Leaf abaxial immunity to powdery mildew in Arabidopsis is conferred by multiple defense mechanisms.

Powdery mildew fungi are obligate biotrophic pathogens that only invade plant epidermal cells. There are two epidermal surfaces in every plant leaf: the adaxial (upper) side and the abaxial (lower) side. While both leaf surfaces can be susceptible to adapted powdery mildew fungi in many plant species, there have been observations of leaf abaxial immunity in some plant species including Arabidopsis. The genetic basis of such leaf abaxial immunity remains unknown. In this study, we tested a series of Arabidopsis mutants defective in one or more known defense pathways with the adapted powdery mildew isolate Golovinomyces cichoracearum UCSC1. We found that leaf abaxial immunity was significantly compromised in mutants impaired for both the EDS1/PAD4- and PEN2/PEN3-dependent defenses. Consistently, expression of EDS1-yellow fluorescent protein and PEN2-green fluorescent protein fusions from their respective native promoters in the respective eds1-2 and pen2-1 mutant backgrounds was higher in the abaxial epidermal cells than in the adaxial epidermal cells. Altogether, our results indicate that leaf abaxial immunity against powdery mildew in Arabidopsis is at least partially due to enhanced EDS1/PAD4- and PEN2/PEN3-dependent defenses. Such transcriptionally pre-programmed defense mechanisms may underlie leaf abaxial immunity in other plant species such as hemp and may be exploited for engineering adaxial immunity against powdery mildew fungi in crop plants.

Reconnaissance of tumor immune microenvironment spatial heterogeneity in metastatic renal cell carcinoma and correlation with immunotherapy response.

A clearer understanding of the tumor immune microenvironment (TIME) in metastatic clear cell renal cell carcinoma (ccRCC) may help to inform precision treatment strategies. We sought to identify clinically meaningful TIME signatures in ccRCC. We studied tumors from 39 patients with metastatic ccRCC using quantitative multiplexed immunofluorescence and relevant immune marker panels. Cell densities were analyzed in three regions of interest (ROIs): tumor core, tumor-stroma interface and stroma. Patients were stratified into low- and high-marker density groups using median values as thresholds. Log-rank and Cox regression analyses while controlling for clinical variables were used to compare survival outcomes to patterns of immune cell distributions. There were significant associations with increased macrophage (CD68+ CD163+ CD206+ ) density and poor outcomes across multiple ROIs in primary and metastatic tumors. In primary tumors, T-bet+ T helper type 1 (Th1) cell density was highest at the tumor-stromal interface (P = 0·0021), and increased co-expression of CD3 and T-bet was associated with improved overall survival (P = 0·015) and survival after immunotherapy (P = 0·014). In metastatic tumor samples, decreased forkhead box protein 3 (FoxP3)+ T regulatory cell density correlated with improved survival after immunotherapy (P = 0·016). Increased macrophage markers and decreased Th1 T cell markers within the TIME correlated with poor overall survival and treatment outcomes. Immune markers such as FoxP3 showed consistent levels across the TIME, whereas others, such as T-bet, demonstrated significant variance across the distinct ROIs. These findings suggest that TIME profiling outside the tumor core may identify clinically relevant associations for patients with metastatic ccRCC.

Biomarkers and new therapeutic targets in renal cell carcinoma.

OBJECTIVE: Renal Cell Carcinoma (RCC) is the most common malignancy in adult kidneys. The American Cancer Society estimated 62,700 new cases and 14,240 deaths in 2018. Although early detection has improved in recent years, the treatment remains a challenge and reliable biomarkers for poor outcomes become necessary for the prevention of metastases and improve the quality of patients' life during and after treatment. Then, the current status of the search for new RCC biomarkers was discussed, as well as the latest discoveries in the RCC risk and metastatic treatment were discussed in this review. MATERIALS AND METHODS: Extensive research was carried out in the online databases and full-free text articles published in the last 5 years, or more when convenient, were evaluated. Articles were included that addressed the proposed theme and were published in the English language. RESULTS: The present state of knowledge on biomarkers for RCC carcinogenesis and progression is still much to be understood about RCC risk factors and molecular pathways resulting in metastatic progression. Newest RCC target therapies were discussed, mainly in relation to immunological therapy, and vaccines that have been tested in numerous trials with different cancer types. CONCLUSIONS: The development of targeted therapies has revolutionized the treatment of advanced and metastatic cancers or non-responder patients. Combined therapy between classical chemotherapy and adjuvant immunotherapies has been modifying the cancer patients prognosis and bringing the hope of a cure in many cases.

