Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases.

BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

A diagnosis of prostate cancer and pursuit of active surveillance is not followed by weight loss: potential for a teachable moment.

BACKGROUND: Obesity is a risk factor for incident prostate cancer (PC) as well as risk of disease progression and mortality. We hypothesized that men diagnosed with lower-risk PC and who elected active surveillance (AS) for their cancer management would likely initiate lifestyle changes that lead to weight loss. METHODS: Patients were enrolled in the Prostate Active Surveillance Study (PASS), a multicenter prospective biomarker discovery and validation study of men who have chosen AS for their PC. Data from 442 men diagnosed with PC within 1 year of study entry who completed a standard of care 12-month follow-up visit were analyzed. We examined the change in weight and body mass index (BMI) over the first year of study participation. RESULTS: After 1 year on AS, 7.5% (33/442) of patients had lost 5% or more of their on-study weight. The proportion of men who lost 5% or more weight was similar across categories of baseline BMI: normal/underweight (8%), overweight (6%) and obese (10%, χ2 test P=0.44). The results were similar for patients enrolled in the study 1 year or 6 months after diagnosis. By contrast, after 1 year, 7.7% (34/442) of patients had gained >5% of their weight. CONCLUSIONS: Only 7.5% of men with low-risk PC enrolled in AS lost a modest (⩾5%) amount of weight after diagnosis. Given that obesity is related to PC progression and mortality, targeted lifestyle interventions may be effective at this 'teachable moment', as men begin AS for low-risk PC.

Aspirin and NSAID use in association with molecular subtypes of prostate cancer defined by TMPRSS2:ERG fusion status.

BACKGROUND: The TMPRSS2:ERG (T2E) gene fusion is the most common rearrangement in prostate cancer (PCa). It is unknown if these molecular subtypes have a different etiology. We evaluated aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in association with T2E fusion status. METHODS: Subjects were from a population-based case-control study of PCa. T2E fusion status for prostatectomy cases (n=346) was determined by fluorescence in situ hybridization. Medication use was determined from questionnaires. Logistic regression, controlling for age, race, PCa family history and PSA screening, was used to evaluate the association of T2E fusion status according to medication use. RESULTS: T2E fusion was present in 171 (49%) cases, with younger cases more likely to be fusion positive (P<0.01). Current aspirin use was associated with a 37% risk reduction of T2E-positive tumors (adjusted odds ratio (OR) 0.63, 95% confidence interval 0.43-0.93). Aspirin use was not associated with T2E negative PCa (adjusted OR 0.99, 0.69-1.42). There were no associations between PCa fusion status and use of nonaspirin NSAIDs or acetaminophen. CONCLUSIONS: Aspirin was associated with a significant reduction in the relative risk of T2E fusion positive, but not T2E negative, PCa. As inflammation and androgen pathways are implicated in prostate carcinogenesis, additional studies of anti-inflammatory medications in relation to these PCa subtypes are warranted.

Metabolic syndrome, dyslipidemia and prostate cancer recurrence after primary surgery or radiation in a veterans cohort.

