C57BL/6 life span study: age-related declines in muscle power production and contractile velocity

Quantification of key outcome measures in animal models of aging is an important step preceding intervention testing. One such measurement, skeletal muscle power generation (force * velocity), is critical for dynamic movement. Prior research focused on maximum power (P max), which occurs around 30-40 % of maximum load. However, movement occurs over the entire load range. Thus, the primary purpose of this study was to determine the effect of age on power generation during concentric contractions in the extensor digitorum longus (EDL) and soleus muscles over the load range from 10 to 90 % of peak isometric tetanic force (P 0). Adult, old, and elderly male C57BL/6 mice were examined for contractile function (6-7 months old, 100 % survival; ~24 months, 75 %; and ~28 months, 50 % P 0). The shape of the force-velocity curve also changed with age (a/P 0 increased). In addition, there were prolonged contraction times to maximum force and shifts in the distribution of the myosin light and heavy chain isoforms in the EDL. The results demonstrate that age-associated difficulty in movement during challenging tasks is likely due, in addition to overall reduced force output, to an accelerated deterioration of power production and contractile velocity under heavily loaded conditions.R01 AG017768 - NIA NIH HHS; F31 AG044108 - NIA NIH HHS; T32 AG029796 - NIA NIH HHS; R01 EY15313 - NEI NIH HHS; R01 EY015313 - NEI NIH HH

Recent Cases

If the instant case, rather than Northway, is to become the accepted rule in the area of discounting, consumers and state lenders will be protected while the national bank-lenders will be burdened only slightly, if at all. National banks located in states that permit state lenders to discount loans at the maximum rate, with-out regard to the actual yield, will not be affected. National banks located in states that permit state lenders to discount only to the extent that the actual yield is within the statutory maximum will need to change their practices merely by charging the statutory rate only when it becomes due, or by charging a lower rate in advance that yields an effective rate not in excess of the maximum. Furthermore, the impact of the instant decision on national banks will be practically limited to consumer loans, because of the usual exemption of corporations from usury laws and of section 85\u27s higher alternative rate for business or agricultural loans. This limited restriction on the national banks will be justified by its beneficent effect on the borrower and on the competing state lenders, who have always been subject to the state restrictions. Linda A. Bunsey ======================= With the instant decision, federal defamation law has advanced within the space of ten years from no constitutional privilege, even for the press in defending against a public person, to the realized prospect of a constitutional privilege so sweeping that it prevents recovery of an element of damages by a public person who has been defamed by an individual. Specifically, the instant court\u27s holding completes a four-part scheme for liability and damages in defamation actions: under Supreme Court decisions, a private figure must prove negligence to receive compensatory damages and actual malice to receive punitive damages, and a public figure must prove actual malice to recover compensatory damages; under the instant decision, a public figure is almost totally precluded from recovering punitive damages. As the Sullivan Court in large measure adopted the minority position concerning fair comment and liability, so too the Maheu court in large measure adopted the minority position concerning punitive damages. Nevertheless, the instant decision was solidly based: the court fully considered the Supreme Court\u27s prior concerns with encouraging debate and discouraging self-censorship, shielding reputation and privacy, and, most importantly, scrutinizing the need for punitive damages. David M. Thompson ============================ In rejecting the State\u27s reliance upon the stated rule of the Brady trilogy and Tollett, the instant Court noted the suggestion originally made in a McMann footnote that an exception might exist if the applicable state law permitted appeal from adverse pretrial rulings despite a subsequent guilty plea. Under New York procedure, a defendant who chooses to plead guilty does not deliberately by-pass state appellate review of certain constitutional claims, and the State acquires no legitimate expectation of finality in the ensuing conviction. As to these constitutional claims, the plea does not constitute a break in the chain, but operates merely as a procedural device to secure review of the adverse pretrial ruling without the necessity of a time-consuming and expensive trial. The Court held that because the respondent\u27s guilty plea was entered in reliance upon a guarantee of the availability of further appellate review of his constitutional claims, it was essentially different from guilty pleas entered in other states that result in an absolute conviction and a waiver of all further state review. Charles K. Campbell, Jr. ======================================== In determining whether the challenged statute met the procedural requirements of the fourteenth amendment, the instant Court looked to the statutory safeguards protecting the debtor\u27s property interest in the absence of prior notice and hearing. Comparing the instant statute to the Fuentes statutes, the Court asserted that the same constitutional infirmities were present. Each statute allowed the seizure of property without prior notice and opportunity for a hearing by the issuance of a writ by a court clerk after the filing of an affidavit containing conclusory allegations. The instant Court restated its belief set forth in Sniadach and Fuentes that even a temporary deprivation of property does not put the seizure beyond scrutiny under due process requirements. The Court then asserted that the Georgia statute had none of the saving characteristics of the Louisiana sequestration statute upheld in Mitchell. According to the Court, the Mitchell statute survived challenge because of the presence of safeguards which imposed judicial control over the process of issuance of the writ; required the creditor\u27s affidavit to contain factual allegations; and provided for an immediate post-seizure hearing at which the debtor could seek dissolution of the writ. Keith B. Simmons ============================== The instant court rejected arguments based mainly on the vague wording of the statute and relied on two basic policies-(1)to compel pro rata distributions of unneeded funds that will be taxable to shareholders and (2) to avoid constructions that lead to inconsistent results in similar fact situations. Also, the court seemed to contemplate two theories of liability available to the Commissioner-first, that the corporation was availed of by permitting funds not used in the redemption to remain accumulated, and secondly, that the corporation was availed of through the redemption itself. The arguments based on the equivalency of the phrases to accumulate and to remain accumulated , the purpose of Congress to reach any corporation with an undue accumulation, and the relevance of past accumulations, plus the remand for determination of whether an unreasonable accumulation actually occurred, relate to the first theory. Other arguments used by the court relate more to the second theory-the repeated idea that preferential distribution of unneeded funds is not a congressionally approved method of abating the penalty tax with respect to those funds, the mention of corporations formed for the proscribed purpose that may be liable without regard to actual accumulation, and especially the concluding statement that the judgment concerning 1967 made liability in 1968 apparent. Thomas C. Hundle

