A perspective on In vitro developmental neurotoxicity test assay results: An expert panel review.

For decades, there has been increasing concern about the potential developmental neurotoxicity (DNT) associated with chemicals. Regulatory agencies have historically utilized standardized in vivo testing to evaluate DNT. Owing to considerations including higher-throughput screening for DNT, reduction in animal use, and potential cost efficiencies, the development of alternative new approach methods (NAMs) occurred; specifically, the advent of the DNT in vitro test battery (DNT IVB). SciPinion convened an expert panel to address specific questions related to the interpretation of in vitro DNT test data. The consensus of the expert panel was that the DNT IVB might be used during initial screening, but it is not presently a complete or surrogate approach to determine whether a chemical is a DNT in humans. By itself, the DNT IVB does not have the ability to capture nuances and complexity of the developing nervous system and associated outcomes including behavioral ontogeny, motor activity, sensory function, and learning/memory. Presently, such developmental landmarks cannot be adequately assessed in the DNT IVB or by other NAMs. The expert panel (all who serve as co-authors of this review) recommended that additional data generation and validation is required before the DNT IVB can be considered for application within global regulatory frameworks for decision-making.

Evidence for spawning aggregations of the endangered Atlantic goliath grouper Epinephelus itajara in southern Brazil.

In this study, seasonal numerical abundance of the critically endangered Atlantic goliath grouper Epinephelus itajara was estimated by conducting scuba dive surveys and calculating sightings-per-unit-effort (SPUE) at three sites in southern Brazil. Seasonal differences in size and reproductive condition of captured or confiscated specimens were compared. The SPUE differed significantly with season, increasing in late spring and peaking during the austral summer months. A significant effect was observed in the number of fish relative to the lunar cycle. All females sampled during the summer were spawning capable, while all those sampled during other seasons were either regressing or regenerating. What these data strongly infer is that the E. itajara spawning aggregation sites have been located in the southern state of Paraná and the northern state of Santa Catarina and summer is the most likely spawning season. Size frequency distributions, abundance and reproductive state were estimated and correlated with environmental variables.

Effects of dalfampridine on multi-dimensional aspects of gait and dexterity in multiple sclerosis among timed walk responders and non-responders.

BACKGROUND: Dalfampridine extended release 10mg tablets (D-ER) have demonstrated improvement in walking for ambulatory persons with multiple sclerosis (pwMS), termed "responders." OBJECTIVE: This study examined the extent additional aspects of gait and dexterity change for patients prescribed D-ER. METHODS: Over 14-weeks, walking endurance, dynamic gait, self-report walking ability and fine and gross dexterity were examined in pwMS prescribed D-ER as a part of routine clinical care. RESULTS: The final results (n=39) validate that a subset of pwMS improve walking speed (Time 25-Foot Walk Test, p<0.0001). Significant improvements in gait and dexterity were observed even among participants who did not improve walking speed. Improvements were evident in gait and dexterity domains including Six Minute Walk Test, p=0.007, Six-Spot Step Test, p<0.0001, Multiple Sclerosis Walking Scale-12, p<0.0001, Nine Hole Peg Test, p<0.0001 dominant and non-dominant sides, and Box and Blocks Test, p=0.005 and 0.002, dominant and non-dominant sides, respectively. CONCLUSIONS: These findings suggest that D-ER may be a potential treatment for gait impairments, beyond walking speed and dexterity in pwMS. Further investigation regarding D-ER response is warranted.

Time since last vaccine dose in PCR-positive and PCR-negative children with suspected pertussis to monitor pertussis vaccine effectiveness.

We evaluated whether the results of diagnostic polymerase chain reaction (PCR) testing combined with time since last vaccine dose could be used to monitor the effectiveness of acellular pertussis vaccines. In 258 consecutive nasopharyngeal swabs from children and adolescents with typical pertussis symptoms, 80 were positive and 178 were negative in PCR for Bordetella pertussis DNA (IS 481). Time since last vaccine dose was available for 152 patients, of which 120 were fully immunised. Among the fully vaccinated patients, the median age of 41 PCR-positive patients was 8.4 years (range 0.9-12.3) and that of 79 PCR-negative cases was 3.3 years (range 0.4-14.1) (p < 0.01). The median time since last pertussis vaccine dose was 6.05 years [95 % confidence interval (CI): 0.5-10.9] in PCR-positive cases and 2.22 years (95 % CI: 0.04-9.23) in PCR-negative cases (p < 0.001). The use of diagnostic PCR results from pertussis cases together with time since last vaccine dose permits estimates of the duration of protection after vaccination with acellular pertussis vaccines that are in keeping with more complex studies.

