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.

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.

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.

Selective deficits in the sense of smell caused by chemical modification of the olfactory epithelium.

A chemically selective procedure for covalent modification of Schiff base-forming binding sites in proteins is demonstrated in vitro. In vivo studies show that the same procedure produces a selective anosmia ("odor blindness") when applied to the olfactory epithelia of experimental animals. Surgical experiments confirm that the sense of smell is specifically affected.

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.

Reinfusion and serial measurements of carboplatin-mobilized peripheral-blood progenitor cells in patients receiving multiple cycles of high-dose chemotherapy.

PURPOSE: To examine the ability of carboplatin to mobilize peripheral-blood progenitor cells (PBPCs) and to examine the impact of infusing these cells on myelosuppression following multiple cycles of high-dose therapy. Fluctuations in circulating progenitor cell concentration following repeated cycles of this therapy were also measured. PATIENTS AND METHODS: Eight patients received a total of 20 cycles of carboplatin 1,200 mg/m2 per course, granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 micrograms/kg/d, and PBPC reinfusion every 28 days. PBPC were collected following 1 week of GM-CSF and following the first and second cycles of chemotherapy. Hematologic toxicity was correlated with the number of progenitor cells reinfused per cycle. The concentration of PBPC per milliliter of blood was measured at study entry, following GM-CSF priming, and after each cycle of chemotherapy. RESULTS: We observed a strong inverse correlation between the number of PBPCs (CD34 and colony-forming unit granulocyte-macrophage [CFU-GM]), but not mononuclear cells (MNCs) reinfused and the days with neutropenia less than 500/microL and platelets less than 20,000/microL. Compared with baseline levels, the circulating PBPC concentration increased up to 27-fold following the first course of chemotherapy, but decreased toward, and eventually below, baseline following the second and third cycles of carboplatin. CONCLUSION: PBPC reinfusion directly correlated with a reduction in myelosuppression following high-dose carboplatin chemotherapy. While high-dose carboplatin plus GM-CSF leads to a substantially greater mobilization of PBPC than GM-CSF alone, this effect is lost after multiple treatment cycles. These results emphasize the importance of early procurement and value of PBPC reinfusion in conjunction with multiple cycles of dose-intensive chemotherapy.

Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte-macrophage colony-stimulating factor and repeated infusions of autologous peripheral-blood progenitor cells: a novel and effective method for delivering multiple courses of dose-intensive therapy.

PURPOSE: The trial was undertaken to study the effect of administering granulocyte-macrophage colony-stimulating factor (GM-CSF) with and without peripheral-blood progenitor cells (PBPC) on the hematologic and nonhematologic toxicity observed with multiple cycles of high-dose carboplatin chemotherapy. PATIENTS AND METHODS: Eighteen patients with a variety of solid tumors received a total of 40 cycles of carboplatin, 1,200 mg/m2 per cycle, administered by continuous infusion over 96 hours. All 40 courses were administered with a daily 4-hour intravenous (IV) infusion of either 5 or 10 micrograms/kg/d of recombinant human Escherichia coli-derived GM-CSF. The first 20 courses were administered without PBPC support (treatment A). Because of severe neutropenia and thrombocytopenia, the next 20 courses of therapy were administered with GM-CSF, PBPC, and oral antibiotic prophylaxis (treatment B). RESULTS: The addition of PBPC support led to a significant reduction in the duration of neutropenia (10.5 v 7.5 days; P = .027) and thrombocytopenia (12.4 v 5.2 days; P = .001), number of RBC transfusions (six v three; P = .01) and platelet transfusions (10.3 v 3.7; P = .013), number of hospital days (12.6 v 2.9; P = .01), and days of IV antibiotics (11.8 v 2.4; P = .007) per cycle. Significant increases in the weekly dose intensity (206 v 285 mg/m2/wk; P = .014) and total dose (2,287 v 3,600 mg/m2; P = .018) of carboplatin delivered were also observed with treatment B. The overall response rate in this study was 70%, with 11 of 16 assessable patients achieving either a complete (three patients) or partial (eight patients) remission. CONCLUSION: This combination of GM-CSF and PBPC infusion represents an effective method for delivering multiple cycles of high-dose carboplatin chemotherapy and may serve as a model for the administration of high-dose chemotherapy in future trials.

Pluripotent and lineage-committed CD34+ subsets in leukapheresis products mobilized by G-CSF, GM-CSF vs. a combination of both.

