Examining the impact of a leisure time intervention on participation in organized out-of-school activities among adolescents: a quasi-experimental study in Franklin County, KY, USA.

Guided by the Icelandic Prevention Model, a community-led coalition in Franklin County, KY, aimed to subsidize costs for participation in supervised organized leisure time programs among its youth via adaptation of the Reykjavik City Leisure Card program, locally known as the 'YES Card' voucher program. This study examined whether the proportion of students participating in supervised out-of-school activities and sports was higher in the YES Card intervention group compared to a similar group of youth who did not receive the voucher across two time points. Two waves of survey data were collected in one intervention middle school and two geographically and demographically similar comparison schools in 2020 (n for intervention = 112, n for comparison = 723) and 2021 (n for intervention = 134, n for comparison = 873). The expected age of students ranged between 12 and 15 years. Analyses were conducted using logistic regression. The YES Card receivers were two-and-a-half times more likely to participate in nonsport organized recreational activities [odds ratio, OR, 2.43 (95% confidence interval, CI, 1.07-5.52)] and almost twice as likely to participate in sports [OR: 1.91 (95%CI: 1.08-3.38)] over the 1-year study period, compared to non-YES Card youth. We conclude that Franklin County in KY in the USA has successfully adapted the Reykjavik City Leisure time voucher program.

Tibetan sound meditation for cognitive dysfunction: results of a randomized controlled pilot trial.

OBJECTIVE: Although chemotherapy-induced cognitive impairment is common among breast cancer patients, evidence for effective interventions addressing cognitive deficits is limited. This randomized controlled trial examined the feasibility and preliminary efficacy of a Tibetan Sound Meditation (TSM) program to improve cognitive function and quality of life in breast cancer patients. METHODS: Forty-seven breast cancer patients (mean age 56.3 years), who were staged I-III at diagnosis, 6-60 months post-chemotherapy, and reported cognitive impairment at study entry were recruited. Participants were randomized to either two weekly TSM sessions for 6 weeks or a wait list control group. Neuropsychological assessments were completed at baseline and 1 month post-treatment. Self-report measures of cognitive function (Functional Assessment of Cancer Therapy (FACT)-Cog), quality of life (SF-36), depressive symptoms (Center for Epidemiologic Studies Depression Scale), sleep disturbance (Pittsburgh Sleep Quality Index), fatigue (Brief Fatigue Inventory), and spirituality (FACT-Sp) were completed at baseline, the end of treatment, and 1 month later. RESULTS: Relative to the control group, women in the TSM group performed better on the verbal memory test (Rey Auditory Verbal Learning Test trial 1) (p = 0.06) and the short-term memory and processing speed task (Digit Symbol) (p = 0.09) and reported improved cognitive function (p = 0.06), cognitive abilities (p = 0.08), mental health (p = 0.04), and spirituality (p = 0.05) at the end of treatment but not 1 month later. CONCLUSIONS: This randomized controlled trial revealed that TSM program appears to be a feasible and acceptable intervention and may be associated with short-term improvements in objective and subjective cognitive function as well as mental health and spirituality in breast cancer patients.

A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor.

Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients. An open-label, randomized, pilot trial examined both the general and differential efficacy of 4 weeks of methylphenidate (MPH) and modafinil (MOD) in 24 brain tumor patients. Participants completed cognitive tests and self-report measures of fatigue, sleep disturbance, mood and quality of life at baseline and after 4 weeks.Following stimulant treatment, there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention. Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy. Inconsistent, differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD. There was also evidence of a general beneficial effect on patient-reported measures of fatigue, mood, and quality of life, with no statistically significant differences between treatment arms in these measures over time. The results from this small pilot study should be interpreted with caution, but appear to warrant additional research, in larger study samples, targeting fatigue, processing speed and executive function, and exploring different doses of stimulants. Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment.

Synergistic interaction of two classes of transforming growth factors from murine sarcoma cells.

