Involvement of superior colliculus in complex figure detection of mice.

Object detection is an essential function of the visual system. Although the visual cortex plays an important role in object detection, the superior colliculus can support detection when the visual cortex is ablated or silenced. Moreover, it has been shown that superficial layers of mouse SC (sSC) encode visual features of complex objects, and that this code is not inherited from the primary visual cortex. This suggests that mouse sSC may provide a significant contribution to complex object vision. Here, we use optogenetics to show that mouse sSC is involved in figure detection based on differences in figure contrast, orientation, and phase. Additionally, our neural recordings show that in mouse sSC, image elements that belong to a figure elicit stronger activity than those same elements when they are part of the background. The discriminability of this neural code is higher for correct trials than for incorrect trials. Our results provide new insight into the behavioral relevance of the visual processing that takes place in sSC.

Erythroid-specific inactivation of Slc12a6/Kcc3 by EpoR promoter-driven Cre expression reduces K-Cl cotransport activity in mouse erythrocytes.

Investigation of erythrocytes from spontaneous or engineered germ-line mutant mice has been instrumental in characterizing the physiological functions of components of the red cell cytoskeleton and membrane. However, the red blood cell expresses some proteins whose germline loss-of-function is embryonic-lethal, perinatal-lethal, or confers reduced post-weaning viability. Promoter regions of erythroid-specific genes have been used to engineer erythroid-specific expression of Cre recombinase. Through breeding with mice carrying appropriately spaced insertions of loxP sequences, generation of erythroid-specific knockouts has been carried out for signaling enzymes, transcription factors, peptide hormones, and single transmembrane span signaling receptors. We report here the use of Cre recombinase expression driven by the erythropoietin receptor (EpoR) promoter to generate EpoR-Cre;Kcc3f/f mice, designed to express erythroid-specific knockout of the KCC3 K-Cl cotransporter encoded by Kcc3/Slc12A6. We confirm KCC3 as the predominant K-Cl cotransporter of adult mouse red cells in mice with better viability than previously exhibited by Kcc3-/- germline knockouts. We demonstrate roughly proportionate preservation of K-Cl stimulation by hypotonicity, staurosporine, and urea in the context of reduced, but not abrogated, K-Cl function in EpoR-Cre;Kcc3f/f mice. We also report functional evidence suggesting incomplete recombinase-mediated excision of the Kcc3 gene in adult erythroid tissues.

Variation of picture angles and its effect on the Concealed Information Test.

BACKGROUND: The reaction time-based Concealed Information Test (RT-CIT) is a memory paradigm used to detect crime-related knowledge. However, this would also imply that the RT-CIT would be vulnerable to factors that are known to compromise object recognition or memory integrity. From this perspective, one key issue is whether "guilty" memory can be detected if the crime-related images are photographed at different angles from what the perpetrator saw, which is almost always the case in the field. To investigate this, here we manipulated the deviation angles, from 0° to 330° in 11 steps, between the study and test phases to assess how the RT-CIT holds up against angular rotations. RESULTS: We observed a robust RT-CIT effect at all deviation angles for both deep-encoders (Experiment 1) and shallow-encoders (Experiment 2). The RT-CIT was effective within the first 250 or so trials for both encoding groups, with smaller probe-irrelevant differences beyond that. CONCLUSIONS: With appropriate encoding and memory strength, RT-CIT images do not necessarily have to match the exact angle of the perpetrator's perspective at the time of the crime. Unnatural angles such as 90° and 270° or unconventional rotational axes may require caution. Trial number under 250 trials show maximal Probe-Irrelevant difference, but more trials may add power to improve detection accuracy.

Genetic disruption of KCC cotransporters in a mouse model of thalassemia intermedia.

