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Background Spinal cord injury (SCI) leads to various degrees of lifelong functional deficits. Most individuals with incomplete SCI experience a certain degree of functional recovery, especially within the first-year postinjury. However, this is difficult to predict, and surrogate biomarkers are urgently needed. Objective We aimed to (1) determine if routine blood chemistry parameters are related to neurological recovery after SCI, (2) evaluate if such parameters could predict functional recovery, and (3) establish cutoff values that could inform clinical decision-making. Methods We performed a post hoc analysis of routine blood chemistry parameters in patients with traumatic SCI (n = 676). Blood samples were collected between 24 and 72 hours as well as at 1, 2, 4, 8, and 52 weeks postinjury. Linear mixed models, regression analysis, and unbiased recursive partitioning (URP) of blood chemistry data were used to relate to and predict walking recovery 1 year postinjury. Results The temporal profile of platelet counts and serum levels of albumin, alkaline phosphatase, and creatinine differentiated patients who recovered walking from those who remained wheelchair bound. The 4 blood chemistry parameters from the sample collection 8 weeks postinjury predicted functional recovery observed 1 year after incomplete SCI. Finally, URP defined a cutoff for serum albumin at 3.7 g/dL, which in combination with baseline injury severity differentiates individuals who regain ambulation from those not able to walk. Specifically, about 80% of those with albumin >3.7 g/dL recovered walking. Conclusions Routine blood chemistry data from the postacute phase, together with baseline injury severity, predict functional outcome after incomplete SCI.

It is controversial whether it is cost-beneficial for late preterm infants to receive respiratory syncytial virus prophylaxis. This study compares community and hospital health care resource utilization (HCRU) of late premature infants (33-36 weeks gestational age) with term infants (>36 weeks gestational age) hospitalized with bronchiolitis. This was a retrospective, population-based, observational study spanning a 9-year period (2004-2012). HCRU data were obtained from the Health Maintenance Organization “Clalit” and included duration of hospitalization, physician visits, laboratory tests, and treatments. Compared with term infants, late preterm infants had significantly longer duration of hospitalization and higher admission rates to pediatric intensive care unit. They also had higher rates of mean outpatients clinic visits, total outpatient clinic and specialist visits, blood chemistry, and virology testing. HCRU of term infants with bronchiolitis was also substantial, indicating that they also can greatly benefit from respiratory syncytial virus prophylaxis. These findings can guide stakeholders in decisions concerning the prevention of bronchiolitis and will be useful in performing further cost-benefit analysis.

Background: Lifestyle interventions, including dietary modifications, play a key role in the treatment of type 2 diabetes. By the second half of the last century, dietary oatmeal interventions had frequently been used in patients with diabetes; however, with the widespread introduction of insulin, this practice gradually fell into disuse. Within the last decades, the original oatmeal intervention, first described in 1903, has been modified towards a hypocaloric, low-fat, and plant-based intervention. Aim: The aim of this review was to investigate the current role of these adapted short-term dietary oatmeal interventions in the treatment of patients suffering from poorly-controlled type 2 diabetes. A special focus was put on opportunities for and barriers to its clinical implementation and its potential mechanisms of action. Methods: The electronic databases of PubMed and Google Scholar were searched using the keywords “oat,” “oats,” “oatmeal,” and “diabetes.” Results: While there are a limited number of clinical studies including hypocaloric short-term dietary oatmeal interventions, there is evidence that these interventions may lead to a significant decrease in mean blood glucose levels and a significant reduction of insulin dosage in patients suffering from poorly-controlled type 2 diabetes. Conclusion: Modified short-term dietary oatmeal interventions are an effective and economical tool in the treatment of patients suffering from poorly-controlled type 2 diabetes.

Background: Metabolic and hormonal disturbances are associated with sleep disturbances and delayed onset of lactogenesis II. Research aims: The aim of this study was to measure sleep using wrist actigraphy during gestation weeks 22 and 32 to determine if sleep characteristics were associated with blood glucose, body mass index, gestational related disease, delayed onset of lactogenesis II, or work schedule. Methods: Demographic data were collected at study intake from primiparous women who wore a wrist actigraph during gestation weeks 22 ( n = 50) and 32 ( n = 44). Start and end sleep time, total nighttime sleep, sleep efficiency, wake after sleep onset, and sleep fragmentation were measured. Night to night variability was assessed with the root mean square of successive difference. Blood glucose levels, body mass index, and gestational disease data were abstracted from medical charts. Timing of lactogenesis II was determined by survey. Results: Between gestation week 22 and 32, sleep efficiency decreased and fragmentation increased ( p < .05). During gestation week 32, blood glucose was negatively correlated with sleep duration, and positively related to fragmentation ( p < .05). Women who experienced delayed lactogenesis II had lower sleep efficiency and greater fragmentation ( p < .05), and greater night-to-night variability in sleep start and end time, efficiency, and duration during gestation week 32 ( p < .05). Conclusion: Women with better sleep efficiency and more stable nightly sleep time are less likely to experience delayed onset of lactogenesis II. Interventions to improve sleep may improve maternal health and breastfeeding adequacy.

Practical relevance: Diabetic ketoacidosis (DKA) is a not uncommon emergency in both newly diagnosed and poorly regulated diabetic cats. When there is a heightened metabolic rate and energy requirement due to concurrent illness, an increase in the release of glucose counter-regulatory hormones causes insulin receptor resistance, lipolysis, free fatty acid release and ketogenesis. This necessitates not only treatment to eliminate the ketosis and control blood glucose, but also investigation of concurrent illnesses. Clinical challenges: A number of metabolic derangements can occur with DKA, requiring a comprehensive diagnostic evaluation, elimination of ketones, careful correction of glucose, electrolyte and acid base abnormalities, and close monitoring. Audience: Any veterinarian that cares for cats in urgent and emergency situations should understand the pathophysiology of DKA in order to address an individual’s clinical signs and metabolic derangements. Evidence base: This review draws evidence from the peer-reviewed literature as well as the author’s personal clinical experience.

The aim of this study was to evaluate the usefulness of simultaneous measurement of plasma steroids, including precursors, for the evaluation of drug effects on adrenal steroidogenesis in vivo. Plasma concentrations of corticosterone and its precursors were examined in rats dosed with compounds that affect adrenal steroidogenesis via different modes of action as well as the relationships of the changes with blood chemistry and adrenal histopathology. Male rats were dosed with tricresyl phosphate, aminoglutethimide, trilostane (TRL), metyrapone (MET), ketoconazole (KET), or mifepristone for 7 days. In the TRL, MET, and KET groups, precursor levels were markedly increased, while there were no significant changes in the corticosterone level, suggesting that the precursors are more sensitive biomarkers to detect the effect on adrenal steroidogenesis. Also, the precursors with increased levels were those that are normally metabolized by the inhibited enzymes, reflecting the modes of action of the compounds. In addition, different patterns of changes were observed in blood chemistry and histopathology, supporting the mechanism suggested by the steroid changes. These results show that simultaneous measurement of plasma steroids, including precursors, can be a valuable method to sensitively evaluate drug effects on adrenal steroidogenesis and to investigate the underlying mechanisms.

Haematological and blood chemistry variables are widely used in ecophysiological research as physiological indices of body condition in various vertebrate taxa. In this study, we analysed relationships between blood glucose and blood haemoglobin concentrations of adult birds in wild populations of Blue Tits ( Cyanistes caeruleus) and Great Tits ( Parus major) during the breeding season in central Poland. We found that blood glucose and blood haemoglobin concentrations are negatively correlated. We also show that individual Blue Tits have higher mean haemoglobin levels adjusted for the common value of glucose concentration than individual Great Tits and that females of both species have higher mean haemoglobin concentrations than males. Our results suggest that haematological as well as biochemical variables may be used in tune as complementary indices of body condition in wild bird populations.

