Host, environment, and anthropogenic factors drive landscape dynamics of an environmentally transmitted pathogen: Sarcoptic mange in the bare-nosed wombat.

Understanding the spatial dynamics and drivers of wildlife pathogens is constrained by sampling logistics, with implications for advancing the field of landscape epidemiology and targeted allocation of management resources. However, visually apparent wildlife diseases, when combined with remote-surveillance and distribution modelling technologies, present an opportunity to overcome this landscape-scale problem. Here, we investigated dynamics and drivers of landscape-scale wildlife disease, using clinical signs of sarcoptic mange (caused by Sarcoptes scabiei) in its bare-nosed wombat (BNW; Vombatus ursinus) host. We used 53,089 camera-trap observations from over 3261 locations across the 68,401 km2 area of Tasmania, Australia, combined with landscape data and ensemble species distribution modelling (SDM). We investigated: (1) landscape variables predicted to drive habitat suitability of the host; (2) host and landscape variables associated with clinical signs of disease in the host; and (3) predicted locations and environmental conditions at greatest risk of disease occurrence, including some Bass Strait islands where BNW translocations are proposed. We showed that the Tasmanian landscape, and ecosystems therein, are nearly ubiquitously suited to BNWs. Only high mean annual precipitation reduced habitat suitability for the host. In contrast, clinical signs of sarcoptic mange disease in BNWs were widespread, but heterogeneously distributed across the landscape. Mange (which is environmentally transmitted in BNWs) was most likely to be observed in areas of increased host habitat suitability, lower annual precipitation, near sources of freshwater and where topographic roughness was minimal (e.g. human modified landscapes, such as farmland and intensive land-use areas, shrub and grass lands). Thus, a confluence of host, environmental and anthropogenic variables appear to influence the risk of environmental transmission of S. scabiei. We identified that the Bass Strait Islands are highly suitable for BNWs and predicted a mix of high and low suitability for the pathogen. This study is the largest spatial assessment of sarcoptic mange in any host species, and advances understanding of the landscape epidemiology of environmentally transmitted S. scabiei. This research illustrates how host-pathogen co-suitability can be useful for allocating management resources in the landscape.

Immunochemical Detection Methods for Gluten in Food Products: Where Do We Go from Here?

Accurate and reliable quantification methods for gluten in food are necessary to ensure proper product labeling and thus safeguard the gluten sensitive consumer against exposure. Immunochemical detection is the method of choice, as it is sensitive, rapid and relatively easy to use. Although a wide range of detection kits are commercially available, there are still many difficulties in gluten detection that have not yet been overcome. This review gives an overview of the currently commercially available immunochemical detection methods, and discusses the problems that still exist in gluten detection in food. The largest problems are encountered in the extraction of gluten from food matrices, the choice of epitopes targeted by the detection method, and the use of a standardized reference material. By comparing the available techniques with the unmet needs in gluten detection, the possible benefit of a new multiplex immunoassay is investigated. This detection method would allow for the detection and quantification of multiple harmful gluten peptides at once and would, therefore, be a logical advancement in gluten detection in food.

The expression of cytokines and chemokines in the blood of patients with severe weight loss from anorexia nervosa: an exploratory study.

Anorexia nervosa (AN) is a serious, potentially life-threatening disorder characterized by severe weight loss, dysregulated eating, and often excessive exercise. While psychiatric illnesses such as depression are associated with increased levels of pro-inflammatory mediators, evidence for such disturbances in patients with AN has been less clear. In an exploratory study of possible disturbances in immune responses in AN, we assayed a panel of cytokines and chemokines in the blood of patients undergoing inpatient treatment, testing the hypothesis that metabolic disturbances in this disease would lead to a pattern of immune disturbances distinct from that of other psychiatric diseases. For this purpose, we evaluated patients by the Beck Depression Inventory-II (BDI-II) and the Eating Disorders Examination-Questionnaire and assessed cytokines and chemokines by enzyme-linked immunosorbent assays. Patients reported a moderate level of depression (mean BDI-II = 22.6) but exhibited few immunologic abnormalities of the kind associated with major depressive disorder [e.g., increased interleukin (IL)-6]; RANTES showed the most frequent elevations and was increased in 4 of the patients studied. Together, these findings suggest that features of AN such as loss of adipose tissue and excessive exercise may attenuate cytokine production and thus modulate the experience of illness that impacts on core features of disease.

Remission, continuation and incidence of eating disorders during early pregnancy: a validation study in a population-based birth cohort.

