A feline model of spontaneously occurring autoimmune limbic encephalitis.

Autoimmune encephalitis (AE) is an important cause of encephalitis in humans and occurs at a similar rate to infectious encephalitis. It is frequently associated with antibodies against the extracellular domain of neuronal proteins. Among human AE, that with antibodies against leucine-rich glioma-inactivated 1 (LGI1) is one of the most prevalent forms, and was recently described in cats with limbic encephalitis (LE). In this study, we describe a large cohort (n = 32) of cats with AE, tested positive for voltage gated potassium channel (VGKC)-antibodies, of which 26 (81%) harboured LGI1-antibodies. We delineate their clinical and paraclinical features as well as long-term outcomes up to 5 years. Similar to human cases, most cats with LGI1-antibodies had a history of focal seizures (83%), clustering in the majority (88%), with interictal behavioural changes (73%). Among feline AE patients, there was no seizure type or other clinical characteristic that could distinguish LGI1-antibody positive from negative cats, unlike the pathognomic faciobrachial dystonic seizures seen in humans. Although six cats were euthanased in the first year for epilepsy-associated reasons, those attaining at least 1-year survival had good seizure control and quality of life with appropriate veterinary care and medication. Acute-phase immunotherapy (prednisolone) was given to the most severely unwell cases and its effect is retrospectively evaluated in 10 cats. Our data show LGI1-antibodies are an important cause of feline encephalitis, sharing many features with human AE. Further research should examine optimal therapeutic management strategies and the cause of LE in seronegative cats, building on paradigms established in the counterpart human disease.

Risk Factors, Epidemiology and Treatment Strategies for Metabolic Bone Disease in Patients with Neurological Disease.

Metabolic bone disease is a major public health concern, especially when it manifests as hip fracture which carries significant morbidity and mortality. Individuals with neurological disease are at higher risk of osteopenia, osteoporosis and fragility fracture compared to age-matched controls, yet this is under-appreciated by these patients. Clinician attention to this topic is therefore of importance and should address the bone health of men as well as women, a group in whom it may be an under-recognised problem. Evidence for optimal management of bone health in neurological disease remains to be defined, but a growing literature provides some useful guidance. This review focuses on two conditions, multiple sclerosis and Parkinson's disease, where research has been active over recent years. In neuroinflammation, shared immunological pathways between bone and brain are a current domain of interest and it will be intriguing to interrogate the action of emerging immunotherapies on these dual compartments.

Abolition of lifelong specific phobia: a novel therapeutic consequence of left mesial temporal lobectomy.

Numerous imaging studies have confirmed the amygdala as prominent within a neural network mediating specific phobia, including arachnophobia. We report the case of a patient in whom arachnophobia was abolished after left temporal mesial lobectomy, with unchanged fear responses to other stimuli. The phenomenon of abolition of specific phobia after amygdala removal has not, to our knowledge, been previously reported.

The role of oestradiol in sexually dimorphic hypothalamic-pituitary-adrena axis responses to intracerebroventricular ethanol administration in the rat.

Systemic ethanol (EtOH) administration activates the hypothalamic-pituitary-adrenal (HPA) axis of rats in a sexually dimorphic manner. The present studies tested the role played by the central nervous system (CNS) in this phenomenon. To localise the effects of the drug to the brain, we utilised an experimental paradigm whereby a small, nontoxic amount of the drug was delivered via intracerebroventricular (i.c.v.) injection. EtoH administered i.c.v. rapidly diffuses throughout the cerebrospinal fluid and brain, and does not cause neuronal damage or have any long-term physiological or behavioural effects. Experimental groups included intact males, intact cycling females, and ovariectomised (OVX) animals with or without replacement oestradiol (E(2)). Intracerebroventricular EtOH-induced HPA hormonal activation was determined by measuring plasma adrenocorticotrophin (ACTH) levels. Activation of brain areas that both regulate HPA function and are responsive to gonadal hormones was determined using expression of the transcription factor c-fos (Fos) as a marker of neuronal activity. We observed sex- and oestrous cycle- dependent differences in HPA activation by EtOH as measured by both these parameters. ACTH secretion was highest in females in pro-oestrus or oestrus, just prior to or after the endogenous peak of E(2), as was Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and the locus coreuleus (LC) of the brainstem. In OVX animals, E(2) replacement caused an increase in PVN and LC Fos expression in response to i.c.v. EtOH compared to OVX controls, but a decrease in ACTH secretion. Taken together, these results indicate that at the level of the CNS, EtOH stimulates HPA activity more robustly at times when the effects of E(2) are high, but that E(2) alone is not responsible for this effect. The data further suggest that the LC plays an important role in the circuitry, which appears to be different from that activated following the systemic administration of EtOH.