Purpose:C-reactive protein (CRP) and white blood cell (WBC) count are routine blood chemistry parameters in monitoring infection. Little is known about the natural history of their serum levels in conservative and operative spondylodiscitis treatment.Methods:Pre- and postoperative serum levels of CRP and WBC count in 145 patients with spondylodiscitis were retrospectively assessed. One hundred and four patients were treated by debridement, spondylodesis, and an antibiotic regime, 41 only with a brace and antibiotics. The results of the surgical group were compared to 156 patients fused for degenerative disc disease (DDD).Results:Surgery had a significant effect on peak postoperative CRP levels. In surgically managed patients, CRP peaked at 2–3 days after surgery (spondylodiscitis: pre-OP: 90 mg/dl vs. post-OP days 2–3: 146 mg/dl; DDD: 9 mg/dl vs. 141 mg/dl; p < 0.001), followed by a sharp decline. Although values were higher for spondylodiscitis patients, dynamics of CRP values were similar in both groups. Nonoperative treatment showed a slower decline. Surgically managed spondylodiscitis showed a higher success rate in identifying bacteria. Specific antibiotic treatment led to a more predictable decline of CRP values. WBC did not show an interpretable profile.Conclusion:CRP is a predictable serum parameter in patients with spondylodiscitis. WBC count is unspecific. Initial CRP increase after surgery is of little value in monitoring infection. A preoperative CRP value, and control once during the first 3 days after surgery is sufficient. Closer monitoring should then be continued. Should a decline not be observed, therapy needs to be scrutinized, antibiotic treatment reassessed, and concomitant infection contemplated.

Objectives In this study, we evaluated the potential association between the habitat types of feral cats and the prevalence of selected infectious pathogens and health status based on a set of blood parameters. Methods We live-trapped 72 feral cats from two different habitat types: an urban area (n = 48) and a rural agricultural area (n = 24). We compared blood values and the prevalence of feline immunodeficiency virus (FIV), feline leukaemia virus (FeLV) and haemotropic Mycoplasma infection in feral cats from the two contrasting habitats. Results Significant differences were observed in several blood values (haematocrit, red blood cells, blood urea nitrogen, creatinine) depending on the habitat type and/or sex of the cat. Two individuals from the urban area were seropositive for FIV (3.0%), and eight (12.1%) were positive for FeLV infection (five from an urban habitat and three from a rural habitat). Haemoplasma infection was more common. Based on molecular analysis, 38 cats (54.3%) were positive for haemoplasma, with a significantly higher infection rate in cats from rural habitats (70.8%) compared with urban cats (47.8%). Conclusions and relevance Our study recorded haematological and serum biochemical values, and prevalence of selected pathogens in feral cat populations from two different habitat types. A subset of important laboratory parameters from rural cats showed values under or above the corresponding reference intervals for healthy domestic cats, suggesting potential differences in the health status of feral cats depending on the habitat type. Our findings provide information about the association between 1) blood values (haematological and serum biochemistry parameters) and 2) prevalence of selected pathogen infections and different habitat types; this may be important for veterinarians who work with feral and/or stray cats and for overall cat welfare management.

We investigated obstetric outcomes and comorbidities during pregnancy in females with preexisting lupus nephritis (LN) and identified predictors for renal flare. In cases of renal flare during pregnancy, we assessed the long-term post-delivery renal outcome. We performed a retrospective analysis of 183 systemic lupus erythematosus (SLE) pregnancies including blood chemistry, urinalysis, urinary protein, and disease activity recorded at prepregnancy, during pregnancy, and at one month, six months, and one year post-delivery. Pregnancies with preexisting LN had a greater frequency of adverse obstetric outcomes and maternal comorbidity. Renal flares occurred in 50.7% of pregnancies with preexisting LN, 89.2% of which were reactivations. Renal flare among pregnancies with SLE was predicted based on preexisting lupus nephritis (OR 17.73; 95% CI, 5.770–54.484), an active disease prior to pregnancy (OR 2.743; 95% CI, 1.074–7.004), and prepregnancy eGFR 2 (OR 11.151; 95% CI, 3.292–37.768). Persistent LN one year after delivery was observed in 33.3% of pregnancies. The median follow-up time after delivery was 5.9 (3.1–9.7) years and chronic kidney disease (CKD) occurred in 21.4% of pregnancies with renal flare. In patients with renal flare, failing to achieve a ≥ 50% reduction in urine protein levels within six months, longer total duration of renal flare, and acute kidney injury at renal flare was associated with CKD development. Females with preexisting LN should achieve remission before pregnancy. When patients experience renal flares during pregnancy, it is important to reduce the proteinuria level by >50% within six months and to achieve early remission for excellent long-term renal outcomes.

The use of appropriate analgesia in laboratory mice may be suboptimal because of concerns about adverse events (AE). Target Animal Safety trials were conducted to determine the safety of an extended-release suspension of buprenorphine. Drug or control suspensions were injected subcutaneously in surgically-treated BALB/c mice anesthetized with ketamine–xylazine to mimic post-operative conditions in which the compound might commonly be administered. Single and repeat five-fold (5×) excesses of the 3.25 mg/kg intended dose were used to provoke potential AE. Trials included prospective measurements of weight changes, blood chemistry, hematology, and histopathology. Clinical and histopathology findings were similar in drug-treated and control mice in a four-day trial using a single 16.25 mg/kg, 5× overdose of the drug. In a 12-day trial, which used a total buprenorphine dose of 48.75 mg/kg, clinical and histopathology values were also similar in control and drug-treated female mice. In the male arm of the repeat-overdose trial, two of eight mice died on the morning of day 12, three days following the third 16.25 mg/kg overdose administration. Histopathology did not reveal a cause of death. In a 14-month trial using a single 3.25 mg/kg dose of the drug, no significant findings identified potential AE. These findings indicate a high tolerance to an extended-release buprenorphine suspension administered post-operatively in mice with appropriate husbandry.

Poor oral health and hygiene are increasingly recognized as major risk factors for pneumonia among the elderly. To identify modifiable oral health–related risk factors, we prospectively investigated associations between a constellation of oral health behaviors and incident pneumonia in the community-living very elderly (i.e., 85 years of age or older). At baseline, 524 randomly selected seniors (228 men and 296 women; mean age, 87.8 years) were examined for oral health status and oral hygiene behaviors as well as medical assessment, including blood chemistry analysis, and followed up annually until first hospitalization for or death from pneumonia. During a 3-year follow-up period, 48 events associated with pneumonia (20 deaths and 28 acute hospitalizations) were identified. Among 453 denture wearers, 186 (40.8%) who wore their dentures during sleep were at higher risk for pneumonia than those who removed their dentures at night (log rank P = 0.021). In a multivariate Cox model, both perceived swallowing difficulties and overnight denture wearing were independently associated with an approximately 2.3-fold higher risk of the incidence of pneumonia (for perceived swallowing difficulties, hazard ratio [HR], 2.31; and 95% confidence interval [CI], 1.11–4.82; and for denture wearing during sleep, HR, 2.38; and 95% CI, 1.25–4.56), which was comparable with the HR attributable to cognitive impairment (HR, 2.15; 95% CI, 1.06–4.34), history of stroke (HR, 2.46; 95% CI, 1.13–5.35), and respiratory disease (HR, 2.25; 95% CI, 1.20–4.23). In addition, those who wore dentures during sleep were more likely to have tongue and denture plaque, gum inflammation, positive culture for Candida albicans, and higher levels of circulating interleukin-6 as compared with their counterparts. This study provided empirical evidence that denture wearing during sleep is associated not only with oral inflammatory and microbial burden but also with incident pneumonia, suggesting potential implications of oral hygiene programs for pneumonia prevention in the community.

