Comparison of Medical Tape Performance Using Skin Response Quantitative Measurements on Healthy Volunteers.

BACKGROUND: Medical tapes can lead to skin damage upon removal in susceptible patients with fragile skin and at higher risk of developing tissue injury. PURPOSE: We compared the effect of medical tapes with silicone-based versus acrylate-based adhesives on the back or volar forearm stratum corneum using analytical techniques to assess skin condition and potential damage post product removal on 88 healthy volunteers. METHODS: Two studies were conducted in separate facilities (Study 1: 3M In-house Clinical Facility, St. Paul, Minnesota; Study 2: DermiCo, LLC, Broomall, Pennsylvania). Four commercially available tapes were the same in both studies, two for each type of adhesive. We evaluated adhesion to the skin, total proteins and corneocytes removed by the tapes, changes in transepidermal water loss (TEWL), and induction of the inflammatory cytokine interleukin-1 alpha (IL-1a). RESULTS: One of the silicone tapes displayed the strongest adhesion at 24 hours, and one of the acrylate tapes had the lowest adhesion, showing differences in performance within adhesive categories. The adhesion forces did not correlate with the amount of total protein or corneocytes removed. Silicone adhesives removed less total protein and corneocytes than acrylate adhesives. Silicone adhesives did not alter TEWL, whereas acrylate adhesives significantly raised TEWL. There were no differences in interleukin-1alpha induction. CONCLUSION: The silicone adhesive tapes were less disruptive to the skin barrier than the acrylate adhesive tapes, even in healthy volunteers whose skin is not as fragile as what is observed in typical patients. This type of data could guide clinical product usage decisions.

The opportunistic protist, Giardia intestinalis, occurs in gut-healthy humans in a high-income country.

Giardia intestinalis, a cosmopolitan gastrointestinal protist, is detected mainly in patients with clinical giardiasis in high-income countries. In contrast, there is very little information on the presence of Giardia in asymptomatic individuals. Therefore, the aim of this study was to determine the presence and prevalence of Giardia in gut-healthy volunteers in the Czech Republic and to perform a comparative evaluation of different diagnostic methods, since Giardia diagnostics is complicated. Our results confirmed that the qPCR method is the most sensitive method for detecting Giardia and revealed a prevalence of 7% (22/296) in asymptomatic individuals. In most cases, the colonization intensity ranged from 10-1-101. A conventional PCR protocol targeting the TPI gene was used to identify the assemblages. However, this protocol had limited sensitivity for Giardia amplification, effectively detecting colonization above an intensity of 104. In addition, Giardia was detected in 19% of the animals, which were closely associated with the study participants. However, due to methodological limitations, zoonotic transmission could not be clearly confirmed. Notably, contact with animals proved to be the only factor that had a significant impact on the incidence of Giardia in gut-healthy humans.

Involvement of Human Volunteers in the Development and Evaluation of Wearable Devices Designed to Improve Medication Adherence: A Scoping Review.

Wearable devices designed to improve medication adherence can emit audible and vibrating alerts or send text messages to users. However, there is little information on the validation of these technologies. The aim of this scoping review was to investigate the involvement of human volunteers in the development and evaluation of wearable devices. A literature search was conducted using six databases (MEDLINE, Embase, Scopus, CINAHL, PsycInfo, and Web of Science) up to March 2020. A total of 7087 records were identified, and nine studies were included. The wearable technologies most investigated were smartwatches (n = 3), patches (n = 3), wristbands (n = 2), and neckwear (n = 1). The studies involving human volunteers were categorized into idea validation (n = 4); prototype validation (n = 5); and product validation (n = 1). One of them involved human volunteers in idea and prototype validation. A total of 782 participants, ranging from 6 to 252, were included. Only five articles reported prior approval by a research ethics committee. Most studies revealed fragile methodological designs, a lack of a control group, a small number of volunteers, and a short follow-up time. Product validation is essential for regulatory approval and encompasses the assessment of the effectiveness, safety, and performance of a wearable device. Studies with greater methodological rigor and the involvement of human volunteers can contribute to the improvement of the process before making them available on the market.

