Disparities in survival after trimodality therapy for esophageal adenocarcinoma.

Trimodality therapy with neoadjuvant chemoradiation followed by surgery has emerged as the standard of care for the treatment of locally advanced esophageal cancer. Yet, there is considerable variation in survival within this population. We sought to analyze factors associated with survival after trimodality therapy in esophageal adenocarcinoma. We identified 4,679 patients from the National Cancer Database (NCDB) of the American College of Surgeons who received chemotherapy and radiation prior to surgery for esophageal adenocarcinoma from 2006 to 2013. We excluded patients with stage IV disease and unknown pathological nodal status. We performed regression analyses using a Cox proportional hazards model to identify independent predictors of overall survival. On multivariate analysis, pathologic characteristics associated with decreased overall survival included stage, lymphovascular invasion, and positive surgical margins. Insurance status, age, and comorbidity index were also associated with decreased survival. We found that pathologically node-positive patients who received additional adjuvant chemotherapy were associated with improved survival. Compared to private insurance, Medicaid (HR 1.45, CI 1.22-1.73, P < 0.0001), Medicare (HR 1.17, CI 1.04-1.31, P = 0.0082), or having no insurance (HR 1.50, CI 1.17-1.92, P = 0.0012) were all negative predictors of overall survival. In patients with esophageal adenocarcinoma who have undergone trimodality therapy, a number of different factors are associated with overall survival. In particular, socioeconomic factors relating to access to care are independent predictors of survival. Despite receiving the standard of care, treatment disparities persist in this population of patients.

Prognostic significance of lymph node yield in ypN0 rectal cancer.

BACKGROUND: Neoadjuvant radiation therapy for locally advanced rectal adenocarcinoma decreases lymph node yield. This study investigated the association between survival and number of lymph nodes evaluated in patients with pathologically negative nodes after neoadjuvant therapy. METHODS: Patients with locally advanced rectal adenocarcinoma who underwent neoadjuvant therapy and had pathologically negative lymph nodes were included from the Surveillance, Epidemiology, and End Results (SEER) database over a 7-year interval (January 2004 to December 2010). Systematic dichotomization for optimal cut-off point identification was performed using statistical modelling. RESULTS: A total of 3995 patients met the inclusion criteria. The majority had T3 (66·7 per cent) and moderately differentiated (71·5 per cent) tumours. The median number of lymph nodes retrieved was 12 (i.q.r. 7-16). An optimal cut-off of nine lymph nodes was identified. Increasing age (P < 0·001), increasing T category (T4 versus T1, P < 0·001; T3 versus T1, P = 0·010), response to neoadjuvant therapy (P < 0·001) and number of nodes evaluated (P < 0·001) were significant factors for overall survival in univariable analysis. After adjustment in the multivariable model, the group with nine or more nodes examined had significantly better overall survival (hazard ratio (HR) 0·76, 95 per cent c.i. 0·65 to 0·88, P < 0·001; 5-year survival 83·2 versus 78·0 per cent) and cancer-specific survival (HR 0·76, 0·64 to 0·92, P = 0·004; 5-year survival 87·9 versus 85·1 per cent) than the group with one to eight nodes examined. CONCLUSION: Overall and cancer-specific survival were worse where fewer than nine lymph nodes were identified after neoadjuvant therapy for locally advanced rectal cancer.

Robotic-assisted laparoscopic radical cystoprostatectomy and extracorporeal continent urinary diversion: highlight of surgical techniques and outcomes.

BACKGROUND: We report our technique for robotic-assisted laparoscopic radical cystoprostatectomy (RARCP) and extracorporeal urinary diversion and present their clinical outcomes. METHODS: Between October 2003 and December 2008 we performed 58 RARCPs with extracorporeal continent urinary diversion. Preoperative, operative and postoperative data was evaluated. RESULTS: Mean patient age was 68 (range 46-89) years, with an average American Society of Anesthesiologists classification of 2.9. Mean operative time was 8 (range 5-11) h. Median blood loss was 450 ml. Thirteen patients received intra-operative blood transfusions and 22 patients received peri-operative blood transfusions. Continent urinary diversions were performed by means of the Studer technique (n = 42) or Indiana pouch (n = 16). Mean number of lymph nodes examined on lymphadenectomy was 27 (range 0-52). CONCLUSIONS: Our RARCP and continent diversion technique is a safe and feasible option for primary urothelial carcinoma of the bladder. Oncological and surgical outcomes are comparable to open cystectomy series.