Seventy-five male cats with urethral obstruction were prospectively enrolled to evaluate gross urine color at urinary catheter placement for correlation with diagnostic findings. Cats with darker red urine were more likely to be azotemic (serum creatinine concentration >2.0 mg/dl [177 µmol/l]), and urine color correlated well with serum creatinine and serum potassium concentrations. Darker urine color was negatively correlated with urine specific gravity. Urine color was not associated with the presence or absence of lower urinary tract stones on radiographs or ultrasound. Cats with darker red urine at the time of urinary catheter placement are likely to have more significant metabolic derangements and may require more aggressive supportive care.

Objective: To report a case of ventricular fibrillation caused by severe hypokalemia probably associated with sertraline use. Case Summary: A 48-year-old male patient experienced ventricular fibrillation and cardiac arrest 2 hours after an uneventful coronary angiography procedure, which revealed normal, unobstructed coronary arteries. Blood chemistry was immediately obtained, revealing a very low potassium (K+) level of 2.44 mEq/L. Other blood electrolytes, including magnesium, ECG, and corrected QT intervals, were all within normal limits. A thorough search for an etiology of hypokalemia, including adrenal gland causes, herbal product consumption, and toxic exposure, did not reveal any identifiable cause. This led us to consider the only drug he was on—sertraline 50 mg per day—as the possible culprit. Discussion: There has been no clear identification of severe hypokalemia associated with sertraline use in the literature. However, there have been a considerable number of self-reported cases of hypokalemia in patients on sertraline therapy. Scoring according to the Naranjo adverse drug reaction scale revealed a probable relationship between severe hypokalemia and sertraline use in our patient. No clear pathogenic mechanism for the effect of sertraline on serum K equilibrium is known. However, considering the number of self-reported incidences and this case report, the effect of sertraline on serum K levels warrants consideration. Conclusions: This is the first documented case report of severe hypokalemia probably associated with sertraline use.

This study evaluated primary practitioners’ perceptions of managing feline diabetics. Surveys distributed during local continuing education events achieved a response rate of 46% (90/195). A mean of 74% feline diabetics required chronic insulin; 26% were transient diabetics. Choice of insulin was most influenced by duration of action: human recombinant protamine zinc insulin was ranked first (42%) and glargine second (27%). Dietary management was always/usually recommended by 97% respondents, with prescription or proprietary low-carbohydrate, high-protein diets recommended in 93% responses. More recent graduates ( P = 0.0419), those who worked in larger practices ( P = 0.0315), and those who saw more transient diabetics ( P = 0.0288) were more likely to recommend dietary change. In-house blood glucose curves (BGCs) were the most popular method of assessing glycemic control, while at-home BGCs were least popular, although their use correlated positively with annual diabetic caseload (r = 0.43, P = 0.0239). Owners mishandling insulin was cited as the most common cause of poor glycemic control, while clinical signs of acromegaly were rarely recognized.

This article describes the development of a new service – the post-anaesthesia care unit (PACU) -that provides extended care in a recovery unit for patients who would have formerly been ‘fast-tracked’ through a high dependency unit (HDU). Patients requiring major surgery who stay in the recovery unit overnight are invasively monitored, have tight fluid management, blood chemistry analysis and frequently have pharmacological support. However, our overnight recovery service is not considered suitable for ventilated patients. Over 90% of patients are able to be discharged to a surgical ward within 24 hours of admission, following medical review.

In a large number of animal experiments, blood collection is crucial for achieving the study aim. Requirements on sampling techniques used include their practicability, their effectiveness in terms of obtaining the desired blood volume, sample quality and low impact on animal's wellbeing. Numerous methods for blood collection from mice have been published. For large blood volumes, submandibular and sublingual bleeding was developed as alternatives to the retrobulbar bleeding method, which is considered controversial as it results in severe tissue damage. Only a few studies report the use of submandibular and sublingual techniques in mice. In particular, the degree of tissue damage or influence on animal's wellbeing due to submandibular bleeding in conscious mice has not yet been clearly assessed. This gap in the knowledge base has been filled by our exploratory study that revealed clear differences between both techniques. Defence movements during submandibular blood collection in conscious mice resulted in more complications and revealed insufficient blood sample quality due to the prolonged duration of blood collection. In addition, it is likely that these movements may have caused lesions to be more pronounced. Changes in red blood cell parameters (red blood cell count, haemoglobin and haematocrit), in glucose and in total protein concentrations observed in anaesthetized animals were most likely related to anaesthesia. Sublingually punctured mice gained significantly more body weight than submandibularly punctured mice, likely due to less severe tissue lesions and improved healing processes. Based on these results, we recommend the sublingual blood collection technique to be used in mice. However, if the submandibular bleeding technique is used, it should be performed in anaesthetized mice only.

The goal of this study was to evaluate a commercially available assay for gadolinium diethylene triamine penta-acetic acid (Gd-DTPA) for use in estimating glomerular filtration rate (GFR) in cats (Gd-DTPA GFR) with a wide range of GFRs. Eighteen adult cats (11 healthy and seven with chronic kidney disease) were included. Plasma concentrations of Gd-DTPA following intravenous injection were measured with an ELISA kit (FIT-GFR). Results for Gd-DTPA GFR were compared with simultaneously obtained values for plasma clearance of iohexol (iohexol GFR), plasma blood urea nitrogen (BUN) and creatinine concentrations. A negative correlation existed between iohexol GFR and plasma concentrations of BUN and creatinine. A positive correlation existed between Gd-DTPA GFR and iohexol GFR. There was no correlation between Gd-DTPA GFR and plasma concentrations of BUN and creatinine. In this study plasma clearance of Gd-DTPA assayed by FIT-GFR did not appear to provide a sufficiently accurate estimation of GFR in cats when compared with plasma clearance of iohexol, and plasma concentrations of BUN and creatinine.

The current study compared the LeadCare® II test kit system with graphite-furnace atomic absorption spectrometry for blood lead (Pb) analysis in 56 cattle accidentally exposed to Pb in the field. Blood Pb concentrations were determined by LeadCare II within 4 hr of collection and after 72 hr of refrigeration. Blood Pb concentrations were determined by atomic absorption spectrometry, and samples that were coagulated ( n = 12) were homogenized before analysis. There was strong rank correlation ( R 2 = 0.96) between atomic absorption and LeadCare II (within 4 hr of collection), and a conversion formula was determined for values within the observed range (3–91 mcg/dl, although few had values >40 mcg/dl). Median and mean blood pb concentrations for atomic absorption were 7.7 and 15.9 mcg/dl, respectively; for LeadCare II, medians were 5.2 mcg/dl at 4 hr and 4.9 mcg/dl at 72 hr, and means were 12.4 and 11.7, respectively. LeadCare II results at 4 hr strongly correlated with 72 hr results ( R 2 = 0.96), but results at 72 hr were lower ( P < 0.01). There was no significant difference between coagulated and uncoagulated samples run by atomic absorption. Although there have been several articles that compared LeadCare with other analytical techniques, all were for the original system, not LeadCare II. The present study indicated that LeadCare II results correlated well with atomic absorption over a wide range of blood Pb concentrations and that refrigerating samples for up to 72 hr before LeadCare II analysis was acceptable for clinical purposes.

