Enhancing human aspects of care with young people with muscular dystrophy: Results from a participatory qualitative study with clinicians.

BACKGROUND: Most research into clinical care of Duchenne or Becker dystrophinopathies (MD) has focused on slowing progressive muscular weakness and extending lifespan. Scarce attention has been paid to the "human" aspects of care such as psychosocial health, living a fulfilling life, or dealing with disability stigma. This study partnered with clinicians to identify and address local and systemic barriers to these human aspects of care. METHODS: We employed a participatory qualitative design at a multidisciplinary MD clinic using 2 methods: (a) ethnographic observations over a 6-month period of clinic visits of children with MD and families, involving 12 clinicians, and (b) 3 "dialogues" (2-way discussions) with these clinicians to collaboratively analyze practices and co-produce recommendations for change. RESULTS: Our methods produced rich data that, when coanalyzed with clinicians and in consultation with a family advisor, provided deep insights into the practices and underlying assumptions of a neuromuscular clinic. Staff recognized the importance of the human aspects of care but, in reviewing the observational data, identified that it was given insufficient attention in (a) routine clinical processes, (b) clinician-family patterns of interaction, and (c) staffing allocations. CONCLUSION: Although the human aspects of care were important to clinicians in the MD clinic, the routines and nature of the clinic meant these were frequently sidelined for biomedical objectives. We present collaboratively produced practical recommendations toward addressing this disjunction between ideals and practice including developing flexibility to tailor appointment frequency, composition, and length; providing time and physical space for psychosocial aspects of care; and clinician skill building to support child/family expression of "negative" emotions; and discussion of sociopolitical aspects of MD such as living with disability stigma. The study offers a set of considerations that, taking into account individual differences, offer insights for similar clinics elsewhere.

Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer.

BACKGROUND: Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer. METHODS: Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0-2 were treated with panitumumab 6 mg kg(-1), GEM 1000 mg m(-2) (10 mg m(-2) min(-1)) and OX 85 mg m(-2) on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival. RESULTS: Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5-24 months) and median overall survival 20.3 months (95% CI 9-25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%. CONCLUSIONS: The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.

The Functional Movement Screen and Self-reported Injury in Senior Military College Cadets.

INTRODUCTION: Secular trend of increasing musculoskeletal injuries (MSKIs) across all branches of the U.S. Military is a critical limiting factor in the effective and efficient process of preparing military personnel for combat. The need to evaluate functional capacity beyond current physical fitness test (PFT) standards is the key in understanding an individual's risk of noncombat-related injury. The purpose of this study is to evaluate the relationship between Functional Movement ScreenTM (FMS) scores, incidence of musculoskeletal injuries, and standardized PFT scores among freshman Cadets during their first 10 weeks of enrollment at a senior military college. MATERIALS AND METHODS: Eighty-two participants (72 male and 10 female participants; mage: 18.2 years) completed the FMS, an institution-specific PFT (2-min maximum pushups, 2-min maximum abdominal crunches, and 1.5 mile timed run), and an Incidence of Injury and Incidence of Pain Questionnaire. Independent t-tests, Spearman's rank correlation coefficients logistic regression analysis, and Receiver Operator Curves were performed to evaluate relationships between the study variables. RESULTS: FMS composite and PFT sex-normed total scores were higher in females (16.4, 236.1) than in males (15.0, 204.9). Ninety percent of all females reported injury or pain during the 10-week survey period compared to 48% of males. CONCLUSIONS: No significant difference between FMS scores and injury and pain was found within both sex groups. Therefore, use of the composite FMS score as an indicator for risk of injury or to predetermine PFT performance is not recommended for this study's population. The rate of incidence of injury or pain in Cadets during a 10-week enrolment period is high. Females outperformed males in the FMS and PFT and reported higher rates of injury and pain. The utility of the FMS may be limited when substantially scaled for implementation across entire military populations. Future research should evaluate performance associations of the FMS with Army Combat Fitness Test components in a population of equally distributed sex and race.

