Six-month nocturnal nasal positive pressure ventilation improves respiratory muscle capacity and exercise endurance in patients with chronic hypercapnic respiratory failure.

BACKGROUND/PURPOSE: This study was designed to investigate the effects of 6 months of nocturnal nasal positive pressure ventilation (NNPPV) on respiratory muscle function and exercise capacity in patients with chronic respiratory failure. METHODS: A prospective, randomized, controlled design was used. Twenty-nine patients with chronic respiratory failure were enrolled and allocated to either the NNPPV (n = 14) or control group (n = 15). Patients in the NNPPV group received bi-level positive pressure ventilation via nasal mask for 6 consecutive months. Arterial blood gas, respiratory muscle assessment and 6-minute walk test (6MWT) were performed before and after the 6-month NNPPV intervention. Respiratory muscle function was assessed using the variables of maximal inspiratory pressure (Pimax), maximal expiratory pressure (Pemax), and maximum voluntary ventilation (MVV). RESULTS: Subjects in the NNPPV group showed a significant improvement in blood gas exchange and increased 6-minute walk distance (6MWD) compared to baseline and the control group. The 6MWD was significantly increased from 257.1 +/- 114.1 to 345.2 +/- 109.9 m (34.3%) in the NNPPV group. NNPPV also significantly improved MVV and Pimax relative to baseline. MVV was significantly increased from 19.2 +/- 6.5 to 22.3 +/- 7.1 L/min (16.1%) in the NNPPV group (p < 0.05). Furthermore, there was a significant correlation between the magnitude of MVV improvement and 6MWD change. CONCLUSION: The 6-month NNPPV treatment significantly decreased the partial pressure of carbon dioxide and improved daytime respiratory muscle function, thus contributing to exercise-capacity increase in patients with chronic respiratory failure.     

Dome-shaped high tibial osteotomy: a long-term follow-up study.

BACKGROUND: High tibial osteotomy (HTO) is a well-established treatment for unicompartmental gonarthrosis of the knee, but its durability and complications remain controversial. We previously introduced a novel dome-shaped HTO, and the long-term follow-up results using this technique are analyzed in this study. METHODS: We treated 25 varus knees in 22 patients with medial gonarthrosis, using a specially designed calibrated cutting jig along with rigid external fixation and early joint motion postoperatively. A total of 16 patients (19 knees) completed the study protocol and were followed up for 13-16 years (mean, 15 years). RESULTS: The surgery attempted to obtain 8 degrees valgus; the actual postoperative alignment averaged 12.4 degrees valgus, which decreased significantly to 7.8 degrees valgus after 5 years. The outcome as assessed by the Hospital for Special Surgery knee score was excellent or good in 18 knees at 5 years postoperatively, and in 13 knees at the final follow-up, showing a significant deterioration with time. Loss of correction with time was not correlated with the postoperative alignment achieved: at 5 years, loss greater than 2 degrees was found in 12 knees, but their mean corrected angle (11.8 degrees valgus) was not significantly different from that of the others (13.3 degrees valgus). Nor was the loss of correction correlated with the knee scores. The mean amount of joint motion after surgery did not change significantly with time: 124 degrees preoperatively and 114 degrees at the final follow-up. The patellar position also did not change from preoperative values during postoperative follow-up: mean Insall-Salvati index was 0.88 before and 0.90 5 years after surgery, neither showing patella baja. CONCLUSION: Dome-shaped HTO is a durable time-buying procedure for patients with unicompartmental medial gonarthrosis, and can avoid subsequent development of patella baja that may complicate further prosthetic arthroplasty.     

Bi-directional interactions between visual areas in the awake behaving cat

The study of the cooperativity among cortical areas is essential to our understanding of brain functioning. Here we investigated the relative contributions of top-down and bottom-up directed interactions between area 17 and area 7 of the cat visual system. Bipolar local field potentials were recorded while the animals performed a go/no-go task or were in a quiet resting state. The data were analyzed by applying measures of interaction based on the Wiener-Granger causality concept. We found that during the visual task top-down directed interactions were of a similar magnitude as the bottom-up component. Second, interareal couplings tended to increase in conditions requiring a discriminative effort. Third, during behaviors not dominated by visual processing non-directed interactions increased.     