Transforming growth factors (TGFs) isolated from murine sarcoma virus-transformed 3T3 cells have been separated by high-pressure liquid chromatography into two subsets. One subset, called TGF alpha, competes with epidermal growth factor (EGF) for receptor sites, whereas the other, called TGF beta, does not. TGB beta, purified by high-pressure liquid chromatography, will not induce formation of large colonies of cells in soft agar in the absence of TGF alpha or EGF. However, the combined action of either TGF alpha or EGF (which by themselves are relatively ineffective in promoting growth of cells in soft agar) together with TGF beta results in a potent synergistic effect, with formation of large colonies. Chemically modified analogs of EGF also potentiate TGF beta activity to the extent that they bind to the EGF receptor. It is suggested that TGF beta may be an important mediator of the known effects of both TGF alpha and EGF on neoplastic transformation.

Vav cooperates with Ras to transform rodent fibroblasts but is not a Ras GDP/GTP exchange factor.

Vav is a proto-oncogene specifically expressed in cells of hematopoietic origin. Its gene product contains a series of structural motifs, including SH2 and SH3 domains, suggestive of a role in signal transduction. The Vav protein also possesses a Dbl-homology (DH) domain previously found in regulators of the Ras superfamily of small GTP-binding proteins. Recently, Vav has been reported to be the major Ras GDP/GTP exchange factor (GEF) in hematopoietic cells [Gulbins et al., Science 260, 822 (1993); J. Immunol. 152, 2123 (1994)]. The following observations are inconsistent with such a role: (i) Vav proteins do not exhibit Ras GEF activity in standard GDP/GTP exchange assays; (ii) Cells overexpressing Vav do not have increased levels of GTP-bound Ras proteins; (iii) Overexpression of Vav does not overcome the growth inhibitory activity of RasN17, a mutant that blocks Ras signaling by inhibiting Ras GEFs; (iv) Transformation of NIH3T3 cells by Vav oncoproteins is not inhibited by a farnesyl transferase inhibitor that completely blocks transformation by both Ras and its well characterized GEF, RasCDC25 and (v) The morphology of Vav-transformed NIH3T3 cells is dramatically different from that induced by Ras and RasCDC25. Whereas these observations make it unlikely that Vav functions either as a RasGEF or as an upstream regulatory element of Ras, we have observed that Vav can cooperate with normal Ras proteins to transform NIH3T3 cells. These results suggest that Vav and Ras may mediate signal transduction by distinct, but interactive mitogenic pathways.

Cognitive function as a predictor of survival in patients with recurrent malignant glioma.

PURPOSE: To determine the contribution of cognitive function in predicting the survival of patients with recurrent malignant brain tumors. PATIENTS AND METHODS: A total of 80 patients with recurrent glioblastoma multiforme or anaplastic astrocytoma were seen for baseline evaluations before beginning a phase I or phase II clinical trial. Each patient received a battery of nine brief tests measuring cognitive function, ability to perform activities of daily living (ADLs), and quality of life (QOL). Tests were given monthly after treatment was begun. RESULTS: Performance on a test of verbal memory was independently and strongly related to survival after accounting for age, Karnofsky performance status score, histology, and time since diagnosis. Models incorporating three of nine and all nine tests in the battery accounted for significantly more variance in survival than did the clinical variables alone. Measures of QOL and ADLs (bathing, feeding, and so on) were not independently related to survival, although they provide clinical information that is important for patient care. CONCLUSION: These results indicate that a multifaceted assessment of cognition, QOL, and patient function is practical for brain tumor patients in clinical trials and can provide information regarding the relative risks versus benefits of new treatment regimens that supplements the information from the usual clinical variables.

Methylphenidate therapy improves cognition, mood, and function of brain tumor patients.

