Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A).

BACKGROUND: The efficacy of ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal IgG4 antibody, was demonstrated in moderate-to-severe psoriasis patients when administered via prefilled syringe (PFS). OBJECTIVE: To evaluate the effect of two drug delivery devices on the pharmacokinetics (PK) of ixekizumab as well as efficacy and safety with both devices. METHODS: In the first 12 weeks of an open-label, phase 3 study, moderate-to-severe psoriasis patients were randomized to ixekizumab delivery via PFS or autoinjector device. Randomization was stratified by weight (<80 kg, 80-100 kg, >100 kg), injection assistance (yes/no) and injection site (arm, thigh or abdomen). Following a 160-mg initial dose at week 0, patients received subcutaneous 80-mg ixekizumab as a single injection every 2 weeks for 12 weeks. Blood samples were collected following the initial 160-mg dose on days 2, 4, 7, 10 and 14 for PK analysis. Primary PK parameters were maximum concentration (Cmax ) and area under the curve (AUC0-tlast ) where tlast is the time of last sample (14 days ± 24 h). Efficacy was assessed by percent improvement on the Psoriasis Area and Severity Index (PASI) at week 12. Adverse event reporting, vital signs and clinical laboratory data were used to evaluate safety. RESULTS: Of 204 randomized patients, 192 were included in the PK analysis (PFS: 94; autoinjector: 98). The PFS and autoinjector showed similar geometric mean Cmax (90% CI) [15.0 µg/mL (13.9-16.1) vs. 14.8 µg/mL (13.8-15.9)] and geometric mean AUC0-tlast (90% CI) [157 µg × day/mL (147-168) vs. 154 µg × day/mL (144-165)]. When comparing Cmax and AUC0-tlast of the autoinjector to PFS, the geometric LS mean ratios were 0.97. At week 12, mean percent PASI improvement (via modified baseline observation carried forward) was similar with the PFS (89.3%) and autoinjector (86.9%). Both devices had safety results that were consistent with the known safety profile of ixekizumab. CONCLUSION: The PK, efficacy and safety of ixekizumab administered subcutaneously by PFS and autoinjector were similar. Clinicaltrials.gov number: NCT01777191 https://clinicaltrials.gov/ct2/show/NCT01777191.

Anatomical variations of the celiac trunk: cadaveric and radiological study.

PURPOSE: The celiac trunk (CT) is a vascular structure of the upper abdomen which gives off the left gastric artery (LGA), the splenic artery and the common hepatic artery. This study aims to compare the vascular patterns of the CT of two different samples (cadaveric and radiological) and to propose a simple classification of CT variations based on previous studies and our results. MATERIALS AND METHODS: To perform this study we examined 43 adult cadavers, 24 males and 19 females, ages ranged from 69 to 92. In addition, we analysed 596 MDCT (multidetector computed tomographic) angiography examinations of 430 males and 166 females, ages ranged from 42 to 82. RESULTS: According to the classification proposed, results were divided into Type I or complete CT (578/639 cases, 90.5 %), Type II or incomplete CT (61/639 cases, 9.5 %), Type III or absence of CT and Type IV or celiacomesenteric trunk with no cases reported. Type I was divided into Type Ia or bifurcated trunk with LGA arising first (368/639 cases, 57.6 %), Type Ib or trifurcated trunk (205/639 cases, 32.1 %) and Type Ic or tetrafurcated trunk with an extra branch (5/639 cases, 0.8 %). Type II included hepatosplenic (29/639 cases, 4.5 %), gastroplenic (32/639, 5 %) and hepatogastric trunks (0/639, 0 %) which represented Types IIa, IIb and IIc respectively. CONCLUSIONS: No significant differences were found between the cadaveric and radiological samples. Gender did not appear to be related to any variability of the structures either. A new, simple and complete classification of the anatomical variations of the CT is proposed.

A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer.

BACKGROUND: Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-κB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype. METHODS: Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform. RESULTS: A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models. CONCLUSIONS: This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre-existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC.

Antimicrobial analysis of honey against Staphylococcus aureus isolates from wound, ADMET properties of its bioactive compounds and in-silico evaluation against dihydropteroate synthase.