Holistic Functioning from a Developmental Perspective: A New Synthesis with a Focus on a Multi-tiered System Support Structure.

While research in specific academic disciplines has individually advanced knowledge and practice for promoting multiple aspects of health and well-being in children and adolescents, still missing is an understanding of the interconnectedness of many critical aspects of development and how to intentionally weave these factors to advance a more holistic approach. The need for a more holistic and inclusive approach to child and adolescent development is increasingly evident to promote long-term health and well-being as the overall percentage of children, adolescents, and adults who suffer from mental health disorders is increasing. To address this issue, our authorship team consists of researchers in the areas of developmental psychology, neuroscience, motor development, exercise science, and mental health. The collective ideas outlined in this paper are aligned to address the need to remove disciplinary-specific boundaries and elucidate synergistic linkages across multiple research domains that support holistic development and lifespan health and wellness. We propose a conceptual framework that comprehensively addresses the integration of physical, cognitive, psychological, social, and emotional domains of child and adolescent development. In addition, we also provide a holistic preventative approach that is aligned with a contemporary intervention structure (i.e., Multi-tiered Systems of Support) to promote, from a developmental perspective, positive trajectories of health and well-being across childhood and adolescence.

Reinvest to Assess: Advancing Approaches to Motor Competence Measurement Across the Lifespan.

Measurement of motor competence is a vital process to advancing knowledge in the field of motor development. As motor competence is being more widely linked to research in other academic domains (e.g., public health, neuroscience, behavioral health), it is imperative that measurement methodology and protocols are reproducible with high degrees of validity and reliability. When addressing the plethora of available assessments, mostly developed for youth populations, there are potential questions and concerns that need to be addressed and/or clarified. One of the most prominent issues is the lack of a lifespan measure of motor competence, which is at odds with the premise of the field of motor development-studying changes in motor behavior across the lifespan. We address six areas of concern in lifespan assessment which include: (1) lack of assessment feasibility for conducting research with large samples, (2) lack of accountability for cultural significance of skills assessed, (3) limited sensitivity and discriminatory capabilities of assessments, (4) developmental and ecological validity limitations, (5) a problematic definition of 'success' in skill performance, and (6) task complexity and adaptability limitations. It is important to critically analyze current assessment methodologies as it will help us to envision the development and application of potential new assessments through a more comprehensive lens. Ultimately, we propose that reinvesting in how we think about assessment will be highly beneficial for integrating motor development from a holistic perspective, impact scientific advancements in other developmental domains, and increase global and lifespan surveillance of motor competence.

Potential relevance of a motor skill "proficiency barrier" on health-related fitness in youth.

This study investigated the potential impact of a motor skill proficiency barrier on measures of cardiorespiratory (CRF) and musculoskeletal (MSF) fitness in youth. A sample of 241 youth (114 girls) aged 10 - 18 years, completed the Motor Competence Assessment battery with composite scores indexed according to age- and gender-adjusted percentile scores. Motor competence (MC) levels were categorized as low (≤ 25%tile - proficiency barrier), moderate (≥ 26%tile to < 75%tile), and high (≥ 75%tile). CRF levels (Health Risk, Needs Improvement, and Healthy) were assessed using the Fitnessgram® 20 m PACER test. Low (≤ 20%tile), moderate (≥ 21%tile to ≤ 80%tile), and high (≥ 80%tile) MSF levels were assessed using grip strength normative data. Two 3 × 3 chi-square tests were conducted to determine the probability of MC level predicting CRF and MSF levels. Results demonstrated statistically significant models for performance on both the PACER (χ2[4, N = 241] = 22.65, p < .001) and grip strength (χ2[4, N = 241] = 23.95, p < .001). Strong evidence of a proficiency barrier impacting CRF was noted, as no low skilled youth met the "Healthy" fitness zone standards for PACER performance. Evidence supporting a barrier with grip strength was not as strong, as 20.8% of youth exhibiting low MC displayed high grip strength. However, all individuals with high levels of MC demonstrated at least moderate grip strength. Results emphasize the importance of developing MC during childhood as it may provide a protective effect against unhealthy CRF and MSF across youth.HighlightsThese data support the notion of Seefeldt's (1980) proficiency barrier as it relates to CRF, as no youth demonstrating low MC met the healthy fitness zone criteria for PACER performance. The development of MC may both directly and indirectly provide a protective effect against unhealthy CRF levels across childhood and adolescence.Evidence supporting a proficiency barrier with MSF as measured by grip strength was not as strong; however, all individuals with high levels of MC demonstrated at least moderate grip strength. Thus, the development of MC may be a protective factor to mitigate low levels of MSF via enhanced neuromuscular function.Promoting the development of MC in a variety of developmentally appropriate activities and settings (e.g. MC skills practice, structured and unstructured play, and performance contexts) is important to promote positive trajectories of CRF and MSF across childhood and adolescence.

