Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial.

AIMS: To assess the pharmacokinetic and pharmacodynamic profile of a single dose of empagliflozin in young people with Type 2 diabetes to identify the appropriate doses for further paediatric development. METHODS: We conducted a single-dose, open-label, randomized, parallel-group study with empagliflozin 5 mg, 10 mg and 25 mg in young people with Type 2 diabetes aged 10-17 years. RESULTS: Of 39 participants screened, 27 were randomized and completed the study; their mean (± sd) age was 14.1±2.0 years and body weight was 96.7±23.5 kg. Compared with similar studies in adults with Type 2 diabetes, the maximum observed plasma concentrations were slightly lower with the 10-mg and 25-mg doses, and the area under the plasma concentration-time curve was slightly lower with the 10-mg but slightly higher with the 25-mg dose. The adjusted mean increases in urinary glucose excretion were 53 g/24 h (95% CI 32,74), 73 g/24 h (95% CI 52,94) and 87 g/24 h (95% CI 68,107), and the adjusted mean decreases in fasting plasma glucose were 0.9 mmol/l (95% CI -1.6,-0.1), 0.9 mmol/l (95% CI -1.7,-0.2) and 1.1 mmol/l (95% CI -1.8,-0.5) for the 5- 10- and 25-mg doses, respectively. There were no serious adverse events and one investigator-reported drug-related event (dehydration). CONCLUSIONS: After a single oral dose of empagliflozin, adults and young people with Type 2 diabetes had similar exposure-response relationships after adjusting for significant covariates. These data support testing 10-mg and/or 25-mg doses of empagliflozin in an upcoming paediatric phase III Type 2 diabetes trial. (ClinicalTrials.gov registration no.: NCT02121483).

Patient outcomes and provider perceptions following implementation of a standardized perioperative care pathway for open liver resection.

BACKGROUND: Enhanced recovery after surgery (ERAS) pathways have been associated with improved perioperative outcomes following several surgical procedures. Less is known, however, regarding their use following hepatic surgery. METHODS: An evidence-based, standardized perioperative care pathway was developed and implemented prospectively among patients undergoing open liver surgery between 1 January 2014 and 31 July 2015. Perioperative outcomes, including length of hospital stay, postoperative complications and healthcare costs, were compared between groups of patients who had surgery before and after introduction of the ERAS pathway. Provider perceptions regarding the perioperative pathway were assessed using an online questionnaire. RESULTS: There were no differences in patient or disease characteristics between pre-ERAS (42 patients) and post-ERAS (75) groups. Although mean pain scores were comparable between the two groups, patients treated within the ERAS pathway had a marked reduction in opioid use on the first 3 days after surgery compared with those treated before introduction of the pathway (all P < 0·001). Duration of hospital stay was shorter in the post-ERAS group (median 5 (i.q.r. 4-7) days versus 6 (5-7) days in the pre-ERAS group; P = 0·037) and there was a lower incidence of postoperative complications (1 versus 10 per cent; P = 0·036). Implementation of the ERAS pathway was associated with a 40·7 per cent decrease in laboratory costs (-US $333; -€306, exchange rate 4 January 2016) and a 21·5 per cent reduction in medical supply costs (-US $394; -€362) per patient. Although 91·0 per cent of providers endorsed the ERAS pathway, 33·8 per cent identified provider aversion to a standardized protocol as the greatest hurdle to implementation. CONCLUSION: The introduction of a multimodal ERAS programme following open liver surgery was associated with a reduction in opioid use, shorter hospital stay and decreased hospital costs. ERAS was endorsed by an overwhelming majority of providers.

A novel intubation technique for minimally invasive longitudinal studies of rat lungs using hyperpolarized 3He magnetic resonance imaging.

