Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4.

Contrary to acute pain, chronic pain does not serve as a warning signal and must be considered as a disease per se. This pathology presents a sensory and psychological dimension at the origin of affective and cognitive disorders. Being largely refractory to current pharmacotherapies, identification of endogenous systems involved in persistent and chronic pain is crucial. The amygdala is a key brain region linking pain sensation with negative emotions. Here, we show that activation of a specific intrinsic neuromodulatory system within the amygdala associated with type 4 metabotropic glutamate receptors (mGlu4) abolishes sensory and affective symptoms of persistent pain such as hypersensitivity to pain, anxiety- and depression-related behaviors, and fear extinction impairment. Interestingly, neuroanatomical and synaptic analysis of the amygdala circuitry suggests that the effects of mGlu4 activation occur outside the central nucleus via modulation of multisensory thalamic inputs to lateral amygdala principal neurons and dorso-medial intercalated cells. Furthermore, we developed optogluram, a small diffusible photoswitchable positive allosteric modulator of mGlu4. This ligand allows the control of endogenous mGlu4 activity with light. Using this photopharmacological approach, we rapidly and reversibly inhibited behavioral symptoms associated with persistent pain through optical control of optogluram in the amygdala of freely behaving animals. Altogether, our data identify amygdala mGlu4 signaling as a mechanism that bypasses central sensitization processes to dynamically modulate persistent pain symptoms. Our findings help to define novel and more precise therapeutic interventions for chronic pain, and exemplify the potential of optopharmacology to study the dynamic activity of endogenous neuromodulatory mechanisms in vivo.

Development of glycinergic transmission in organotypic cultures from auditory brain stem.

We investigated whether glycinergic transmission develops organotypically in auditory brain stem cultures. Slices of the medial nucleus of the trapezoid body and the lateral superior olive were incubated in medium with a raised extracellular K+ concentration. As in vivo, glycine receptor alpha1 subunit immunoreactivity increased and became clustered on somata and proximal dendrites. Together with organotypic expression of glycine transporter GLYT2, this indicates that molecular components of glycinergic synapses form properly. In contrast, glycinergic synaptic currents did not develop as in vivo: after 7 days in vitro they were still similar to those at the time of culture preparation. We suggest that for organotypic development of glycine receptors and transporters, Ca2+ influx due to elevated K+ is sufficient. The development of functional synaptic transmission, however, may require patterned electrical activity.

Immune compromise and prevalence of Candida vulvovaginitis in human immunodeficiency virus-infected women.

OBJECTIVE: To investigate the effect of human immunodeficiency virus (HIV) infection on vaginal yeast colonization and symptomatic vulvovaginitis and to explore the effects of immune compromise on these conditions in HIV-positive women. METHODS: Between September 1991 and May 1993, 223 HIV-positive women without AIDS-defining conditions were enrolled for prospective follow-up and compared with 289 HIV-negative women enrolled in a concurrent study. Standardized gynecologic assessment was carried out. RESULTS: Cultures from 81 of 223 (36%) HIV-positive women and 72 of 289 (25%) HIV-negative women were positive for any yeast. The most commonly isolated yeasts were Candida albicans and Torulopsis glabrata; the proportion of non-C albicans isolates (26%) did not differ by serostatus. The rates of C albicans colonization and vulvovaginitis among immunocompetent (CD4 count at least 500 cells/mm3) HIV-positive women did not differ from those among HIV-negative women. Among HIV-positive women, risks for colonization and for symptomatic vulvovaginitis were increased approximately threefold and fourfold respectively, in women with CD4 counts below 200 cells/mm3 compared with either immunocompetent HIV-positive women or HIV-negative women. CONCLUSION: The yeast species isolated from HIV-positive and HIV-negative women were similar. Rates of vaginal colonization and vaginitis were similar among nonimmunocompromised HIV-positive women and HIV-negative women. Elevated rates of yeast colonization and vaginitis were not seen among this population of HIV-infected women before immune compromise. Both vaginal colonization and symptomatic vaginitis increased with immune compromise among HIV-positive women, especially at CD4 counts below 200 cells/mm3.

Uncertain lifetime, life protection, and the value of life saving.

