Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor

We used KO mice lacking either TNF receptor 1 (TNFR-1) or receptor 2 (TNFR-2) to determine whether signaling at the start of liver regeneration after partial hepatectomy (PH) involves only one or both TNF receptors and to analyze in more detail the abnormalities caused by lack of TNFR-1 receptor, which is required for the initiation of liver regeneration. Lack of TNFR-2 had little effect on NF-kappaB and STAT3 binding, and no effect in interleukin-6 production after PH, but caused a delay in AP-1 and C/EBP binding and in the expression of c-jun and c-myc messenger RNA (mRNA). In contrast to mice lacking TNFR-1, which had deficient hepatocyte DNA synthesis and massive lipid accumulation in hepatocytes, TNFR-2 KO mice had normal liver structure and similar levels of hepatocyte DNA replication as those of wild type mice. We conclude that TNFR-1, but not TNFR-2, is necessary for liver regeneration, and that NF-kappaB and STAT3 binding are activated by signals transduced by TNFR-1. Inhibition of AP-1 and C/EBP binding and in the expression of c-jun and c-myc mRNA in the first 4 hours after PH, as well as the apparent lack of Fos in AP-1 complexes, had no effect on the timing or extent of DNA replication.     

Investigation of the presynaptic effects of quinine and quinidine on the release and uptake of monoamines in rat brain tissue

Quinine and quinidine are reported to potentiate the behavioural effects of serotonergic agents and monoamine uptake inhibitors. We have therefore investigated the presynaptic actions of quinine and quinidine on monoamine uptake and release in rat brain tissue in vitro. Quinidine evoked the release of [3H]5-HT, [3H]noradrenaline and [3H]dopamine from pre-loaded rat brain slices in a concentration dependent manner with EC50 values of 175, 486 and 150 microM, respectively. Quinine induced [3H]monoamine release with similar potencies. Both quinine and quinidine also inhibited the active uptake of [3H]5-HT, [3H]noradrenaline and [3H]dopamine into rat brain synaptosomes with IC50 values in the range 0.13-12.4 microM. The potency of each drug to inhibit [3H]5-HT uptake was significantly higher than that for [3H]noradrenaline or [3H]dopamine. The relative potency of quinidine compared to quinine was more marked in the case of [3H]5-HT (58-fold) than for [3H]noradrenaline (3-fold) or [3H]dopamine (4-fold). The inhibition of [3H]5-HT uptake by quinine and quinidine was competitive in nature and corresponded with the potencies of these drugs to inhibit [3H]paroxetine binding. No correlation was observed between the potencies of quinine and quinidine to induce the release of [3H]monoamines and to inhibit their uptake, suggesting that these effects are mediated by two distinct mechanisms. We conclude that the presynaptic actions of quinine and quinidine on monoamine uptake and release may be implicated in their potentiation of the effects of serotonergic agents and uptake blockers.     

Comparative evaluation of FUNGITEST and broth microdilution methods for antifungal drug susceptibility testing of Candida species and Cryptococcus neoformans

The FUNGITEST method (Sanofi Diagnostics Pasteur, Paris, France) is a microplate-based procedure for the breakpoint testing of six antifungal agents (amphotericin B, flucytosine, fluconazole, itraconazole, ketoconazole, and miconazole). We compared the FUNGITEST method with a broth microdilution test, performed according to National Committee for Clinical Laboratory Standards document M27-A guidelines, for determining the in vitro susceptibilities of 180 isolates of Candida spp. (50 C. albicans, 50 C. glabrata, 10 C. kefyr, 20 C. krusei, 10 C. lusitaniae, 20 C. parapsilosis, and 20 C. tropicalis isolates) and 20 isolates of Cryptococcus neoformans. Overall, there was 100% agreement between the methods for amphotericin B, 95% agreement for flucytosine, 84% agreement for miconazole, 83% agreement for itraconazole, 77% agreement for ketoconazole, and 76% agreement for fluconazole. The overall agreement between the methods exceeded 80% for all species tested with the exception of C. glabrata (71% agreement). The poorest agreement between the results for individual agents was seen with C. glabrata (38% for fluconazole, 44% for ketoconazole, and 56% for itraconazole) and C. tropicalis (50% for miconazole). The FUNGITEST method misclassified as susceptible 2 of 12 (16.6%) fluconazole-resistant isolates, 2 of 10 (20%) itraconazole-resistant isolates, and 4 of 8 (50%) ketoconazole-resistant isolates of several Candida spp. Further development of the FUNGITEST procedure will be required before it can be recommended as an alternative method for the susceptibility testing of Candida spp. or C. neoformans.     

