Know thy neighbor: a survey of diseases and complex syndromes that map to chromosomal regions encoding TRP channels.

On the basis of their ever-expanding roles, not only in sensory signaling but also in a plethora of other, often Ca(2+)-mediated actions in cell and whole body homeostasis, it is suggested that mutations in TRP channel genes not only cause disease states but also contribute in more subtle ways to simple and complex diseases. A survey is therefore presented of diseases and syndromes that map to one or multiple chromosomal loci containing TRP channel genes. A visual map of the chromosomal locations of TRP channel genes in man and mouse is also presented.

Is thought-action fusion specific to obsessive-compulsive disorder?: a mediating role of negative affect.

Thought-action fusion (TAF) is a cognitive bias presumed to underlie the development of obsessional problems (i.e. obsessive-compulsive disorder; OCD). Previous studies have found that TAF is related to not only OCD, but also to other anxiety disorders. In the present study we compared levels of TAF in OCD patients and in patients with other anxiety disorders, depression, and healthy controls to examine whether TAF is characteristic of individuals with emotional distress in general, as opposed to anxiety disorders per se. We also examined whether negative affect (i.e. anxiety and depression) mediates the relationship between OCD and TAF. Results indicated that OCD patients were characterized by higher scores on likelihood-self and likelihood-other TAF, but that this difference was predominately due to differences in negative affect. These findings support a model in which negative affect mediates the relationship between OCD and TAF.

Thought control strategies in obsessive-compulsive disorder: a replication and extension.

Previous research suggests that individuals with OCD use maladaptive strategies to control their unpleasant thoughts (Behav Res Ther (1977) 35, 775). These include worry and self-punishment strategies. In the present study we replicated and extended the previous findings by comparing thought control strategies used by patients with OCD to strategies used by anxious and non-anxious control participants. We also examined changes in thought control strategies for OCD patients who underwent cognitive-behavioral therapy. Compared to controls, OCD patients reported more frequent use of worry and punishment strategies, and less frequent use of distraction. Following successful treatment, OCD patients evidenced increased use of distraction and decreased use of punishment. Findings are discussed in terms of the cognitive model of OCD.

Acute onset of obsessive-compulsive disorder in males following childbirth.

Research on postpartum onset obsessive-compulsive disorder (OCD) has focused exclusively on females. However, the authors present four cases of males with OCD onset that coincide with a spouse's pregnancy or delivery. The rapid onset and content of obsessions and compulsions are remarkably similar to those reported in previous studies of postpartum OCD in females. Each patient also responded to cognitive-behavioral therapy using exposure procedures. The implications of these cases for etiological models of postpartum OCD and future research directions are discussed.

Ouabain-induced signaling and vascular smooth muscle cell proliferation.

The hypothesis of this study is that the sodium pump complex acts as an intracellular signal-transducing molecule in canine vascular smooth muscle cells through its interaction with other membrane and cytoskeletal proteins. We have demonstrated that 1 nm ouabain induced transactivation of the epidermal growth factor receptor (EGFR), resulting in increased proliferation and bromodeoxyuridine (BrdUrd) uptake. Immunoprecipitation and Western blotting showed that the EGFR and Src were phosphorylated within 5 min of 10(-9) m ouabain stimulation. Both ouabain-induced DNA synthesis (BrdUrd uptake) and MAPK42/44 phosphorylation were inhibited by the Src inhibitor PP2, the EGFR kinase inhibitor AG1478, the tyrosine kinase inhibitor genistein, and the MEK1 inhibitor PD98059. Ouabain concentrations higher than 1 nm had little or no stimulating effect on proliferation or BrdUrd uptake but did minimally activate ERK1/2. Thus, low concentrations of ouabain, which do not inhibit the sodium pump sufficiently to perturb the resting cellular ionic milieu, initiate a transactivational signaling cascade leading to vascular smooth muscle cell proliferation.

Memory and memory confidence in obsessive-compulsive disorder.

Pathological doubt, often found in individuals with obsessive-compulsive disorder (OCD), has been theoretically linked to memory deficits, but empirical evidence for such deficits has been mixed. In contrast, many studies suggest that individuals with OCD have low confidence in their memories. The present study aimed to build upon previous research by measuring memory accuracy and confidence in OCD using ecologically valid, idiographically-selected stimuli. Individuals with OCD (OCs), anxious controls (ACs), and nonanxious controls (NACs) were exposed to a set of objects that the OCs had identified as safe, unsafe, or neutral. Participants were then asked to recall as many objects as possible and to rate their confidence in each memory. This process was repeated 6 times, using the same stimuli for each trial. Contrary to hypothesis, no group differences emerged in memory accuracy. However, OCs' memory confidence for unsafe objects showed a progressive decline over repeated trials. This pattern was not observed among NACs or ACs. Furthermore, OCs with primary checking reported lower confidence in long-term memory than did OCs without primary checking. These results suggest that when OCs are repeatedly exposed to threat-related stimuli (such as repeated checking), their level of confidence in remembering these stimuli paradoxically decreases.

