Towards prevention of ischemia-reperfusion kidney injury: Pre-clinical evaluation of 6-chromanol derivatives and the lead compound SUL-138✰.

Acute kidney injury (AKI) is a global healthcare burden attributable to high mortality and staggering costs of dialysis. The underlying causes of AKI include hypothermia and rewarming (H/R), ischemia/reperfusion (I/R), mitochondrial dysfunction and reactive oxygen species production. Inspired by the mechanisms conferring organ protection in hibernating hamster, 6-chromanol derived compounds were developed to address the need of effective prevention and treatment of AKI. Here we report on the pre-clinical screening of 6-chromanol leads that confer protection during I/R to select compounds with favorable profiles for clinical testing in AKI. A library of 6-chromanols (n = 63) was screened in silico for pharmacochemical properties and druggability. Selected compounds (n = 15) were screened for the potency to protect HEK293 cells from H/R cell death and subjected to a panel of in vitro safety assays. Based on these parameters, SUL-138 was selected as the lead compound and was found to safeguard kidney function and decrease renal injury after I/R in rats. The compound was without cardiovascular or respiratory effects in vivo. SUL-138 pharmacokinetics of control animals (mouse, rat) and those undergoing I/R (rat) was identical, showing a two-phase elimination profile with terminal half-life of about 8 h. Collectively, our phenotype-based screening approach led to the identification of 3 candidates for pre-clinical studies (5%, 3/64). SUL-138 emerged from this small-scale library of 6-chromanols as a novel prophylactic for AKI. The presented efficacy and safety data provide a basis for future development and clinical testing. SECTION ASSIGNMENTS: : Drug discovery and translational medicine, renal, metabolism SIGNIFICANCE STATEMENT: : Based on in silico druggability parameters, a 63 compound 6-chromanol library was narrowed down to 15 compounds. These compounds were subjected to phenotypical screening of cell survival following hypothermia damage and hit compounds were identified. After subsequent assessment of in vivo efficacy, toxicity, pharmacokinetics, and cardiovascular and respiratory safety, SUL-138 emerged as a lead compound that prevented kidney injury after ischemia/reperfusion and demonstrated a favorable pharmacokinetic profile unaffected by renal ischemia.

Electric vehicle sound stimuli data and enhancements.

Data for six electric vehicle WOT interior sound measurements and eight enhanced sound signatures are presented. The measurement of electric vehicle interior sound signature data and the enhancement of these stimuli are documented in this data article. The procedures and equipment that were used to record the data, as well as the transposition, harmony and order addition, frequency filtering and modulation enhancement techniques that were applied to these stimuli are explained in detail. The transient frequency content of the 12 sound stimuli is presented in acoustic spectrograms along with the audio files in.mp3 format.

Ground-based assessment of the bias and long-term stability of fourteen limb and occultation ozone profile data records.

The ozone profile records of a large number of limb and occultation satellite instruments are widely used to address several key questions in ozone research. Further progress in some domains depends on a more detailed understanding of these data sets, especially of their long-term stability and their mutual consistency. To this end, we made a systematic assessment of fourteen limb and occultation sounders that, together, provide more than three decades of global ozone profile measurements. In particular, we considered the latest operational Level-2 records by SAGE II, SAGE III, HALOE, UARS MLS, Aura MLS, POAM II, POAM III, OSIRIS, SMR, GOMOS, MIPAS, SCIAMACHY, ACE-FTS and MAESTRO. Central to our work is a consistent and robust analysis of the comparisons against the ground-based ozonesonde and stratospheric ozone lidar networks. It allowed us to investigate, from the troposphere up to the stratopause, the following main aspects of satellite data quality: long-term stability, overall bias, and short-term variability, together with their dependence on geophysical parameters and profile representation. In addition, it permitted us to quantify the overall consistency between the ozone profilers. Generally, we found that between 20-40 km the satellite ozone measurement biases are smaller than ±5 %, the short-term variabilities are less than 5-12% and the drifts are at most ±5% decade-1 (or even ±3 % decade-1 for a few records). The agreement with ground-based data degrades somewhat towards the stratopause and especially towards the tropopause where natural variability and low ozone abundances impede a more precise analysis. In part of the stratosphere a few records deviate from the preceding general conclusions; we identified biases of 10% and more (POAM II and SCIAMACHY), markedly higher single-profile variability (SMR and SCIAMACHY), and significant long-term drifts (SCIAMACHY, OSIRIS, HALOE, and possibly GOMOS and SMR as well). Furthermore, we reflected on the repercussions of our findings for the construction, analysis and interpretation of merged data records. Most notably, the discrepancies between several recent ozone profile trend assessments can be mostly explained by instrumental drift. This clearly demonstrates the need for systematic comprehensive multi-instrument comparison analyses.

