Digital platforms to facilitate physical activities for people with physical or sensory disabilities: A scoping review.

BACKGROUND: People with disabilities (PWD) commonly experience difficulties in accessing their environments, which can lead to restricted participation in outdoor leisure-time physical activity. Participating in outdoor leisure-time physical activity (OLTPA) provides health and social benefits to PWD and benefits to the communities in which they live. OBJECTIVE: The aim of the study was to identify features existing in digital platforms that facilitate access to OLTPA for PWD. METHODS: A scoping review was conducted in four library databases and in Google advance search to identify relevant scientific and grey literature, and websites. Each step of the review was independently conducted by two co-authors who confirmed consensus of results. Descriptive data analyses were performed. RESULTS: Seven scientific studies and ten websites were included in the scoping review. Seven presented mobile apps, nine presented a website and one presented an online database. Sources reported five main obstacles to using digital platforms that support access to physical activities (e.g., lack of digital literacy, technical issues, unintuitive design), and 10 facilitators (e.g., possibility to personalize your online space, accessibility features of the navigation). Among these sources, a trend emerged in the most important factors and features to consider for the visuals and navigation of the platforms. CONCLUSION: The features of digital platforms that facilitate access to OLTPA include intuitive design compliant with accessibility guidelines and supported by navigation tools, personalization of the online space, and features for social interactions.

Effectiveness of wheelchair skills training for improving manual wheelchair mobility in children and adolescents: protocol for a multicenter randomized waitlist-controlled trial.

BACKGROUND: Self-directed mobility during childhood can influence development, social participation, and independent living later in life. For children who experience challenges with walking, manual wheelchairs (MWCs) provide a means for self-directed mobility. An effective MWC skills training program exists for adults, but controlled trials have not yet been documented in children and adolescents. This paper outlines the protocol for a multi-centre randomized wait-list controlled trial. The primary objective is to test the hypothesis that children and adolescents who receive MWC skills training will have higher MWC skills capacity compared to children and adolescents in the control group who receive usual care. The secondary objectives are to explore the influence of MWC skills training in children and adolescents (MWC use self-efficacy and satisfaction with participation in meaningful activities), and parents (perceived MWC skills); and to measure retention three months later. METHODS: A multi-centre, parallel-group, single-blind randomized wait-list controlled trial will be conducted. A sample of 60 children and adolescents who use MWCs will be recruited in rehabilitation centres, specialized schools, and the communities of three Canadian cities. Participants will be randomized (1:1) to the experimental (Wheelchair Skills Training Program [WSTP]) or wait-list control group (usual care). Performance-based and self-report measures will be completed at baseline (T1), three months (post-intervention, T2), and three months post-intervention (T3). The primary outcome will be MWC skills capacity post-intervention. Secondary outcomes will be MWC use self-efficacy and satisfaction with participation of the child/adolescent, and parent-perceived MWC skills. The WSTP will consist of 12 sessions, 45-60 min each, delivered 1-2 times per week by trained personnel with health professions education. Training will be customized according to the child's baseline skills and participation goals that require the use of the MWC. The wait-list control group will receive usual care for 3 months and then receive the WSTP after completing T2 evaluations. Data will be analysed using ANCOVA (controlling for baseline scores). DISCUSSION: MWC skills training may be one way to improve self-directed mobility and related outcomes for children and adolescents. The results of this multi-centre randomized wait-list controlled trial will allow for the effectiveness of the intervention to be evaluated in a variety of clinical contexts and geographical regions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05564247, Version October 3, 2022.

Barriers and facilitators of public transport use among people with disabilities: a scoping review.