The Relationship Between Functional Motor Competence and Performance on the Army Combat Fitness Test in Army Reserve Officer Training Corps Cadets.

INTRODUCTION: The development of functional motor competence (FMC; i.e., neuromuscular coordination and control required to meet a wide range of movement goals) is critical to long-term development of health- and performance-related physical capacities (e.g., muscular strength and power, muscular endurance, and aerobic endurance). Secular decline in FMC among U.S. children and adolescents presents current and future challenges for recruiting prospective military personnel to successfully perform the physical demands of military duty. The purpose of the current study was to examine the relationship between FMC and physical military readiness (PMR) in a group of Cadets enrolled in an Army Reserve Officer Training Corps program. MATERIALS AND METHODS: Ninety Army Reserve Officer Training Corps Cadets from a southeastern university and a military college in the southeast (females = 22; Mage = 19.5 ± 2.5) volunteered for participation in the study. Cadets performed a battery of eight FMC assessments consisting of locomotor, object projection, and functional coordination tasks. To assess PMR, Cadets performed the Army Combat Fitness Test (ACFT).Values from all FMC assessments were standardized based on the sample and summed to create a composite FMC score. ACFT scores were assigned to Cadets based upon ACFT scoring standards. We used Pearson correlations to assess the relationships between individual FMC assessment raw scores, FMC composite scores, and total ACFT points. We also evaluated the potential impact of FMC on ACFT in the entire sample and within each gender subgroup using hierarchical linear regression. Finally, we implemented a 3 × 2 chi-squared analysis to evaluate the predictive utility of FMC level on pass/fail results on the ACFT by categorizing Cadets' composite FMC score into high (≥75th percentile) moderate (≥25th percentile and <75th percentile), and low (<25th percentile) based on the percentile ranks within the sample. ACFT pass/fail results were determined using ACFT standards, requiring a minimum of 60 points on each the ACFT subtests. RESULTS: FMC composite scores correlated strongly with total ACFT performance (r = 0.762) with individual FMC tests demonstrating weak-to-strong relationships ACFT performance (r = 0.200-0.769). FMC uniquely accounted for 15% (95% CI: -0.07 to 0.36) of the variance in ACFT scores in females (R2 = 0.516, F2,19 = 10.11, P < 0.001) and 26% (95% CI: 0.09-0.43) in males (R2 = 0.385, F2,65 = 20.37, P < 0.001), respectively, above and beyond the impact of age. The 3 × 2 chi-squared analysis demonstrated 74% of those with low, 28% with moderate, and 17% with high FMC failed the ACFT (χ2 [1, N = 90] = 27.717, V = 0.555, P < 0.001). CONCLUSION: FMC composite scores are strongly correlated with ACFT scores, and low levels of FMC were a strong predictor of ACFT failure. These data support the hypothesis that the development of sufficient FMC in childhood and adolescence may be a critical antecedent for PMR. Efforts to improve FMC in children and adolescents may increase PMR of future military recruits.