BACKGROUND: Metabolic syndrome (MetS) has been hypothesized to be associated with cancer, including prostate cancer (PCa), but the relationship is not well characterized. We analyze the relationship between MetS features and localized PCa recurrence after treatment. METHODS: Men having primary treatment for localized PCa were included from a multi-site regional veteran network. Recurrence was defined as nadir PSA +2 ng ml(-1) (radiation) or PSA⩾0.2 ng ml(-1) (prostatectomy). MetS was based on consensus professional society guidelines from the American Heart Association and International Diabetes Federation (three of: hypertension >130/85 mm Hg, fasting blood glucose ⩾100 mg dl(-1), waist circumference >102 cm, high-density lipoprotein <40 mg dl(-1), triglycerides ⩾150 mg dl(-1)). Closely related abnormality in low-density lipoprotein (LDL; >130 mg dl(-1)) was also examined. Analysis of PCa recurrence risk included multivariable Cox proportional hazards regression with propensity adjustment. RESULTS: Of the 1706 eligible men, 279 experienced recurrence over a median follow-up period of 41 months (range 1-120 months). Adjustment variables associated with PCa recurrence included: index PSA, Gleason, and tumor stage. Independent variables of interest associated with PCa recurrence were hyperglycemia and elevated LDL. Elevated LDL was associated with PCa recurrence (multivariable hazard ratio (HR) 1.34, 95% confidence interval (CI) 1.03, 1.74; propensity adjusted HR 1.33, 95% CI 1.03, 1.72). There was also an association between impaired fasting glucose and PCa recurrence in (multivariable HR 1.54, 95% CI 1.10, 2.15; propensity adjusted HR 1.41, 95% CI 1.01, 1.95). MetS was not associated with PCa recurrence (multivariable: HR 0.96, 95% CI 0.61, 1.50; propensity adjusted HR 1.04, 95% CI 0.67, 1.62). CONCLUSIONS: PCa recurrence is not associated with MetS but is associated with elevated LDL and impaired fasting glucose. If confirmed, these data may help provide modifiable targets in preventing recurrence of PCa.

Hyperglycemia and prostate cancer recurrence in men treated for localized prostate cancer.

BACKGROUND: Obesity is consistently linked with prostate cancer (PCa) recurrence and mortality, though the mechanism is unknown. Impaired glucose regulation, which is common among obese individuals, has been hypothesized as a potential mechanism for PCa tumor growth. In this study, we explore the relationship between serum glucose at time of treatment and risk of PCa recurrence following initial therapy. METHODS: The study group comprised 1734 men treated with radical prostatectomy (RP) or radiation therapy (RT) for localized PCa between 2001-2010. Serum glucose levels closest to date of diagnosis were determined. PCa recurrence was determined based on PSA progression (nadir PSA+2 for RT; PSA≥0.2 for RP) or secondary therapy. Multivariate Cox regression was performed to determine whether glucose level was associated with biochemical recurrence after adjusting for age, race, body mass index, comorbidity, diagnosis of diabetes, Gleason Sum, PSA, treatment and treatment year. RESULTS: Recurrence was identified in 16% of men over a mean follow-up period of 41 months (range 1-121 months). Those with elevated glucose (≥100 mg/dl) had a 50% increased risk of recurrence (HR 1.5, 95% CI: 1.1-2.0) compared with those with a normal glucose level (<100 mg/dl). This effect was seen in both those undergoing RP (HR 1.9, 95% CI: 1.0-3.6) and those treated with RT (HR 1.4, 95% CI: 1.0-2.0). CONCLUSIONS: Glucose levels at the time of PCa diagnosis are an independent predictor of PCa recurrence for men undergoing treatment for localized disease.

Pulmonary hypertension and vascular oxidative damage in cigarette smoke exposed eNOS(-/-) mice and human smokers.

CONTEXT: Cigarette smoke is known to be associated with pulmonary hypertension in humans and in animal models. Although the etiology of pulmonary hypertension in smokers is not understood, recent work has suggested a role for inducible nitric oxide synthase (iNOS) in inducing oxidative stress. OBJECTIVE AND METHODS: To further evaluate this question, we assessed eNOS-/- mice exposed to air or cigarette smoke for the presence of pulmonary hypertension and examined vascular remodeling and expression of nitrotyrosine, a marker of reactive nitrogen species-induced oxidative damage, using immunohistochemistry. To ascertain whether oxidants may play a role in humans, we also examined lung tissue from nonsmokers, and patients with chronic obstructive pulmonary disease (COPD) with and without pulmonary hypertension. RESULTS: We found that eNOS(-/-) mice developed increased pulmonary arterial pressure after six months cigarette smoke exposure, and this was associated with vascular remodeling and increased vascular nitrotyrosine staining. iNOS gene expression was decreased in the pulmonary arteries of the smoke exposed animals, and no protein was detectable by immunohistochemistry. In humans, vascular nitrotyrosine staining intensity was increased in smokers with COPD compared to nonsmokers, and further increased in smokers with combined COPD and pulmonary hypertension. CONCLUSIONS: We conclude that cigarette smoke-induced pulmonary hypertension is associated with evidence of oxidative vascular damage by reactive nitrogen species, but that iNOS does not appear to be the major contributor to such damage. Most likely the source of reactive nitrogen species is the cigarette smoke itself.

