Distribution of calbindin and parvalbumin in the developing somatosensory cortex and its primordium in the rat: an immunocytochemical study. Immunocytochemical techniques were used to analyze the distribution of the calcium-binding proteins calbindin and parvalbumin during the pre- and postnatal development of the rat somatosensory cortex. Calbindin occurs in most early differentiated neurons that form the primordial plexiform layer at embryonic day 14. This expression in transient; during the perinatal period, calbindin becomes immunologically undetectable within the structures derived from the primordial plexiform layer, i.e., the prospective layers I and VIb. Immunoreactive neurons are also absent from adult layers I and VIb. Calbindin is also detected in a second population of neurons which, from embryonic day 18 onwards, distributes diffusely within the cortical plate. Some neurons of this population show morphological traits of immaturity, while others show complete dendritic arborization. The definitive pattern of distribution of calbindin-immunoreactive neurons is achieved by postnatal day 22. Infragranular layers contain intensely-immunoreactive cells whose numerical density decreases during postnatal development, whereas in supragranular layers similar neurons are interspersed among numerous faintly-stained neurons. Parvalbumin is detected for the first time at postnatal day 6, within a small group of neurons located in cortical layer V, and extends afterwards through the whole thickness of the cerebral cortex. At this same postnatal stage, groups of immunoreactive puncta are also found in layer IV of the somatosensory cortex; these puncta increase in density progressively and, at embryonic day 13, immunoreactive cells appear also grouped at this level. At this postnatal age, parvalbumin immunostaining delineates the somatosensory map in cortical layer IV. From this stage to adulthood, the number of immunoreactive neurons increases in the whole thickness of the somatosensory cortex. Barrels in layer IV become less distinct as immunoreactive cells and processes invade the septa. Layer IV in the adult somatosensory cortex appears more densely populated by parvalbumin immunoreactive neurons and puncta than in the surrounding areas.


The distribution of clones of neurons in the rat somatosensory cortex. We have labelled clones of neurons in the cerebral cortex of rats by introducing a retroviral vector, called BAG, into the cerebral vesicles of embryos in utero. BAG encodes the enzyme beta-galactosidase, which acts as a histochemical marker for the subsequent identification of clones derived from infected precursor cells. We have studied the distribution of neuronal clones in the rat somatosensory cortex, and have asked whether clonally-related neurons were dispersed randomly. We have discovered that they are not. Rather, clones disperse predominantly such that the earliest progeny of ventricular zone cell are found posterolateral to later generated cells. This distribution fits with what would be expected were neurons dispersed passively in accordance with the lateral to medial cortical neurogenic gradient.


Ultrastructural localization of calcium in mechanoreceptors of the oral mucosa. Cytochemical localization of Ca2+ in Meissner corpuscles and Merkel cell-neurite complexes in the palatine mucosa of the Mongolian gerbil was studied by a combined oxalate antimonate-microwave irradiation procedure. The reaction products obtained were identified as calcium antimonate by EGTA solubility and X-ray microanalysis. Meissner corpuscles in the normal palatine rugae could be roughly classified into three types by amount and localization of Ca2+. Type I corpuscles were characterized by a high Ca2+ content in both the terminal axoplasm and caveolae of the lamellar plates, type II, by a low Ca2+ content in the terminal axoplasm and a high Ca2+ content in the lamellar cytoplasm. Type III corpuscles showed intermediate characteristics. Palatine rugae stimulated mechanically during fixation contained an increased number of type I corpuscles. On the other hand, two patterns were distinguished in the distribution of Ca2+ in Merkel cells in palatine rugae fixed under normal conditions. One showed abundant Ca2+ dispersed throughout the cell, while in the other, Ca2+ was specifically localized in the Golgi apparatus and mitochondria. Similar distribution patterns also were observed in palatine rugae that had received mechanical stimulus during fixation. Axon terminals of most Merkel cell-neurite complexes in normal palatine rugae were poor in axoplasmic Ca2+, whereas those in most Merkel cell-neurite complexes in mechanically stimulated palatine rugae contained abundant Ca2+ in their axoplasm.


Influence of an endogenous lectin substrate on cultured dorsal root ganglion cells. Dorsal root ganglion neurons normally contain a 14,500 molecular weight lactose-binding lectin, designated L-14. Although this lectin is developmentally regulated, and is localized to specific neurons as well as to specific areas of the rat spinal cord, its function in the nervous system is not known. In an effort to study the possible role of this lectin on peripheral neurons, they were dissociated and grown on substrates consisting of either L-14 or laminin, a molecule known to support neurite outgrowth. In contrast to the random distribution and fine neurites displayed by neurons on laminin, those growing on L-14 formed large aggregates with highly fasciculated neurite bundles. Experiments using plant lectins with sugar-binding specificity similar to that of L-14, as well as another endogenous rat lectin not present in neurons, resulted in essentially no neuronal attachment or neurite outgrowth. In addition, the effects induced by L-14 were not blocked by high concentrations of competing sugars, suggesting that it interacts with neurons by a domain distinct from its carbohydrate-binding site.


Topography of opsin within disk and plasma membranes revealed by a rapid-freeze deep-etch technique. Rod outer segments in fresh rat retinas were examined by a rapid-freeze, deep-etch technique to explore how membrane proteins are organized at the macromolecular level. Cross-fractures revealed that intradiscal membranes are adherent to each other except at the rim. When an isolated fresh retina was incubated in a hypotonic solution for a few minutes, the interdiscal space was expanded and the cytoplasmic surface of the disk membrane was found to be covered with protrusions except at the rim. A few particles were scattered among the protrusions and were attached to the cytoplasmic surface. Since the distribution density of the cytoplasmic surface protrusions was similar to that of the P-face particles, which are known to reflect opsins, the protrusions were considered to be portions of opsins extending into the cytoplasm. The intradiscal surfaces in chemically-fixed retinas were rather smooth and were labelled with anti-opsin antibodies and wheat germ agglutinin. The true surfaces of the plasma membrane were found to be similar in fine structure to those of the disk. A model of the macromolecular organization of rod outer segments is proposed on the basis of these observations. The model shows apposed opsins within a disk membrane adhering to one another except at the rim. These opsins, as well as those in the plasma membrane, are minimally exposed to the extracellular surface, but protrude deeply into the cytoplasm.


Electron microscopic immunocytochemistry of GAP-43 within proximal and chronically denervated distal stumps of transected peripheral nerve. Growth-associated protein, GAP-43 was initially described as a neuron-specific molecule thought to play a critical role in axonal growth and regeneration. However, it is also expressed in vitro in certain CNS glia, Schwann cell precursors and non-myelinating Schwann cells. In this paper, we report the subcellular localization of GAP-43 in vivo in chronically-denervated Schwann cells in the distal stumps of previously transected rat sciatic nerve. We have used a progressive lowering of temperature method combined with the non-polar acrylic resin Lowicryl HM20 and a post-embedding labelling regime to visualize the distribution of GAP-43, S-100 (marker for Schwann cells), RT97 and NF68 (markers for different subunits of the neurofilament molecule). We report that (1) the smallest calibre regrowing axons were GAP-43-positive, sometimes NF68-positive but always RT97-negative; (2) regenerating myelinated axons and larger unmyelinated axons (> 0.7 microns diameter) were NF68-positive, RT97-positive but GAP-43-negative; (3) cytoplasmic processes within Schwann cell basal lamina tubes in the distal stumps were S-100-positive, GAP-43-positive but RT97- and NF68-negative. The similar localization of GAP-43 within regrowing axons and denervated Schwann cells suggests that GAP-43 may function similarly in both situations, and may thus be involved in motility and/or elongation of axons and Schwann cells during regeneration.


An assessment of the usefulness of demographic data provided by surrogate respondents in a case-control study of Parkinson's disease. This study, based upon data from 40 non-demented Parkinson's disease cases and 101 community controls, and similar data provided by either the spouse (n = 110) or an adult child (n = 31) of each index subject, attempted to assess the usefulness of various demographic data provided by the surrogate respondents for the index subjects. The data were collected by personal interview using a structured questionnaire specifically developed for this study. Ninety-one percent of the index subjects and their surrogates provided information on the annual family income and 98% provided other demographic information. The analysis was done by three groups: the case-surrogates, the control-surrogates and the combined index subject-surrogates, and within each group by the two types of surrogates for the index subjects: the spouse vs adult child. The overall percent agreement between the index subjects and their surrogates varied from moderate for annual family income (54.1%), to good for educational level (61.6%) and to excellent for ethnic origin (82.6%), for age +/- 1 year (97.9%) and for marital status (100.0%). No significant differences in agreement were found for any of these demographic variables either between the case-surrogate group and the control-surrogate group, or between the spouse surrogates and the child surrogates. These findings suggest that spouses and adult children can provide valid information and are equally reliable informants concerning the demographic characteristics of index subjects in a case-control study of Parkinson's disease and, possibly, of other diseases.


Diagnostic tools in Lyme borreliosis: clinical history compared with serology. The occurrence of a history of clinical Lyme borreliosis and the prevalence of positive antibodies to Borrelia burgdorferi were studied in 431 Dutch hunters. The majority of the hunters (336 or 78%) did not report any complaints and had no positive IgG antibodies to B. burgdorferi. Sixty-five hunters (15.1%) had no clinical manifestations but did not have positive antibodies to B. burgdorferi. Only 1.9% of the population studied had had past symptoms of definite or probable Lyme borreliosis. Likelihood ratios were high (21.3) for the recognition of erythema migrans, but much lower for tick bites (3.6) or positive IgG Lyme serology (3.5). Clinical history turned out to be a more powerful diagnostic tool than Lyme serology.


The logistic modeling of interobserver agreement. An approach to the logistic modeling of interobserver agreement is described that allows for the estimation of a commonly employed measure of agreement. The dependent variable is defined to be 1 if the two raters agree, and 0 otherwise. Covariates may be included in the regression equation in order to obtain adjusted or subgroup-specific estimates of percent agreement. As an empirical example, logistic models were fitted to data from a validation study of the agreement between interview information and physician records on the history of post-menopausal estrogen use, from a case-control study of breast cancer conducted on Oahu, Hawaii. Variables found to be related to agreement in previous univariate analyses were examined as covariates in the logistic model. The directly calculated estimates of percent agreement agreed well with the modeled estimates derived from the regression coefficients. Thus, the logistic model may provide a useful alternative to existing methods for the description of interobserver agreement.