Oestrogen administration can alter experimental stroke outcomes. Soy as a source of phytoestrogens may therefore modulate responses in ‘oestrogen-sensitive’ stroke models, thus potentially confounding results. We evaluated the effects of dietary soy on acute infarct volumes in a pilot study using a rat focal stroke model. We hypothesized that ovariectomized (OVX) rats fed a soy-rich diet would have smaller acute infarct volumes than rats fed a soy-free diet. OVX rats were randomly assigned to a soy-free ( n = 6) or a soy-rich ( n = 6) diet for four weeks and weighed weekly. Following the dietary trial, rats underwent 2 h of middle cerebral artery occlusion (MCAO). Mean arterial blood pressure, rectal and temporalis muscle temperatures, arterial blood gases and blood glucose were recorded peri-ischaemia. Rats were euthanized 22 h following 2 h of MCAO. Brains were stained with 2,3,5-triphenyl tetrazolium chloride for acute infarct volume analysis. Uterine weight and histology were also evaluated as additional internal oestrogen-sensitive controls. Rats on the soy-free diet had greater gains in body weight (259 ± 6% baseline body weight) than rats on the soy-rich diet (238 ± 4% baseline body weight). No differences were seen in uterine weight and histology, peri-ischaemic physiological parameters and infarct volumes between the treatment groups. The results of this pilot study suggest that the dietary soy level tested may not alter acute infarct volumes in ischaemic female rat brain. More studies addressing the potential confounding effects of dietary soy in ‘oestrogen-sensitive’ stroke models are needed if investigators are to make informed choices regarding diets used in experimental stroke research.

Hydrogen-dissolved water has been suggested to be effective for alleviating the oxidative stress. In the present study, neutral-pH hydrogen-enriched electrolyzed water (NHE-water; dissolved hydrogen: 0.90—1.14 parts per million [ppm]; oxido-reduced potential: —150 ∼ —80 mV), which was prepared with a water-electrolysis apparatus equipped with a non-diaphragm cell and a highly compressed activated-carbon block, was evaluated for the mutagenic and genotoxic potentials, at concentrations up to 100% dose/plate, and for the subchronic toxicity. NHE-water did not induce reverse mutations in Salmonella typhimurium strains TA100, TA1535, TA98 and TA1537, and Escherichia coli strain WP2uvrA, in either the absence or presence of rat liver S9 for exogenous metabolic activation. Similarly, NHE-water did not induce chromosome aberrations in Chinese hamster lung fibroblast cells (CHL/IU), in short-term (6-hour) tests, with or without rat liver S9, or in a continuous treatment (24-hour) test. To evaluate the subchronic toxicity, Crj:CD(SD) specific pathogen free (SPF)-rats were administered with NHE-water at a dose of 20 mL/kg/day for 28 days via intragastric infusion. NHE-water-related toxic changes were not seen in terms of any items such as clinical symptoms, body weight, food consumption, urinalysis, hematology, blood chemistry, necropsy, each organ weight and histopathology. Thus, the no-observable-adverse-effect level (NOAEL) for NHE-water was estimated to be greater than 20 mL/kg/day under the conditions examined, demonstrating the consistency with the expected safety for a human with a body weight of 60 kg to drink the NHE-water up to at least 1.2 L/day.

To further evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate, CAS No. 205687-03-2), a 26—week gavage toxicity study was conducted in Sprague-Dawley rats (20/sex/group). Test animals received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle (medium-chain triglyceride) by gavage and were observed for antemortem and postmortem signs of toxicity including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. After the end of the dosing period, reversibility was assessed (10/sex/group for the control and 1000 mg/kg groups) following a 4-week recovery period. There were no adverse or toxicological changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, blood chemistry, organ weights, or histopathology. It was concluded that the no observable adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both sexes in this 26—week gavage study.

Several previous studies have suggested that n-3 polyunsaturated fatty acids ( n-3 PUFA) can exert favourable effects in patients with heart failure, but the mechanisms involved are not fully understood. This study was designed to investigate the effects of n-3 PUFA on circulating inflammatory markers and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with heart failure. Seventy-six patients with heart failure were randomly assigned to receive 2 g/day of n-3 PUFA or placebo for 3 months. Treatment with n-3 PUFA significantly decreased plasma levels of tumour necrosis factor, interleukin-6, intercellular adhesion molecule 1 and NT-proBNP. Left ventricular ejection fraction showed a small, non-significant improvement. High-sensitivity C-reactive protein levels decreased significantly in smokers after n-3 PUFA treatment. Thus, n-3 PUFA can reduce levels of plasma inflammatory markers and NT-proBNP as biomarkers of risk stratification in patients with heart failure. n-3 PUFA may offer a novel therapy for heart failure.

A series of safety tests were undertaken on a novel galacto-oligosaccharide (GOS) produced from lactose by a two-step enzymatic process involving Sporobolomyces singularis and Kluyveromyces lactis. Bacterial reverse mutation and chromosomal aberration tests, with or without metabolic activation, were performed. These tests showed no mutagenesis in the Ames assay or in Escherichia coli WP2uvrA, and no chromosomal aberrations in cultured fibroblast cells from Chinese hamster lungs (CHL/IU). Micronuclei were not induced in the reticulocytes of mouse peripheral blood following oral administration of GOS. In a 90-day repeated oral dose toxicity study in rats, GOS was administered at 0, 500, 1000 and 2000 mg/kg to male and female Sprague-Dawley rats. There were no GOS-related changes in clinical signs, body weight, water intake, feed intake, urinalysis, ophthalmology, haematology, blood chemistry, organ weights, gross pathology or histopathology in any of the treatment groups compared to the control group. The no observed adverse effect level (NOAEL) of GOS was at least 2000 mg/kg/day in both males and females.

A 6-year-old male elk presented in August with a 4-month history of weight loss and a 1-day history of being recumbent and unable to rise. The elk's body condition score was 1.5/5. Hematology and blood chemistry showed an inflammatory leukogram, mild electrolyte abnormalities, and elevated liver enzyme activities. Because of poor prognosis, the owner elected euthanasia. On necropsy, 8 diverticula were in the duodenum distal to the common bile duct, which was dilated and filled with feed material. Many intrahepatic bile ducts were dilated up to 5 cm, were filled with ingesta and gritty material, and had walls thickened up to 1.5 mm. On histologic examination, mural thickening of dilated bile ducts was because of increased fibrous connective tissue with inflammatory cell infiltration and hyperplastic and hypertrophic epithelial lining. Portal tracts diffusely contained hyperplastic bile ducts and had increased amounts of fibrous connective tissue. Abscesses that contained bacteria were scattered throughout the liver. Duodenal diverticula lacked the tunica muscularis, and the muscularis mucosa was hypertrophied. Caudal to some diverticula, the duodenal lumen was narrowed. An additional finding was embolic pneumonia with fungi morphologically and immunohistochemically consistent with Aspergillus spp.

Dihydrocapsiate, (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2) is a naturally occurring capsinoid compound found in nonpungent chili peppers. Although the safety of synthetically produced dihydrocapsiate has been previously evaluated, the purpose of this 13-week gavage toxicity study is to evaluate dihydrocapsiate produced with a slightly modified manufacturing process. Sprague-Dawley rats, 10 rats/sex/group, 6 weeks of age at study initiation, were administered the dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100,300, or 1000 mg/kg/day. The rats were observed for antimortem and postmortem signs of toxicity, including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry that were attributable to the administration of dihydrocapsiate. The only change observed attributable to the dihydrocapsiate administration involved the liver and that change occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (i.e., hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses ≤300 mg/kg or in females at any of the doses tested (≤1000 mg/kg). It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13 week gavage study.

The safety and pharmacokinetics of capsinoids, physiologically active ingredients of CH-19 Sweet extract, were investigated in 16 healthy male volunteers following a single oral ingestion of CH-19 Sweet extract. The study subjects consumed soft gel capsules containing either capsinoids (15 or 30 mg/person) or placebo. Capsinoids were well tolerated, and no clinically significant changes in physical examinations, blood pressure, heart rate, body temperature, electrocardiogram, hematology, blood chemistry, and urinalysis were observed at either the 15 or 30 mg dose. Body temperature tended to increase after the ingestion of capsinoids, but remained within the normal range. Plasma levels of capsinoids and their metabolite, vanillyl alcohol, were below the lower limit of quantitation. In addition, some study subjects showed increases in urinary excretion of 3-methoxy-4-hydroxyphenylglycol that, when compared to the group receiving the placebo, did not achieve statistical significance.

