Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin.

The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers.

Comparison of lipid and calorie loss from donor human milk among 3 methods of simulated gavage feeding: one-hour, 2-hour, and intermittent gravity feedings.

PURPOSE: The objective of this study was to compare the differences in lipid loss from 24 samples of banked donor human milk (DHM) among 3 feeding methods: DHM given by syringe pump over 1 hour, 2 hours, and by bolus/gravity gavage. DESIGN: Comparative, descriptive. There were no human subjects. METHODS: Twenty-four samples of 8 oz of DHM were divided into four 60-mL aliquots. Timed feedings were given by Medfusion 2001 syringe pumps with syringes connected to narrow-lumened extension sets designed for enteral feedings and connected to standard silastic enteral feeding tubes. Gravity feedings were given using the identical syringes connected to the same silastic feeding tubes. All aliquots were analyzed with the York Dairy Analyzer. Univariate repeated-measures analyses of variance were used for the omnibus testing for overall differences between the feeding methods. Lipid content expressed as grams per deciliter at the end of each feeding method was compared with the prefed control samples using the Dunnett's test. The Tukey correction was used for other pairwise multiple comparisons. RESULTS: The univariate repeated-measures analysis of variance conducted to test for overall differences between feeding methods showed a significant difference between the methods (F = 58.57, df = 3, 69, P < .0001). Post hoc analysis using the Dunnett's approach revealed that there was a significant difference in fat content between the control sample and the 1-hour and 2-hours feeding methods (P < .0001), but we did not find any significant difference in fat content between the control and the gravity feeding methods (P = .3296). Pairwise comparison using the Tukey correction revealed a significant difference between both gravity and 1-hour feeding methods (P < .0001), and gravity and 2-hour feeding method (P < .0001). There was no significant difference in lipid content between the 1-hour and 2-hour feeding methods (P = .2729). CONCLUSIONS: Unlike gravity feedings, the timed feedings resulted in a statistically significant loss of fat as compared with their controls. These findings should raise questions about how those infants in the neonatal intensive care unit are routinely gavage fed.

Considering elderly competence when consenting to treatment.

The older adult population is growing rapidly with various comorbidities for health care providers to consider. Additional treatments and procedures are often implemented to care for the aging adults with comorbidities. Informed consent is involved with any invasive procedure or treatment and requires a cognizant patient who can give verbal or written consent, often a challenge for caregivers of the elderly. This article provides examples of assessment tools to utilize while assessing the older adults. Increased awareness of the available options to aid in determining cognitive function of the older adults is paramount when obtaining informed consent.

Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology.

BACKGROUND: Reporting methodology is highly variable and nonstandardized, yet surgical outcomes are utilized in clinical trial design and evaluation of healthcare provider performance. OBJECTIVE: We sought to define the type, incidence, and severity of early postoperative morbidities following radical cystectomy (RC) using a standardized reporting methodology. DESIGN, SETTING, AND PARTICIPANTS: Between 1995 and 2005, 1142 consecutive RCs were entered into a prospective complication database and retrospectively reviewed for accuracy. All patients underwent RC/urinary diversion by high-volume fellowship-trained urologic oncologists. MEASUREMENTS: All complications within 90 d of surgery were analyzed and graded according to the Memorial Sloan-Kettering Cancer Center complication grading system. Complications were defined and stratified into 11 specific categories. Univariate and multivariate regression models were used to define predictors of complications. RESULTS AND LIMITATIONS: Sixty-four percent (735/1142) of patients experienced a complication within 90 d of surgery. Among patients experiencing a complication, 67% experienced a complication during the operative hospital admission and 58% following discharge. Overall, the highest grade of complication was grade 0 in 36% (n=407), grade 1-2 in 51% (n=582), and grade 3-5 in 13% (n=153). Gastrointestinal complications were most common (29%), followed by infectious complications (25%) and wound-related complications (15%). The 30-d mortality rate was 1.5%. CONCLUSIONS: Surgical morbidity following RC is significant and, when strict reporting guidelines are incorporated, higher than previously published. Accurate reporting of postoperative complications after RC is essential for counseling patients, combined modality treatment planning, clinical trial design, and assessment of surgical success.

Chemopreventive efficacy of topical difluoromethylornithine and/or triamcinolone in the treatment of actinic keratoses analyzed by karyometry.

