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PubMed1989

Differential effects of flunitrazepam on human sleep in combination with flumazenil.

The experiments reported here were designed to characterize in detail the spectrum of activity of flunitrazepam in human sleep. The direct and residual effects of flunitrazepam, as well as the antagonism by flumazenil, an antagonist of benzodiazepine receptors, were studied in 28 normal subjects recorded in the sleep laboratory. The five categories of variables--sleep-wake balance, sleep organization, orthodox sleep, phasic events in sleep, and sleep waveforms--were all modified by flunitrazepam. Some of these modifications were observed only on the drug night and were antagonized by flumazenil, whereas others persisted in the placebo postdrug night and were not antagonized by flumazenil. A few variables showed changes intermediate between these two types of reactivity. The results do not fit well with the multiple benzodiazepine receptors theory, but instead support the concept of spare receptors. Along these lines, the study of the reactivity of sleep components to ligands of benzodiazepine receptors can contribute to the better understanding of the neuronal systems involved in their control.

Adult↗
PubMed1986

Physiographic, stand, and environmental effects on individual tree growth and growth efficiency in subalpine forests.

Annual volume growth of subalpine trees in the central Rocky Mountains was studied in relation to site and stand conditions. Growth of individual trees was most strongly influenced by estimated potential absorbed radiation, which varied with physiographic conditions and tree leaf area. Growth efficiency was estimated by the ratio of annual volume growth to potential radiation absorption by the crown. Growth efficiency was higher in young lodgepole pine (Pinus contorta var. latifolia Engelm.) than in Engelmann spruce (Picea engelmannii Parry ex Engelm.) or subalpine fir (Abies lasiocarpa (Hook.) Nutt.). In all species, growth efficiency declined sharply with age, and suppressed and overtopped trees had growth efficiencies equal to the highest efficiencies observed for dominant/codominant or intermediate trees. Lodgepole pine growth was most responsive to site and stand variables, Engelmann spruce was intermediate, and subalpine fir was rather unresponsive.

Journal Article↗
PubMed1998

Benign myoepithelioma of the skin.

A case of cutaneous myoepithelioma is reported. The tumor was composed of spindle-shaped, epithelioid, and plasmacytoid (hyaline) cells. It exhibited a widespread immunoreactivity for low molecular weight keratins and protein S-100, being irregularly positive for smooth muscle actin. Ultrastructural studies of tumor cells showed a variable content of intermediate filaments, with focal densities resembling smooth muscle dense bodies. A well-developed basal lamina, pinocytotic vesicles, and some desmosomes were also observed. In spite of being accepted as an individual entity, myoepitheliomas probably belong to a family of lesions that include mixed tumors. Therefore, this case can be considered as a salivary-gland-type tumor, probably originating from myoepithelial cells of sweat glands. The existence of this unique neoplasm provides further support to the debated role of myoepithelial cells in the development of mixed tumors.

Actins↗
PubMed1994

The evolving concept of the healthy worker survivor effect.

The "healthy worker survivor effect" describes a continuing selection process such that those who remain employed tend to be healthier than those who leave employment. In an analysis of exposure-response patterns in an occupational study, the healthy worker survivor effect generally attenuates an adverse effect of exposure. In practical terms, such attenuation will be more problematic when evaluating subtle rather than strong associations. The use of an internal referent does not guarantee elimination of this effect, since by definition, it manifests within an occupational cohort. Although documented over 100 years ago, there is little consensus regarding the most appropriate method to control for the healthy worker survivor effect. Four methods have been proposed for its control: (1) restriction of the cohort to survivors of a fixed number of years of follow-up, (2) lagging the exposure to exclude recent exposure incurred by those who remained on the job, (3) adjusting for employment status as a confounder, and (4) treating the healthy worker survivor effect simultaneously as an intermediate and confounding variable by means of the G-null test or its extension, G-estimation analysis, using structurally nested failure time models. This paper reviews the concept of the healthy worker survivor effect and the four methods to control for it.

Bias↗
PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

Aged↗
PubMed2001

The evolution of body armor in mammals: plantigrade constraints of large body size.