Human neural progenitor cells (hNPCs) have been proposed as a potential source of cells for ex vivo gene therapy. In this pilot study, three 5-year-old female cynomolgus monkeys received a single intracarotid infusion of MPTP, followed 1 week later by MRI-guided stereotaxic intrastriatal and intranigral injections of male hNPCs transgenic for GDNF. Immunosupression with oral cyclosporine (30–40 mg/kg) began 48 h before hNPC transplants and continued throughout the study. We monitored the animals using a clinical rating scale (CRS). Three months postsurgery, we euthanized the animals by transcardiac perfusion, then retrieved and processed their brains for morphological analysis. Our findings include the following. 1) hNPCs survived and produced GDNF in all animals 3 months postsurgery. 2) hNPCs remained in the areas of injection as observed by GDNF immunostaining and in situ hybridization for the human Y chromosome. 3) A “halo” of GDNF expression was observed diffusing from the center of the graft out into the surrounding area. 4) We observed increased TH- and VMAT2-positive fibers in areas of GDNF delivery in two of the three animals. The two animals with TH- and VMAT2-positive fibers also showed reductions in their CRS scores. 5) Some GFAP-positive perivascular cuffing was found in transplanted areas. 6) General blood chemistry and necropsies did not reveal any abnormalities. Therefore, we conclude that hNPCs releasing GDNF may be a possible alternative for intracerebral trophic factor delivery in Parkinson's disease.

Manual methods of blood glucose monitoring are labor-intensive, costly, prone to error, and expose the caregiver to blood. The VIA(R) blood chemistry monitor for glucose can automatically measure plasma glucose (PG) every 5 minutes for 72 hours using blood sampled from a peripheral vein/artery or a central vein.VIA performance was evaluated in eight normal and five type 1 diabetic (T1DM) subjects in 15 separate experiments. The VIA device was connected to a peripheral vein and reported a PG value every 5 minutes during each 510-minute experiment. Blood samples were collected manually every 10 minutes and assayed using a HemoCue(R) beta-glucose analyzer (HC). Whole blood HC measurements were corrected to PG values. Paired HC/VIA measurements (n = 717) were analyzed.Mean PG was 90 +/- 14 and 96 +/- 12 mg/dl in normal subjects and 194 +/- 64 and 173 +/- 48 mg/dl in T1DM subject as measured by the HC and VIA, respectively. Clark error grid analysis revealed 86% points in zone A, 11% points in zone B, and 2% points in zone D. Linear regression analysis yielded the following equation: VIA = 0.732 x HC + 30.5 (r(2) = 0.954). Residual analysis revealed a glucose-dependent bias between the HC and the VIA. VIA data were transformed using the linear regression equation to correct for bias. After the correction, the mean absolute relative difference between the VIA and the HC was less than 10%, and 99.6% of data were in zones A and B. The VIA was able to sample blood automatically every 5 minutes for more than 8 hours in the laboratory setting. On average, the VIA reported glucose values for 94% of the samples it attempted to obtain.This study demonstrated that the VIA blood chemistry monitor for glucose can reliably sample blood frequently for a prolonged period of time safely and effectively in diabetic and nondiabetic volunteers. Agreement between the two devices was the closest at normal glucose concentrations. After correcting for a glucose-dependent bias between the devices, the MARD was consistently less than 10% for all glucose ranges.

Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD50 values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m3 identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal tox-icity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, ororgan weight changes. A6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day-1), Poloxamer 235 (tested up to 1.0 g/kg day-1), and Poloxamer 338 (at 0.2 or 1.0 g/kg day-1) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day-1) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day-1 for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anti-carcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multidrug-resistant cancer cells. In clinical testing, Poloxamer 188 increased the hydration of feces when used in combination with a bulk laxative treatment. Compared to controls, one study of angioplasty patients receiving Poloxamer 188 found a reduced myocardial infarct size and a reduced incidence of reinfarction, with no evidence of toxicity, but two other studies found no effect. Poloxamer 188 given to patients suffering from sickle cell disease had decreased pain and decreased hospitilization, compared to controls. Clinical tests of dermal irritation and sensitization were uniformly negative. The Cosmetic Ingredient Review (CIR) Expert Panel stressed that the cosmetic industry should continue to use the necessary purification procedures to keep the levels below established limits for ethylene oxide, propylene oxide, and 1,4-dioxane. The Panel did note the absence of reproductive and developmental toxicity data, but, based on molecular weight and solubility, there should be little skin penetration and any penetration of the skin should be slow. Also, the available data demonstrate that Poloxamers that are introduced into the body via routes other than dermal exposure have a rapid clearance from the body, suggesting that there would be no risk of reproductive and/or developmental toxicity. Overall, the available data do not suggest any concern about carcinogenesis. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used, and at what concentration, indicates a pattern of use. Based on these safety test data and the information that the manufacturing process can be controlled to limit unwanted impurities, the Panel concluded that these Poloxamers are safe as used.

Ubiquinol is the two-electron reduction product of ubiquinone (coenzyme Q10or CoQ10) and functions as an antioxidant in both mitochondria and lipid membranes. In humans and most mammals, including dogs, the predominant form of coenzyme Q is coenzyme Q10, whereas the primary form in rodents is coenzyme Q9(CoQ9). Therefore, the subchronic toxicity of ubiquinol was evaluated and compared in Sprague-Dawley rats and beagle dogs. In the initial rat study, males and females were given ubiquinol at doses of 0, 300, 600, or 1200 mg/kg or ubiquinone at 1200 mg/kg by gavage for 13 weeks. This was followed by the second study, where females were given with doses of 75, 150, 200, or 300 mg/kg/day in order to determine a no observed adverse effect level (NOAEL). In the dog study, the test material was administered to males and females at dose levels of 150, 300, and 600 mg/kg, and ubiquinone was included at 600 mg/kg. Clinical observations, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, blood biochemistry, gross findings, organ weights, and histopathological findings were examined. In both species, determination of plasma and liver ubiquinol concentrations, measured as total coenzyme Q10, were performed. There were no deaths or test article–related effects in body weight, food consumption, ophthalmology, urinalysis, or hematology in rats. Histopathological examinations revealed test article–related effects on the liver, spleen, and mesenteric lymph node in female rats but not in male rats. In the liver, fine vacuolation of hepatocytes was observed in the ubiquinol groups at 200 mg/kg and above. These changes were judged to be of no toxicological significance because they were not considered to induce cytotoxic changes. Microgranuloma and focal necrosis with accumulation of macrophages were observed in the ubiquinol groups at 300 mg/kg and above. These findings were accompanied by slight increases in blood chemistry enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase [LDH]), which was suggestive of either potential hepatotoxicity or a normal physiological response to ubiguinol loading. Microgranuloma, and focal necrosis were judged to be only adverse effects induced by test article based on their incidence and pathological characteristics. These changes observed in liver were thought due to uptake of the administered ubiquinol by the liver as an adaptive response to xenobiotics, and the microgranulomas and focal necrosis were considered the results of excessive uptake of ubiquinol, which exceeded the capacity for adaptive response. Based on these findings the NOAEL in rats was conservatively estimated to be 600 mg/kg/day for males and 200 mg/kg/day for females. In dogs, there were no deaths or ubiquinol-related toxicity findings during the administration period. No test article–related effects were observed in body weight, food consumption, ophthalmology, electrocardiogram, urinalysis, hematology, or blood chemistry. Histopathological examination revealed no effects attributable to administration of ubiquinol or ubiquinone in any organs examined. Based on these findings, a NOAEL for ubiquinol in male and female dogs was estimated to be more than 600 mg/kg/day under the conditions of this study.