OBJECTIVE: To determine whether low-dose topical applications of difluoromethylornithine (DFMO) with or without Triamcinolone (Fougena, Melville, New York, U.S.A.) to moderately sun-damaged skin with actinic skin keratoses are efficacious. STUDY DESIGN: There were 4 topically administered, 6-month treatments, DFMO + Eucerin (Beiersdorf Inc., Hamburg, Germany), DFMO + Triamcinolone, Triamcinolone + Eucerin and Eucerin + Eucerin (to serve as double placebo). Participant eligibility included evidence of at least 2 actinic keratoses on each posterolateral forearm as well as moderate to severe evidence of sun-damaged skin, as evaluated by a board certified dermatologist. High resolution digitized imagery of nuclei from histologic sections of 4-mm punch biopsies from sun-damaged skin on the posterolateral forearms was recorded, at baseline and at the end of 6 months of study. RESULTS: With 102 participants and 185 skin biopsies, a total of 16,395 skin cell nuclei were recorded. The nuclei were analyzed to assess the changes in the pattern of the nuclear chromatin. Two specific measures of end point evaluation were computed, including the percentage of nuclei with high values of nuclear abnormality and the reduction of the percentage of nuclei assigned by a discriminant function to the baseline data set. All 3 active interventions, including low-dose topical DFMO, topical Triamcinolone and topical DFMO + Triamcinolone, led to statistically significant reductions of both the number of nuclei with high nuclear abnormality as well as the number of nuclei assigned to the baseline data set. These reductions were found for all 3 treatments involving DFMO or Triamcinolone. For the placebo data sets only small, statistically insignificant increases or decreases of these percentages were observed. CONCLUSION: The low-dose, topical drug interventions were all effective in reducing skin biopsy nuclear abnormality by a statistically significant 15-20%, whereas there was no evidence of a double placebo effect by karyometric assessment. These effects were greater than the case-to-case sampling error.

Cross-validation of murine UV signal transduction pathways in human skin.

Acute UVB irradiation of mouse skin results in activation of phospatidyinositol-3 (PI-3) kinase and mitogen-activated protein kinase (MAPK) pathways leading to altered protein phosphorylation and downstream transcription of genes. We determined whether activation of these pathways also occurs in human skin exposed to 4x minimal erythemic dose of UVB in 23 volunteers. Biopsies were taken prior to, at 30 min, 1 and 24 h post-UVB. In agreement with mouse studies, the earliest UV-induced changes in epidermis were seen in phospho-CREB (two- and five-fold at 30 min and 1 h) and in phospho-MAPKAPK-2 (three-fold at both 30 min and 1 h). At 1 h, phospho-c-JUN and phospho-p38 were increased five- and two-fold, respectively. Moreover, phospho-c-JUN and phospho-p38 were further increased at 24 h (12- and six-fold, respectively). Phospho-GSK-3beta was similarly increased at all time points. Increases in phospho-p53 (12-fold), COX-2 (four-fold), c-FOS (14-fold) and apoptosis were not seen until 24 h. Our data suggest that UVB acts through MAPK p38 and PI-3 kinase with phosphorylation of MAPKAPK-2, CREB, c-JUN, p38, GSK-3beta and p53 leading to marked increases in c-FOS, COX-2 and apoptosis. Validation of murine models in human skin will aid in development of effective skin cancer chemoprevention and prevention strategies.

The WORD (wholeness, oneness, righteousness, deliverance): a faith-based weight-loss program utilizing a community-based participatory research approach.

Despite multidisciplinary efforts to control the nation's obesity epidemic, obesity has persisted as one of the U.S.'s top public health problems, particularly among African Americans. Innovative approaches to address obesity that are sensitive to the unique issues of African Americans are needed. Thus, a faith-based weight-loss intervention using a community-based participatory research approach was developed, implemented, and evaluated with a rural African American faith community. A two-group, quasi-experimental, delayed intervention design was used, with church as the unit of assignment (treatment n=2, control n=2) and individual as the unit of observation (treatment n=36, control n=37). Weekly small groups led by trained community members met for 8 weeks and emphasized healthy nutrition, physical activity, and faith's connection with health. The mean weight loss of the treatment group was 3.60+/-0.64 lbs. compared to the 0.59+/-0.59-lb loss of the control group.

Exercise and hypertension.

BACKGROUND: Exercise is advocated for the prevention, treatment and control of hypertension. However, the treatment effect of exercise on hypertension is difficult to determine as many studies are poorly controlled and involve small sample sizes. OBJECTIVE: This article reviews current knowledge about exercise and blood pressure (BP), and provides a guideline for exercise prescription that considers the health status and age of the patient. DISCUSSION: An evidence based literature analysis by the American College of Sports Medicine indicates that an isolated exercise session (acute effect) lowers BP an average of 5-7 mmHg. Depending upon the degree the patient's BP has been normalised by drug therapy, regular aerobic exercise significantly reduces BP the equivalent of 1 class of antihypertensive medication (chronic effect). For most hypertensive patients exercise is quite safe. Caution is required for those over 50 years of age, and those with established cardiovascular disease (CVD) (or at high CVD risk) and in these patients, the advice of a clinical exercise physiologist is recommended.