The acute, systemic effects of aerobic exercise in recently concussed adolescent student-athletes: preliminary findings.

OBJECTIVES: Examine the acute effects (pre-, during, post-intervention) of two different intensities of aerobic exercise or rest on autonomic, oculomotor, and vestibular function and symptom burden in patients with a recent sport-related concussion (SRC) and compare their responses to sex-matched, age-stratified, non-concussed (HEALTHY) student-athletes. METHODS: Student-athletes between the ages of 13 and 18 that presented to the sports medicine clinic within Day 3-7 post-SRC and from local schools were recruited for a randomized controlled trial (RCT). The participants were administered the Vestibular/Ocular Motor Screening (VOMS), King-Devick (K-D), and Post-Concussion Symptom Scale (PCSS) before and after the intervention. Heart rate variability (HRV) and mean arterial pressure (MAP) were collected before, during, and after the intervention. The intervention was either a single, 20-min session of treadmill walking at 40% (40HR) or 60% of age-predicted max heart rate (60HR), or seated, rest (NOEX). RESULTS: 30 participants completed the intervention with the SRC group treated 4.5 ± 1.3 days post-injury. Pre-exercise HRV and MAP were significantly different (p's < 0.001) during treatment but returned to pre-exercise values within 5 min of recovery in both the SRC and HEALTHY groups. Both the SRC and HEALTHY groups exhibited similar reductions pre- to post-intervention for symptom severity and count (p's < 0.05), three VOMS items (p's < 0.05) but not K-D time. CONCLUSIONS: To date, this is the first adolescent RCT to report the acute, systemic effects of aerobic exercise on recently concussed adolescent athletes. The interventions appeared safe in SRC participants, were well-tolerated, and provided brief therapeutic benefit. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT03575455.

Getting in Front of Chronic Wasting Disease: Model-Informed Proactive Approach for Managing an Emerging Wildlife Disease.

Continuing geographic spread of chronic wasting disease (CWD) poses a serious threat to the sustainable future of cervids and hunting in North America. Moreover, CWD has been detected in captive cervids in South Korea and, in recent years, in free-ranging reindeer in Europe (Norway). Management of this disease is limited by logistical, financial, and sociopolitical considerations, and current strategies primarily focus on reducing host densities through hunter harvest and targeted culling. The success of such strategies in mitigating the spread and prevalence of CWD only upon detection is questionable. Here, we propose a proactive approach that emphasizes pre-emptive management through purposeful integration of virtual experiments (simulating alternate interventions as model scenarios) with the aim of evaluating their effectiveness. Here, we have used a published agent-based model that links white-tailed deer demography and behavior with CWD transmission dynamics to first derive a CWD outbreak trajectory and then use the trajectory to highlight issues associated with different phases of the CWD outbreak (pre-establishment/transition/endemic). Specifically, we highlight the practical constraints on surveillance in the pre-establishment phase and recommend that agencies use a realistic detection threshold for their CWD surveillance programs. We further demonstrate that many disease introductions are "dead ends" not leading to a full epidemic due to high stochasticity and harvesting in the pre-establishment phase of CWD. Model evaluated pre-emptive (pre-detection) harvest strategies could increase the resilience of the deer population to CWD spread and establishment. We conclude it is important to adaptively position CWD management ahead of, rather than behind, the CWD front.

Quantification of tantalum sedimentation rates in liquid embolic agents.

Background Endovascular treatment (EVT) of brain arteriovenous malformations has evolved from cyanoacrylate derivatives such as N-butyl cyanoacrylate, an adhesive glue, to ethylene vinyl copolymer-based liquid embolics such as Onyx® and SQUID® dissolved in dimethyl sulfoxide. Although these agents offer several advantages, their rapidly decreasing radiopacity, as a result of the sedimentation of tantalum powder, compromises visual control during EVT. This study aims to quantify and compare tantalum sedimentation rates of several liquid embolic agents, and determine their effects on radiopacity. Methods The rate of sedimentation of liquid embolics Onyx 18®, SQUID 12®, and SQUID 18® was measured after preparation by single x-ray exposures for a period of 30 minutes. The signal-to-noise ratios (SNRs) of the suspension of each liquid embolic was calculated at various time points as tantalum settled out of the suspension. Precipitating Hydrophobic Injectable Liquid (PHIL®) was imaged as a control. Results Onyx 18® demonstrated the fastest sedimentation rate of the liquid embolics analyzed and demonstrated a threefold faster drop in SNR compared to SQUID 18® over 30 minutes. Onyx 18® demonstrated a one and a half times faster drop in SNR compared to SQUID 12®. Although PHIL 25® maintained constant SNR over the same time, it was lower at baseline immediately after preparation compared to tantalum-based liquids. Conclusion Caution during long injections using tantalum-based agents is advised. Onyx 18® has a significantly faster drop in radiopacity compared to SQUID 12® and SQUID 18®. Covalently bonded iodine-based embolics like PHIL® demonstrate constant radiopacity over time.