Using college alumni populations in epidemiologic research: the UNC Alumni Heart Study. The UNC Alumni Heart Study (UNCAHS) is a prospective study of the role of psychosocial factors, in particular hostility, in the development of coronary heart disease. The target population is composed of persons who completed the Minnesota Multiphasic Personality Inventory while attending the University of North Carolina in the mid-1960s. Logistic regression analyses were used to determine whether hostility, demographic and other variables were significant determinants of the subjects' locatability and participation. It was found that MMPI hostility scores at initial testing were unrelated to either potential or actual locatability or participation. Thus there is no evidence that hostility is the source of selection bias in the UNCAHS. Selection into the study was predicted by age, sex, degree status and variables concerned with the conditions under which the MMPI was administered. It is concluded that follow-up studies of college cohorts may have study-specific sources of selection bias.


Meta-analysis adjusting for compliance: the example of screening for breast cancer. Randomized controlled trials are usually analysed by the group to which the patient was randomized, i.e. by "intention-to-treat", regardless of the degree of compliance. However, the "explanatory" effect, i.e. the effect that would occur if we had 100% compliance, is often of interest. This "explanatory" effect is diluted by poor compliance, and hence meta-analyses should ideally avoid both the heterogeneity of effect due to variation in compliance rates among studies, and the undeserved weight given to trials with poor compliance. Newcombe's deattenuation method, which adjusts estimates for the degree of compliance, is extended and applied to a meta-analysis of the five reported randomized controlled trials of mammographic screening. Compliance with screening varied across studies: from 61 to 93% assigned to screening had one or more mammograms. The adjusted estimate of the reduction in breast cancer mortality at 9 years follow-up is 0.37 (95% confidence interval: 0.21, 0.49).


Intrauterine growth retardation and blood pressure at age seven and eighteen. The association between intrauterine growth retardation and blood pressure in middle childhood and early adulthood was examined. At age 7, after adjusting for sex and weight, the differences between normal children and those who had experienced intrauterine growth delay were 0.9 mmHg (95% CI -0.1 to 2.2) for systolic and 0 mmHg (-1.7 to 2.0) for diastolic blood pressure respectively. The differences between the blood pressures of intrauterine growth retarded infants with an appropriate ponderal index and those with a low ponderal index were 4.4 mmHg (-0.9 to 7.9) for systolic, and 3.8 mmHg (0.2 to 7.3) for diastolic blood pressure respectively. At age 18 the differences were much less pronounced. The association between blood pressure and the placental weight was also examined. The evidence from this sample lends weak support to the findings of other studies which suggest that there is an association between factors occurring before or around the time of birth and blood pressure in later life.


Oxygen as a cause of blindness in premature infants: "autopsy" of a decade of errors in clinical epidemiologic research. Several intellectual "autopsies" have recently reviewed errors in clinical epidemiologic studies of causation, such as the original claim that amyl nitrite "poppers" caused AIDS. The current autopsy was done to determine why it took more than a decade--1942 to 1954--to end an iatrogenic epidemic in which high-dose oxygen therapy led to retrolental fibroplasia (RLF) in premature infants, blinding about 10,000 of them. The autopsy revealed a museum of diverse intellectual pathology. When first noted, RLF was regarded as neither a new disease nor a postnatal effect. In early investigations, the ophthalmologists did not establish explicit criteria for diagnosis and confused RLF with malformations previously seen in full-term infants. Because the patients were not referred until months after birth, the ophthalmologists assumed that the lesion, which resembled an embryologic structure, must have occurred prenatally. Other events suggesting a prenatal cause for RLF were its strong statistical associations with fetal anomalies, multiple gestations, and maternal infections. Although these events were also associated with prematurity, it was ignored when the RLF cases were compared with controls who were mainly full-term infants. The postnatal timing of RLF was eventually recognized when investigators did cohort studies in premature infants and found that RLF could develop in eyes that were normal at birth. As the search for a cause turned to events occurring after birth, statistical associations were produced for agents such as light, vitamins, iron, vitamin E deficiency, and hypoadrenalism. Each study had its own methodologic flaws: controls were missing for light; co-maneuvers were ignored for vitamins and iron; objective diagnosis was not used for vitamin E deficiency; and the research on hypoadrenalism contained biases in susceptibility and detection as well as problems of a competing outcome event. When the role of oxygen administration was first considered, the statistical association with RLF was stronger for vitamin- and iron-therapy than for oxygen. In addition, many investigators were dissuaded by contradictory evidence from institutions in which RLF was either absent despite high-dose oxygen or persistent despite reduced dosage. The contradictory evidence was later regarded as erroneous because of unsatisfactory delivery systems for the oxygen or failure to check the actual oxygen concentrations. An alternative explanatory hypothesis, rejecting the role of high-dose and long-duration oxygen, was the idea that RLF was due to "relative hypoxia", produced by overly rapid weaning from oxygen therapy rather than the duration of oxygen treatment itself.(ABSTRACT TRUNCATED AT 400 WORDS)


Diagnostic problems with meningococcal disease in general practice. Based on general practitioners' referral letters and hospital records, we made a retrospective analysis of a cohort of 177 consecutive cases of meningococcal disease that occurred during a period of 10 years in the County of North Jutland, Denmark. The analysis concerned diagnostic problems in general practice, prognosis, pre-hospital antibiotic treatment and its effect on subsequent cultures, and degree of obligatory notification. The referring doctor suspected meningococcal disease/central nervous infection in 123 patients (69.5%). Neck stiffness and petechiae were related to a correct referral diagnosis, in contrast to the occurrence of a non-petechial rash. The presence of disseminated intravascular coagulation was associated with the mortality rate, which was 0.062. The therapeutic recommendations of the Danish Health Authorities were followed in only 25 of the 98 patients who fulfilled the criteria for pre-hospital parenteral antibiotic treatment. Pre-hospital antibiotic treatment was related to negative culture of spinal fluid or blood. Seven of the 177 patients were not notified according to the rules. Difficulties in pre-hospital diagnosis seem not to influence the lethal course of the disease.


Quality of life and functional health of primary care patients. Quality of life and functional health were measured cross-sectionally for 314 adult ambulatory primary care patients in a rural clinic and found to be much better for patients with low severity of illness who required no confinement to home because of health problems, than for patients with high severity of illness who required confinement. Severity of illness was the strongest predictor for patient-reported physical health function and for patient quality of life when assessed by the health provider. Confinement was the strongest predictor for patient quality of life when assessed by the patient. There was very little agreement between patient-assessed and provider-assessed quality of life. Family stress was the strongest predictor of function in terms of mental health, social health, general health, self-esteem, anxiety, and depression. These data suggest that clinicians should direct increased attention to patient-assessed quality of life, patient-reported functional health status, and psychosocial factors such as family stress in an effort to improve medical outcomes.


Functional ability of community dwelling elderly. Criterion-related validity of a new measure of functional ability. Criterion-related validity of a new measure of functional ability was conducted according to a causal model based on conceptual models employed in the area of rehabilitative and geriatric medicine. The criteria variables included concurrent diagnosed diseases, global self-rated health, drug consumption and general practitioner (GP) consultations. The measure of functional ability was developed with the intention of achieving a high degree of discrimination among a group of community dwelling elderly. Data were derived from a sample survey of 70-year-old men and women conducted in 1984 in the county of Copenhagen (Denmark). Altogether 366 men and 368 women participated in each of the two phases of the study--a comprehensive medical examination at the county hospital at Glostrup followed by a home visit conducted by an occupational therapist 1-2 weeks later. The analysis included four different unidimensional index scales of functional ability divided into two types, with reduced speed and tiredness as subdimensions. The two scale types were mobility function and lower limb function. Early losses of ability together with global self-rated health were treated as outcome measures of diagnosed chronic diseases. At the same time these outcome measures together with diagnosed diseases were considered to predict drug consumption and GP consultations. It was shown that functional ability as measured by the new index scales were strongly influenced by diagnosed diseases: arteriostenosis and osteoarthrosis in lower extremities, obesity, shoulder impairments and bronchitis among women, and glucose intolerance, arteriostenosis in lower extremities and shoulder impairments among men. Global self-rated health was strongly associated with the new functional ability rating system. Early losses of ability but not self-rated health was a strong predictor for drug consumption and frequent contacts with GP. It is concluded that the new measure of functional ability is suitable for health studies of community dwelling elderly, in particular as a summary statement of the individual's health status.


Glucose tolerance and the risk of cardiovascular disease: the Zutphen Study. The impact of glucose tolerance on the incidence of ischemic heart disease (IHD), cerebrovascular disease (CVA), and peripheral arterial disease (PAD) was investigated in the Zutphen Study. In 1970 a complete oral glucose tolerance test (GTT) was carried out on 400 normoglycemic men aged 50-70 yr. A morbidity follow-up was completed in 1985. With GTT classified as the dichotomous variable using the median value of the area under the curve, elevated risks for IHD (RR = 1.6, p < 0.05), fatal IHD (RR = 2.3, p < 0.01), and CVA (RR = 1.9, p < 0.10) were observed, adjusted for potential confounders. No association with PAD was found. Also the risk among non-insulin-dependent diabetics (n = 46) was assessed. These men were clinically diagnosed between 1960 and 1985, median year of diagnosis being 1973, at age 61 yr. Compared with 230 matched non-diabetics increased risks were observed for fatal IHD (p = 0.05), CVA (p = 0.10) as well as PAD (p = 0.05). Thus an elevated risk for IHD, and possibly CVA, may have been found with lower levels of glucose than assumed previously, suggesting a continuous risk gradient. For PAD the relations with glucose tolerance are more complex.


Rising mortality due to Parkinson's disease and amyotrophic lateral sclerosis: a manifestation of the competitive nature of human mortality. Over the past 15 yr, a marked increase in crude mortality rates from Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) has occurred in the U.S. This is often attributed to as yet undefined environmental factors. The deterministic risk of general mortality and mortality due to PD, ALS, ischemic heart disease (IHD), and stroke for the years 1963, 1977, and 1986 in the U.S., as defined by the method of longitudinal Gompertzian analysis, were calculated and compared. When the rise in PD and ALS mortality is viewed from the perspective of deterministic and competitive mortality dynamics, it becomes evident that the major force increasing mortality from these two neurologic diseases is the declining mortality from IHD and stroke. Consequently, there is no need to invoke intrinsic etiologic alterations in the environment to account for the observed increases in PD and ALS mortality. Recognition of the competitive nature of human mortality illustrates the inherent risk of making etiopathogenic conclusions based upon single disease mortality data.