Hyperpolarized noble gas (HNG) magnetic resonance imaging (MRI) has been shown to be useful for studying rodent models of lung disease. Image quality can be substantially degraded by signal loss from molecular oxygen entering the airway, requiring invasive surgery to ensure a good seal between the endotracheal (ET) tube and trachea. A modified Foley catheter having an inflatable cuff near the tip provides a novel approach for ensuring image quality for HNG MRI, thereby enabling longitudinal studies and reducing animal numbers. A Foley catheter was modified for rodent intubation and to minimize dead space. Three pairs of age-matched male Sprague Dawley rats 400 (30) g were used. Two pairs were intubated using the Foley and the third with an intravenous catheter. Leak rates were measured from pressure versus time curves within each animal. The pairs were euthanized immediately or six days postrecovery to assess the effects of the procedure on animal health, as reflected by histological examination. The Foley catheter resulted in minimal leak rates (-0.20 (0.03) versus -0.16 (0.05) cmH(2)O/s), and were shown to be well below upper-limit leak rates of -0.5 and -0.7 cmH(2)O/s. Tracheal samples from rats in a separate Foley group (not mechanically ventilated) showed superficial damage six days postextubation (grade = 0). (3)He imaging performed using the Foley showed good image quality. Though some technical issues remain to be solved, a modified Foley catheter used as an ET tube offers the potential to enable longitudinal studies in rodents and reduce animal numbers.

Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites.

OBJECTIVE: To compare the phenotype of primary-appearing dystonia due to variant ataxia-telangiectasia (A-T) with that of other dystonia ascertained for genetics research. METHODS: Movement disorder specialists examined 20 Canadian Mennonite adult probands with primary-appearing dystonia, as well as relatives in 4 families with parent-child transmission of dystonia. We screened for the exon 43 c.6200 C>A (p. A2067D) ATM mutation and mutations in DYT1 and DYT6. Clinical features of the individuals with dystonia who were harboring ATM mutations were compared with those of individuals without mutations. RESULT: Genetic analysis revealed a homozygous founder mutation in ATM in 13 members from 3 of the families, and no one harbored DYT6 or DYT1 mutations. Dystonia in ATM families mimicked other forms of early-onset primary torsion dystonia, especially DYT6, with prominent cervical, cranial, and brachial involvement. Mean age at onset was markedly younger in the patients with variant A-T (n = 12) than in patients with other dystonia (n = 23), (12 years vs 40 years, p < 0.05). The patients with A-T were remarkable for the absence of notable cerebellar atrophy on MRI, lack of frank ataxia on examination, and absence of ocular telangiectasias at original presentation, as well as the presence of prominent myoclonus-dystonia in 2 patients. Many also developed malignancies. CONCLUSION: Ataxia and telangiectasias may not be prominent features of patients with variant A-T treated for dystonia in adulthood, and variant A-T may mimic primary torsion dystonia and myoclonus-dystonia.

Proteomic analysis of ovomucoid hypersensitivity in mice by two-dimensional difference gel electrophoresis (2D-DIGE).

There is a need to develop reliable methods to assess the safety of genetically modified and other novel foods. The aim of this study was to identify protein biomarkers of food allergy in mice exposed to ovomucoid (OVM), a major food allergen found in chicken egg white. BALB/c mice were repeatedly sensitized by gavage with OVM and cholera toxin (CT) and control mice were exposed to a mixture of amino acids with CT. At the endpoint, all mice were challenged intraperitoneally with OVM and alum. Type-1 hypersensitivity was confirmed in OVM-sensitized mice by observation of clinical signs of anaphylaxis and elevated levels of plasma histamine, OVM-specific IgE and OVM-specific IgG by ELISA. Differential protein expression was assessed in albumin-depleted plasma as well as in mesenteric lymph node, liver, spleen, and ileum by two-dimensional difference gel electrophoresis (2D-DIGE). Differentially expressed proteins were identified by liquid chromatography with tandem mass spectrometry. Plasma proteins overexpressed in OVM-sensitized mice included haptoglobin (41-fold), serum amyloid A (19-fold) and peroxiredoxin-2 (1.9-fold). Further validation of these plasma proteins in other animal models of food allergy with different food allergens is required to assess their potential as candidate biomarkers for use in evaluating the allergenicity of novel foods.

