Bile salt composition is secondary to bile salt concentration in determining hydrocortisone and progesterone solubility in intestinal mimetic fluids

Simulated intestinal fluids (SIFs) used to assay the solubility of orally administered drugs are typically based on a single bile salt; sodium taurocholate (STC). The aim of this study was to develop mimetic intestinal fluids with a closer similarity to physiological fluids than those reported to date by developing a mixed bile salt (MBS) system (STC, sodium glycodeoxycholate, sodium deoxycholate; 60:39:1) with different concentrations of lecithin, the preponderant intestinal phospholipid. Hydrocortisone and progesterone were used as model drugs to evaluate systematically the influence of SIF composition on solubility. Increasing total bile salt concentration from 0 to 30 mM increased hydrocortisone and progesterone solubility by 2- and ～25-fold, respectively. Accordingly, higher solubilities were measured in the fed-state compared to the fasted-state SIFs. Progesterone showed the greatest increases in solubility in STC and MBS systems (2-7-fold) compared to hydrocortisone (no significant change; P>0.05) as lecithin concentration was increased. Overall, MBS systems gave similar solubility profiles to STC. In conclusion, the addenda of MBS and lecithin were found to be secondary to the influence of BS concentration. These data provide a foundation for the design of more bio-similar media for pivotal decision-guiding assays in drug development and quality control settings.     

Coping With a Diagnosis of Breast Cancer-Literature Review and Implications for Developing Countries

Abstract:  Breast cancer is the most common cancer affecting women worldwide. Women are at an increased risk of developing both physical and psychological morbidity after diagnosis; however, many use different strategies to cope with the disease. The aim of this article is to review the available literature on the impact of breast cancer diagnoses and the strategies used by women to cope with this disease. The implications of these emerging findings are extrapolated within the context of health services provided in developing countries. Electronic databases were used to search the relevant literature. The findings showed that women who were diagnosed with breast cancer are at risk of developing several psychological morbidities such as depression, anxiety, fatigue, negative thoughts, suicidal thoughts, fear of dying, sense of aloneness, sexual and body images problems, as well as an overall decrease in the quality of life. Several strategies are used by women with breast cancer to cope with the disease, including positive cognitive restructuring, wishful thinking, emotional expression, disease acceptance, increased religious practice, family and social support, and yoga and exercise. Breast cancer diagnoses have been associated with several devastating psychological consequences; however, many women have used different coping strategies to adjust their lives accordingly. Healthcare professionals in developing countries, who work with women with breast cancer, should be aware of the different coping mechanisms that women use when diagnosed with cancer. Integrating a coping strategy into the treatment regimen would constitute an important milestone in the palliative care of patients with breast cancer.     

Depression and nursing home admission among hospitalized older adults with coronary artery disease: a propensity score analysis

Admission to a nursing home is considered a poor outcome for community-dwelling older adults. The objective of this study was to determine whether depression increased the risk of nursing home admission. Using the National Hospital Discharge Survey 2001-2003 datasets, the authors identified 28,172 community-dwelling older adults, 65 years and older, discharged alive with a primary discharge diagnosis of coronary artery disease. The objective of this study was to determine the association between depression and subsequent nursing home admissions in these patients. Propensity scores for depression, calculated for each patient using a multivariable logistic regression model, were used to match 686 depressed patients with 2058 nondepressed patients who had similar propensity scores. Logistic regression analyses were used to determine the association between depression and nursing home admission. Patients had a mean age +/- SD of 77+/-8 years, and 61% were women. Compared with 9% of nondepressed patients, 13% of depressed patients were admitted to nursing homes (relative risk, 1.42; 95% confidence interval, 1.12-1.78). When adjusted for various demographic, clinical, and care-related covariates, the association became somewhat stronger (adjusted relative risk, 1.55; 95% confidence interval, 1.21-1.99). In ambulatory older adults hospitalized with coronary artery disease, a secondary diagnosis of depression was associated with a significantly increased risk of nursing home admission.     

SNPs on chips: the hidden genetic code in expression arrays.

Gene expression microarray analysis in postmortem brains is one of the fastest growing fields of psychiatric research. Here we show that common polymorphisms (SNPs) present on probe sets can masquerade as significant "gene expression" differences. After first observing this artifact in the Catechol-O-methyl transferase (COMT) gene, we replicate the finding in two additional genes predicted to show this artifact. Many Affymetrix chips contain thousands of SNPs that are both common and in the central probe region affecting hybridization, and thus have the potential to confound expression analysis.     