Enhanced bioavailability and pharmacokinetics parameters of Enalapril solid self nanoemulsifying oral dispersible tablet: formulation, in vitro and in vivo evaluation.

Enalapril (EN) is an antihypertensive drug that is sparingly soluble in water with limited oral bioavailability. Successfully prepared self-nanoemulsifying systems (SNES) loaded with EN were developed. The solubility of EN in different oils, surfactants, and cosurfactants was tested. Pseudoternary phase diagrams were developed, and various SNES formulations were prepared and evaluated regarding content uniformity, emulsification time, droplet size (DS), and zeta potential (ZP). The selected system was examined using transmission electron microscopy. Solid Self-Nanoemulsifying Systems (SSNES) were formulated using Avicel® PH101 carrier and Aerosil® 200 adsorbent to form a free-flowing powder. The powder was formulated as an oral disintegrating tablet (ODT) using superdisintegrants and tested for physicochemical properties and stability. Finally, an in vivo pharmacokinetic study in healthy human volunteers was carried out. The composition of the selected SNES was 10% Labrafil®, 60% Tween 80, and 30% Transcutol® HP. It developed with an emulsification time of 21 sec, DP range of 60.16 nm, ZP of 1.17 mV, and spherical-shaped globules. The accelerated stability testing proved that there was no significant difference in physical properties after storage for 3 months. The percentage of relative bioavailability for formula F2 was 112.04%. The results of this study proved that the prepared EN-SSNES ODT represents a novel formulation alternative to the currently marketed tablet.

The Pharmaceutical Formulation Plays a Pivotal Role in Hydroxytyrosol Pharmacokinetics.

Current evidence supports the use of extra virgin olive oil (EVOO) and its minor components such as hydroxytyrosol or 3,4-dihydroxyphenyl ethanol (DOPET), to improve cardiovascular and metabolic health. Nevertheless, more intervention studies in humans are needed because some gaps remain in its bioavailability and metabolism. The aim of this study was to investigate the DOPET pharmacokinetics on 20 healthy volunteers by administering a hard enteric-coated capsule containing 7.5 mg of bioactive compound conveyed in EVOO. The treatment was preceded by a washout period with a polyphenol and an alcohol-free diet. Blood and urine samples were collected at baseline and different time points, and free DOPET and metabolites, as well as sulfo- and glucuro-conjugates, were quantified by LC-DAD-ESI-MS/MS analysis. The plasma concentration versus time profiles of free DOPET was analyzed by a non-compartmental approach, and several pharmacokinetic parameters (Cmax, Tmax, T1/2, AUC0-440 min, AUC0-∞, AUCt-∞, AUCextrap_pred, Clast and Kel) were calculated. Results showed that DOPET Cmax (5.5 ng/mL) was reached after 123 min (Tmax), with a T1/2 of 150.53 min. Comparing the data obtained with the literature, the bioavailability of this bioactive compound is about 2.5 times higher, confirming the hypothesis that the pharmaceutical formulation plays a pivotal role in the bioavailability and pharmacokinetics of hydroxytyrosol.

A Cross-Sectional Study on the Occurrence of the Intestinal Protist, Dientamoeba fragilis, in the Gut-Healthy Volunteers and Their Animals.

Dientamoeba fragilis is a cosmopolitan intestinal protist colonizing the human gut with varying prevalence depending on the cohort studied and the diagnostic methods used. Its role in human health remains unclear mainly due to the very sporadic number of cross-sectional studies in gut-healthy populations. The main objective of this study was to expand knowledge of the epidemiology of D. fragilis in gut-healthy humans and their animals. A total of 296 stool samples from humans and 135 samples from 18 animal species were analyzed. Using qPCR, a prevalence of 24% was found in humans in contrast to conventional PCR (7%). In humans, several factors were found to influence the prevalence of D. fragilis. A more frequent occurrence of D. fragilis was associated with living in a village, traveling outside Europe and contact with farm animals. In addition, co-infection with Blastocystis spp. was observed in nearly half of the colonized humans. In animals, D. fragilis was detected in 13% of samples from eight species using qPCR. Our molecular phylogenies demonstrate a more frequent occurrence of Genotype 1 in gut-healthy humans and also revealed a likely a new protist species/lineage in rabbits related to D. fragilis and other related organisms.