Chemoreflexes: an experimental study

HYPOTHESIS: Transmyocardial laser revascularization (TMLR) will not denervate the heart, because it does not destroy all of the afferents. This study was designed to determine if stimulation of cardiac sympathetic and vagal afferents from an area of the left ventricle treated with TMLR could evoke reflex effects, and thus whether TMLR would denervate the heart. METHODS: The effect of TMLR on reflexes evoked by chemically stimulating cardiac afferents was examined in 9 dogs. Bradykinin and capsaicin were applied topically or injected into the left anterior descending coronary artery before and after TMLR and after bilateral vagotomy and sympathectomy. Aortic (AoP) and left ventricular pressures (LVP) and electrocardiography were monitored. The first derivatives of LVP (dP/dt) were calculated. RESULTS: Topical bradykinin elicited variable hemodynamic responses. Topical capsaicin evoked pressor responses, increasing mean (+/- SEM) AoP (105+/-9 to 115+/-9 mm Hg; P<.001) and positive dP/dt (+dP/dt) (1032+/-81 to 1159+/-10 mm Hg/s; P<.01) before TMLR. Intracoronary capsaicin evoked a depressor response before TMLR. Pressor responses remained intact after TMLR with increases in mean AoP and +dP/dt (115+/-6 to 128+/-5 mm Hg and 1039+/-98 to 1136+/-100 mm Hg/s, respectively; P<.01). Depressor responses also remained intact after TMLR (91+/-10 vs 101+/-11 mm Hg [P<.02], and 865+/-104 vs 931+/-104 mm Hg/s [P<.05], respectively). Hemodynamic responses were diminished after bilateral vagotomy and abolished after bilateral sympathectomy. CONCLUSION: Since activation of cardiac afferent nerves and reflex responses remained intact after TMLR, but changed after vagotomy or sympathectomy, TMLR does not denervate the heart sufficiently to be the cause of improved angina after TMLR.     

Rhodostomin inhibits thrombin-enhanced adhesion of ROS 17/2.8 cells through the blockade of alphavbeta3 integrin.

Osteosarcoma is a very malignant bone tumor which has a high metastatic potential and usually lead to poor prognosis. The adhesion of tumor cells to the endothelium or extracellular matrix (ECM) is an essential step in the metastatic cascade. We investigated the effect of thrombin on the adhesion activity of the osteosarcoma cell line, ROS 17/2.8. Incubation with the low concentrations of thrombin (0.01-5 U/ml, 5 min to 24 h) elevated the adhesion activity of ROS 17/2.8 to both human umbilical vein endothelial cells (HUVEC) and extracellular matrix, with the peak effect at the concentration of 0.5 U/ml for 30 min at 37 degrees C. The ROS 17/2.8 cells responded to thrombin by a peak effect of increased adhesion to HUVEC (5.5 folds vs. control) and fibronectin (4.8 folds) after thrombin pretreatment (0.5 U/ml, 30 min, 37 degrees C). Pretreatment with monoclonal antibodies against beta3 integrins, including anti-alphavbeta3, 10E5 and 7E3, effectively antagonized the thrombin-enhanced cell adhesion activity, whereas anti-alpha3beta1 and anti-alpha5beta1 did not antagonize the enhanced cell adhesion. Rhodostomin, an Arg-Gly-Asp (RGD)-containing snake venom peptide, and synthetic peptide RGDS also blocked the thrombin-enhanced ROS 17/2.8 cell adhesion. This study demonstrated that thrombin enhanced the cell adhesion of ROS 17/2.8 cells to HUVEC or ECM through an upregulation of beta3 integrins, and rhodostomin was a strong inhibitor on thrombin-enhanced cell adhesion, either to HUVEC or fibronectin substratum.     

Association between paternal age and risk of schizophrenia: a nationwide population–based study

PurposeTo study the association between paternal age and schizophrenia in offspring.MethodsThis report describes a nationwide population-based cohort study from 1997 to 2013. Data from Taiwan’s National Health Insurance Research Database were utilized to answer the research question. A total of 17,649 offspring with schizophrenia were selected from 11 million offspring in the general population. Additionally, we established the offspring without schizophrenia as the comparison group by matching the study cohort by age, gender in a 1:4 ratio (n = 70,596).ResultsThe median age at first presentation with schizophrenia was 20 years (interquartile range (IQR), 17 to 24). Comparison of the schizophrenia and non-schizophrenia groups indicated that father’s age at birth (30.0 (IQR), 27 to 33 vs. 29.0 (IQR), 26 to 32 years), mother’s age at birth (26.0 (IQR), 24 to 29 vs. 26.0 (IQR), 23 to 29 years), paternal schizophrenia (2.6% vs. 0.6%), and maternal schizophrenia (4.4% vs. 0.7%) were all significantly greater in the schizophrenia group. In addition, each 5-year increase in father’s age increased the odds of being diagnosed with schizophrenia (model 1: aOR = 1.22; 95% CI 1.20, 1.24; model 2: aOR = 1.20; 95% CI 1.18, 1.23). Subgroup analysis showed that each 5-year increase in father’s age increased the odds of being diagnosed with schizophrenia in male and female offspring, as well as in offspring of mothers and fathers with or without schizophrenia (aOR = 1.20 to 2.20, all p values < 0.01).ConclusionThis study indicated that advanced paternal age increased the risk of schizophrenia in offspring. Offspring born to fathers older by 5-year increments were at heightened risk of schizophrenia.     