BACKGROUND: One of the main challenges of wound healing is infection with multi-drug resistant (MDR) bacteria such as Staphylococcus aureus. The spectrum of antibiotics used to treat them is declining; thus, there is a need for alternatives. Our study was designed to evaluate the antimicrobial properties of honey, its pharmacokinetics (ADMET) properties and in-silico analysis of its bioactive compounds against dihydropteroate synthase of S. aureus using trimethoprim as control. METHODS: Standard protocols were employed in collection and preparation of samples, generation of canonical strings, and conduction of microbiological analyses. Bioactive compounds' ADMET properties were evaluated using the SWISSADME and the MCULE toxicity checker tools. The MCULE one-click docking tool was used in carrying out the dockings. RESULTS: The gas chromatography-mass spectrophotometry revealed twenty (20) bioactive compounds and was dominated by sugars (> 60%). We isolated a total of 47 S. aureus isolates from the wound samples. At lower concentrations, resistance to trimethoprim (95.74 to 100.00%) was higher than honey (70.21 to 96.36%). Only seven (7) isolates meet Lipinski's rule of five and ADMET properties. The docking scores of the bioactive compounds ranged from -3.3 to -4.6 while that of trimethoprim was -6.1, indicating better binding or interaction with the dihydropteroate synthase. The bioactive compounds were not substrates to P450 cytochrome enzymes (CYP1A2, CYP2CI9 and CYP2D6) and p-glycoprotein, indicating better gastrointestinal tract (GIT) absorption. CONCLUSION: The favourable docking properties shown by the bioactive compounds suggest they could be lead compounds for newer antimetabolites for management of MDR S. aureus.

Circulation of hepatitis B virus genotype-E among outpatients in tertiary hospitals in the Niger-Delta region of Nigeria.

Introduction: Hepatitis B virus (HBV) infection continues to be a significant public health challenge globally, with higher disease burden in developing countries. HBV genotypes are associated with different geographical regions and clinical outcomes. Limited information exists on epidemiology of HBV in the Niger-Delta region (South-South) of Nigeria. Consequently, this study was designed to characterise hepatitis B virus infection among outpatients in selected tertiary hospitals in the region. Methodology: Between June and August 2017, consenting nine hundred asymptomatic out-patients were enrolled and initially screened for HBV infection using one step Hepatitis B surface antigen (HBsAg) strip and subsequently re-tested using HBsAg and Hepatitis B core total antibody (anti-HBc) specific Enzyme-Linked Immunosorbent Assay (ELISA). Blood serum with detectable HBsAg were subsequently subjected to DNA extraction, S-gene amplification using a nested polymerase chain reaction (PCR) protocol, gel electrophoresis, sequencing and phylogenetic analysis. Results: Seroprevalence of HBsAg was 4.6% (95% CI 2.5-7.1) and anti-HBc was 10.1% (95% confidence interval (CI) 6.1-15.3). Of the 41 HBsAg positive samples subjected to DNA extraction and HBV S-gene specific PCR, only 6 (14.6%) yielded the expected ∼408bp band. Phylogenetic analysis based on HBV pre-S/S sequences identified all six typable samples as genotype E, subtype ayw4 of the West African clade. Conclusion: Results of the study confirm the presence and circulation of HBV genotype-E in the Niger-Delta region of Nigeria, thus corroborating the inclusion of the country in the Genotype E crescent. The authors advocate value-added HBV intervention in the region and the country at large.

Microbiological and biochemical assessment of the surface area of breast nipples and breast milk of lactating women in Calabar, southeastern Nigeria.

Microbiological and biochemical analyses of 59 breast nipple swab samples and 15 manually expressed breast milk samples of lactating mothers aged 15 to 40 years, was carried out using standard procedures. The incidence of bacterial species in swab samples was Staphylococus aureus (63.8%), Streptococcus sp (25.5%), Escherichia coli (6.4%) and Klebsiella sp (4.26%), indicating the poor sanitary status of the lactating mothers. S. aureus was recovered from only 1 (6.7%) of the milk samples, indicating that breast milk is relatively sterile. The nutritional values for the breast milk were 22.5 mg/ml (protein), 0.3 mg/ml (calcium), 3.5 mg/ml (sugar) and 300 microg/ml (vitamin A) in age group 15-20 years, and 16.4 mg/ml (protein), 0.16 mg/ml (calcium), 1.8 mg/ml (sugar) and 100 microg/ml (vitamin A) in the age group 36-40 years. In conclusion, the nutritive and antimicrobial properties of breast milk decrease with increasing age of lactating mothers. The need for public health enlightenment of lactating mothers regarding hygiene, and the provision of oral vitamin A supplement to infants, is discussed.

Incidence of enteric bacterial pathogens in water found at the bottom of commercial freezers in calabar, southeastern Nigeria.