Symbiosis of nurse and machine through fuzzy logic: improved specificity of a neonatal pulse oximeter alarm

This article describes the theoretical underpinnings that preceded the design of a new neonatal pulse oximeter alarm that differentiates true from false alarms based on an artificial intelligence theory called "fuzzy logic." The connection between the intuition and sense of advocacy gained through neonatal primary nursing and the application of fuzzy logic to solve the problem of false alarms--that is, the symbiosis between nurse and machine--are explained. Emphasis is placed throughout on the importance of involving nurses in the development of the technology for which they are responsible.     

Longitudinal analysis of utilization of inpatient treatment based on insurance data of mandatory health insurance

AIM: To investigate which of the routinely collected claims data from the German "Legal sickness funds" on hospital utilisation may be used, in addition to that prescribed by the legislator. DESIGN: We used claims data to study a cohort of sickness fund beneficiaries who were insured during the complete year 1992 (n = 81,309). Six utilisation parameters, using the number of cases and in hospital days overall as well as diseases specific (i.e. readmission rates, in-hospital days per person with [at least] one hospital stay) were calculated. RESULTS: There are 88 persons with (at least) one hospital stay, 116 hospital cases and a total of 1306 in-hospital days per 1000 insured persons in the study cohort. The average hospital days per person (14.8 days) are ca. 30% higher than the average length of stay (11.2 days). Hospital utilisation increases with age. Hospital stays associated with ICD-239 (neoplasms of unknown origin) resulted in a higher than average number of hospital days in total although the mean length of stay is not above the average. This is due to a high readmission rate. Hospital stays associated with elective surgical procedures have a high prevalence rate but a low readmission ratio and short length of stay. CONCLUSION: The parameters related to insured persons, cases and specifically personal parameters of hospital utilisation allow a detailed analysis of hospital care; different utilisation and user patterns can be investigated and possible determinants of utilisation can be identified. After technical transformation, routine data of the sickness funds can be used to obtain information relevant for health care planners as well as for quality management.     

Prediction of indications for valve replacement among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and normal left ventricular performance

BACKGROUND: Optimal criteria for valve replacement are unclear in asymptomatic/minimally symptomatic patients with aortic regurgitation (AR) and normal left ventricular (LV) performance at rest. Moreover, previous studies have not assessed the prognostic capacity of load-adjusted LV performance ("contractility") variables, which may be fundamentally related to clinical state. Therefore, 18 years ago, we set out to test prospectively the hypothesis that objective noninvasive measures of LV size and performance and, specifically, of load-adjusted variables, assessed at rest and during exercise (ex), could predict the development of currently accepted indications for operation for AR. METHODS AND RESULTS: Clinical variables and measures of LV size, performance, and end-systolic wall stress (ESS) were assessed annually in 104 patients by radionuclide cineangiography at rest and maximal ex and by echocardiography at rest; ESS was derived during ex. During an average 7.3-year follow-up among patients who had not been operated on, 39 of 104 patients either died suddenly (n = 4) or developed operable symptoms only (n = 22) or subnormal LV performance with or without symptoms (n = 13) (progression rate=6.2%/y). By multivariate Cox model analysis, change (delta) in LV ejection fraction (EF) from rest to ex, normalized for deltaESS from rest to ex (deltaLVEF-deltaESS index), was the strongest predictor of progression to any end point or to sudden cardiac death alone. Unadjusted deltaLVEF was almost as efficient. Symptom status modified prediction on the basis of the deltaLVEF-deltaESS index. The population tercile at highest risk by deltaLVEF-deltaESS progressed to end points at a rate of 13.3%/y, and the lowest-risk tercile progressed at 1.8%/y. CONCLUSIONS: Currently accepted symptom and LV performance indications for valve replacement, as well as sudden cardiac death, can be predicted in asymptomatic/minimally symptomatic patients with AR by load-adjusted deltaLVEF-deltaESS index, which includes data obtained during exercise.     

Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects

CONTEXT: Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population. OBJECTIVE: To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors"). DESIGN: Convenience sample. SUBJECTS: Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. SETTING: University-based medical centers and affiliated hospitals. MAIN OUTCOME MEASURES: Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences. RESULTS: The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas. CONCLUSIONS: Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.     

Primate vocalizations during social separation and aggression: effects of alcohol and benzodiazepines

The most common group of squirrel monkey vocalizations, peeps, are emitted during different social situations including social separation, affiliative interactions, feeding and aggressive confrontations. The present experiments investigated whether peeps and other vocalizations emitted during different social contexts are pharmacologically altered in a similar manner. First, vocalizations were characterized during (1) social separation in juveniles, and (2) "resident-intruder" aggressive confrontations between dominant monkeys from different social groups. Then, the effects of alcohol (EtOH) and the benzodiazepine chlordiazepoxide (CDP) on vocalizations during social separation and during aggression were examined. Isolated juveniles emitted only one type of call, the isolation peep. Resident monkeys primarily emitted peeps, but also emitted cackles, chucks, noisy calls and pulsed calls. Aggressive peeps were similar in structure and frequency (kHz) to isolation peeps, but were shorter in duration. At the same doses, both CDP (0.3-3 mg/kg) and EtOH (0.1-1.0 g/kg) reduced explosive motor behaviors and isolation peeps in juvenile monkeys during social separation and increased threat displays and aggression peeps in resident monkeys during confrontations with an intruder monkey from a different social group. Thus, similarly structured vocalizations that were emitted during social separation and aggression were very sensitive to EtOH and CDP, but the social context determined the direction and magnitude of effects.     

Development of a scoring system to assess disability in an Italian elderly population. Evaluation of a disability questionnaire

Patients with idiopathic and symptomatic restless legs syndrome (RLS) suffer from "dyskinesia while awake" or "daytime myoclonus" when at rest preceded by sensory symptoms. In order to characterise the RLS either as reflex movement or as voluntary movement we measured movement-related cortical potentials in 5 idiopathic and 8 uraemic RLS patients. Movements from both legs were polygraphically recorded concomitantly with cortical activity 2000 msec before to 500 msec after onset of EMG activity. These data were compared with a voluntary simulation of each patient's movement pattern and with 5 age-matched controls performing dorsiflexion of the right, left and both feet. Cortical activity preceding daytime myoclonus was absent in RLS patients whereas self-initiated leg movements in patients elicited onset times (1180-1380 msec) and amplitudes of Bereitschaftspotential (readiness potential) not significantly different from readiness potentials in control subjects (P > 0.05). Lack of movement-related potentials in myoclonus and/or dyskinesias during daytime in RLS patients is compatible with an involuntary mechanism of induction and points towards a subcortical or spinal origin of RLS.     

Congenital diseases of the equine head

Many questions concerning heritability arise when a veterinarian is asked to supervise and treat disease of congenital origin. Genetic counseling, ethics, and legality are often confronted in discussions between animal health professionals and laymen in animal industry. Guidelines have been offered as in the 1984 statement of the Judicial Council of the American Veterinary Medical Association: "Performance of surgical procedures in all species for the purpose of concealing genetic defects in animals to be shown, raced, bred, or sold as breeding animals is unethical. However, should the health or welfare of the individual patient require correction of such genetic defects, it is recommended that the patient be rendered incapable of reproduction." The Australian Veterinary Law, Ethics, Etiquette and Convention declares it fraud to alter a defect for sale purposes and unethical for a veterinarian to perform such treatments. It is permissible to correct defects causing discomfort or inconvenience, but the veterinarian is required to advise appropriate breeding counseling. Genetic counseling has progressed significantly in human medicine. This has been supported by better diagnostic methods for genetic disorders, greater acceptance of preventive measures, and extended screening programs to identify carriers of specific abnormal genes or chromosomal aberrations. Congenital diseases in veterinary medicine are constantly under investigation. The veterinary practitioner must continue to operate with an appreciation of the incomplete understanding of most of these abnormalities and act in accordance with personal ethical judgment and the guidance of the American Veterinary Medical Association when treating the affected individual animal patient.