Interobserver variability in medical record review: an epidemiological study of asthma. Interobserver variability during the data collection for a large retrospective study of asthma was assessed. After extensive training by three physician investigators, two nurses collected study data from existing medical records using an explicit protocol. At four time intervals, samples of records already abstracted by one nurse were reviewed and re-abstracted by another nurse assigned to the project. The unweighted kappa coefficient was used to evaluate observer reliability. Most of the kappa coefficients were > or = 0.6, suggesting good to excellent agreement. Agreement was highest for demographic, clinical and medication variables, while judgement variables had the lowest kappa coefficients. The well known dependence of kappa on the prevalence of the variable studied was evident in these data. We strongly recommend periodic monitoring of observer reliability in any study using more than one individual to collect data to ensure reliable data collection.


Risk of kidney cancer in analgesics users. The risk of kidney cancer was examined in a cohort of people discharged from Danish hospitals from 1977-1987 with a diagnosis of rheumatoid arthritis, osteoarthrosis or backpain. These individuals are presumably more or less regular users of mild analgesics. A total of 155,554 people were identified. The risk of cancer of the urinary tract was slightly increased [relative risk (RR) = 1.31], almost exclusively because of an increased risk of renal cell carcinoma (RR = 1.40). The relative risk was higher in individuals with rheumatoid arthritis than among individuals with osteoarthrosis or backpain, and higher among women than men. Although this study lacks information on the actual analgesics consumption of the individual, and various biases may be present, these findings offer little support to the concern that increased analgesics use raises the risk of kidney cancer.


Alcohol and epithelial ovarian cancer.

Alcohol and epithelial ovarian cancer. The relationship between alcohol consumption and the risk of epithelial ovarian cancer was analysed using data from a case-control study of 801 histologically confirmed epithelial ovarian cancers and 2114 controls in hospital for acute, non-neoplastic, gynecological, or hormone-related conditions, admitted to a network of teaching and general hospitals in the greater Milan area, northern Italy, i.e. a region with comparatively frequent alcohol consumption by women. Compared to alcohol abstainers, the multivariate relative risks (RRs) were 1.0 [95% confidence interval (CI), 0.7 to 1.4] for less than one, 1.1. (95% CI 0.9 to 1.6) for one to two, 1.2 (95% CI 1.0 to 1.5) for two to three and 1.3 (95% CI 0.9 to 1.8) for three or more drinks per day. A significant direct trend in risk with dose emerged. This finding chiefly derived from an association between ovarian cancer risk and consumption of wine (which accounts for over 90% of alcohol intake in this female population). Although no significant interaction between the effect of alcohol consumption and various women's characteristics emerged, there was a hint that the adverse influence of alcohol consumption is more marked in middle-age and less educated women. Thus, the results of this study suggest that relatively elevated alcohol intake (of the order of 40 g per day or more) may cause a modest increase of epithelial ovarian cancer risk.


Trends in the utilization of non-steroidal anti-inflammatory drugs in the United States, 1986-1990. National estimates of NSAID utilization were obtained from two databases available from IMS America. These data illustrate that in contrast to the rapid rise in NSAID prescriptions from 1973 (27.5 million) to 1983 (66.7 million), NSAID prescriptions have recently been remarkably stable. Over the same time period, a 46 fold increase in the use of gastro-protective and/or anti-ulcer drugs concomitantly with NSAID was demonstrated. It is hypothesized that the stabilization of NSAID prescription usage coupled with the dramatic increase in usage of concomitant anti-ulcer and gastro-protective agents has occurred due to physician awareness of the increased relative risk for adverse gastrointestinal events among NSAID users compared to non-users.


The role of diagnostic inconsistency in changing rates of occurrence for coronary heart disease. The ante-mortem (in vivo) and post-mortem diagnoses of coronary heart disease (CHD) were compared in necropsies at a university hospital for 1965, 1975, and 1985. The secular trends showed gradually rising proportions in both true positive and false negative ante-mortem diagnoses. Both types of change in diagnostic error would progressively lower the counted numbers of CHD in official vital statistics. With suitable statistical corrections, the occurrence rates of CHD in Connecticut became much higher and showed less dramatic trends in secular decline. The results indicate that major improvements in accuracy are needed before vital statistics data are accepted at face value and analyzed for biologic explanations of the changing numbers.


Decision making during serious illness: what role do patients really want to play? Two surveys were conducted to determine what roles people actually want to assume in selecting cancer treatments. 436 newly diagnosed cancer patients and 482 members of the general public participated. Preferences were elicited using two card sort procedures, each of which described five potential roles in decision making. Findings suggested that the impact of being diagnosed with a life-threatening illness may influence preferences to participate. The majority (59%) of patients wanted physicians to make treatment decisions on their behalf, but 64% of the public thought they would want to select their own treatment if they developed cancer. Most patients (51%) and members of the public (46%) wanted their physician and family to share responsibility for decision making if they were too ill to participate. Sociodemographic variables accounted for only 15% of variance in preferences. These variables are not particularly useful in making predictions about which groups want more or less active roles in medical decision making.


Some observations on the variation in height coefficients in prediction equations for forced vital capacity. Intercept and height coefficients in prediction equations for forced vital capacity (FVC) are highly correlated and highly variable, due in part to the small coefficient of variation of height (4%). This degree of imprecision and relationship was observed among the coefficients of a set of 26 unrelated published prediction equations, and appeared to dominate any systematic differences between them in methodology and technique. The findings indicate that care needs to be taken when using equations for predicting the FVC of people at the extremes of height. They also demonstrate the need for careful planning in the design of studies intended for the compilation of prediction equations, including provision for sufficient numbers of observations. Support is also given to the use of a composite formula based on the averaging of many individual prediction equations. The results are applicable to other similar and commonly used lung function equations (e.g. that for forced expiratory volume in 1 second, FEV1) that employ height as a predictor variable.


A prospective study of familial aggregation of blood pressure in young children. In a prospective study, we evaluated familial aggregation of blood pressure in a sample of 175 normotensive families with children 3 to 6 yr old. Systolic and diastolic blood pressure measurements of parents and children were correlated at 1, 2, and 3 yr intervals. Spearman rank-order correlation coefficients between parents and children were significant for mother-son pairs. In particular, mother-son blood pressure correlation coefficients were significant for systolic blood pressure across all 3 yr and for diastolic blood pressure during yr 2. Further analyses were performed adjusting for body mass index (BMI), age, physical activity, sodium intake, potassium intake, and parental smoking status, and alcohol use. The Spearman correlation coefficients for mother-son pairs remained significant for yr 1 and 3 after adjusting for these blood pressure correlates. These results are consistent with cross-sectional studies and suggest that both genetic and environmental contributions to blood pressure status are important in young children.


Precision of blood cholesterol measurement and high blood cholesterol case-finding and treatment. Imprecise blood cholesterol measurement can be expected to adversely affect large scale efforts to detect and treat high blood cholesterol. Using protocols specified by the National Cholesterol Education Program (NCEP), we used computer simulation techniques to quantify the effects of blood cholesterol measurement variability on misclassification rates, costs, effectiveness, and cost-effectiveness of high blood cholesterol case-finding and treatment. At the time of initial case-finding, increased measurement variability was associated with a moderate decrease in the proportions assigned to a treatment state and in the positive predictive value of such an assignment. After 10 years of continual case-finding and treatment, measurement variability dramatically affected proportions assigned to drug treatment and diminished the percent on drugs with blood cholesterol levels truly above NCEP cutpoints. Extreme variability in blood cholesterol measurement increased per capita costs by 14-18% and diminished cost-effectiveness by at least 11-12%. The adverse effects of measurement variability on cost-effectiveness were much more pronounced if adjustments to life-expectancy were made to recognize the lower quality of life associated with drug treatment. Misclassification rates can be decreased and cost-effectiveness improved by performing repeated measurements of blood cholesterol before increasing intensity of treatment. Improvement in the precision of measurement are especially beneficial for low-risk individuals.


Within-subject diastolic blood pressure variability: implications for risk assessment and screening. Because of variability in diastolic blood pressure within an individual, repeated measurements increase precision in assessing an individual's underlying mean pressure and so also aid risk classification. Data from a cohort of 11,299 middle-aged men is used to model the variability in diastolic pressure between annual measurements. A simple model with pressure normally distributed about an underlying mean with standard deviation increasing with level fits the data very well. In modelling risk of cardiovascular mortality, a strong association is found with observed diastolic pressure level but not to trends in or variability between observed values. The effect of regression dilution is clear with the risk relationship appearing greater as one uses the mean of an increasing number of measurements. A method of adjusting for this regression dilution is described so giving an estimate of the relationship with underlying mean diastolic pressure. Using this survival model and the model for blood pressure variability, a method is presented for estimating both underlying mean pressure and absolute risk of cardiovascular disease given a sequence of blood pressure measurements from screening. This allows a sequential strategy for determining whether (a) antihypertensive intervention is desirable, (b) no further screening is necessary, or (c) further screening would aid the assessment, and emphasizes the need to consider blood pressure in the context of multiple risk factors.


Twenty year trends in hospital discharges for asthma among members of a health maintenance organization. We examined trends in hospitalizations for asthma from 1967 to 1987 among members of a large health maintenance organization. During this time asthma discharges increased significantly among children, and especially among boys under the age of 5 years. Ninety-five percent of the increase in discharges among boys was explained by a corresponding increase in the number of boys who were hospitalized. Increased readmissions did not account for the rise. Changes in the International Classification of Diseases coding of asthma and diagnostic shift by physicians accounted for only part of the increase. A decline in hospitalizations since 1984 may reflect changes in the management of asthma in the emergency room and not a decline in severe asthma episodes.