To define an optimal regimen for mobilizing blood-derived progenitor cells from healthy donors for allogeneic transplantation, we have studied the early and lineage-committed CD34+ subsets in the leukapheresis products after mobilization with G-CSF (10 micrograms/kg/d), GM-CSF (10 micrograms/kg/d), and the combination of G-CSF and GM-CSF (G/GM, 5 micrograms/kg/d of each). We used three color and five dimensional flow cytometry with a panel of monoclonal antibodies against CD3, CD7, CD10, CD11b, CD15, CD33, CD34, CD38, CD45, CD61, and CD71. As reference, we also analyzed CD34+ subsets in samples from umbilical cord blood (UCB) and from adult bone marrow (BM). The level of total CD34+ cells was 0.04 +/- 0.03% (mean +/- SD) in peripheral blood at baseline, and reached a maximum on day 5 or day 6 of administration of growth factors. The percentages of CD34+ cells in the leukapheresis products were 1.06 +/- 0.37% (mean +/- SD) with G-CSF mobilization, 0.35 +/- 0.24% with GM-CSF, and 0.92 +/- 0.61% with the combination of both. Among the CD34+ subsets, the percentage of cells that were CD34+/CD38- was highest in UCB (7.18 +/- 5.58%) and lowest in G-CSF mobilized peripheral blood (0.80 +/- 0.22%), whereas GM-CSF or G/GM mobilized products gave rise to intermediate levels (4.43 +/- 3.40%, 3.61 +/- 2.42%, respectively). The differences between G/GM and G-CSF, between UCB and G-CSF, or between UCB and BM are significant. The absolute numbers of CD34+/CD38- and CD34+/CD38-/HLA-DR+ subsets are also significantly higher in the G/GM mobilized products than in G-CSF products. The cloning efficiency of G/GM mobilized CD34+ cells was 2 times higher than that of G-CSF mobilized CD34+ cells, albeit the difference was statistically marginal. The profile of CD34+ subsets mobilized by the combination of G/GM approaches that found in UCB. Our data illustrate that different growth factors and regimens can preferentially mobilize different CD34+ subsets from normal donors, and that the combination of G-CSF and GM-CSF might be an optimal regimen.

High-dose carboplatin chemotherapy with GM-CSF and peripheral blood progenitor cell support: a model for delivering repeated cycles of dose-intensive therapy.

High-dose chemotherapy regimens can cure a number of otherwise incurable diseases, such as Hodgkin's disease, non-Hodgkin's lymphoma, neuroblastoma, acute leukemia (in remission), and breast cancer. Trials of high-dose chemotherapy have generally used autologous bone marrow transplant or peripheral blood stem cell support to ensure hematologic recovery after intensive chemotherapy and/or radiation. This report describes an approach in which high-dose carboplatin chemotherapy was followed initially by granulocyte-macrophage colony-stimulating factor (GM-CSF; Escherichia coli. Sandoz-Schering, East Hanover and Kenilworth, NJ) and in subsequent patients, by both GM-CSF and repeated cycles of peripheral blood progenitor cell (PBPC) collection and administration. The addition of PBPC to this regimen led to significant reductions in the duration of neutropenia and thrombocytopenia, the requirement for erythrocyte and platelet transfusions, the length of hospital stay, and the use of intravenous antibiotics in this group relative to those patients who received GM-CSF alone. In addition, laboratory studies are presented that show a direct correlation between the number of progenitor cells reinfused and the duration of neutropenia and thrombocytopenia. The report also reviews data indicating that circulating progenitor cells are depleted by this approach. This suggests that the number of progenitor cells available for mobilization is finite. Finally, the magnitude of these effects, and their implications for future trials with repetitive cycles of dose-intensive therapy, are discussed.

The Pseudomonas putida ML2 plasmid-encoded genes for benzene dioxygenase are unusual in codon usage and low in G+C content.

Benzene dioxygenase, catalyzing the oxidation of benzene to cis-1,2-dihydroxy-cyclohexa-3,5-diene, comprises four polypeptides that are encoded by plasmid pHMT112 of Pseudomonas putida ML2. In this study, the nucleotide (nt) sequences of four genes encoding this enzyme (bedC1C2BA) were determined, and the amino acid (aa) sequences were deduced. The sequence showed significant homology with the chromosomally encoded benzene dioxygenase and toluene dioxygenase genes (73-77% for nt and 83-99% for aa), but not the plasmid-encoded naphthalene dioxygenase genes (20-26% for nt and 32-36% for aa). A conserved motif (Cys-Xaa-His-15-to-17 aa-Cys-Xaa2-His, where Xaa is any aa), proposed to bind the Rieske-type [2Fe-2S] cluster, was identified in the deduced aa sequence of the iron-sulfur proteins. Three regions were also identified in the flavoprotein which are likely to be involved in FAD and NAD+ binding. The gene order of bedC1C2BA is consistent with most ring-hydroxylating dioxygenases isolated from Pseudomonas. However, the G+C content of 47% is in contrast to the high G+C content of the Pseudomonas chromosome (63%) and other Pseudomonas plasmids (57%), and with its unique codon usage preference this suggests that bedC1C2BA originated from a host derived from a different genus.

A dose-escalation study of carboplatin/cyclophosphamide/etoposide along with autologous bone marrow or peripheral blood stem cell rescue.