The merits of cytology in the workup for upper tract urothelial carcinoma - a contemporary review of a perplexing issue.

INTRODUCTION: The importance of upper tract cytology for evaluating tumors is unclear. We correlated upper tract cytology with histologic findings in patients who underwent nephroureterectomy for upper tract urothelial carcinoma (UTUC) at a single tertiary care referral center. MATERIALS AND METHODS: 137 patients underwent nephroureterectomy between 2004 and 2012. 18 patients were excluded (benign tumors, atrophic kidneys with the remaining 119 patients serving as our study population). Upper tract cytology from the renal pelvis and/or ureter were retrospectively reviewed and analyzed with final pathology data in the remaining patients with UTUC. RESULTS: 57% (68/119) had preoperative upper tract cytology collected. 73% (50/68) patients had abnormal cytology (positive, suspicious) with a sensitivity of 74% (which increased to 90% if atypical included), specificity of 50% and a positive predictive value of 98%. High grade tumors were more common than expected (77% high grade vs. 20% low grade). Abnormal cytology did not predict T stage or tumor grade. Interestingly, positive upper tract cytology was found in all of the UTUC CIS specimen. CONCLUSIONS: Upper tract cytology has been utilized to support the diagnosis of upper tract urothelial carcinoma. Our data demonstrates that abnormal cytology correlates well with the presence of disease but does not predict staging or grading in these respective patients.

The merits of cytology in the workup for upper tract urothelial carcinoma - a contemporary review of a perplexing issue

Introduction The importance of upper tract cytology for evaluating tumors is unclear. We correlated upper tract cytology with histologic findings in patients who underwent nephroureterectomy for upper tract urothelial carcinoma (UTUC) at a single tertiary care referral center. Materials and Methods 137 patients underwent nephroureterectomy between 2004 and 2012. 18 patients were excluded (benign tumors, atrophic kidneys with the remaining 119 patients serving as our study population). Upper tract cytology from the renal pelvis and/or ureter were retrospectively reviewed and analyzed with final pathology data in the remaining patients with UTUC. Results 57% (68/119) had preoperative upper tract cytology collected. 73% (50/68) patients had abnormal cytology (positive, suspicious) with a sensitivity of 74% (which increased to 90% if atypical included), specificity of 50% and a positive predictive value of 98%. High grade tumors were more common than expected (77% high grade vs. 20% low grade). Abnormal cytology did not predict T stage or tumor grade. Interestingly, positive upper tract cytology was found in all of the UTUC CIS specimen. Conclusions Upper tract cytology has been utilized to support the diagnosis of upper tract urothelial carcinoma. Our data demonstrates that abnormal cytology correlates well with the presence of disease but does not predict staging or grading in these respective patients. .

Adult prostate sarcoma: the M. D. Anderson Cancer Center Experience.

PURPOSE: Sarcoma of prostate origin is rare. Historically, long-term survival rates for adult patients with prostate sarcoma are poor. We analyzed the experience of 1 institution with prostate sarcoma during the last 3 decades. MATERIALS AND METHODS: The records of 21 patients with prostate sarcoma were reviewed to identify symptoms at presentation, diagnostic procedures, presence and development of metastases, staging evaluation, histological subtype, grade and size of the primary tumor, and treatment sequence, including surgery, and preoperative and postoperative therapies. Several clinicopathological variables were assessed for prognostic importance. RESULTS: Most patients presented with urinary obstruction. The diagnosis of prostate sarcoma was usually established with ultrasound guided biopsy or transurethral resection. Histological subtypes were leiomyosarcoma in 12, rhabdomyosarcoma in 4, malignant fibrous histiocytoma in 1 and unclassified sarcoma in 4 patients. At last followup, 8 patients had no evidence of disease after a median of 81.5 months (range 10 to 197). The remaining 13 patients died of sarcoma (median survival 18 months, range 3 to 94). The 1, 3 and 5-year actuarial survival rates for all 21 patients were 81%, 43% and 38%, respectively. Factors predictive of long-term survival were negative surgical margins (p = 0.0005) and absence of metastatic disease at presentation (p = 0.0004). Tumor size and grade, and the histological subtype of prostate sarcoma had no significant influence on actuarial survival. CONCLUSIONS: The long-term disease specific survival rate for adults with prostate sarcoma is poor. Early diagnosis and complete surgical resection offer patients the best chance for cure.

Respiratory muscle blood flows during physiological and chemical hyperpnea in the rat.