The 56 kd platelet-derived growth factor (PDGF)-related protein is phosphorylated and the most stable form in human glioma cells. We report herein the presence of a 56 kd platelet derived growth factor (PDGF)-related protein as a phosphorylated form in human glioma cells. The phosphorylation of the 56 kd form was found to be the longest of all PDGF-related proteins. By Western blotting using a monoclonal anti-PDGF B-chain, the 80 kd, 56 kd, 40 kd, 28 kd and 17 kd PDGF-related proteins were detected, while after treatment among the nitrocellulose membrane transblotted cell extracts with alkaline phosphatase, 40 kd was the most densely observed while the 56 kd and 80 kd PDGF-related proteins were also detected. In a 32P flush labeling study, it was revealed that PDGF-related proteins incorporated with 32P were detected at 28, 32, 35, 40, 56 and 80 kd but the 17 kd monomer was not labeled. Among the labeled PDGF-related proteins, the 56 kd PDGF-related protein alone remained intracellularly for at least 16 hours. These results indicated that the PDGF-related proteins in human glioma cells are synthesized in a phosphorylated form and partly remain in a 56 kd phosphorylated form intracellularly. The 56 kd form may thus be the most stable form and likely has a substantial biological effect.


Effect of intracarotid infusion of etoposide with angiotensin II-induced hypertension on the blood-brain barrier and the brain tissue. This study investigated the effects of the intracarotid infusion of etoposide in combination with angiotensin II (AT II)-induced hypertension on the blood-brain barrier (BBB) and brain tissue in rats. Eighty rats were divided into five groups: Group 1, intravenous infusion of AT II to increase arterial blood pressure; Group 2, intracarotid infusion of etoposide at 22.5 mg/m2 for 10 minutes; Group 3, intracarotid infusion of etoposide at 75.0 mg/m2 for 10 minutes; Group 4, intracarotid infusion of etoposide at 75.0 mg/m2 for 20 minutes; Group 5, intracarotid infusion of etoposide at 75.0 mg/m2 for 10 minutes with AT II-induced hypertension. Evans blue staining of the brain was used as a monitor of BBB disruption. Mean arterial blood pressure over the experimental period in Group 1 increased from 86.3 +/- 1.3 mmHg (mean +/- SEM) to 139.0 +/- 2.4 mmHg, and Group 5 from 85.9 +/- 1.8 mmHg to 137.3 +/- 2.4 mmHg. None of the animals in Group 1 and 2 showed any obvious neurological change, while all the animals in Group 3, 4 and 5 exhibited diminished activity as their sole neurological change throughout the course of the experiment. Slight evidence of BBB disruption was seen in only 25% of the animals in Group 1. Significant BBB disruption was found in the animals in Group 2, 3, 4 and 5. No histological change was observed in any animal in Group 1 and 2.(ABSTRACT TRUNCATED AT 250 WORDS)


Temporal trends among childhood brain tumor biopsies. The Childhood Brain Tumor Consortium. We sought temporal trends in the demographic, clinical, histologic feature, diagnostic class, and quality of life data over the interval 1930-1979 in the Childhood Brain Tumor Consortium database. The proportion of children younger than eight years old declined from 72% to 55% and the proportion of those older than ten more than doubled from 12% to 27%. The relative frequency of tumors in the supratentorial compartment increased significantly, while infratentorial tumors decreased. We found significant declines in supratentorial ependymomas and pilocytic astrocytomas. Similarly, some infratentorial tumors, especially ependymomas, decreased and brain stem tumors increased. Infratentorial medulloblastoma (primitive neuroectodermal tumor) increased significantly. Some individual histologic features which are markers of anaplasia increased in frequency in both supratentorial and infratentorial tumors. There was a significant increase in biopsies that contained nonneoplastic neural tissue in addition to tumor for both compartments and among supratentorial tumors there was a marked increase in the proportion of cases containing an indistinct neural tissue boundary. The probability of postoperative death declined, but the probability of survival five or ten years after surgery did not improve significantly for children who had tumors in either compartment. Among children who survived five years after the initial craniotomy, the proportion who had significant long term deficits increased. Most of this increase occurred in the last decade (1970-79). In this decade, the proportion of children for whom no deficits were reported five years following operation was 4% if they had a supratentorial tumor and 27% if they had an infratentorial tumor. The proportions of children alive five years following first surgery who had arachnoidal metastases increased significantly for infratentorial tumors.


Treatment of recurrent metastatic medulloblastoma with intensive chemotherapy and allogeneic bone marrow transplantation. We report here the first known case of a patient with recurrent metastatic medulloblastoma to achieve long-term disease-free survival following treatment with allogeneic bone marrow transplantation. A 27 year old white male with recurrent metastatic medulloblastoma involving lymph nodes, bone and bone marrow was treated with multi-agent chemotherapy followed by allogeneic bone marrow transplantation from an HLA-identical sibling donor. Morbidity was acceptable with moderate to severe mucositis in the immediate post transplant period and clinical grade I graft versus host disease of the skin controlled with modest doses of corticosteroids. The patient continues in unmaintained complete remission in excess of 28 months with a performance status of 100%. Allogeneic marrow transplantation following cytoreductive salvage chemotherapy is an aggressive strategy that may offer an improved likelihood of disease eradication and ultimate cure for poor prognosis patients with recurrent metastatic medulloblastoma.


The role of radiotherapy in the treatment of subtotally resected benign meningiomas. Thirty-six patients with benign meningioma were treated for primary or recurrent disease by subtotal resection and external beam irradiation from 1968-1986 at Massachusetts General Hospital. Comparison is made with 79 patients treated by subtotal surgery alone from 1962-1980. Progression-free survival for 17 patients irradiated after initial incomplete surgery was 88% at 8 years compared with 48% for similar patients treated by surgery alone (p = 0.057). 16 patients incompletely resected at time of first recurrence were irradiated and 78% were progression-free at 8 years while 11% of a similar group treated by surgery alone were progression free (p = 0.001). Long term overall survival was high and similar in both control and study groups. Two patients were irradiated at second recurrence and 1 patient at third recurrence. Twenty-five patients were treated with photons alone and have a median follow-up of 57 months, 6 patients have recurred at doses 45-60 Gy. Eleven patients were treated with combined 10 MV photons and 160 MV protons utilizing 3-D treatment planning. These patients have been followed for a median of 53 months and none have failed to date. Eight of 11 received 54-60.4 Gy and 3/11 greater than 64.48 Gy. Sex, age, pathology grade and score, surgery and timing of radiation therapy were not associated with significant differences in failure patterns within the irradiated study group (p less than 0.1). Complications have been seen in 6 irradiated patients.


Low grade gliomas: comparison of intraoperative ultrasound characteristics with preoperative imaging studies. Thirty-three patients with low grade gliomas were evaluated with preoperative computed tomography (CT), magnetic resonance (MR) and intraoperative ultrasound (IOUS). Six patients had undergone previous surgical exploration. Tumor borders were marked with cortical letters and corresponding depths calculated. Resection of tumor corresponded to these ultrasound dimensions. The histology of biopsy specimens from tumor and ultrasound determined margins was studied on formalin fixed permanent sections using hematoxylin and eosin (H&E) and immunocytochemistry (GFAP). Tumors were all seen on preoperative MR studies and most commonly showed a decreased T1 and increased T2 signal. Seven tumors showed variable enhancement with gadolinium. On CT two tumors were not seen, twenty-three tumors were hypodense and eight hyperdense. Three tumors showed variable CT contrast enhancement. All tumors were hyperechoic on ultrasound. Twenty-five (75%) tumors were well defined with distinct margins compared to adjacent brain. Eight tumors had poorly defined borders on ultrasound; five (62%) of these lesions had previously undergone surgery. Eight tumors invaded functional brain identified by stimulation mapping techniques (e.g., speech cortex), thus limiting the resection. Five resections were limited because of involvement of important anatomical structures (e.g., corpus callosum). Of the remaining 20 tumors, seventeen (85%) had ultrasound defined margins that were histologically free of solid tumor (normal brain or sparse atypical cells only). Low grade gliomas are readily identified and their margins well defined by intraoperative ultrasound regardless of preoperative imaging patterns. The results suggest that IOUS may enhance intraoperative delineation and extent of resection for low grade gliomas.


Growth of human acoustic neuromas, neurofibromas and schwannomas in the subrenal capsule and sciatic nerve of the nude mouse. To develop a reproducible in vivo model for the growth of human acoustic neuromas and neurofibromas, we implanted tumor specimens (6 acoustic neuromas; 4 neurofibromas; 3 schwannomas arising in skin and soft tissues) from 13 different patients into the subrenal capsules of 67 nude mice and sciatic nerves of 64 nude mide. The animals were anesthetized and the tumors were microscopically implanted. Serial tumor volumes were determined at intervals up to 2 months by reopening the incision and directly measuring the tumor size with a micrometer. The percentages of acoustic neuromas that survived or grew were 57.1% in the subrenal capsule and 88.9% in the sciatic nerves; the percentages of neurofibromas that survived and grew were 50% in the subrenal capsule and 70% in the sciatic nerves; and the percentages of schwannomas that survived and grew were 57.1% in the subrenal capsule and 94.1% in the sciatic nerve. Tumors in the sciatic nerve also survived and grew for a longer period than those in the subrenal capsules. Tumor enlargement and stability correlated with neovascularity. At 1 or 2 months after engraftment, the tumors showed histologic appearances similar to the original tumors and immunohistochemical analysis of cryostat sections demonstrated staining of the tumors, but not the host mouse tissues for human beta 2-microglobulin, a species-specific marker. Furthermore, analysis of genomic DNA from implanted tumors revealed its human origin. We conclude that human acoustic neuromas, neurofibromas and schwannomas are readily grown in two sites in nude mice and that they retain their morphologic features and genomic identities. These tumors grow better and more consistently in the sciatic nerve than in the subrenal capsule. These are useful model systems for studying tumor growth and cellular modulation.


Extraneural metastases in ependymoma.