PURPOSE: Patients with malignant glioma develop progressive neurobehavioral deficits over the course of their illness. These are caused both by the effects of the disease and the effects of radiation and chemotherapy. We sought to determine whether methylphenidate treatment would improve these patients' neurobehavioral functioning despite their expected neurologic deterioration. PATIENTS AND METHODS: Thirty patients with primary brain tumors underwent neuropsychologic assessment before and during treatment with methylphenidate. Ability to function in activities of daily living and magnetic resonance imaging (MRI) findings were also documented. Patients were assessed on 10, 20, and 30 mg of methylphenidate twice daily. RESULTS: Significant improvements in cognitive function were observed on the 10-mg twice-daily dose. Functional improvements included improved gait, increased stamina and motivation to perform activities, and in one case, increased bladder control. Adverse effects were minimal and immediately resolved when treatment was discontinued. There was no increase in seizure frequency and the majority of patients on glucocorticoid therapy were able to decrease their dose. Gains in cognitive function and ability to perform activities were observed in the setting of progressive neurologic injury documented by MRI in half of the subjects. CONCLUSION: This study demonstrated improved patient function in the setting of a progressive neurologic illness. Methylphenidate should be more widely considered as adjuvant brain tumor therapy.

Evaluation of the neurobehavioral functioning of patients before, during, and after bone marrow transplantation.

PURPOSE: To evaluate the cognitive and emotional functioning of patients undergoing bone marrow transplantation (BMT) in the protected environment (PE). PATIENTS AND METHODS: Patients were given tests of cognition and mood before their hospitalization in the PE, after 2 weeks, at discharge, and at 8 months post-BMT. Locus of control, degree of social support, previous biotherapy, and on-treatment psychiatric consultation were also analyzed. RESULTS: Before BMT, 20% of patients had mild cognitive dysfunction, and nearly 40% had significant anxiety. Although few patients developed problems with cognition or mood during the study, short-term memory deficits nearly doubled at follow-up compared with baseline. Anxiety decreased significantly during hospitalization and remained low at follow-up. In contrast, depression increased throughout hospitalization, but decreased at follow-up. Pre-BMT emotional status and cognitive functioning were highly related to long-term outcome. Type of BMT, locus of control, and degree of social support were related to psychologic distress and cognitive functioning, both during and after BMT. Patient age was not a predictor of neurobehavioral symptoms during or after BMT. CONCLUSION: Pretransplant emotional and cognitive functioning are important determinants of long-term outcome and quality of life (QOL) in BMT patients. In addition, a few patients undergoing BMT develop short-term memory difficulties and mood disturbance that may persist. Pretransplant identification of patients at risk for neurobehavioral difficulties may guide early interventions during hospitalization. Posttransplant assessment may then be used to develop rehabilitation programs and other interventions for individuals with persisting complaints.

Solution structure of the Grb2 N-terminal SH3 domain complexed with a ten-residue peptide derived from SOS: direct refinement against NOEs, J-couplings and 1H and 13C chemical shifts.

Refined ensembles of solution structures have been calculated for the N-terminal SH3 domain of Grb2 (N-SH3) complexed with the ac-VPPPVPPRRR-nh2 peptide derived from residues 1135 to 1144 of the mouse SOS-1 sequence. NMR spectra obtained from different combinations of both 13C-15N-labeled and unlabeled N-SH3 and SOS peptide fragment were used to obtain stereo-assignments for pro-chiral groups of the peptide, angle restraints via heteronuclear coupling constants, and complete 1H, 13C, and 15N resonance assignments for both molecules. One ensemble of structures was calculated using conventional methods while a second ensemble was generated by including additional direct refinements against both 1H and 13C(alpha)/13C(beta) chemical shifts. In both ensembles, the protein:peptide interface is highly resolved, reflecting the inclusion of 110 inter-molecular nuclear Overhauser enhancement (NOE) distance restraints. The first and second peptide-binding sub-sites of N-SH3 interact with structurally well-defined portions of the peptide. These interactions include hydrogen bonds and extensive hydrophobic contacts. In the third highly acidic sub-site, the conformation of the peptide Arg8 side-chain is partially ordered by a set of NOE restraints to the Trp36 ring protons. Overall, several lines of evidence point to dynamical averaging of peptide and N-SH3 side-chain conformations in the third subsite. These conformations are characterized by transient charge stabilized hydrogen bond interactions between the peptide arginine side-chain hydrogen bond donors and either single, or possibly multiple, acceptor(s) in the third peptide-binding sub-site.