Effects of calcium antagonists on (Na+ + K+)-ATPase, Mg2+-ATPase and Ca2+-ATPase activities of rat cortical synaptosomes

1. The effects of 11 calcium antagonists on (Na+ + K+)-ATPase, Mg2+-ATPase and Ca2+-ATPase activities of rat cortical synaptosomes were studied. 2. All the calcium antagonists studied had inhibitory effects on ouabain-sensitive (Na+ + K+)-ATPase, Mg2+-ATPase and Ca2+-ATPase activities in synaptosomes at high concentrations (10 or 100 microM). 3. Calcium antagonists such as trifluoperazine, flunarizine and cinnarizine had inhibitory effects on Ca2+-ATPase activity at low concentrations (1-10 microM). 4. Trifluoperazine and La3+ had inhibitory effects on Mg2+-ATPase activity at low concentration (1 microM). 5. Our results suggest that most of the calcium antagonists studied have little effects on neuronal (Na+ + K+)-ATPase, Mg2+-ATPase and Ca2+-ATPase activities at therapeutic dose ranges (1 microM or lower).     

An Investigation of Oral Exposure Variability and Formulation Strategy: A Case Study of PI3Kδ Inhibitor and Physiologically Based Pharmacokinetic Modeling in Beagle Dogs

It is well acknowledged that drugs with poor aqueous solubility are often associated with poor oral absorption. Fortunately, drugs with a basic pKa can take advantage of solubilization in the stomach under the acidic environment to improve exposure. Consequently, high in vivo variability is often observed when stomach pH is altered. When issue encountered, enabling formulations are often used to solve the problem. However, each enabling formulation has its limitations and the situation can be further complicated by other absorption distribution metabolism elimination parameters. Therefore, formulation strategies need to consider various scenarios in order to be effective. Compound 1 is a potent phosphoinositide 3-kinase delta inhibitor with poor intrinsic solubility and 2 basic pKas. It was dosed as a suspension in dogs and found to have mediocre oral bioavailability with high variability. It was hypothesized that this variability was caused by their stomach pH variability. Pharmacokinetic modeling suggested that the issue could be improved with particle size reduction. Meanwhile, it was found that although the Madin-Darby canine kidney permeability was reasonable, Madin-Darby canine kidney transfected with human MDR1 gene (MDCK-MDR1) suggested that Compound 1 is an efflux transporter substrate. Findings were integrated into the design for in vivo studies in dogs. Data obtained from those studies allowed us to quickly narrow down the formulation approaches.     

Acute Intravenous Injection Toxicity Study of IBZM and BZM in Rats

S-3-iodo-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide (IBZM) is one of the several benzamide derivatives showing a high affinity for the central nervous system (CNS) D2 dopamine receptor. Carrier-free [123I]IBZM is potentially useful as a nuclear medicine imaging agent for investigating the CNS D2 dopamine receptor in humans. This study describes the acute toxicity of IBZM and S-N-(1-ethyl-2-pyrrolidinyl)methyl-2-hydroxy-6-methoxybenzamide (BZM) in the rats. Treated rats were administered with IBZM at dose levels of 1 and 5 μg/kg and BZM at dose levels of 250 and 1250 μg/kg with dose volumes of 1 and 5 mL/kg. The control rats were administered 5 mL/kg of vehicle control. The rats were observed for 14 days. Observations included general demeanor, clinical signs, mortality, body weights/total body weight gains, and gross necropsy findings. None of the animals died during the 14-day study period. In female rats, the body weight gained at the first week of BZM treatment at a dose level of 1250 μg/kg and the total body weight gains of both IBZM treated groups were significantly higher than the control group (p < 0.05).