Assessment of Risk for Interference by Circulating Biotin in Samples Received for High Sensitivity Troponin-T, Thyrotropin, and for Prostate Specific Antigen Testing by Immunoassays.

BACKGROUND: Biotin interference in streptavidin-based immunoassays is known and may lead to erroneous results and thus to diagnostic error. The recent increase in reports of biotin interference in immunoassay-based testing has been attributed to increased intake of biotin supplements by the public and to the high dose biotin therapy in patients with neurological and inherited disorders. Circulating biotin levels greater than 20 ng/mL are reported to exhibit interference in high sensitivity troponin T (hs-TnT), thyroid stimulating hormone (TSH), and in prostate specific antigen (PSA) among other assays when using our Cobas® 6000 immunoassay analyzer (Roche Diagnostics, IN, USA). This study aims to examine the risk for biotin interference among our patient population. METHODS: Serum and plasma leftover samples from 183 different patients were collected following completion of hs-TnT (53 samples), TSH (45 samples), and PSA (85 samples) testing. Aliquots were stored frozen at -20°C until analysis. Biotin concentrations in these samples were measured using an ELISA (ALPCO, Salem, NH, USA) according to the manufacture's protocol. Samples with biotin levels of 20 ng/mL or greater were considered as high-risk samples (HRS) for biotin interference. RESULTS: The overall concentrations of biotin in our patients' samples ranged from 0.02 ng/mL to 11.38 ng/mL (median 0.42 ng/mL). The median and (range) biotin concentrations in hs-TnT, TSH, and PSA samples were 0.27 ng/mL (0.02 - 6.86 ng/mL), 0.39 ng/mL (0.08 - 11.38 ng/mL), and 0.47 ng/mL (0.09 - 7.73 ng/mL), respectively. Although there was no significant difference between biotin levels in samples for TSH or PSA measurement (p = 0.85), biotin in samples for PSA and for hs-TnT and in samples for TSH and hs-TnT were significantly different (p = 0.049 and 0.089), respectively. None of the samples had biotin levels greater than or equal to 20 ng/mL. CONCLUSIONS: Using representative samples with requests for hs-TnT, TSH, and PSA testing, where reliable performance for the selected assays at their lowest measurement range is required for clinical intervention, among our study population the risk was considered minimal as their circulating biotin levels were less than 20 ng/mL. However, educating clinicians and laboratory users regarding the potential of biotin interference is always recommended.

Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy.

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

Wooden traps can replace coral stone traps harvesting the wild lobster seed in mitigating the negative impact on the marine environment.

Lobster seacage aquaculture has a significant social-economic contribution to many coastal communities throughout the central provinces of Vietnam. One of the issues of lobster aquaculture is that the industry entirely relies on the wild juvenile lobster (lobster seed) captured using traps made of coral stones, which affects the coastal ecology and environment. The present study was carried out to compare the catch efficiency of traps made of round timber poles (wooden trap) with conventional dead corals (coral stones) during the juvenile lobster fishing season in 2019 in the coastal area of Nha Trang city, Vietnam. Results showed that experimental wooden traps maintained the conventional catch rate level, with a significant proportion of Panulirus ornatus caught at larger carapace length than those caught by the coral stone traps. Our findings show the biological and environmental benefits of using alternative fishing methods would eliminate collecting coral stones to make lobster seed traps and contribute to coastal protection while maintaining the fishing operation and seed supplies for the lobster seacage farmers.

Growth Performance, Survival, Blood Chemistry, and Immune Gene Expression of Channel Catfish (Ictalurus punctatus) Fed Probiotic-Supplemented Diets.