Financial support . This study was financially supported by The Western Norway Regional Health Authority, The Norwegian Council on Cardiovascular Diseases, Faculty of Medicine, University of Bergen and The Frank Mohn Foundation, Norway. Introduction. This study investigated whether two levels of mean arterial pressure (MAP) during cardiopulmonary bypass did influence per-operative fluid shifts. Methods. Sixteen pigs underwent 60 minutes of normothermic cardiopulmonary bypass (CPB) followed by 90 minutes of hypothermic CPB. Eight animals had a MAP of 60—80 mmHg by norepinephrine (HP group). Another 8 animals had a MAP of 40—45 mmHg by phentolamine (LP group). Blood chemistry, plasma/interstitial colloid osmotic pressures, plasma volume, fluid balance, fluid extravasation rate and tissue water content were measured or calculated. Results. The plasma volume was significantly lower in the HP group compared with the LP group after 60 minutes of CPB. Net fluid balance was 0.18 (0.05) ml·kg-1·min -1 in the HP group and 0.21 ml·kg- 1·min-1 in the LP group (P > 0.05) while fluid extravasation rate was 1.18 (0.5) and 1.13 (0.4) ml·kg -1·min-1 in the HP group and the LP group during CPB (P > 0.05). Conclusion. Net fluid balance and fluid extravasation rate were similar in the animals with elevated and with lowered MAP during CPB. Perfusion (2007) 22, 273—278.

This study used a population-based sample of 407 Seventh-day Adventists in Barbados to determine the relationship between physical activity, blood sugar, hypertension, and cholesterol levels. A systematic random sampling technique was used to select participants: 37.6% were male and 62.4% female. No significant association was found between exercise and the outcome variables: blood sugar, blood pressure, and cholesterol levels of participants. However, females appeared to be more sedentary when compared to males. A significant association was seen between weekly exercise and triglycerides, but only in male participants.

Objective:To report a case of probable fenofibrate-induced gynecomastia.Case Summary:A 56-year-old white hypercholesterolemic man was treated with fenofibrate 160 mg/day for 1 year. During the course of treatment, he developed gynecomastia on the left side, which resolved after the drug was stopped and replaced with alpha tocopherol acetate. Sixteen months after fenofibrate discontinuation, the patient was rechallenged and subsequently developed gynecomastia symptoms on the right side. The usual etiologies of gynecomastia were excluded by careful assessment of the patient's medical history, physical examination, and results of diagnostic tests such as chest X-ray, mammography, scrotal ultrasonography, routine blood chemistry, and extensive hormonal panel. Gynecomastia again resolved after discontinuation of fenofibrate.Discussion:In this case, the resolution of gynecomastia on discontinuation of fenofibrate and recurrence after rechallenge highly suggest the role of fenofibrate. Use of the Naranjo probability scale registered causality as probable. Case reports of gynecomastia caused by different drugs have been previously published, but, to our knowledge, this is the first report linking gynecomastia to the use of fenofibrate. The pathogenesis of this adverse drug reaction remains unclear.Conclusions:Although fenofibrate-induced gynecomastia appears to be uncommon, patients receiving this medication should be monitored for this adverse drug reaction.

Present tooth-bleaching techniques are based upon hydrogen peroxide as the active agent. It is applied directly, or produced in a chemical reaction from sodium perborate or carbamide peroxide. More than 90% immediate success has been reported for intracoronal bleaching of non-vital teeth, and in the period of 1–8 years’ observation time, from 10 to 40% of the initially successfully treated teeth needed re-treatment. Cervical root resorption is a possible consequence of internal bleaching and is more frequently observed in teeth treated with the thermo-catalytic procedure. When the external tooth-bleaching technique is used, the first subjective change in tooth color may be observed after 2–4 nights of tooth bleaching, and more than 90% satisfactory results have been reported. Tooth sensitivity is a common side-effect of external tooth bleaching observed in 15%-78% of the patients, but clinical studies addressing the risk of other adverse effects are lacking. Direct contact with hydrogen peroxide induced genotoxic effects in bacteria and cultured cells, whereas the effect was reduced or abolished in the presence of metabolizing enzymes. Several tumor-promoting studies, including the hamster cheek pouch model, indicated that hydrogen peroxide might act as a promoter. Multiple exposures of hydrogen peroxide have resulted in localized effects on the gastric mucosa, decreased food consumption, reduced weight gain, and blood chemistry changes in mice and rats. Our risk assessment revealed that a sufficient safety level was not reached in certain clinical situations of external tooth bleaching, such as bleaching one tooth arch with 35% carbamide peroxide, using several applications per day of 22% carbamide peroxide, and bleaching both arches simultaneously with 22% carbamide peroxide. The recommendation is to avoid using concentrations higher than 10% carbamide peroxide when one performs external bleaching. We advocate a selective use of external tooth bleaching based on high ethical standards and professional judgment.

Background The long-term risks of renal failure and hypertension are statistically low for living kidney donors as a group, but can have serious consequences for the individual. Objectives To describe the experience with a transplant coordinator-led living donor follow-up clinic. Method Living kidney donors are reviewed on an annual basis by a designated coordinator (registered nurse). A 24-hour urine collection estimates renal function. Blood pressure and blood chemistry are measured and urinalysis performed. Current health status and wound discomfort are assessed. Any medical problems identified are referred to a specialist hospital department or to the donor's family practitioner. Results Fifty-nine appointments were booked and 12 (20%) donors did not attend. Renal function was within acceptable limits for all attending donors. Three donors had raised blood glucose levels and 8 donors were hypertensive; all were referred to family practitioners. Forty-seven donors (35 new, 12 return) completed a questionnaire on the follow-up provided. Thirty-eight (81%) were satisfied with the follow-up, and 47 (100%) agreed this clinic provided adequate follow-up. Thirty-three (70%) donors stated they preferred that the transplant coordinator performed the follow-up, 3 (6%) preferred the family practitioner, and 11 (23%) had no preference. Conclusions There are many possible solutions to the provision of lifelong care of living kidney donors. The model of a transplant coordinator-led clinic appears to have a high degree of patient acceptance, perhaps because of the continuity of care provided by a known member of the transplant team. Further work is required to identify reasons for nonattendance.

The efficacy of meso-2,3-dimercaptosuccinic acid (DMSA) was evaluated in workers occupationally exposed to lead (Pb; blood level >50 mg //dL). Ten men were given 600 mg of DMSA per orem daily, for five days. Pb concentrations of whole blood and urine were determined throughout therapy. Hematology analyses, blood chemistry, and urinalysis were obtained at the start of the study, at the end of the DMSA treatment, and at 72 hours after the administration of the final dose. DMSA therapy had no influence on hepatic, hematologic, or renal functions and was effective in decreasing the concentration of blood Pb in all the subjects without adverse drug reactions.

The nonnucleoside inhibitor (NNI) of HIV-1 reverse transcriptase, PHI-346 ( N -[2-(1-cyclohexenyl)ethyl]- N'-[2-(5-bromopyridyl)]-thiourea), is a dual-function spermicidal agent with potent anti-HIV activity against drug-sensitive as well as drug-resistant HIV-1 strains with genotypic and phenotypic NNI resistance. PHI-346 was formulated via a lipophilic gel-microemulsion for intravaginal use as a potential dual-function microbicide. To evaluate the toxicity potential of short-term intravaginal exposure to PHI-346, groups of 15 female B6C3F 1 and CD-1 mice were exposed intravaginally to a gel-microemulsion containing 0, 0.5, 1.0, or 2.0% PHI-346, 5 days per week for 13 consecutive weeks. On a molar basis, these concentrations of PHI-346 are 350 to 1,400-times higher than its spermicidal EC50 and nearly 5 × 106 to 2 × 107 times higher than its in vitro anti-HIV IC50. After 13 weeks of intravaginal treatment, B6C3F 1 mice were evaluated for survival, body weight gain, absolute and relative organ weights. Blood was analyzed for hematology and clinical chemistry profiles. Microscopic examination was performed on hematoxylin and eosin-stained tissue sections from each study animal. Placebo control and PHI-346 dosed female CD-1 mice were mated with untreated males in order to evaluate if PHI-346 has any deleterious effects on the reproductive performance. There were no treatment-related mortalities. Mean body weight gain during the dosing period was not reduced by PHI-346 treatment. The hemogram or blood chemistry profiles revealed lack of systemic toxicity following daily intravaginal instillation of PHI-346 for 13 weeks. No clinically significant changes in absolute and relative organ weights were noted in PHI-346 dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three PHI-346 dose groups. Repeated intravaginal exposure of CD-1 mice to increasing concentrations of PHI-346 for 13 weeks had no adverse effect on their subsequent reproductive capability, perinatal outcome, growth, and development of offspring. Collectively, these findings demonstrate that repetitive intravaginal administration of PHI-346 at concentrations as high as 1,400-times its spermicidal EC50 and 2 ×107 times its in vitro anti-HIV IC50 was not associated with local or systemic toxicity and did not adversely affect the reproductive performance in mice. PHI-346 may be useful as an active ingredient of a safe vaginal microbicide for prevention of the sexual transmission of multidrug-resistant HIV-1.