ß-thalassemia (ß-Thal) is caused by defective ß-globin production leading to globin chain imbalance, aggregation of free alpha chain in developing erythroblasts, reticulocytes, and mature circulating red blood cells. The hypochromic thalassemic red cells exhibit increased cell dehydration in association with elevated K+ leak and increased K-Cl cotransport activity, each of which has been linked to globin chain imbalance and related oxidative stress. We therefore tested the effect of genetic inactivation of K-Cl cotransporters KCC1 and KCC3 in a mouse model of ß-thalassemia intermedia. In the absence of these transporters, the anemia of ß-Thal mice was ameliorated, in association with increased MCV and reductions in CHCM and hyperdense cells, as well as in spleen size. The resting K+ content of ß-Thal red cells was greatly increased, and Thal-associated splenomegaly slightly decreased. Lack of KCC1 and KCC3 activity in Thal red cells reduced red cell density and improved ß-Thal-associated osmotic fragility. We conclude that genetic inactivation of K-Cl cotransport can reverse red cell dehydration and partially attenuate the hematologic phenotype in a mouse model of ß-thalassemia.

Combined genetic disruption of K-Cl cotransporters and Gardos channel KCNN4 rescues erythrocyte dehydration in the SAD mouse model of sickle cell disease.

Excessive red cell dehydration contributes to the pathophysiology of sickle cell disease (SCD). The densest fraction of sickle red cells (with the highest corpuscular hemoglobin concentration) undergoes the most rapid polymerization of deoxy-hemoglobin S, leading to accelerated cell sickling and increased susceptibility to endothelial activation, red cell adhesion, and vaso-occlusion. Increasing red cell volume in order to decrease red cell density can thus serve as an adjunct therapeutic goal in SCD. Regulation of circulating mouse red cell volume and density is mediated largely by the Gardos channel, KCNN4, and the K-Cl cotransporters, KCC3 and KCC1. Whereas inhibition of the Gardos channel in subjects with sickle cell disease increased red cell volume, decreased red cell density, and improved other hematological indices in subjects with SCD, specific KCC inhibitors have not been available for testing. We therefore investigated the effect of genetic inactivation of KCC3 and KCC1 in the SAD mouse model of sickle red cell dehydration, finding decreased red cell density and improved hematological indices. We describe here generation of mice genetically deficient in the three major red cell volume regulatory gene products, KCNN4, KCC3, and KCC1 in C57BL6 non-sickle and SAD sickle backgrounds. We show that combined loss-of-function of all three gene products in SAD mice leads to incrementally increased MCV, decreased CHCM and % hyperchromic cells, decreased red cell density (phthalate method), increased resistance to hypo-osmotic lysis, and increased cell K content. The data show that combined genetic deletion of the Gardos channel and K-Cl cotransporters in a mouse SCD model decreases red cell density and improves several hematological parameters, supporting the strategy of combined pharmacological inhibition of these ion transport pathways in the adjunct treatment of human SCD.

Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through eIF2α phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic.

Amino acid sequence differences in the variable region of immunoglobulin (Ig) cause wide variations in secretion outputs. To address how a primary sequence difference comes to modulate Ig secretion, we investigated the biosynthetic process of 2 human IgG2κ monoclonal antibodies (mAbs) that differ only by one amino acid in the light chain complementarity-determining region 1 while showing ∼20-fold variance in secretion titer. Although poorly secreted, the lower-secreting mAb of the 2 was by no means defective in terms of its folding stability, antigen binding, and in vitro biologic activity. However, upon overexpression in HEK293 cells, the low-secreting mAb revealed a high propensity to aggregate into enlarged globular structures called Russell bodies (RBs) in the endoplasmic reticulum. While Golgi morphology was affected by the formation of RBs, secretory pathway membrane traffic remained operational in those cells. Importantly, cellular protein synthesis was severely suppressed in RB-positive cells through the phosphorylation of eIF2α. PERK-dependent signaling was implicated in this event, given the upregulation and nuclear accumulation of downstream effectors such as ATF4 and CHOP. These findings illustrated that the underlining process of poor Ig secretion in RB-positive cells was due to downregulation of Ig synthesis instead of a disruption or blockade of secretory pathway trafficking. Therefore, RB formation signifies an end of active Ig production at the protein translation level. Consequently, depending on how soon and how severely an antibody-expressing cell develops the RB phenotype, the productive window of Ig secretion can vary widely among the cells expressing different mAbs.

Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson's disease.

BACKGROUND: IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD). METHODS: In this open-label study, patients underwent 6weeks of conversion to IPX066 from their prior controlled-release (CR)±immediate-release (IR) CD-LD therapy and 6months of maintenance (with an additional 6months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance. RESULTS: Among 43 patients initiated on IPX066, 33 completed conversion. The mean LD conversion ratio was 1.8 among 30 patients previously on CR plus IR (and 1.5 among 3 previously taking CR alone). The mean IPX066 dosing frequency was 3.5times/day compared with 2.6times/day for CR plus 4.6times/day for IR previously (and 4.7times/day for CR alone). By patient and clinician global improvement ratings after 6-month maintenance, ≥43.8% of patients were much or very much improved from their previous treatment, and ≥68.8% were at least minimally improved. Adverse events were consistent with those reported in prior IPX066 studies. CONCLUSIONS: These results suggest that advanced PD patients using CR CD-LD±IR can be safely converted to IPX066, with high likelihood of achieving a stable regimen, less frequent LD dosing, and improved overall clinical benefit. TRIAL REGISTRATION: Clinicaltrials.govNCT01411137.

Clinical Pharmacokinetics of IPX066: Evaluation of Dose Proportionality and Effect of Food in Healthy Volunteers.

OBJECTIVES: IPX066 is an oral, extended-release capsule formulation of carbidopa-levodopa (CD-LD) available in 4 strengths. The goals of this investigation were to assess the dose proportionality of IPX066 and to study the effects of a high-fat, high-calorie meal and of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 in healthy volunteers. METHODS: Three open-label studies were conducted. In the first study, subjects received 1 capsule of each IPX066 strength (23.75-95, 36.25-145, 48.75-195, and 61.25-245 mg of CD-LD). In the second study, subjects received 1 and 2 capsules of IPX066 245-mg LD under fasting conditions. In the third study, subjects received 2 capsules of IPX066 245-mg LD under 3 conditions: fasting; following a high-fat, high-calorie breakfast; and with the capsule contents sprinkled on applesauce under fasting conditions. RESULTS: Peak plasma concentrations (Cmax) and systemic exposure (AUCt, AUCinf) for LD and CD increased dose-proportionally over the range of the IPX066 capsule strengths. Comparison of 1 and 2 IPX066 245-mg LD capsules showed dose-proportional pharmacokinetics for Cmax and AUCt. Sprinkling the capsule contents on applesauce did not affect the pharmacokinetics. A high-fat, high-calorie meal delayed the initial increase in LD concentration by approximately 1 to 2 hours, reduced Cmax by 21%, and increased AUCinf by 13% compared with the fasted state. CONCLUSIONS: IPX066 shows dose-proportional pharmacokinetics. Sprinkling the capsule contents on applesauce does not affect the pharmacokinetics; a high-fat, high-calorie meal delayed absorption by 1 to 2 hours, slightly reduced Cmax, and slightly increased extent of absorption.

Conversion to IPX066 from Standard Levodopa Formulations in Advanced Parkinson's Disease: Experience in Clinical Trials.

BACKGROUND: Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours. OBJECTIVE: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. METHODS: Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided. RESULTS: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. CONCLUSIONS: Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

Long-Term Treatment with Extended-Release Carbidopa-Levodopa (IPX066) in Early and Advanced Parkinson's Disease: A 9-Month Open-Label Extension Trial.

BACKGROUND AND OBJECTIVE: IPX066 is a multiparticulate extended-release formulation of carbidopa-levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson's disease (PD). METHODS: Participants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson's Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings. RESULTS: Among 268 early PD patients, 53.4 % reported adverse events (AEs) and 1.1 % (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6 %) and insomnia (5.6 %). Among 349 advanced patients, 60.2 % reported AEs and 3.7 % (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9 %) and fall (6.6 %). At month 9 (or early termination), 78.3 % of early patients were taking IPX066 three times daily (median: 720 mg/day) and 87.7 % of advanced patients were taking IPX066 three or four times daily (median: 1450 mg/day). Adjusting for 70 % bioavailability relative to immediate-release (IR) carbidopa-levodopa, the median dosages correspond to ~500 and ~1015 mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension. CONCLUSION: During 9 months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy.

Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066) with immediate-release carbidopa-levodopa (Sinemet(®)), sustained-release carbidopa-levodopa (Sinemet(®) CR), and carbidopa-levodopa-entacapone (Stalevo(®)).

IPX066 (extended-release carbidopa-levodopa [ER CD-LD]) is an oral extended-release capsule formulation of carbidopa and levodopa. The single-dose pharmacokinetics of ER CD-LD (as 2 capsules; total dose, 97.5 mg-390 mg CD-LD) versus immediate-release (IR) CD-LD (25 mg-100 mg), sustained-release (CR) CD-LD (25 mg-100 mg), and CD-LD-entacapone (25 mg-100 mg-200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax ) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD-LD and CD-LD-entacapone, LD Cmax occurred at 1.5 hours, and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD-LD and IR CD-LD and faster than for CR CD-LD and CD-LD-entacapone. LD concentrations from ER CD---LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose-normalized LD Cmax values for ER CD-LD were significantly lower (P< .05) than for the other CD-LD products. Bioavailability of LD from ER CD-LD was 83.5%, 78.3%, and 58.8% relative to IR CD-LD, CR CD-LD, and CD-LD-entacapone, respectively.

Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients.

BACKGROUND: IPX066, an investigational extended-release carbidopa-levodopa (CD-LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CD-LD plus entacapone (CL + E). METHODS: At baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LD-entacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily "off" time during waking hours (from patient diaries). RESULTS: Of 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL + E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL + E, IPX066 demonstrated a lower percent "off" time (24.0% vs. 32.5%; p < 0.0001), lower "off" time (3.8 vs. 5.2 h/day; p < 0.0001), and higher "on" time without troublesome dyskinesia (11.4 vs. 10.0 h/day; p < 0.0001). Other endpoints, including patient-reported treatment preference, also favored IPX066 (p < 0.05). During double-blind treatment, 20.2% and 13.6% of patients reported adverse events on IPX066 and CL + E, respectively. The most common were dyskinesia (4 patients), insomnia (3), and confusional state (3) for IPX066, and fall (2) for CL + E. CONCLUSIONS: In advanced PD, IPX066 showed improved efficacy, compared with CL + E, and appeared to be well tolerated.

Pulmonary alveolar proteinosis.

We report a 68-year-old female who presented with chronic cough and progressive dyspnoea. Computed tomography of the thorax and subsequent bronchoscopy confirmed the diagnosis of pulmonary alveolar proteinosis (PAP), which was treated with whole lung lavage. This case is reported in view of the low incidence of PAP.

Randomized trial of IPX066, carbidopa/levodopa extended release, in early Parkinson's disease.

OBJECTIVE: IPX066 is an extended release carbidopa/levodopa formulation designed to rapidly attain and maintain therapeutic plasma concentrations for a prolonged duration, allowing dosing intervals of approximately 6 h. The objective was to assess the efficacy, safety, and impact on quality of life of IPX066 in the treatment of levodopa-naive Parkinson's disease (PD) patients. METHODS: This was a randomized, double-blind, placebo-controlled, 30-week study of 381 levodopa-naïve patients assigned to placebo or IPX066 containing 145, 245 or 390 mg of levodopa administered three times daily (TID). The primary efficacy measure was change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (Part II) + motor scores (Part III), at 30 weeks. Secondary outcome measures included UPDRS total and subscores, patient and clinician global impressions (PGI-I, CGI-I), and the Parkinson's Disease Questionnaire (PDQ-39). RESULTS: All IPX066 dosages were superior to placebo throughout the study and at 30 weeks (P < 0.0001). The mean improvement in UPDRS Parts II + III at 30 weeks compared to baseline was 11.7, 12.9, and 14.9 points for the three dosages and 0.6 points for placebo (P < 0.0001, all dosages). PDQ-39 total scores improved with IPX066 (P ≤ 0.034, all dosages). The most commonly reported adverse events with IPX066 included nausea, dizziness, and headache. No unexpected drug-related serious adverse events were reported. CONCLUSION: IPX066 provided significant clinical benefits at the three dosages tested compared to placebo and was well tolerated in levodopa-naive PD patients. Of the dosages tested, IPX066 145 mg TID appeared to provide the best overall balance between efficacy and safety.