Barriers to public transport use may be experienced differently by people with various types of disabilities (e.g., physical, intellectual, cognitive, sensory). Thus, it is important to identify the variable needs within each element of the travel chain. For example, the unavailability or low volume of auditory announcements in a stop or station or on the public transport vehicle may be a barrier to people with visual disability who rely on hearing the information. Consequently, this could provoke negative emotions and unpleasant experiences, which may not be the case for people with physical disabilities. The primary objective was to describe the barriers and facilitators to using public transport experienced by people with disabilities (PWD). The secondary aim was to explore experiences in terms of self-efficacy and satisfaction, when using public transport among people with disabilities. A scoping review was conducted. The search was performed in MEDLINE, TRANSPORT DATABASE, PsycINFO, EMBASE, and WEB OF SCIENCE from 1995 to 2023. Of 6,820 citations identified, 34 articles were included in the review for extraction. The main physical and social barriers included lack of ramp, long walking distance, long waiting time, unavailability of information at bus stop or station, and drivers' negative attitudes towards PWD. Personal factors that prevented the use of public transport included lack of confidence, and decreased satisfaction with public transport use. Strategies such as providing ramps on public transport vehicles, availability of kneeling buses and courtesy of bus drivers, and travel training were considered as enablers to the use of public transport that can lead the improved self-efficacy and satisfaction. In conclusion, this review identified the physical and social barriers and facilitators in travel chain, and highlighted issues related to lack of confidence or self-efficacy and decreased satisfaction when PWD and older adults are using public transport. Identifying and understanding the barriers and facilitators to the use of public transport by PWD is a milestone that may help policy makers and transport operators around the world to develop and implement interventions enabling access, use and inclusion of this mode of transport, as the experiences of PWD when using this mode of transport have an impact on their well-being.

Exploring the Change in Metabolic Cost of Walking before and after Familiarization with a Passive Load-Bearing Exoskeleton: A Case Series.

OCCUPATIONAL APPLICATIONSMilitary personnel are at greater risk of injuries due to frequent load carriage. Novel exoskeleton technology may have benefits for soldiers, such as reduced physical burden through load carriage support that may result in decreased metabolic cost, reduced fatigue, and lower risk of injuries during walking. However, as for most assistive devices, a familiarization period is likely necessary to obtain the full potential of the device. Our results show that the metabolic cost of walking (MWC) was initially increased significantly upon provision of the passive exoskeleton, though it returned to baseline values after a 9-day familiarization period. The exoskeleton remained effective after a three-month pause, with a MCW below baseline. These results suggest that to properly assess the assistance of an exoskeleton, a sufficient familiarization period should be mandatory.

Background: Military load carriage has been shown to alter gait patterns, resulting in an increased metabolic cost during walking (MCW). Soldiers' burden could be mitigated by wearing a passive exoskeleton, but the additional payload of the device can alter movement patterns during gait, rendering it detrimental. Integrating principles of motor learning during a familiarization period could allow users to develop adaptive motor strategies, thereby decreasing MCW.Purpose: The aim of this study was to explore the influence of a familiarization period on MCW when soldiers wear a passive, load-bearing, prototype exoskeleton (Exo).Methods: Three male soldiers walked on a treadmill with a 38 kg payload at eight speeds (1.8-6.0 km/h) under five conditions: 1) no exoskeleton (NoExo); 2) exoskeleton pre-familiarization (Exo_Pre); 3) exoskeleton post-familiarization (Exo_Post); 4) no exoskeleton follow-up (NoExo_FU); and 5) exoskeleton follow-up (Exo_FU). Each experimental trial consisted of 10 minutes of standing followed by 10 minutes of walking at a constant speed. Metabolic data were normalized to walking speed (J/kg·m) to obtain the MCW. The familiarization period consisted of 9 days of activities with the exoskeleton using a standardized protocol. Differences in MCW with and without the Exo were compared at the eight walking speeds using a nonparametric analysis of Longitudinal Data.Results: There was a statistically significant decrease in MCW after familiarization with the Exo, particularly during Exo_FU with a relative treatment effect of 0.11 − 0.19. There were also significant reductions in MCW during Exo_FU when compared to NoExo_FU [participant 01 = 0.37; participant 02 = 0.27; participant 03 = 0.35].Conclusions: A first exposure to the exoskeleton increased MCW. After familiarization, however, the MCW with the Exo returned to the NoExo level or below with a payload of 38 kg among three soldiers. A familiarization period of 3 hours per day over 2 weeks of familiarization may optimize the use of an exoskeleton.