Morphometry of lumbar muscles in the seated posture with weight-bearing MR scans.

Conventional imaging studies of human spine are done in a supine posture in which the axial loading of the spine is not considered. Upright images better reveal the interrelationships between the various internal structures of the spine. The objective of the current study is to determine the cross-sectional areas, radii, and angulations of the psoas, erector spinae, and multifidus muscles of the lumbar spine in the sitting posture. Ten young (mean age 31 ± 4.8 years) asymptomatic female subjects were enrolled. They were seated in an erect posture and weight-bearing T1 and T2 MRIs were obtained. Cross-sectional areas, radii, and angulations of the muscles were measured from L1-L5. Two observers repeated all the measurements for all parameters, and reliability was determined using the inter- and intra-class coefficients. The Pearson product moment correlation was used for association between levels, while level differences were used using a linear regression model. The cross-sectional areas of the psoas and multifidus muscles increased from L1 to L5 (1.9 ± 1.1 to 12.1 ± 2.5 cm2 and 1.8 ± 0.3 to 5.7 ± 1.4 cm2). The cross-sectional area of the erector spinae was greatest at the midlevel (13.9 ± 2.2 cm2) and it decreased in both directions. For the angle, the range for psoas muscles was 75-105°, erector spinae were 39-46° and multifidus was 11-19°. Correlations magnitudes were inconsistent between levels and muscle types. These quantitated data improve our understanding of the geometrical properties in the sitting posture. The weight-bearing MRI-quantified morphometrics of human lumbar spine muscles from this study can be used in biomechanical models for predicting loads on spinal joints under physiological and traumatic situations.

Oleic acid-based vesicular nanocarriers for topical delivery of the natural drug thymoquinone: Improvement of anti-inflammatory activity.

The topical administration of a drug compound remains the first choice for the treatment of many local skin ailments. Many skin diseases can be treated by applying the active formulation directly to the skin, but unfortunately some drugs are unable to overcome the stratum corneum and exert their pharmacological action. An example is thymoquinone, a naturally derived drug obtained from Nigella sativa L. and potentially effective in the treatment of inflammatory and oxidative skin conditions. Since its physico-chemical properties are not suitable for overcoming the stratum corneum, we wanted to circumvent the problem by proposing new lipid-based nanovesicles called "oleoethosomes", made up of naturally derived ingredients, for its delivery. Among several formulations of oleoethosomes, the sample made up of 2% (w/w) oleic acid:PL90G 1:1 (molar ratio), and ethanol 15% showed the best physico-chemical characteristics and above all it showed the capacity to contain a suitable amount of thymoquinone (2 mg/ml). The formulation was tested in vitro on stratum corneum and viable epidermis membranes confirming its ability to induce the passage of thymoquinone through the human stratum corneum and to act as a permeation enhancer. In fact, it showed thymoquinone permeation values of 22.63 ± 1.49% regarding the applied drug amount. Oleoethosomes were compared with oleosomes, another kind of naturally derived nanosystems but free of ethanol. The experimental data confirmed that ethanol was an important component that enhanced the activity of the oleoethosomes when tested on the skin of healthy volunteers. The thymoquinone-loaded oleoethosome treatment demonstrated a significantly greater extent of anti-inflammatory activity than the treatment with thymoquinone-loaded oleosomes or the conventional dosage form of the drug. These in vivo results confirmed the synergic effect between oleic acid and ethanol on the lipid and protein compartments of the outermost skin layer, thus promoting a greater penetration capacity.

Investigating the Role of the Reduced Solubility of the Pirfenidone-Fumaric Acid Cocrystal in Sustaining the Release Rate from Its Tablet Dosage Form by Conducting Comparative Bioavailability Study in Healthy Human Volunteers.