Neurotoxicity of CI-980, a novel mitotic inhibitor.

CI-980 is a chemotherapeutic agent currently in Phase II trials that arrests cellular division by binding to tubulin. It is structurally and functionally similar to colchicine, a potent nonreversible neurotoxin, and is able to cross the blood-brain barrier. In Phase I studies, neurotoxicity was noted. The neurotoxicity of CI-980 was prospectively evaluated in two Phase II studies by neurological evaluation, quantitative sensory testing, and neuropsychological assessment of cognitive functioning. The results revealed a significant but reversible decline in recent memory functioning after each course of CI-980, with no effect on overall mental status or neurological function. Sixty-seven percent of patients performed in the impaired range on the memory test after their first infusion, whereas only one exhibited a decline on a brief cognitive screen. The results are consistent with the known effects of colchicine on the brain. Colchicine selectively blocks choline acetyltransferase in the hippocampus and basal forebrain, the area of the brain responsible for memory consolidation. Although the effect of CI-980 was reversible at the dose and schedule used, this study suggests that careful monitoring of cognitive function in patients receiving this agent should be performed if dose or schedule parameters are changed. In addition, this study demonstrates the feasibility of incorporating neuropsychological assessment in clinical trials of new anticancer agents having potential neurotoxic side effects.

A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix.

A Phase I study of the novel angiogenesis inhibitor TNP-470 was performed. Patients with inoperable recurring or metastatic squamous cell cancer of the cervix with evaluable disease, no coagulopathy, and adequate renal, hepatic, and hematological function were eligible. One course of treatment consisted of an i.v. infusion of TNP-470 over 60 min every other day for 28 days, followed by a 14-day rest period. The starting dose was 9.3 mg/m2. Eighteen evaluable patients were treated, with a median age of 48 years (range 27-55) and performance status Zubrod 1 (range 0-2). Grade 3 neurotoxicities consisting of weakness, nystagmus, diplopia, and ataxia were encountered in two patients receiving the 71.2 mg/m2 dose. An intermediate dose level of 60 mg/m2 was evaluated and found to be well tolerated by three patients. Only one patient experienced grade 3 nausea on the 60 mg/m2 dose level. No myelosuppression, retinal hemorrhage, weight loss, or significant alopecia were observed. One patient had a complete response, which continues for 26 months, and three patients with initially progressive disease stage had stable disease for 5, 7.7, and 19+ months. Other Phase I studies, including over 200 patients, were performed concurrently with this study. Based on this experience, the dose of TNP-470 recommended for further studies is 60 mg/m2 as a 60-min i.v. infusion every Monday, Wednesday, and Friday. Neurotoxicity was dose limiting, but appears to be reversible. Otherwise, the treatment was well tolerated. The drug may be active in squamous cell cancer of the cervix. Further studies of TNP-470 in squamous cell cancer of the cervix are warranted.

Potent, highly selective inhibition of growth hormone secretion by position 4 somatostatin analogs.

Aromatic position 4 somatostatin (SS) analogs were synthesized by solid phase methodology and assayed in vivo for their effects on pentobarbital-stimulated GH levels in fed rats and insulin and glucagon levels in fasted rats. [F5-Phe4]SS was approximately 3 times more active than somatostatin in inhibiting all three hormones. [Phe4,D-Trp8]SS inhibited GH about 4 times more effectively than somatostatin and was only twice as active as somatostatin in the pancreas. [rho-NH2-Phe4]SS exhibited strong selectivity toward inhibition of GH, being 4 times more potent than somatostatin in the pituitary while only about 40% as active in the pancreas. [rho-NH2-Phe4,D-Trp8]SS maintained this same degree of selectivity toward GH inhibition and exhibited a striking 15-fold increase in activity in the pituitary compared to somatostatin. All four analogs inhibited GH for a longer period of time than somatostatin when administered sc at a dose of 10 microgram/100 g BW. [rho-NH2-Phe4,D-Trp8]SS was the longest acting of these analogs, with approximately a 2-h duration of inhibition of GH. [Phe4]SS, administered iv at a dose of 50 microgram/100 g BW, also inhibited GH for approximately 2 h. These data further support the feasibility of developing long-acting somatostatin analogs with selectivity toward a given hormone.