Bacteriological analysis of water that accumulates at the bottom of freezers in restaurants when the power was cut in Calabar, southeastern Nigeria, was carried out using standard procedures. Mean heterotrophic bacterial counts and Escherichia coli counts ranged from 3.1 +/- 0.02 to 7.1 +/- 0.30 x 10(4) cfu/ml and 0.2 +/- 0.10 to 0.6 +/- 0.50 x 10(4) cfu/ml, respectively, indicating heavy bacterial contamination whose source was mostly fecal. There was no significant difference (p > 0.05, 0.01) in bacterial counts between freezers. Some biochemically identified enteric bacterial pathogens were Salmonella typhi, Shigella sp, enteropathogenic E. coli, Yersinia sp, Klebsiella pneumoniae, Vibrio cholerae O1 and Vibrio parahaemolyticus. This reveals that the hygienic quality of the food items stored in the freezers and the hygienic status of the restaurants are in doubt. Infection could be going on unnoticed and thus endemicity maintained in the area. The pathogens showed alarming antibiotic resistance. The water in the freezers was a "soup" in which different species of the enteric pathogens were close to each other and could transfer drug resistance among themselves. Public health education of restaurant operators in southeastern Nigeria is recommended.

[Influenza vaccination among health-care workers. Vaccination rates in universitary hospital of Besançon, winter 2003-2004]. / La vaccination antigrippale du personnel hospitalier. Enquête de prévalence au CHU de Besançon, hiver 2003-2004.

BACKGROUND: Influenza vaccination reduces the mortality of the patients when the vaccination rates of healthcare workers is important. PURPOSE AND METHOD OF THE STUDY: To investigate the vaccination rates at the Universitary Hospital of Besançon by anonymous questionnaire. RESULTS: Three thousand hundred seventy-seven answers were analyzed (228 men and 1145 women). Two hundred seventy-seven persons declared receiving the vaccine (20.1%) corresponding to sixty-three men (27.6%) and two hundred thirteen women (18.6%) (P = 0.001). The average age of the healthcare workers vaccined was of 38.9+/-11 years. Among most than 50 years, 34% was vaccined. Among the doctors, 40.5% were vaccined against 20.6% of the nurses. In the services of geriatrics, 78.5% of the staff was vaccined. CONCLUSIONS: Our results indicate a weak rate of influenza vaccination in our establishment and a misunderstanding of the character nosocomial of the influenza among the nurse.

Similar effect of proteolipid apoproteins from human myelin (lipophilin) and bovine white matter on the lipid phase transition.

The proteolipid apoprotein from bovine white matter has been reported to increase the phase transition temperature of dimyristoyl phosphatidylcholine, in contrast to a proteolipid apoprotein fraction from human myelin, called lipophilin, which decreases the enthalpy without altering the phase transition temperature. Since these results lead to different conclusions concerning the structure and amount of boundary lipid surrounding these proteins, the effects of the two proteins on the phase transition of dimyristoyl phosphatidylcholine were compared. Neither protein has any effect on the phase transition temperature, regardless of the method of delipidation of the protein, the amount of residual lipid, the method of incorporation into vesicles, or heating rates used for differential scanning calorimetry. However, a higher melting component was observed when decomposition of the lipid to lysophosphatidylcholine had occurred. Addition of as little as 6% of the decomposition products of dimyristoyl phosphatidylcholine, lysodimyristoyl phosphatidylcholine and myristic acid, is enough to produce a higher-temperature peak. The intensity of this peak increases with increasing protein concentration similar to the reported result on the bovine white matter proteolipid. The question as to whether the protein-induced decrease in enthalpy is due to boundary lipid or entrapment of lipid in protein aggregates was also addressed by studying the appearance of the intramembranous protein particles by freeze-fracture electron microscopy at temperatures above and below the phase transition and between the premelt and main transitions. The protein is randomly dispersed above the phase transition. At low concentrations, below the phase transition, it clusters, forming particle-free and particle-rich areas, but does not aggregate. At higher concentrations it is randomly dispersed below the premelt and main transition but is clustered between the premelt and main transition. Since the protein is more randomly dispersed above the transition than below, the reduction in enthalpy of the freezing transition was compared to that of the melting transition and was found to be identical, suggesting that the withdrawal of lipid from the phase transition is probably not due to lipid entrapment but due to the formation of a boundary lipid interface between the protein and the bulk lipid.

