Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo

The novel alkylating dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) was evaluated for acute toxicity and antitumor activity in mice, with melphalan as a reference. To determine a safe and tolerable dose for efficacy studies the acute toxicity following intravenous injection in the tail vein was monitored using a 14-day schedule with up to four doses. The highest tested dose, 25 micromoles/kg, was considered close to this level, with minor effects on body weight gain but significant effects on hematological parameters. Melphalan and J1 appeared equitoxic with no statistically significant differences. Subsequently a mouse hollow fiber model was employed with subcutaneous implantation of fibers containing human tumor cells. Three different human tumor cell lines as well as two samples of primary human tumor cells (ovarian carcinoma and chronic lymphatic leukemia) were used as tumor models. At the dose level tested there was a marked and statistically significant decrease in both T-cell leukemia CCRF-CEM and small cell lung cancer NCI-H69 tumor cell growth and viability in response to J1 as compared with both placebo and melphalan treated groups. In primary ovarian carcinoma cells only J1 treatment resulted in significant tumor regression (net cell kill). In summary the results indicate that, despite an expected short half time in the blood circulation, the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation. At equal doses of alkylating units J1, compared to melphalan, was more active in the mouse hollow-fiber model, but showed similar general toxicity.     

Effects of Crotalus durissus collilineatus venom in the isolated rat kidney.

Ophidian accidents caused by the subspecies Crotalus durissus are responsible for high morbity and mortality rates. Acute renal failure is a common complication observed in these accidents. The aim of the present study was to investigate the renal effects promoted by the venom of C. d. collilineatus and its fractions, crotoxin and phospholipase A2. C. d. collilineatus (Cdc; 30 microg mL(-1)), crotoxin (CTX; 10 microg mL(-1)) and phospholipase A2 (PLA2; 10 microg mL(-1)) were tested in isolated rat kidney. The first 30 min of each experiment were used as an internal control and Cdc or its fractions, CTX and PLA2 were added to the system after this period. All experiments lasted 120 min. The venom of Cdc decreased perfusion pressure (PP; control120 = 110.3 +/- 3.69 mmHg; Cdc120 = 96.7+/-8.1 mmHg), renal vascular resistance (RVR; control120 = 6.42+/-0.78 mmHg mL g(-1) min(-1); Cdc120 = 4.8+/-0.56 mmHg/mL g(-1) min(-1)), urinary flow (UF; control120 = 0.19+/-0.03 mL g(-1) min(-1); Cdc120 = 0.12 +/- 0.01 mL g(-1) min(-1)), and glomerular filtration rate (GFR; control120 = 0.79 +/- 0.07 mL g(-1) min(-1); Cdc120 = 0.53 +/- 0.09 mL g(-1) min(-1)), but had no effect on the percent of sodium tubular transport (%TNa+), percent of chloride tubular transport (%TK+) and percent of potassium tubular transport (%TCl-). CTX and PLA2 reduced the GFR, while UF, PP and RVR remained stable during the full 120 min of perfusion. Crotoxin administration also diminished the %TK+ (control120 = 69.94 +/- 6.49; CTX120 = 33.28 +/- 4.78) and %TCl- (control120 = 79.53 +/- 2.67; CTX120 = 64.62 +/- 6.93). PLA2 reduced the %TK+, but exerted no effect on the %TNa+ or on that of TCl-. In conclusion, the C. d. collilineatus venom altered the renal functional parameters evaluated. We suggest that crotoxin and phospholipase A2 were involved in this process, since the renal effects observed would be due to the synergistic action of the components of the venom.     

Fundus lesions in malignant hypertension. III. Arterial blood pressure, biochemical, and fundus changes

Malignant (accelerated) renovascular arterial hypertension was produced in 57 adult rhesus monkeys by clamping the renal artery (one-kidney model in 25 animals and two-kidney model in 32). The animals were investigated before renal artery clamping and serially thereafter by recording systolic arterial blood pressure (BP), biochemical changes, and changes in the fundus of the eye; the latter was evaluated by ophthalmoscopy, stereoscopic color fundus photography, and fluorescein fundus angiography. All of the animals developed arterial hypertension. The data on BP, biochemical, and fundus findings were analyzed and correlated. The findings of this study clearly showed that the various fundus lesions seen in these hypertensive animals fall into three distinct categories: (1) hypertensive retinopathy, (2) hypertensive choroidopathy, and (3) hypertensive optic neuropathy. The appearance of the retinopathy was significantly earlier than that of the choroidopathy or optic neuropathy (P less than 0.01), but the difference between the times of appearance of the choroidopathy and neuropathy was not significant. There was no significance in the order in which the three types of fundus changes reached their maximum severity. There was no significant difference between the mean BPs when the retinopathy, choroidopathy, or optic neuropathy first appeared, nor between the BPs at the time of their appearance and at the time when they were most marked. In monkeys of the one-kidney model, the rise in BP developed significantly (P = 0.01) faster and the fundus lesions appeared significantly (P = 0.00001) earlier than in those with the two-kidney model.     