Pirfenidone (PFD) is the first pharmacological agent approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). The recommended daily dosage of PFD in patients with IPF is very high (2403 mg/day) and must be mitigated through additives. In the present work, sustained-release (SR) formulations of the PFD-FA cocrystal of two different strengths such as 200 and 600 mg were prepared and its comparative bioavailability in healthy human volunteers was studied against the reference formulation PIRFENEX (200 mg). A single-dose pharmacokinetic study (200 mg IR vs 200 mg SR) demonstrated that the test formulation exhibited lower Cmax and Tmax in comparison to the reference formulation, which showed that the cocrystal behaved like an SR formulation. Further in the multiple-dose comparative bioavailability study (200 mg IR thrice daily vs 600 mg SR once daily), the test formulation was found bioequivalent to the reference formulation. In conclusion, the present study suggests that cocrystallization offers a promising strategy to reduce the solubility of PFD and opens the door for potential new dosage forms of this important pharmaceutical.

Low levels of fine particulate matter increase vascular damage and reduce pulmonary function in young healthy adults.

BACKGROUND: Fine particulate matter (PM2.5) related mild inflammation, altered autonomic control of cardiovascular function, and changes to cell function have been observed in controlled human exposure studies. METHODS: To measure the systemic and cardiopulmonary impacts of low-level PM exposure, we exposed 20 healthy, young volunteers to PM2.5, in the form of concentrated ambient particles (mean: 37.8 µg/m3, SD 6.5), and filtered air (mean: 2.1 µg/m3, SD 2.6). In this double-blind, crossover study the exposure order was randomized. During the 4 h exposure, volunteers (7 females and 13 males) underwent light intensity exercise to regulate ventilation rate. We measured pulmonary, cardiac, and hematologic end points before exposure, 1 h after exposure, and again 20 h after exposure. RESULTS: Low-level PM2.5 resulted in both pulmonary and extra-pulmonary changes characterized by alterations in systematic inflammation markers, cardiac repolarization, and decreased pulmonary function. A mean increase in PM2.5 concentration (37.8 µg/m3) significantly increased serum amyloid A (SAA), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1), 1 h after exposure by 8.7, 9.1, 10.7, and 6.6%, respectively, relative to the filtered air control. SAA remained significantly elevated (34.6%) 20 h after PM2.5 exposure which was accompanied by a 5.7% decrease in percent neutrophils. Decreased pulmonary function was observed 1 h after exposure through a 0.8 and 1.2% decrease in forced expiratory volume in 1 s (FEV1) and FEV1/ forced vital capacity (FEV1/FVC) respectively. Additionally, sex specific changes were observed in repolarization outcomes following PM2.5 exposure. In males, P-wave and QRS complex were increased by 15.4 and 5.4% 1 h after exposure. CONCLUSIONS: This study is the first controlled human exposure study to demonstrate biological effects in response to exposure to concentrated ambient air PM2.5 particles at levels near the PM2.5 US NAAQS standard. CLINICAL TRIAL REGISTRATION INFORMATION: clinicaltrials.gov ; Identifier: NCT03232086 . The study was registered retrospectively on July 25, 2017, prior to final data collection on October 25, 2017 and data analysis.

Word Meaning Contributes to Free Recall Performance in Supraspan Verbal List-Learning Tests.