Thrombocytopenia is a common phenomenon in patients suffering from systemic lupus erythematosus (SLE). The cause of thrombocytopenia in SLE, however, is poorly understood. In this study, 100 patients with SLE were evaluated for serum thrombopoietin levels, anti-thrombopoietin antibodies and routine laboratory parameters such as peripheral blood counts, parameters of blood chemistry and immunologic parameters of SLE.The median platelet count of SLE patients was 230 g/l and 19 were thrombocytopenic(range 8–148 g/l). Thrombopoietin levels in SLE patients were found to be significantly higher than in healthy controls (n=96; median, 117 pg/ml vs 64 pg/ml, P < 0.01). When excluding thrombocytopenic SLE patients, thrombopoietinlevels in SLE were still above controls (111 pg/ml, P < 0.01). The thrombopoietin levels were correlated to erythrocyte sedimentation rate and ECLAM score of disease activity, and inversely correlated to complement factor C4, but not to the platelet count. Anti-thrombopoietin antibody reactivity was found in 23% of SLE patients. Interestingly, these patients had lower platelet counts than SLE patients without anti-thrombopoietin antibodies (median 174 g/l and 253 g/l, respectively, P < 0.01), but thrombopoietin levels were not significantly different.Taken together, thrombopoietin levels are significantly higher in the sera of SLE patients than in healthy controls and anti-thrombopoietin antibodies are frequently found.

In this 12-week study with 29 subjects, the effect of Prokarin™ (n =22), a proprietary blend of histamine and caffeine, was compared to placebo group (n=7) for the following outcomes: 1) fatigue as measured by the Modified Fatigue Impact Scale (MFIS); 2) lower limb function as measured by timed walk test; 3) upper limb function as measured by the pegboard test; 4) cognitive function as measured by the Paced Auditory Serial Additions Test (PASAT); 5) serum caffeine level; 6) change in brain chemistry as measured by quantitative magnetic resonance spectroscopy assay of N-acetyl aspartate (NAA); and 7) safety as measured by routine blood chemistry, TSH and urinalysis. Data were acquired at baseline, 4, 8 and 12 weeks. The Prokarin™ group MFIS mean was significantly different from the mean of the placebo group at 12 weeks (df=24, t=2.08, P=

The safety and tolerability of ispaghula husk, which can now be used as an adjunct to diet for the treatment of mild-to-moderate hypercholes terolaemia, was assessed in 93 healthy subjects over a 52-week period. The study looked at the nutritional, biochemical, and haematological effects of ispaghula. Over the study period there were small but statistically significant changes in some measurements of minerals and vitamin lev els, and in some haematological and biochemical parameters. However, none of these were of clini cal significance, with the possible exception of changes in vitamin B12 levels. A daily dose of 10.5 g ispaghula was well tolerated and the major ity of adverse events recorded were minor, of short duration and either unrelated or possibly related to the study treatment. The results suggest that ispaghula husk can be used with confidence for the long-term treatment of mild-to-moderate hypercholesterolaemia.

The Biologic-DTPF System™ (DTPF), an extracorporeal blood treatment device with potential to treat sepsis, was tested in a preliminary study using a canine endotoxemia model. Six dogs were used and they formed four treatment groups, as control group (n=1) and three groups based on the type of sorbent present in the plasma filter (PF) system: sham treatment with no sorbent (n=1), charcoal as sorbent (n=2), and charcoal/silica as sorbent (“silica” group, n=2). Cardiodynamic data were recorded before treatment and every 30 minutes, and blood samples were collected to determine blood chemistry and to detect the levels of endotoxin and selected plasma cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). The dogs were given Escherichia coli endotoxin (2 mg/kg) as an intravenous drip (extended over a period of 30 minutes). Thirty minutes after the end of infusion all animals except the control were treated with the DTPF system for four hours. To determine the effect of treatment, data collected at one hour from the initiation of treatment until the end of treatment were compared between control and treated dogs. The endotoxin levels in the control dog were higher (P < 0.05) than other groups. The control dog had lower levels of TNF than other groups. The control dog had similar levels of IL-1 (P > 0.05) and higher levels (P < 0.05) at 4 hours into treatment compared to other groups. The control dog had similar levels of IL-6 as other groups (P > 0.05). In the control dog, the mean arterial pressure (MAP) fell and then remained low but stable at 1–4 hours. The charcoal group had lower MAP than the control dog at 1–4 hours (P < 0.05). The silica group had higher MAP levels similar to the control dog. After treatment, the control dog had higher (P < 0.05) values of hematocrit, hemoglobin, calcium, potassium, and albumin compared to the treated groups. As expected for a system removing plasma during sepsis, the DTPF System had some adverse effects on the physiologic status of the dogs, especially when loaded with charcoal sorbent only. The findings of the present study suggest that the filters are capable of eliminating endotoxin and there is some evidence of cytokine removal. Although the charcoal dogs did poorly, addition of silica to the sorbent offset any negative effects. Further work is underway to improve the efficiency of the system, primarily, to enhance the capacity of the sorbents for cytokines. A more realistic canine sepsis model with mortality after several days (the Escherichia coli- infected intraperitoneal clot) will also be considered in future studies.

As an alternative to kidney transplantation in conditions of renal failure, an in situ kidney of a healthy individual may be used. The present study utilizes the kidney of a healthy rabbit as a hemoperfusion unit for another, uremic, animal. The study comprised 17 experimental models, each of which consisted of 2 adult New Zealand rabbits. One animal of each model was rendered uremic by means of bilateral nephrectomy. The blood chemistry (urea, creatinine, sodium, potassium, pH and base deficit) was examined pre- and 4-hourly post-operatively. When after 48 hours post-nephrectomy, the blood chemistry had reached a level sufficient to endanger the animal's life, homohemodialysis was performed. The anticoagulated blood was circulated from the uremic animal to the normal one and then back to the uremic animal through the femoral vessels using a tube system. The blood chemistry was determined every 10 minutes and pH and base deficit every 30 minutes. All animals died or were sacrificed within 21 hours after shunting was started, and autopsy was done. Serum sodium was the first to normalize within the first 10 minutes post-shunting, followed by serum potassium and pH in 30 minutes. Blood urea and creatinine reached normal levels in 40 minutes and base deficit in 60 minutes post-shunting. The pathologic examination of specimens from the vital organs of both the normal and uremic animals showed different degrees of cellular damage probably due to hypotension or acute effects of the unbalanced animal homeostasis. The cellular damage was much less in the normal than in the uremic animals. In conclusion, homohemodialysis proved to be effective in normalizing the concentrations of the different substances retained in the blood of uremic animals within only 60 minutes of dialysis.

