Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina

Retinal neural transmission represents a key function of the eye. Identifying the molecular components of this vital process is helped by studies of selected human genetic eye disorders. For example, mutations in the calcium channel subunit gene CACNA1F cause incomplete X-linked congenital stationary night blindness (CSNB2 or iCSNB), a human retinal disorder with abnormal electrophysiological response and visual impairments consistent with a retinal neurotransmission defect. To understand the subcellular basis of this retinal disorder, we generated a mouse with a loss-of-function mutation by inserting a self-excising Cre-lox-neo cassette into exon 7 of the murine orthologue, Cacna1f. Electroretinography of the mutant mouse revealed a scotopic a-wave of marginally reduced amplitude compared with the wild-type mouse and absence of the post-receptoral b-wave and oscillatory potentials. Cone ERG responses together with visual evoked potentials and multi-unit activity in the superior colliculus were also absent. Calcium imaging in Fluo-4 loaded retinal slices depolarized with KCl showed 90% less peak signal in the photoreceptor synapses of the Cacna1f mutant than in wild-type mice. The absence of post-receptoral ERG responses and the diminished photoreceptor calcium signals are consistent with a loss of Ca((2+)) channel function in photoreceptors. Immunocytochemistry showed no detectable Ca(v)1.4 protein in the outer plexiform layer of Cacna1f-mutant mice, profound loss of photoreceptor synapses, and abnormal dendritic sprouting of second-order neurons in the photoreceptor layer. Together, these findings in the Cacna1f-mutant mouse reveal that the Ca(v)1.4 calcium channel is vital for the functional assembly and/or maintenance and synaptic functions of photoreceptor ribbon synapses. Moreover, the outcome of this study provides critical clues to the pathophysiology of the human retinal channelopathy of X-linked incomplete CSNB.     

Region-specific changes of calcium/calmodulin-dependent protein kinase IV in the mouse brain following chronic morphine treatment

In this study, we examined changes in expression of calcium/calmodulin-dependent protein kinase IV (CaMKIV) in the mouse brain following chronic morphine treatment. Double immunohistochemical staining showed strong colocalization of CaMKIV with mu-opioid receptors. Chronic treatment with morphine produced an increase in expression of CaMKIV and phosphorylated cAMP response element-binding protein (pCREB) in the CA3 region of the hippocampus, whereas a decrease in CaMKIV and pCREB expression was observed in the caudate putamen. Interestingly, chronic morphine induced a decrease in protein expression of CaMKIV in the basolateral amygdale and the primary somatosensory cortex without any concomitant changes in pCREB. These findings suggest that CaMKIV-dependent signaling may play a role in chronic morphine-induced neuroplasticity in a brain region-specific manner.     

Carbenoxolone inhibition of voltage-gated Ca channels and synaptic transmission in the retina

We show that carbenoxolone, a drug used to block hemichannels in the retina to test the ephaptic model of horizontal cell inhibitory feedback, has strong inhibitory effects on voltage-gated Ca channels. Carbenoxolone (100 microM) reduced photoreceptor-to-horizontal cell synaptic transmission by 92%. Applied to patch-clamped, isolated cone photoreceptors, carbenoxolone inhibited Ca channels with an EC(50) of 48 microM. At 100 microM, it reduced cone Ca channel current by 37%, reduced depolarization-evoked [Ca(2+)] signals in fluo-4 loaded retinal slices by 57% and inhibited Ca channels in Müller cells by 52%. A synaptic transfer model suggests that the degree of block of Ca channels accounts for the reduction in synaptic transmission. These results suggest broad inhibitory actions for carbenoxolone in the retina that must be considered when interpreting its effects on inhibitory feedback.     

Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm³/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p=0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.     

Chronometry of visual word recognition during passive and lexical decision tasks: an ERP investigation

In order to investigate the neuroanatomical chronometry of word processing, two experiments using: Event-Related Potentials (ERPs) have been performed. The first one was designed to test the effects of orthographic, phonologic, and lexical properties of linguistic items on the pre-semantic components of ERPs during a passive reading task and massive repetition used to reduce familiarity effect between words and nonwords. In a second study, the level of familiarity was investigated by varying stimulus repetition and frequency in a lexical decision task. Overall results suggest a functional discrimination between orthographic and nonorthographic stimuli begun as early as 170 ms (N170 component) whereas the next components (N230 and N320) were sensitive to the orthographic nature of the stimuli, but also to their lexical/phonologic proprieties. The N320 associated to phonological processing (Bentin et al., 1999) was modulated by word frequency and massive repetition caused its disappearance. This suggests that this component may reflect a nonobligatory phonologic stage of grapheme-phoneme conversion postulated by the DRC model (Coltheart et al., 2001) or semantic phonologically mediated pathway (Harm & Seidenberg, in press).     