Supraspan verbal list-learning tests, such as the Rey Auditory Verbal Learning Test (RAVLT), are classic neuropsychological tests for assessing verbal memory. In this study, we investigated the impact of the meaning of the words to be learned on three memory stages [short-term recall (STR), learning, and delayed recall (DR)] in a cohort of 447 healthy adults. First, we compared scores obtained from the RAVLT (word condition) to those of an alternative version of this test using phonologically similar but meaningless items (pseudoword condition) and observed how each score varied as a function of age and sex. Then, we collected the participants' self-reported strategies to retain the word and pseudoword lists and examined if these strategies mediated the age and sex effects on memory scores. The word condition resulted in higher memory scores than pseudoword condition at each memory stage and even canceled out, for the learning stage, the detrimental effect of age that was observed for the short-term and DR. When taking sex into account, the word advantage was observed only in women for STR. The self-reported strategies, which were similar for words and pseudowords, were based on the position of the item on the list (word: 53%, pseudoword: 37%) or the meaning of the item (word: 64%, pseudoword: 58%) and were used alone or in combination. The best memory performance was associated with the meaning strategy in the word condition and with the combination of the meaning and position strategies in the pseudoword condition. Finally, we found that the word advantage observed in women for STR was mediated by the use of the meaning strategy. The RAVLT scores were thus highly dependent on word meaning, notably because it allowed efficient semantic knowledge-based strategies. Within the framework of Tulving's declarative memory model, these results are at odds with the depiction of the RAVLT as a verbal episodic memory test as it is increasingly referred to in the literature.

Enhanced Extraction Technique of Omarigliptin from Human Plasma-Applied to Biological Samples from Healthy Human Volunteers.

Enhancing drug extraction from human plasma is a challenging approach that critically affects pharmacokinetic and any further clinical studies based on the drug Cmin and Cmax values. It also has a serious impact on the sensitivity and the lower limit of quantification (LLOQ) value of the bio-analytical methods. An advanced liquid chromatography tandem mass spectrometry (LC-MS/MS) bio-analytical method of omarigliptin (25-1000 nM) was established in human plasma using one-step liquid-liquid extraction. Alogliptin was used as an internal standard (IS) to attain good recovery and reproducibility while reducing the effects of the matrix. Enhanced plasma extraction of omarigliptin was successfully achieved with tertiary butyl methyl ether-diethyl ether (TBME-DEE) mixture as the extracting solvent, while using acetonitrile as the diluent solvent for the IS to effectively decrease the formed emulsion. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 399.2 to 153.0 for omarigliptin and m/z 340.2 to 116.0 for alogliptin was employed in positive Electro Spray Ionization (ESI) mode. Human plasma samples were collected after 1.5 h (tmax) of Marizev® (12.5 mg) tablets administration to healthy human volunteers showing average concentration of 292.18 nM. Validation results were all satisfactory including successful stability studies with bias below 12%. The proposed study will be valuable for ethnicity comparison studies that will be commenced on omarigliptin in Egypt by the authors in prospective study, following the FDA recommends, to evaluate possible sub-group dissimilarities that include pharmacokinetic parameters.

The effect of vehicle countermeasures and age on human volunteer kinematics during evasive swerving events.

Objective: Emergency maneuvers such as evasive swerving often precede a crash. These events are typically low-acceleration, time-extended events where the inertial forces have the potential to cause changes to the occupant's initial state (initial posture, position, muscle tension). The objective of this study was to systematically quantify the kinematics of pediatric and adult human volunteers during simulated pre-crash evasive swerving maneuvers and evaluate the effect of age and two vehicle-based countermeasures.Methods: A novel laboratory device was designed to expose subjects to non-injurious loading conditions that mimic real-world evasive swerving events. A four-cycle oscillatory lateral pulse with a maximum acceleration of 0.72 g (0.53 g for the first lateral movement in the first cycle) was applied. Forty seat belt restrained subjects across four age groups - 9-11 years (n = 10), 12-14 years (n = 10), 15-17 years (n = 10) and 18-40 years (n = 10) - were exposed to a series of test conditions (baseline, pre-pretensioned seat belt, sculpted vehicle seat with and without inflated torso bolsters) while their kinematics were captured using 3 D motion capture and muscle activity was recorded. Reaction loads were collected from the shoulder belt and footrest. Data are presented for the first cycle only.Results: Pre-pretensioning the shoulder belt before the onset of acceleration had the greatest restraining effect on the head and trunk for all age groups. In the pre-pretensioning trials, compared to baseline, subjects exhibited 34% and 33% less head excursion, into and out of the shoulder belt respectively. Similar reductions were observed with pre-pretensioning for trunk excursion (45% and 53% reductions, in and out of the belt respectively). Inflating seat torso bolsters reduced lateral kinematics relative to baseline but to a lesser extent than the pre-pretensioner (Head Out of belt: 11%; Head Into Belt: 32% and Trunk Out of Belt: 15%; Trunk Into Belt: 27%). Although there was no overall effect of age on the magnitude of lateral displacement, different age groups employed various neuromuscular strategies to control their kinematics.Conclusion: A pre-pretensioner was an effective vehicle countermeasure during evasive swerving maneuvers as it substantially reduced lateral head and trunk displacement for all age groups. Providing lateral restraint via a sculpted vehicle seat was less effective as the geometry of the torso bolsters when inflated did not provide substantial lateral support.