Performance of commercial enzyme-linked immunosorbent assays for detection of antibodies to Bordetella pertussis.

Measuring antibodies to Bordetella pertussis antigens is mostly done by enzyme-linked immunosorbent assays (ELISAs). We compared the performance of ELISA kits that were commercially available in Germany. Eleven measured IgG antibodies, and nine measured IgA antibodies. An in-house ELISA with purified antigens served as a reference method. Samples included two WHO reference preparations, the former Food and Drug Administration (FDA)/Center for Biologics Evaluation and Research (CBER) reference preparations, serum samples from patients with clinically suspected pertussis, and serum samples from patients having received a combined tetanus, diphtheria, and pertussis (Tdap) vaccination. Kits using pertussis toxin (PT) as an antigen showed linearity compared to the WHO Reference preparation (r2 between 0.82 and 0.99), and these kits could quantify antibodies according to the reference preparation. ELISA kits using mixed antigens showed no linear correlation to the reference preparations. Patient results were compared to results of in-house ELISAs using a dual cutoff of either ≥100 IU/ml anti-PT IgG or ≥40 IU/ml anti-PT IgG together with ≥12 IU/ml anti-PT IgA. The sensitivities of kits measuring IgG antibodies ranged between 0.84 and 1.00. The specificities of kits using PT as an antigen were between 0.81 and 0.93. The specificities of kits using mixed antigens were between 0.51 and 0.59 and were thus not acceptable. The sensitivities of kits measuring IgA antibodies ranged between 0.53 and 0.73, and the specificities were between 0.67 and 0.94, indicating that IgA antibodies may be of limited diagnostic value. Our data suggest that ELISAs should use purified PT as an antigen and be standardized to the 1st International Reference preparation.

Preparation of Bordetella pertussis DNA from respiratory samples for real-time PCR by commercial kits.

Bordetella pertussis is increasingly detected by real-time PCR, but most kits for extracting Bordetella-DNA from respiratory samples are not validated for this material. Respiratory clinical materials were spiked with Bordetella pertussis cells. Four ion-exchange chromatography methods from one manufacturer were used for DNA preparation. Two real-time PCRs detecting the IS481 of Bordetella pertussis and based either on a hybridisation probes format (LightCycler) or on a TaqMan format were used. All kits effectively prepared DNA for Bordetella pertussis real-time PCR. The procedures were linear over a broad range, and the lower level of sensitivity was similar. Sensitivities measured as CT values were different. Inter-assay CVs were between 6.8% and 17.3%. Two kits did not effectively remove inhibitory substances from the respiratory samples. Commercial kits are useful for preparing Bordetella pertussis DNA from respiratory samples, but even kits from one manufacturer show significant differences in effectiveness and removal of inhibitory substances.

Schizophrenia trials in China: a survey.

OBJECTIVE: China's biomedical research activity is increasing and this literature is becoming more accessible online. Our aim was to survey all randomized control schizophrenia trials (RCTs) in one Chinese bibliographic database. METHOD: Chinese Academic Journals was electronically searched for RCTs and all relevant citations were also sought on PubMed to ascertain global accessibility. RESULTS: The search identified 3275 records, of which 982 were RCTs relevant to schizophrenia. A total of 71% (699) could be found by using English phrases. All the main body of text of the 982 papers was in Mandarin. On average, these trials involved about 100 people, with interventions and outcome measures familiar to schizophrenia trialists worldwide. Four of the 982 records (<1%) were identified on PubMed. CONCLUSION: Those undertaking systematic reviews should search the Chinese literature for relevant material. Failing to do this will leave the results of systematic reviews prone to random error or bias, or both.

Active immunisation during an outbreak of hepatitis A in a German day-care centre.