Direct stimulatory effect of insulin-like growth factor-I on monocyte and macrophage tumor necrosis factor-alpha production.

GH has been demonstrated to play a physiological role in the priming of macrophages for tumor necrosis factor-alpha (TNF alpha) synthesis. Although evidence has been presented that GH exerts this effect by an indirect mechanism, the mediators of GH stimulation of TNF alpha synthesis have not been identified. Because insulin-like growth factor-I (IGF-I) is a major mediator of many GH effects, in the present study we investigated the direct in vitro effect of this growth factor on macrophage TNF alpha production. Treatment of murine macrophages with physiological concentrations of IGF-I (0.13-130 nM) enhanced both basal and lipopolysaccharide-stimulated macrophage TNF alpha release and messenger RNA levels. Induction of basal TNF alpha production was also observed after treatment of the cells with supraphysiological concentrations of insulin (130-1300 nM). Exposure of human monocytes to IGF-I led to a similar increase of basal TNF alpha production and messenger RNA expression. Preexposure of macrophages with specific antibodies against IGF-I and IGF-I receptor before IGF-I addition resulted in a complete abrogation of the stimulatory effect of IGF-I on TNF alpha production, indicating that specific binding of IGF-I to its receptor is required for macrophage TNF alpha induction by IGF-I. In contrast to the stimulatory effect of IGF-I, neither GH (0.1-10 micrograms/ml) nor IGF-II (0.13-130 nM) enhanced macrophage TNF alpha release in vitro. To assess the role of the tyrosine kinase system in mediating IGF-I-induced basal TNF alpha production, macrophages were preincubated with the specific tyrosine kinase inhibitors, genistein and tyrphostin A9, before IGF-I exposure. Addition of these compounds resulted in a dose-dependent inhibition of the stimulatory effect of IGF-I on macrophage TNF alpha release, indicating that protein tyrosine kinase activation is required for TNF alpha stimulation by IGF-I. Taken together, these results demonstrate that IGF-I is a monocyte/macrophage activating factor that enhances TNF alpha production, and that such effect is mediated via the IGF-I receptor and involves tyrosine kinase activation.

Temporal changes in tissue glutathione in response to chemical form, dose, and duration of selenium treatment. Relevance to cancer chemoprevention by selenium.

Selenium has been reported to affect glutathione (GSH) concentrations in short-term animal-feeding experiments. Given the central role that this tripeptide plays in maintaining cellular homeostasis, it was hypothesized that perturbations in glutathione metabolism induced by selenium might account for its cancer chemopreventive activity. In the present study, four experiments were conducted in which the effect of acute, short-, or long-term exposure to selenium was assessed. Selenium was provided as either sodium selenite or D,L-selenomethionine. Selenite was observed to induce a biphasic response in total liver GSH. Injected selenium caused an acute reduction in GSH, whereas short-term feeding (up to 8 wk) increased both total GSH and oxidized glutathione (GSSH), an effect that gradually diminished in magnitude with prolonged feeding. Our data suggest that such changes are unlikely to account for the chemopreventive activity of selenium for the following reasons: Perturbations in glutathione metabolism occurred only at doses of selenite that approached toxicity. These doses are higher than what would be required for producing cancer chemoprevention. The transient nature of these changes also contrasts with the need for a continuous supplementation of selenite in suppression of tumorigenesis. Furthermore, selenomethionine was found to have little activity in altering glutathione metabolism, even though it compares favorably with selenite as a cancer chemopreventive agent. Nonetheless, these findings do not discount the possibility that sulfhydryl compounds, such as glutathione, might be used to modify the toxicity and/or enhance the cancer prophylactic activity of selenium compounds.

The Uyo Trauma Registry-developed for sustainable audit of trauma care and cause in Nigeria.

The Cape Town Trauma Registry (CTTR) was developed as a minimum data set for low-resource settings and was applied in a southern Nigerian tertiary hospital. Based on the outcome of the study, the CTTR was modified to produce the Uyo Trauma Registry. Using the CTTR, data was obtained prospectively from injured patients who presented to the Accident and Emergency Department of the University of Uyo Teaching Hospital over a 7 week period in June and July 2012. The final data set was determined based on the ease of capture of each item and its relative importance to injury surveillance. The goal for satisfactory data capture was chosen as ≥ 80%. The Uyo Trauma Registry has 19 patient-variable items and may be the first locally relevant hospital based injury surveillance tool in Nigeria. The Uyo Trauma Registry has provided the resource constrained setting in Nigeria with a simplified tool in order to sustainably obtain trauma data and thus engage in objective locally relevant efforts at injury prevention and improved care of the injured patient.