BACKGROUND: We internally validated previously published rates of remission, continuation and incidence of broadly defined eating disorders during pregnancy in the Norwegian Mother and Child Cohort (MoBa) at the Norwegian Institute of Public Health. METHOD: A total of 77 267 pregnant women enrolled at 17 weeks gestation between 2001 and 2009 were split into a training sample (n = 41 243) from the version 2 dataset and a validation sample (n = 36 024) from the version 5 dataset who were not in the original study. Internal validation of original rate models involved fitting a calibration model to compare model parameters between the two samples and bootstrap estimates of bias in the entire version 5 dataset. RESULTS: Remission, continuation and incidence estimates remained stable. Pre-pregnancy prevalence estimates in the validation sample were: anorexia nervosa (AN; 0.1%), bulimia nervosa (BN; 1.0%), binge eating disorder (BED; 3.3%) and eating disorder not otherwise specified-purging disorder (EDNOS-P; 0.1%). In early pregnancy, estimates were: BN (0.2%), BED (4.8%) and EDNOS-P (<0.01%). Incident BN and EDNOS-P during pregnancy were rare. The highest rates were for full or partial remission for BN and EDNOS-P and continuation for BED. CONCLUSIONS: We validated previously estimated rates of remission, continuation and incidence of eating disorders during pregnancy. Eating disorders, especially BED, during pregnancy were relatively common, occurring in nearly one in every 20 women. Pregnancy was a window of remission from BN but a window of vulnerability for BED. Training to detect eating disorders by obstetricians/gynecologists and interventions to enhance pregnancy and neonatal outcomes warrant attention.

TMEM163 Regulates ATP-Gated P2X Receptor and Behavior.

Fast purinergic signaling is mediated by ATP and ATP-gated ionotropic P2X receptors (P2XRs), and it is implicated in pain-related behaviors. The properties exhibited by P2XRs vary between those expressed in heterologous cells and in vivo. Several modulators of ligand-gated ion channels have recently been identified, suggesting that there are P2XR functional modulators in vivo. Here, we establish a genome-wide open reading frame (ORF) collection and perform functional screening to identify modulators of P2XR activity. We identify TMEM163, which specifically modulates the channel properties and pharmacology of P2XRs. We also find that TMEM163 is required for full function of the neuronal P2XR and a pain-related ATP-evoked behavior. These results establish TMEM163 as a critical modulator of P2XRs in vivo and a potential target for the discovery of drugs for treating pain.

Reduced amounts and abnormal forms of phospholipase C zeta (PLCzeta) in spermatozoa from infertile men.

BACKGROUND: In mammals, oocyte activation at fertilization is thought to be induced by the sperm-specific phospholipase C zeta (PLCzeta). However, it still remains to be conclusively shown that PLCzeta is the endogenous agent of oocyte activation. Some types of human infertility appear to be caused by failure of the sperm to activate and this may be due to specific defects in PLCzeta. METHODS AND RESULTS: Immunofluorescence studies showed PLCzeta to be localized in the equatorial region of sperm from fertile men, but sperm deficient in oocyte activation exhibited no specific signal in this same region. Immunoblot analysis revealed reduced amounts of PLCzeta in sperm from infertile men, and in some cases, the presence of an abnormally low molecular weight form of PLCzeta. In one non-globozoospermic case, DNA analysis identified a point mutation in the PLCzeta gene that leads to a significant amino acid change in the catalytic region of the protein. Structural modelling suggested that this defect may have important effects upon the structure and function of the PLCzeta protein. cRNA corresponding to mutant PLCzeta failed to induce calcium oscillations when microinjected into mouse oocytes. Injection of infertile human sperm into mouse oocytes failed to activate the oocyte or trigger calcium oscillations. Injection of such infertile sperm followed by two calcium pulses, induced by assisted oocyte activation, activated the oocytes without inducing the typical pattern of calcium oscillations. CONCLUSIONS: Our findings illustrate the importance of PLCzeta during fertilization and suggest that mutant forms of PLCzeta may underlie certain types of human male infertility.

Patterns and prevalence of disordered eating and weight control behaviors in women ages 25-45.