Whether the diaphragm retains a vasodilator reserve at maximal exercise is controversial. To address this issue, we measured respiratory and hindlimb muscle blood flows and vascular conductances using radiolabeled microspheres in rats running at their maximal attainable treadmill speed (96 +/- 5 m/min; range 71-116 m/min) and at rest while breathing either room air or 10% O(2)-8% CO(2) (balance N(2)). All hindlimb and respiratory muscle blood flows measured increased during exercise (P < 0.001), whereas increases in blood flow while breathing 10% O(2)-8% CO(2) were restricted to the diaphragm only. During exercise, muscle blood flow increased up to 18-fold above rest values, with the greatest mass specific flows (in ml. min(-1). 100 g(-1)) found in the vastus intermedius (680 +/- 44), red vastus lateralis (536 +/- 18), red gastrocnemius (565 +/- 47), and red tibialis anterior (602 +/- 44). During exercise, blood flow was higher (P < 0.05) in the costal diaphragm (395 +/- 31 ml. min(-1). 100 g(-1)) than in the crural diaphragm (286 +/- 17 ml. min(-1). 100 g(-1)). During hypoxia+hypercapnia, blood flows in both the costal and crural diaphragms (550 +/- 70 and 423 +/- 53 ml. min(-1). 100 g(-1), respectively) were elevated (P < 0.05) above those found during maximal exercise. These data demonstrate that there is a substantial functional vasodilator reserve in the rat diaphragm at maximal exercise and that hypoxia + hypercapnia-induced hyperpnea is necessary to elevate diaphragm blood flow to a level commensurate with its high oxidative capacity.

Glycolate metabolism by Hep G2 cells.

The pathways of oxalate synthesis in humans are not well defined despite their clinical significance in primary hyperoxaluria and idiopathic calcium oxalate nephrolithiasis. Furthermore, the functional roles, if any, of this synthesis have not been elucidated. This study examines pathways of oxalate synthesis from glycolate in Hep G2 cells, a human hepatoma cell line. Incubation of these cells with glycolate has revealed that a pathway may function to synthesize oxalate from glycolate that does not depend on the oxidation of glycolate to glyoxylate by glycolate oxidase. Labeling cells with 14C-glycolate and chromatographic analyses indicated that detectable amounts of 14C-glyoxylate were not formed. A radioactive peak that coeluted with oxalate on ion exclusion chromatography was the only peak yet identified. A detailed examination of glycolate metabolism in these cells should help clarify the terminal steps associated with oxalate synthesis and aid in our understanding of two-carbon metabolism.

Diagnostic and therapeutic laparoscopy for the adult cryptorchid testicle.

Laparoscopy can be utilized in the management of male patients with impalpable gonads. However, there have been few reports of its application in the management of adult men with cryptorchidism. Fourteen adult men with 15 undescended testicles were referred to our urology department over 6 years. Eight testicles from seven men could not be localized clinically or radiographically to the inguinal canal. Laparoscopy was utilized to assess for the presence and location of the gonad and to perform orchiectomy when testicular tissue was encountered. The average age of the seven men undergoing laparoscopy was 40 years. Three testicles were found proximal to the internal ring and were removed using laparoscopic techniques. The ipsilateral testicular vessels and vas deferens were visualized entering the internal ring in three cases and dense ipsilateral adhesions from previous inguinal surgery prevented adequate visualization of the cord structures in one individual, leading to four inguinal explorations in the same setting. Two inguinal orchiectomies were performed and two vanishing testicles were identified. Gonadal vessels were absent in the remaining patient as demonstrated by extensive laparoscopic dissection. The average total operative time was 105 minutes, which included additional procedures in four patients. No patient experienced an intraoperative or postoperative complication. Six of seven patients were discharged on the day of surgery. An intratesticular germ cell neoplasm was found in one of seven specimens, which stresses the importance of diagnosing and managing this uncommon problem in the adult man.

Skeletal muscle microcirculatory structure and hemodynamics in diabetes.