The channel catfish (Ictalurus punctatus) farming industry is the largest and one of the oldest aquaculture industries in the United States. Despite being an established industry, production issues stemming from disease outbreaks remain problematic for producers. Supplementing fish diets with probiotics to enhance the immune system and growth potential is one approach to mitigating disease. Although considerable laboratory data demonstrate efficacy, these results do not always translate to natural modes of disease transmission. Hence, the present work was conducted in the laboratory but incorporated flow-through water from large catfish pond production systems, allowing for natural exposure to pathogens. Two feeding trials were conducted in an 18-tank aquaria system housing two different sizes, 34.8 ± 12.5 g and 0.36 ± 0.03 g, of channel catfish. Channel catfish in the first trial were fed three experimental diets over six weeks. Commercial diets were top-coated with two selected spore-forming Bacillus spp. probiotics, Bacillus velezensis AP193 (1 × 106 CFU g−1) and BiOWiSH (3.6 × 104 CFU g−1), or a basal diet that contained no dietary additive. In the second eight-week trial, diets were top-coated with BiOWiSH at three concentrations (1.8, 3.6, and 7.3 × 104 CFU g−1), along with one basal diet (no probiotic). At the completion of these studies, growth performance, survival, hematocrit, blood chemistry, and immune expression of interleukin 1ß (il1ß), tumor necrosis factor-alpha (tnf-α), interleukin-8 (il8), transforming-growth factor ß1 (tgf-ß1), and toll-like receptor 9 (tlr9) were evaluated using qPCR. Trial results revealed no differences (p > 0.05) among treatments concerning growth, survival, or hematological parameters. For immune gene expression, interesting trends were discerned, with substantial downregulation observed in B. velezensis AP193-fed fish for il1ß, tnf-α, and tlr9 expression within splenic tissue, compared to that of the basal and BiOWiSH diets (p < 0.05). However, the results were not statistically significant for anterior kidney tissue in the first trial. In the second trial, varied levels of probiotic inclusion revealed no significant impact of BiOWiSH's products on the expression of il1ß, tnf-α, il8, and tgf-ß1 in both spleen and kidney tissue at any rate of probiotic inclusion (p > 0.05). Based on these findings, more research on utilizing probiotics in flow-through systems with natural infection conditions is crucial to ensure consistency from a controlled laboratory scale to real-world practices.

Extended Center for Vein Restoration study assessing comparative outcomes for the treatment of chronic venous insufficiency in Medicare- and non-Medicare-eligible patients.

BACKGROUND: We previously reported that chronic venous insufficiency treatment of Medicare-eligible patients achieved outcomes similar to those for non-Medicare-eligible patients. The goal of the present investigation was to assess the long-term treatment outcomes and the effect of race in a larger patient cohort. METHODS: From January 2015 to December 2019, we retrospectively reviewed the data from 131,268 patients who had presented for a lower extremity venous evaluation. We divided the patients into two groups by age: group A was aged ≥65 years and group B, <65 years. The treatments analyzed in each group were axial thermal ablation (TA), axial Varithena ablation (VA), TA plus phlebectomy, VA plus phlebectomy, and TA or VA with phlebectomy and ultrasound-guided foam sclerotherapy (UGFS). The treatment outcomes were assessed using the revised venous clinical severity score (rVCSS) and Chronic Venous Insufficiency Quality of Life 20-item questionnaire (CIVIQ-20) scores at the initial consultation and 1, 6, and 12 months after completion of the treatment plan. RESULTS: Of the 131,268 patients, 40,020 were in group A and 91,248 in group B, with an average age of 74.4 ± 6.6 and 49.9 ± 10.6 years, respectively. Of the 40,020 patients in group A, 15,697 (n = 25,234 limbs) had undergone TA and 1910 (n = 3222 limbs) had undergone VA. Of the 91,248 patients in group B, 35,220 (n = 53,717 limbs) had undergone TA and 2178 (n = 3672 limbs) had undergone VA. For the TA subgroups, all rVCSSs had significantly improved after treatment at each evaluation point (P ≤ .001). For the TA and VA plus phlebectomy with or without UGFS subgroup, the older patients (group A) required 6 months to develop the same degree of improvement as the younger patients (group B) at 1 month. When subdivided by race, all initial and 6-month rVCSSs and CIVIQ-20 scores within a race had improved and were better in group B, except for Asian and Hispanic patients (P ≤ .001). After TA or VA plus phlebectomy, with or without UGFS, the CIVIQ-20 outcomes had improved by 1 month in both groups, although the rVCSS lagged by 6 months in group A. No differences in the rVCSSs or CIVIQ-20 scores were observed between the groups treated with TA or VA. CONCLUSIONS: Medicare-eligible beneficiaries demonstrated improved outcomes similar to those of non-Medicare-eligible beneficiaries after ablation. When TA or VA plus phlebectomy with or without UGFS were examined, group A required 6 months to demonstrate rVCSSs equivalent to those of group B at 1 month. The CIVIQ-20 scores had improved by 1 month in both groups, regardless of the treatment modality. The difference in rVCSSs appeared to be driven by African American and white patients because Hispanic and Asian patients demonstrated equivalent results regardless of age. Patients treated with TA or VA demonstrated equivalent results.