Raloxifene (LY156758) produces antimetastatic responses and extends survival in the PAIII rat prostatic adenocarcinoma model.

The benzothiophene antiestrogen, raloxifene (LY156758), has selective estrogen pharmacological antagonist activity in rats. The PAIII rat prostatic adenocarcinoma model was used to evaluate the effects of this agent on the lymphatic and pulmonary metastasis and survival in tumor-bearing male Lobund-Wistar (LW) rats. Raloxifene was inactive against colony formation of PAIII cells in vitro. Similarly, following subcutaneous (s.c.) implantation of 10(6) PAIII cells in the tail, s.c. administration of raloxifene (2.0, 10.0, or 20.0 mg/kg/day) for 30 days failed to demonstrate cytoreductive activity against primary tumor growth in the tail. However, in these same animals, raloxifene administration produced significant (P < 0.05) inhibition of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximal responses = 89% and 81% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by raloxifene treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (P < 0.05) reduced by raloxifene administration in a dose-related manner (maximal reduction = 97% from control values). In these animals, maximal regression of 20% for ventral prostate and 21% for seminal vesicle were also seen after raloxifene administration (P < 0.05 for both). Coadministration of E2B and raloxifene had no consistent antagonistic effect upon the antitumor responses produced by raloxifene. Raloxifene (40.0 mg/kg/day for 28 days) produced marked decreases in PAIII metastasis in the lymphatic and pulmonary components. Continued administration of the compound produced significant (P < 0.05) extension of survival of PAIII-bearing rats. Further studies are needed to define the maximal antitumor efficacy and the mechanism of action of raloxifene in urogenital solid tumor animal models. These data support the contention that raloxifene represents a class of active antimetastatic agents with potential efficacy in the treatment of hormone-insensitive human prostatic cancer.

LY207320 (6-methylene-4-pregnene-3,20-dione) inhibits testosterone biosynthesis, androgen uptake, 5 alpha-reductase, and produces prostatic regression in male rats.

LY207320 is an in vitro inhibitor (estimated IC50 = 0.06 microM) of steroid 5 alpha-reductase that catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT). In contrast, LY207320 was only moderately active against rat prostatic 5 alpha-reductase in vivo (32% inhibition at 50.0 mg/kg single dose). LY207320 did, however, inhibit the in vivo uptake of [3H]-T by the prostate. The antiprostatic and endocrine effects of this agent were evaluated following daily (21 days) administration to castrated, androgen-supplemented castrate, and intact rats. LY207320, which has modest progestational competitive binding activity, does not bind to rat prostatic androgen or uterine estrogen cytosolic receptors. In the castrated male rat, subcutaneously (s.c.) administered LY207320 had no androgen agonist activity, as evidenced by a lack of accessory sex organ weight gains. Administration of s.c. LY207320 to intact rats for 21 days at doses greater than 5.0 mg/kg-day produced significant (P < 0.05) reductions of seminal vesicle and ventral prostatic weights (maximal regression = -65% and -40% from control values, respectively at 50.0 mg/kg-day). The compound had no regressive activity on male accessory sex organs when administered orally. LY207320 did not alter circulating prolactin, LH, or corticosterone levels, but at high doses (> or = 50.0 mg/kg-day), lowered circulating T[-67% from intact control levels (P < 0.05)]. Histological analysis of the rat ventral prostates (RVPs) in LY207320-treated rats was consistent with an androgen-deprived state. Decreased circulating androgens and prostatic regression are associated with inhibition of testicular 17 alpha-hydroxy/C17,20-lyase enzyme activity (IC50 = 0.06 microM). These findings support the contention that LY207320 is a physiological antagonist of androgen action in male rats, and that its effects are mediated primarily through inhibition of testicular androgen production rather than accessory sex organ 5 alpha-reductase.