Human volunteer, in vitro, and molecular level evaluation of an optimized taste-masked isoniazid-chitosan spray-dried microparticle matrix.

For the first time, isoniazid (INH) bitterness value, threshold, and sensitivity (low, moderate, high, and extremely high) was determined in six human volunteers. INH demonstrated a large range in bitterness sensitivity. The current work demonstrates the design of a taste-masked isoniazid (INH)-loaded chitosan microspheres (INH-LCM) using an ionic-gelation and spray drying technique. A 24 full factorial design with three center points was employed to optimize and study the independent variables (chitosan concentration, sodium tripolyphosphate (TPP)-volume, feed rate, and air inlet temperature) effects on the critical quality attributes (percent yield [PY] and entrapment efficiency [EE]). Statistically significant models were developed for PY (p = 0.0357; adjusted R2 = 0.6078) and EE (p = 0.0190; adjusted R2 = 0.6713). A multicriteria prediction profiler was utilized to determine the optimum formulation and process parameters. Two verification batches confirmed excellent predictability and lot-to-lot consistency. In vitro dissolution was used to evaluate the taste masking ability of INH-LCM. The in vitro dissolution test of the optimized INH-LCM suggested that taste masking would be accomplished for the "low" and "moderate" bitterness taste sensitivity groups. Further in vitro and human volunteer taste panel studies with INH-LCM are required for better understand the potential taste masking capability for the "high" and "extremely high" bitterness taste sensitivity groups. The in vitro dissolution method and FTIR data analysis support that TPP crosslinked chitosan may provide taste masking by two mechanisms: (1) acts as a physical barrier and delays INH dissolution; and (2) provides a chemical barrier by forming hydrogen bonds between INH's bitter tasting amino group and chitosan.

Down-regulation of the inflammatory response after short-term exposure to low levels of chemical vapours.

OBJECTIVE: To investigate the relation between signs and symptoms of irritation and biomarkers of inflammatory markers in blood in healthy volunteers exposed to different chemical vapours for 2 or 4 hours in an exposure chamber. METHODS: The investigated chemicals were: acetic acid (5 and 10 ppm), acrolein (0.05 and 0.1 ppm), 1,4-dioxane (20 ppm), n-hexanal (2 and 10 ppm), hydrogen peroxide (0.5 and 2.2 ppm), 2-propanol (150 ppm), m-xylene (50 ppm), standard and dearomatised white spirit (100 and 300 mg/m3). C reactive protein (CRP), serum amyloid A protein and interleukin 6 were measured in plasma immediately before and 2 or 4 hours after the exposures. Symptoms were rated from 0 to 100 mm in Visual Analogue Scales and covered 10 questions whereof four related to irritation: discomfort in the eyes, nose and throat and dyspnoea. The effect measurements included blink frequency by electromyography, nasal swelling by acoustic rhinometry and lung function by spirometry. RESULTS: Logistic quantile regression analyses revealed no significant associations except a negative relation between ratings of irritation and CRP. CONCLUSION: The results suggest a down-regulation of CRP after short-term exposure to low levels of vapours of irritating chemicals. This response might be mediated by the cholinergic anti-inflammatory pathway and further studies are recommended in order to refute or confirm this hypothesis.

Proliferation of enterotoxigenic Escherichia coli strain TW11681 in stools of experimentally infected human volunteers.