Adverse drug reactions causing admission to a paediatric hospital: a pilot study.

WHAT IS KNOWN AND OBJECTIVE: It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital. METHODS: Prospective observational study over a 2-week period. RESULTS AND DISCUSSION: There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance. WHAT IS NEW AND CONCLUSION: This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations (internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population.

Bacterial diversity in cases of lung infection in cystic fibrosis patients: 16S ribosomal DNA (rDNA) length heterogeneity PCR and 16S rDNA terminal restriction fragment length polymorphism profiling.

The leading cause of morbidity and mortality in cystic fibrosis (CF) patients stems from repeated bacterial respiratory infections. Many bacterial species have been cultured from CF specimens and so are associated with lung disease. Despite this, much remains to be determined. In the present study, we characterized without prior cultivation the total bacterial community present in specimens taken from adult CF patients, extracting DNA directly from 14 bronchoscopy or sputum samples. Bacterial 16S ribosomal DNA (rRNA) gene PCR products were amplified from extracted nucleic acids, with analyses by terminal restriction fragment length polymorphism (T-RFLP), length heterogeneity PCR (LH-PCR), and sequencing of individual cloned PCR products to characterize these communities. Using the same loading of PCR products, 12 distinct T-RFLP profiles were identified that had between 3 and 32 T-RFLP bands. Nine distinct LH-PCR profiles were identified containing between one and four bands. T-RFLP bands were detected in certain samples at positions that corresponded to pathogens cultured from CF samples, e.g., Burkholderia cepacia and Haemophilus influenzae. In every sample studied, one T-RFLP band was identified that corresponded to that produced by Pseudomonas aeruginosa. A total of 103 16S rRNA gene clones were examined from five patients. P. aeruginosa was the most commonly identified species (59% of clones). Stenotrophomonas species were also common, with eight other (typically anaerobic) bacterial species identified within the remaining 17 clones. In conclusion, T-RFLP analysis coupled with 16S rRNA gene sequencing is a powerful means of analyzing the composition and diversity of the bacterial community in specimens sampled from CF patients.

Expression of benzene dioxygenase from Pseudomonas putida ML2 in cis-1,2-cyclohexanediol-degrading pseudomonads.

Benzene dioxygenase (BDO; EC 1.14.12.3) from Pseudomonas putida ML2 dihydroxylates benzene to produce cis-1,2-dihydroxy-cyclohexa-3,5-diene. As well as oxidising benzene and toluene, cell-free extracts of Escherichia coli JM109 expressing recombinant BDO oxidised cyclohexene, 1-methylcyclohexene and 3-methylcyclohexene. In an attempt to construct a novel metabolic pathway for the degradation of cyclohexene (via an initial BDO-mediated dihydroxylation of cyclohexene), cis-1,2-cyclohexanediol-degrading bacteria were isolated by enrichment culture. The bedC1C2BA genes encoding BDO (under the control of the tac promoter) were sub-cloned into pLAFR5, successfully conjugated into seven of the Gram-negative cis-1,2-cyclo-hexanediol-degrading isolates and stably maintained and expressed in three of them. However, despite their ability to grow on cis-1,2-cyclohexanediol as sole carbon source, express an active BDO and oxidise cyclohexene, none of the three strains was able to grow on cyclohexene as sole carbon source. Analysis revealed that BDO oxidised cyclohexene to a mixture of two products, a monohydroxylated (2-cyclohexen-1-ol) product and a dihydroxylated (cis-1,2-cyclohexanediol) product; and failure to grow on cyclohexene was attributed to the toxicity of metabolic intermediates accumulating from the 2-cyclohexen-1-ol metabolism.

Master of laboratory animal science program: teaching the science of laboratory animal science.

The administrators of the only program of its kind in the US explain the demand for a Master's degree in Laboratory Animal Science, the value of the degree, and plans to expand the program to make it available for distance learning.

High-dose chemotherapy and hematopoietic stem cell rescue for breast cancer: experience in California.