A study of energy-related injuries from hospital admissions among children and adults in South Africa.

INTRODUCTION: Burn and ingestion injuries are common in developing countries because of poor access to safe energy sources, crowded living conditions, and insufficient knowledge of potential risks. The purpose of this study is to understand the scope of burn and ingestion injuries due to various energy source usages in South Africa. METHODS: Patients at 16 regional hospitals throughout South Africa presenting with an energy-related injury between 2006 and 2012 were interviewed to obtain demographics and injury characteristics. RESULTS: A total of 12,443 patients were included in this study. Children aged 1-2 years predominantly experienced burn and ingestion injuries (21%). Liquid burns (30%) were more common than flame burns (14%). Chi-squared tests show that age was significantly related to degree of burn, type of burn, and severity of burn (p<0.001). Non-intentional injuries (45%) were more frequent than self-inflicted or assault injuries. Temporal and seasonal injury trends reflect usage patterns. Burn injuries result in longer hospital length of stay than ingestion injuries. CONCLUSION: Non-intentional liquid burns and ingestions to infants and babies were most common in this study, with many injuries also occurring among young adults. It is advised that interventions targeting low-income communities be conducted to increase awareness of burn and ingestion injuries.

Effect of ammonium-iron-hexa-cyanoferrate and of the covariates age, gender, weight, season and calendar time on radiocaesium contamination of wild boars living in the wild in Bavaria.

Feed with Ammonium-iron-hexa-cyanoferrate (AFCF; 1250 mg AFCF/kg) was fed between March 2009 and March 2011 to wild boars in a territory of 4.5 km(2) (experimental group, EXP). One hundred and forty similar territories in the same county (500 km(2) , spruce forest, agriculture) served as control (CON). Data for comparison from all territories were available from March 2005 to March 2011. Wild boars could move between, into and from the territories. Lean skeletal muscle meat (500 g) of all wild boars that were killed by humans (hunting and traffic accidents) was investigated for gamma-radiation from (137) Cs with a becquerel monitor with a sodium iodide scintillator crystal (range of detection 20-9999 Bq/kg). The wild boars were weighed, and gender and age were determined. For the analyses of effects, multivariable regression models were fitted with the (137) Cs concentration as response variable. There was a significant difference between the (137) Cs contamination of wild boars from CON (563 ± 932 Bq/kg meat, n = 1253) and EXP (236 ± 276 Bq/kg meat; n = 45). (137) Cs contamination decreased with increasing body weight by -5 Bq/kg meat/kg body weight increase (p < 0.05). Females had higher Bq measurements than males (by +80 Bq/kg meat, p < 0.05). Piglets were lower than adults, but turn-coats higher. From November to May, contamination was higher (by +500 to +600 Bq/kg meat, p < 0.05) than during the rest of the year. In 2010, contamination was higher (by +200 to + 300 Bq/kg meat, p < 0.05) in comparison with the other years under observation. When all covariates were controlled for, the effect of AFCF was highly significant. Interaction analyses showed that the intervention decreased (137) Cs contamination by -500 Bq/kg meat during November to May and by -200 Bq/kg meat during the rest of the year. In summary, AFCF feeding reduces (137) Cs contamination of wild boars living in the wild significantly, particularly during the season from November to May.