OBJECTIVE: The current study describes detailed eating behaviors, dieting behaviors, and attitudes about shape and weight in 4023 women ages 25 to 45. METHOD: The survey was delivered on-line and participants were identified using a national quota-sampling procedure. RESULTS: Disordered eating behaviors, extreme weight loss measures, and negative cognitions about shape and weight were widely endorsed by women in this age group and were not limited to White participants. Thirty-one percent of women without a history of anorexia nervosa or binge eating reported having purged to control weight, and 74.5% of women reported that their concerns about shape and weight interfered with their happiness. DISCUSSION: Unhealthy approaches to weight control and negative attitudes about shape and weight are pervasive even among women without eating disorders. The development of effective approaches to address the impact of these unhealthy behaviors and attitudes on the general well-being and functioning of women is required.

Detailed analysis of the expression of an alpha-gliadin promoter and the deposition of alpha-gliadin protein during wheat grain development.

BACKGROUND AND AIMS: Alpha-gliadin proteins are important for the industrial quality of bread wheat flour, but they also contain many epitopes that can trigger celiac (coeliac) disease (CD). The B-genome-encoded alpha-gliadin genes, however, contain very few epitopes. Controlling alpha-gliadin gene expression in wheat requires knowledge on the processes of expression and deposition of alpha-gliadin protein during wheat grain development. METHODS: A 592-bp fragment of the promotor of a B-genome-encoded alpha-gliadin gene driving the expression of a GUS reporter gene was transformed into wheat. A large number of transgenic lines were used for data collection. GUS staining was used to determine GUS expression during wheat kernel development, and immunogold labelling and tissue printing followed by staining with an alpha-gliadin-specific antibody was used to detect alpha-gliadin protein deposited in developing wheat kernels. The promoter sequence was screened for regulatory motifs and compared to other available alpha-gliadin promoter sequences. KEY RESULTS: GUS expression was detected primarily in the cells of the starchy endosperm, notably in the subaleurone layer but also in the aleurone layer. The alpha-gliadin promoter was active from 11 days after anthesis (DAA) until maturity, with an expression similar to that of a 326-bp low molecular weight (LMW) subunit gene promoter reported previously. An alpha-gliadin-specific antibody detected alpha-gliadin protein in protein bodies in the starchy endosperm and in the subaleurone layer but, in contrast to the promoter activity, no alpha-gliadin was detected in the aleurone cell layer. Sequence comparison showed differences in regulatory elements between the promoters of alpha-gliadin genes originating from different genomes (A and B) of bread wheat both in the region used here and upstream. CONCLUSIONS: The results suggest that additional regulator elements upstream of the promoter region used may specifically repress expression in the aleurone cell layer. Observed differences in expression regulator motifs between the alpha-gliadin genes on the different genomes (A and B) of bread wheat leads to a better understanding how alpha-gliadin expression can be controlled.

Psychophysical analysis of contrast processing segregated into magnocellular and parvocellular systems in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy.

We examined achromatic contrast discrimination in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy (LHON 18 controls) and 18 age-match were also tested. To evaluate magnocellular (MC) and Parvocellular (PC) contrast discrimination, we used a version of Pokorny and Smith's (1997) pulsed/steady-pedestal paradigms (PPP/SPP) thought to be detected via PC and MC pathways, respectively. A luminance pedestal (four 1 degree x 1 degree squares) was presented on a 12 cd/m2 surround. The luminance of one of the squares (trial square, TS) was randomly incremented for either 17 or 133 ms. Observers had to detect the TS, in a forced-choice task, at each duration, for three pedestal levels: 7, 12, 19 cd/m2. In the SPP, the pedestal was fixed, and the TS was modulated. For the PPP, all four pedestal squares pulsed for 17 or 133 ms, and the TS was simultaneously incremented or decremented. We found that contrast discrimination thresholds of LHON carriers were significantly higher than controls' in the condition with the highest luminance of both paradigms, implying impaired contrast processing with no evidence of differential sensitivity losses between the two systems. Carriers' thresholds manifested significantly longer temporal integration than controls in the SPP, consistent with slowed MC responses. The SPP and PPP paradigms can identify contrast and temporal processing deficits in asymptomatic LHON carriers, and thus provide an additional tool for early detection and characterization of the disease.

Functional domains on von Willebrand factor. Recognition of discrete tryptic fragments by monoclonal antibodies that inhibit interaction of von Willebrand factor with platelets and with collagen.