The analytic innovation is treating life's end as uncertain, and life expectancy as partly the product of individuals' efforts to self-protect against mortality and morbidity risks. The demand for self-protection is modeled in a stochastic, life-cycle framework under alternative insurance options. The model helps explain the trend and systematic diversity in life expectancies across different population groups, as well as the wide variability in reported "value of life saving" estimates. The analysis yields a closed-form solution for individuals' value of life saving that is estimable empirically. It reflects the impacts of specific personal characteristics and alternative insurance options on both life expectancy and its valuation.

Excretion of lipids by the liver fluke (Fasciola Hepatica L).

Adult liver flukes kept in a glucoseenriched medium were found to excrete lipids. Analysis of the incubation medium showed that both neutral lipids (including cholesterol and its esters) and polar lipids were released. The rate of lipid excretion was greatly reduced when the excretory pores and mouths of the flukes were ligated. Histochemical examination of the flukes indicated that such lipids, released through the excretory pores, originate in the cells lining the excretory ducts.

A symposium on surgery for coronary artery disease. Patient selection and preoperative evaluation.

Patient selection based upon preoperative evaluation is a complex problem. In using a procedure with the tremenduous implications and applications seen in aortocoronary bypass grafting, excesses in enthusiasm and criticism are the rule rather than the exception. With patience and careful evaluation,,the correct place for the procedure will be found and, though it is not quite the panacea once claimed for patients with coronary artery disease, aortocoronary bypass surgery will remain an important and valuable therapeutic tool, perhaps the most significant development in cardiovascular treatment of the past decade.

The market for offences and the public enforcement of laws: an equilibrium analysis.

The general proposition developed in this paper is that the frequency of offences of specific types is determined, by and large, not as the capricious outcome of biological or social idiosyncracies, but as the result of the equilibrating interplay of systematic 'supply and demand' forces. The role of public intervention via police, courts, correctional institutions, and economic policy in general, is then viewed in terms of its impact on the equilibrium level of activity in illegitimate markets, rather than in terms of its effect on either the supply or the demand sides of these markets separately. From a policy perspective the implication is that the efficacy of public intervention in the 'business of crime' must be assessed through the relevant comparative statics or dynamics of market equilibrium, rather than by reference to partial settings. For example, one would seek to know not just whether a rehabilitative project can enhance the likelihood that a group of known offenders will be successfully absorbed in legitimate or socially desirable pursuits, but whether the rehabilitative project, even if successful, would lead to a corresponding reduction in the overall volume of crime. Recognition of the existence and role of the 'market for offences' is shown to lead to important modifications in previous economic analyses of illegitimate activities concerning not only the efficacy of rehabilitation and other means of direct control of individual offenders, but of means of general deterrence as well. The paper states conditions under which individual control is efficacious and shows that it will be ineffective precisely whereas general deterrence is effective. Generally, the relatively efficacy of all means of public enforcement of laws is shown to be a function of both supply and demand elasticities rather than a function of supply elasticities alone. The analysis includes a brief discussion of what is meant by the supply and demand notions is crime, and, indeed, by the more provocative concept of the 'market for offences'.

The problem of population and growth: a review of the literature from Malthus to contemporary models of endogenous population and endogenous growth.

PIP: This review traces the evolution of literature on population and economic growth through the main paradigms suggested to explain the observed covariation of per capita income and population levels (or their rates of growth) over time and space, and determine which public policies will improve the human condition. As the main paradigms evolved, key variables were progressively treated as endogenous (instead of exogenous) to the growth process. After the introduction, section 2 looks at the "classical model" of Malthusian population theory and its refinements. Section 3 identifies empirical data that bears on the secular and cross-sectional association between levels of rates of growth of population and per capita income. The inconsistency of these data with the classical model helps explain declining interest in this model over time and increased interest in a more systematic type of population and growth theory. The beginning of this new interest is traced in section 4 with a look at the "neo-classical growth model" and the reformulated theory of population, which was based on Becker's work on fertility behavior. The first line of inquiry branching from these theoretical works (section 5) treats population as an endogenous variable in static and dynamic settings. The second line of inquiry (section 6) analyzes population and growth within a unified model of growth and development. In section 7, recent studies of key policy issues (population control policies, mandatory social security schemes) are surveyed. The concluding section notes that contemporary research must face the challenge of providing additional insights into longevity as an aspect of economic growth and development and of developing a model of endogenous population and economic growth based on heterogeneous agents.^ieng

Neurotransmitters acting via different G proteins inhibit N-type calcium current by an identical mechanism in rat sympathetic neurons.