During an outbreak in a German day-care centre (DCC) caring for 100 children HAV vaccination was recommended for children, employees and household members of cases. A retrospective cohort study was done to evaluate vaccine uptake and identify possible risk factors for disease. Between 19 December 2004 and 30 January 2005 eight DCC children and seven household members fulfilled the case definition, i.e. had clinical hepatitis (14) or were diagnosed with asymptomatic HAV infection (1). Following the recommendation to vaccinate, given on 23 December 2004, 66.7% (46/69) of DCC children, 15.8% (29/184) of household members and 5/5 of employees were vaccinated, and three vaccinated children and two not vaccinated children fell ill. One of 11 children who received human normal immunoglobulin (HNIG) and four of 58 children who did not receive HNIG fell ill. In households in which the DCC child received HAV vaccine and/or HNIG, seven (5.6%) of 125 household members fulfilled the case definition. In households of non-immunised children none of the 59 household members fell ill. We conclude that, although most vaccinations were administered promptly, they may not have been timely enough to impact the course of the outbreak.

De-confusing the THOG problem: the Pythagorean solution.

Sources of facilitation for Needham and Amado's (1995) Pythagoras version of Wason's THOG problem were systematically examined in three experiments with 174 participants. Although both the narrative structure and figural notation used in the Pythagoras problem independently led to significant facilitation (40-50% correct), pairing hypothesis generation with either factor or pairing the two factors together was found to be necessary to obtain substantial facilitation (> 50% correct). Needham and Amado's original finding for the complete Pythagoras problem was also replicated. These results are discussed in terms of the "confusion theory" explanation for performance on the standard THOG problem. The possible role of labelling as a de-confusing factor in other versions of the THOG problem and the implications of the present findings for human reasoning are also considered.

Activation of the cardiac interleukin-6 system in advanced heart failure.

OBJECTIVES: The study objective was to assess the cardiac expression of interleukin-6 (IL6) and its receptor (IL6R) in advanced heart failure. BACKGROUND: While IL6 plasma levels are elevated and associated with an impaired prognosis in advanced heart failure, little is known about the intracardiac expression of the IL6 system. METHODS: Heart tissue was obtained from 20 patients (n=10, idiopathic dilated cardiomyopathy, age 44+/-15 years; n=10, ischemic cardiomyopathy, age 55+/-8 years) at the time of transplantation. Left and right ventricular tissue was subjected to in situ hybridization, Northern blot analysis, and RT-PCR. Signals were quantified by densitometric scanning and corrected for G3PDH-mRNA levels. Right ventricular biopsy specimens (n=11) of patients with arrhythmias and normal cardiac function served as controls. In addition, data were correlated with cardiac catheterization and echocardiography data obtained at transplant evaluation. RESULTS: Ventricular IL6 and IL6R transcripts were detected in all explant specimens examined. Expression of both mRNA species was higher than in controls (P=0.001). Left ventricular IL6 mRNA levels correlated positively with heart rate (r=0.77; P=0.009), pulmonary capillary wedge pressure (r=0.53; P=0.03), right atrial pressure (r=0.77; P=0.003), and inversely with left ventricular ejection fraction (r=-0.61; P=0.03). Right ventricular IL6 mRNA levels correlated inversely with cardiac index (r=-0.48; P=0.05). IL6R expression did not correlate with hemodynamic data. CONCLUSIONS: In advanced heart failure, cardiac IL6/IL6R mRNA expression is increased and may play a role in the pathophysiology of advanced heart failure.

MR-guided biopsy of musculoskeletal lesions in a low-field system.

Thirty magnetic resonance (MR)-guided biopsies were obtained from 20 skeletal and 10 soft-tissue lesions in 31 patients using an open 0.2 T MR system equipped with interventional accessories. The results from aspiration (N = 3), core biopsy (N = 15), and transcortical trephine biopsy (N = 12) were evaluated for accuracy and clinical efficacy. Specimens were successfully obtained from 29 patients. Results were clinically effective in 23 patients, rated definitive in 16, nonconclusive in 9, and unspecific in 2 patients. A false diagnosis due to sampling error occurred in 2 patients, and biopsy sampling was impossible in one case. The best diagnostic yield was achieved from nontranscortical biopsies of osteolytic or soft-tissue masses. Results from transcortical biopsies were less specific due to the predominance of benign lesions. MR fluoroscopy for needle guidance was applied in 13 patients. Complete needle placement inside the magnet could be performed in 16 patients. MR-guided biopsy using an open low-field MR imager is feasible and clinically effective and will become a valuable tool in the management of musculoskeletal lesions. J. Magn. Reson. Imaging 2001;13:761-768.