U.S. Fresh Fruit and Vegetable Marketing: Emerging Trade Practices, Trends, and Issues

In the past year, trade practices between fresh produce shippers and food retailers gained national attention. Shippers are concerned that recent retail consolidation has led to market power and the growing incidence of fees and services. Retailers argue that these new trade practices reflect their costs of doing business and the demands of consumers. Trade practices include fees such as volume discounts and slotting fees, as well as services like automatic inventory replenishment, special packaging, and requirements for third-party food safety certification. Trade practices also refer to the overall structure of a transaction-for example, long-term relationships or contracts versus daily sales with no continuing commitment. This study compares trade practices in 1999 with those prevalent in 1994, placing them in the broader context of the evolving shipper/retailer relationship. Most shippers and retailers reported that the incidence and magnitude of fees and services associated with transactions has increased over the last 5 years. Fees paid to retailers are usually around 1-2 percent of sales for most of the commodities we examined, but 1-8 percent for bagged salads. Information on the incidence and magnitude of these new practices is scarce. To augment information that is publicly available, we interviewed a limited number of shippers, retailers, and wholesalers about their firms and trade practices. We received a high level of voluntary cooperation from the interviewed firms.produce, fresh fruit and vegetables, fresh-cut produce, trade practices, fees and services, slotting fees, retail consolidation, produce shipper consolidation, Crop Production/Industries, Marketing,

Integrated Analysis of Clinical and Microbiome Risk Factors Associated with the Development of Oral Candidiasis during Cancer Chemotherapy.