Racial disparities in the outcomes of superficial vein treatments for chronic venous insufficiency.

BACKGROUND: Chronic venous disease (CVD) affects >20 million people in the United States. Despite this huge prevalence, there are few data on whether the effectiveness of current CVD therapies for symptomatic superficial vein reflux is affected by race. The goal of this investigation was to evaluate CVD treatment outcomes in various races in the United States. METHODS: From January 2015 to December 2017, we retrospectively reviewed and prospectively collected data from 66,621 patients who presented for CVD evaluation. We divided patients into five racial groups: African American, Asian, Hispanic, other (race not recorded), and white. Presenting signs and symptoms, treatment modalities, number of procedures per patient, and preintervention and postintervention revised Venous Clinical Severity Scores (rVCSSs) were evaluated. All racial groups were stratified by Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) class for subgroup analysis. RESULTS: The average age of the entire cohort was 56.8 ± 14.7 years, with 51,393 women (77%) and 15,228 men (23%). Prevalence by race was 17% African American, 3% Asian, 18% Hispanic, 8% others, and 55% white. There was a higher incidence of C0 disease in whites (44%) and African Americans (31%); C1 and C2 disease in whites (46% and 55%) and Hispanics (28% and 25%); and C3, C4, C5, and C6 disease in whites (60%, 57%, 58%, and 61%) and African Americans (19%, 17%, 19%, and 21%). Pain as an initial presenting symptom was more common in African Americans, Asians, and Hispanics (29%, 29%, and 31%). Swelling was highest in African Americans (18%) and cramping in Hispanics (14%). Skin changes and venous ulcers were most common in African Americans (16% and 21%) and whites (63% and 61%). With regard to the average number of procedures performed, Hispanics (1.98 ± 1.24) and others (2.07 ± 1.25) required fewer stand-alone ablations compared with whites (2.31 ± 1.56), Asians (2.36 ± 1.58), and African Americans (2.27 ± 1.56; P ≤ .0001. With the addition of phlebectomies to ablations, Hispanics (3.78 ± 2.08) continued to require fewer procedures, and Asians required the greatest number of phlebectomies compared with all groups (P ≤ .001). When ultrasound-guided foam sclerotherapy was added to ablation and phlebectomy, African Americans required more procedures compared with all races (4.38 ± 2.59; P ≤ .01). For stand-alone ablations, Hispanics (2.18 ± 2.34) and Asians (1.91 ± 2.35) demonstrated lower postprocedure rVCSSs compared with African Americans (2.79 ± 2.88) and whites (2.8 ± 2.85; P ≤ .0001). For ablations with phlebectomies, all races demonstrated similar results except for Hispanics (2.19 ± 2.14), who did better than whites (2.85 ± 2.75; P ≤ .002). For ablations with phlebectomies and ultrasound-guided foam sclerotherapy, all races had similar results (P ≤ .0001). CONCLUSIONS: In the United States, CVD is primarily observed in white women. There are differences in the incidence and prevalence of disease severity and symptom presentation based on race. The incidence of CVD decreases with age in all racial groups except whites. Hispanics required the fewest procedures and African Americans required the most for optimal results. Postintervention rVCSSs equalized in all races when ablations were combined with phlebectomies and ultrasound-guided foam sclerotherapy.