Preventive services use among women seen by gynecologists, general medical physicians, or both

OBJECTIVE: To estimate how preventive services and counseling differ for women seen by general medical physicians and gynecologists, and whether seeing both types of physicians had a greater impact on delivery of gender-specific and gender-neutral preventive care than by either type of physician alone. METHODS: Using data from the 2000 National Health Interview Survey, we studied the association of provider type with Pap tests, tobacco use screening, and exercise and diet counseling among women 18-64 years (n=7,317), and these services along with clinical breast examinations, mammograms, and colon cancer screening among women aged 50-64 years (n=1,551). We modeled care using multivariable logistic regression and used propensity score techniques to limit selection bias from choice of provider. RESULTS: In the study sample, 15% were seen by general medical physicians, 62% by gynecologists, and 23% by both. Overall rates of gender-specific services (Pap test, clinical breast examination, mammography) were high (88-95%), whereas gender-neutral services were low (23-53%). Patients of gynecologists only were more likely to have Pap tests (adjusted relative risk [RR] 1.26, 95% confidence interval [CI] 1.24-1.27), tobacco use screening (adjusted RR 1.08, 95% CI 1.02-1.14), mammography (adjusted RR 1.25, 95% CI 1.20-1.28), and clinical breast examination (adjusted RR 1.25, 95% CI 1.19-1.29). In general, combined gynecologist and general care did not increase the likelihood of preventive care. Propensity score analyses confirmed these results. CONCLUSION: Patients of gynecologists receive more preventive services compared with patients of general medical physicians, although rates of gender-neutral services were low regardless of provider type. These findings validate gynecologists' roles as providers of basic preventive care services but demonstrate that considerable room exists to improve delivery of preventive care to women.     

The effect of learning to drum on behavior and brain function in autistic adolescents