Extraneural metastases in ependymoma. Ependymomas, glial neoplasms usually arising in the posterior fossa or spinal cord, rarely metastasize outside the central nervous system. We have reviewed all 81 ependymomas evaluated at MSKCC between 1956-1989. Five (6.2%) had extraneural metastases (ENM). The primary tumor was in spinal cord in 3 patients and the cerebral hemisphere in 2. Two tumors were histologically anaplastic; 3 were histologically benign. The 5 patients were 3, 3, 3.5, 16 and 37 years old. Time from initial diagnosis to development of ENM was 0, 15, 35, 40, and 288 months. At the time of ENM the primary tumor was progressing in 4/5 patients. Prior therapy had included resection plus radiation therapy (RT) (1), RT plus chemotherapy (1), resection plus RT plus chemotherapy (2). One patient had not received prior therapy because ENM were present at diagnosis. The sites of ENM included lung and thoracic lymph nodes (2), pleura and peritoneum (2), and liver (1). Both patients with peritoneal ENM had had ventriculoperitoneal shunts. ENM did not correlate with histologic grade, age, or degree of surgical resection. When patients with ependymoma develop signs or symptoms of systemic disease such as abdominal pain, cough, or adenopathy, ENM should be considered.


A case of treatment-related leukoencephalopathy: sequential MRI, CT and PET findings. A case of treatment-related leukoencephalopathy is presented. A patient with medulloblastoma was postoperatively treated with craniospinal axis irradiation. One month after irradiation, weekly intrathecal administration of methotrexate was performed 4 times to treat cerebrospinal fluid dissemination of the tumor. Two months after the initiation of intrathecal chemotherapy, the patient became somnolent and developed decerebrate posturing. Magnetic resonance imaging showed diffuse leukoencephalopathy. Positron emission tomography revealed a diffuse decrease in glucose uptake in the deep white matter. Auditory evoked potential also showed diffuse abnormalities, not only in the cerebrum, but also in the brain stem. High dose intravenous leucovorin rescue was attempted without any neurologic improvement.


Chemotherapy with vincristine (VCR) and etoposide (VP-16) in children with low-grade astrocytoma. Twenty patients, aged 6 months to 20 years, with low-grade astrocytoma (LGA) participated in a chemotherapy trial of vincristine (VCR) and etoposide (VP-16). Fourteen children had recurrent progressive disease at entry on study. Prior treatment consisted of surgical resection alone (6), surgical resection and irradiation (4), surgical resection, irradiation and chemotherapy (2), surgery and chemotherapy (1), and irradiation and chemotherapy (1). Six patients were treated at initial diagnosis of LGA because they were less than 5 years old (5) or for a second primary tumor (1). Four recurrent patients and 3 newly diagnosed patients underwent surgical debulking of their tumors immediately prior to study entry. Tumors were located in the optic nerve/chiasm/hypothalamus (8), brain stem/cerebellum (4), cerebral hemispheres (3), midline structures (3), and spinal cord (2). The treatment plan administered in an out-patient setting consisted of weekly VCR 1.5 mg/m2 for 7 to 8 weeks and VP-16 100 mg/m2 for 5 days repeated every 6 weeks for a total of 18 months of therapy. Responses were evaluated by computerized tomography or magnetic resonance imaging. Of the 20 patients, 1 exhibited a partial response maintained for 12+ months, 3 exhibited minor responses maintained for a period of 10+ to 35 months, and 11 maintained stable disease for 10 to 42 months. Of the 11 patients with stable disease, 2 were withdrawn early from the study without further therapy. Five of the 20 patients developed progressive disease; for 4 of these 5, this occurred during the first course of therapy. Subsequently, these 5 died due to tumor.(ABSTRACT TRUNCATED AT 250 WORDS)


Intrathecal ACNU treatment of B16 melanoma leptomeningeal metastasis in a new athymic rat model. To evaluate new cytotoxic drugs for intrathecal treatment we developed an experimental model of leptomeningeal metastasis by intracisternal injection of 10(4) B16-F10 melanoma cells in nude rats. One hour in vitro incubation with 20 micrograms/ml ACNU (area under the drug concentration-time curve = 1200 microgramsxmin/ml) induced a 4-log kill of B16 melanoma cells. A single or repeated non-toxic dose of 1 mg/kg was injected into the cisterna magna of rats inoculated with tumor (area under the drug concentration-time curve assuming an even cerebrospinal fluid distribution greater than 7000 microgramsxmin/ml). Median survival free of symptoms was 16 days (range 14-27) for controls (n = 9) and 18 days (range 17-23) for rats treated with ACNU on day 4 (n = 9). Animals treated both on day 2 and 8 (n = 8) developed symptoms on day 21 (range 13-35). Neurological symptoms and neuropathological examination in animals with increased survival indicated local suppression of tumor growth in the cisterna magna but increased spinal seeding and mass growth. From these results and the available pharmacokinetic data on ACNU it is concluded that bolus injection of ACNU--although locally effective--is not a sufficient treatment of widespread leptomeningeal metastasis. An increased therapeutic efficacy might be achieved by ventriculolumbar perfusion.


A motor area rostral to the supplementary motor area (presupplementary motor area) in the monkey: neuronal activity during a learned motor task. 1. The rostromesial agranular frontal cortex of macaque monkey (Macaca fuscata), traditionally defined as the supplementary motor area (SMA), was studied using various physiological techniques to delineate two different areas rostrocaudally. 2. Field and unitary responses to electrical stimulation of the primary motor cortex were distinct in the caudal part, but minimal or absent in the rostral part. Intracortical microstimulation readily evoked limb or orofacial movements in the caudal part, but only infrequently in the rostral part. Neuronal responses to visual stimuli prevailed in the rostral part, but somatosensory responses were rare. The opposite was true in the caudal part. 3. The rostral part, roughly corresponding to area 6a beta, was operationally defined as the presupplementary motor area (pre-SMA). The caudal part was redefined as the SMA proper. 4. Single-cell activity in the pre-SMA was quantitatively compared with that in the SMA proper in relation to a trained motor task. 5. Phasic responses to visual cue signals indicating the direction of forthcoming arm-reaching movement were more abundant in the pre-SMA. 6. Activity changes during the preparatory period, which lasted until the occurrence of the trigger signal for the reaching movement, were more frequent in the pre-SMA. 7. Phasic, movement-related activity was more frequent in the SMA, and its onset was often time locked to the movement onset. In the pre-SMA, the occurrences of response time locked to the movement-trigger signal were more frequent than in the SMA. 8. Among neurons in both areas, directional selectivity was found in all the cue, preparatory, and movement-related responses.


Action of brain stem reticular afferents on lagged and nonlagged cells in the cat lateral geniculate nucleus. 1. The A-laminae of the cat lateral geniculate nucleus (LGN) contain two distinct groups of relay neurons: lagged and nonlagged cells. The groups differ in the pattern, timing, and amplitude of response to flashing spots. At spot onset, nonlagged cells discharge at short latency with an excitatory transient; in lagged cells this transient is supplanted by an inhibitory dip and a delayed latency to discharge. At spot offset, lagged cell discharge decays more slowly than in nonlagged cells. Here we have investigated the facilitatory influence of the brain stem reticular formation on the response properties of lagged X-cells (XL) and nonlagged X- and Y-cells (XN and YN). We were particularly interested in whether the inhibitory dip and sluggish response of lagged cells could be reversed during brain stem activation and the cells induced to respond like nonlagged cells. The peribrachial region (PB) of the pontine reticular formation was stimulated electrically with the use of 1,100-ms-long pulse trains that were paired with flashing spot stimuli. 2. Stimulation of PB led to an increase in the amplitude of visually evoked discharge in lagged and nonlagged cells. Compared with their response to spot stimulation alone, the average PB-evoked increase in mean discharge rate was greater than 50% in both groups. The mean discharge rate during PB plus spot stimulation was somewhat higher for XN-cells than for YN- and XL-cells, reflecting the relatively higher discharge rate among XN-cells during spot stimulation alone. 3. Two measures of response timing characterize lagged and nonlagged cells: latency to half-maximal discharge at spot onset (half rise) and latency to half-minimal discharge at spot offset (half fall). Among XN- and YN-cells, PB stimulation had no significant effect on these two latencies; among XL-cells, both latencies were reduced by 43 and 35%, respectively, on average. 4. During spot stimulation alone, all lagged cells were distinguishable from all nonlagged cells in having half-rise and half-fall latencies greater than 60 ms. Despite the reduction among XL-cells in these 2 latencies during PB stimulation, all but 2 of the 40 XL-cells maintained laggedlike latencies. The majority (95%) of XL-cells remained unambiguously lagged on these measures during brain stem stimulation. 5. During spot stimulation alone, 30 of 40 XL-cells tested displayed a prominent and often long-lasting inhibitory dip in discharge starting approximately 45 ms after spot onset. During PB stimulation only three cells lost the dip.(ABSTRACT TRUNCATED AT 400 WORDS)


GABAergic inhibition of neuronal activity in the primate motor and premotor cortex during voluntary movement. 1. The functional role of GABAergic inhibition in neuronal activity in the forearm-hand area of the motor cortex and the postarcuate premotor cortex was studied while monkeys pressed and released a lever in response to a visual cue. gamma-Aminobutyric acid (GABA), its agonist muscimol (MUS), and its antagonist bicuculline methiodide (BMI), as well as acetylcholine, noradrenaline, and sodium glutamate, were applied iontophoretically to isolated single neurons whose activity was recorded via glass micropipettes that contained carbon fibers. 2. The activity from single neurons recorded in the motor and premotor cortex showed changes during the press or release of the lever by movement of the contralateral wrist. Discharge of most of the movement-related neurons (greater than 90%) was decreased or completely suppressed by iontophoretically applied GABA or MUS. 3. The activity of the movement-related neurons increased after application of BMI. In 70% of neurons tested, the activity during application of BMI was specifically enhanced at or near the phase of their peaks of activity, with or without a noticeable elevation in background activity. 4. About 10% of the neurons that had been unidirectional (i.e., neurons that showed a change in activity at either the lever-press or lever-release phase) became bidirectional (i.e., they showed changes in activity at both phases) when GABA transmission was blocked by the application of BMI. Bidirectional neurons also showed a reduction in the value of the directionality index. 5. One-half of the silent neurons, which had not shown any activity during either the lever-release or the lever-press phase, became active during the movement phases that followed application of BMI. 6. Most of the cortical neurons in layers II-VI in the motor area were found to be subject to GABAergic inhibition during voluntary movement. 7. We conclude that GABAergic inhibition plays a role in regulating the population of task-related neurons, and the levels of the task-related activity. GABAergic inhibition also improves directionality index in the motor cortex neurons to control the activity of target muscles.