The noradrenergic system is necessary for survival of vulnerable midbrain dopaminergic neurons: implications for development and Parkinson's disease.

The cause of midbrain dopaminergic (mDA) neuron loss in sporadic Parkinson's disease (PD) is multifactorial, involving cell autonomous factors, cell-cell interactions, and the effects of environmental toxins. Early loss of neurons in the locus coeruleus (LC), the main source of ascending noradrenergic (NA) projections, is an important feature of PD and other neurodegenerative disorders. We hypothesized that NA afferents provide trophic support for vulnerable mDA neurons. We demonstrate that depriving mDA neurons of NA input increases postnatal apoptosis and decreases cell survival in young adult rodents, with relative sparing of calbindin-positive subpopulations known to be resistant to degeneration in PD. As a mechanism, we propose that the neurotrophin brain-derived neurotrophic factor (BDNF) modulates anterograde survival effects of LC inputs to mDA neurons. We demonstrate that the LC is rich in BDNF mRNA in postnatal and young adult brains. Early postnatal NA denervation reduces both BDNF protein and activation of TrkB receptors in the ventral midbrain. Furthermore, overexpression of BDNF in NA afferents in transgenic mice increases mDA neuronal survival. Finally, increasing NA activity in primary cultures of mDA neurons improves survival, an effect that is additive or synergistic in the presence of different concentrations of BDNF. Taken together, our results point to a novel mechanism whereby LC afferents couple BDNF effects and NA activity to provide anterograde trophic support for vulnerable mDA neurons. Early loss of NA activity and anterograde neurotrophin support may contribute to degeneration of vulnerable neurons in PD and other neurodegenerative disorders.

The Center for Vein Restoration Study on presenting symptoms, treatment modalities, and outcomes in Medicare-eligible patients with chronic venous disorders.

BACKGROUND: Chronic venous disorders (CVDs) have been estimated to affect up to 20 million Americans. Despite this huge prevalence, the signs, symptoms, and treatment outcomes in patients 65 years of age and older are not well defined. Our goal was to determine the presentation and treatment outcomes in elderly patients compared with a cohort of patients younger than 65 years. METHODS: From January 2015 to December 2016, we retrospectively reviewed prospectively collected data from 38,750 patients with CVD from the Center for Vein Restoration's electronic medical record (NextGen Healthcare Information Systems, Irvine, Calif). We divided patients into two groups; group A patients were younger than 65 years, and group B patients were 65 years of age or older. Medical and surgical history, presenting symptoms, treatment modalities, and revised Venous Clinical Severity Score before and after intervention were evaluated. A multivariate logistic regression analysis was performed to determine the predictive value of presenting and associated symptoms. Groups A and B were subdivided by Clinical, Etiology, Anatomy, and Pathophysiology class for subgroup analysis. Data were analyzed with GraphPad Prism (GraphPad Software Inc, La Jolla, Calif) or SAS version 9.4 statistical software package (SAS Institute, Cary, NC). RESULTS: There were 27,536 patients in group A and 11,214 in group B. Women constituted 78% of all patients. Group B demonstrated a higher incidence of chronic diseases compared with group A (P ≤ .003). As initial presenting symptoms, pain, heaviness, fatigue, and aching were more common in group A than in group B (61% vs 55%, 30% vs 27%, 27% vs 24%, and 17% vs 12%, respectively; P ≤ .001). Swelling, skin discoloration, and venous ulceration were more common in group B than in group A (29% vs 23%, 12% vs 6%, and 5% vs 2%; P ≤ .001). Ablations were more commonly performed in group B patients with C4 to C6 disease (P ≤ .004). The revised Venous Clinical Severity Scores before and 1 month after intervention were similar between groups. Treatment improvement was statistically significant in both groups (P ≤ .001). Multivariate logistic regression analysis indicated that varices, bleeding, swelling, skin changes, venous ulceration, aching, heaviness, pain, fatigue, cramping, and restless legs were associated with the presence of CVD (P ≤ .001). CONCLUSIONS: Medicare beneficiaries presented with more chronic diseases and more severe disease. Initial and associated symptoms were highly associated with the presence of CVD. Despite requiring more interventions than patients younger than 65 years, Medicare beneficiaries demonstrated the same degree of clinical improvement. Medicare should not develop coverage policy decisions that prevent access to therapies that alleviate CVD-induced symptoms.