Twenty patients have received 21 courses of high-dose cyclophosphamide (6 g/m2 over 4 days), etoposide (1,800 mg/m2 over 3 days), and carboplatin (800 to 1,600 mg/m2 by continuous infusion over 96 hours) and autologous bone marrow or peripheral blood stem cell rescue. The maximum tolerated dose of this regimen included these doses of cyclophosphamide and etoposide with a total of 1,600 mg/m2 carboplatin. Acute renal failure was the dose-limiting toxicity and, at the maximum tolerated dose, was observed in two patients of 14 evaluable courses. Nonhematologic toxicity was otherwise modest, and the overall response rate was 70% in patients with a wide variety of solid hematologic neoplasms.

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.

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.

Cloning and expression of the plasmid-encoded benzene dioxygenase genes from Pseudomonas putida ML2.

Hybridization using heterologous dioxygenase gene probes indicated the presence of the genes encoding the enzyme benzene dioxygenase on a 112 kb plasmid from Pseudomonas putida ML2. They were identified as benzene dioxygenase genes (bed ABC1C2) by cloning in Escherichia coli and analysis of expression by Western blotting using antibodies raised to the four polypeptides of purified benzene dioxygenase.

Glucose control of staphylococcal enterotoxin A synthesis and location is mediated by cyclic AMP.

The regulation of staphylococcal enterotoxin A (SEA) synthesis in a defined medium was studied using continuous culture techniques. SEA production was repressed by glucose and repression could be overcome by addition of exogenous cyclic AMP. As well as this classical catabolite repression control, addition of glucose to de-repressed steady-state cultures resulted in rapid disappearance of toxin from the medium (also mediated by loss of cyclic AMP). When the toxin dissappeared from the medium, it was taken up again by the bacteria without apparent modification.

Trigeminally mediated odor aversions in starlings.

Electrophysiological and psychophysical evidence has demonstrated that trigeminal receptors in the nasal cavity respond to odorants. Despite these demonstrations of trigeminal chemoreception, it is not clear whether naso-trigeminal stimulation can be used to mediate learned behaviors in contexts such as feeding. Here, we report that starlings will learn aversions to odorant volatiles in a feeding context and that these aversions can be mediated by trigeminal cues.

Nasal trigeminal chemoreception: responses to n-aliphatic alcohols.

Odorant molecules can stimulate nasal trigeminal receptors, but the properties of such molecules which make them effective stimuli are largely unknown. In the present study, we obtained integrated multiunit responses from the ethmoid branch of the rat trigeminal nerve to a homologous series of aliphatic alcohols. Our aim was to determine whether lipid solubility might correlate with stimulus efficacy. Response thresholds (ranging from 3000 ppm for methanol to 3 ppm for octanol) decreased with increasing carbon chain length, suggesting that lipid solubility is important for stimulus effectiveness. One plausible explanation for the importance of lipophilicity is that the more lipid soluble a substance, the more easily it can penetrate epithelial layers to reach chemoreceptive trigeminal nerve endings. Since all stimuli at vapor saturation elicited responses within 0.5 s, and because diffusion of stimulus molecules through epithelium is slow, we speculate that trigeminal nerve endings lie closer to the epithelial surface than previously thought.

Rat trigeminal, olfactory and taste responses after capsaicin desensitization.

Experiment 1 showed that capsaicin injections severely reduced or eliminated nasal trigeminal responses to 3 odorants. Experiments 2 and 3 investigated whether desensitized animals could behaviorally detect and discriminate odors. Capsaicin treated animals had no measurable deficits in locating buried food, in odor aversion learning, or in operant odor detection and discrimination. Experiment 4 examined whether behavioral responsiveness to salty, sour and bitter tastes was affected by desensitization. Capsaicin injections did not affect responsiveness to salty or sour, but may have raised rejection thresholds for bitter. Broadly, the present results suggest that substance P-containing fibers mediate trigeminal responsiveness to odorants and irritants but that the loss of this responsiveness does not appreciably affect smell or taste, per se.

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.

Maternal ingestion of ortho-aminoacetophenone during gestation affects intake by offspring.

Ingested flavor chemicals cross the placental barrier and occur in the fetal blood and amniotic fluid. This occurrence is detectable by the fetus, and can influence post parturition feeding. In the present experiment, pregnant mice were offered either 0.1% ortho-aminoacetophenone emulsions (OAP) or water throughout gestation. OAP is normally avoided by mice, apparently on the basis of chemosensory characteristics. Subsequently, offspring were offered 0.5%, 0.25%, or 0.1% OAP in one-bottle tests at 26 or 88 days of age. Offspring of mothers given OAP drank greater amounts of OAP than did offspring of mothers given water. Enhanced acceptance of OAP was not detected in mice exposed to 0.1% OAP as adults for a duration similar to that given during gestation. We conclude that fetal experiences with OAP lowered sensitivity and/or raised tolerance for the compound.