Predictions associated with opposing selection generating minimum variance in basal metabolic rate (BMR) in mammals at a constrained body mass (CBM; 358 g) were tested. The CBM is presumed to be associated with energetic constraints linked to predation and variable resources at intermediate sizes on a logarithmic mass scale. Opposing selection is thought to occur in response to energetic constraints associated with predation and unpredictable resources. As body size approaches and exceeds the CBM, mammals face increasing risks of predation and daily energy requirements. Fast running speeds may require high BMRs, but unpredictable and low resources may select for low BMRs, which also reduce foraging time and distances and thus predation risks. If these two selection forces oppose each other persistently, minimum BMR variance may result. However, extreme BMR outliers at and close to the CBM should be indicative of unbalanced selection and predator avoidance alternatives (escapers vs. defenders), and may therefore provide indirect support for opposing selection. It was confirmed that body armor in defenders evolves at and above the CBM, and armored mammals had significantly lower BMRs than their nonarmored counterparts. However, analyses comparing the BMR of escapers--the fastest nonarmored runners (Lagomorpha)--with similar-sized counterparts were inconclusive and were confounded by limb morphology associated with speed optimization. These analyses suggest that the risks and costs of predation and the speed limitations of the plantigrade foot may constrain the evolution of large body sizes in plantigrade mammals.

Animals↗
PubMed1975

Histamine receptors in the synovial microcirculation.

This study was designed to investigate the respective roles of H(1) and H(2) receptors in the control of the microcirculation by examining the effectiveness of the H(2) receptor antagonist metiamide (Met.) and H(1) receptor antagonist mepyramine is blocking the action of histamine on synovial perfusion. Synovial perfusion was monitored indirectly by calculating the half-life (T1/2 min.) of the clearance rate of 133-Xe from canine diarthrodial joints. The 133-Xe clearance rate, unaffected by metiamide alone, was consistently increased by histamine alone. Metiamide produced a dose related effect on the histamine response with consistent abolition of response at high dose ratios of metiamide to histamine variable response at intermediate and a pronounced histamine response at low dose ratios. Mepyramine produced no such antagonism of the histamine response and in certain doses, by itself caused an increase in 133-Xe clearance rate. This effect of mepyramine was thought to be related to its histamine releasing properties a view supported by the reduction in this vasodilator response following certain doses of metiamide. The response of the 133-Xe clearance rate to histamine returned approximately one hour after treatment with metiamide (500 mug) and metiamide did not antagonise the effects of alpha and beta adrenergic agents on the 133-Xe clearance rate. Thus, this study has provided evidence for the presence of H(2) but not H(1) receptors in the synovial microcirculation.

Animals↗
PubMed1998

Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.

N-methyl-D-aspartic acid (NMDA) receptors transiently transfected into mammalian HEK-293 cells were characterized with subunit-specific antibodies and electrophysiological recordings. Deactivation time course recorded in response to fast-glutamate pulses were studied in isolated and lifted cells, as well as in outside-out membrane patches excised from cells expressing recombinant NR1 subunits in combination with the NR2A, NR2B, NR2C, or NR2D NMDA receptor subunits. Transfected cells were preidentified by the fluorescence emitted from the coexpressed Aequorea victoria jellyfish Green Lantern protein. Currents generated by NR1/NR2A channels displayed double exponential deactivation time course being faster than that in NR1/NR2B or NR1/NR2C channels. However, a large decay variability was observed within each cotransfection, suggesting that mechanisms additional to subunit composition may also regulate deactivation time course. NR1/NR2D channels displayed slowly deactivating currents. Channel deactivation was fast and comparable among receptors obtained by cotransfecting five distinct spliced variants of the NR1 subunit, each with the NR2A subunit. Additionally, recovery from desensitization was slower for NR1/NR2B than for NR1/NR2A channels. The average deactivation time course of responses to brief L-glutamate applications in cells where NR1/NR2A/NR2B cDNAs were cotransfected at variable ratio was intermediate between those of the NR1/NR2A and NR1/NR2B channels. Although immunocytochemical evidence indicates that the majority of cells are cotransfected by all plasmids in triple transfection, our experimental condition did not allow for a tight control of the expression of NMDA receptor subunits. This produced the result that many cells were characterized by deactivation time course and haloperidol sensitivities of separate NR1/NR2A and NR1/NR2B subunit heteromers. We also speculate on the possible formation of channels resulting from the coassembly in the same receptor of NR1/NR2A/NR2B subunits from a minority of cells that gave responses to brief application of L-glutamate characterized by slow deactivation time course and decreased haloperidol sensitivity.