Dose-response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys.

BACKGROUND AND PURPOSE: The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. EXPERIMENTAL APPROACH: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. KEY RESULTS: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. CONCLUSIONS AND IMPLICATIONS: The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.

Human islet oxygen consumption rate and DNA measurements predict diabetes reversal in nude mice.

There is a need for simple, quantitative and prospective assays for islet quality assessment that are predictive of islet transplantation outcome. The current state-of-the-art athymic nude mouse bioassay is costly, technically challenging and retrospective. In this study, we report on the ability of 2 parameters characterizing human islet quality: (1) oxygen consumption rate (OCR), a measure of viable volume; and (2) OCR/DNA, a measure of fractional viability, to predict diabetes reversal in nude mice. Results demonstrate that the probability for diabetes reversal increases as the graft's OCR/DNA and total OCR increase. For a given transplanted OCR dose, diabetes reversal is strongly dependent on OCR/DNA. The OCR and OCR/DNA (the 'OCR test') data exhibit 89% sensitivity and 77% specificity in predicting diabetes reversal in nude mice (n = 86). We conclude that the prospective OCR test can effectively replace the retrospective athymic nude mouse bioassay in assessing human islet quality prior to islet transplantation.

Surgical vs wire-guided cricothyroidotomy: a randomised crossover study of cuffed and uncuffed tracheal tube insertion.

Using an airway mannequin and artificial lung model, we compared surgical cricothyroidotomy with a 6.0-mm cuffed Portex tracheostomy tube with wire-guided cricothyroidotomy using a 5.0-mm cuffed Melker or 6.0-mm uncuffed Melker tube. The trial was carried out by 27 anaesthetists using a randomised, crossover design. Surgical cricothyroidotomy proved significantly faster (mean (SD) time to first breath 44.3 (12.5) s for Portex surgical, 87.2 (21.6) s for cuffed Melker, 87.8 (19.2) s for uncuffed Melker, p < 0.001). With a standardised ventilator model, the cuffed tubes provided more effective ventilation (mean (SD) tidal volume 446 (41) ml Portex, 436 (52) ml cuffed Melker, 19 (5) ml uncuffed Melker, p < 0.001). Fourteen of the participants preferred the wire-guided system. We conclude that, in this model, a cuffed device is preferable when cricothyroidotomy is needed. In addition, the surgical method is quicker than a wire-guided approach.

Immunoglobulin therapy in non-menstrual streptococcal toxic shock syndrome.

We describe a case of non-menstrual streptococcal toxic shock syndrome requiring high doses of noradrenaline. The intravenous administration of pooled immunoglobulin was associated with improved haemodynamics and weaning of vasoconstrictors.

Surgical palliation at a cancer center: incidence and outcomes.

HYPOTHESIS: Surgical intervention in palliative care is common; however, the indications, risks, and outcomes are not well described. DESIGN: Retrospective review of surgical cases during a 1-year period with a minimum 1-year survival update. SETTING: A National Cancer Institute-designated comprehensive cancer center. PATIENTS: Patients with a cancer diagnosis undergoing operative procedures. MAIN OUTCOME MEASURES: Number of palliative surgeries and analysis of length of stay, morbidity, and mortality. RESULTS: Palliative surgeries comprised 240 (12.5%) of 1915 surgical procedures. There were 170 major and 70 minor procedures. Neurosurgical (46.0%), orthopedic (31.3%), and thoracic (21.5%) surgical procedures were frequently palliative. The most common primary diagnoses were lung, colorectal, breast, and prostate cancers. Length of hospital stay was 12.4 days (range, 0-99 days), with 21.3% of procedures performed on an outpatient basis. The 30-day mortality was 12.2%, with 5 patients dying within 5 days of their procedure. The overall mortality was 23.3% (56/240). Mortality for surgical procedures classified as major was 21.9% (44/170) and 10.0% (7/70) for those classified as minor (Fisher exact test, P<.01). CONCLUSIONS: Significant numbers of palliative procedures are performed at our cancer center. Overall morbidity and mortality were high; however, a significant number of patients had short hospital stays and low morbidity. Palliative surgery should remain an important part of end-of-life care. Patients and their families must be aware of the high risks and understand the clear objectives of these procedures.

Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716.

BACKGROUND: SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. METHODS: Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration. RESULTS: Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all subjects. CONCLUSIONS: SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.

Reproductive factors and risk of intermediate- or high-grade B-Cell non-Hodgkin's lymphoma in women.

PURPOSE: The incidence rates of non-Hodgkin's lymphoma (NHL) unrelated to human immunodeficiency virus infection are lower for women than for men; yet, few factors have been identified that may account for this difference in risk. NHL is difficult to study epidemiologically because this disorder represents a group of malignancies that differ in terms of morphologic presentation, immunologic features, genetic characteristics, prognosis, and etiology. PATIENTS AND METHODS: We conducted a population-based case-control study in women to determine whether reproductive factors or hormonal exposures might be related to the risk of high- or intermediate-grade B-cell NHL. We interviewed 177 female residents of Los Angeles County who were diagnosed with high- or intermediate-grade B-cell NHL between 1989 and 1992; each case patient was individually matched on age and race to a control subject who lived in her neighborhood. RESULTS: Women who had used oral contraceptives had significantly lower risk of intermediate- or high-grade NHL (multivariate odds ratio [OR] = 0.47; 95% confidence interval [CI], 0.26 to 0.86) than women who had never used these compounds. Among parous women, those who had used lactation suppressants (which contain high levels of estrogen) had significantly lower risk of NHL (multivariate OR = 0.50; 95% CI, 0.29 to 0.85) than unexposed women. Postmenopausal women had a somewhat greater risk of NHL than premenopausal women, whereas those postmenopausal women who had used hormone replacement therapy (HRT) (primarily estrogen) had somewhat lower risk than those who had not used HRT. CONCLUSION: Exogenous estrogens seem to have a protective effect on the risk of high- and intermediate-grade B-cell NHL. Although the mechanisms for such protection are not known, alterations in immune reactivity, cytokine expression, or B-cell modulation may play a role.

Testicular recrudescence in the male black bear (Ursus americanus): changes in testicular luteinizing hormone-, follicle-stimulating hormone-, and prolactin-receptor ribonucleic acid abundance and dependency on prolactin.

Testicular recrudescence in male black bears (Ursus americanus) is initiated in January and completed in May. The goals of this study in the black bear were to determine 1) if testicular abundance of LH-receptor (LHr), FSH-receptor (FSHr), and prolactin-receptor (PRLr) mRNA changes during recrudescence; 2) if these changes in mRNA abundance are associated with changes in serum LH, PRL, and testosterone (T) concentrations; and 3) if the spring increase in serum PRL concentrations is required for testicular recrudescence. Serum was obtained monthly from nine male bears for 2 yr, except in July and August. To suppress endogenous PRL, four bears were treated with Parlodel LAR, 50 mg per 70 kg body weight, monthly from January through May, whereas five bears served as controls. Testicular biopsies were obtained in January, March, and May and analyzed for LHr, FSHr, and PRLr mRNA abundance using reverse transcriptase-competitive polymerase chain reaction. The LHr and PRLr mRNA abundance was low in January, increased in March, and remained high in May, whereas the FSHr mRNA abundance remained constant. Serum concentrations of PRL and T increased in March, coincident with the increase in testicular LHr and PRLr mRNA abundance. Suppression of serum PRL concentrations during testicular recrudescence 1) prevented the increase in testicular LHr and PRLr mRNA abundance observed among control bears in March, 2) lowered serum T concentrations in March and April, and 3) resulted in reduced testis size in May. We conclude that testicular LHr and PRLr mRNA are seasonally regulated, and that PRL has a role in testicular recrudescence in the black bear.