Paradoxical effects of thought suppression: a meta-analysis of controlled studies.

Research has shown that attempts to suppress a thought can cause an increase in the frequency of the thought. These paradoxical effects of thought suppression play a key role in cognitive-behavioral models of several emotional disorders. Laboratory studies of this phenomenon, however, have yielded mixed results; and narrative summaries of the literature have not been able to draw firm conclusions about the effects of thought suppression. We used meta-analysis to quantitatively examine the magnitude of thought suppression effects across controlled studies. Moreover, we explored whether the variability in effect sizes could be explained by methodological differences within and between studies. Results indicated a small to moderate rebound effect of thought suppression that varied in magnitude depending on the nature of the target thought and the method by which thought frequency was measured. Participants with clinical diagnoses did not show larger rebound effects than nonclinical or analogue participants, however, only a few studies included clinical samples. Findings are discussed in terms of implications for the ironic process theory of thought suppression, and avenues for future research on this phenomenon.

Fixity of belief, perceptual aberration, and magical ideation in obsessive-compulsive disorder.

Clinicians and researchers have pondered the intersection of obsessive-compulsive disorder (OCD) and psychosis. We examined the records of 395 individuals seeking treatment for OCD and classified participants according to their most frequent or distressing obsession and compulsion. All participants completed measures of fixity of belief, perceptual distortions, magical ideation, and psychotic symptoms. Results indicated that individuals who reported fear of harming self or others via overwhelming impulse or by mistake, and those with religious obsessions, had poorer insight and more perceptual distortions and magical ideation than did individuals with other types of obsessions. These results did not appear to reflect mere differences in OCD severity. Results are discussed in light of previous findings showing that psychotic-like symptoms are associated with attenuated treatment outcome in OCD. More research is needed to assess the absolute magnitude of psychotic-like features in OCD patients with impulse/mistake and religious obsessions and to examine whether these features interfere with standard cognitive-behavioral therapy.

Effectiveness of exposure and ritual prevention for obsessive-compulsive disorder: randomized compared with nonrandomized samples.

The efficacy of exposure and ritual prevention (EX/RP) for reducing symptoms of obsessive-compulsive disorder (OCD) has been demonstrated in several randomized controlled trials (RCTs). However, procedures used in these studies to maximize experimental control may have limited their generalizability to typical clinical practice. Treatment outcome data from 110 clinical patients receiving EX/RP on an outpatient fee-for-service basis were compared with findings from 4 RCTs of EX/RP. Adult patients in the clinical sample were not excluded because of treatment history, concomitant pharmacotherapy, psychiatric comorbidity, age, or OCD severity. Clinical patients achieved substantial and clinically meaningful reductions in their OCD and depressive symptoms following EX/RP, which were comparable with those reported in the RCTs. Findings indicate that EX/RP is a potent treatment for OCD, and its benefits are not limited to select patient samples.

Expression of plasma membrane calcium ATPases in phenotypically distinct canine vascular smooth muscle cells.

Our laboratory has identified at least two types of vascular smooth muscle cells (VSMCs) that exist in canine arteries and veins: type 1 cells, located in the media express muscle specific proteins but do not proliferate in culture; and type 2 cells, located in both media and adventitia, do not express muscle specific protein but proliferate in culture. Plasma membrane Ca(2+)-ATPases (PMCAs) have been implicated in proliferation control. The present study examines the expression of PMCA isoforms and calmodulin-binding domain splice variants in these two types of canine VSMCs. PMCA protein was found in both type 1 and type 2 cells. Reverse transcriptase-polymerase chain reaction assays were developed for canine PMCA calmodulin-binding domain splice variants. We cloned and sequenced isolates corresponding to PMCA1b, 4a and 4b from canine VSMCs. PMCA 2 and 3 were not detected. Freshly isolated type 1 cells expressed PMCA 1b, 4a and 4b, while freshly isolated type 2 cells expressed PMCA1b and 4b. Upon placement in culture, type 2 cells originating from either carotid artery or saphenous vein demonstrated a time-dependent upregulation of PMCA4a mRNA. Treatment with the phosphoinositide 3-kinase inhibitor wortmannin produced concentration-dependent inhibition of both PMCA4a upregulation and [(3)H]thymidine incorporation. These findings suggest a role for phosphoinositide 3-kinase in regulating PMCA expression, which may be important in the control of Ca(2+)-sensitive VSMC functions.

Health concerns in patients with obsessive-compulsive disorder.