Within skeletal muscle, insulin-dependent (Type 1) diabetes produces straighter, narrower capillaries. To test the hypothesis that these microvascular alterations would be associated with impaired capillary hemodynamics, intravital microscopy techniques were used to study the in vivo spinotrapezius muscle microcirculation of age-matched control (C) and streptozotocin (STZ) induced diabetic (D) rats. D rats exhibited a marked reduction in body weight (C, 266 +/- 5 g; D, 150 +/- 6 g; P < 0.001). At resting sarcomere lengths (i.e. approximately 2.7 microm), the additional capillary length arising from tortuosity and branching was less in D muscle (C, 10.5 +/- 0.8%; D, 5.3 +/- 1.0%, P < 0.01). Capillary diameter was reduced in D muscle (C, 5.4 +/- 0.1 microm; D, 4.6 +/- 0.1 microm; P < 0.001), and was positively correlated (r = 0.71) with the decreased proportion of capillaries sustaining flow (C, 85 +/- 5%; D, 53 +/- 3%; P < 0.001). Within those 'flowing' capillaries, red blood cell (RBC) velocity and flux were reduced 29 and 43%, respectively in D muscle (both P < 0.05). This reduced calculated O2 delivery by 57% per unit tissue width and 41% per unit muscle mass. Capillary 'tube' hematocrit was unchanged from control values (C, 0.22 +/- 0.02; D, 0.22 +/- 0.02). We conclude that, in the diabetic state, microvascular remodeling is associated with a reduced proportion of 'flowing' capillaries and a reduction in RBC velocity and flux in these vessels such that skeletal muscle O2 delivery is markedly reduced.

Effects of emphysema on diaphragm blood flow during exercise.

Chronic hyperinflation of the lung in emphysema displaces the diaphragm caudally, thereby placing it in a mechanically disadvantageous position and contributing to the increased work of breathing. We tested the hypothesis that total and regional diaphragm blood flows are increased in emphysema, presumably reflecting an increased diaphragm energetic demand. Male Syrian Golden hamsters were randomly divided into emphysema (E; intratracheal elastase 25 units/100 g body wt) and control (C; saline) groups, and experiments were performed 16-20 wk later. The regional distribution of blood flow within the diaphragm was determined by using radiolabeled microspheres in hamsters at rest and during treadmill exercise (walking at 20 feet/min, 20% grade). Consistent with pronounced emphysema, lung volume per unit body weight was greater in E hamsters (C, 59.3 +/- 1.8; E, 84.5 +/- 5.0 ml/kg; P < 0.001) and arterial PO2 was lower both at rest (C, 74 +/- 3; E, 59 +/- 2 Torr; P < 0.001) and during exercise (C, 93 +/- 3; E, 69 +/- 4 Torr; P < 0.001). At rest, total diaphragm blood flow was not different between C and E hamsters (C, 47 +/- 4; E, 38 +/- 4 ml . min-1 . 100 g-1; P = 0.18). In both C and E hamsters, blood flow at rest was lower in the ventral costal region of the diaphragm than in the dorsal and medial costal regions and the crural diaphragm. During exercise in both C and E hamsters, blood flows increased more in the dorsal and medial costal regions and in the crural diaphragm than in the ventral costal region. Total diaphragm blood flow was greater in E hamsters during exercise (C, 58 +/- 7; E, 90 +/- 14 ml . min-1 . 100 g-1; P = 0.03), as a consequence of significantly higher blood flows in the medial and ventral costal regions and crural diaphragm. In addition, exercise-induced increases in intercostal (P < 0.005) and abdominal (P < 0.05) muscle blood flows were greater in E hamsters. The finding that diaphragm blood flow was greater in E hamsters during exercise supports the contention that emphysema increases the energetic requirements of the diaphragm.

Comparison of long-term outcomes of penile prostheses and intracavernosal injection therapy.