We have identified two functional domains on the von Willebrand factor (VWF) moiety of the Factor VIII-von Willebrand factor complex (FVIII-VWF), one interacting with blood platelets, and one interacting with vessel wall collagens, by means of two monoclonal antibodies directed against the VWF molecule, CLB-RAg 35 and CLB-RAg 201. The monoclonal antibody CLB-RAg 35 inhibited virtually all platelet adherence to artery subendothelium and to purified vessel wall collagen type III, at relatively high wall shear rates. CLB-RAg 35 also inhibited the ristocetin-induced platelet aggregation and the binding of FVIII-VWF to the platelet in the presence of ristocetin but did not affect the binding of FVIII-VWF to collagen. The monoclonal antibody CLB-RAg 201 inhibited the binding of FVIII-VWF to purified vessel wall collagen type I and III and all platelet adherence to collagen type III and the platelet adherence to subendothelium that was mediated by FVIII-VWF in plasma. The two functional domains on FVIII-VWF that were recognized by CLB-RAg 35 and CLB-RAg 201 were identified by means of immunoprecipitation studies of trypsin-digested FVIII-VWF. The domains resided on different polypeptide fragments, with a Mr of 48,000 for the collagen binding domain and a Mr of 116,000 for the platelet binding domain. The 116,000-mol wt fragment consisted of subunits of 52,000/56,000 mol wt and 14,000 mol wt after reduction. The 52,000/56,000-mol wt subunits possessed the epitope for CLB-RAg 35.

Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood.

Previous studies of postnatal synaptic development in human frontal cortex have shown that synaptic density rises after birth, reaches a plateau in childhood and then decreases to adult levels by late adolescence. A similar pattern has been seen in nonhuman primate cortex. These earlier studies in human cortex are limited, however, by significant age gaps in study subjects at critical inflection points of the developmental curve. Additionally, it is unclear if synaptic development occurs in different patterns in different cortical layers in prefrontal cortex (PFC). The purpose of this study was to examine synaptic density in human PFC across development by measuring two synaptic marker proteins: synaptophysin (presynaptic), and postsynaptic density protein 95 (PSD-95; postsynaptic). Western blotting was used to assess the relative levels of synaptophysin and PSD-95 in dorsolateral PFC of 42 subjects, distributed in age from 18 weeks gestation to 25 years. In addition, synaptophysin immunoreactivity was examined in each layer of areas 9 and 46 of PFC in 24 subjects, ranging in age from 0.1-25 years. Synaptophysin levels slowly increased from birth until age 5 and then increased more rapidly to peak in late childhood around age 10. Synaptophysin subsequently decreased until the adult level was reached by mid-adolescence, around age 16. PSD-95 levels increased postnatally to reach a stable plateau by early childhood with a slight reduction in late adolescence and early adulthood. The pattern of synaptophysin immunoreactivity seen with immunohistochemistry was similar to the Western experiments but the changes across age were more subtle, with little change by layer within and across age. The developmental patterns exhibited by these synaptic marker proteins expand upon previous studies of developmental synaptic changes in human frontal cortex; synaptic density increases steadily from birth to late childhood, then decreases in early adolescence to reach adult levels by late adolescence.

Measuring brain volume by MR imaging: impact of measurement precision and natural variation on sample size requirements.

BACKGROUND AND PURPOSE: To determine the sample size needed to provide adequate statistical power in studies of brain volume by MR imaging, we examined the precision and variability of measurements in healthy controls. MATERIALS AND METHODS: A cohort of 52 people (mean age, 25.1 years) was examined at weeks 0 and 12 at 1.5 T. We used an axial multisection T1-weighted sequence and a contiguous proton-attenuation/T2-weighted sequence. Data were registered to a probabilistic brain atlas, and an automated atlas-based program was used to segment brain tissue by type and by lobe. We assumed that there were no changes in volume because there were no intervening neurologic events. Sample sizes required to yield 80% statistical power in detecting a significant difference in volume were calculated for various experimental designs, assuming a patient-control volume difference of 5% or 2%. RESULTS: The precision of most measurements was excellent, but required sample sizes were larger than anticipated. If the goal was to detect a 5% difference in whole brain volume in a 2-sample cross-sectional study, the required sample was 73 patients and 73 controls because brain volume varies between individuals in a way that is not informative about disease effects. For a similar 2-sample longitudinal study, the required sample size was just 5 patients and 5 controls. CONCLUSIONS: Our results argue strongly for longitudinal studies in preference to cross-sectional studies, especially as research budgets decline. Our findings also suggest that there may be more uncertainty than expected in published MR imaging brain volume studies.

Early postnatal development of corpus callosum and corticospinal white matter assessed with quantitative tractography.