In the present study, individuals with obsessive-compulsive disorder (OCD) who also had excessive health concerns (n = 56) were compared with OCD individuals without such concerns (n = 343) regarding their OCD symptom severity, types of obsessions and compulsions, insight into the irrationality of their obsessions, and prevalence of generalized anxiety disorder. While the presence of health concerns did not affect the severity of OCD symptoms, the groups differed with respect to the types of symptoms displayed: those with health concerns had more somatic and harm obsessions, and checking compulsions: whereas those without such concerns had more contamination obsessions and washing compulsions. The insight of both groups ranged from poor to excellent, yet the number of individuals with poor insight was greater among those with health concerns than those without. Generalized anxiety disorder was also more prevalent among OCD individuals with excessive health concerns.

Worries and obsessions in individuals with obsessive-compulsive disorder with and without comorbid generalized anxiety disorder.

Participants from the DSM-IV field trial for OCD (N = 381) were divided into two groups based on the SCID interview: those who met current criteria for obsessive-compulsive disorder (OCD) but not generalized anxiety disorder (GAD) and those who met current diagnostic criteria for both. The groups were compared on their severity of obsessive and compulsive symptoms, as well as on the percent of individuals who reported excessive worry concerning everyday issues (e.g. health, finances). The comorbidity rate was 20%. While the presence of GAD did not elevate OCD symptoms per se, it was associated with more pathological responsibility and indecisiveness. Excessive worries were significantly more common in those with comorbid OCD and GAD. The relationship between obsessions and worries is discussed.

High glucose enhances growth factor-stimulated nitric oxide production by cultured rat mesangial cells.

Nitric oxide (NO) contributes to the alterations in glomerular hemodynamics and extracellular matrix accumulation observed in diabetic nephropathy. High glucose concentrations directly inhibit NO production by rat mesangial cells (RMC). However, the role of peptide growth factors and chemokines in regulating NO synthesis by RMC under normal and high glucose conditions has not been studied. Therefore, we examined the effect of IGF-I, EGF, TGF-beta and RANTES on NO production by RMC maintained in normal (5.6 mM) or high glucose (33.3 mM) for 48 h. No synthesis was determined by measuring nitrite accumulation in conditioned media with the Greiss reaction. In normal glucose media, IGF-I, EGF, and RANTES had no effect on nitrite accumulation while TGF-beta inhibited NO synthesis. In high glucose conditions, IGF-I and EGF significantly enhanced NO production. The effects of RANTES and TGF-beta were unchanged by an elevated glucose concentration. EGF-induced stimulation of NO production in high glucose media was associated with parallel alterations in iNOS gene and protein expression. The modest enhancement in nitrite accumulation provoked by IGF-I in high glucose conditions was not accompanied by demonstrable increases in iNOS mRNA abundance or protein content. In conclusion, peptide growth factors modulate the direct inhibitory effect of high glucose on NO production by cultured mesangial cells. These actions in vivo may limit the adverse consequences of reduced NO production in promoting diabetic nephropathy.

Plasma membrane calcium ATPase isoform expression in cultured rat mesangial cells.

The maintenance of intracellular ionized calcium (iCa2+) in the submicromolar range is important for mesangial cell (MC) function, and, as in most mammalian cells, plasma membrane Ca(2+)-ATPases (PMCA) play an important role in the homeostatic process. Molecular studies have demonstrated four PMCA isoforms, each with multiple splice variants. The present study examines the expression of PMCA isoforms and calmodulin-binding region splice variants in cultured MC from Sprague-Dawley rats and from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats before and after the onset of hypertension in SHR. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analyses, we have demonstrated PMCA1, -3, and -4, but not PMCA2, to be present in MC from these rat strains. Splice variant analysis revealed PMCA1a and -1b, PMCA3a, -3b, and -3c, and PMCA4a and -4b to be expressed in MC from all three strains. The relative quantities of PMCA1 and PMCA4 mRNA were not different in age-matched SHR vs. WKY rats, correlating with similar iCa2+ measurements. The expression of all three isoforms declined with age in SHR and WKY.

Effectiveness of psychological and pharmacological treatments for obsessive-compulsive disorder: a quantitative review.

Quantitative review of the controlled treatment outcome literature for obsessive-compulsive disorder (OCD) showed that exposure with response prevention was highly effective in reducing OCD symptoms. Cognitive approaches were also found to be at least as effective as exposure procedures. It appears that both cognitive and exposure interventions involve some overlapping procedures and capitalize on similar mechanisms of change. Serotonergic medication, particularly clomipramine, also substantially reduced OCD symptoms. However, clomipramine may not be particularly superior to other serotonergic medication. The relationship between side effects and effect size in medication trials was explored.

Ca-ATPase and bone cell mineralization.