Endocrine and antiprostatic effects of raloxifene (LY156758) in the male rat.

The benzothiophene anti-estrogen, raloxifene [LY156758; (6-hydroxy-2-(4-hydroxyphenyl) benzo(b)thien-3-yl)(4-(2-1-piperidinyl)ethoxy)phenyl methanone hydrochloride] has selective estrogen pharmacological antagonist activity in female rats. The present studies were done in the male rat to assess activity of raloxifene related to inhibition of prostatic growth and effects on the hypothalamic-pituitary-gonadal axis. Raloxifene did not compete for binding of the androgen, [3H]-methyltrienolone (R1881) in cytosolic extracts of ventral prostate. Similarly, the compound did not inhibit prostatic 5 alpha-reductase or testicular 17 alpha-hydroxy/C17,20-lyase activities. Raloxifene had no effect on the ventral prostatic uptake of [3H]-R1881 in vivo. Administration of estradiol to castrated male rats stimulated fourfold increases of in vitro ventral prostatic binding of [3H]-R1881. Raloxifene was devoid of agonist activity in castrated animals, because the compound had no stimulatory effect on prostatic androgen receptor binding activity. When raloxifene was coadministered with estradiol, the compound markedly antagonized the estrogen-induced increase of prostatic [3H]-R1881 binding, confirming its antiestrogenic properties in male rats. Serum prolactin was also elevated significantly (P < 0.05) with a single injection of raloxifene (20.0 mg/kg). In these same animals, serum FSH was significantly (P < 0.05) decreased by one dose (10.0 mg/kg) of the compound. Luteinizing hormone levels in castrated male rats were unaffected by raloxifene administration. Raloxifene treatment of castrated males significantly (P < 0.05) antagonized the stimulatory response of the ventral prostate (VP) to exogenous androgens in a dose-dependent manner. Raloxifene treatment of intact male rats for 14 and 28 days produced significant (P < 0.05) dose-dependent regression of the VP and seminal vesicles (SV). The VP regressive responses to raloxifene were associated with a decline in serum testosterone levels. Histological analysis of the VPs in raloxifene-treated rats was consistent with an androgen-deprived state. These findings support the contention that raloxifene is a pure estrogen antagonist and a physiological antagonist of androgen action in male rats. These pharmacological properties provide support for further structure-activity and mechanistic investigations with benzothiophenes in the medical management of prostatic neoplasia.

Androgens lower prostaglandin E2 levels in neonatal mouse bulbourethral gland in in vitro cultures.

The neonatal mouse bulbourethral gland (BUG) in vitro culture model is useful to study hormone-induced genitourinary (GU) tract growth and differentiation. Like the prostate, the BUG is a derivative of the urogenital sinus and may have relevance to understanding growth processes involved in normal and pathological GU tract development. Previous studies have reported androgen-induced elevation of prostaglandin E2 (PgE2) levels in mouse GU tract in vivo. PgE2 has been proposed to mediate neonatal GU tract masculinization. In our studies, tissues were obtained from neonatal male mice and cultured in serum-free Dulbecco's Modified Eagle's Medium-Ham's F-12 Medium (1:1) supplemented with varying concentrations of androgen. PgE2 levels were measured by RIA in the medium, and tissue specimens were cultured for 7 days or less. During this period, androgens induced proliferation and glandular morphogenesis in the BUGs. In the absence of androgen, tissue and medium PgE2 levels increased over 7 days. Significant (P < 0.05) PgE2 increases over day 1 control values were observed from days 5-7 in tissues and on day 7 in media. During this same time period, androgen supplementation decreased PgE2 levels. Significant (P < 0.05) PgE2 decreases from day 1 cultures were observed from days 3-7 in tissues and on day 7 in media. PgE2 was decreased significantly (P < 0.05) by androgen compared to control values from days 3-7 in tissues and from days 5-7 in media. On day 7 of culture, PgE2 levels were significantly (P < 0.05) inhibited by androgen in a concentration-dependent fashion in tissues and media. Maximal androgen-induced inhibition of PgE2 levels was 96% and 99% in tissues and media, respectively. Although the addition of indomethacin to control cultures markedly inhibited PgE2 production, BUG morphology was unaffected. In addition, the morphology of androgen-stimulated BUGs does not appear to be affected by the addition of exogenous PgE2. We conclude that although androgens induce development and decrease PgE2 levels, PgE2 does not appear to play a major role in in vitro BUG postnatal growth and morphogenesis. The BUG in vitro culture model may mimic growth and morphogenetic processes occurring in the human GU tract. Further understanding of the role of steroid hormones and PG metabolism may yield additional insight into developmental and proliferative GU tract disorders.