Adulthood relocation: implications for personality, future orientation, and social partner choices.

The purpose of this study was to learn the reasons why individuals relocate and whether relocaters differ from nonrelocaters on demographic, social, and personality factors. One hundred participants from three age groups, 34 to 46 (young/middle-aged), 54 to 66 (young-old), and 69 to 93 (older) years, were designated as relocaters or residents as a function of months of residence. Relocaters did not differ from residents in age, income, health, or marital status. Reasons provided for relocating revealed the following differences: young/middle-aged moved for employment reasons, young-old moved for reasons of retirement, and older adults relocated to be closer to family members. No differences in network size occurred and older relocaters selected more cards in a social partner selection task. Most interesting was the finding that relocaters scored higher on Openness to Experience and future orientation. These data suggest personality may be an important trait that explains why some individuals are more likely to relocate.

Elementary, my dear Wason: the role of problem representation in the THOG task.

The present study was concerned with Wason's THOG problem, a hypothetico-deductive reasoning task for which performance over the past 20 years has typically been very poor (< 20% correct). We examined the hypothesis that incorporating a quasi-visual context into the problem statement would make both the binary, symmetric tree structure and solution principle of the THOG task clearer and thus facilitate performance. A version of O'Brien et al.'s (Q J Exp Psychol 42A:329-351) Blackboard THOG problem, that specifies each branch of the tree by describing a specific location for each possible color-shape combination, was used to test this hypothesis. Substantial facilitation was both observed (68% correct) and replicated (73% correct), and it was also shown that it is necessary to provide a representation of both sides of the tree to obtain this level of facilitation. The implications of these results for human deductive reasoning are considered.

Differential expression of canalicular membrane Ca2+/Mg(2+)-ecto-ATPase in estrogen-induced and obstructive cholestasis in the rat.

Extracellular adenosine triphosphate (ATP) may regulate hepatocyte and cholangiocyte functions, and under some conditions it may have deleterious effects on bile secretion and cause cholestasis. The canalicular membrane enzyme Ca2+/Mg2+-ecto-ATPase (ecto-ATPase) hydrolyzes ATP/adenosine diphosphate (ATP/ADP) and regulates hepatic extracellular ATP concentration. Changes in liver ecto-ATPase in estrogen-induced cholestasis were examined in male rats receiving 17alpha-ethinylestradiol (E groups) for 1, 3, or 5 days (5 mg/kg/day, sc) and compared with changes in rats subjected to obstructive cholestasis (O groups) for 1, 3, or 8 days. Activity of ecto-ATPase, protein mass in canalicular membranes and bile (estimated by Western blotting), steady state mRNA levels (by Northern blotting), and cellular and acinar distributions of the enzyme (histochemistry and immunocytochemistry) were assessed in these groups. Activity of ecto-ATPase, protein mass in isolated canalicular membranes, and enzyme mRNA levels were significantly increased in E group rats as compared with controls. In contrast, these parameters were markedly decreased in O group rats, and the enzyme protein was undetectable in bile. The ecto-ATPase histochemical reaction was markedly increased in the canalicular membrane of E group rats, extending from acinar zone 2 to zone 1, whereas it decreased in the O group. The ecto-ATPase immunocytochemical reaction was present in the canalicular membrane and pericanalicular vesicles in control and E group hepatocytes, but it decreased in obstructive cholestasis and was localized only to the canalicular membrane. Thus, significant changes in liver ecto-ATPase were apparent in 17alpha-ethinylestradiol-induced cholestasis that were opposite to those observed in obstructive cholestasis. Assuming that the alterations observed in obstructive cholestasis are the result of the cholestatic phenomenon, we conclude that changes in ecto-ATPase in 17alpha-ethinylestradiol-treated rats might be either primary events or part of an adaptive response in 17alpha-ethinylestradiol-induced cholestasis.