Tele-education in emergency care.

The use of telemedicine is becoming routine and accepted in certain limited areas such as electrocardiogram and radiograph/computed tomographic scan telemetry. Tele-education has thus far had limited applications although in emergency medicine it has been shown to be an effective medium for the education of senior house officers and emergency nurse practitioners in remote or peripheral units. Despite apparent clinical and cost benefits and government support, the full potential of two way video conferencing and tele-presence has yet to be realised by the clinician, educator and manager.

Prevalence and healthcare burden of illegal drug use among emergency department patients.

OBJECTIVES: Illegal drug use is common in emergency department (ED) patients, but previous prevalence studies have relied upon approaches that may underestimate the true extent of the problem. The aim of this study was to examine illegal drug use in a typical adult ED. METHODS: We employed an independent researcher to prospectively and anonymously interview patients attending an inner city adult ED throughout all 168 hours of a typical week. Additional information collected from the treating clinician indicated whether each presentation was directly or indirectly related to illegal drug use. RESULTS: We found that 6.9% of all patient attendances were directly or indirectly related to illegal drug use, and hospital admission was required in nearly half of these. The majority of drug related problems were acute injuries, overdose, and the medical complications of drug use. CONCLUSIONS: This suggests that the emergency healthcare burden related to illegal drug use is substantial, and higher than previously reported.

Occupational toxicology and the control of exposure to pharmaceutical agents at work.

BACKGROUND: The pharmaceutical industry employs >350 000 people worldwide in operations including research and development (R&D), manufacturing, sales and marketing. Workers employed in R&D and manufacturing sectors are potentially exposed to drug substances in the workplace that are designed to modify physiology and also to chemical precursors that are potentially hazardous to health. Pharmaceutical workers are at risk from adverse health effects, including occupational asthma, pharmacological effects, adverse reproductive outcomes and dermatitis. AIM: This study aimed to describe the approaches taken by pharmaceutical companies for identifying and communicating potential adverse health effects that may result from workplace exposures and in setting 'in-house' exposure control limits and to highlight the challenges in controlling workplace exposures to increasingly potent compounds. METHOD: The literature was reviewed by searching the Medline and HSELine databases. RESULTS: The findings are presented in five sections, covering: test methods and approaches to occupational toxicology; hazard communication; approaches to setting health-based occupational exposure limits for pharmaceutically active agents; recent approaches to risk control; and occupational hygiene and exposure controls. CONCLUSION: Significant efforts have been directed at predicting and evaluating potential occupational health hazards in the pharmaceutical industry. The pharmaceutical industry has provided leadership in controlling exposure to hazardous substances. Much of this work has been driven by a real need to control occupational exposures to substances that can have profound adverse health effects in exposed employees and that are becoming increasingly more potent.

Learning and forgetting in schizophrenia.

Recent studies of patients with schizophrenia have consistently demonstrated marked deficits on measures of initial learning. However, contradictory results have been reported concerning retention and forgetting. The present study examined the level of initial and delayed recall of stories and visual figures in a group of 76 patients with schizophrenia and 51 normal controls. Schizophrenia patients demonstrated marked impairments in initial and delayed recall as well as significantly worse percentage retention scores. However, schizophrenia patients and healthy controls individually matched on level of initial recall had nearly identical delayed recall performance. The results suggest a primary deficit in the initial acquisition of information rather than an accelerated rate of forgetting in schizophrenia.