Comparative antitumor effects of hormonal ablation, estrogen agonist, estrogen cytotoxic derivative, and antiestrogen in the PAIII rat prostatic adenocarcinoma.

The effects of hormonal ablation, estrogen, estrogen-derived cytotoxic agent, and estrogen antagonist therapies used clinically were evaluated on in vitro colony formation, in vivo growth, and lymphatic and pulmonary metastasis of the PAIII tumor. Ventral prostatic and seminal vesicle weights were evaluated in the same animals to assess androgen-related responses. Estradiol, estramustine phosphate, and testosterone had no effects on PAIII colony formation in vitro. Castration, hypophysectomy, estradiol benzoate, and estramustine phosphate treatment of PAIII-bearing Lobund Wistar rats produced significant (P less than 0.05) regression of male accessory sex organs. Of these treatments, only hypophysectomy had significant (P less than 0.05) inhibitory effects on primary PAIII growth and lymphatic and pulmonary metastasis. LY117018 [6-hydroxy-2-(p-hydroxyphenyl)benzo(b)thien-3-yl-p-2-(l-pyrrolidin yl)ethoxy phenyl ketone] has antiestrogenic activity but produces no significant agonist responses. LY117018 had no effect upon PAIII colony formation in vitro. Following s.c. implantation of PAIII cells, LY117018 (2.0, 10.0, or 20.0 mg/kg s.c.) had no effect on primary tumor growth in the tail. In vitro LY117018 administration produced marked antimetastatic effects. In a dose-dependent manner, LY117018 inhibited PAIII metastasis to the gluteal (97%) and iliac lymph nodes (88%) (P less than 0.05 for both). LY117018 also maximally inhibited pulmonary metastasis by 86% (P less than 0.05). Maximal regression of 42% for ventral prostatic and 35% for seminal vesicle weights were also seen after LY117018 administration (P less than 0.05 for both). Co-administration of estradiol benzoate had no antagonistic effect upon the antitumor responses produced by LY117018. The mechanism of action of LY117018 is not known. The failure of estradiol benzoate to affect PAIII growth and metastasis supports the contention that the responses to LY117018 are not attributable to simple antagonism of estrogen action. LY117018 may be exerting its antitumor effects through autocrine, paracrine, or endocrine mechanisms. LY117018 represents a class of agents with potential utility in treating metastatic cancer of the prostate.

Inhibition of PAIII rat prostatic adenocarcinoma growth and metastasis by a new diarylsulfonylurea antitumor agent, LY181984.