The role of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell rescue in breast cancer is still controversial. We analyzed the outcomes of 1111 consecutive patients with histologically proven breast cancer who underwent HDCT at 5 major California medical centers. The overall treatment-related mortality (TRM) was 2.3%. TRM was not influenced by disease stage or the HDCT regimen delivered, but it was influenced by hematopoietic graft source. The TRM was 6.1% when bone marrow with or without blood stem cells was used, but only 1.4% when blood stem cells alone were used (P < .001). With a median follow-up of 2.8 years (range, 0.1-8.2 years) after HDCT and autologous hematopoietic stem cell rescue, the estimated 5-year event-free survival (EFS) and overall survival (OS) for stage II/IIIA patients with > or =10 involved axillary lymph nodes were 67% and 76%, respectively. Patients with metastatic breast cancer (MBC) (median follow-up, 1.9 years [range, 0.03-8.3 years]) achieving a complete response (CR) to conventional-dose chemotherapy or rendered to a "no evidence of disease" status before HDCT had significantly better estimated 5-year EFS and OS (28% and 57%, respectively) than those achieving a partial response before HDCT (19% and 27%, respectively; P < or = .0001). Our data suggest that HDCT with hematopoietic stem cell rescue is safe and can be beneficial to patients with high-risk primary breast cancer and for those with MBC achieving CR/no evidence of disease.

A randomized phase 2 study of PBPC mobilization by stem cell factor and filgrastim in heavily pretreated patients with Hodgkin's disease or non-Hodgkin's lymphoma.

This randomized, controlled study compared the ability to mobilize and collect an optimal target yield of 5 x 10(6) CD34+ cells/kg using stem cell factor (SCF; 20 microg/kg/day) plus filgrastim (G-CSF; 10 microg/kg/day) vs filgrastim alone (10 microg/kg/day) in 102 patients diagnosed with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD), who were prospectively defined as being heavily pretreated. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield was reached, or until a maximum of five leukaphereses had been performed. Compared with the filgrastim-alone group (n = 54), the SCF plus filgrastim group (n = 48) showed an increase in the proportion of patients reaching the target yield within five leukaphereses (44% vs 17%, P = 0.002); reduction in the number of leukaphereses required to reach the target yield (P = 0.003); reduction in the proportion of patients failing to reach a minimum yield of 1 x 10(6) CD34+ cells/kg to proceed to transplant (16% vs 26%, P = NS); increase in the median yield of CD34+ cells per leukapheresis (0.73 x 10(6)/kg vs 0.48 x 10(6)/kg, P = 0.04); and an increase in the median total CD34+ cells collected within five leukaphereses (3.6 x 10(6)/kg vs 2.4 x 10(6)/kg, P = 0.05). All patients receiving SCF were premedicated (antihistamines and albuterol), and treatment was generally well tolerated. Five patients experienced severe mast cell-mediated reactions, none of which were life-threatening. In this study of heavily pretreated lymphoma patients, SCF plus filgrastim was more effective than filgrastim alone for mobilizing PBPC for harvesting and transplantation after high-dose chemotherapy.

Development and testing of seven new synthetic coyote attractants.

Available evidence indicates that effective coyote attractants are blends of volatile substances. Typically, attractants are a combination of biological substances such as fermented glandular materials, urines, and rotted meats. Although effective, these attractants have several distinct disadvantages. Among these is the possibility that they are unnecessarily complex and variable and, thus, difficult to replicate from one batch to the next. Although attractants containing a few reagent grade materials are available, the chemicals selected and their concentrations are not derived from actual attractants. For this reason, commercially available coyote attractants were analyzed with the intention of developing relatively simple synthetic alternatives. Purge and trap headspace analysis with gas chromatography/mass selective detection was employed to identify the volatile components of known conventional and synthetic attractants. All identified compounds were grouped according to chemical functionality, and one compound from each functional group was chosen to represent the group. Using only these representative compounds, seven synthetic attractants were formulated. Bioassays with captive coyotes (Canis latrans) were conducted to compare behavioral responses elicited by the seven new attractants, a currently available synthetic attractant, and a control. The results indicated that the attractants elicited significantly different behavioral profiles.

An apparatus for studying operant activity of captive coyotes.

We describe a portable apparatus designed to examine the free-operant food preferences of captive coyotes in their home kennels. Because lever-pressing for food access was the dependent variable, we measured food preference independently of food ingestion. Using successive approximation, we trained 8 out of 19 coyotes (42%) to use the apparatus. This percentage is similar to training rates for dogs. We used fixed and variable ratio schedules of reinforcement to further test 4 of the trained coyotes. All 4 produced response curves similar to those of other species on similar schedules of reinforcement.