Development and preliminary testing of a patient decision aid to assist pharmaceutical care in the prevention of cardiovascular disease

STUDY OBJECTIVE: To develop and test a decision aid for patients with hypertension and/or dyslipidemia because a decision aid may assist in pharmaceutical care by providing relevant evidence-based information. DESIGN: Before and after use of a decision aid. SETTING: Hypertension clinic of a university hospital and a specialized coronary heart disease-prevention clinic. PATIENTS: A convenience sample of 16 patients receiving pharmacologic treatment for hypertension and/or dyslipidemia. INTERVENTION: A face-to-face interview was conducted before using the decision aid. This was followed by a telephone interview after the patient used the decision aid to assess the acceptability of the decision aid to the patient, as well as the patient's knowledge, risk perception, and decisional conflict. MEASUREMENTS AND MAIN RESULTS: The decision aid consists of a booklet containing general, evidence-based information and a personal worksheet. The worksheet provides information on patient risk factors, personal estimates of cardiovascular disease (CVD) risk, the benefits of treatment options, and values clarification exercise. It invites patients to specify an action plan and follow their own progress over time. Most patients (86-93%) rated the presentation of the information as excellent or very good, 80% judged the information about lifestyle changes and drug therapy to be balanced, 93% rated the amount of information "just right," and 100% found the decision aid useful. After using the decision aid, patients had higher knowledge scores for general risk factors (before, 91%; after, 100%, p=0.014), personal risk factors (73%, 92%, p=0.016), and treatment options (68%, 99%, p<0.001). More patients were able to estimate correctly their CVD risk category (50%, 93%, p=0.03) and their absolute 10-year CVD risk (0%, 93%, p<0.001), whereas the overall decisional conflict score decreased (p=0.007). CONCLUSION: The decision aid was acceptable to patients and improved their knowledge, risk perception, and decisional conflict. Therefore, the feasibility and impact of using the decision aid in community pharmacies and medical clinics should be assessed.     

Multiple-level thoracolumbar burst fractures in teenaged patients

The purpose of this study was to examine the characteristics of multiple-level burst fractures in teenaged patients. Five teenaged patients were identified with this injury pattern. The mean age at injury was 17.6 years. All five patients underwent a posterior fusion and an attempted decompression through ligamentotaxis. One of the five went on to have an anterior decompression. Four of the five patients had spinal instrumentation. Neurologic deficit was present in four patients. The proximal fracture was most often responsible for the neurologic deficit when present. The average length of follow-up was 4.5 years. There was no significant neurologic recovery after hospital discharge. Three of the five patients had minimal or no back pain at latest follow-up. The authors conclude that multiple burst fractures should be treated individually based on their clinical and radiographic characteristics.     

Why do young women diet? The roles of body fat, body perception, and body ideal

BACKGROUND: To assess the relative roles of body fat, body perception, and body ideals as motivations for dieting in college women. METHOD: We compared 45 college women who reported having dieted with 32 who had not, using a novel computerized test of body image called the somatomorphic matrix. RESULTS: As expected, the difference in body fat between subjects' "perceived body" and "ideal body" was significantly greater in dieters than in nondieters (p < .001). Remarkably, however, this difference remained highly significant even after adjusting for the subjects' actual measured body fat (p = .002). Further analysis revealed that this difference persisted, not because dieters had unrealistic ideals of thinness, but because they had distorted perceptions of their fatness. CONCLUSION: Distorted body image perception, a potentially treatable condition, may play an unexpectedly large role in motivating young women to diet.     

The effects of a mild stressor on spontaneous alternation in mice

Adult mice of the C57BL/6J strain were subjected to an acute mild stress at different periods before the choice trial of a spontaneous alternation test. The stressful event was either inescapable (forced exploration in a brightly lit open field) or escapable (temporary entries into an adjacent dark chamber). While unstressed control mice alternated above chance in each condition, mice subjected to inescapable stress did not alternate when forced exposure to the open field occurred during the entire retention interval. The same effect was seen when forced exposure to the open field occurred after a post-forced trial delay period. However, no change in the alternation rate was observed when the inescapable stress occurred before the forced trial, or if the delay intervened between the stressful event and the choice trial. The escapable stressful event had no effect on spontaneous alternation. These results indicate the role of cognitive mediation in the behavioral effects of inescapable stress, causing either a retrieval deficit or neophobia.