BACKGROUND: As part of the effort to develop an enterotoxigenic Escherichia coli (ETEC) human challenge model for testing new heat-stable toxin (ST)-based vaccine candidates, a controlled human infection model study based on the ST-producing ETEC strain TW11681 was undertaken. Here, we estimate stool TW11681 DNA concentration and evaluate its association with dose, clinical symptoms, and with levels of antibodies targeting the CfaB subunit of the ETEC Colonization Factor Antigen I and the E. coli mucinase YghJ. Nine volunteers ingested different doses of the strain and were subsequently followed for 9 days with daily stool specimen collection and clinical examination. Stool DNA was purified by using a newly developed microplate-based method, and DNA originating from TW11681 was quantified by using a probe-based quantitative PCR assay. Antibody levels against CfaB and YghJ were measured in serum collected before and 10 and 28 days after TW11681 was ingested by using a bead-based flow cytometry immunoassay. RESULTS: For 6 of the 9 volunteers, the stool TW11681 DNA concentration increased sharply a median 3.5 (range 2-5) days after dose ingestion, peaking at a median of 5.4% (range 3.3-8.2%) of the total DNA in the specimen. The concentration then fell sharply during the subsequent days, sometimes even before the onset of antibiotic treatment. The size or timing of these proliferation peaks did not seem to be associated with the number of TW11681 bacteria ingested, but the 2 volunteers who developed diarrhea and all five who experienced abdominal pains or cramps had these peaks. The 3 volunteers who did not have the proliferation peaks experienced fewer symptoms and they generally had relatively low CfaB- and YghJ-specific antibody levels before ingesting the strain and subsequently weaker responses than the other volunteers afterwards. CONCLUSIONS: Since the lack of proliferation peaks appears to be associated with fewer clinical symptoms and lower serum antibody responses to virulence factors of the infecting strain, it may be important to account for proliferation peaks when explaining results from controlled human infection model studies and for improving the accuracy of protective efficacy estimates when testing new ETEC diarrhea vaccine candidates.

Stimuli to differentiate the neural response at successive stages of visual processing using the VEP from human visual cortex.

BACKGROUND: Clarifying the enigmatic relationship between stimulus property, neural response and the evoked potential is essential if non-invasive functional imaging is to make a meaningful contribution to the understanding of how maturational or degenerative processes influence brain activity. Visual cortex has proven a favourite target to elucidate this relationship. However, to date most studies involving the visual system have yielded inconsistent results or have been strongly criticised. NEW METHOD: We developed a set of three visual stimuli, two of which either had the same low- or high spatial frequency characteristic. Adult volunteers viewed these as pattern reversing stimuli while the scalp electric potential was recorded using a 10-10 array of electrodes. RESULTS: Established processing mechanisms of the primate visual system enabled us to link the amplitude of the N75 and P100 to the size of the neural population processing the temporal luminance contrast, and the amplitude of the N135 and P240 to the size of the neural processing the spatial luminance contrast in our stimuli. Calculating the distribution of current source density enabled us to identify the neural source of each VEP component. CONCLUSIONS: Demonstrating a direct relationship between the temporal- and spatial luminance contrast properties of our stimuli and the size of the neural population involved provides a better understanding of the nature of the relationship between stimulus property, neural response and the VEP. It also shows that EEG can contribute in a significant manner to the study of the influence of maturational or degenerative processes on brain activity.

Transmission of Methicillin-Resistant Staphylococcus aureus to Human Volunteers Visiting a Swine Farm.