Flavor avoidance learning and its implications in reducing strychnine baiting hazards to nontarget animals.

In reforested areas, underground strychnine baiting to control pocket gophers (Thomomys mazama) poses a hazard to golden mantled ground squirrels (Spermophilus lateralis) and yellow pine chipmunks (Eutamias amoenus). We designed this study to assess whether: 1) chemical insensitivity to bitter tastes might explain the ingestion of strychnine; 2) pocket gophers would avoid four bitter-tasting compounds: quebracho (QUEB), sucrose octaacetate (SOA), quinine hydrochloride (QHCl), and denatonium benzoate (DB); and 3) nontarget species could be trained to avoid strychnine paired with the most aversive compound. Our results showed that while all species readily consumed strychnine, the nontarget species could be conditioned to avoid it. Moreover, while high (0.1%) concentrations of DB, quinine hydrochloride, and quebracho reduced consumption by pocket gophers, 0.05% DB was inoffensive. Nontarget animals readily avoided 0.05% DB, and avoidance was stronger after conditioning. Together, our results suggest that all of the rodents tested are insensitive to strychnine, high concentrations of some bitter tastes may be effective pocket gopher repellents, and lower concentrations of DB may selectively repel nontarget animals from strychnine baits.

Identification of chlorobenzene dioxygenase sequence elements involved in dechlorination of 1,2,4,5-tetrachlorobenzene.

The TecA chlorobenzene dioxygenase and the TodCBA toluene dioxygenase exhibit substantial sequence similarity yet have different substrate specificities. Escherichia coli cells producing recombinant TecA enzyme dioxygenate and simultaneously eliminate a halogen substituent from 1,2,4,5-tetrachlorobenzene but show no activity toward benzene, whereas those producing TodCBA dioxygenate benzene but not tetrachlorobenzene. A hybrid TecA dioxygenase variant containing the large alpha-subunit of the TodCBA dioxygenase exhibited a TodCBA dioxygenase specificity. Acquisition of dehalogenase activity was achieved by replacement of specific todC1 alpha-subunit subsequences by equivalent sequences of the tecA1 alpha-subunit. Substrate transformation specificities and rates by E. coli resting cells expressing hybrid systems were analyzed by high-performance liquid chromatography. This allowed the identification of both a single amino acid and potentially interacting regions required for dechlorination of tetrachlorobenzene. Hybrids with extended substrate ranges were generated that exhibited activity toward both benzene and tetrachlorobenzene. The regions determining substrate specificity in (chloro)benzene dioxygenases appear to be different from those previously identified in biphenyl dioxygenases.

Ciprofloxacin-associated acute renal failure in patients undergoing high-dose chemotherapy and autologous stem cell rescue.

The broad spectrum of activity of ciprofloxacin makes it an ideal drug for the prophylaxis of bacterial infections in patients undergoing high-dose chemotherapy (HDC) with autologous stem cell rescue. We present two cases of ciprofloxacin-associated acute renal failure (ARF) in patients undergoing HDC. Maintaining a high index of suspicion for this complication will allow a prompt diagnosis, with discontinuation of the drug usually resulting in a reversal of renal failure. Renal biopsy usually reveals changes compatible with interstitial nephritis, but is not always possible in these patients due to severe thrombocytopenia following HDC. A brief course of steroid therapy may be beneficial although the role of glucocorticoids is difficult to ascertain in the absence of data regarding its efficiency in this clinical setting.

Induction of molecular remission by donor peripheral blood leukocyte therapy in patients relapsing with extramedullary blastic phase chronic myeloid leukemia after allogeneic bone marrow transplantation.

Two patients with chronic myeloid leukemia (CML) who relapsed in blastic transformation after allogeneic bone marrow transplantation (BMT) were treated with infusions of leukapheresed peripheral blood mononuclear cells from their original donor. At relapse, their disease was characterized by symptomatic extramedullary deposits of leukemia with minimal (PCR positive, cytologically negative) involvement of bone marrow. Treatment with donor cell infusions was associated with clinical remission, return of full donor chimerism and loss of the BCR-ABL transcript detectable in bone marrow before donor leukocyte infusion (molecular remission). Donor leukocyte infusions should be considered for therapy of relapsed blastic phase CML after allogeneic BMT, especially when the relapse is primarily extramedullary and responsive to local and systemic cytoreductive therapy. However, severe GVHD and CNS relapse remain obstacles to achieving a successful long-term outcome.