Modulation of leukocyte phagocytic and oxidative burst responses by human seminal plasma.

The typical absence of immune responses to spermatozoa in the female reproductive tract at the time of insemination, despite the presence of a marked leukocytic infiltrate into the cervical mucus is intriguing. It may be that localised immunoregulatory mechanisms exist and this study used whole blood flow cytometry to determine the effects of human seminal plasma on neutrophil and monocyte function. Seminal plasma inhibited the proportion of neutrophils and monocytes phagocytosing E. coli, and the intensity of neutrophil phagocytosis, but enhanced the magnitude of the phagocytic response of those monocytes that escaped inhibition relative to PBS treated controls. Oxidative burst responses to E. coli were also inhibited and this effect was mediated by low molecular weight species, as dialysis totally abrogated the inhibitory activity. Seminal plasma had no effect on the neutrophil burst response to fMLP when compared to the controls, however there was a significant difference between the responses of undialysed and dialysed seminal plasma treated samples. Undialysed seminal plasma significantly inhibited the proportion of monocytes undergoing the burst response to fMLP and there were significant differences between the proportion of cells responding and their intensity in undialysed and dialysed seminal plasma treated samples. In summary, this study reports differential modification of neutrophil and monocyte function by human seminal plasma. The residual capacity of these cells to undergo phagocytosis and generate oxidative burst responses suggests that localised innate immune function remains intact and is possibly enhanced in the female reproductive tract at the time of insemination. Other mechanisms must protect inseminated sperm at this time.

Combined antagonism of leukotrienes and histamine produces predominant inhibition of allergen-induced early and late phase airway obstruction in asthmatics.

We defined the contribution of histamine and leukotrienes to allergen-induced airway obstruction in asthmatics; 12 subjects with allergic asthma underwent identical allergen bronchoprovocations on four occasions. At a control session, all subjects displayed early (EAR) and late asthmatic (LAR) reactions. The mean (+/- SE) drop in FEV1 during EAR (0-2 h) and LAR (2-12 h) was 29 +/- 2% and 28 +/- 4%, respectively. Thereafter, the influence of 1 wk randomized pretreatment with the leukotriene receptor antagonist zafirlukast (Accolate) (80 mg twice daily), the antihistamine loratadine (10 mg twice daily), and the combination of both antagonists was assessed. Expressed as AUC FEV1 in percent of the control reaction, zafirlukast reduced the response during EAR and LAR by 62 +/- 11% and 55 +/- 12%, respectively (p < 0.05 versus control). Loratadine inhibited EAR and LAR by 25 +/- 14% and 40 +/- 16%, respectively (p < 0.05 versus control). Zafirlukast was significantly more effective than loratadine during EAR but not during LAR. The combination of zafirlukast and loratadine reduced the AUC FEV1 during EAR and LAR further, by 75 +/- 8% and 74 +/- 14%, respectively (p < 0.05 versus control). The combination was significantly (p < 0.05) more effective than either drug alone during the LAR. The findings indicate that leukotrienes and histamine together mediate the major part of both the EAR and the LAR following exposure of asthmatics to allergen. Combination of leukotriene antagonism and antihistamines may represent a new strategy for treatment of airway obstruction in asthma.

p53 gene product expression in resected non-small cell carcinoma of the lung, with studies of concurrent cytological preparations and microwave antigen retrieval.

AIM: To document the frequency and extent of p53 gene product expression in paraffin sections of resected non-small cell carcinoma of the lung and in cytological preparations of the same tumours; to determine the effect of microwave antigen retrieval on antigen detection. METHODS: Representative paraffin sections of 50 non-small cell carcinomas were stained with an antibody to p53 gene product (DO-7) both with and without prior microwave antigen retrieval. Cytoblocks and cell smears obtained from 19 cases were similarly stained. RESULTS: Using a histochemical scoring system (0-300) which takes into account staining intensity and extent, 78% (n = 39) of microwave pretreated paraffin sections and 52% (n = 26) of non-pretreated sections scored between 5 and 300; p = 0.001; 56% (n = 28) of microwave pretreated sections and only 2% (n = 1) of non-pretreated sections scored between 100 and 300 (p = 0.0001); 75% of direct smears of tumours and 80% of cytoblocks stained similarly to the paraffin sections of the resected specimens. No smears or cytoblocks stained positively when the sections of the resected specimen were negative. CONCLUSIONS: As up to 78% of non-small cell lung carcinomas overexpress p53 gene product, this may prove to be a valuable diagnostic method in biopsy or cytological material when the morphological diagnosis is uncertain. Microwave antigen retrieval is effective on formalin fixed tissue.