This current study aimed to investigate the impact of drum training on behavior and brain function in autistic adolescents with no prior drumming experience. Thirty-six autistic adolescents were recruited and randomly assigned to one of two groups. The drum group received individual drum tuition (two lessons per week over an 8-wk period), while the control group did not. All participants attended a testing session before and after the 8-wk period. Each session included a drumming assessment, an MRI scan, and a parent completing questionnaires relating to the participants’ behavioral difficulties. Results showed that improvements in drumming performance were associated with a significant reduction in hyperactivity and inattention difficulties in drummers compared to controls. The fMRI results demonstrated increased functional connectivity in brain areas responsible for inhibitory control, action outcomes monitoring, and self-regulation. In particular, seed-to-voxel analyses revealed an increased functional connectivity in the right inferior frontal gyrus and the right dorsolateral prefrontal cortex. A multivariate pattern analysis demonstrated significant changes in the medial frontal cortex, the left and right paracingulate cortex, the subcallosal cortex, the left frontal pole, the caudate, and the left nucleus accumbens. In conclusion, this study investigates the impact of a drum-based intervention on neural and behavioral outcomes in autistic adolescents. We hope that these findings will inform further research and trials into the potential use of drum-based interventions in benefitting clinical populations with inhibition-related disorders and emotional and behavioral difficulties.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder characterized by deficits in social communication and social interactions as well as a range of restricted, repetitive interests, activities, and behaviors (1). Over recent decades, incidence estimates for ASD have increased (2), with a prevalence of 1 in 59 children in the United States (3) and over 600,000 people in the United Kingdom, which is equivalent to a population prevalence of ∼1% (4, 5). In this context of increased autism prevalence, there is an existing need to develop interventions that offer new insights and perspectives and help address the specifically high demand for services for autistic adolescents and young adults (6). [The term “autistic” is used throughout this paper because of a large percentage of the UK autism community’s preference for the identity-first construction (e.g., “autistic person”) over the person-first phrase (e.g., “person with autism”) (7).] Indeed, autistic young people often face discontinuity in care provision in the transitionary period from child and adolescent services to adult services, just when their care needs are most pressing, making their transition into adulthood particularly difficult (8). In particular, mismatches across services, such as differences in eligibility criteria or age cutoffs, mean that many autistic young adults fall through the care gap after exiting high school (8). Autistic individuals are particularly vulnerable during this period because they often face high unemployment rates, increased levels of comorbid psychiatric diagnoses such as anxiety and depression, and, more broadly, greater reliance on assistance from others when it comes to carrying out adulthood-related daily activities (9–11).A growing body of research suggests that key social domains of the ASD symptomatology may be related to atypical executive functioning (12, 13). Inhibitory control, one of the core executive functions (EFs), corresponds to the ability to delay the onset of behavioral responses, or withhold behaviors that are prepotent but contextually inappropriate (14, 15). It works in concert with other EFs, such as cognitive flexibility and working memory, to exert top-down control on behavioral responses, enable self-regulation, and help navigate social relationships, therefore supporting transition into adulthood and independent living (16, 17). More specifically, it is thought that atypical inhibitory control in autism may underlie significant strengths but may also exacerbate key features of the ASD symptomatology, such as struggling with change and uncertainty, or having difficulty interpreting social cues (18–21). Impaired performance on inhibitory control tasks is frequent in autistic individuals (12, 13, 22, 23). In particular, it has been associated with severe restricted and repetitive behaviors (19, 24, 25), as well as a deficit in proactive response slowing [the ability to slow the initiation of a behavioral response in preparation for stopping during conditions of uncertainty (19)]. At the neuroimaging level, prior studies have revealed atypical recruitment of frontal regions in autistic adolescents (20), and impaired functional connectivity (FC) of the inferior frontal junction, key regions for inhibitory control, in autistic children (26).Autistic individuals often report being preoccupied with certain topics (27) and struggling with anxiety and anger management (28, 29). In a study by Van Hees et al. (30), higher-education autistic students described feeling overwhelmed by the demands placed on them while facing significant difficulties with planning, information processing, time management, organizational skills, and sensory overload. These difficulties may reflect impaired attention and inhibition abilities, complementary processes that allow individuals to pursue the achievement of a particular goal while remaining flexibly responsive to environmental demands (21, 31). A research study on a population-based twin sample of 17,000 children (9 y to 12 y old) concluded that the vast majority of children with ASD traits also exhibit cooccurring attention deficit and hyperactivity disorder (ADHD) traits (32). More specifically, the authors demonstrated that 82% of the boys and 95% of the girls with high ASD traits on all three ASD domains (social impairments, communication impairments, and restricted repetitive behaviors and interests) exhibited difficulties on at least one of the three ADHD domains (attentional difficulties, hyperactivity, and impulsivity). Additionally, they reported that repetitive and restricted behaviors in ASD correlated with ADHD domains, particularly with impulsivity and attentional difficulties. This is in line with a previous twin study in adults, which reported the highest phenotypic and genetic overlap between ADHD traits and “nonsocial” autistic-like traits such as attention switching difficulties (33).Music has long been known to promote cognitive and emotional wellbeing in both clinical and healthy populations (34, 35). Rhythm-based musical training, in particular, has been shown to enhance higher-order cognition and motor control (31). There is growing evidence that activities designed to improve beat synchronization skills may provide an effective approach to developing neurological processes that underpin self-regulation and EF skills (36). Indeed, EF deficits have been linked with poor rhythm perception in children (37) and poor sensorimotor synchronization in young adults (38). Using the Integrated Visual and Auditory Plus Continuous Performance Test (39), Slater et al. (31) highlighted that drumming practice is associated with better scores in inhibitory control and selective attention in adult percussionists compared to nonmusicians.More specifically, learning to drum requires error monitoring and temporal accuracy and therefore both attentional and inhibitory control (31, 40). In a recent study, Lowry et al. (40) used a mixed-methods analysis to investigate behavioral changes in children with emotional and behavioral difficulties, after learning to drum. Following drum training, the participants displayed enhanced attentional focus and reduced hyperactivity and peer problems (40). These results concur with Draper et al.’s (41) recent findings showing that drumming improves motor control and attentional focus and reduces emotional and peer problems in autistic children. It is important to note that motor control is particularly relevant in the context of ASD. Indeed, recent studies have consistently demonstrated motor impairments across the autism spectrum (42, 43), including gross and fine motor difficulties (44, 45) and delays with motor planning (46). Sokhadze et al. (47) showed that ∼80% of autistic individuals also present with clumsiness or motor dyspraxia, which can manifest as having difficulty with motor coordination as well as concentration, planning, and organization. These difficulties may impact the individual’s ability to carry out daily activities, which, in turn, can lead to rejection from peers and social isolation (48). Similarly, motor impairments in balance, motor accuracy, and object manipulation scores have been reported to be predictive of social dysfunction in young autistic boys (49). In this context, learning to drum could be regarded as particularly beneficial because it involves not only musicality but also the development of multimodal skills such as body coordination, sensorimotor integration, and cardiovascular exercise processes (50). Additionally, it is appealing and accessible to everyone regardless of age, gender, ethnicity, or musical background (51, 52).In our proof-of-concept study, Amad et al. (53) showed that the brain is capable of neuroplastic modifications through drum-based practice in neurotypical adolescents. In particular, changes in FC were observed post drum training in brain regions known to exhibit atypical functioning in autism, such as areas associated with motor skills and the mirror neuron system.In the present study, we investigated the impact of drum training on brain function in 36 autistic adolescents who were split into two age- and gender-matched groups: a drum group (n = 19), who were evaluated before and after learning to drum, and a control group (n = 17), who were also evaluated longitudinally but with no intervention. We explored behavioral outcomes related to drum practice in this clinical population and examined their association with changes in FC between the two groups (i.e., drum group vs. control group) over time (i.e., before vs. after drum training).We hypothesized that drumming performance would improve in the drum group over time, while no improvement would be observed in the control group. Furthermore, we hypothesized that changes in hyperactivity, attentional difficulties, problem behaviors, and repetitive and restricted behaviors would be observed in the drum group. We also hypothesized that cooccurring changes in FC in brain areas responsible for attentional focus and inhibitory control would be identified following drum training.