Transmission of methicillin-resistant Staphylococcus aureus (MRSA) from animals to humans is of great concern due to the implications for human health and the health care system. The objective was to investigate the frequency and duration of MRSA carriage in human volunteers after a short-term exposure in a swine farm. The experimental study included 34 human volunteers staying 1 h in a MRSA-positive swine farm in four trials. In two of the trials, the influence of farm work involving pig contact was studied using a crossover design. The quantities of MRSA in nasal swabs, throat swabs, and air samples were measured at different time points and analyzed in relation to relevant covariates. This investigation showed that, overall, 94% of the volunteers acquired MRSA during the farm visit. Two hours after the volunteers left the stable, the nasal MRSA count had declined to unquantifiable levels in 95% of the samples. After 48 h, 94% of the volunteers were MRSA-negative. Nasal MRSA carriage was positively correlated to personal exposure to airborne MRSA and farm work involving pig contact and negatively correlated to smoking. No association was observed between MRSA carriage and face touching behavior, nasal methicillin-susceptible Staphylococcus aureus (MSSA) carriage, age, or gender. The increase in human MRSA carriage among the volunteers with pig contact seems to be dependent on the increased concentration of airborne MRSA of the surrounding air and not directly on physical contact with pigs. MRSA was not detected in any of the throat samples.IMPORTANCE The experimental approach made it possible to elucidate the contributions of airborne MRSA levels and farm work to nasal MRSA carriage in a swine farm. Short-term exposure to airborne MRSA poses a substantial risk for farm visitors to become nasal carriers, but the carriage is typically cleared within hours to a few days. The risk for short-term visitors to cause secondary transmissions of MRSA is most likely negligible due to the observed decline to unquantifiable levels in 95% of the nasal samples after only 2 h. The MRSA load in the nose was highly correlated to the amount of MRSA in the air and interventions to reduce the level of airborne MRSA or the use of face masks might consequently reduce nasal contamination.

Enhanced LC-MS/MS analysis of alogliptin and pioglitazone in human plasma: Applied to a preliminary pharmacokinetic study.

A new fast LC-MS/MS method was developed for determination of alogliptin and pioglitazone in human plasma. Linearity ranges of 10-400ngmL-1 for alogliptin and 25-2000ngmL-1 for pioglitazone, were found to be suitable for their bioanalysis covering the Cmin and Cmax values of the drugs. Direct precipitation technique was used for simultaneous extraction of the drugs successfully from human plasma samples. Chromatographic separation was achieved on a BEH C18 column (50mm×2.1mm, 1.7µm) with 0.1% aqueous formic acid: acetonitrile (40:60, v/v) at a flow rate of 0.3mLmin-1. The validated method was applied to a preliminary pharmacokinetic study on human volunteers. Monitoring the transition pairs of m/z 340.18 to 116.08 for alogliptin and m/z 356.99 to 133.92 for pioglitazone, using triple quadrupole mass spectrometer with multiple reaction monitoring, was achieved in the positive mode. The validated method is accurate and suitable for further clinical applications and possible bioequivalence studies.

Self-Nanoemulsifying Lyophilized Tablets for Flash Oral Transmucosal Delivery of Vitamin K: Development and Clinical Evaluation.

Owing to limited solubility, vitamin K undergoes low bioavailability with large inter-individual variability after oral administration. This article aimed to prepare self-nanoemulsifying lyophilized tablets (SNELTs) for the flash oral transmucosal delivery of vitamin K. Twenty-one formulae of vitamin K self-nanoemulsifying drug delivery systems (SNEDDS) were prepared using different concentrations of vitamin K, Labrasol, and Transcutol according to mixture design. The SNEDDS was loaded on porous carriers and formulated as lyophilized tablets. The release profile and the pharmacokinetic parameters of vitamin K SNELTs were evaluated in comparison with commercial tablets and ampoules on human volunteers. Results revealed that the optimized SNEDDS showed the smallest and most stable nanoemulsion globules. SNELTs were prepared successfully and showed substantial superiority drug release compared with the commercial tablets. Interestingly, SNELTs enhanced both rate and extent of vitamin K absorption as well as relative bioavailability (169.67%) in healthy subjects compared with the commercial tablets. SNELTs revealed promising no significant difference in the area under the curve compared with the commercial intramuscular injection. SNELTs enhanced dissolution and bioavailability that expected to have the strong impact on the efficiency of vitamin K in the prophylaxis and treatment of bleeding disorders in patients with hepatic dysfunction.