Associations Between Estimates of Arterial Stiffness and Cognitive Functioning in Adults With HIV.

BACKGROUND: Vascular aging, a precursor of arterial stiffness, is associated with neurocognitive impairment (NCI) and cardiovascular disease. Although HIV is associated with rapid vascular aging, it is unknown whether arterial stiffness mediates changes in cognitive function. We explored whether estimated markers of vascular aging were associated with NCI indices in HIV-positive individuals. METHODS: This study was a secondary analysis of an observational study. Neurocognitive functioning was assessed using a battery of 7 domains (verbal fluency, executive functioning, speed of information processing, attention/working memory, memory [learning and delayed recall], and motor skills). Vascular aging was assessed using estimated markers of arterial stiffness (ie, estimated pulse wave velocity, pulse pressure, and vascular overload index). A multivariable regression adjusted for demographics, cardiovascular disease risk factors, and HIV clinical variables was used to examine the association between vascular aging and NCI outcomes. RESULTS: Among 165 people with HIV, the mean age was 51.5 ± 6.9 years (62% men and 83% African American/Black or Other). In fully adjusted models, an increase in estimated pulse wave velocity and pulse pressure was associated with lower T scores in learning (-2.95 [-5.13, -0.77]) and working memory (-2.37 [-4.36, -0.37]), respectively. An increase in vascular overload index was associated with lower T scores in working memory (-2.33 [-4.37, -0.29]) and learning (-1.85 [-3.49, -0.21]). CONCLUSIONS: Estimated markers of arterial stiffness were weakly associated with neurocognitive functioning, suggesting that vascular aging may have a role in cognitive decline among people with HIV.

Inflammatory and Cardiovascular Correlates of Physical Activity and Sedentary Behavior in Older Adults Living With HIV.

BACKGROUND: Inflammation is an indicator of oxidative stress that may contribute to cardiovascular diseases in older people living with HIV (OPWH). Physical activity (PA) may reduce these biomarkers in OPWH, but little is known about the association of PA with inflammatory and cardiovascular biomarkers. We sought to examine the inflammatory and cardiovascular biomarker correlates of PA and sedentary behavior in OPWH. METHODS: We included 101 OPWH with complete assessments of PA, sedentary behavior, and biomarker data to examine the association between the volume of PA and inflammatory and cardiovascular biomarkers. RESULTS: In this cohort of OPWH (mean age 55.9 y), 68% were male and 83% were African American/Black. Among OPWH, greater volume of PA (ie, walking, moderate, vigorous, and/or total) was associated with lower systolic (P < .05) and diastolic blood pressure (P < .05), pulse pressure (P < .05), and tumor necrosis factor-alpha (P < .05). Greater duration of sitting was associated with greater triglycerides, interleukin-6, and tumor necrosis factor-alpha (P < .05). CONCLUSIONS: Although adherence to regular PA among OPWH is low and sedentary behavior is high, the associations between biomarkers and PA suggest a greater volume of PA could attenuate the inflammatory and cardiovascular derangements experienced by OPWH.

Differences between preemptive and non-preemptive physical activity among 'drunkorexia'-positive college students.

Objective: 'Drunkorexia' is characterized by compensating for alcohol-related calories using physical activity (PA). Drunkorexia is common on college campuses but little is known about the PA behaviors within the drunkorexia paradigm. Methods: First-year college students living on campus completed an online survey collecting drunkorexia, PA, and alcohol consumption data. A total of 127 participants reported engaging in drunkorexia behaviors. Results: Fifty-three participants were classified as preemptively physically active (e.g., PA and drink on Tuesday) compared to 74 as non-preemptively physically active. Preemptively physically active participants consumed more alcohol on Fridays and Saturdays than those non-preemptively physically active. Preemptively physically active participants engaged in significantly greater amounts PA. Females accounted for all significant differences between groups. Discussion: Among drunkorexia-positive participants, many made preemptive efforts to control their calories before consuming alcohol, which may predispose them to higher incidences of adverse outcomes such as alcohol poisoning, unwanted sexual advances, and death.

Predictors of breastfeeding duration in a predominantly Maori population in New Zealand.