Parallel processing in rabbit first (SI) and second (SII) somatosensory cortical areas: effects of reversible inactivation by cooling of SI on responses in SII. 1. Previous observations on the effect of ablation or inactivation of the primary somatosensory cortex (SI) on the responses of neurons within the second somatosensory area (SII) to tactile stimuli point to profound differences between monkeys and certain other mammals in the organization of thalamocortical systems. In the cat, for example, tactile information appears to be conveyed in parallel from the thalamus to both SI and SII, whereas, in macaque and marmoset monkeys, it is conveyed in a serial (or hierarchical) scheme from the thalamus to SI and thence to SII. The present study examined the responses of individual SII neurons during reversible, cooling-induced inactivation of SI in another nonprimate placental mammal, the rabbit, to obtain further evidence on whether the above differences might reflect a fundamental distinction between simian primates and other mammalian species. 2. When the temperature at the face of a silver cooling block over the forepaw and hindpaw regions of SI was lowered to 5-13 degrees C, the SI surface potentials evoked by brief tactile stimuli were abolished (indicative of SI inactivation), whereas SII potentials remained intact. 3. The responses of 25 SII neurons to controlled tactile stimuli (consisting of 1- to 1.5-s trains of vibration or rectangular mechanical pulses) were studied before, during, and after inactivation of SI. The effects on the spontaneous activity of a further three SII neurons that lacked identified receptive fields were also studied. 4. The response or activity levels of 26 of the 28 SII neurons examined (93%) were unaffected by SI inactivation.(ABSTRACT TRUNCATED AT 250 WORDS)


Relationship between receptive and dendritic field size of amacrine cells in the rabbit retina. 1. Intracellular recordings were obtained from 40 amacrine cells in the isolated, superfused retina eyecup of the rabbit. Cells were subsequently labeled with horseradish peroxidase for morphological identification. Many of these cells displayed dendritic morphology consistent with that of amacrine cells described in prior anatomic studies, including starburst, A17, AII, and DAPI-3 cells. 2. The center receptive field of amacrine cells was measured with a 50- or 95-microns-wide, 6.0-mm-long rectangular slit of light that was displaced along its minor axis (parallel to the visual streak) in increments as small as 3 microns. The extent of the receptive field was calculated as the total distance over which the displaced slit could evoke a center response. Area summation of amacrine cells was measured with concentric spots of light with increasing diameters centered over the cell. 3. For a single amacrine cell, the receptive field size was comparable to the extent of its dendritic arbor. For the total population of amacrine cells, there was a strong, linear relationship between receptive field and dendritic field size. The receptive fields were, on average, 27% larger than the corresponding dendritic arbors, but this discrepancy can be accounted for entirely by tissue shrinkage associated with histological processing and a small imprecision of the light stimuli. Area summation measurements were consistent with those of receptive fields and were also related linearly to the dendritic field size of cells. 4. These findings indicate that even when the slit of light was placed at the distal edges of the dendritic arbor, synaptic inputs activated there were propagated effectively to the soma and recorded by microelectrodes placed there. In addition, amacrine cells were capable of summating synaptic inputs distributed throughout the entire arbor. 5. These results are inconsistent with the findings of prior computational modeling studies of passive, dendritic current flow in A17 and starburst amacrine cells that synaptic inputs on distal dendritic branches are isolated electrically from the soma and that these branches form autonomous, functional subunits. 6. The majority of amacrine cells encountered displayed light-evoked and/or spontaneous action potentials. These action potentials often took the form of high-amplitude somatic and low-amplitude dendritic spikes. On average, spiking amacrine cells showed considerably larger dendritic fields than nonspiking amacrine cells. In fact, all amacrine cells with arbors greater than 436 microns, which formed 45% of the total population, displayed spike activity.(ABSTRACT TRUNCATED AT 400 WORDS)


Some properties of receptive fields of olfactory mitral/tufted cells in the frog. 1. Different regions of the frog's olfactory epithelium were stimulated with nine glass micropipettes either individually or simultaneously in different combinations. The stimulus was a positive electrical pulse (4 s) consisting of a progressive increase, a plateau, and a progressive decrease in current intensity. Extra- and intracellular recordings were made from olfactory bulb mitral/tufted cells. Some of these cells were identified by intracellular injection of Lucifer yellow. 2. The action potential response patterns of mitral/tufted cells during the different phases of the stimulation were coded according to whether the activity was increased or decreased compared with its spontaneous level just before stimulation. Neural responses were classified into 11 types: individual neurons responded with different response types to stimuli delivered at different epithelial sites. On the basis of these response types, it was found that neurons could be classified into two groups. All response types in one group included an initial phase of increased discharge (excitation), whereas all types in the other group included an initial phase of decreased activity (suppression). Neurons that displayed response types belonging to one group never displayed those of the other group. It was thus concluded that a given neuron responded either always with an increased activity or always with a decreased activity, whatever the location of the stimulus. 3. The receptive field of a mitral/tufted cell appeared to be homogenous and not divided into areas of different properties, at least under the present experimental conditions. The extent of a receptive field was estimated by determining the number of effective epithelial sites (where an electrical stimulus evoked a response from a bulbar neuron).(ABSTRACT TRUNCATED AT 400 WORDS)


Expression of the mRNAs for the Kv3.1 potassium channel gene in the adult and developing rat brain. 1. The gene for a mammalian Shaw K+ channel has recently been cloned and has been shown, by alternative splicing, to give rise to two different transcripts, Kv3.1 alpha and Kv3.1 beta. To determine whether these channels are associated with specific types of neurons and to determine whether or not the alternately spliced K+ channel variants are differentially expressed, we used ribonuclease (RNase) protection assays and in situ hybridization histochemistry to localize the specific subsets of neurons containing Kv3.1 alpha and Kv3.1 beta mRNAs in the adult and developing rat brain. 2. In situ hybridization histochemistry revealed a heterogeneous expression pattern of Kv3.1 alpha mRNA in the adult rat brain. Highest Kv3.1 alpha mRNA levels were expressed in the cerebellum. High levels of hybridization were also detected in the globus pallidus, subthalamus, and substantia nigra reticulata. Many thalamic nuclei, but in particular the reticular thalamic nucleus, hybridized well to Kv3.1 alpha-specific probes. A subpopulation of cells in the cortex and hippocampus, which by their distribution and number may represent interneurons, were also found to contain high levels of Kv3.1 alpha mRNA. In the brain stem, many nuclei, including the inferior colliculus and the cochlear and vestibular nuclei, also express Kv3.1 alpha mRNA. Low or undetectable levels of Kv3.1 alpha mRNA were found in the caudate-putamen, olfactory tubercle, amygdala, and hypothalamus. 3. Kv3.1 beta mRNA was also detected in the adult rat brain by both RNase protection assays and by in situ hybridization experiments. Although the beta splice variant is expressed at lower levels than the alpha species, the overall expression pattern for both mRNAs is similar, indicating that both splice variants co-expressed in the same neurons. 4. The expression of Kv3.1 alpha and Kv3.1 beta transcripts was examined throughout development. Kv3.1 alpha mRNA is detected as early as embryonic day 17 and then increases gradually until approximately postnatal day 10, when there is a large increase in the amount of Kv3.1 alpha mRNA. Interestingly, the expression of Kv3.1 beta mRNA only increases gradually during the developmental time frame examined. Densitometric measurements indicated that Kv3.1 alpha is the predominant splice variant found in neurons of the adult brain, whereas Kv3.1 beta appears to be the predominant species in embryonic and perinatal neurons. 5. Most of the neurons that express the Kv3.1 transcripts have been characterized electrophysiologically to have narrow action potentials and display high-frequency firing rates with little or no spike adaptation.(ABSTRACT TRUNCATED AT 400 WORDS)


ATP-gated current in dissociated rat nucleus solitarii neurons. 1. The excitatory response of extracellularly applied ATP was investigated in freshly dissociated rat nucleus tractus solitarii neurons under whole-cell configuration using the "concentration-clamp" technique. 2. At a holding potential of -70 mV, 100 microM ATP evoked inward current that was slowly desensitized in the continuous presence of ATP. The ATP-gated current increased in a concentration-dependent manner over the concentration range between 10 microM and 1 mM. The half-maximum concentration was 31 microM and the Hill coefficient was 1.2. 3. The potency of ATP analogues for the purinergic receptor was in the order of ATP = 2-methylthio-ATP much greater than ADP greater than alpha,beta-methylene ATP. Neither adenosine nor AMP evoked any responses. The order was consistent with a P2y receptor subtype. 4. The current-voltage relationship for the 100 microM ATP response showed a clear inward rectification at positive potentials beyond -50 mV. The reversal potential of the ATP-gated current was +13 mV. 5. The time constants of activation and inactivation of the ATP-gated current solution were dependent on the extracellular ATP concentration, and both kinetics became faster at higher ATP concentrations. 6. The ATP-gated current was also elicited in an external solution containing Ca2+ as a permeable cation. The inactivation kinetics in an external solution containing 75 mM Ca2+ were faster than those in an external solution with 150 mM Na+. 7. Calculated relative permeability ratios were PNa/PCs = 1.64 ([Na+]o = 30-150 mM), PCa/PCs = 2.17 ([Ca2+]o = 2 mM). Anions were not measurably permeable in this preparation.