Individual differences in the attribution of incentive salience to reward-related cues: Implications for addiction

Drugs of abuse acquire different degrees of control over thoughts and actions based not only on the effects of drugs themselves, but also on predispositions of the individual. Those individuals who become addicted are unable to shift their thoughts and actions away from drugs and drug-associated stimuli. Thus in addicts, exposure to places or things (cues) that has been previously associated with drug-taking often instigates renewed drug-taking. We and others have postulated that drug-associated cues acquire the ability to maintain and instigate drug-taking behavior in part because they acquire incentive motivational properties through Pavlovian (stimulus-stimulus) learning. In the case of compulsive behavioral disorders, including addiction, such cues may be attributed with pathological incentive value ("incentive salience"). For this reason, we have recently begun to explore individual differences in the tendency to attribute incentive salience to cues that predict rewards. When discrete cues are associated with the non-contingent delivery of food or drug rewards some animals come to quickly approach and engage the cue even if it is located at a distance from where the reward will be delivered. In these animals the reward-predictive cue itself becomes attractive, eliciting approach towards it, presumably because it is attributed with incentive salience. Animals that develop this type of conditional response are called "sign-trackers". Other animals, "goal-trackers", do not approach the reward-predictive cue, but upon cue presentation they immediately go to the location where food will be delivered (the "goal"). For goal-trackers the reward-predictive cue is not attractive, presumably because it is not attributed with incentive salience. We review here preliminary data suggesting that these individual differences in the tendency to attribute incentive salience to cues predictive of reward may confer vulnerability or resistance to compulsive behavioral disorders, including addiction. It will be important, therefore, to study how environmental, neurobiological and genetic interactions determine the extent to which individuals attribute incentive value to reward-predictive stimuli.     

Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans

BACKGROUND: Reduced bioavailability of endothelium-derived nitric oxide associated with reperfusion could potentially exacerbate the inflammatory response during reperfusion. Evidence suggests the pharmacologic effects of inhaled nitric oxide may extend beyond the pulmonary vasculature, and this is attributed to nitric oxide-derived complexes in blood that ultimately orchestrate antiinflammatory effects. In this study, the authors evaluated the potential for inhaled nitric oxide (80 ppm) to attenuate inflammation instigated by ischemia-reperfusion in a human model using patients undergoing knee surgery where a tourniquet was used to produce a bloodless surgical field. METHODS: Inhaled nitric oxide (80 ppm) was administered before tourniquet application and continued throughout reperfusion until the completion of surgery. Venous blood samples were collected before and after reperfusion, for the measurements of nitrate and nitrite, CD11b/CD18, soluble P-selectin, and lipid hydroperoxide. Muscle biopsies were obtained from the quadriceps muscle before skin closure and analyzed for myeloperoxide, conjugated dienes, and nuclear factor-kappaB translocation. RESULTS: Administration of inhaled nitric oxide (80 ppm) significantly attenuated the inflammatory response characterized by reduced expression of CD11b/CD18, P-selectin, and nuclear factor kappaB compared with the control group. This was accompanied by increased plasma levels of nitrate and nitrite and reduced oxidative stress. CONCLUSIONS: Administration of inhaled nitric oxide at 80 ppm significantly reduces inflammation in lower extremity ischemia-reperfusion in humans. This observation supports the concept that during diseases characterized by dysfunction in nitric oxide metabolism, inhaled nitric oxide may be an effective therapy to replenish systemic nitric oxide, thus retarding inflammatory-mediated injury.     

Mitochondrial involvement in psychiatric disorders

Recent findings of mitochondrial abnormalities in brains from subjects with neurological disorders have led to a renewed search for mitochondrial abnormalities in psychiatric disorders. A growing body of evidence suggests that there is mitochondrial dysfunction in schizophrenia, bipolar disorder, and major depressive disorder, including evidence from electron microscopy, imaging, gene expression, genotyping, and sequencing studies. Specific evidence of dysfunction such as increased common deletion and decreased gene expression in mitochondria in psychiatric illnesses suggests that direct examination of mitochondrial DNA from postmortem brain cells may provide further details of mitochondrial alterations in psychiatric disorders.