What is the patient really taking? Discrepancies between surgery and anesthesiology preoperative medication histories.

BACKGROUND: Surgical patients may be at risk for medication discrepancies that may lead to medication errors because both the anesthesiologist and the surgeon write separate preoperative medication histories. METHODS: A prospective observational study was conducted to examine the extent of medication and allergy discrepancies between surgical and anesthesia preoperative medication histories for patients admitted to two surgical intensive care units in an academic medical center. RESULTS: Of the 79 patient records reviewed, 58 (73%) contained at least one discrepancy, 23% had different allergy information, 56% had different preoperative medications, and 43% had different doses or dosing frequencies listed in the medication histories. Of the 988 allergies, medications, and doses or dosing frequencies documented in the two histories, 456 (46%) contained discrepancies. Of these discrepancies, 20 (5%) were due to different allergies, 293 (64%) to different medications, and 143 (31%) to different doses or dosing frequencies. CONCLUSIONS: Discrepancies in preoperative medication histories between surgical and anesthesia records occur in most patients and further work is required to help improve agreement of patient medication histories between services.

Evaluation of a novel, rapid-acting, sterilizing solution at room temperature.

Test data are presented for a novel chemical germicide formulation capable of sterilizing reusable medical devices in 30 minutes at 20 degrees C in an open tray. The tests conducted with this rapid-acting sterilizing solution (RSS) included sporicidal, mycobactericidal, and virucidal studies performed in accordance with Association of Official Analytical Chemist International or Environmental Protection Agency published guidelines, by using RSS stressed for as long as 7 days. Sporicidal assays were performed at 20 degrees C with a 30-minute exposure time by using both Clostridium sporogenes and Bacillus subtilis spores dried on porcelain penicylinders or suture loops (n = 60 carriers per treatment). For comparison, identical carriers were exposed to a commercial glutaraldehyde-based sterilizing solution stressed to a maximum-use time of 14 days and exposed per manufacturer's requirements (10 hours at 25 degrees C). The RSS sterilized 100% of the carriers of both spore types. The glutaraldehyde solution demonstrated 100% sterilization of C sporogenes -treated carriers but had difficulty sterilizing B subtilis spore-laden carriers (ie, no sterilization of suture loops and only 57% sterilization of porcelain penicylinders). Similarly, Mycobacteria bovis and selected fungal and viral agents were exposed to stressed solution for 5 minutes or less at 20 degrees C. In each case, the resulting log decrease in viable microorganisms significantly supported a claim for rapid high-level disinfection. Based on these data, RSS demonstrates high-level disinfection in 5 minutes and sterilization in 30 minutes at 20 degrees C.

Development of a wheelchair occupant injury risk assessment method and its application in the investigation of wheelchair securement point influence on frontal crash safety.

To promote proper wheelchair securement in transportation, the proposed ANSI/RESNA Standard on Wheelchairs Used as Seats in Motor Vehicles will require that all transit wheelchairs be equipped with four securement points compatible with strap-type tiedowns. Through computer simulations, the location of these securement points has been found to influence wheelchair user response to a frontal crash. This study develops and employs an injury risk assessment method to compare the crashworthiness of various securement point configurations. The comparative injury risk assessment method is designed to predict the risk associated with internalized crash forces, as well as risk associated with secondary occupant impact with the vehicle interior. Injury criteria established by Federal Motor Vehicle Safety Standards and General Motors, along with excursion limitations set by the Society of Automotive Engineers (SAE) J2249 Wheelchair Tiedowns and Occupant Restraint Systems (WTORS) Standard were used as benchmarks for the risk assessment method. The simulation model subjected a secured commercial powerbase wheelchair with a seated 50th percentile male Hybrid III test dummy to a 20 g/30 mph crash. The occupant was restrained using pelvic and shoulder belts, and the wheelchair was secured with four strap-type tiedowns. Results indicated that securement points located 1.5 in to 2.5 in above the evaluated wheelchair's center of gravity provide the most effective occupant protection.