BACKGROUND AND PURPOSE: The early postnatal period is perhaps the most dynamic phase of white matter development. We hypothesized that the early postnatal development of the corpus callosum and corticospinal tracts could be studied in unsedated healthy neonates by using novel approaches to diffusion tensor imaging (DTI) and quantitative tractography. MATERIALS AND METHODS: Isotropic 2 x 2 x 2 mm(3) DTI and structural images were acquired from 47 healthy neonates. DTI and structural images were coregistered and fractional anisotropy (FA), mean diffusivity (MD), and normalized T1-weighted (T1W) and T2-weighted (T2W) signal intensities were determined in central midline and peripheral cortical regions of the white matter tracts of the genu and splenium of the corpus callosum and the central midbrain and peripheral cortical regions of the corticospinal tracts by using quantitative tractography. RESULTS: We observed that central regions exhibited lower MD, higher FA values, higher T1W intensity, and lower T2W intensity than peripheral cortical regions. As expected, MD decreased, FA increased, and T2W signal intensity decreased with increasing age in the genu and corticospinal tract, whereas there was no significant change in T1W signal intensity. The central midline region of the splenium fiber tract has a unique pattern, with no change in MD, FA, or T2W signal intensity with age, suggesting different growth trajectory compared with the other tracts. FA seems to be more dependent on tract organization, whereas MD seems to be more sensitive to myelination. CONCLUSIONS: Our novel approach may detect small regional differences and age-related changes in the corpus callosum and corticospinal white matter tracts in unsedated healthy neonates and may be used for future studies of pediatric brain disorders that affect developing white matter.

Limited influence of olanzapine on adult forebrain neural precursors in vitro.

We evaluated the activity of the atypical antipsychotic drug olanzapine on differentiation and gene expression in adult neural precursor cells in vitro. Neural precursors obtained from forebrain subventricular zone (SVZ)-derived neurospheres express a subset (13/24) of receptors known to bind olanzapine at high to intermediate affinities; in contrast, all 24 are expressed in the SVZ. In the presence of 10 nM, 100 nM or 1 microM olanzapine, there is no significant change in the frequency of oligodendrocytes, neurons, GABAergic neurons and astrocytes generated from neurosphere precursors. In parallel, there is no apparent change in cell proliferation in response to olanzapine, based upon bromodeoxyuridine incorporation. There are no major changes in cytological differentiation in response to the drug; however, at one concentration (10 nM) there is a small but statistically significant increase in the size of glial fibrillary acidic protein-labeled astrocytes derived from neurosphere precursors. In addition, olanzapine apparently modulates expression of one serotonin receptor -- 5HT2A -- in differentiating neurosphere cultures; however, it does not modify expression of several other receptors or schizophrenia vulnerability genes. Thus, olanzapine has a limited influence on differentiation and gene expression in adult neural precursor cells in vitro.

Olanzapine and haloperidol in first episode psychosis: two-year data.

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

A proposed role for all-trans retinal in regulation of rhodopsin regeneration in human rods.

In order to account for the multi-phasic dynamics of photopigment regeneration in human rods, we developed a new model of the retinoid cycle. We first examined the relative roles of the classical and channeling mechanisms of metarhodopsin decay in establishing these dynamics. We showed that neither of these mechanisms alone, nor a linear combination of the two, can adequately account for the dynamics of rhodopsin regeneration at all bleach levels. Our new model adds novel inhibitory interactions in the cycle of regeneration of rhodopsin that are consistent with the 3D structure of rhodopsin. Our analyses show that the dynamics of human rod photopigment regeneration can be accounted for by end-product regulation of the channeling mechanism where all-trans retinal (tral) inhibits the binding of 11-cis retinal to the opsin.tral complex.

Human factor VIII: purification from commercial factor VIII concentrate, characterization, identification and radiolabeling.

Human factor VIII was purified from commercial factor VIII concentrate with a 12% yield. The specific coagulant activity of purified factor VIII was 8,000 units/mg. In the presence of SDS the purified factor VIII consisted of a variety of polypeptides on polyacrylamide gels, ranging between Mr 80,000 and Mr 208,000. In the absence of SDS the purified factor VIII showed an apparent molecular weight of 270,000 upon Sephadex G200 gel-filtration. The purified factor VIII could be activated by thrombin, which resulted in the disappearance of Mr 108,000-208,000 polypeptides in favor of an Mr 92,000 polypeptide. Treatment with factor Xa also activated factor VIII, whereas treatment with activated protein C resulted in the inactivation of coagulant activity. Coagulant-active 125I-factor VIII was prepared using a lactoperoxidase radioiodination procedure. This 125I-factor had the same characteristics as unlabeled factor VIII. All polypeptides could be precipitated with monoclonal antibodies directed against factor VIII. With 125I-factor VIII a pIapp of 5.7 was found in the presence of urea.