Antibodies, Monoclonal↗
PubMed2000

A subependymal giant cell astrocytoma in a cat.

A 6-year-old spayed female Domestic Shorthair cat presented with a 1 to 2-month history of blindness and altered behavior. At necropsy, a 1-cm-diameter, firm white mass was found arising from the subependymal region of the right lateral ventricular wall that protruded into and partially filled the lumen. Histologically, there was a well-demarcated, expansile paraventricular neoplasm composed of moderately pleomorphic cells within a richly fibrillar matrix arranged in interlacing streams and perivascular pseudorosette-like patterns. Neoplastic cells varied in morphology from small spindloid cells to larger polygonal cells with eccentric vesicular nuclei to neuronlike cells with vesicular nuclei and prominent nucleoli. The mitotic index was low. Immunohistochemically, neoplastic cells were positive for S-100 protein, glial fibrillary acidic protein, and neuron-specific enolase and negative for neurofilament protein. Ultrastructurally, the cells contained few to abundant bundles of intermediate filaments with variable numbers of mitochondria, endoplasmic reticulum, and ribosomes. These features are characteristic of subependymal giant cell astrocytoma (SEGA) in humans. To our knowledge, this is the first reported case of SEGA in domestic animals.

Animals↗
PubMed1977

Dependency, temporal contiguity, and response-independent reinforcement.

A comparison was made of the effects of variable-interval, variable-time, and tandem variable-interval fixed-time schedules on key-peck responding of pigeons. The variable-interval component of the tandem schedule retained the response-reinforcement dependency; the fixed-time component allowed the temporal proximity between responding and reinforcement to vary, constrained only by the duration of the fixed-time interval. Response rates were highest during the variable-interval and lowest during the variable-time schedule. Intermediate response rates occurred during the tandem schedule. The results of a yoked control condition showed that the effects of the tandem schedule were not due simply to changes in reinforcement distribution or frequency. The results suggest that substantial reductions in responding occur when reinforcement is response-dependent but not necessarily contiguous with the response required to produce reinforcement.

Journal Article↗
PubMedDate not supplied

[The arterial system of the greater omentum].

The aim of our study is to establish a pattern of distribution of the arteries of greater omentum. Right omental arteries supply the anterior lamina and the left ones the posterior lamina (in 82% there is an initial independent left-right distribution). In 18% it is mixed, the two territories being supplied by both anterior and posterior omental arteries. The classic pattern with three main arterial arches (one infra-gastric and two inferior marginal) was identified in 24% cases. More frequent (45%) is the pattern with two transverse main arteries, one superior and the other inferior (with a variable number of intermediate arteries). In 51% cases the infra-colic arch is dominant; in 14% cases it is thinner. The absence of arterial arches may be partly substituted by a dense capillary network. The laminar arterial distribution of greater omentum was expressed into more patterns.

Adult↗
PubMed1991

Prognostic modeling of clinical outcomes: an illustration with data from patients with membranous nephropathy.

Probabilities that a patient will occupy any of five clinically defined compartments at different future times are generated and graphed by a personal computer. The probabilities are functions of a patient's relevant baseline characteristics (treated or control group), clinical status, and follow-up time at which the prognosis is made. The illustrative prognostic model is based on a reanalysis of detailed individual records for 81 patients with idiopathic membranous nephropathy (42 treated with methylprednisolone and chlorambucil; 39 controls) in a randomized clinical trial. The compartments to and from which patients may pass are identified as (1) complete remission, (2) partial remission, (3) the nephrotic syndrome, (4) renal failure, and (5) death. Estimated risk functions for transitions between compartments involve baseline treatment, and intermediate and temporal variables, together with their relevant interactions. The model illustrates how, despite the overall advantage of treated over control patients, the comparative prognoses can change greatly and can even sometimes be reversed, depending on a variety of follow-up experiences.

Computer Simulation↗
PubMed1989

Pharmacokinetics in pregnancy and placental drug transfer.