Variance components for live weight, body measurements and reproductive traits of pair-mated ostrich females.

Estimates of genetic parameters for reproductive traits, live weight and body measurements were obtained using data from a pair-mated ostrich flock at Oudtshoorn in South Africa. Reproductive traits included total egg and chick production, along with hatchability percentage. Live weight, chest circumference and tail circumferences were recorded at the commencement and cessation of breeding. Heritability estimates (h(2)) were 0.23 for egg production, 0.20 for chick production, 0.10 for hatchability, 0.20 to 0.34 for live weight, 0.12 for chest circumference and 0.30 to 0.38 for tail circumference. Female permanent environmental effects (c(2)) amounted to 0.18 for egg production, 0.18 for chick production, 0.21 for hatchability, 0.32 to 0.36 for live weight and 0.23 to 0.32 for chest circumference. Service sire exerted significant effects only on hatchability (0.22) and subsequently chick production (0.09). Genetic correlations of reproductive traits with live weight were low to moderate, variable in sign, and did not differ significantly from zero. Correlations between live weight recorded at the beginning and end of the breeding season were unity for additive genetic and permanent environmental effects. Egg and chick production were highly correlated genetically and phenotypically, with the genetic correlation exceeding the theoretical limit. In unconstrained analyses, hatchability was positively related to chick production, including at the service sire level. Selection gains in the current flock and future generations are likely. No significant adverse relationships were found between live weight, body measurements and reproductive traits.

Cigarette use among male and female grade 8-10 students of different ethnicity in South African schools.

OBJECTIVES: To provide data on the prevalence of cigarette use by male and female South African students of different ethnic backgrounds in grades 8-10 (ages < or = 11 to > or = 17 years), their age of initiation of cigarette use, as well as their access to cigarettes through underage sales. DESIGN: A nationally representative survey was conducted using self administered questionnaires translated into seven languages. SETTING: School based. PARTICIPANTS: Students in grades 8-10 in all of South Africa's nine provinces. OUTCOME MEASURES: The prevalence data for current users of cigarettes (smoked on one or more days in 30 days preceding the survey), and for the age of initiation (first smoking cigarettes before the age of 10) were analysed. RESULTS: Of the 160 selected schools, 123 schools participated in the survey. The completed survey comprised 6045 of 7074 selected students; 23% of the sample reported being current users of cigarettes. Significantly more males (28.8%) than females (17.5%), and significantly more "Coloured" students than "Black/African" students were classified as current smokers. Sex was the strongest contributor to the prediction of current smoking status. On the issue of age of initiation, 18.5% of students reported having first smoked cigarettes before the age of 10 years with more "Black/African" students than "Coloured" having done so. CONCLUSIONS: In order to tailor tobacco control programmes to the needs of students, historical "racial"/ethnic and sex differences have to be taken into account. Specific determinant studies are needed to understand these differences and to develop appropriate responses.

Preliminary results on the use of diagnostic ultrasonography as a management tool to quantify egg production potential in breeding ostrich (Struthio camelus australis) females.