Clinical deficits in Huntington disease correlate with reduced striatal uptake on iodine-123 epidepride single-photon emission tomography.

Huntington disease (HD) is characterized by severe abnormalities in neurotransmitter concentrations and neuroreceptor density. Quantitative changes in dopamine D(2) receptors occur in the early stages of HD and may be detectable with functional neuroimaging techniques. The aim of this study was to determine whether dopamine D(2) receptor imaging with single-photon emission tomography (SPET) identifies preclinical abnormalities in HD. The study population comprised 32 subjects from families affected by HD: 11 were genetically normal while 21 were genetically positive for HD (seven asymptomatic, six early, three moderate and five advanced findings). Disease severity was determined using a standardized quantitative neurological examination (QNE) and the mini-mental status examination (MMSE). Subjects underwent brain SPET imaging 120 min following intravenous injection of iodine-123 epidepride. Ratios of target (striatal) to nontarget (occipital or whole-brain) uptake were calculated from the reconstructed image data. Striatum to occiput and striatum to whole-brain count ratios correlated negatively with disease stage (P=0.002 and P=0.0002) and QNE (P<0. 002 and P=0.0002), and positively with the MMSE (P=0.001 and P<0. 001). Uptake was significantly reduced in the moderate-advanced subjects but was still normal for the asymptomatic and early symptomatic stages. It is concluded that reductions in striatal dopamine D(2) receptor density can be detected with (123)I epidepride at moderate or advanced stages of HD. In contrast to other reports, we could not identify abnormalities in clinically unaffected or early stages of HD.

Ropinirole and pramipexole, the new agonists.

Ropinirole and pramipexole are non-ergoline dopamine agonists which are relatively specific for the D2 family of dopamine receptors. They have side-effect profiles linked to peripheral and central dopaminergic stimulation, amenable to tolerance through a slow titration or the addition of domperidone in sensitive patients. They do not have the uncommon but problematic ergot-related side effects of bromocriptine and pergolide. Ropinirole and pramipexole have both been shown to be efficacious when used as monotherapy in early Parkinson's disease (PD), and have been suggested as being less likely than levodopa to lead to the early development of motor fluctuations and dyskinesias in this clinical setting. They have also been shown to be useful as adjunctive therapy to levodopa in advanced PD and to have a levodopa-sparing effect in these patients. Dose equivalents amongst the available dopamine agonists is difficult to know with certainty but has been estimated as follows: 30 mg of bromocriptine, 15 mg of ropinirole, 4.5 mg of pramipexole, and 3.0 mg of pergolide.

Computer simulation and sled test validation of a powerbase wheelchair and occupant subjected to frontal crash conditions.

The Americans with Disabilities Act (ADA) has led to an increased number of wheelchair users seeking transportation services. Many of these individuals are unable to transfer to a vehicle and are instead required to travel seated in their wheelchairs. Unfortunately, wheelchairs are not typically designed with the same occupant protection features as motor vehicle seats, and wheelchair seated occupants may be at higher risk for injury in a crash. To study the effects of crash level forces on wheelchairs and their occupants, it is useful to simulate crash conditions using computer modeling. This study has used a dynamic lumped mass crash simulator, in combination with sled impact testing, to develop a model of a secured commercial powerbase and restrained occupant subjected to a 20 g/30 mph frontal motor vehicle crash. Time histories profiles of simulation-generated wheelchair kinematics, occupant accelerations, tiedown forces and occupant restraint forces were compared to sled impact testing for model validation. Validation efforts for this model were compared to validation results found acceptable for the ISO/SAE surrogate wheelchair model. This wheelchair-occupant simulation model can be used to investigate wheelchair crash response or to evaluate the influence of various factors on occupant crash safety.