Visuospatial working memory in patients with schizophrenia.

Recent investigations have documented abnormalities in working memory related processes in schizophrenics on tasks assessing the central executive component of this cognitive model. This preliminary study investigated the function of another component of the working memory system, the visuospatial scratch pad in schizophrenia. The "scratch pad's" passive visual store--responsible for the temporary retention of visual material--was assessed via a computerized spatial delayed response task, whereas its active spatial rehearsal subsystem--specialized for retaining the temporal properties--was explored through visual block span. To assess elemental visual spatial abilities we used the Judgment of Line Orientation test. Thirty-two schizophrenics and 27 controls were tested. Although we discovered the basic perceptual abilities of patients to be intact, we determined that whenever memory was necessitated on spatial tasks, patients demonstrated marked deficits. This pattern of cognitive dysfunction is consistent with impairments in a neural network involving prefrontal and/or posterior brain regions in schizophrenia.

Establishing guidance for the handling and containment of new chemical entities and chemical intermediates in the pharmaceutical industry.

This information is intended to guide scientists and technicians working with pharmaceutical substances early in development, before occupational exposure levels (OELs) can be set. The focus is on determining hazard categories, or occupational exposure bands, which may be applied temporarily until full health-based OEL's are in place.

A comparison of pathological methods of measuring lung cancer volume.

AIM: To determine which of several pathological methods of measuring lung cancer volume compared most favourably with the gold standard. METHODS: Three pathological methods were used on 54 resected lung cancers: (1) measuring the maximum dimension and assuming a spherical shape; (2) measuring three dimensions and assuming an ellipsoidal shape; and (3) deriving the volume from the area of tumour on sequential 1 cm slices using a photocopier and an image analysis system. The gold standard was obtained from the area of whole mount tumour sections on sequential 0.1 cm slices of eight cancers. RESULTS: Volumes derived from 1 cm lung slices gave results closest to our gold standard but assuming tumours were ellipsoidal was only a slightly less accurate and less time consuming method. Assuming cancers were spherical resulted in gross overestimation of the tumour volumes. CONCLUSIONS: For practical purposes, it is reasonable to measure three dimensions of a lung tumour at sectioning and calculate the volume using the formula for an ellipsoid (V = 4/3 pi d.e.f, where d, e and f are the semi-axes).

The protective effect of inhaled leukotriene D4 receptor antagonist ICI 204,219 against exercise-induced asthma.

Leukotrienes are potent bronchoconstrictors, and they are present in the airways of asthmatic subjects. Leukotriene receptor antagonists given intravenously or orally prior to exercise attenuate the bronchoconstrictor response to exercise in asthma. We have determined the prophylactic effect of an inhaled leukotriene D4-receptor antagonist ICI 204,219 (400 micrograms) against exercise-induced bronchoconstriction in nine asthmatic subjects in a randomized, placebo-controlled, double-blind, cross-over study. Exercise challenge was performed on a cycle ergometer at a predetermined work load that was kept constant throughout the study. A "screening" and a "run-in" exercise test were performed to determine the reproducibility of the challenge. ICI 204,219 or matched placebo was given 30 min prior to exercise challenge, and bronchoconstriction after exercise was assessed as change in FEV1 over 30 min. There was no significant effect on baseline airway caliber at 20 min after inhalation of ICI 204,219. ICI 204,219 significantly inhibited the bronchoconstrictor response to exercise. The mean maximal percentage fall in FEV1 after exercise was 14.5% as compared with the placebo of 30.2% (p = 0.043), and the area under curve (AUC) for FEV1 during the first 30 min (AUC0-30) after exercise was significantly reduced (p = 0.043). The time for recovery of FEV1 to 5% of baseline was also significantly shorter with ICI 204,219 than with placebo (median, 20 versus 60 min; p = 0.018). The protection against exercise-induced bronchoconstriction provided by ICI 204,219 was variable, with almost complete inhibition of the response in three subjects, partial inhibition in another three subjects, and no protection in three subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Hexavalent chromium produces DNA strand breakage but not unscheduled DNA synthesis at sub-cytotoxic concentrations in hepatocytes.