Dendritic origin of late events in optical recordings from salamander olfactory bulb. 1. Optical recordings of membrane-potential changes were used to characterize the origin and properties of the electrical signals from the dendritic level in slices of the salamander olfactory bulb. 2. The optical events were correlated with field-potential waves recorded simultaneously. Both responses exhibited patterns similar to those found in other species. 3. Orthodromic stimulation evoked a compound action potential in the olfactory nerve fibers, followed by two additional principal waves (N1 and N2). These field-potential waves reflected excitatory postsynaptic potentials at the primary mitral/tufted and granule cell dendrites, respectively. 4. Extrinsic optical signals from horizontal slices stained with the pyrazo-oxonal dye RH-155 showed a characteristic sequence of depolarizing and hyperpolarizing events. All of the signals exhibited a wavelength dependence expected for this dye and were abolished in the presence of high K+ in the bath. 5. According to their time courses, depolarizing responses under normal recording conditions were divided into two components, fast and slow. Orthodromic stimuli evoked a fast presynaptic response that represents synchronous compound action potentials from olfactory nerve fibers. At subglomerular levels, additional fast responses could often be recorded at the peri/subglomerular level and in the mitral/tufted somata region. These postsynaptic responses partially coincided with the rising phase of a different depolarizing signal, a slow component characterized by its prolonged time course. 6. With orthodromic stimulation, this slow signal attained its largest amplitude in the zone between the glomeruli and the superficial part of the external plexiform layer (EPL). Antidromic stimuli evoked a signal with some similarities to the one evoked orthodromically, but originating in deeper EPL regions. 7. Slow components were characterized by their Ca dependence. Low Ca2+ medium, or calcium channel blockers, suppressed this optical component, whether evoked orthodromically, antidromically, or by direct stimulation. In addition, Ba2+ (2.5-3.6 mM) in the bath did not abolish these responses, suggesting that they do not reflect a glial depolarization in response to elevated extracellular K+ concentration ([K+]o). 8. Locally applied stimuli next to the glomerular layer elicited these signals in 5-10 microM tetrodotoxin (TTX) or in low extracellular Na+ concentration ([Na+]o) medium, but antidromic or orthodromic stimuli failed to evoke the response under these conditions. The sizes of the responses to local stimuli remained constant, but an increase in their duration was observed in either TTX or low [Na+]o. 9. gamma-Aminobutyric acid (GABA) and baclofen reduced the size of the slow components in a dose-dependent manner.(ABSTRACT TRUNCATED AT 400 WORDS)


Acoustic reflex frequency selectivity in single stapedius motoneurons of the cat. 1. The sound frequency selectivities of single stapedius motoneurons were investigated in ketamine anesthetized and in decerebrate cats by recording from axons in the small nerve fascicles entering the stapedius muscle. 2. Stapedius motoneuron tuning curves (TCs) were very broad, similar to the tuning of the overall acoustic reflexes as determined by electromyographic recordings. The lowest thresholds were usually for sound frequencies between 1 and 2 kHz, although many TCs also had a second sensitive region in the 6- to 12-kHz range. The broad tuning of stapedius motoneurons implies that inputs derived from different cochlear frequency regions (which are narrowly tuned) must converge at a point central to the stapedius motoneuron outputs, possibly at the motoneuron somata. 3. There were only small differences in tuning among the four previously described groups of stapedius motoneurons categorized by sensitivity to ipsilateral and contralateral sound. The gradation in high-frequency versus low-frequency sensitivity across motoneurons suggests there are not distinct subgroups of stapedius motoneurons, based on their TCs. 4. The thresholds and shapes of stapedius motoneuron TCs support the hypothesis that the stapedius acoustic reflex is triggered by summed activity of low-spontaneous-rate auditory nerve fibers with both low and high characteristic frequencies (CFs). Excitation of high-CF auditory nerve fibers by sound in their TC "tails" is probably an important factor in eliciting the reflex. 5. In general, the most sensitive frequency for stapedius motoneurons is higher than the frequency at which stapedius contractions produce the greatest attenuation of middle ear transmission. We argue that this is true because the main function of the stapedius acoustic reflex is to reduce the masking of responses to high-frequency sounds produced by low-frequency sounds.


Responses of neurons in the gracile nucleus of cats to innocuous and noxious stimuli: basic characterization and antidromic activation from the thalamus. 1. Responses to innocuous and noxious mechanical and thermal stimuli were recorded from 90 neurons in the gracile nucleus of anesthetized cats. Cells were tested by antidromic activation for projections to the contralateral ventrobasal thalamus. 2. Cells were characterized broadly by their responses to mechanical stimuli as 1) responding only to tapping (16%), 2) fast-adapting to low-intensity mechanical stimuli (33%), or 3) slowly adapting (51%; most with a fast-adapting component to their responses). All fast-adapting cells and those slowly adapting cells that were tested with noxious heat were further categorized on the basis of their patterns of firing and responses to stimuli. These plus the tap-responsive cells comprised a more restricted sample of 76 categorized cells. 3. Many (22) slowly adapting cells responded to noxious heat (69% of tested slowly adapting cells; 29% of all categorized cells), either on the first application (9 cells) or after sensitization (13 cells), indicating input originating in nociceptors. Nearly all of these (21) responded more to intense pressure than to innocuous pressure. The majority of slowly adapting cells not responsive to noxious heat (5 of 8) or not tested with it (8 of 12) also responded more to intense than to innocuous pressure, suggesting possible input originating in nociceptors. Most cells that responded to noxious heat also had both rapidly and slowly adapting responses with low thresholds. Many were recorded in the range of the cluster region of the gracile nucleus. 4. Cells antidromically activated from the thalamus projected to the rostral part of the ventral posterior lateral nucleus, regardless of their physiological category, and included many with nociceptive input. Latencies of antidromic activation were shorter at more caudal locations in the gracile nucleus, indicating higher conduction velocities to the thalamus. Responses of antidromically activated cells to low-intensity phasic stimuli tended to be greater than those of cells not antidromically activated. 5. Background activity of the neurons was low, most firing at less than one spike/s. Antidromically activated cells had higher background activity than cells not antidromically activated. 6. The results indicate a greater proportion and more widespread distribution of cells with nociceptive input in the cat gracile nucleus than has been previously recognized. Many of these projected to the ventrobasal thalamus, showing that information originating in nociceptors can reach the thalamus through a dorsal column-medial lemniscal pathway in cats.


Metabotropic glutamate receptor-mediated suppression of L-type calcium current in acutely isolated neocortical neurons. 1. The effects of metabotropic glutamate receptor (mGluR) stimulation on whole-cell Ca2+ currents were studied in pyramidal neurons isolated from the dorsal frontoparietal neocortex of rat. The selective mGluR agonist cis-(+/-)-1-aminocyclopentane-1,3-dicarboxylic acid [trans-ACPD (100 microM)] suppressed the peak high-threshold Ca2+ current by 21 +/- 1.7% (mean +/- SE) in 40 of 43 cells from 10- to 21-day-old rats. Consistent with previous findings for mGluR, glutamate, quisqualate, and ibotenate [but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)] reduced the Ca2+ currents, and the responses were not blocked by the ionotropic glutamate receptor antagonists 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonovaleric acid (APV). EC50S for Ca2+ current suppression were 29 nM for quisqualate, 2.3 microM for glutamate, and 13 microM for trans-ACPD. 2. The low-threshold Ca2+ current was not modulated by trans-ACPD. The component of the high-threshold CA2+ current suppressed by mGluR was determined by pharmacology; the responses were not affected by omega-conotoxin GVIA but were occluded by the dihydropyridine Ca2+ antagonist nifedipine. Ca2+ tail currents prolonged by the dihydropyridine Ca2+ agonist (+)-SDZ 202-79] were suppressed by mGluR stimulation in parallel with the peak current. These findings strongly suggest that L-type Ca2+ channels are modulated by mGluR. 3. In neurons dialyzed with 100 microM guanosine 5'-(gamma-thio)triphosphate (GTP-gamma-S), Ca2+ current suppression was elicited by the first application of trans-ACPD (in 5 of 6 cells), but not by subsequent applications. Responses in neurons dialyzed with 2 mM guanosine 5'-(beta-thio)diphosphate (GDP-beta-S) were significantly smaller than controls. The results are consistent with mGluR acting via linkage to a G protein. 4. The responses to mGluR agonists were smaller when the external Ca2+ was replaced by Ba2+, indicating that some part of the mechanism underlying the current suppression is Ca2+ dependent. Because mGluR stimulates phosphoinositide turnover and release of Ca2+ from intracellular stores in other types of neurons, the possibility of released Ca2+ mediating inactivation of Ca2+ channels was considered. However, the Ca2+ current suppression was not attenuated by strong intracellular Ca2+ buffering [20 mM bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA)], by dialysis with 100 microM inositol-1,4,5-triphosphate (IP3), or by external application of 1 microM thapsigargin. 5. We conclude that in neocortical neurons, one action of mGluR is to suppress the component of high-threshold Ca2+ current conducted by L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 400 WORDS)


Sensory processing and corollary discharge effects in the mormyromast regions of the mormyrid electrosensory lobe. I. Field potentials, cellular activity in associated structures. 1. This is the first of a series of papers on the electrosensory lobe and closely associated structures in electric fish of the family Mormyridae. The study describes the neuronal responses to sensory stimuli and to corollary discharge signals associated with the motor command that drives the electric organ discharge (EOD). The study is focused on the regions of the electrosensory lobe where primary afferent fibers from mormyromast electroreceptors terminate. 2. This first paper of the series describes the field potentials in the caudal lobe of the cerebellum and in the electrosensory lobe. It also describes the different types of unit activity in the caudal lobe of the cerebellum. Granule cells of the caudal lobe of the cerebellum provide the parallel fibers for most of the molecular layer of the electrosensory lobe. Determination of the input and responses of these cells is therefore an important part of the effort to understand the electrosensory lobe. 3. Corollary discharge field potentials evoked by the EOD motor command are very prominent in the caudal lobe of the cerebellum and in the electrosensory lobe. The potentials indicate that corollary discharge excitation affects first the granule cells of the caudal lobe and then, a few milliseconds later, the deeper cellular layers of the electrosensory lobe. The prominence and complexity of the field potentials indicate that corollary discharge signals have an important and varied role in the processing of electrosensory information by the mormyrid electrosensory lobe. 4. The field potentials evoked by electrosensory stimuli suggest that direct primary afferent excitation is limited to the granule and intermediate layers of the electrosensory lobe, as is indicated also by anatomic studies. 5. Proprioceptive units are the most common type of unit recorded in the granule cell region of the caudal lobe of the cerebellum (eminentia granularis posterior). These units have a regular discharge rate that changes tonically in response to slight bending of the trunk, bending of the tail, or bending of individual fins. Proprioceptive input will have a strong effect on the molecular layer of the electrosensory lobe and will thus modulate the responses of electrosensory lobe cells to electrosensory stimuli. Such proprioceptive input to the electrosensory lobe would allow the expected effects of body position changes to be accounted for in the processing of electrosensory information. 6. Units with stereotyped, short-latency corollary discharge bursts to the EOD motor command were the next most common type of unit in the eminentia granularis posterior. These corollary discharge units were not affected by sensory stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)