Postural changes with aging in tetraplegia: effects on life satisfaction and pain.

OBJECTIVES: (1) To measure kyphosis and scoliosis in individuals with tetraplegia; (2) to examine the relation between kyphosis and scoliosis and years since injury; and (3) to determine the association between kyphosis and scoliosis and measures of pain, depression, and life satisfaction. DESIGN: Cross-sectional, case-control study. SETTING: University medical center and a free-standing university-affiliated rehabilitation hospital. PARTICIPANTS: (1) Ten individuals with tetraplegia I to 3 years postinjury (NT); (2) 10 individuals with tetraplegia 10 to 20 years postinjury (OT); and (3) 10 control individuals (C) matched to the other subjects on the basis of age, height, and weight. MAIN OUTCOME MEASURES: Radiographic measurements of kyphosis and scoliosis taken in a seated position, pain as measured by the short form of the McGill Pain Questionnaire (SF-MPQ), depression as measured by the Center for Epidemiological Studies-Depression Scale (CES-D), and life satisfaction as measured by the Life Satisfaction Index Assessment (LSIA) and the Craig Handicap Assessment and Reporting Technique (CHART). RESULTS: No significant differences were seen between the OT and NT groups with respect to age, height, or weight. In addition, no significant differences were found between the NT and OT groups with respect to measures of kyphosis and scoliosis. Individuals with tetraplegia had significantly higher (p < .05) measures of kyphosis (42 + 16.0 ) and scoliosis (14 degrees +/-9.2 degrees) than the C subjects (kyphosis, 32 degrees +/- 7.9 degrees ; scoliosis, 5 degrees+/-3.8 degrees). No correlation was found between scores on the SF-MPQ and degree of kyphosis or scoliosis. Significant differences were seen between the NT and OT groups on both CES-D (NT, 15.2+/-8.1; OT, 5.8+/-5.5) and LSIA (NT, 9.9+/-2.8; OT, 14.4+/-2.9). CONCLUSION: This study indicates that seated kyphosis and scoliosis develop early in individuals with tetraplegia and may not be progressive. No association was seen between pain and kyphosis or scoliosis in this relatively young sample (mean age of OT and NT combined, 34.8 years). Future research is needed to determine whether pain becomes a problem in individuals with significant kyphosis or scoliosis as they age.

Development and evaluation of a new alcohol-based surgical hand scrub formulation with persistent antimicrobial characteristics and brushless application.

BACKGROUND: Since the introduction in the 1970s of surgical hand scrub formulations that contain 4% chlorhexidine gluconate (CHG), new surgical scrub formulations that have improved efficacy, persistence, or significantly improved use characteristics have not been forthcoming. In addition, the manufacturer's labeling for popular hand scrub products generally requires scrub times in excess of 6 minutes, whereas current practical needs call for products with substantially shorter scrub times. A new alcohol-based surgical scrub formulation, which has ingredients that provide emollient, surfactant, and antimicrobial persistence characteristics to complement the rapid and broad-spectrum antiseptic qualities of alcohol, has been developed in an effort to address these current practical needs. METHODS: The relative efficacy of a new alcohol-based surgical scrub formulation that contains ingredients that provide surfactant and antimicrobial persistence characteristics was compared with that of commercial 4% CHG and 7.5% povidone iodine (PVPI) formulations with use of human subjects. Hand antimicrobial count sampling was performed by using standardized "glove juice" methodology. RESULTS: The efficacy and persistence results of the new formulation showed statistically significant improvement over both CHG and PVPI at a substantially lessened scrub time (3 minutes). In addition, use of the new formulation without a scrub brush produced results statistically similar to 3-minute applications with either a brush or a sponge. CONCLUSIONS: The new alcohol-based formulation demonstrates promise as a new surgical hand scrub formulation with antimicrobial and use characteristics that are significantly improved over current CHG and PVPI formulations. These studies demonstrate the suitability of this formulation for use as a surgical hand scrub and for brushless application.