Total body water increases in pregnancy and while the uterus, placenta, fetus, and amniotic fluid constitute part of this increase, the largest component is in the extracellular water. Fat stores also increase and thus the distribution volumes of all drugs expand, but the major effect is seen in polar drugs which are confined to the extracellular space. Cardiac output and renal function also increase and elimination of polar drugs is accelerated. In contrast, the elimination of lipophilic drugs may be retarded, and the effect on intermediate drugs is variable. Polar drugs cross the placenta slowly and accumulate in amniotic fluid and therefore in the fetal gut lumen. Lipophilic drugs cross the placenta rapidly and their transplacental distribution is dependent on relative maternal and fetal affinity: this is determined largely by protein binding on either side of the placenta. The fetus and neonate dispose of all drugs less rapidly than adults, the most efficient elimination processes being sulphate conjugation and renal excretion.

Adrenergic beta-Agonists↗
PubMed1989

[An immunohistochemical and ultrastructural study on 76 cases of meningioma].

Seventy-six cases of meningioma of various light microscopic features were studied immunohistochemically by using 6 kinds of antibodies directly against epithelial, mesenchymal and neural components. Except for hemangiopericyte meningiomas which only showed vimentin positive, expressions of vimentin and EMA were obtained in almost all the meningiomas. Thirteen meningiomas were investigated by electron microscopy. The electron micrograph of meningiomatous cell showed presence of interdigitation of the adjacent cell membrane with desmosome and variable amounts of intermediate filaments in cytoplasm, although the re were different varieties of cell types. 2 hemangiopericyte meningiomas showed presence of different ultrastructures, which contained many pericytes and cells with a large number of RER. These results provide evidences of the fact that meningioma possessed the features of both mesenchymal and epithelial tissue. In regard to histogenesis, findings reported suggest that meningioma most probably arise from the arachnoid cap cells. Additionally, some distinct subtypes of meningioma are reported, including secretory meningioma, microcystic meningioma and oncocytic meningioma.

Diagnostic Errors↗
PubMed1987

[Multiparameter evaluation of tricuspid insufficiency using two-dimensional echocardiography, Doppler and contrast echocardiography].

The evaluation of the presence and severity of tricuspid insufficiency is still difficult even if many criteria of grading are available for different techniques. In this study the data obtained from Doppler mapping of the right atrium, from the analysis of the hepatic vein flow and from the contrast echocardiography of the inferior vena cava in 56 patients with mitral or mitral-aortic valvulopathy and with clinically suspected tricuspid insufficiency were submitted to the cluster analysis. This analysis was used to redistribute the study population according to the following parameters: diameter of the inferior vena cava, maximal systolic and diastolic flow of the hepatic veins, the length of regurgitant jet in right atrium and the duration of contrast in vena cava. The aim was to identify the variability range of each degree of severity. None of the analyzed parameters "per se" identifies the regurgitation severity because there is a large variability in the intermediate degrees. The cluster analysis shows a definite pattern of parameters for each cluster (1 = no significant regurgitation, 2 = mild, 3 = moderate, 4 = severe insufficiency).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1981

Selective effect of gonadotrophins on cell coupling, nuclear maturation and protein synthesis in mammalian oocytes.

Individual gonadotrophic hormones were used to examine the degree to which changes in intercellular coupling between somatic and germ cells initiate meiotic maturation, regulate protein synthesis or alter the ultrastructure of the ovine oocyte. Follicle Stimulating Hormone (FSH; 50 ng ml-1) suppressed intercellular coupling to the same extent as that observed during oocyte maturation in vivo. At low concentrations FSH did not, however, initiate resumption of meiosis. By contrast, luteinising hormone (LH; 100-500 ng ml-1) invariably initiated meiosis in oocytes cultured within the follicle but did not disrupt intercellular coupling. We conclude that nuclear maturation is not dependent upon the disruption of cell contact between the oocyte and the surrounding follicle cells. The profile of proteins synthesized by untreated oocytes differed greatly from that of oocytes matured for 18 h in follicles treated with a combination of FSH and LH. Pretreatment of follicles with either FSH or LH at low concentrations resulted in the synthesis of an intermediate and more variable pattern of proteins. No correlation was found between changes in protein synthesis and the extent of junctional communication between the cumulus cells and oocyte. Membrane vesiculation and lysosomal change in the transzonal processes are early structural changes associated with the suppression of intercellular coupling in oocytes. These changes in coupling probably result in the relocation of intracellular organelles in the final stages of oocyte maturation.