LY181984 is a compound in a series of orally active diarylsulfonylureas with broad spectrum in vivo activity against syngeneic rodent and human xenograft tumor models. The PAIII rat prostatic adenocarcinoma model was used to evaluate the effects of this antitumor agent on the lymphatic and pulmonary metastasis of the tumor in male Lobund Wistar rats. LY181984 was inactive against the proliferation of PAIII cells in vitro. Following subcutaneous implantation of 10(6) PAIII cells in the tail, oral administration of LY181984 (25.0, 50.0, or 100.0 mg./kg./day) for 30 days had no significant effects on body weight gain. LY181984 treatment produced significant (p less than 0.05) dose-dependent inhibition of primary tumor growth in the tail (max. inhibition = 46% from untreated control levels). In these same animals, LY181984 administration produced significant (p less than 0.05) dose-dependent inhibiton of PAIII metastasis from the primary tumor in the tail to the gluteal and iliac lymph nodes (maximal responses = 79% and 80% from control values, respectively). PAIII metastasis to the lungs was significantly inhibited by oral LY181984 treatment. Numbers of pulmonary foci in PAIII-bearing rats were significantly (p less than 0.05) reduced by LY181984 administration in a dose-dependent manner (maximal reduction = 78% from control values). While the non-toxic doses (less than 100.0 mg./kg./day for 28 days) of LY181984 produced marked decreases in tumor growth and metastasis, administration of the compound had no effect on the survival of PAIII-bearing rats. These data support the contention that LY181984 represents a new class of orally active antitumor and antimetastatic agents with potential efficacy in the treatment of hormone-insensitive prostatic cancer. Further studies are needed to define maximal efficacy of LY181984 and other sulfonylurea agents in urogenital solid tumor animal models.

Endocrine effects of a new histamine H2-receptor antagonist, nizatidine (LY139037), in the male rat.

A new orally active histamine H2-receptor antagonist, nizatidine (LY139037), was evaluated in male rats for effects on mechanisms regulating accessory sex organ growth and function. Cimetidine antagonized androgen binding to cytosolic receptors in vitro while nizatidine had no effect. Nizatidine and cimetidine were administered at the ED50, 5 X ED50, or 10 X ED50 doses for inhibition of gastric acid secretion previously determined using in vivo dog and rat models. The relative potencies of both agents to antagonize histamine H2-receptor-mediated gastric acid secretory responses have been confirmed in human clinical trials. Neither nizatidine nor cimetidine antagonized the in vivo uptake or nuclear translocation of radiolabeled androgen into the hypothalamic-preoptic-amygdala, pituitary, or ventral prostate. Nizatidine, given at doses equal to and 10 X the ED50 gastric acid secretion inhibitory values, and cimetidine (10 X ED50 value) had no effect on the response of male accessory sex organs to a submaximally stimulating dose of androgen in castrated rats. High doses of dietary nizatidine (greater than 500 mg/kg-day) administered for 6 months did not alter intact rat male accessory sex organ weights or circulating androgen levels relative to untreated controls. Acute administration of either nizatidine or cimetidine produced transient elevations in plasma prolactin (PRL) levels. Cimetidine was more potent and consistent than nizatidine in producing these increases in circulating PRL. The data described herein support the contention that unlike cimetidine, nizatidine is not a pharmacological antagonist of androgen action and has less of a stimulatory effect upon plasma prolactin. Taken together, these studies indicate that in the male rat, nizatidine exhibits a large therapeutic index between its gastric antisecretory activity and potential endocrinological effects.

Experimental induction of neoplasia in the accessory sex organs of male Lobund-Wistar rats.

Experimental induction of neoplasia in the urogenital tract was studied in male Lobund-Wistar rats. Animals were given single 30.0-mg/kg i.v. injections of N-nitroso-N-methylurea (NMU) followed 7 days later by s.c. implantation of a 2.0-cm Silastic capsule containing testosterone propionate (TP). Additional rats were given the NMU or TP treatments individually. Control animals were given a single i.v. injection of saline followed by implantation of an empty Silastic capsule. The Silastic implants for each group were replaced every 2 months. This hormone treatment regimen produced significantly (P less than 0.05) elevated serum testosterone concentrations relative to control for 42 days following implantation. Animals were killed at 92, 177, 259, 361, or 427 days post-NMU injection. A high treatment-related incidence of adenocarcinoma occurred in the dorsal and lateral prostatic lobes of animals given the combined NMU-TP treatment. In addition, a few animals had adenocarcinomas of the coagulating gland or the seminal vesicle. The estimated probability of neoplasia in the accessory sex organs by 427 days after initiation of the NMU-TP treatment was 68%, with no occurrence before 9 months. The NMU-TP treatment was also associated with an incidence of focal dysplasia in the accessory sex organs, particularly in the coagulating gland. These findings indicate that NMU-TP treatment of Lobund-Wistar rats can provide a useful experimental system to study the biochemical and molecular events involved in the induction of accessory sex organ neoplasia.