An ostrich breeding flock, joined as individual breeding pairs (n = 136 pairs), was used to investigate the possibility of diagnostic ultrasonography as a method to predict the reproductive performance of ostrich females during a breeding season. Follicular activity was easily detected and quantified by using diagnostic ultrasonography. One to 8 follicles were recorded in 25% of females scanned at the beginning of the 9-month breeding season. At the end of the breeding season, 1-3 follicles were observed in 28.7% females. Females in which follicular activity was observed came into production earlier than those in which no follicles were observed, with the mean (+/- SE) number of days to the production of the 1st egg being 22.3 +/- 12.5 and 87.4 +/- 7.2 days, respectively. Females in which follicular activity was observed at the beginning of the breeding season, produced on average 181% more eggs during the 1st month of the breeding season (P < 0.01) than females in which no follicular activity was observed (6.67 +/- 0.70 vs 2.37 +/- 0.41 eggs). Egg production over the first 2 months of breeding and over the entire breeding season were similarly affected (P < 0.01), with the mean number of eggs produced over the first 2 months of the breeding season being 14.7 +/- 1.5 for females with observed follicular activity and 7.4 +/- 0.9 eggs for females with no observed follicular activity. Females in which follicular activity was observed at the end of the breeding season produced on average 108% more eggs (P < 0.01) during the last month of the breeding season than females in which no follicular activity was observed (2.77 +/- 0.43 vs. 1.33 +/- 0.27 eggs). There was a tendency (P = 0.06) for egg production over the last 2 months to be similarly affected (6.10 +/- 0.85 vs 4.19 +/- 0.54 eggs). No relationship with egg production over the entire breeding season was found for the end-of-the-breeding-season observations. Diagnostic ultrasonography can thus be used as a management tool to identify reproductively healthy ostrich females and also females with a higher egg production potential over a period of 2 months after or prior to assessment. Future studies should focus on the development of the technique to predict reproductive performance over entire breeding seasons for selection purposes.

Development of ultratrace laser spectrometry techniques for measurements of arsenic.

Several techniques based on laser induced fluorescence (LIF) spectrometry and laser enhanced ionization (LEI) spectrometry have been investigated for ultratrace measurements of arsenic. Studies by our group in this area that have been published previously are reviewed here, and are presented along with the results of recent studies that have not yet been published. The techniques presented include LIF detection in the inductively coupled plasma atomizer, the electrothermal atomizer, the tungsten coil atomizer, the flame atomizer and LEI detection in the flame atomizer, and include approaches that utilize hydride generation or laser ablation sample introduction. Recent efforts have been directed towards developing speciation approaches for arsenic that utilize LIF spectrometric detection. The capabilities of each technique are summarized including the sensitivity and limits of detection, which range from sub-pg ml(-1) to ng ml(-1) levels. Selected applications of the techniques are presented to demonstrate their utility for environmental and biological samples, and areas for future investigation and further development are discussed.

Development of an electrothermal atomization laser-excited atomic fluorescence spectrometry procedure for direct measurements of arsenic in diluted serum.

A procedure for the direct determination of arsenic in diluted serum by electrothermal atomization laser-excited atomic fluorescence spectrometry (ETA-LEAFS) is reported. Laser radiation needed to excite As at 193.696 and 197.197 nm is generated as the second anti-Stokes stimulated Raman scattering output of a frequency-doubled dye laser operating near 230.5 and 235.5 nm, respectively. Two different LEAFS schemes have been utilized and provide limits of detection of 200-300 fg for As in aqueous standards. When measurements of serum samples diluted 1:10 with deionized water are performed, a stable background signal is observed that can be accounted for by taking measurements with the laser tuned off-wavelength. No As is detected in any of the bovine or human serum samples analyzed. Measurements of 100 pg/mL standard additions of As to a diluted bovine serum sample utilizing either inorganic or organic As species demonstrate a linear relationship of the fluorescence signal to As spike concentration, but exhibit a sensitivity of approximately half that observed in pure aqueous standards. The limit of detection for As in 1:10 diluted serum samples is 65 pg/mL or 650 fg absolute mass, which corresponds to 0.65 ng/mL As in undiluted serum. To our knowledge, the ETA-LEAFS procedure is currently the only one capable of directly measuring As in diluted serum at these levels.

Establishing networks for health promoting schools in South Africa.