Animals↗
PubMed1980

Supranucleosomal organization of sea urchin sperm chromatin in regularly arranged 40 to 50 nm large granular subunits.

The organization of the chromatin of sperm nuclei of sea urchin (Parcentrotus lividus and Sphaerechinus granularis) was studied by electron microscopy using thin sections of fixed cells and spread preparations of chromatin obtained after various procedures involving incubation in low salt buffers. In fixed cells and in moderately dispersed preparations chromatin appeared in the form of fibrillar chains formed by closely apposed, distinctly sized granules that were larger than chromatin subunit structures so far described in other kinds of chromatin (mean diameters of particle units determined were 36 nm, in thin sections, and 47 nm, in spread preparations). Upon prolonged incubation in low salt buffer an increasing number of these large granular units was transformed into extended nucleosomal chains (nucleofilaments). Estimations indicated that the large granules contained 20 to 26 nucleosomes, i.e. 4.8 to 6.2 kb DNA, resulting in a linear DNA contraction ratio of 33 to 55, which is in a similar range as values reported for the supranucleosomal chromatin particle of the SV40 minichromosome but greater than contraction ratios of "superbead" structures. The unravelling of the large supranucleosomal granule into the extended nucleofilament chain in low salt buffers seemed to be a gradual process since intermediate stages of variable particles sizes and shapes were observed. This novel type of chromatin particle is considered to represent an example of a naturally occurring globular supranucleosomal packing unit of chromatin which is predominating, if not the only forms of supranucleosomal levels of chromatin organization and in relation to the special DNA content and histone composition of sea urchin sperm nucleosomes.

Animals↗
PubMed1996

Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients.

PURPOSE: In 215 consecutive patients with advanced metastatic renal cell carcinoma seen at a single institution the efficacy and tolerance of different subcutaneous recombinant interleukin-2 based home therapies were assessed. MATERIALS AND METHODS: Treatment consisted of subcutaneous recombinant interleukin-2 alone and subcutaneous recombinant interleukin-2 in combination with recombinant interferon-alpha 2 with or without intravenous 5-fluorouracil. RESULTS: Overall objective response rate in 215 patients was 33% (95% confidence interval 26 to 39%). Among 16 patients receiving recombinant interleukin-2 alone there was 1 partial remission (overall response 6%). In 79 patients receiving recombinant interleukin-2 and interferon-alpha 2 in combination 6 complete and 16 partial remissions occurred (overall response 28%). Of 120 patients receiving a combination of recombinant interleukin-2, recombinant interferon-alpha 2 and 5-fluorouracil 13 achieved a complete and 34 a partial remission (overall response 39%). Of all patients 5% achieved long-lasting remissions and remain disease-free. Multivariate analyses identified pretreatment erythrocyte sedimentation rate greater than 70 mm. per hour and lactic dehydrogenase greater than 280 units per l. as independent prognostic factors of major significance (p < or = 0.0001) in metastatic renal cell carcinoma. Additionally, neutrophil count greater than 6,000/microliters., hemoglobin less than 100 gm./l., extrapulmonary metastases and bone lesions were identified as minor (p < or = 0.006) prognostic variables. Patients were assigned to 1 of 3 risk categories according to cumulative risk score defined as the function of the sum of all 6 independent variables. In 116 intermediate risk patients 2-year survival was 65% (median survival not reached after 32 months) with recombinant interleukin-2, recombinant interferon-alpha 2 and 5-fluorouracil, as opposed to 27% 2-year survival (median survival 15 months) with recombinant interleukin-2 and interferon-alpha 2 (p < 0.0001), and 0% (median survival 4.8 months) with single agent recombinant interleukin-2. In the majority of patients systemic toxicity of subcutaneous recombinant interleukin-2 based protocols was limited to grade 1 or 2 constitutional symptoms, that is fever, chills, malaise and anorexia, which allowed for outpatient therapy. CONCLUSIONS: The present outpatient recombinant interleukin-2 triple drug combination protocol was as effective as the most aggressive intravenous recombinant interleukin-2 regimen available. Combination home therapy eliminated the need for inpatient and/or intensive care as required for intravenous cytokine administration and, thereby, it substantially improved the therapeutic index and cost-effectiveness of recombinant interleukin-2 therapy in metastatic renal cell carcinoma stratified for risk.

Antineoplastic Agents↗