A multicenter phase II trial of single-agent cetuximab in advanced esophageal and gastric adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in a significant proportion of esophageal and gastric carcinomas. Although previous studies have examined tyrosine kinase inhibitors of EGFR, there remains limited data regarding the role of EGFR-directed monoclonal antibody therapy in these malignancies. We carried out a multi-institutional phase II study of cetuximab, a monoclonal antibody against EGFR, in patients with unresectable or metastatic esophageal or gastric adenocarcinoma. PATIENTS AND METHODS: Thirty-five patients with previously treated metastatic esophageal or gastric adenocarcinoma were treated with weekly cetuximab, at an initial dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Patients were followed for toxicity, treatment response, and survival. RESULTS: Treatment with cetuximab was well tolerated; no patients were taken off study due to drug-related adverse events. One (3%) partial treatment response was noted. Two (6%) patients had stable disease after 2 months of treatment. Median progression-free survival and overall survival were 1.6 and 3.1 months, respectively. CONCLUSION: Although well tolerated, cetuximab administered as a single agent had minimal clinical activity in patients with metastatic esophageal and gastric adenocarcinoma. Ongoing studies of EGFR inhibitors in combination with other agents may define a role for these agents in the treatment of esophageal and gastric cancer.

A cellular mechanism of classical conditioning in Aplysia: activity-dependent amplification of presynaptic facilitation.

A training procedure analogous to differential classical conditioning produces differential facilitation of excitatory postsynaptic potentials (EPSP's) in the neuronal circuit for the siphon withdrawal reflex in Aplysia. Thus, tail shock (the unconditioned stimulus) produces greater facilitation of the monosynaptic EPSP from a siphon sensory neuron to a siphon motor neuron if the shock is preceded by spike activity in the sensory neuron than if the shock and spike activity occur in a specifically unpaired pattern or if the shock occurs alone. Further experiments indicate that this activity-dependent amplification of facilitation is presynaptic in origin and involves a differential increase in spike duration and thus in Ca2+ influx in paired versus unpaired sensory neurons. The results of these cellular experiments are quantitatively similar to the results of behavioral experiments with the same protocol and parameters, suggesting that activity-dependent amplification of presynaptic facilitation may make a significant contribution to classical conditioning of the withdrawal reflex.

Utilization of outer-midplane collector probes with isotopically enriched tungsten tracer particles for impurity transport studies in the scrape-off layer of DIII-D (invited).

Triplet sets of replaceable graphite rod collector probes (CPs), each with collection surfaces on opposing faces and oriented normal to the magnetic field, were inserted at the outboard mid-plane of DIII-D to study divertor tungsten (W) transport in the Scrape-Off Layer (SOL). Each CP collects particles along field lines with different parallel sampling lengths (determined by the rod diameters and SOL transport) giving radial profiles from the main wall inward to R-R sep ∼ 6 cm. The CPs were deployed in a first-of-a-kind experiment using two toroidal rings of distinguishable isotopically enriched, W-coated divertor tiles installed at 2 poloidal locations in the divertor. Post-mortem Rutherford backscatter spectrometry of the surface of the CPs provided areal density profiles of elemental W coverage. Higher W content was measured on the probe side facing along the field lines toward the inner target indicating higher concentration of W in the plasma upstream of the CP, even though the W-coated rings were in the outer target region of the divertor. Inductively coupled plasma mass spectroscopy validates the isotopic tracer technique through analysis of CPs exposed during L-mode discharges with the outer strike point on the isotopically enriched W coated-tile ring. The contribution from each divertor ring of W to the deposition profiles found on the mid-plane collector probes was able to be de-convoluted using a stable isotope mixing model. The results provided quantitative information on the W source and transport from specific poloidal locations within the lower divertor region.

Isoproterenol inhibits rod outer segment phagocytosis by both cAMP-dependent and independent pathways.