The plasma membrane Ca-ATPases play an important role in the regulation of intracellular Ca2+ ion concentration by pumping Ca2+ out of the cell into the extracellular fluid at the expense of ATP. These pumps potentially play an important role in the delivery of Ca2+ during mineralization of hard tissues such as bone. The properties of the plasma membrane Ca2+ pump are compared with those of the sarco(endo)plasmic reticulum and the factors regulating pump function are presented. The different gene products for the plasma membrane Ca-ATPases are described as well as their known functional significance. Particular attention is paid on the plasma membrane Ca2+ pumps present in mineralizing tissues and evidence supporting a role for these pumps in the transcellular delivery of Ca2+ during the process of mineralization is also presented.

Differential expression of plasma membrane calcium pump mRNA isoforms in rat osteoblast-like cells.

This study was conducted to identify the plasma membrane Ca2+ transport ATPase (PMCA) mRNA isoforms expressed in rat osteoblast-like cells as PMCAs are likely to participate in calcium deposition in bone. We designed oligonucleotide primers for each PMCA isoform based on rat cDNA sequences in order to develop reverse transcription polymerase chain reaction (RT-PCR) assays. Rat kidney total RNA was used to validate the assays as we have shown that each isoform is present in kidney. When used in RT-PCR assays each primer pair gave rise to a single major product of the appropriate size. Southern blot analysis of the PCR products with oligonucleotide probes specific for each isoform revealed that each probe hybridized only to the expected product. Reamplification of purified PCR products with probe and antisense primers gave rise to products of appropriate size, further confirming the identity of the products. Using these primers we have identified the presence of transcripts for PMCA1, 2 and 4 in RNA from UMR-106 osteoblasts and PMCA1 in RNA from ROS 17/2.8 osteoblasts. We conclude that the two major rat cell lines used as models to study osteoblast function differentially express PMCA mRNA isoforms.

Colocalization of TRH mRNA and Fos-like Immunoreactivity in Limbic Structures Following Amygdala Kindling.

Previous studies have demonstrated that the immediate-early gene, Fos, and Fos-related antigens (Fras) are increased with discrete anatomical localization following kindled seizures. Other studies have shown that transcription of several neuropeptide genes, which may be regulated by Fos and Fras, is also altered in circumscribed anatomical structures with kindling. The patterns of Fos and thyrotropin-releasing hormone (TRH) mRNA induction following kindling were found to be remarkably similar. The present study examined whether TRH mRNA and Fos-like immunoreactivity (Fos-LI), with an antibody that recognizes both Fos and Fras, are colocalized following amygdala kindling. Rats were sacrificed 5 h after a generalized kindled seizure and the brains processed for in situ hybridization of TRH mRNA and immunohistochemistry of Fos-LI. The percentage of Fos-LI cells with TRH mRNA was 70% in the entorhinal cortex, 62% in the pyriform cortex, and 79% in the perirhinal cortex. Very dense expression of Fos-LI and TRH mRNA was also found in the granule cell layer of the dentate gyrus, but the colocalization was too numerous to count. Sham-kindled control rats had fewer Fos-LI cells and almost no TRH mRNA in any of these regions. In contrast to the limbic cortices and the dentate gyrus, Fos-LI and TRH mRNA were expressed in the hypothalamus of both sham and kindled rats, but were not colocalized. These results demonstrate that the induction of Fos, Fras, and TRH mRNA following kindled seizures are colocalized in limbic structures known to be important for kindling.

Reconstitution and partial purification of calcium transport activity from rat kidney cortex.

An ATP-dependent Ca2+ uptake system from rat renal cortical basolateral membranes was solubilized with Triton X-100 and reconstituted into liposomes with lecithin. In the presence of Mg2+, Ca2+ uptake in the reconstituted vesicles was time and ATP dependent and was inhibited by vanadate. Ca2+ uptake in basolateral membrane vesicles depleted of endogenous calmodulin was enhanced by exogenous calmodulin and depressed by R-24571. This sensitivity to calmodulin and R-24571 was lost upon reconstitution in the presence and absence of leupeptin. Vesicles containing Ca2+ uptake activity were separated by gradient centrifugation after Ca2+ was taken up and accumulated as calcium phosphate in the vesicles. This resulted in Ca2+ uptake activity that was enriched 25 times. However, Ca(2+)-dependent adenosinetriphosphatase (ATPase) activity was not enriched significantly. This Ca(2+)-ATPase had two kinetic forms for Ca2+: one was a high-affinity low-capacity form; the other had a low affinity and high capacity. The Ca(2+)-ATPase activity also had two kinetic forms for ATP. All kinetic forms were inhibited by Mg2+. Vanadate, calmodulin, and R-24571 had no effects on Ca(2+)-ATPase activity. A protein doublet of Ca(2+)-dependent hydroxylamine-sensitive phosphorylated intermediates was demonstrated at 125 and 136 kDa in the purified vesicles. This doublet was not altered by addition of leupeptin throughout the purification.