Rat hepatocytes were used to investigate the possible induction of unscheduled DNA synthesis (UDS) and the extent of DNA strand breaks induced by sodium dichromate (a representative chromium(VI) compound) and chromium acetate hydroxide (chromium(III)) in vitro. Cytotoxicity, measured using tetrazolium salt (MTT) reduction assay, was found at a much higher dose of chromium(III), (> 50 microM), compared to that of chromium(VI), (> 2.5 microM), in cultured hepatocytes over 20 h treatment at 37 degrees C. Chromium(VI), but not chromium(III), stimulated minimal UDS in hepatocytes at sub-cytotoxic concentrations. A positive UDS response was only observed at cytotoxic concentration. DNA strand breaks in hepatocytes were induced by chromium(VI) following incubation at 37 degrees C for 1 h at doses of 10, 20 and 40 microM sodium dichromate. The subsequent ligation of such strand breaks in hepatocytes treated with 40 microM chromium(VI) for 1 h at 37 degrees C was demonstrated. The majority of strand breaks was repaired within 30 min following removal of the chromate. In conclusion, chromate-induced DNA strand breakage, possibly involving the formation of oxygen radicals and lack of significant UDS have some analogy to those produced by ionizing radiation.

Induction of DNA strand breaks in peripheral lymphocytes by soluble chromium compounds.

1. Incubation of human lymphocytes with sodium dichromate (CrVI) at 37 degrees C for 3 h resulted in a dose-dependent increase in DNA strand breaks without concurrent cytotoxicity. In contrast, chromium acetate hydroxide (CrIII) failed to induce DNA strand breaks at sub-cytotoxic concentrations. 2. DNA strand breaks were also detected in the peripheral lymphocytes of Wistar rats, 24 h after intratracheal instillation of sodium dichromate (1.3 and 2.5 mg kg-1). Instillation of chromium acetate hydroxide (up to 21.8 mg kg-1) failed to induce DNA strand breaks in peripheral lymphocytes. In accord with previous studies, hexavalent chromium was found to be more readily absorbed from the lungs into the peripheral blood than chromium in its trivalent form. 3. The results of this study indicate that fluorometric analysis of DNA unwinding (FADU) in peripheral lymphocytes might be a convenient method of measuring an important biological effect of chromium in occupationally-exposed workers.

Kinetics and mechanism of uptake of platinum-based pharmaceuticals by the rat small intestine.

The absorption of two platinum-based pharmaceuticals, cisplatin and carboplatin, was studied using in vitro and in situ models. By utilizing everted rat small intestine, it was found that absorption of both drugs was linear with time up to 60 min and was not saturable up to a concentration of 1.0 mM. Moreover, uptake against a concentration gradient could not be demonstrated and absorption was not reduced by metabolic inhibition or anoxic conditions. These results indicate the lack of involvement of an active transport mechanism for cisplatin and carboplatin and imply that absorption across the gastrointestinal tract is by passive diffusion. Cisplatin was absorbed more readily than carboplatin, both in vitro and in situ. In situ both drugs were found to disappear from the intestinal lumen following first-order kinetics. The results of in situ studies indicate that a decrease in pH of the perfusion medium leads to an increase in absorption of carboplatin into the systemic blood. This report establishes the fact that both cisplatin and carboplatin are absorbed across the gastro-intestinal tract and indicates that preclinical trials involving oral administration of platinum-based pharmaceuticals could be justified.