South African schools were segregated by years of discriminatory practice. Apartheid policies adversely affected the health and social status of children in South Africa. The conceptual framework suggested by the health promoting schools movement was adopted in South Africa to address school health comprehensively. This approach provides a useful framework because it focuses not on the curriculum but on the school environment, community involvement, policy development, and appropriate health and social services. Currently, several initiatives in South Africa focus on developing networks of health promoting schools. Initiatives seen as a mechanism to address the historical inequities among children in South Africa are described.

Ozone differential absorption lidar algorithm intercomparison.

An intercomparison of ozone differential absorption lidar algorithms was performed in 1996 within the framework of the Network for the Detection of Stratospheric Changes (NDSC) lidar working group. The objective of this research was mainly to test the differentiating techniques used by the various lidar teams involved in the NDSC for the calculation of the ozone number density from the lidar signals. The exercise consisted of processing synthetic lidar signals computed from simple Rayleigh scattering and three initial ozone profiles. Two of these profiles contained perturbations in the low and the high stratosphere to test the vertical resolution of the various algorithms. For the unperturbed profiles the results of the simulations show the correct behavior of the lidar processing methods in the low and the middle stratosphere with biases of less than 1% with respect to the initial profile to as high as 30 km in most cases. In the upper stratosphere, significant biases reaching 10% at 45 km for most of the algorithms are obtained. This bias is due to the decrease in the signal-to-noise ratio with altitude, which makes it necessary to increase the number of points of the derivative low-pass filter used for data processing. As a consequence the response of the various retrieval algorithms to perturbations in the ozone profile is much better in the lower stratosphere than in the higher range. These results show the necessity of limiting the vertical smoothing in the ozone lidar retrieval algorithm and questions the ability of current lidar systems to detect long-term ozone trends above 40 km. Otherwise the simulations show in general a correct estimation of the ozone profile random error and, as shown by the tests involving the perturbed ozone profiles, some inconsistency in the estimation of the vertical resolution among the lidar teams involved in this experiment.

Laser-induced fluorescence of se, as, and sb in an electrothermal atomizer.

Trace detection of Se, As, and Sb atoms has been performed by electrothermal atomization laser-induced fluorescence (ETA-LIF) approaches. Production of far-UV radiation necessary for excitation of As atoms at 193.696 nm and Se atoms at 196.026 nm was accomplished by stimulated Raman shifting (SRS) of the output of a frequency-doubled dye laser operating near 230 nm. Both wavelengths were obtained as second-order anti-Stokes shifts of the dye laser radiation and provided up to 10 µJ/pulse, which was shown through power dependence studies to be sufficient for saturation in the ETA. An excited-state direct line fluorescence approach using excitation at 206.279 nm was also investigated for the LIF detection of Se. High-sensitivity LIF of Sb atoms was accomplished using 206.833-nm excitation and detection at 259.805 nm. The accuracy of the ETA-LIF approaches was demonstrated by determining the As and Se content of aqueous reference samples. The limits of detection (absolute mass) were 200 fg by ground-state LIF and 150 fg by excited-state direct line fluorescence for Se, 200 fg for As, and 10 fg for Sb; these LODs compare favorably with results reported previously in the literature for ETA-LIF, GFAAS, and ICP-MS methods.

Perinatal mortality in lambs of ewes exposed to cultures of Diplodia maydis (= Stenocarpella maydis) during gestation. A study of the central-nervous-system lesions.

Previously published results of dosing trials, involving 82 ewes, revealed that 66% of the offspring of dams exposed to cultures of Diplodia maydis in the second trimester of pregnancy and 87% of lambs of ewes exposed in the third trimester, were born dead or died soon afterwards. Spongiform degeneration of myelin of varying degree was present in the brains of all the stillborn and non-viable lambs in these trials. Myelin lamellae were separated at the intraperiod line. The spongiform degeneration occurred throughout the central nervous system in severely affected animals, whereas in mildly affected lambs the lesions had a predilection for the white matter, particularly of the cerebellum and cerebrum. In 28 lambs the spongiform degeneration progressed to lytic necrosis, and hydrocephalus was recorded in two animals.