Correlation of the in vivo anticoagulant, antithrombotic, and antimetastatic efficacy of warfarin in the rat.

Fibrin formation has been hypothesized to be an element of the metastatic process in cancer, and pharmacological interference with such fibrin formation has been proposed as a means of antimetastatic therapy. We have tested this hypothesis through an in vivo study of warfarin in two independent rat disease models--a model of chemical-injury-induced arterial thrombosis, and a model of spontaneous metastasis. We found 0.50 mg/kg-day warfarin to be uniformly lethal after two weeks treatment. The chronic dose of 0.25 mg/kg-day was non-toxic and produced effective anticoagulation and marked antithrombotic and antimetastatic activity. The 0.125 mg/kg-day dose produced a reduction in factor IIc (50%) and factor VIIc (70%), and resulted in statistically significant antithrombotic and antimetastatic activity. The 0.0625 mg/kg-day dose failed to reduce the vitamin K-dependent clotting factors, and failed to produce any antithrombotic or antimetastatic effects. The substantial correlation (very similar dose-response effects) among the anticoagulant, antithrombotic and antimetastatic efficacies of warfarin in the rat suggests that anticoagulation provides the pharmacological mechanism underlying both the antithrombotic and the antimetastatic effects. The poor therapeutic index we observed in the rat may be the attribute which limits the efficacy of warfarin in the treatment of human cancer.

Mesenchymal-epithelial interactions as factors influencing male accessory sex organ growth in the rat.

Mesenchyme (UGM) and epithelium (UGE) isolated from the urogenital sinuses (UGS) of 17-day male and female rat embryos were separated by using a trypsinization procedure, grown on soft agar, transplanted into syngeneic pubertal male hosts as subcapsular renal grafts, and then collected after 29-30 days. Neither UGM nor UGE underwent prostatic morphogenesis when grown under these conditions. However, tissue recombinants composed of UGM + UGE grew and produced prostatic glands with acinar secretory material. Further, UGM + UGE recombinants were made by varying the proportions of mesenchymal and epithelial tissues. The size of the implants was a function of the absolute amount of mesenchyme; increasing the absolute amount of UGM produced larger specimens whereas varying the UGE had no effect. The UGM was also found to be essential for supporting the growth of small glandular elements derived from the ventral prostate of pubescent rats. Segments isolated from the terminal vesicles (TIPs) and from prostatic tissue adjacent to the urethra (PDCT) regressed when implanted alone under the kidney capsule. However, combination of the prostatic segments with UGM produced prostatic glands with relative wet weight and DNA content responses of the following order: UGM + TIP greater than UGM + PDCT = UGM + UGE. Two-dimensional gel electrophoretic protein patterns from UGM + PDCT and UGM + TIP specimens had differential expression of three protein regions unique to the ventral prostate Quantitative and qualitative responses of the TIP and PDCT segments to UGM inductive influences indicate that differences exist between the epithelia of the TIP and PDCT regions of the ventral lobes of the rat prostate.

Inhibitory effect of warfarin on the metastasis of the PAIII prostatic adenocarcinoma in the rat.