PURPOSE: The authors studied the involvement of cAMP-dependent second messenger systems in the inhibition of rod outer segment (ROS) phagocytosis by isoproterenol (ISO) and forskolin (FSK) using two membrane-permeant analogs of cyclic adenosine monophosphate (cAMP), the Rp and Sp diastereoisomers of cyclic adenosine 3',5' monophosphothioate (cAMPS). Rp-cAMPS is a potent competitive inhibitor of cAMP-dependent protein kinase I and II (PKA I and II), whereas Sp-cAMPS is a potent activator of these enzymes. METHODS: ROS phagocytosis was quantitated in cultured rat RPE cells using a previously described double immunofluorescence assay. RESULTS: Sp-cAMPS showed a dose-dependent inhibition of ROS phagocytosis, whereas 100 microM Rp-cAMPS had no effect on this process. Rp-cAMPS fully prevented the inhibitory effect of Sp-cAMPS and FSK but was able to prevent only partially the inhibition of ROS phagocytosis induced by ISO. Isoproterenol plus FSK showed an additive effect on the inhibition of phagocytosis, suggesting that they act at two independent sites. However, ISO plus Sp-cAMPS or FSK plus Sp-cAMPS showed no additivity. CONCLUSIONS: Results suggest that FSK inhibits ROS phagocytosis by RPE cells through a cAMP-dependent pathway, whereas ISO inhibits ROS phagocytosis by RPE cells through cAMP-dependent and cAMP-independent pathways.

The phagocytosis of rod outer segments is inhibited by drugs linked to cyclic adenosine monophosphate production.

PURPOSE: To study the effect of drugs that increase intracellular cyclic adenosine monophosphate on the ability of rat retinal pigment epithelial cells to phagocytize rod outer segments (ROS). METHODS: Cultured rat retinal pigment epithelial cells were treated with cholera toxin, forskolin, isoproterenol, or isobutylmethylxanthine and the phagocytosis of ROS by such treated cells was compared to that of control specimens. RESULTS: All of the drugs examined inhibited the ingestion, but not the binding of ROS by cultured retinal pigment epithelial cells. Cell viability was not compromised by the drug treatment because they rapidly recovered their ability to ingest ROS when the drug was removed. Dose-response curves for the inhibition of ROS phagocytosis by forskolin and isoproterenol demonstrated that this process is exquisitely sensitive to these agonists, with an IC50 for these drugs of 33 nmol/l. The results showed no measurable quantitative correlation between cyclic adenosine monophosphate levels and the inhibition of ROS phagocytosis. CONCLUSIONS: Results showed that the ingestion of ROS by retinal pigment epithelial cells was inhibited by agents that increase intracellular cyclic adenosine monophosphate, but seems to be independent of the level of this second messenger. Alternatively, ROS phagocytosis may be exquisitely sensitive to changes in the intracellular concentration of cyclic adenosine monophosphate, which are too small to measure by available methods.

Stimulation of A2 adenosine receptors inhibits the ingestion of photoreceptor outer segments by retinal pigment epithelium.

PURPOSE: Recent studies have shown that A2 adenosine receptors are present in retinal pigment epithelium (RPE). In this study, the effect of adenosine and adenosine analogues on photoreceptor outer segment (ROS) phagocytosis by RPE was investigated. METHODS: Primary cultures of RPE cells were incubated with isolated outer segments in the presence of various adenosine derivatives. Changes in adenylyl cyclase activity was measured by cyclic adenosine monophosphate (cAMP) production using a radioimmunoassay detection system. RESULTS: Adenosine inhibited the ingestion phase of phagocytosis (IC50 = 50 microM), and this effect was potentiated 80-fold in the presence of dipyridamole (IC50 = 0.6 microM). In the presence of 10 microM 8-phenyltheophylline, the inhibitory effect of 100 microM adenosine was reduced from 80% inhibition of ROS ingestion to 33% inhibition. The rank order of potency of adenosine analogues to inhibit ROS ingestion by RPE was N6-cyclohexyladenosine/5'-[N-ethylcarboxamido]-adenosine (NECA) = NECA > adenosine >> [R]-N6-[2-phenylisopropyl]-adenosine. The greatest stimulation of cAMP production was observed with 33.3 microM NECA: The production of cAMP reached its maximum level after 2 minutes of incubation, and after 10 minutes the levels of cAMP were back to basal. CONCLUSIONS: These results suggest that adenosine and adenosine analogues modulate ROS ingestion by RPE via activation of adenosine A2b receptors, possibly through the cAMP intracellular signaling pathway.