BACKGROUND: Although breastfeeding duration in New Zealand's indigenous Maori is shorter than in non-Maori, we know little about barriers or motivators of breastfeeding in this community. The aim of this analysis was to identify predictors for extended duration of breastfeeding amongst participants drawn from predominantly Maori communities in regional Hawke's Bay. METHODS: Mother/baby dyads were recruited from two midwifery practices serving predominantly Maori women in mostly deprived areas, for a randomised controlled trial comparing the risks and benefits of an indigenous sleeping device (wahakura) and a bassinet. Questionnaires were administered at baseline (pregnancy) and at one, three and six months postnatal. Several questions relating to breastfeeding and factors associated with breastfeeding were included. The data from both groups were pooled to examine predictors of breastfeeding duration. RESULTS: Maori comprised 70.5% of the 197 participants recruited. The median time infants were fully breastfed was eight weeks and Maori women were more likely to breastfeed for a shorter duration than New Zealand European women with an odds-ratio (OR) of 0.45 (95% CI 0.24, 0.85). The key predictors for extended duration of breastfeeding were the strong support of the mother's partner (OR = 3.64, 95% CI 1.76, 7.55) or her mother for breastfeeding (OR = 2.47, 95% CI 1.27, 4.82), longer intended duration of maternal breastfeeding (OR = 1.02, 95% CI 1.00, 1.03) and being an older mother (OR = 1.07, 95% CI 1.02, 1.12). The key predictors for shorter duration of breastfeeding were pacifier use (OR = 0.28, 95% CI 0.17, 0.46), daily cigarette smoking (OR = 0.51, 95% CI 0.37, 0.69), alcohol use (OR = 0.54, 95% CI 0.31, 0.93) and living in a more deprived area (OR 0.40, 95% CI 0.22, 0.72). CONCLUSIONS: Breastfeeding duration in this group of mainly Maori women was shorter than the national average. Increasing the duration of breastfeeding by these mothers could be further facilitated by ante and postnatal education involving their own mothers and their partners in the support of breastfeeding and by addressing pacifier use, smoking and alcohol use.

Analytical and clinical performance of progesterone receptor antibodies in breast cancer.

OBJECTIVE: Comparison of analytical and immunohistochemical performance of progesterone receptor (PR) antibodies with correlation to recurrence of invasive breast cancer treated with endocrine therapy. METHODS: The binding-affinity kinetics of PR clones 1E2, 1A6, 16 and 636 were compared using synthetic peptides derived from identified epitopes on a Biacore T200. A cohort of 351 cases (Hormone Receptor (HR)+/HER2-) were stained for PR expression with immunohistochemistry (IHC) and scored according to ASCO/CAP criteria. RESULTS: The stability of the antigen/antibody complex was greater for the 1E2 clone compared to 1A6, 16 and 636 clones. PR IHC on archival tissue resulted in 94.3% (299/317) concordance with clones. CONCLUSION: Clones evaluated in this study had a high level of concordance with IHC despite PR (1E2) demonstrating higher analytical binding properties than other clones. In a minority of cases (1.3% for 1E2 and 2.5% for 636) IHC results could convert estrogen receptor (ER)-/PR- to ER-/PR+ tumors, making these patients potentially eligible for endocrine therapy.

Reproductive and hormonal factors and the risk of nonsmall cell lung cancer.

Although exposure to estrogen may directly influence or modify the association between cigarette smoking and lung cancer risk, results from epidemiologic studies examining the association between reproductive and hormonal factors and risk of lung cancer among women have been inconsistent. Between 1998 and 2008, 430 women diagnosed with nonsmall cell lung cancer, 316 hospital controls and 295 population controls were recruited into the multi-center Maryland Lung Cancer Study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) according to reproductive and hormonal exposures adjusting for age, smoking, passive smoking, education and household income. Results were similar for hospital and population based controls, so the control groups were combined. Reduced risks of lung cancer were observed among women with greater parity (≥ 5 vs. 1-2 births: OR = 0.50, 95% CI = 0.32, 0.78, p-trend = 0.002) and later ages at last birth (≥ 30 vs. <25 years old: OR = 0.68, 95% CI = 0.48, 0.98, p-trend = 0.04). After mutual adjustment parity, but not age at last birth, remained significantly inversely associated with risk (p-trend = 0.01). No associations were found for nonsmall cell lung cancer risk with age at menarche, age at first birth, menopausal status, oral contraceptive use or menopausal hormone use, including use of oral estrogens. Compatible with findings from recent epidemiologic studies, we observed a reduction in the risk of nonsmall cell lung cancer with increasing number of births. Other reproductive and hormonal exposures, including menopausal hormone therapy use, were not associated with risk.

An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo.