Tazarotene, a member of a novel class of synthetic acetylenic retinoids, is the first topical retinoid to demonstrate both efficacy and an acceptable patient tolerability profile in the treatment of psoriasis. The subchronic and chronic toxicity of topically applied tazarotene gel (0.025-0.1%; 0.05-0.5 mg/kg/d) was evaluated in Hanford miniswine in two separate, prospective, randomized, vehicle-controlled studies of 3 months' and 12 months' duration. Although tazarotenic acid, the active metabolite of tazarotene, was detected in the blood of animals in both studies, no signs of systemic toxicity could be detected in hematology, blood chemistry, posttreatment physical examination, necropsy, or histopathological examination of organ tissues. In both studies, the reversible signs and symptoms of cutaneous irritation caused by topical application of tazarotene gel were consistent with those effects commonly produced by other topical and oral retinoids.

Laboratory based NIR analysers have been available for some time. The recent development of more portable equipment such as the commercially available Futrex-9000 NIR transmittance blood chemistry analyser, which can be used to analyse relatively opaque samples for a mixture of components, shows promise but requires further evaluation for routine clinical use. NIR equipment for general use has only recently become available and is therefore relatively expensive. However, as the development of new applications occurs the instrumentation will become more widely used, which will inevitably result in reduced capital cost. The advantages of NIR systems are speed, portability, lack of consumables, dry chemistry, non-invasive, modest running costs, virtually no moving parts and almost infinite applications in clinical biochemical analysis. It is likely that the first applications of NIR will be where there is a requirement for multiple assays such as glucose, urea and bilirubin and where sample size is a limitation. Thus non-invasive near patient testing may become common in the future in settings such as neonatal units, renal units, diabetic clinics and intensive care units.

The growing public awareness regarding the relationship between elevated cholesterol levels and coronary artery disease (CAD), paired with the rapid technological advances in the health field, have led to a rising demand for quickly and easily implemented cholesterol screenings such as those seen at health promotion fairs and worksites. Manufacturers have responded to this demand by releasing tabletop lipid analyzers, thought to be highly accurate, which allow for simple analysis of blood lipids. The Cholestech L.D-X (Cholestech Corp., Hayward, California) is a compact system that allows for whole blood and serum full-lipid analyses. Although numerous studies are available regarding other compact lipid analyzers, ]-5 only three are published in reference to the LoDoX system. 5-7 Of these three studies, only one has looked at a specific population, v but it did not use the standard finger-stick protocol as described by the manufacturer. Therefore, this study set out to determine whether measured total cholesterol (TC), high-density lipoprotein (HDL), and triglyceride (TG) levels obtained from whole blood and serum analyses on the tabletop system were comparable to those values obtained using a standard venipuncture technique in a healthy population. The comparison was made using methods consistent with those suggested by the Centers for Disease Control and Prevention (CDC) Lipid Standardization Program as a reference. In addition to comparing TC, HDL, and TG measuremerits, the calculations for low-density lipoprotein (LDL) and TC/HDL were also examined.

Data from animal experiments with mechanical circulatory support systems (MCSS) performed in Groningen and Marseille over the past years were used to obtain normal values of hematological, coagulation, rheological and blood chemistry parameters in calves. These parameters were divided between two groups: a limited number of parameters necessary to assess biocompatibility properties of MCSS quickly and a more extensive number of parameters suitable for more detailed biological evaluation of blood pumps. All applied tests can be examined in calf blood as well as in human blood. Parameters were selected on clinical relevance and usefulness for standardization procedures. The obtained data were compared with normal values in human beings derived from the literature.

The antiherpes compound (-)9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G) has been found to suppress the multiplication of SIVsm and HIV-2 in cynomolgus monkeys. This was seen as a delay in the appearance of viral antigen in serum during the primary infection at drug concentrations of 3×10 mg kg−1 day−1 and higher, when H2G was given subcutaneously. These effects of H2G on SIVsm and HIV-2 replication in monkeys were similar to those observed using the same dose of 3′-azidothymidine (AZT). A complete prevention of HIV-2 infection was observed in one of four animals treated with 3×10 mg kg−1 day−1 of H2G. The enantiomeric mixture (+)H2G at 3×25 mg kg−1 day−1 also delayed the appearance of SIVsm antigen but the (+)enantiomer of H2G at 3×10 mg kg−1 day−1 had no effect on primary SIVsm infection in monkeys, indicating that only the (−)enantiomer (H2G) was inhibitory and that this effect was not influenced by the presence of the (+)enantiomer. No adverse effects on blood chemistry or haematology were observed in monkeys given 25 mg kg−1 day−1 of H2G for 9 weeks or 3×25 mg kg−1 day−1 for 10 days.

In their article "The Negative Effects of Positive Reinforcement in Teaching Children with Developmental Delay," Biederman, Davey, Ryder, and Franchi (1994) sought to determine "the relative efficiency of hand-over-hand (active) instruction versus passive observation" (p. 460). Passive observation was contrasted with hand-over-hand instruction with and without verbal reinforcement. The finding of Biederman et al. was that "the verbal reinforcement used in the interactive modeling accounted for poor performance" (p. 462). They concluded from this finding that verbal reinforcement, in combination with interactive modeling strategies, may produce confusion in children with language and learning difficulties; the child may be uncertain about exactly what behavior is being reinforced, or the reinforcement may serve to distract the child from what is for him or her, a difficult sequence of behavior" (p. 464). In this response, I assert that Biederman et al. (1994) have misunderstood the phenomenon of reinforcement. At issue is the definition and measurement of the independent and dependent variables that have led to an unwarranted conclusion. I maintain that their finding cannot be functionally related to the independent variable they called "positive reinforcement" and described as "verbal feedback and other sorts of reinforcement" because they did not use measurement tactics that were able to document the phenomenon of reinforcement. THE PROBLEM OF DEFINITION There is an old adage that begins, "If it looks like a duck, sounds like a duck, walks like a duck ..." This adage (in all its variants) is commonly used to make the case that if something appears as it appears, then it probably is the thing it appears to be. As a general rule of thumb the adage is probably good advice. As a scientific rule it is insufficient as an explanatory mechanism. My contention is that the criteria one uses to assess phenomena such as reinforcement must be those that define its existence. In defining a duck, zoologists would not be limited to its physical appearance (e.g., shape, size); they would observe its behavior (e.g., quacking, waddling) and at times assess its structure and biology (e.g., skeleton and blood chemistry). There are two necessary and sufficient criteria used in examining the phenomenon of reinforcement: its operational description and its process or functional effect. "As an operation, reinforcement refers to the occurrence of a consequence subsequent to a behavior. As a process, reinforcement refers to the increase in responding as a function of the occurrence of the consequence" (Cooper, Heron, & Heward, 1987, p. 257). The existence of either criteria without the other inhibits an analysis of reinforcement. Consequences that increase behavior are called reinforcers (Cooper et al., 1987). In contrast, consequences that decrease the probability of occurrence of a behavior are termed punishers; and the phenomenon is termed punishment. Reinforcement and punishment are commonly confused and misunderstood. Part of the problem lies in the failure to use the term reinforcement for the phenomenon when behavior increases following the contingent application of a reinforcer, and the term punishment for the phenomenon when behavior decreases following the contingent application of a punisher. Often, if it looks like reinforcement, and sounds like reinforcement, it is assumed to be reinforcement. However, the only criteria that adequately define reinforcement (or punishment) are (a) the temporal relation between the behavior and its reinforcer and (b) the effect that consequences have on the occurrence of behavior (Alberto & Troutman, 1990; Cooper et al., 1987; Malott, Whaley, & Malott, 1993; Martin & Pear, 1983; Skinner, 1953). Thus the theme of this commentary is: "It may look and sound like a reinforcer, but unless it increases the frequency of the behavior it follows, it's not a reinforcer. …