cAMP production via the adenylyl cyclase pathway is reduced in RCS rat RPE.

cAMP production was investigated in retinal pigment epithelium (RPE) cells isolated from normal rats and from rats with an inherited retinal dystrophy (Rdy/p+). In normal RPE cells, 5'-[N-Ethylcarboxamido]-adenosine (A2 receptors) produced a fivefold increase in the level of cyclic adenosine monophosphate (cAMP) over basal levels. However, only a onefold increase in cAMP was observed in dystrophic cells. cAMP production by prostaglandins E1 and E2 (prostaglandin receptors) in dystrophic RPE cells was only 29-38% of the level observed in normal cells. Direct stimulation of adenylyl cyclase by 10 mumol/l forskolin increased cAMP levels in normal RPE cells by 90 fold over basal, but only by sixfold in the dystrophic cells. These data suggest there may be a defect in the adenylyl cyclase signaling pathway in dystrophic RPE cells.

An improved method for isolation and culture of rat retinal pigment epithelial cells.

Retinal pigment epithelial cells from normal, Long Evans (LE) and retinal dystrophic (RCS) rats can be grown in vitro (Edwards, 1977). An improved technique is described which permits a more rapid isolation of RPE cells, and routinely gives high cell yields (30,000-40,000/eye), excellent cell viability (95%), and high plating efficiencies (95-100%). Whole eyes are treated with hyaluronidase and collagenase followed by trypsin. These enzymes degrade components of the extracellular matrix, releasing sheets of RPE from adherent attachments to the retina and choroid. Trypsin was then used to dissociate the sheets into single cells. RPE cells are grown to confluence in primary culture. This technique permits RPE cell isolation from both normal and retinal dystrophic (RCS) rats, 8-15 days of age. Normal cells isolated by this technique consistently show excellent phagocytosis in vitro.

Carbachol does not correct the defect in the phagocytosis of outer segments by Royal College of Surgeons rat retinal pigment epithelial cells.

PURPOSE: To investigate the effect of carbachol on the phagocytosis of photoreceptor outer segments (OS) in cultures of normal Long-Evans and dystrophic Royal College of Surgeons (RCS) rat retinal pigment epithelial (RPE) cells. METHODS: Retinal pigment epithelial cells from normal and RCS rats were grown in tissue culture. On reaching confluence, they were presented with OS suspended in Krebs-Henseleit buffer in the presence or absence of carbachol and LiCl. The number of bound and ingested OS was quantitated using double immunofluorescence staining. RESULTS: LiCl inhibited the ingestion of OS by more than 90% but had no effect on the binding of OS by Long-Evans RPE cells. The addition of carbachol further reduced OS ingestion. Carbachol alone decreased OS ingestion by normal RPE cells by 30% but had no effect on OS binding. The effect of LiCl and carbachol on RCS RPE cells was similar to their effect on normal RPE cells. CONCLUSIONS: Carbachol does not increase OS phagocytosis in normal or RCS rat RPE cells. The phagocytic defect in RCS rat RPE cannot be reversed or overcome by stimulation of the IP3 pathway by carbachol. LiCl strongly inhibits the ingestion of OS by normal and by RCS RPE cells, and this effect is enhanced by carbachol.

In Aplysia sensory neurons, the neuropeptide SCPB and serotonin differ in efficacy both in modulating cellular properties and in activating adenylyl cyclase: implications for mechanisms underlying presynaptic facilitation.