Closing the gap between insecticide treated net ownership and use for the prevention of malaria.

BACKGROUND: Malaria is the leading cause of morbidity and mortality in children younger than 5 years old and pregnant women in sub-Saharan Africa. Insecticide-treated nets (ITNs) reduce clinical malaria by more than 50% and all cause mortality in young children by 15% to 30%. However, use of these nets is poor across sub-Saharan Africa, limiting the potential impact of this effective tool in the fight against malaria. OBJECTIVE: We sought to improve the use of ITNs using a community-created and -implemented approach, and measure the change in ITN use over the year after implementation. METHODS: Using a community-based participatory research approach, we created and implemented an intervention to improve ITN use in a rural village. Our intervention involved providing hands-on instructions and assistance in hanging of nets, in-home small group education, and monthly follow-up by trained community members. ITN use was measured for all individuals in a subset of the community (61 households, 759 individuals) at baseline and at 6 months and 1 year after distribution. RESULTS: Rates of individual usage increased significantly from 29% at baseline to 88.7% (p < .001) at 6 months and to 96.6% (p < .001) at 12 months. For children under age 5, usage rates increased from 46% at baseline to 95.7% (p < .001) at 6 months and 95.4% (p < .001) at 12 months. CONCLUSION: Our study demonstrates that rapidly achieving and sustaining almost universal ITN usage rates is possible using a community-based approach. Closing the gap between ITN ownership and use will help communities to realize the full potential of ITNs in the prevention of malaria.

Dynamics of the ventilatory response to hypoxia in humans.

Dynamic responses of the ventilatory system to rapid variations in isocapnic hypoxia were studied in five subjects. Sawtooth-shaped inputs were presented at constant amplitude with periods of 120, 90, 60, 45 and 30 sec, and square-wave inputs at different amplitudes with periods of 120, 60 and 30 sec. A breath-by-breath model fitting technique was used to assess whether any of a number of first order models of hypoxic ventilatory dynamics could fit the data adequately. The following was found: 1) An equation for the desaturation of haemoglobin provided a better expression for hypoxia in the model than did a hyperbolic function of PO2. 2) The gain and/or offset model parameters varied significantly between experiments, but the time constant and pure delay terms did not. 3) The time constants, and to a lesser extent the pure delays, were found to vary significantly between sawtooth experiments of different frequencies. The failure of a single set of dynamic parameters to describe all the responses suggests that the model is incomplete. 4) There was significant asymmetry in the hypoxic response with the on-transient dynamics faster than the off-transient dynamics. The results of the model fitting study suggest that a first order model cannot fully describe the hypoxic ventilatory dynamics.

Latency of the ventilatory chemoreflex response to hypoxia in humans.

Latencies for the ventilatory response to hypoxia have been estimated from data from experiments in which square waves of isocapnic hypoxia (periods 30 sec and 60 sec) were presented to 5 subjects. Distorted steps were excluded from the analysis, and the remaining steps were time-aligned relative to the step and then averaged. For the 30 sec data, the median latency for the response to the step into hypoxia was 1 breath or 5.1 sec (time to mid-point of first significantly different breath) and for the step out of hypoxia was 1 breath or 4.7 sec. The number of transients analyzed averaged 87 per subject per transition type. For the 60 sec data, the median latency for the step into hypoxia was 2 breaths or 6.8 sec, and for the step out of hypoxia was 2 breaths or 6.0 sec. The number of transients analyzed averaged 40 per subject per transition type. These latencies are generally shorter than those reported previously and suggest that the ventilatory variability may have served to lengthen the measured latency of response in previous studies.

The human ventilatory response to step changes in end-tidal PO2 of differing amplitude.

This study assessed whether the form of the peripheral chemoreflex response to hypoxia depends on the magnitude of the stimulus. Two amplitudes of square-wave hypoxic stimulation were employed: small amplitude (SO) PETO2 from 63.2 to 54.9 Torr, and large amplitude (LO) PETO2 from 73.0 to 48.0 Torr. Each was studied at two levels of PETCO2: 2 Torr above resting PETCO2 (EC), and 7 Torr above resting PETCO2 (HC). Each protocol was repeated 6 times on 5 subjects. To assess the form of the response, a simple first-order model was fitted to the data which incorporated a pure delay (Td) and time constant (tau). Average parameter values (sec) were: ECSO tau = 4.07, Td = 6.69; ECLO tau = 8.82, Td = 4.91; HCSO tau = 5.22, Td = 7.08; HCLO tau = 9.96, Td = 4.39. ANOVA demonstrated modest but significant differences for loge(tau) (P < 0.01) and Td (P < 0.02) between the two hypoxic step magnitudes, with tau longer and Td shorter for the larger step size, but no differences were found between the parameter values for the two CO2 levels. We conclude that the form of the response of the peripheral chemoreflex to hypoxia depends upon the magnitude of the stimulus.