The PI3K-Akt pathway is dysregulated in the majority of solid tumors. Pharmacological inhibition of Akt is a promising strategy for treating tumors resistant to growth factor receptor antagonists due to mutations in PI3K or PTEN. We have developed allosteric, isozyme-specific inhibitors of Akt activity and activation, as well as ex vivo kinase assays to measure inhibition of individual Akt isozymes in tissues. Here we describe the relationship between PK, Akt inhibition, hyperglycemia and tumor efficacy for a selective inhibitor of Akt1 and Akt2 (AKTi). In nude mice, AKTi treatment caused transient insulin resistance and reversible, dose-dependent hyperglycemia and hyperinsulinemia. Akt1 and Akt2 phosphorylation was inhibited in mouse lung with EC50 values of 1.6 and 7 µM, respectively, and with similar potency in other tissues and xenograft tumors. Weekly subcutaneous dosing of AKTi resulted in dose-dependent inhibition of LNCaP prostate cancer xenografts, an AR-dependent tumor with PTEN deletion and constitutively activated Akt. Complete tumor growth inhibition was achieved at 200 mpk, a dose that maintained inhibition of Akt1 and Akt2 of greater than 80% and 50%, respectively, for at least 12 hours in xenograft tumor and mouse lung. Hyperglycemia could be controlled by reducing C(max), while maintaining efficacy in the LNCaP model, but not by insulin administration. AKTi treatment was well tolerated, without weight loss or gross toxicities. These studies supported the rationale for clinical development of allosteric Akt inhibitors and provide the basis for further refining of pharmacokinetic properties and dosing regimens of this class of inhibitors.

Elevated lung cancer risk is associated with deficiencies in cell cycle checkpoints: genotype and phenotype analyses from a case-control study.

Cell cycle checkpoints play critical roles in the maintenance of genomic integrity and inactivation of checkpoint genes are frequently perturbed in most cancers. In a case-control study of 299 non-small cell lung cancer cases and 550 controls in Baltimore, we investigated the association between gamma-radiation-induced G(2)/M arrest in cultured blood lymphocytes and lung cancer risk, and examined genotype-phenotype correlations between genetic polymorphisms of 20 genes involving in DNA repair and cell cycle control and gamma-radiation-induced G(2)/M arrest. The study was specifically designed to examine race and gender differences in risk factors. Our data indicated that a less efficient DNA damage-induced G(2)/M checkpoint was associated with an increased risk of lung cancer in African American women with an adjusted odds ratio (OR) of 2.63 (95% CI = 1.01-7.26); there were no statistically significant associations for Caucasians, or African American men. When the African American women were categorized into quartiles, a significant reverse trend of decreased G(2)/M checkpoint function and increased lung cancer risk was present, with lowest-vs.-highest quartile OR of 13.72 (95% CI = 2.30-81.92, p(trend) < 0.01). Genotype-phenotype correlation analysis indicated that polymorphisms in ATM, CDC25C, CDKN1A, BRCA2, ERCC6, TP53, and TP53BP1 genes were significantly associated with the gamma-radiation-induced G(2)/M arrest phenotype. This study provides evidence that a less efficient G(2)/M checkpoint is significantly associated with lung cancer risk in African American women. The data also suggested that the function of G(2)/M checkpoint is modulated by genetic polymorphisms in genes involved in DNA repair and cell cycle control.

Allosteric inhibitors of Akt1 and Akt2: discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with potent and balanced activity.

A series of [1,2,4]triazolo[3,4-f][1,6]naphthyridine allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been shown to have potent dual Akt1 and 2 cell potency. The representative compound 13 provided potent inhibitory activity against Akt1 and 2 in vivo in a mouse model.

Occupation, gender, race, and lung cancer.

OBJECTIVE: To examine associations between occupation and lung cancer by gender and race. METHODS: We used data from the Maryland Lung Cancer Study of nonsmall cell lung carcinoma (NSCLC), a multicenter case control study, to estimate odds ratios (ORs) of NSCLC in different occupations. RESULTS: After adjusting for smoking, environmental tobacco smoke, and other covariates, NSCLC ORs among women but not men were elevated in clerical-sales, service, and transportation-material handling occupations; ORs were significantly increased in all three categories (OR [95% confidence interval]: 4.07 [1.44 to 11.48]; 5.15 [1.62 to 16.34]; 7.82 [1.08 to 56.25], respectively), among black women, but only in transportation-material handling occupations (OR [95% confidence interval[: 3.43 [1.02 to 11.50]) among white women. CONCLUSIONS: Women, especially black women, in certain occupations had increased NSCLC ORs.

Discovery of potent and cell-active allosteric dual Akt 1 and 2 inhibitors.

This paper describes the improvement of cell potency in a class of allosteric Akt 1 and 2 inhibitors. Key discoveries include identifying the solvent exposed region of the molecule and appending basic amines to enhance the physiochemical properties of the molecules. Findings from the structure-activity relationships are discussed.

The design and synthesis of potent and cell-active allosteric dual Akt 1 and 2 inhibitors devoid of hERG activity.