Exercise training and prescription for the elderly.

Most exercise programs designed for healthy persons older than 65 emphasize fitness development, but the maintenance of functional capacity and quality of life are equally important. The basic guidelines for frequency, intensity, and duration of training and the mode of activity recommended by the American College of Sports Medicine for healthy adults are also appropriate for the elderly. The difference in the exercise prescription for the elderly participant is the manner in which it is applied. Given that the elderly person is more fragile and has more physical-medical limitations than the middle-aged participant, the intensity of the program is usually lower while the training frequency and duration are increased. The mode of training should avoid high-impact activities, and the progression of training should be more gradual. The prescribed training heart rate for the elderly at 40% to 80% of maximal heart rate reserve is slightly lower than the 50% to 85% recommended for young and middle-aged participants, but its relationship to relative metabolic work (50% to 85% of maximal oxygen uptake) and rating of perceived exertion are similar to those found for younger participants. Because of the importance of maintaining muscle mass and bone in middle and old age, a well-rounded program including strength/resistance exercise of the major muscle groups is recommended. Hence the exercise prescription for the elderly should emphasize low to moderate intensity and low-impact activities, avoid heavy static-dynamic lifting, and allow a gradual progression in training.

Differential absorption lidar system for routine monitoring of tropospheric ozone.

A differential absorption lidar system for routine profiling of tropospheric ozone for daytime and nighttime operation is described. The system uses stimulated Raman scattering in hydrogen and deuterium of 266-nm radiation from a quadrupled Nd:YAG laser. Ozone profiles from altitudes of 600 m to approximately 5 km have been obtained with analog detection. Implementing corrections for differential Rayleigh scattering, differential absorption from oxygen, sulphur dioxide, and nitrogen dioxide, and differential aerosol extinction and backscatter can reduce the total system inaccuracy to 5-15% for a clear day and 20-30% for a hazy day, except at the top of the mixed layer. Photon counting must be installed to increase the measurement range from 5 to 15 km. An example of an application of routine measurements of tropospheric ozone profiles is given.

Nest microclimate and incubation water loss of eggs of the African ostrich (Struthio camelus var. domesticus).

The microclimate of the nest and the rates of egg water loss were studied at weekly intervals throughout the 41-day incubation period in six ostrich nests. Overall mean values were a central egg temperature of 34.9 degrees C associated with saturation vapor pressure of 42 torr, a mean nest vapor pressure of 11 torr, and an ambient vapor pressure of 8.4 torr. The egg water loss increased from 4,000 to 4,800 mg X day-1 over the incubation period, and the total water loss was equal to 13.2% of the initial egg mass of 1,368 gm. The mean rate of water loss (4,403 mg X day-1) divided by the water vapor conductance of the shell (147 mg X day-1 X torr-1) equals 30 torr. When this value is added to the nest vapor pressure of 11 torr, it predicts an egg saturation vapor pressure of 41 torr, similar to that derived from the central egg temperature.

The tolerability and efficacy of a 6-month antituberculosis regimen containing rifampicin, isoniazid and pyrazinamide.

The tolerability and efficacy of a 6-month daily regimen of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) were tested in 130 hospitalized patients, mostly Black, with previously untreated pulmonary tuberculosis. PZA was discontinued at the end of the 2nd month. In 6 cases treatment was discontinued because of drug intolerance. The symptoms were severe rash, mild thrombocytopenia, deteriorating haematological and renal condition and in the remaining 3 patients hyperbilirubinaemia. Of the 125 patients who could be assessed bacteriologically, 110 were infected with organisms which were fully susceptible to INH and RMP, and 95% of their cultures and 77% of their smears had converted to negative after 2 months of treatment. Similar results were obtained for all but 2 of the 15 patients with drug-resistant bacilli. Cavitation of the lungs was reduced in 78% of the patients and the extent of other tuberculous lesions diminished in 87%.