PURPOSE: Intracavernosal injection therapy is one of the most popular therapies for erectile dysfunction today. Yet, most clinicians consider intracavernosal injection a palliative treatment for erectile dysfunction because of the high patient initiated dropout rate. In contrast, penile prostheses appear to offer a more permanent cure for erectile dysfunction. We compare the long-term outcomes of both therapies in contemporaneously treated patients and determine the reasons for failure of each. MATERIALS AND METHODS: Telephone survey and chart review was conducted on the first 115 patients treated with intracavernosal injection and 65 patients undergoing insertion of a penile prosthesis during the same period at our institution. Mean patient age was 57 and 60 years, respectively, and mean followup of all patients was 5.4 years (range of 3.3 to 16). RESULTS: An equal percentage of patients were lost to followup in both groups, including 19% of the intracavernosal injection group and 18% of the penile prosthesis group. Of the intracavernosal injection patients 6 (6%) died during followup and 10 (19%) of the prosthetic patients died (p < 0.05). At the time of contact only 41% of the patients were still using intracavernosal injection. In contrast, 70% of the patients were still sexually active with the prosthesis (p < 0.01). Mean duration of use of the penile prosthetics was 63 months compared to 37 months for intracavernosal injection (p < 0.001). The most common reasons for discontinuing intracavernosal injection were inadequate erections (16 cases), lack of spontaneity (14), side effects (12), lack of partner (10), loss of sexual interest (6) and spontaneous return of normal erections (4). More than half of the patients (61%) who discontinued intracavernosal injection remain sexually active with other therapies, including penile prosthesis in 11, vacuum devices in 4, vascular surgery in 1 and oral medication in 1, and 14 without any therapy. We could not identify any significant clinical parameters that would accurately predict which patients most benefited by the long-term use of intracavernosal injection therapy. In contrast, only 6 patients discontinued use of the implant because of complications (infection, erosion and malfunction) and 7 for reasons independent of the implant (that is lack of partner, loss of sexual interest and co-morbidity). CONCLUSIONS: Intracavernosal injection serves as only a palliative therapy for the majority of patients with erectile dysfunction but there exists a core group who derives long-term satisfaction with its use. The majority of patients who discontinue intracavernosal injection remain sexually active yet do not progress to more invasive or effective therapies. The reason for discontinuing therapies for erectile dysfunction is often unrelated to the actual therapeutic modality. Our findings suggest that further improvements in intracavernosal injection therapy and the development of alternative methods of delivery of vasoactive agents will have only a limited impact on the overall outcome of therapy for erectile dysfunction and that increased attention to issues separate from the erection is warranted.

Diaphragm structure and function in health and disease.

The diaphragm is the primary muscle of inspiration, and as such uncompromised function is essential to support the ventilatory and gas exchange demands associated with physical activity. The normal healthy diaphragm may fatigue during intense exercise, and diaphragm function is compromised with aging and obesity. However, more insidiously, respiratory diseases such as emphysema mechanically disadvantage the diaphragm, sometimes leading to muscle failure and death. Based on metabolic considerations, recent evidence suggests that specific regions of the diaphragm may be or may become more susceptible to failure than others. This paper reviews the regional differences in mechanical and metabolic activity within the diaphragm and how such heterogeneities might influence diaphragm function in health and disease. Our objective is to address five principal areas: 1) Regional diaphragm structure and mechanics (GAF). 2) Regional differences in blood flow within the diaphragm (WLS). 3) Structural and functional interrelationships within the diaphragm microcirculation (DCP). 4) Nitric oxide and its vasoactive and contractile influences within the diaphragm (MBR). 5) Metabolic and contractile protein plasticity in the diaphragm (SKP). These topics have been incorporated into three discrete sections: Functional Anatomy and Morphology, Physiology, and Plasticity in Health and Disease. Where pertinent, limitations in our understanding of diaphragm function are addressed along with potential avenues for future research.

Is radiographic evaluation of the chest necessary following flank surgery?

PURPOSE: We determined whether routine postoperative chest radiography is warranted after flank surgery to assess for pneumothorax. MATERIALS AND METHODS: A retrospective study of 253 adult flank operations performed during a 6-year period was conducted. RESULTS: Incidental pleurotomy occurred in 63 cases (24.9%). The performance of rib resection and the level of rib removed as well as female gender had a significant impact on this occurrence. Pleurotomy was treated by a simple evacuation technique and tube thoracostomy was not necessary. Only 2 patients (0.8%) had a postoperative pneumothorax without intraoperative recognition of pleurotomy, which resolved without intervention. CONCLUSIONS: Routine postoperative chest radiography to assess for pneumothorax following open flank surgery is not necessary.

Immunity to hepatitis B, poliomyelitis and measles in fully vaccinated aboriginal and Torres Strait Island children.

OBJECTIVE: To determine the immunity to hepatitis B, poliomyelitis and measles in fully vaccinated Aboriginal and Torres Strait Island children in north Queensland. METHODOLOGY: A cross-sectional survey of immunity in a sample of children; 101 fully vaccinated Aboriginal and Torres Strait Island children, with a median age of 24.5 months, from 10 communities in North Queensland participated in this study. The main outcome measures were the prevalence of adequate antibody levels against hepatitis B, poliomyelitis and measles. RESULTS: Only 54% (95% CI 44-63%) of the children had adequate immunity (> or = 10 m iu/mL) to hepatitis B, and one child had been infected despite vaccination. Although all the children (95% CI 96-100%) had adequate immunity (i.e. neutralizing antibodies at a dilution of > or = 1:8) to poliovirus 2, only 93% (95% CI 86-96%) and 60% (95% CI 50-69%) had adequate immunity to polioviruses 1 and 3, respectively. Nearly all (96%; 95% CI 90-98%) of the children had adequate immunity (i.e. detectable IgG antibody) to measles. CONCLUSIONS: Although a relatively low proportion of the children had adequate antibody levels against hepatitis B the clinical significance of this observation is uncertain. Further studies are needed to determine whether fully vaccinated Torres Strait Island children have been adequately protected and whether they require a booster dose of hepatitis B vaccine. A substantial proportion of fully vaccinated Aboriginal and Torres Strait Island children are inadequately protected against poliomyelitis, and therefore any such child with acute flaccid paralysis should be investigated fully for poliomyelitis. Vaccinated Aboriginal and Torres Strait Island children are well protected against measles, as are other Australian children.

