under this model, a cancer cell is generated following the occurrence of two critical mutations in a single stem cell. Initiated cells that have sustained the first mutation undergo a stochastic birth-death process resulting in clonal expansion of the initiated cell population. In this article, we consider the analysis of longitudinal data on the number and size of premalignant clones, formed by clonal expansion of initiated cells. In particular, the joint distribution of the number of premalignant clones observed at different points in time in the same subject is derived. The application of these results in the statistical analysis of longitudinal data on the number and size of premalignant clones observed in initiation-promotion experiments is indicated.

The role of US signal value in contingency, drug conditioning, and learned helplessness.

In Pavlovian conditioning, organisms can learn that a conditioned stimulus (CS) signals the delivery of an unconditioned stimulus (US). The present paper first reviews research showing that organisms can also learn that a stimulus, normally considered to be a US, signals the delivery of another US. Second, the paper shows how such signal value may contribute to three conditioning phenomena that are of interest to many psychologists: contingency, drug conditioning, and learned helplessness. In addition to showing how such signal value may contribute to these three phenomena, suggestions for further research, as well as current gaps in the knowledge base, are outlined.

Serial feature negative training to a target unconditioned stimulus.

In serial feature-negative (SFN) training to a target unconditioned stimulus (US), eight rats received two types of intermingled trials: (1) trials in which a tone was followed by the delivery of a single food pellet US, and (2) trials in which the delivery of a single food pellet US was followed by three additional food pellets. Following SFN training, the tone showed little transfer to a partially reinforced light cue and the tone's negative modulation was eliminated after tone extinction. Implications for theories of occasion-setting are discussed.

Changing to core biopsy in an NHS breast screening unit.

We recently changed from using fine needle aspiration cytology to using core biopsy exclusively in the assessment of screen detected abnormalities. Two hundred and two biopsies (1% of women screened) were performed. Surgical histological confirmation was obtained in 111 patients (101 malignant and 10 benign). The remaining patients were either returned to standard 3-yearly screening or early repeat screening after 1 year. Analysis of the results was performed in accordance with the standards specified in the National Health Service Breast Screening Programme (NHSBSP) Publication Number 22. Absolute sensitivity was 89.3%, complete sensitivity was 93.2%, specificity (including patients undergoing both surgical excision and follow-up) was 88.7%. The predictive value of a positive (malignant) core biopsy result was 100%. The false negative rate was 3.9%. Twelve (5.9%) biopsies were classified inadequate for diagnosis. Core biopsy is a safe and accurate way of assessing screen detected abnormalities and can be used as a substitute for fine needle aspiration cytology with results that exceed the National Health Service Breast Screening Programme target standards, even in the learning phase.

Audit of necropsy reporting in East Anglia.

AIMS: To establish criteria for the information to be included in a necropsy report, and to improve the quality of necropsy reporting in the Anglia Region. METHODS: Discussion between Anglia histopathologists, based on the guidelines of the Royal College of Pathologists, led to a consensus about the ideal content of a necropsy report. Fifteen consecutive necropsies subsequently undertaken by each consultant were assessed against agreed standards. Reaudit was undertaken nearly two years later, without prior announcement. RESULTS: The initial standards achieved for demographic details (70%), history (87%), external examination (43-97%), internal examination (76-95%), organ weights (73%), cause of death in OPCS format (94%), and conclusion (90%) were discussed by the group. Changes to necropsy reporting documentation were proposed. Reaudit showed improvement in nearly all categories. CONCLUSIONS: Necropsy reporting in East Anglia is currently carried out to a reasonably high standard, and improvements have occurred as a result of the audit. There was no evidence that reports on coroners' necropsies were of a lower standard than those done for the hospital. Improvement in the format of the documentation increases the likelihood that all relevant and important data are recorded.

The use of histopathology in the practice of necropsy.

AIM: To examine current practice and to establish criteria for the use of histopathology in necropsy practice. METHODS: During an audit of necropsy reporting, consensus could not be reached about the use of routine histopathology. Therefore local guidelines were formulated and current practice was compared with these guidelines. Fifteen consecutive necropsies undertaken by each consultant were reviewed and the use of histopathology noted. RESULTS: In general, the standard of necropsy reporting was reasonably high. Tissue was retained for histopathology in 25% of necropsies and 72% of these necropsy reports included a histopathology report. Using the guidelines, the assessors judged that histopathology might have been valuable in a further 19%. It was felt that routine histopathology would not have been helpful in determining the cause of death in the remaining 56%. The importance of the pathologist's clinical judgement in individual cases was stressed. At reaudit, nearly two years later, there was no significant change in practice, reflecting the lack of consensus. CONCLUSIONS: Even when histopathology might contribute to finding the cause of death, it was not always done. However, the assumption that histology is invariably helpful in determining the cause of death is challenged.

Effect of amiodarone on the lung shown by polarized light microscopy.

OBJECTIVE: To show lipid deposits in the lung of patients treated with amiodarone. MATERIALS AND METHODS: Formalin-fixed, unstained frozen sections were used to reveal lipid deposits by means of polarized light. Lung tissues obtained at the postmortem examination of one patient and the surgical biopsy of another were available. RESULTS: Birefringent lipid deposits were seen in the alveolar lining cells and macrophages, as well as in the walls of arterioles and venules. CONCLUSIONS: To assess the effect of amiodarone on the lung, polarized light microscopy of unstained, frozen sections is a simple and rapid method.

Effect of US signal value on blocking of a CS-US association.

When an unconditioned stimulus (US) signals the delivery of a second US, there is poor conditioned responding to a conditioned stimulus (CS) that signals the second US. Using an appetitive conditioning preparation with rats, 3 experiments examined the factors that contribute to this poor conditioned responding. In Experiment 1, conditioned responding was improved when US-alone presentations came before, but not after, CS training. Experiment 2 showed that the effect in Experiment 1 was not due to context extinction, and Experiment 3 showed that context-US associations do not significantly contribute to responding in the US-US training procedure. The results show that poor conditioned responding is an acquisition deficit, arising from US, rather than context, signal value.

Epithelial-myoepithelial carcinoma of the parotid gland. An unusual cause of ear canal stenosis.

Epithelial-myoepithelial carcinoma (EMC) accounts for approximately one per cent of salivary gland tumours. This tumour is gaining wider recognition following inclusion into the WHO histological classification of salivary gland tumours in 1990. Salivary gland tumours characteristically present with an enlarging mass. We describe an unusual presentation of a salivary gland tumour with stenosis of the external ear canal in the absence of a palpable mass. EMC usually arises from the salivary glands but isolated cases have been described arising primarily from the paranasal sinuses, trachea and lacrimal gland. The management of this tumour is still evolving with surgical excision being the main-stay of treatment. The efficacy of radiotherapy has not yet been established but high local recurrence rates despite apparently adequate excision and the possibility of a multicentric origin of the tumour may herald an increasing role for radiotherapy in the future. We stress the importance of awareness of adjacent structures when considering the cause of cartilaginous canal stenosis.