Effects of different levels of end-tidal PO2 on ventilation during isocapnia in humans.

The purpose of this investigation was to examine how the ventilatory decline observed during sustained, eucapnic hypoxia (HVD) is affected by different levels of hypoxia. Six subjects were each studied 3-6 times at each of 5 different levels of isocapnic hypoxia (end-tidal PO2 equal to 45, 50, 55, 65 and 75 Torr) in random order. The following variables were linearly related to saturation: (1) the rapid increase in ventilation at the onset of hypoxia; (2) the decline in ventilation over the period of hypoxia; and (3) the undershoot in ventilation below the pre-hypoxic control values at the relief of hypoxia. The rapid decrease in ventilation at the relief of hypoxia, however, was not linearly related to saturation. The mean time to peak ventilation was 2.13 +/- 0.07 min (+/- SE) at the onset of hypoxia, which was significantly longer (P less than 0.05) than the time to minimum ventilation at the relief of hypoxia of 1.23 +/- 0.18 min. The recovery from the undershoot in ventilation was 95% +/- 3% complete after 5 min, whereas the recovery in sensitivity to hypoxia was only 35% +/- 13% complete after 5 min of euoxia.

Antibody precipitation of lipid vesicles containing myelin proteins: dependence on lipid composition.

Antibody binding to human CNS myelin basic protein and to rabbit sciatic nerve myelin P-2 in their lipid-bound and water-soluble conformations has been investigated. 125I-labeled basic protein or P-2 was bound to the surface of liposomes (vesicles) of different acidic lipids, phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidic acid (PA), phosphatidylglycerol (PG), and cerebroside sulfate (CBS). The antibody was prepared against aqueous solutions of basic protein and P-2. Antibody binding to the proteins in liposomes was measured by precipitation of the liposomes by using a double antibody radioimmunoassay. The amount of 125I-basic protein precipitated was lest when the protein was bound to PA and increased in the order PA less than PS less than PG less than CBS less than PE approximately equal to basic protein in solution, suggesting that the antigenic determinants were lest exposed or most altered for PA and most exposed for PE. This agreed fairly well with previously published biophysical studies that suggested that hydrophobic segments of the protein penetrated into the lipid bilayer and that this penetration decreased in the order PA approximately equal to PG greater than PS greater than CBS greater than or equal to PE. The amount of 125I-P-2 precipitated was least for PA and CBS and increased in the order PA approximately equal to CBS less than PS less than PG less than PE approximately equal to P-2 in solution. However, the differences were less than for basic protein and the effect of CBS was different for the 2 proteins. Less is known about the conformation of P-2 in these lipids but it is known that lipids increase its disease-inducing activity. These results indicate that interaction with lipid may sequester or alter the conformation of antigenic determinants such that antibody binding decreases.

Changes in peripheral chemoreflex sensitivity during sustained, isocapnic hypoxia.

One hypothesis concerning the origin of hypoxic ventilatory decline is that hypoxia acts centrally to depress peripheral chemoreflex loop activity. To investigate possible changes in peripheral chemoreflex loop activity during sustained, isocapnic hypoxia, the ventilatory responses to four one minute pulses of either extra hypoxia (45 Torr) or carbon dioxide (8 Torr above resting levels) were measured in man at minutes 2, 7, 12, and 17 of a 23 min isocapnic, hypoxic period (50 Torr). For hypoxia, the first pulse response (130%) was significantly greater (P less than 0.05) than the fourth response (74%). For CO2, pulse responses 2 and 3 (101 and 103%, respectively) were significantly greater (P less than 0.05) than the fourth response (91%). A central depression of peripheral chemoreflex loop activity should affect peripheral sensitivities to CO2 and hypoxia equally. Our results suggest that the peripheral sensitivity to hypoxia declined more than that to CO2, implying a peripheral chemoreceptor origin for hypoxic ventilatory decline.