p53 mutations isolated in yeast based on loss of transcription factor activity: similarities and differences from p53 mutations detected in human tumors.

p53 is a transcriptional activator that plays a key role in the integration of signals inducing cell division arrest and programmed cell death. Moreover, p53 is a tumor suppressor gene, mutations of which are the most commonly detected mutations in diverse malignancies. In order to better understand the significance of p53 mutations to human cancer, we isolated mutant alleles of p53 that had lost transcription factor activity in yeast. These mutant alleles were evaluated for their precise changes, their activity against three different p53 responsive enhancers and their ability to act in a transdominant fashion to the wild type allele. While many of the mutations isolated in yeast resembled those found in human tumors, consistent with the importance of transcription factor activity for p53 in mammalian cells, the mutational spectrum obtained was dependent upon the p53 enhancer employed for the selection. Some mutations specifically inactivated p53 in yeast for a single enhancer element. Virtually all missense mutations tested had a dominant inhibitory effect on wild type p53 in yeast. Since some of these transdominant mutations are virtually unknown in human tumors we conclude that transdominance, per se, fails to predict which mutations occur frequently in cancer.

Comparison of an in vitro skin model to normal human skin for dermatological research.

EpiDerm, an in vitro human skin equivalent (HSE), was compared to normal human breast skin (NHS) to morphologically and biochemically assess its feasibility for dermatological research. Intralot and interlot variability was studied in day 0, 1, 2, and 3 in vitro cultures and in day 0, 3, 5, and 7 NHS. For NHS, light microscopy (LM) at day 0 showed stratified epidermis which exhibited an increase in vacuoles and dark basal cells as storage increased to 3, 5, and 7 days. Transmission electron microscopy (TEM) revealed typical organelles in the epidermis and a convoluted basement membrane at day 0. With increased storage, vacuoles and paranuclear clefts became numerous, necrosis increased, tonofilaments became less organized, and overall cellular integrity decreased. Biochemical data showed consistent MTT and glucose utilization (GU) through day 5, while lactate production decreased to 75% by day 3. By LM, day 0 HSE consisted of a thick, compact, stratum corneum that sent projections between the stratum granulosum cells. By TEM, the configuration organization, differentiation, distribution, and frequency of the organelles differed slightly from NHS. In addition, the basement membrane of the HSE was not completely differentiated, and the dermis was thin and acellular. Although day 1 and 2 cultures showed little change, day 3 exhibited an overall degeneration. Biochemical analysis showed GU and the lactate production decreased through day 3. In conclusion, the EpiDerm HSE, although exhibiting slight differences, was morphologically and biochemically similar to normal human epidermis and may be a valuable model in assessing the toxicology, metabolism, or pharmacology of nonvesicating compounds.

Botulinum toxin injection for cervicogenic headache.

We report a 28-year-old woman with a 5-year history of cervicogenic headache following a whiplash injury. Her unilateral neck pain, if aggravated by exertion, would create a predictable sequence of events leading to a hemicephalgia. She proved medically refractory to usual therapies, but had a striking response to a single botulinum toxin Injection in her symptomatic trapezius muscle. Repeated Injections every 3 months have been required to maintain this benefit. The Implications of this observation are discussed.

Wheeled mobility device database for transportation safety research and standards.

To address the issue of safely accessing and securing wheeled mobility devices in motor vehicles, more information characterizing current-production devices was needed. In a recent effort, frame characteristics of wheeled mobility devices were defined and a database developed for recording characteristics relevant to access and securement. A representative number of devices have been surveyed to measure key characteristics, and these measures have been recorded in the database. This paper details the development of the database and frame characterization scheme, the methods used to survey currently available wheeled mobility devices, and some descriptive statistics resulting from an analysis of the data. A discussion of how this information is being used in research aimed at developing technology and safety standards to ensure vehicle access and safe transportation, as well as other potential uses, is also included.