Pentobarbital enhances gamma-aminobutyric acid-mediated excitation without altering synaptic plasticity in rat hippocampus.

BACKGROUND: Synaptic plasticity is thought to provide a molecular mechanism for learning and memory. N-methyl-d-aspartate receptor-mediated plasticity requires that N-methyl-d-aspartate receptor activation coincides with postsynaptic depolarizing potentials (DPSP(A)'s). Pentobarbital, in high concentrations, enhances DPSP(A)'s, but high concentrations suppress synaptic plasticity, probably by impairing glutamatergic transmission. Here we tested the hypothesis that low concentrations of pentobarbital can enhance DPSP(A)'s and modify the induction of synaptic plasticity. METHODS: Studies were performed in vitro on rat hippocampal slices. With glutamate transmission blocked, intracellular recording from CA1 neurons was used to investigate the influence of 5 microM pentobarbital on DPSP(A)'s and neuron excitability evoked by high frequency (100 Hz) stimulation. With glutamate transmission intact, extracellular recording was used to examine the effect of 5 microM pentobarbital on the induction of long-term depression and long-term potentiation of synaptic transmission by conditioning stimuli applied to the Schaffer collateral pathway. RESULTS: High frequency stimulation generated typical DPSP(A)'s that were mediated by gamma-aminobutyric acid(A) receptors and dependent upon HCO3-. Pentobarbital (5 microM) increased the amplitude, but not the width, at half-maximal amplitude of DPSPA's (P < 0.01). Pentobarbital increased the probability of action potential generation during the DPSP(A)'s. Pentobarbital did not alter the induction of long-term depression or long-term potentiation. CONCLUSIONS: Despite increasing the amplitude of DPSP(A)'s, 5 microM pentobarbital did not alter the induction of synaptic plasticity by a range of conventional conditioning stimuli. These results do not support the hypothesis that excitatory effects of pentobarbital may alter synaptic plasticity.

Impaired TrkB Signaling Underlies Reduced BDNF-Mediated Trophic Support of Striatal Neurons in the R6/2 Mouse Model of Huntington's Disease.

The principal projection neurons of the striatum are critically dependent on an afferent supply of brain derived neurotrophic factor (BDNF) for neurotrophic support. These neurons express TrkB, the cognate receptor for BDNF, which activates signaling pathways associated with neuronal survival and phenotypic maintenance. Impairment of the BDNF-TrkB pathway is suspected to underlie the early dysfunction and prominent degeneration of striatal neurons in Huntington disease (HD). Some studies in HD models indicate that BDNF supply is reduced, while others suggest that TrkB signaling is impaired earlier in disease progression. It remains important to determine whether a primary defect in TrkB signaling underlies reduced neurotrophic support and the early vulnerability of striatal neurons in HD. Using the transgenic R6/2 mouse model of HD we found that prior to striatal degeneration there are early deficits in striatal protein levels of activated phospho-TrkB and the downstream-regulated protein DARPP-32. In contrast, total-TrkB and BDNF protein levels remained normal. Primary neurons cultured from R6/2 striatum exhibited reduced survival in response to exogenous BDNF applications. Moreover, BDNF activation of phospho-TrkB and downstream signal transduction was attenuated in R6/2 striatal cultures. These results suggest that neurotrophic support of striatal neurons is attenuated early in disease progression due to defects in TrkB signal transduction in the R6/2 model of HD.

Chronic administration of citalopram in olfactory bulbectomy rats restores brain 5-HT synthesis rates: an autoradiographic study.