Evidence for vasoconstriction mediated by the endothelin-B receptor in domestic swine.

Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in a number of cardiovascular diseases, including congestive heart failure, neointimal hyperplasia associated with restenosis, and hypertension. The vasoconstriction induced by ET-1 is thought to be mediated mainly by its action on ET(A) receptors on vascular smooth muscle cells. Recent studies have indicated that vasoconstriction also may be mediated by stimulation of an ET(B)-receptor subtype. Increased use of the pig as a cardiovascular model prompted us to examine the receptor profile in this species using ABT-627, a potent, nonpeptide antagonist of the ET(A) receptor. The precursor to ET-1, big ET-1 (0.02 nmol/kg/min), was infused intravenously in domestic swine, resulting in a sustained increase in mean blood pressure of 38 +/- 3 mm Hg. After stabilization of the pressor response, ABT-627 (0.1-10 microg/kg/min) or vehicle was infused for 30 min. Whereas vehicle infusion had no appreciable effect, a dose-related reversal of the pressor response to big ET-1 (11-100%) was observed by the end of the ABT-627 infusion. Blood samples were assayed for plasma concentrations of ABT-627; peak levels ranged from 9 +/- 2 to 937 +/- 168 ng/ml. In a separate group of pigs, the highest dose of ABT-627 produced only a modest reversal of the hypertensive response to an infusion of angiotensin II (300 ng/kg/min). Additional results indicate that the vasoconstrictor effects produced by sarafotoxin 6C (0.03 and 0.3 nmol/kg), an agonist of the ET(B) receptor, are not blocked by treatment with ABT-627 (10 microg/kg/min). However, complete blockade of the S6C response could be achieved using the ET(B) antagonist, A-192621 (0.33 mg/kg/min). Our results define the dose-response relation for the ET(A)-receptor antagonist ABT-627 in the vasculature of the domestic pig and suggest the presence of an ET(B)-receptor subtype that mediates vasoconstriction in this species.

Managing the complexities of group practice. An interview with ACMPE president Robert Nelson.

Robert A. Nelson, FACMPE, the new president of the American College of Medical Practice Executives (ACMPE) and a principal with the Canon Group, Santa Barbara, Calif., took time to share his vision of the ACMPE and the state of group practice with the MGM Journal. A past president of MGMA. Nelson was honored in 1999 with the ACMPE's Harry J. Harwick Award--the College's highest recognition for health care executives.

Prognostic factors for hearing preservation in vestibular schwannoma surgery.

OBJECTIVE: To determine whether prognostic indicators for hearing preservation could be identified in patients with vestibular schwannoma undergoing middle fossa craniotomy resection. STUDY DESIGN: Prospective case review. SETTING: Private practice tertiary referral center. PATIENTS: 333 patients with serviceable hearing and vestibular schwannoma resected by middle fossa craniotomy from 1992 to 1998. MAIN OUTCOME MEASURES: Potential prognostic indicators, including tumor size and nerve of origin, preoperative pure-tone average, speech discrimination, distortion product otoacoustic emission testing, age, auditory brainstem response (ABR), and electronystagmography. RESULTS: Postoperative hearing near preoperative levels was attained in 167 patients (50%), with an American Academy of Otolaryngology-Head and Neck Surgery Class A hearing result in 33% and a Class B result in 26%. Comparison of potential prognostic indicators between groups with hearing preserved and the group with no measurable hearing revealed significant differences in preoperative hearing, ABR, and tumor origin data. Better preoperative hearing, shorter intraaural wave V latency, shorter absolute wave V latency, and superior vestibular nerve origin were associated with higher rates of hearing preservation. CONCLUSIONS: Preoperative hearing status, ABR, and intraoperative tumor origin data were shown to be of value as prognostic indicators.

Use of infrared thermographic calorimetry to determine energy expenditure in preterm infants.