Murine erythrocytes contain high levels of lysophospholipase activity.

Murine erythrocytes were found to be unique in the high levels of lysophospholipase activity in the cytosol of these cells. The specific activity of the enzyme in the cytosol of the murine cells is 10-times higher than in the cytosol of rabbit erythrocytes and approximately three orders of magnitude higher than those in the red cells of rat, man, pig and ox.

Multiple steps of phosphorylation of activated rhodopsin can account for the reproducibility of vertebrate rod single-photon responses.

Single-photon responses (SPRs) in vertebrate rods are considerably less variable than expected if isomerized rhodopsin (R*) inactivated in a single, memoryless step, and no other variability-reducing mechanisms were available. We present a new stochastic model, the core of which is the successive ratcheting down of R* activity, and a concomitant increase in the probability of quenching of R* by arrestin (Arr), with each phosphorylation of R* (Gibson, S.K., J.H. Parkes, and P.A. Liebman. 2000. Biochemistry. 39:5738-5749.). We evaluated the model by means of Monte-Carlo simulations of dim-flash responses, and compared the response statistics derived from them with those obtained from empirical dim-flash data (Whitlock, G.G., and T.D. Lamb. 1999. Neuron. 23:337-351.). The model accounts for four quantitative measures of SPR reproducibility. It also reproduces qualitative features of rod responses obtained with altered nucleotide levels, and thus contradicts the conclusion that such responses imply that phosphorylation cannot dominate R* inactivation (Rieke, F., and D.A. Baylor. 1998a. Biophys. J. 75:1836-1857; Field, G.D., and F. Rieke. 2002. Neuron. 35:733-747.). Moreover, the model is able to reproduce the salient qualitative features of SPRs obtained from mouse rods that had been genetically modified with specific pathways of R* inactivation or Ca2+ feedback disabled. We present a theoretical analysis showing that the variability of the area under the SPR estimates the variability of integrated R* activity, and can provide a valid gauge of the number of R* inactivation steps. We show that there is a heretofore unappreciated tradeoff between variability of SPR amplitude and SPR duration that depends critically on the kinetics of inactivation of R* relative to the net kinetics of the downstream reactions in the cascade. Because of this dependence, neither the variability of SPR amplitude nor duration provides a reliable estimate of the underlying variability of integrated R* activity, and cannot be used to estimate the minimum number of R* inactivation steps. We conclude that multiple phosphorylation-dependent decrements in R* activity (with Arr-quench) can confer the observed reproducibility of rod SPRs; there is no compelling need to invoke a long series of non-phosphorylation dependent state changes in R* (as in Rieke, F., and D.A. Baylor. 1998a. Biophys. J. 75:1836-1857; Field, G.D., and F. Rieke. 2002. Neuron. 35:733-747.). Our analyses, plus data and modeling of others (Rieke, F., and D.A. Baylor. 1998a. Biophys. J. 75:1836-1857; Field, G.D., and F. Rieke. 2002. Neuron. 35:733-747.), also argue strongly against either feedback (including Ca2+-feedback) or depletion of any molecular species downstream to R* as the dominant cause of SPR reproducibility.

Borderline and schizotypal personality disorders treated with low-dose thiothixene vs placebo.

Fifty outpatients with borderline and/or schizotypal personality disorder were randomly allocated to thiothixene (Navane) or placebo treatment that was continued for 12 weeks. The mean daily dosage of thiothixene hydrochloride in the final week of the study was 8.7 mg, a lower dosage than is used in outpatient schizophrenics. Significant drug-placebo differences were found, regardless of diagnosis, on "illusions," "ideas of reference," "psychoticism," "obsessive-compulsive symptoms," and "phobic anxiety," but not on "depression." Thiothixene seems to have more than an antipsychotic effect. Since response to treatment studies are a means for reformulating diagnostic concepts, we suggest a subdiagnosis defined by those symptoms that are drug-responsive, some of which are not included in current diagnostic criteria. Patients with borderline and schizotypal disorder without the foregoing symptoms probably would not profit from thiothixene and might needlessly be placed at risk for adverse drug effects.