RATIONALE: The olfactory bulbectomized (OBX) rat model is widely accepted as an animal model of depression with a proposed serotonergic imbalance in the brain. OBJECTIVE: To study the effects of chronic administration of citalopram on serotonin (5-HT) synthesis rates. METHOD: Serotonin synthesis was evaluated using the alpha-[(14)C]methyl-L: -tryptophan (alpha-MTrp) autoradiographic method in OBX rats. Citalopram was administered continuously (10 mg kg(-1) day(-1)) for 14 days using a subcutaneous osmotic minipump. RESULTS: The OBX rats treated with citalopram (OBX-CTP) have the same 5-HT synthesis rates as the sham-operated rats treated with citalopram (Sham-CTP). The OBX-CTP rats, relative to the OBX rats treated with saline (OBX-SAL), showed a reduction in the majority of the terminal brain structures, suggesting a normalization of 5-HT synthesis in the OBX-CTP rats following treatment. The OBX-SAL rats have significantly greater synthesis than the Sham-SAL rats in a majority of the terminal structures, but lower rates in the dorsal raphe. A few structures in the OBX-CTP group have lower synthesis than in the Sham-SAL group (e.g., dorsal raphe, hippocampus, amygdala). The data suggest that receptors in some brain areas are likely still responsive to the elevated levels of the extracellular 5-HT produced by citalopram. CONCLUSION: There is no significant global or individual structure difference in the synthesis between the Sham-CTP and OBX-CTP groups. The similarity in the synthesis between the OBX-CTP, Sham-CTP and Sham-SAL groups is likely a result of changes in the sensitivity of the receptors through which 5-HT synthesis is controlled. Because of some of the differences in the synthesis between the Sham-CTP and Sham-SAL groups, the data suggest that receptors throughout the brain are not fully desensitized.

Selective 5-HT1B receptor agonist reduces serotonin synthesis following acute, and not chronic, drug administration: results of an autoradiographic study.

The effects of acute and chronic administration of the serotonin (5-HT)1B agonist CP-93,129, on 5-HT synthesis rates were evaluated using the alpha-[14C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method. In the acute treatment study, CP-93,129 (7 mg/kg) was injected intraperitoneally 30 min before the alpha-MTrp injection (30 microCi over 2 min). A single dose of CP-93,129 caused a significant increase in the synthesis in the median raphe nucleus (MR) without a significant influence on the dorsal raphe nucleus (DR). There was a reduction in 5-HT synthesis in almost all of the projection areas. In the chronic treatment study, CP-93,129 was administered continuously (7 mg/kg/day) for 14 days using an osmotic minipump implanted subcutaneously. The chronic treatment with CP-93,129 did not produce a significant change in 5-HT synthesis in the raphe nuclei nor in the nerve terminal structures, except for the medial frontal bundle and the visual and sensory-motor cortices. The unaltered 5-HT synthesis rates in the chronic treatment study probably reflect a normalization of the synthesis as a result of the desensitization of 5-HT1B autoreceptors and/or heteroreceptors.

Prospective comparison of valve regurgitation quantitation by cardiac magnetic resonance imaging and transthoracic echocardiography.

BACKGROUND: Both transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging allow quantification of chronic aortic regurgitation (AR) and mitral regurgitation (MR). We hypothesized that CMR measurement of regurgitant volume (RVol) is more reproducible than TTE. METHODS AND RESULTS: TTE and CMR performed on the same day in 57 prospectively enrolled adults (31 with AR, 26 with MR) were measured by 2 independent physicians. TTE RVol(AR) was calculated as Doppler left ventricular outflow minus inflow stroke volume. RVol(MR) was calculated by both the proximal isovelocity surface area method and Doppler volume flow at 2 sites. CMR RVol(AR) was calculated by phase-contrast velocity mapping at the aortic sinuses and RVol(MR) as total left ventricular minus forward stroke volume. Intraobserver and interobserver variabilities were similar. For AR, the Bland-Altman mean interobserver difference in RVol was -0.7 mL (95% confidence interval [CI], -5 to 4) for CMR and -9 mL (95% CI, -53 to -36) for TTE. The Pearson correlation was higher (P=0.001) between CMR (0.99) than TTE readers (0.89). For MR, the Bland-Altman mean difference in RVol between observers was -4 mL (95% CI, -21 to 13) for CMR compared with 0.7 mL (95% CI, -30 to 32) for the proximal isovelocity surface area and -10 mL (95% CI, -76 to 56) for TTE volume flow at 2 sites. Correlation was similar for CMR (0.94) versus TTE readers (0.90 for the proximal isovelocity surface area). CONCLUSIONS: Compared with TTE, CMR has lower intraobserver and interobserver variabilities for RVol(AR), suggesting CMR may be superior for serial measurements. Although RVol(MR) is similar by TTE and CMR, variability in measured RVol by both approaches suggests that caution is needed in clinical practice.