Costal diaphragm blood flow heterogeneity at rest and during exercise.

To gain insight into diaphragm functional heterogeneity, blood flow (expressed as ml.min-1 x 100 g-1) was measured using radiolabeled microspheres in the ventral, medial, and dorsal regions of the costal diaphragm and in the crural diaphragm of sedentary control (S) and exercise trained (ET) female Wistar-Kyoto rats at rest and during treadmill exercise. ET animals had performed moderate intensity exercise training on a motorized treadmill (22 m/min, 10% grade, 60 min/d) for 12 months, while S were cage-confined. The efficacy of exercise training was demonstrated by a 12% increase (P < 0.05) in ventricular weight-to-body weight ratio and increases (P < 0.05) in citrate synthase activity in hindlimb skeletal muscles of ET. At rest, blood flow in the ventral costal diaphragm (16 +/- 1) averaged approximately 61% of that in the medial (26 +/- 3) and dorsal (25 +/- 2) costal regions (P = 0.035), and crural diaphragm flow was 23 +/- 3. During treadmill exercise (5 min at 22 m/min, 10% incline), blood flow increased an average of 5-fold (P < 0.001) throughout the diaphragm, but the heterogeneous flow pattern persisted; i.e., blood flow remained lower (P = 0.003) in the ventral region (77 +/- 7) than either the medial (135 +/- 15) or dorsal (127 +/- 11) costal regions. Flow in the crural diaphragm during exercise was intermediate (105 +/- 9). Exercise training did not alter either the magnitude of blood flows or the flow distribution pattern within the diaphragm. Citrate synthase activity was two-fold that of the plantaris muscle and was uniform across the ventral, medial, and dorsal costal and the crural diaphragm of a second group of age-matched rats (P = 0.57). These data demonstrate that, although oxidative capacity is uniform throughout the diaphragm, there is a significant regional heterogeneity of blood flow within the rat diaphragm both at rest and during locomotory exercise. The greater flow in the medial and dorsal regions of the costal diaphragm suggests that these regions sustain a greater portion of the inspiratory work load at rest and during exercise compared to the ventral region.

Vascular adaptations in rat hindlimb skeletal muscle after voluntary running-wheel exercise.

To test the hypothesis that voluntary running-wheel exercise would elicit vascular adaptations in rat skeletal muscle, male Sprague-Dawley rats (202 +/- 5 g) were cage confined (C, n = 11) or housed in cages with free access to running wheels (R, n = 13) for 12 wk. Vascular transport capacity was determined in maximally vasodilated (papaverine) hindquarters of C and R rats with measurements of total and regional (radiolabeled microspheres) flow capacity and capillary filtration coefficient. R rats voluntarily ran 29 +/- 4 km/wk over the 12-wk period; however, performance of individual rats varied greatly (range 4-74 km/wk). Citrate synthase activity was increased in the medial head (81%, P < 0.001) and the red long head (88%, P < 0.001) of the triceps brachii muscle in R rats but not in the white long head (25%, P = 0.06). Capillary filtration coefficient was 27% greater in R compared with C rats (0.040 +/- 0.003 vs. 0.031 +/- 0.002 ml.min-1.100 g-1.mmHg-1, respectively, P < 0.001) suggesting that there was an increase in microvascular surface area available for fluid exchange. Total hindquarters flow was increased in R rats (P < 0.05) at all perfusion pressures examined, indicative of an increased flow capacity. Regional flows revealed that skin flow was unchanged in R rats and that the increase in total flow was due to increased skeletal muscle flow capacity. These results indicate that voluntary running-wheel exercise elicits adaptive increases in skeletal muscle vascular transport capacity and oxidative capacity comparable to those seen in treadmill-trained rats and support the use of voluntary running-wheel exercise as a less stressful training modality in exercise studies using rats.