Ventricular enlargement after closed head injury.

To study the relationship between enlargement of the cerebral ventricles and neuropsychological deficit after closed head injury (CHI), we measured the area of the lateral ventricles on computed tomographic scans obtained at least 30 days after severe CHI in 32 young adults and a control group of similar age. Enlargement of the lateral ventricles was demonstrated in 72% of the head-injured subjects, as defined by the ventricle-brain percent ratio (VBR). Ventricular dilation was related to the duration of coma after high-speed motor vehicle accidents and to intellectual and memory defects. The VBR may be a useful index of the severity of brain damage in certain categories of head-injured patients.

Mutism after closed head injury.

Prospective study of patients admitted to a hospital for closed head injury showed that nine patients (nearly 3%) became mute for varying periods despite recovery of consciousness and communication through a nonspeech channel. Computed tomography (CT) showed subcortical lesions situated primarily in the putamen and internal capsule of four patients, whereas four of the five patients without subcortical lesions had left-hemisphere cortical injury. The patients without subcortical injury visualized by CT exhibited a longer duration of impaired consciousness consistent with severe diffuse brain injury and they showed more long-term linguistic deficits. We related our findings to recent studies of atypical aphasia after occlusive vascular lesions of the basal ganglia.

Cognitive functioning in cancer patients: effect of previous treatment.

Neuropsychological analysis of 47 cancer patients with widely metastatic disease and significant previous treatment indicated that 34% had cognitive deficits. Previous treatment with biologic response modifiers was associated with a 53% frequency of cognitive abnormalities, whereas only 18% of patients who were never treated with biologics had such impairments. The possibility that neurobehavioral abnormalities will result from metastatic disease and treatment regimens is an important factor in determining the risks and benefits of therapy.

Persistent neurotoxicity of systemically administered interferon-alpha.

Fourteen cancer patients had evidence of persistent neurotoxicity of interferon-alpha therapy long after their treatment was discontinued. Although most of the cognitive symptoms were mild to moderate in severity, they were incapacitating to these individuals in their usual work. The neuropsychological test abnormalities were not attributable to subsequent therapy, disease status, or other medical problems. The pattern of deficits was consistent with frontal-subcortical dysfunction. Of the four patients who had follow-up assessment, two had improved and two had deteriorated. These findings suggest that in some cases interferon neurotoxicity is not reversible.

Pattern of neurobehavioral deficits associated with interferon alfa therapy for leukemia.

We evaluated the neuropsychological and personality profiles of 25 patients with chronic myelogenous leukemia treated with interferon alfa (IFN-alpha). This group of persons performed well below expectation on tests of cognitive speed, verbal memory, and executive functions. Personality changes included depression, increased somatic concern, and stress reactions. A control group of leukemia patients not treated with IFN-alpha had significantly better cognitive speed and mood. The pattern of cognitive and personality changes in patients receiving IFN-alpha is highly suggestive of frontal-subcortical brain dysfunction.

Mood and cognitive side effects of interferon-alpha therapy.