1. We studied the mechanism of voltage-dependent inhibition of N-type calcium current by norepinephrine (NE) and vasoactive intestinal peptide (VIP) in adult rat superior cervical ganglion (SCG) neurons using the whole cell patch-clamp technique. 2. The voltage dependence of inhibition is manifest in the reversal of inhibition by strong depolarization. We tested the hypothesis that this voltage dependence results from disruption of G proteins binding to calcium channels. According to this hypothesis, the kinetics of calcium current reinhibition following a strong depolarization should become faster for higher concentrations of active G proteins. 3. Assuming that larger inhibitions result from higher concentrations of active G proteins, we used different concentrations of NE to alter the amplitude of inhibition and, thus, the active G protein concentration. We found that the kinetics of reinhibition at -80 mV following a depolarizing pulse to +80 mV were faster for larger inhibitions. 4. VIP induces voltage-dependent inhibition of N-current via a different G protein (Gs) than that of NE (Go). We found that the effect of VIP on reinhibition kinetics was identical to that produced by NE. 5. Combined application of NE and VIP did not greatly increase the amplitude of the inhibition but significantly increased the rate of reinhibition. Thus NE plus VIP appear to greatly increase the concentration of the molecule binding to the channel (G protein according to the hypothesis). 6. The kinetics of calcium current disinhibition during strong depolarization (step to +80 mV) did not change with the size of the inhibition induced by NE, VIP or application of NE and VIP together. 7. Both the concentration-dependent reinhibition kinetics and concentration-independent disinhibition kinetics are consistent with the hypothesis that active G proteins bind directly to N-type calcium channels to modulate their activity in rat sympathetic neurons.

Shift from depolarizing to hyperpolarizing glycine action in rat auditory neurones is due to age-dependent Cl- regulation.

1. The inhibitory neurotransmitter glycine can elicit depolarizing responses in immature neurones. We investigated the changes in glycine responses and their ionic mechanism in developing neurones of the rat lateral superior olive (LSO), an auditory brainstem nucleus involved in sound localization. 2. Whole-cell and gramicidin perforated-patch recordings were performed from visually identified LSO neurones in brain slices and glycine was pressure applied for 3-100 ms to the soma. Glycine-evoked currents were reversibly blocked by strychnine. They were mostly monophasic, but biphasic responses occurred in approximately 30 % of P8-11 neurones in perforated-patch recordings. 3. In whole-cell recordings from P2-11 neurones, the reversal potential of glycine-evoked currents (EGly) was determined by the transmembranous Cl- gradient and corresponded closely to the Nernst potential for Cl-, regardless of age. This indicates that Cl- is the principle ion permeating glycine receptors, but is also consistent with a low relative (10-20 %) permeability for HCO3-. The Cl- gradient also determined the polarity and amplitude of glycine-evoked membrane potential changes. 4. Leaving the native intracellular [Cl-] undisturbed with gramicidin perforated-patch recordings, we found a highly significant, age-dependent change of EGly from -46.8 +/- 1.8 mV (P1-4, n = 28) to -67.6 +/- 3.3 mV (P5-8, n = 10) to -82.2 +/- 4.1 mV (P9-11, n = 18). The majority of P1-4 neurones were depolarized by glycine ( approximately 80 %) and spikes were evoked in approximately 30 %. In contrast, P9-11 neurones were hyperpolarized. 5. In perforated-patch recordings, EGly was influenced by the voltage protocol and the glycine application interval; it could be shifted in the positive and negative direction. For a given application interval, these shifts were always larger in P1-4 than in P8-11 neurones, pointing to less effective Cl- regulation mechanisms in younger neurones. 6. Furosemide (frusemide), a blocker of cation-Cl- cotransporters, reversibly shifted EGly in the negative direction in P2-4 neurones, yet in the positive direction in P8-10 neurones, suggesting the blockade of net inward and net outward Cl- transporters, respectively. 7. Taken together, age-dependent changes in active Cl- regulation are likely to cause the developmental shift from depolarizing to hyperpolarizing glycine responses. A high intracellular [Cl-] is generated in neonatal LSO neurones which decreases during maturation.

Axon regeneration in organotypic slice cultures from the mammalian auditory system is topographic and functional.