The PAIII rodent metastatic prostatic adenocarcinoma model was employed to evaluate the effects of dietary warfarin, a prototypic antagonist of thrombin generation on the lymphatic and pulmonary metastases of the tumor from the tail site of subcutaneous transplantation in male Lobund Wistar (LW) rats. In addition, the anticoagulant effects of warfarin were determined in the same animals. Warfarin, administered in the diet at concentrations equivalent to 0.063, 0.125 or 0.250 mg./kg. b.w. for 30 days had no effect on final body weight, gluteal or iliac lymph node weights. Significant (p less than 0.05) dose-dependent extensions of whole blood prothrombin (WBPT), activated partial thromboplastin (WBAPTT) and clotting times (WBCT) over control values were observed with warfarin treatment. Preliminary studies demonstrated that the 0.500 mg./kg. dose produced 50 per cent mortality at +14 days. Warfarin produced significant (p less than 0.05) dose-dependent decreases in the number of PAIII pulmonary metastases as indicated by reductions in dry lung weights and lung colony numbers when compared to untreated tumor-bearing controls. While the therapeutic index of warfarin is a limiting factor in clinical use as an antimetastatic agent, these results suggest that compounds capable of altering hemostatic mechanisms may be potential inhibitors of tumor metastasis. The PAIII prostatic adenocarcinoma model may be a useful system to quantitatively evaluate potential antimetastatic and cytotoxic agents.

Metastatic spread of the PAIII prostatic adenocarcinoma after implantation in the tail of the rat.

The spontaneous metastatic spread of a suspension of PAIII prostatic adenocarcinoma cells from the tail site of implantation was analyzed over a period of 5 weeks in male Lobund-Wistar (LW) rats. Following subcutaneous injection of the PAIII cells, the tumor metastasized through the primary lymphatic drainage. PAIII microfoci were evident in the gluteal and iliac lymph nodes prior to colonization of the lungs. Growth of the primary tumor was evidenced by significant weight differences of the tails of PAIII-bearing and control rats 1 week after tumor implantation. Time-dependent sequential spread of the adenocarcinoma was quantitated. Significant differences were noted between PAIII-bearing and control animals with respect to the gluteal lymph node weights (+2 weeks), iliac lymph node weights (+3 weeks), dry lung weights, and lung colony numbers (+4 weeks) after tumor implantation. During the course of these studies, the whole blood prothrombin, activated partial thromboplastin, and recalcification times for the PAIII-bearing animals were similar to those of the control group. These findings indicate that there were no gross changes in systemic blood coagulation accompanying the metastasis of PAIII cells from the primary tumor. The tumor in LW rats produced a consistent pattern of growth and metastasis that is suitable for quantitation. The PAIII prostatic adenocarcinoma is a sensitive and reproducible system that may be useful to evaluate potential antimetastatic and cytotoxic agents for the treatment of hormone-insensitive prostatic cancer.

A new inhibitor of norepinephrine uptake devoid of affinity for receptors in rat brain.

LY135252, (+/-)-N-methyl-gamma-(2-methylphenoxy) phenylpropylamine hydrochloride, is a competitive inhibitor of norepinephrine uptake in synaptosomes of rat hypothalamus. The resolved optical (-)-isomer, LY139603, is 2 and 9 times more effective than the racemate and the (+)-isomer, LY139602, with inhibitor constants (Ki) of 1.9, 3.4 and 16.8 nM, respectively. All three compounds are relatively weak in the inhibition of dopamine and serotonin uptake, with Ki values at least two orders of magnitude greater. The racemate and the two optical isomers in vivo are potent inhibitors of norepinephrine uptake with relative effectiveness being parallel with their K1 values. The most potent and long-acting compound was the (-)-isomer, LY139603, which inhibited norepinephrine uptake ex vivo with an ED50 value of 2.2 mg/kg i.p, and a half-life of 6.4 hr. In comparison with the tricyclic antidepressants desipramine and imipramine, LY139603 is a relatively weak ligand for alpha-1, alpha-2, and beta adrenergic receptors, acetylcholine-muscarinic receptors, histaminergic H1 receptors and the receptors of gamma-aminobutyric acid and benzodiazepines. Thus, LY139603 is a remarkably specific inhibitor of norepinephrine uptake. Its potential as an antidepressant is discussed.