N-ethylmaleimide activates a Cl(-)-independent component of K(+) flux in mouse erythrocytes.

The K-Cl cotransporters (KCCs) of mouse erythrocytes exhibit higher basal activity than those of human erythrocytes, but are similarly activated by cell swelling, by hypertonic urea, and by staurosporine. However, the dramatic stimulation of human erythroid KCCs by N-ethylmaleimide (NEM) is obscured in mouse erythrocytes by a prominent NEM-stimulated K(+) efflux that lacks Cl(-)-dependence. The NEM-sensitivity of Cl(-)-independent K(+) efflux of mouse erythrocytes is lower than that of KCC. The genetically engineered absence of the K-Cl cotransporters KCC3 and KCC1 from mouse erythrocytes does not modify Cl(-)-independent K(+) efflux. Mouse erythrocytes genetically devoid of the Gardos channel KCNN4 show increased NEM-sensitivity of both Cl(-)-independent K(+) efflux and K-Cl cotransport. The increased NEM-sensitivity and stimulation magnitude of Cl(-)-independent K(+) efflux in mouse erythrocytes expressing transgenic hypersickling human hemoglobin SAD (HbSAD) are independent of the presence of KCC3 and KCC1, but absence of KCNN4 reduces the stimulatory effect of HbSAD. NEM-stimulated Cl(-)-independent K(+) efflux of mouse red cells is insensitive to ouabain and bumetanide, but partially inhibited by chloroquine, barium, and amiloride. The NEM-stimulated activity is modestly reduced at pH6.0 but not significantly altered at pH8.0, and is abolished at 0°C. Although the molecular identity of this little-studied K(+) efflux pathway of mouse erythrocytes remains unknown, its potential role in the pathophysiology of sickle red cell dehydration will be important for the extrapolation of studies in mouse models of sickle cell disease to our understanding of humans with sickle cell anemia.

Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial.

BACKGROUND: IPX066 is an oral, extended-release, capsule formulation of carbidopa-levodopa. We aimed to assess this extended-release formulation versus immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations. METHODS: We did a phase 3, randomised, double-blind, double-dummy study at 68 academic and clinical centres in North America and Europe. Patients with Parkinson's disease who had at least 2·5 h per day of off-time underwent 3 weeks of open-label immediate-release carbidopa-levodopa dose adjustment followed by 6 weeks of open-label extended-release carbidopa-levodopa dose conversion. These patients were then randomly allocated (1:1), by use of an interactive web-response system, to 13 weeks of double-blind treatment with extended-release or immediate-release carbidopa-levodopa plus matched placebos. The primary efficacy measure was off-time as a percentage of waking hours in all patients randomly allocated to treatment groups, adjusted for baseline value. This study is registered with ClinicalTrials.gov, number NCT00974974. FINDINGS: Between Sept 29, 2009, and Aug 16, 2010, we enrolled 471 participants, of whom 393 (83%) were randomly allocated in the double-blind maintenance period and were included in the main efficacy analyses. As a percentage of waking hours, 201 patients treated double-blind with extended-release carbidopa-levodopa (mean 3·6 doses per day [SD 0·7]) had greater reductions in off-time than did 192 patients treated double-blind with immediate-release carbidopa-levodopa (mean 5·0 doses per day [1·2]). Covariate-adjusted end-of-study means were 23·82% (SD 14·91) for extended-release carbidopa-levodopa and 29·79% (15·81) for immediate-release carbidopa-levodopa (mean difference -5·97, 95% CI -9·05 to -2·89; p<0·0001). Extended-release carbidopa-levodopa reduced daily off-time by, on average, an extra -1·17 h (95% CI -1·69 to -0·66; p<0·0001) compared with immediate-release carbidopa-levodopa. During dose conversion with extended-release carbidopa-levodopa, 23 (5%) of 450 patients withdrew because of adverse events and 13 (3%) withdrew because of a lack of efficacy. In the maintenance period, the most common adverse events were insomnia (seven [3%] of 201 patients allocated extended-release carbidopa-levodopa vs two [1%] of 192 patients allocated immediate-release carbidopa-levodopa), nausea (six [3%] vs three [2%]), and falls (six [3%] vs four [2%]). INTERPRETATION: Extended-release carbidopa-levodopa might be a useful treatment for patients with Parkinson's disease who have motor fluctuations, with potential benefits including decreased off-time and reduced levodopa dosing frequency. FUNDING: Impax Laboratories.