Series "matrix metalloproteinases in lung health and disease": Matrix metalloproteinases in COPD.

There is considerable evidence that matrix metalloproteinases (MMPs) are up- and/or downregulated in chronic obstructive pulmonary disease (COPD), particularly in emphysema, in which they probably participate in proteolytic attack on the alveolar wall matrix. Recent data suggest that MMPs also have major roles in driving inflammation or shutting it down, as well as modifying the release of fibrogenic growth factors, processes that are important in the genesis of the various lesions of COPD. In cigarette smoke-induced animal models of emphysema, MMP-12 appears to play a consistent and important role, whereas the data for other MMPs are difficult to interpret. In human lungs, evidence for a role for MMPs is more tenuous and there are numerous contradictions in the literature. Little is known about the effects of MMPs in small airway remodelling, smoke-induced pulmonary hypertension and chronic bronchitis, but MMP-12 participates in experimental small airway modelling. To date, the accumulated data suggest that selective inhibition of MMP-12 might be a viable therapy for emphysema and small airway remodelling, but subtle differences in the functions of MMP-12 in animals and humans mandate caution with this approach. Whether inhibition of other MMPs might be useful is unclear.

Racial disparity in estrogen receptor positive breast cancer patients receiving trimodality therapy.

INTRODUCTION: We assessed racial differences in progression-free survival (PFS) and overall survival (OS) in relation to subtype in uniformly treated stage II-III breast cancer patients. METHODS: We reviewed records of 582 patients receiving post-mastectomy radiation (PMRT) between 1/1999 and 12/2009 and evaluated the effect of demographic, tumor, and treatment characteristics on PFS and OS. RESULTS: Median follow up was 44.7 months. 24% of patients were black and 76% white. All had mastectomy and PMRT; 98% had chemotherapy; Estrogen receptor (ER)+ patients received endocrine therapy. Black patients were more likely to have ER- (56% vs. 38%, p=0.0001), progesterone receptor (PR)- (69% vs. 54%, p = 0.002), and triple negative (TN) (46% vs. 24%, p < 0.0001) tumors. Overall, black patients had worse PFS (60.6% vs. 78.3%, p = 0.001) and OS (72.8% vs. 87.7%, p < 0.0001). There was no racial difference in PFS (p = 0.229 and 0.273 respectively) or OS (p = 0.113 and 0.097 respectively) among ER- or TN. Among ER+, black patients had worse PFS (55% vs. 81%, p < 0.001) and OS (73% vs. 91%, p < 0.0001). The difference in PFS was seen in the ER+/PR+/HER2- subgroup (p = 0.002) but not ER+/PR-/HER2- (p = 0.129), and in the post-menopausal ER+/HER2- subgroup (p = 0.004) but not pre/peri-menopausal ER+/HER2- (p = 0.150). CONCLUSIONS: Black women had worse survival outcomes in this cohort. This disparity was driven by (1) a higher proportion of ER- and TN tumors in black women and (2) worse outcome of similarly treated black women with ER+ breast cancer. The underlying causes of racial disparity within hormone receptor categories must be further examined.

Investigation of intrathecal transport of NPT002, a prospective therapeutic based on phage M13, in nonhuman primates.

Presently, there are no effective treatments for conditions characterized by protein misfolding, such as Alzheimer's, Parkinson's, and other diseases involving CNS. Since misfolding occurs at the earliest stage of the disease, it is likely to be involved in subsequent pathological developments. It has been found that NPT002 (bacteriophage M13) directly dissociates aggregates of misfolded proteins that form amyloid, including amyloid-ß, tau and α-synuclein. For CNS applications, NPT002 requires delivery to the brain parenchyma, the target tissue. NPT002 is an elongated ~950 nm particle that cannot penetrate into the brain from the blood. Furthermore, phage particles, due to their size, cannot be effectively transported in vivo by diffusion. Considering the physiology of the leptomeningeal space, intrathecal administration appears to be a promising convection-driven avenue for NPT002 delivery. In this paper, we use positron emission tomography to investigate the transport of NPT002 in Macaca fascicularis. The data suggest that approximately 50 % of the administered dose can reach the cerebral leptomeningeal space after a single lumbar intrathecal injection. A biologically significant fraction of the phage then enters the brain, resulting in potentially therapeutic cortical and subcortical exposure.

AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase.

N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1ß. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases.

Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation.

We assessed differences in locoregional outcome based on receptor status combinations in a cohort of stage II-III breast cancer patients treated with modern trimodality therapy. Medical records of 582 consecutively treated patients receiving post-mastectomy radiation (PMRT) between 1/1999 and 12/2009 were reviewed. Rate of local regional recurrence (LRR) was estimated by the method of cumulative incidence allowing for competing risks. The effect of prognostic factors was examined by Gray's test and by Fine and Gray's modeling approach. Median follow-up was 44.7 months. Five-year progression-free survival (PFS) was 73.9% and overall survival (OS) was 84%. The cumulative 5-year incidence of LRR as first site of failure was 6.2% (95% CI 4.2-8.7). Five-year cumulative incidence of LRR was 8.6 versus 4.4% for estrogen receptor (ER) negative versus ER positive (P = 0.017), 8.5 versus 3.4% for progesterone receptor (PR) negative versus PR positive (P = 0.011), and 1.7 versus 7.5% for HER2 positive (86% received trastuzamab) versus HER2 negative (P = 0.032). Five-year cumulative incidence of LRR was 11.8% for the triple negative subtype and 3.9% for other receptor combinations (P < 0.001). Among patients whose disease is ER positive, 5-year LRR rate was 7.8 versus 3.4% for PR negative versus PR positive (P = 0.130). The prognostic value of the triple negative and HER2 negative subtypes was maintained on multivariate analysis. In the era of HER-2 targeted therapy, tumors that are HER-2 over expressing and are treated with trastuzumab have a very low rate of LRR. ER negative, PR negative, and triple negative status are associated with increased risk of LRR.

Randomized clinical trial of long-acting oxytetracycline, foot trimming, and flunixine meglumine on time to recovery in sheep with footrot.

BACKGROUND: Internationally, foot trimming is used by most farmers, and parenteral antibacterials by some, to treat sheep with footrot. Nonsteroidal anti-inflammatory drugs (NSAID) are sometimes used. No clinical trials have compared these treatments. OBJECTIVES: To investigate the above treatments on time to recovery from lameness and foot lesions in sheep with footrot. ANIMALS: Fifty-three sheep with footrot on a commercial farm in England. METHODS: In a randomized factorial design, the sheep were allocated to 6 treatment groups. The treatments were oxytetracycline spray to all sheep (positive control) and one or more of parenteral administration of long-acting oxytetracycline, flunixine meglumine, and foot trimming on day 1 or 6 of diagnosis. Follow-up was for 15 days. Time to recovery from lameness and lesions was investigated with discrete-time survival models. RESULTS: There was significant association (P < .05) between recovery from lameness and lesions. Sheep receiving antibacterials parenterally recovered faster from lameness (odds ratio [OR]: 4.92 [1.20-20.10]) and lesions (OR: 5.11 [1.16-22.4]) than positive controls, whereas sheep foot trimmed on day 1 (lameness-OR: 0.05 [0.005-0.51]; lesions-OR: 0.06 [0.008-0.45]) or day 6 of diagnosis (lameness OR: 0.07 [0.01-0.72]; lesions OR: 0.07 [0.01-04).56]) recovered more slowly than positive controls. NSAID had no significant effect on recovery. CONCLUSIONS AND CLINICAL IMPORTANCE: If foot trimming on day 1 or 6 of diagnosis was stopped and parenteral antibacterials were used, then over 1 million sheep/annum lame with footrot in the United Kingdom would recover more rapidly with benefits to productivity. Globally, this figure would be much higher.