The facilitatory transmitters serotonin (5-HT) and the molluscan neuropeptides SCPA and SCPB both activate adenylyl cyclase in Aplysia mechanosensory neurons and produce multiple modulatory effects that contribute to increasing transmitter release from these cells. This enhancement of transmitter release from sensory neurons contributes to increased behavioral response during sensitization and classical conditioning in Aplysia. Recently, specific examples of modulation in these sensory neurons have been described that are more effectively initiated by 5-HT than by the SCPs. For example, in the present study, 5-HT produces 55% greater broadening of the normal sensory neuron action potential than did SCPB. These differences in the modulatory actions of the facilitatory transmitters have been interpreted as suggesting that 5-HT produces its modulatory effects at least partly via a cAMP-independent mechanism. However, we have found that the two types of facilitatory transmitters are not equally effective in activating adenylyl cyclase. In both whole CNS membranes and sensory neuron membranes, SCPB was less effective than 5-HT in stimulating adenylyl cyclase activity measured in steady state assays. Because electrophysiological experiments suggested that the response to the SCPs desensitizes rapidly, we further compared cyclase stimulation in perfused membrane assays that enable continuous monitoring of cyclase activity; however we observed that 5-HT was also more effective than SCPB in stimulating cyclase at the onset of transmitter exposure. We discuss the possibility that lower peak stimulation of cyclase by SCPB and a faster rate of desensitization could account for some of the differences between the SCPs and 5-HT in modulating sensory neurons.

Sequence-dependent interactions between transient calcium and transmitter stimuli in activation of mammalian brain adenylyl cyclase.

Recent evidence implicates Ca2+/CaM-sensitive adenylyl cyclase (AC) as a molecular coincidence detector for temporally paired stimuli during associative learning. During conditioning in Aplysia, AC is optimally activated when Ca2+ influx, the cellular signal for the conditioned stimulus (CS), precedes binding of modulatory transmitter, the cellular signal for the unconditioned stimulus (US). This sequence preference of the AC for Ca2+-before-transmitter, parallels the CS-preceding-US pairing requirement of classical conditioning. In this study, we have examined the response of AC from rat cerebellum to brief exposures to Ca2+ and to transmitter in a perfused membrane assay. We observed modest synergism between Ca2+ and transmitter in activating AC. Activation was more effective when a Ca2+ stimulus immediately preceded a transmitter stimulus than when the two stimuli were delivered in the reverse order. Thus, rat cerebellar AC displayed a sequence preference for optimal activation by paired stimuli similar to that observed in Aplysia; this sequence dependence could contribute to the CS-US sequence requirement observed in most mammalian classical conditioning paradigms.

Changes in the parous rat mammary gland environment are involved in parity-associated protection against mammary carcinogenesis.

Parity in rats results in protection from methylnitrosourea (MNU)-induced mammary cancer. Our goal was to determine if systemic alterations in the mammary gland environment after a full-term pregnancy rendered the parous rat an inadequate host for promotion of initiated mammary epithelial cells to become cancerous. Lewis rat MNU-treated mammary epithelial cells were transplanted into uniparous (UP), age-matched virgin (AMV) (both 130-150 d), or young virgin (YV) (50-60 d) syngeneic hosts to examine if differences in the systemic environments of the three hosts had an effect on hyperplasia and cancer formation. More transplants in YV and AMV hosts contained hyperplasias and adenocarcinomas as compared to transplants in UP hosts. In addition, UP host transplants had significantly fewer numbers of hyperplastic lesions than transplants from the virgin hosts. The evidence presented here shows that the uniparous host environment is less supportive than that of the virgin host for hyperplasia and cancer development.

Burn survivors and the Americans with Disabilities Act.

In this article the major provisions of the recently revised Americans with Disabilities Act (ADA) and its application to burn survivors are explained. For professionals working with this population, the ADA is a model for dealing with issues of follow-up and long-term patient adjustment. An overview of previous laws applying to the rights of the disabled in the USA is followed by a brief history of the ADA's development. Each of the five major provisions of the act is discussed in detail. Case studies of burn survivors are used to demonstrate the way in which knowledge of the ADA can be used to anticipate and deal with potential complications of re-entry after hospitalization.