Population pharmacodynamics of IPX066: an oral extended-release capsule formulation of carbidopa-levodopa, and immediate-release carbidopa-levodopa in patients with advanced Parkinson's disease.

A pharmacodynamic model is presented to describe the motor effects (tapping rate, Unified Parkinson's Disease Rating Scale [UPDRS] Part III, and investigator-rating of ON/OFF, including dyskinesia) of levodopa (LD) in patients with advanced idiopathic Parkinson's disease (PD) treated with immediate-release (IR) carbidopa-levodopa (CD-LD) or an extended-release (ER) formulation of CD-LD (IPX066). Twenty-seven patients participated in this open-label, randomized, single- and multiple-dose, crossover study. The pharmacodynamic models included a biophase effect site with a sigmoid E(max) transduction for tapping and UPDRS and an ordered categorical model for dyskinesia. The pharmacodynamics of LD was characterized by a conduction function with a half-life of 0.59 hours for tapping rate, and 0.4 hours for UPDRS Part III and dyskinesia. The LD concentration for half-maximal effect was 1530 ng/mL, 810 ng/mL, and 600 ng/mL for tapping rate, UPDRS Part III, and dyskinesia, respectively. The sigmoidicity of the transduction was 1.53, 2.5, and 2.1 for tapping rate, UPDRS Part III, and dyskinesia, respectively. External validation of the pharmacodynamic model using tapping rate indicated good performance of the model.

Older HIV-positive adults in Xiangxi, China: infection modes and associated risk factors.

OBJECTIVE: An unusual increase in HIV/AIDS cases among rural older adults was reported between 2005 and 2008 in Xiangxi Prefecture, Hunan Province. We explored the reasons for this increase and suggested preventive measures for the future control of HIV infection in this population. METHODS: A cross-sectional study was conducted using an HIV/AIDS registry in Hunan Province, China, to explore the likely transmission mode and risk factors of HIV/AIDS among older adults. The data were collected by face-to-face interview. RESULTS: A total of 80 participants including 5 couples were interviewed. Among them, 46 (57.5%) participants were male and 34 (42.5%) were female. Of 46 male HIV-positive participants, 45 (97.8%) reported to have sexual intercourse with commercial sex workers. None of the female HIV-positive participants reported to have engaged in commercial sex activities. Among 46 male participants' spouses, 71.7% of them had received HIV testing and 48.5% were HIV-positive. Among 34 female participants' spouses, 92.2% of them had received HIV testing and 87.1% were HIV-positive. Ninety-seven percent of the participants reported never using condoms during sexual intercourse with their marital partners or commercial sex workers before knowing their HIV status. Eighty-two percent of participants did not know that condoms could prevent HIV/AIDS/STIs. CONCLUSION: Chinese older adults are an underappreciated at-risk population for HIV/AIDS. The likely transmission mode of HIV/AIDS among rural older adults was unprotected sex. The HIV/AIDS/STIs knowledge among this population is very limited.