Oral candidiasis is a common side effect of cancer chemotherapy. To better understand predisposing factors, we followed forty-five subjects who received 5-fluorouracil- or doxorubicin-based treatment, during one chemotherapy cycle. Subjects were evaluated at baseline, prior to the first infusion, and at three additional visits within a two-week window. We assessed the demographic, medical and oral health parameters, neutrophil surveillance, and characterized the salivary bacteriome and mycobiome communities through amplicon high throughput sequencing. Twenty percent of all subjects developed oral candidiasis. Using multivariate statistics, we identified smoking, amount of dental plaque, low bacteriome and mycobiome alpha-diversity, and the proportions of specific bacterial and fungal taxa as baseline predictors of oral candidiasis development during the treatment cycle. All subjects who developed oral candidiasis had baseline microbiome communities dominated by Candida and enriched in aciduric bacteria. Longitudinally, oral candidiasis was associated with a decrease in salivary flow prior to lesion development, and occurred simultaneously or before oral mucositis. Candidiasis was also longitudinally associated with a decrease in peripheral neutrophils but increased the neutrophil killing capacity of Candida albicans. Oral candidiasis was not found to be associated with mycobiome structure shifts during the cycle but was the result of an increase in Candida load, with C. albicans and Candida dubliniensis being the most abundant species comprising the salivary mycobiome of the affected subjects. In conclusion, we identified a set of clinical and microbiome baseline factors associated with susceptibility to oral candidiasis, which might be useful tools in identifying at risk individuals, prior to chemotherapy

Crucial Role for Ecto-5′-Nucleotidase (CD73) in Vascular Leakage during Hypoxia

Extracellular adenosine has been widely implicated in adaptive responses to hypoxia. The generation of extracellular adenosine involves phosphohydrolysis of adenine nucleotide intermediates, and is regulated by the terminal enzymatic step catalyzed by ecto-5′-nucleotidase (CD73). Guided by previous work indicating that hypoxia-induced vascular leakage is, at least in part, controlled by adenosine, we generated mice with a targeted disruption of the third coding exon of Cd73 to test the hypothesis that CD73-generated extracellular adenosine functions in an innate protective pathway for hypoxia-induced vascular leakage. Cd73 (−/−) mice bred and gained weight normally, and appeared to have an intact immune system. However, vascular leakage was significantly increased in multiple organs, and after subjection to normobaric hypoxia (8% O(2)), Cd73 (−/−) mice manifested fulminant vascular leakage, particularly prevalent in the lung. Histological examination of lungs from hypoxic Cd73 (−/−) mice revealed perivascular interstitial edema associated with inflammatory infiltrates surrounding larger pulmonary vessels. Vascular leakage secondary to hypoxia was reversed in part by adenosine receptor agonists or reconstitution with soluble 5′-nucleotidase. Together, our studies identify CD73 as a critical mediator of vascular leakage in vivo

Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis.

BACKGROUND: Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues. RESULTS: Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity. CONCLUSIONS: Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis

Measuring retention within the adolescent brain cognitive development (ABCD)SM study

The Adolescent Brain Cognitive Development (ABCD

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors

Maternal Dioxin Exposure Combined with a Diet High in Fat Increases Mammary Cancer Incidence in Mice

BackgroundRESULTS from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk.ObjectivesBecause both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility.MethodsWe exposed pregnant female FVB/NJ mice (12.5 days postcoitus) to 1 microg/kg TCDD or vehicle; at parturition, the dams were randomly assigned to a low-fat diet (LFD) or a high-fat diet (HFD). Female offspring were maintained on the same diets after weaning and were exposed to 7,12-dimethylbenz[a]anthracene on postnatal days (PNDs) 35, 49, and 63 to initiate mammary tumors. A second cohort of females was treated identically until PND35 or PND49, when mammary gland morphology was examined, or PND50, when mammary gland mRNA was analyzed.ResultsWe found that maternal TCDD exposure doubled mammary tumor incidence only in mice fed the HFD. Among HFD-fed mice, maternal TCDD exposure caused rapid mammary development with increased Cyp1b1 (cytochrome P450 1B1) expression and decreased Comt (catechol-O-methyltransferase) expression in mammary tissue. Maternal TCDD exposure also increased mammary tumor Cyp1b1 expression.ConclusionsOur data suggest that the HFD increases sensitivity to maternal TCDD exposure, resulting in increased breast cancer incidence, by changing metabolism capability. These results provide a mechanism to explain epidemiological data linking early-life TCDD exposure and diets high in fat to increased risk for breast cancer in humans