This letter details the attenuation of hERG in a class of Akt inhibitors through heteroatom insertions into aromatic rings. The development of a cell-active dual Akt 1 and 2 inhibitors devoid of hERG activity is discussed using structure-activity relationships.

Greenhouse gas emissions from two soils receiving nitrogen fertilizer and swine manure slurry.

The interactive effects of soil texture and type of N fertility (i.e., manure vs. commercial N fertilizer) on N(2)O and CH(4) emissions have not been well established. This study was conducted to assess the impact of soil type and N fertility on greenhouse gas fluxes (N(2)O, CH(4), and CO(2)) from the soil surface. The soils used were a sandy loam (789 g kg(-1) sand and 138 g kg(-1) clay) and a clay soil (216 g kg(-1) sand, and 415 g kg(-1) clay). Chamber experiments were conducted using plastic buckets as the experimental units. The treatments applied to each soil type were: (i) control (no added N), (ii) urea-ammonium nitrate (UAN), and (iii) liquid swine manure slurry. Greenhouse gas fluxes were measured over 8 weeks. Within the UAN and swine manure treatments both N(2)O and CH(4) emissions were greater in the sandy loam than in the clay soil. In the sandy loam soil N(2)O emissions were significantly different among all N treatments, but in the clay soil only the manure treatment had significantly higher N(2)O emissions. It is thought that the major differences between the two soils controlling both N(2)O and CH(4) emissions were cation exchange capacity (CEC) and percent water-filled pore space (%WFPS). We speculate that the higher CEC in the clay soil reduced N availability through increased adsorption of NH(4)(+) compared to the sandy loam soil. In addition the higher average %WFPS in the sandy loam may have favored higher denitrification and CH(4) production than in the clay soil.

Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model.

A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.

Development of pyridopyrimidines as potent Akt1/2 inhibitors.

This communication reports a new synthetic route of pyridopyrimidines to facilitate their structural optimization in a library fashion and describes the development of pyridopyrimidines that have excellent enzymatic and cell potency against Akt1 and Akt2. This series also shows a high level of selectivity over other closely related kinases and significantly improved caspase-3 activity with the more optimized compounds.

Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors.

This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmacokinetic profile of an optimized inhibitor that has low clearance and long half-life in dogs.

Rapid assembly of diverse and potent allosteric Akt inhibitors.

This paper describes the rapid assembly of four different classes of potent Akt inhibitors from a common intermediate. Among them, a pyridopyrimidine series displayed the best intrinsic and cell potency against Akt1 and Akt2. This series also showed a promising pharmacokinetic profile and excellent selectivity over other closely related kinases.

Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity.

This letter describes the development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved aqueous solubility (approximately 18 mg/mL) that translates into enhanced cell activity and caspase-3 induction.

Fighting disease with fruit.

Otitis media and chronic suppurative otitis media are common conditions in Aboriginal communities, and are associated with poor nutrition, overcrowding and passive smoking. This article reports on an extension of our nutrition program, which was first reported in Australian Family Physician under the title 'Are there health benefits from improving basic nutrition in a remote Aboriginal community?'

How is the indoor environment related to asthma?: literature review.

AIMS: This paper reports a review conducted to identify the factors in the indoor environment that have an evidence-based link with the exacerbation or development of asthma and to identify measures that healthcare professionals can promote to reduce exposure to these risk factors in the home. BACKGROUND: The indoor environment, particularly at home, has been recognized as a major source of exposure to allergens and toxic chemicals. Exposure to allergens and toxins is thought to exacerbate respiratory conditions, in particular, asthma. METHODS: Searches were made of health and indoor environment databases, including Cochrane Library, National Health Services Centre for Reviews and Assessment Reports, British Medical Journal, CINAHL and Ovid library, MEDSCAPE/MEDLINE, EMBASE, INGENTA, Science Citation Index, Web of Science. Searches were also made of other Internet-based resources, including those of international and government bodies. The following keywords were used: allergens, allergen avoidance, asthma, asthma prevention, cat, damp, Der p 1, dog, environmental control, house dust mites, indoor air quality, indoor environment, meta analysis, mould, pets, remedial actions, respiratory illnesses and systematic reviews. FINDINGS: There is evidence of a link between asthma and a small number of indoor environmental factors. There is currently only reasonable evidence for one causative factor for asthma in the indoor environment and that is house dust mite allergen. Although there are many studies of different remedial actions that can be taken in the home, often these give evidence of reduced risk of exposure but not clinical improvement in asthma. Although there is a lack of medical evidence for the reduction of known sensitizers such as mould, this is because of a dearth of research rather than evidence of no association. CONCLUSIONS: There is some evidence of a link between the indoor environment and asthma. There are measures, which could be promoted by healthcare professionals to alleviate asthmatic symptoms.