The central nervous system side effects associated with interferon-alpha (IFN-alpha) therapy, including depression and cognitive changes, can compromise otherwise effective immunotherapy. The term "depression" has multiple meanings ranging from a feeling of sadness to a neuropsychiatric disorder with defined diagnostic criteria. A syndrome of mood disturbance with memory impairment, cognitive slowing, and impaired executive function is common with IFN-alpha therapy and is consistent with mild subcortical dementia. Cognitive deficits and mood disorder may occur independently, and in some cases depression is a reactive phenomenon. Risk factors for development of IFN-alpha neurotoxicity include duration of treatment, high-dose therapy, and prior cranial irradiation or neurologic illness. Past or current psychiatric illness also may put the patient at risk. Subtypes of major depression are associated with neuroendocrine and neurochemical alterations that are consistent with the observed activities of IFN-alpha. This may provide insight into the etiology of IFN-alpha neurotoxicity, as well as possible interventions. Assessment of the neuropsychiatric status of patients treated with IFN-alpha should be a standard of care. Possible pharmacologic interventions to decrease the neurotoxicity associated with IFN-alpha therapy include antidepressants, psychostimulants, and opioid antagonists. Preliminary clinical and research experience suggests that it is possible to effectively palliate IFN-alpha toxicity.

Neurocognitive effects of therapeutic irradiation for base of skull tumors.

PURPOSE: To determine whether radiation therapy delivered to the paranasal sinuses causes any long-term impairment in neurocognitive function as a result of incidental brain irradiation. METHODS AND MATERIALS: Nineteen patients who received paranasal sinus irradiation at least 20 months and up to 20 years before assessment were given a battery of neuropsychologic tests of cognitive function. Radiation was delivered by a three-field (one anteroposterior and two lateral) technique. The median radiation dose was 60 Gy (range 50-68 Gy) in fractions of 1.8 to 2 Gy. The volume of irradiated brain was calculated from planning computed tomography slices or simulation films. The results of the neuropsychologic tests were compared to normative control values. RESULTS: Memory impairment was found in 80% of the patients, and one-third manifested difficulty with visual-motor speed, frontal lobe executive functions, and fine motor coordination. Two of the patients had frank brain necrosis with resultant dementia and blindness, and three had evidence of brain atrophy. Three of the fourteen patients without documented cerebral atrophy or necrosis were disabled from their normal activities. Three patients also developed pituitary dysfunction. Neurocognitive symptoms were related to the total dose of radiation delivered but not to the volume of brain irradiated, side of radiation boost, or chemotherapy treatment. The pattern of test findings was consistent with radiation injury to subcortical white matter. CONCLUSIONS: Radiation therapy for paranasal sinus cancer may cause delayed neurocognitive side effects. Currently, however, the development of severe adverse effects appears to be decreasing because of improvements in the techniques used to deliver radiation. Lowering the total dose and improving dose distributions should further decrease the incidence of delayed brain injury due to radiation.

Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation.

PURPOSE: Cognitive deficits after treatment for small cell lung cancer (SCLC) have been attributed to prophylactic cranial irradiation (PCI). A prospective study of neuropsychological function was undertaken to document the evolution and magnitude of neuropsychologic deficits. METHODS AND MATERIALS: Thirty patients with limited stage SCLC who responded well (29 complete response (CR), 1 partial response (PR)) to combination chemotherapy plus thoracic irradiation or resection were studied with neuropsychological tests in the cognitive domains of intelligence, frontal lobe function, language, memory, visual-perception, and motor dexterity prior to a planned course of PCI. Nine patients had a neurologic history that could influence testing. RESULTS: An unexpected 97% (29 out 30) of patients had evidence of cognitive dysfunction prior to PCI. The most frequent impairment was verbal memory, followed by frontal lobe dysfunction, and fine motor incoordination. Of the patients with no prior neurologic or substance abuse history, 20 out of 21 (95%) had impairments on neuropsychological assessment. This neurologically normal group was just as impaired as the group with such a history with respect to delayed verbal memory and frontal lobe executive function. Eleven patients had neuropsychological testing 6 to 20 months after PCI; no significant differences were found from their pretreatment tests. CONCLUSIONS: A high proportion of neurologically normal patients was limited SCLC and favorable responses to combination chemotherapy have specific cognitive deficits before receiving PCI. Short-term (6 to 20 months) observations after PCI have shown no significant deterioration.