In vitro models have frequently been employed to investigate the specificity of the formation of axonal projections during both development and regeneration. Such studies demonstrated pathway, target, and laminar specificity, yet they did not tackle the problem of topography. Here, we addressed the issue of regeneration of spatial specificity at the topographic level by lesioning a precisely organized projection from the auditory system of neonatal rats in organotypic slice culture and by analyzing regeneration capacity. Lesioning had no effect on the survival of axotomized neurons or the structure of the auditory nuclei. Anterograde and retrograde biocytin tracing demonstrated that the projection regenerated topographically at the supracellular level. Whole-cell patch-clamp recordings revealed that the regenerated projection was functional. Topographic regeneration was not impaired by blocking spike activity with tetrodotoxin or glycinergic transmission with strychnine. However, if lesioning was performed after the slices had been incubated for 1 week, regeneration capacity was lost despite good survival of neurons. The loss of the regeneration capacity in vitro occurs at a developmental stage that corresponds to the age when the capacity for axonal reorganization is lost in vivo. We conclude that the developmental processes occurring in vivo and in vitro are comparable in this system, which is why we think that essential aspects of the loss of regeneration capacity may be addressed with our culture model in the future.

Reproductive health hospitalizations among women with human immunodeficiency virus infections.

OBJECTIVE: Our goal was to determine types of inpatient admissions among human immunodeficiency virus-infected women both before and after the human immunodeficiency virus diagnosis, so that we might outline opportunities for intervention. STUDY DESIGN: A total of 292 human immunodeficiency virus-infected women were interviewed about the reproductive history and prior hospitalizations. A reproductive health hospitalization was defined as either an obstetric admission or a gynecologic admission. Other admissions were categorized as either human immunodeficiency virus related, possibly human immunodeficiency virus related, or not human immunodeficiency virus related. Assignments were made independently by two human immunodeficiency virus specialists. If there was a conflict, a third reviewer was used. RESULTS: In the 10 years before study entry 44.4% of women had at least one obstetric admission, 30.4% had at least one gynecologic admission, 3.1% had at least one human immunodeficiency virus-related admission, 18.1% had at least one admission that was possibly human immunodeficiency virus related, and 13.3% had at least one admission that was not human immunodeficiency virus related. Overall, 226 (77%) women had been admitted to the hospital; of these, 201 (69%) had been admitted for reproductive health reasons. Similar patterns were seen in the year before diagnosis and the time after diagnosis. Reproductive health admissions were more common among women who were younger, who used drugs, and who had higher CD4+ cell counts. CONCLUSION: Women with human immunodeficiency virus infection are often admitted to hospitals for reproductive health reasons before and after the human immunodeficiency virus status is known. Clinicians providing reproductive health care must be actively engaged in efforts to reduce the heterosexual and perinatal transmission of human immunodeficiency virus, to identify human immunodeficiency virus-infected women early in the course of the disease, and to provide ongoing care to human immunodeficiency virus-infected women.

Lightweight cassette for mobile-unit radiography.

The authors have developed a cassette system for mobile-unit radiography, using a soft-vinyl cassette in a Lucite housing faced with aluminum. This system performs as well as conventional radiographic cassettes and weighs approximately one-half to one-third as much.

Predictors and risk-taking consequences of drug use among HIV-infected women.

OBJECTIVE: To determine rates of drug use among women with HIV, and to examine associations between drug use, health, risk behavior, and sexually transmitted diseases (STD). DESIGN: A longitudinal cohort study of 260 women with confirmed HIV-positive serostatus. METHODS: Each participant contributed a self-report interview, a clinical examination, laboratory testing of cultures for Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, and urinalysis for the presence of metabolites of cocaine and opiates. Data were examined on 140 women at 1-year follow-up. Women were defined as drug users if they reported crack, cocaine, or heroin use in the 6 months before the interview or if they had a positive toxicologic test result for cocaine or opiates. RESULTS: 34% of those in the sample were classified as positive for drug use. Drug use was associated with the number of sexual partners, age at first intercourse, prevalence of STDs, and lower quality of life. STDs were present at baseline in 33.7% and 15.5% of drug users and nonusers, respectively. Drug use among this population was also associated at both baseline and follow-up with the likelihood of having a Karnofsky score below 80, and with overall perceived general health. CONCLUSIONS: Drug users in this cohort were more likely to engage in behaviors that place them at risk for STDs, to have elevated STD prevalence, and to have lower perceived health across several indices. Identification of drug use and treatment for it need to be a central component of HIV care for women.