Acute effects of combining citalopram and pindolol on regional brain serotonin synthesis in sham operated and olfactory bulbectomized rats.

The olfactory bulbectomized (OBX) rat is considered to be a good model of the pathology of human depression and also of the functional actions of antidepressant drug therapy. It has been proposed that antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) can be accelerated by blocking 5-HT(1A/B) autoreceptors with pindolol. The underlying mechanism is thought to involve acute unrestricting of 5-HT release and, consequently, relatively enhanced 5-HT turnover throughout the forebrain serotonergic networks. The effect of this combination on 5-HT turnover in sham operated or OBX rats can be assessed at the level of 5-HT synthesis, a very important presynaptic step in serotonergic neurotransmission, using the alpha-[(14)C]methyl-l-tryptophan autoradiography method. In sham rats, acute citalopram (20mg/kg) treatment increased synthesis at almost all serotonergic terminal regions but slightly decreased synthesis at serotonergic cell body regions (i.e. dorsal and median (not significant) raphe; approximately 16%). Combining pindolol (10mg/kg) with citalopram further increased synthesis at many regions in sham rats (relative to treatment with only citalopram). In OBX rats, citalopram decreased synthesis at a few terminal regions and greatly decreased synthesis at the dorsal and median raphe ( approximately 45%; relative to OBX rats treated with saline). Combining pindolol with citalopram greatly increased synthesis at almost all regions in OBX rats (relative to treatment with only citalopram). These results suggest that acute citalopram effects result in elevated terminal 5-HT synthesis, but these effects are restrained by 5-HT(1A/B) autoreceptor feedback to different degrees in sham and OBX rats. Moreover, 5-HT(1A/B) autoreceptor feedback is stronger in OBX rats and may underlie the delay of SSRI effects in OBX rats and, correspondingly, in human depression. Pindolol acceleration and augmentation of SSRI antidepressant therapy for human depression may be mediated by attenuation of 5-HT(1A/B) autoreceptor feedback, permitting unhindered SSRI effects on serotonergic terminals.

Regional brain serotonin synthesis is increased in the olfactory bulbectomy rat model of depression: an autoradiographic study.

Serotonin synthesis rates were evaluated using alpha-[14C]methyl-l-tryptophan (alpha-MTrp) autoradiographic methods in olfactory bulbectomized (OBX) rats. They were significantly (p < 0.05) increased in the frontal (50%) and parietal (40%) cortices, superior olive (over 30%), and the substantia nigra (30%) in the OBX rats as compared to the sham operated animals. There were also increases in 5-hydroxytryptamine (5-HT) synthesis in some limbic areas: the cingulate (32%), the medial forebrain bundle (58%), the hippocampus (13-25%) and the thalamus (22-40%). The largest increase in 5-HT synthesis after OBX was observed in the sensory-motor cortex (67%). 5-HT synthesis rates were significantly decreased in the dorsal and medial raphe nuclei, but there was no significant change the ventral tegmental area and the locus coeruleus following OBX. These results indicate that olfactory bulbectomy causes an imbalance in 5-HT synthesis in some projection areas by disproportionally increasing 5-HT synthesis rates in specific brain regions and making more 5-HT available for neurotransmission. This imbalance in 5-HT synthesis and the subsequent elevation of tissue 5-HT may be responsible for the creation of non-physiological circuitry which may, in part, be reflected in the symptoms resembling human depression.