BACKGROUND: Measurement of infant energy expenditure in the clinical setting is difficult and is rarely done. Both indirect and direct calorimetry require long measurement periods and frequent calibration. OBJECTIVE: The objective of this study was to validate in infants a newly developed method of determining energy expenditure, infrared thermographic calorimetry (ITC), against an established method, respiratory indirect calorimetry (IC). ITC measures mean infant body surface temperature. ITC was used in conjunction with heat loss theory to calculate radiant, convective, evaporative, and conductive heat losses and thereby determine total energy expenditure. DESIGN: Ten healthy preterm infants were studied by obtaining concurrent ITC and IC measurements over a 3.5-5.5-h study period. Continuous IC measurements were compared with ITC measurements taken every 10 min during study periods. IC values were summed over 10-min intervals covering the 5 min before and 5 min after each ITC measurement, to allow comparisons between the 2 methods. RESULTS: Comparison of paired ITC and IC mean measurements for all 10 infants over the entire study period showed no significant difference between the 2 methods. However, individual paired IC and ITC values were significantly different for 7 of 10 infants. The overall mean difference between the 2 methods was 1.3%. CONCLUSIONS: ITC is an accurate, noninvasive method for measurement of heat loss and energy expenditure in healthy preterm infants, and therefore it may be a useful clinical and research tool.

The HRAS1 minisatellite locus and risk of ovarian cancer.

Approximately 10% of ovarian cancers are due to mutations in highly penetrant inherited cancer susceptibility genes. The highly polymorphic HRAS1 minisatellite locus, located just downstream from the proto-oncogene H-ras-1 on chromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for cancers of the breast, colorectum, and bladder, and it was found that BRCAI mutation carriers with at least one rare HRAS1 allele have a greater risk of ovarian cancer than BRCA1 carriers with only common HRAS1 alleles. There are no conclusive studies of HRAS1 alleles in sporadic epithelial ovarian cancer. A case-control study of HRAS1 alleles was performed on DNA from 136 Caucasian patients with ovarian cancer and 108 cancer-free controls using conventional (Southern blot) and PCR-based methods to determine the frequency of rare HRAS1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression methods. A single degree of freedom test was used to assess the significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRAS1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated with a relative risk of 1.66 (95% CI, 0.91-3.01), whereas having two rare alleles increased the relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRAS1 allele types by the age of the case at diagnosis revealed that younger cases (<45 years) had a borderline statistically significant increased association with rare HRAS1 alleles compared to older cases (> or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRAS1 alleles contribute to ovarian cancer predisposition in the general population. Thus, the HRAS1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in both sporadic and hereditary ovarian cancer.

Effect of recombinant human erythropoietin combined with granulocyte/ macrophage colony-stimulating factor in the treatment of patients with myelodysplastic syndrome. GM/EPO MDS Study Group.

This randomized, placebo-controlled trial was designed to assess the efficacy and safety of therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (epoetin alfa) in anemic, neutropenic patients with myelodysplastic syndrome. Sixty-six patients were enrolled according to the following French-American-British classification: refractory anemia (20), refractory anemia with excess blasts (35), refractory anemia with ringed sideroblasts (9), and refractory anemia with excess blasts in transformation (2). Patients were stratified by their serum erythropoietin levels (less than or equal to 500 mU/mL, n = 37; greater than 500 mU/mL, n = 29) and randomized, in a 2:1 ratio, to either GM-CSF (0.3-5.0 microg/kg.d) + epoetin alfa (150 IU/kg 3 times/wk) or GM-CSF (0.3-5.0 microg/kg.d) + placebo (3 times/wk). The mean neutrophil count rose from 948 to 3831 during treatment with GM-CSF +/- epoetin alfa. Hemoglobin response (increase greater than or equal to 2 g/dL, unrelated to transfusion) occurred in 4 of 45 (9%) patients in the GM-CSF + epoetin alfa group compared with 1 of 21 (5%) patients with GM-CSF + placebo group (P = NS). Percentages of patients in the epoetin alfa and the placebo groups requiring transfusions of red blood cells were 60% and 92%, respectively, for the low-endogenous erythropoietin patients and 95% and 89% for the high-endogenous erythropoietin patients (P = NS). Similarly, the average numbers of units of red blood cells transfused during the 12-week study in the epoetin alfa and the placebo groups were 5.9 and 9.5, respectively, in the low-endogenous erythropoietin patients and 9.7 and 8.6 in the high-endogenous erythropoietin patients (P = NS). GM-CSF +/- epoetin alfa had no effect on mean platelet count. Treatment was well tolerated in most patients, though 10 withdrew from the study for reasons related predominantly to GM-CSF toxicity. (Blood. 2000;95:1175-1179)