Risk factors for increased rates of sole ulcers, white line disease, and digital dermatitis in dairy cattle from twenty-seven farms in England and Wales.

Claw lesion treatment records were recorded by farmers on 27 dairy farms (3,074 cows, 36,432 records) in England and Wales between February 2003 and February 2004. These were combined with farm environment and management data collected using a combination of direct observations, interviews with farmers, and milk recording data. Multilevel models were constructed for the 3 most frequently reported lesions related to lameness, namely, sole ulcers, white line disease, and digital dermatitis. Risks associated with an increased incidence of sole ulcers were parity 4 or greater, the use of roads or concrete cow tracks between the parlor and grazing, the use of lime on free stalls, and housing in free stalls with sparse bedding for 4 mo or more. The risks for white line disease were increasing parity and increasing herd size, cows at pasture by day and housed at night, and solid grooved concrete floors in yards or alleys. Solid grooved flooring was also associated with an increased risk of digital dermatitis, and cows 6 or more months after calving had a decreased risk of a first case of digital dermatitis. These results improve our understanding of the specific risks for 3 important lesions associated with bovine lameness and could be used as interventions in future clinical studies targeted at the reduction of specific lesions.

Short-term exposure to cigarette smoke induces endothelial dysfunction in small intrapulmonary arteries: analysis using guinea pig precision cut lung slices.

The pathogenesis of cigarette smoke-induced pulmonary hypertension is not understood. We have previously shown that smoke rapidly and persistently, but discoordinately, upregulates gene expression of mediators that control vasoconstriction, vasoproliferation, and vasorelaxation in small intrapulmonary arteries. To investigate the possibility that smoke also induces endothelial dysfunction, a finding common to other forms of pulmonary hypertension, we exposed guinea pigs to smoke or air (control) daily for 2 wk and then prepared precision-cut lung slices. After exposure to endothelin-1, a vasoconstrictor, intra-acinar arteries in lung slices derived from smoke-exposed animals constricted more rapidly (greater constriction at a given concentration of endothelin) than did vessels from air-exposed animals. To examine relaxation responses, arteries were constricted with the vasoconstrictor U-46619 and then relaxed with progressively increasing doses of acetylcholine. Vessels from smokers had a delayed response to acetylcholine compared with vessels from controls. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester reduced relaxation in both control and smoke-exposed arteries, whereas the NO donor sodium nitroprusside increased relaxation of the smoke-exposed arteries, confirming that endothelial dysfunction with decreased effective NO production is present. These findings show that precision cut lung slices can be used to examine the physiological effects of cigarette smoke on intra-acinar pulmonary arteries and indicate that even relatively short-term exposure to smoke produces endothelial dysfunction with a resulting tendency to earlier constriction and later relaxation in cigarette smokers. These changes may be important in the development of pulmonary hypertension.

Associations between sole ulcer, white line disease and digital dermatitis and the milk yield of 1824 dairy cows on 30 dairy cow farms in England and Wales from February 2003-November 2004.

The milk yields of 1824 cows were used to investigate the effect of lesion-specific causes of lameness, based on farmer treatment and diagnosis of lame cows, on milk yield. A three-level hierarchical model of repeated test day yields within cows within herds was used to investigate the impact of lesion-specific causes of lameness (sole ulcer, white line disease, digital dermatitis and other causes) on milk yield before and after treatment compared with unaffected cows. Cattle which developed sole ulcer (SU) and white line disease (WLD) were higher yielding cattle before they were diagnosed. Their milk production fell to below that of the mean of unaffected cows before diagnosis and remained low after diagnosis. In cattle which developed digital dermatitis (DD) there was no significant difference in milk yield before treatment and a slightly raised milk yield immediately after treatment. The estimated milk loss attributable to SU and WLD was approximately 570 and 370 kg, respectively. These results highlight that specific types of lameness vary by herds and within herds they are associated with higher yielding cattle. Consequently lesion-specific lameness reduction programmes targeting the cow and farm specific causes of lameness might be more effective than generic recommendations. They also highlight the importance of milk loss when estimating the economic impact of SU and WLD on the farms profitability.