Sensory processing and corollary discharge effects in mormyromast regions of mormyrid electrosensory lobe. II. Cell types and corollary discharge plasticity. 1. This is the second of a series of papers on the electrosensory lobe and closely associated structures in electric fish of the family Mormyridae. The focus of the study is on the regions of the electrosensory lobe where primary afferent fibers from mormyromast electroreceptors terminate. 2. This second paper examines the responses of single cells in the mormyromast regions of the electrosensory lobe to electrosensory stimuli and to corollary discharge signals associated with the motor command that drives the electric organ to discharge. All recordings were extracellular. 3. Two major types of cells were identified: I cells, which were inhibited by electrosensory stimuli in the center of their receptive fields; and E cells, which were excited by such stimuli. 4. I cells and E cells shared a number of common features. Both types could have small receptive fields limited to only a few electroreceptors (3-5), and both types were markedly affected by the corollary discharge of the electric organ discharge (EOD) motor command. Cells of both types also showed clear plasticity in their responses to the corollary discharge or to the corollary discharge plus a stimulus. 5. I cells could be subdivided into three subtypes, I1, I2, and I3, on the basis of corollary discharge responses in the absence of sensory stimuli. I1 and I2 cells showed consistent corollary discharge bursts with little or no additional activity beyond the duration of the burst. The corollary discharge bursts of I1 cells were more stereotyped and of shorter latency than those of I2 cells. I3 cells had more spontaneous activity than I1 or I2 cells and minimal cells had more spontaneous activity than I1 or I2 cells and minimal corollary discharge responses in the absence of sensory stimuli. Field potentials indicated that all three subtypes of I cells were recorded in or near the ganglion layer of the electrosensory lobe. 6. Corollary discharge responses were plastic and depended on recent pairing of a sensory stimulus with the EOD motor command. Such plasticity was clearer in I2 and I3 cells than in I1 cells. Inhibitory sensory stimuli were paired with the EOD motor command for periods of a few seconds to several minutes. Such pairing resulted in a marked enhancement of the corollary discharge response in I2 cells, as shown by examining the effect of the motor command after turning off the stimulus. In I3 cells, such pairing resulted in a clear corollary burst to the command at the time of the previously paired inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)


Influence of velocity and direction of surface-parallel cutaneous stimuli on responses of mechanoreceptors in feline hairy skin. 1. The responses of cutaneous mechanoreceptors in feline hairy skin were examined in vivo with systematic variations in the velocity and direction of stimulus motion across the receptive fields (RF). The mechanoreceptor classes studied were guard hair afferents, field afferents, down hair afferents, and slowly adapting type I (SAI) mechanoreceptors. A camel's hair brush, moved by a high-precision motor, provided surface-parallel stimulation at velocities ranging from 0.4 to 100 cm/s. The stimulating device and protocols were similar to those previously used to evaluate human perception, thus allowing direct comparison of the two sets of data. 2. Each mechanoreceptor produced highly reliable mean firing rates with repeated stimulation. All mechanoreceptors showed a growth in evoked activity with increased stimulus velocity. With few exceptions, the relationship between brush velocity and mean firing rate was well described by a power function throughout the range of velocities tested. The exponents of these power functions, reflecting the degree of velocity dependency for each mechanoreceptor, were largest for the field type 1 units (F1) and guard hair type 1 units (G1). 3. The capacity of the mechanoreceptors to discriminate velocity was examined in the context of signal detection theory. For each unit, a velocity discriminability estimate (velocity delta'e) was calculated for responses to 5 versus 10 cm/s brushing and 10 versus 20 cm/s. The G1 and F1 units exhibited the largest velocity delta'e values, which were comparable to human velocity discriminability (d'e) values. Thus these data show the quantitative parallel between the velocity discriminability of G1 and F1 mechanoreceptors and of human perception similarly tested. 4. Most mechanoreceptors generated different response rates with stimuli moving in opposing directions (in the proximal-distal axis of the hindlimb). However, no mechanoreceptor class showed a consistently preferred direction of movement. A directional delta'e value was calculated for each mechanoreceptor at each stimulus velocity. These values were quite variable, even within a single mechanoreceptor class. In general, a mechanoreceptor's directional delta'e value either 1) decreased with increasing velocity or 2) remained constant across velocities. The way in which human directional discriminability varies with stimulus velocity did not parallel the way in which mechanoreceptor's directional delta'e values varied with the same range of stimulus velocities. 5. Some mechanoreceptors were tested with both the standardized brush, which was smaller than most mechanoreceptors' RFs, and a much larger brush, which was at least twice the size of the mechanoreceptors' RFs.(ABSTRACT TRUNCATED AT 400 WORDS)


Mechanisms of gastric rhythm generation in the isolated stomatogastric ganglion of spiny lobsters: bursting pacemaker potentials, synaptic interactions, and muscarinic modulation. 1. The gastric central pattern generator (CPG), located in the stomatogastric ganglion (STG) of the spiny lobster (Panulirus interruptus), is nonrhythmic when deprived of neuromodulatory inputs from anterior ganglia. Leaving these inputs intact in vitro can sustain a gastric rhythm but also introduces numerous, uncontrolled and largely unknown modulatory and synaptic influences that greatly complicate analysis of this CPG. 2. Here we induced gastric rhythms in the isolated STG, by superfusing a specific modulator, the muscarinic agonist, pilocarpine. Muscarinic agents sustain vigorous gastric rhythms in the isolated STG. Our aim was to analyze the pattern-generating functions of the restricted gastric circuit, free of complicating influences from other ganglia, and under specific (muscarinic) modulation. 3. We used combinations of multiple cell hyperpolarizations, photodeletions, and synaptic blockade by picrotoxin to assess the pattern-generating role of individual gastric neurons and to study the activity of subcircuits. 4. Four identified gastric neurons [lateral gastric (LG), dorsal gastric (DG), 2 electrically coupled lateral posterior gastric (2LPGs)] acted as pattern-generating cells. They showed bursting pacemaker potentials (BPPs), i.e., plateau (or driver) potentials that underlay bursts of axonal spikes and slow, interburst depolarizing potentials that underlay repetitive burst activity. LG and DG, at least, became conditional bursters, able to burst repetitively because of intrinsic oscillations. The other gastric neurons behaved mainly as follower cells and derived their rhythmic bursting from synaptic coupling to the pattern-generator cells and from their own intrinsic (but nonoscillatory) properties. 5. The pattern-generating neurons form a novel "kernel" circuit that works by the cooperative interaction of cellular properties and synaptic connectivity. 6. This study constitutes the first complete and fully consistent analysis of pattern generation in the gastric network of the isolated STG. These mechanisms pertain to muscarinic rhythms in particular but also, we suggest, to gastric rhythm generation and CPG function in general. We suggest that 1) rhythmicity normally depends on the induction of bursty membrane properties in at least some component neurons; 2) different subcircuits can produce rhythmic patterns and may be activated by different modulators; and 3) the gastric network shares several important "building blocks" with CPGs that have been analyzed in other systems. 7. Muscarinic inputs are implicated as an important gastric regulator. We compare these responses with the reported modulatory actions of the anterior pyloric modulator (AMP), an identified, putatively cholinergic input interneuron that may act via muscarinic mechanisms.


Changes in motor responses induced by cerebellar stimulation during classical forelimb flexion conditioning in cat. 1. The ability of somaesthetic sensory inputs to produce structural changes in the connectivities of the central nervous structures involved in motor activity was tested with an alpha type of classical conditioning in chronically prepared adult cats. Repetitive sensory stimulation was applied at constant intervals after the activation of the motor circuits originating in the neurons or efferent axons of the cerebellar nuclei. A conditional stimulation (CS) applied to interpositus neurons was consistently paired with an unconditional stimulation (UCS) applied to the dorsal skin of the forelimb extremity to induce associative sensorimotor conditioning. The sites at which the conditional and unconditional stimuli were applied set up a simplified sensorimotor circuit including pathways transmitting both these stimuli and others mediating the expression of the conditioned responses. 2. To test the changes resulting from the conditioning, electrodes were implanted into the various relay structures on the cerebellar efferent pathways (ventrolateral nucleus motor cortex). The forelimb motor responses elicited by stimulating these relay structures were recorded with a potentiometer placed at the elbow joint. The angular displacement (amplitude) and latency of the responses and the percentage response rates were systematically quantified throughout the conditioning procedure and at test sessions carried out after the daily conditioning routines. 3. It was observed that daily repetition of paired CS-UCS led to an increase in the response rates and amplitudes of the forelimb flexions, which already began to occur very slightly on the first 4 or 5 days in response to the alpha conditioning, whereas the CS when applied alone failed to produce any changes in this initial response. Likewise, after the acquisition phase, repeated presentation of either the CS alone or the CS preceded by the UCS led to the extinction of the conditioned response, thus indicating that the observed changes were of an associative nature and that they depended on interactions between the motor and sensory inputs occurring somewhere in the CNS. In fact, the effects of conditioning were not generalized, but involved only a circumscribed circuit originating in the cerebellar neurons stimulated by the CS, which were activated concomitantly with the sensory pathways. 4. The conditioned response amplitudes were enhanced by 2.5-3 times their initial value. This enhancement persisted at the end of acquisition or after several days of consolidation, even when the paired CS-UCS sessions were interrupted for a period of 15 days to 2 mo.(ABSTRACT TRUNCATED AT 400 WORDS)


Mechanical response of frog saccular hair bundles to the aminoglycoside block of mechanoelectrical transduction. 1. Deflections of the mechanosensory hair bundles on frog saccular hair cells were measured interferometrically, with submillisecond temporal and submicrometer spatial resolution, and with subnanometer displacement sensitivity. 2. The direction of the initial bundle deflection (toward the taller stereocilia) in response to a sudden application of aminoglycoside antibiotics shows that the mechanosensory channels are blocked in their mechanically open state. 3. The magnitude of the initial deflection is consistent with published data on the gating swing as derived from the gating compliance. 4. A delayed relaxation and frequently a reversal of the initial deflection were observed and are attributed to the previously reported mechanical adaptation mechanism, which is at least partially controlled by the influx of Ca2+ through the transduction channels. 5. Increases of low-frequency spontaneous motion were found at intermediate blocker concentrations. They can be well accounted for by the fluctuating force exerted on the bundle by the random binding and unbinding of blocker molecules. 6. The mechanical response of the hair bundle to aminoglycosides may be related to their acute and specific ototoxicity.