Cloning and sequence analysis of the extracellular region of the polar bear (Ursus maritimus) luteinizing hormone receptor (LHr), follicle stimulating hormone receptor (FSHr), and prolactin receptor (PRLr) genes and their expression in the testis of the black bear (Ursus americanus).

Male black bears undergo seasonal changes in testicular activity. The testes are fully functional from May through July, regress from July through December, and recrudesce from January until May. The mechanisms responsible for the initiation of testicular recrudescence in the bear are unknown. The objectives of this study were to: (1) clone and sequence a substantial fragment of the extracellular portion of the luteinizing hormone receptor (LHr: 646 bp) and follicle stimulating hormone receptor (FSHr: 852 bp), and the extracellular/transmembrane portion of the prolactin receptor (PRLr: 680 bp) in the bear using reverse transcription-polymerase chain reaction (RT-PCR); and (2) determine whether the expression of LH-, FSH-, and PRL-receptor mRNA transcripts differs between the beginning and terminal stages of testicular recrudescence. Comparisons of the partial cDNA and predicted amino acid sequences of ursine receptors with the corresponding sequences from the pig, cow, human, and rat suggest that the LHr and FSHr are highly conserved (LHr: 87.1-93.7%; FSHr: 86.0-92.7%) whereas the PRLr is less well conserved (81-87%). Testicular LHr mRNA was more abundant during the breeding season in May than during the non-breeding season (early stage of recrudescence) in January. In contrast, testicular FSHr mRNA abundance was greater in January than in May. Testicular PRLr mRNA appeared equally abundant in January and May; however, two additional transcripts were present during the breeding season in May. This study provides molecular tools for future investigations of the control of testicular recrudescence in the black bear and demonstrates that the expression of testicular gonadotropin and PRL receptor mRNA is seasonally regulated. Mol. Reprod. Dev. 55:136-145, 2000.

Profile of recombinant pro-urokinase given by intraarterial versus intravenous routes of administration in a canine thrombosis model.

Catheter-directed thrombolysis has gained increasing acceptance for the treatment of patients who present with vascular occlusion; however, intravenous injection may be preferable in selected patients. Recombinant prourokinase (r-proUK) is a recently-developed fibrin-selective thrombolytic agent with specificity for clot-bound plasminogen. To compare the effects of r-proUK on clot lysis and restoration of blood flow when injected by either intraarterial or intravenous routes of administration, we utilized a dog model of arterial thrombosis in which a radiolabelled clot is formed in the femoral artery. The r-proUK was given by intravenous infusion to one group of 18 animals in doses ranging from 10,000 IU/kg to 100,000 IU/kg; a second group of 27 dogs was treated with r-proUK administered by the intra-arterial route in a dose range from 300 IU to 10,000 IU. Clot lysis was measured by monitoring the loss of counts from the radiolabelled clot over time; blood flow was also monitored throughout the experimental period. Animals which received intravenous treatment showed dose-related clot lysis ranging from 14% to 70% at 2 h, while those which received intra-arterial infusions showed lysis ranging from 22% to 79% over the same period. For similar degrees of clot lysis attained at the highest dose levels of 100,000 IU/kg and 10,000 IU, blood flow was restored to 77% and 35% of control levels in dogs which received intravenous and intraarterial treatment, respectively. The hemostatic protein fibrinogen was not reduced in any of the treatment groups. The results indicate that 100 times more intravenous than intra-arterial r-proUK is required to produce similar clot lysis in this canine model, and that the agent can be administered at this level without induction of a systemic lytic state.