Pressure-garment therapy for preventing hypertrophic scarring after burn injury.

BACKGROUND: Burn damage to skin often results in scarring; however in some individuals the failure of normal wound-healing processes results in excessive scar tissue formation, termed 'hypertrophic scarring'. The most commonly used method for the prevention and treatment of hypertrophic scarring is pressure-garment therapy (PGT). PGT is considered standard care globally; however, there is continued uncertainty around its effectiveness. OBJECTIVES: To evaluate the benefits and harms of pressure-garment therapy for the prevention of hypertrophic scarring after burn injury. SEARCH METHODS: We used standard, extensive Cochrane search methods. We searched CENTRAL, MEDLINE, Embase, two other databases, and two trials registers on 8 June 2023 with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing PGT (alone or in combination with other scar-management therapies) with scar management therapies not including PGT, or comparing different PGT pressures or different types of PGT. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected trials for inclusion using predetermined inclusion criteria, extracted data, and assessed risk of bias using the Cochrane RoB 1 tool. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 15 studies in this review (1179 participants), 14 of which (1057 participants) presented useable data. The sample size of included studies ranged from 17 to 159 participants. Most studies included both adults and children. Eight studies compared a pressure garment (with or without another scar management therapy) with scar management therapy alone, five studies compared the same pressure garment at a higher pressure versus a lower pressure, and two studies compared two different types of pressure garments. Studies used a variety of pressure garments (e.g. in-house manufactured or a commercial brand). Types of scar management therapies included were lanolin massage, topical silicone gel, silicone sheet/dressing, and heparin sodium ointment. Meta-analysis was not possible as there was significant clinical and methodological heterogeneity between studies. Main outcome measures were scar improvement assessed using the Vancouver Scar Scale (VSS) or the Patient and Observer Scar Assessment Scale (POSAS) (or both), pain, pruritus, quality of life, adverse events, and adherence to therapy. Studies additionally reported a further 14 outcomes, mostly individual scar parameters, some of which contributed to global scores on the VSS or POSAS. The amount of evidence for each individual outcome was limited. Most studies had a short follow-up, which may have affected results as the full effect of any therapy on scar healing may not be seen until around 18 months. PGT versus no treatment/lanolin We included five studies (378 participants). The evidence is very uncertain on whether PGT improves scars as assessed by the VSS compared with no treatment/lanolin. The evidence is also very uncertain for pain, pruritus, adverse events, and adherence. No study used the POSAS or assessed quality of life. One additional study (122 participants) did not report useable data. PGT versus silicone We included three studies (359 participants). The evidence is very uncertain on the effect of PGT compared with silicone, as assessed by the VSS and POSAS. The evidence is also very uncertain for pain, pruritus, quality of life, adverse events, adherence, and other scar parameters. It is possible that silicone may result in fewer adverse events or better adherence compared with PGT but this was also based on very low-certainty evidence. PGT plus silicone versus no treatment/lanolin We included two studies (200 participants). The evidence is very uncertain on whether PGT plus silicone improves scars as assessed by the VSS compared with no treatment/lanolin. The evidence is also very uncertain for pain, pruritus, and adverse events. No study used the POSAS or assessed quality of life or adherence. PGT plus silicone versus silicone We included three studies (359 participants). The evidence is very uncertain on the effect of PGT plus silicone compared with silicone, as assessed by the VSS and POSAS. The evidence is also very uncertain for pain, pruritus, quality of life, adverse events, and adherence. PGT plus scar management therapy including silicone versus scar management therapy including silicone We included one study (88 participants). The evidence is very uncertain on the effect of PGT plus scar management therapy including silicone versus scar management therapy including silicone, as assessed by the VSS and POSAS. The evidence is also very uncertain for pain, pruritus, quality of life, adverse events, and adherence. High-pressure versus low-pressure garments We included five studies (262 participants). The evidence is very uncertain on the effect of high pressure versus low pressure PGT on adverse events and adherence. No study used the VSS or the POSAS or assessed pain, pruritus, or quality of life. Different types of PGT (Caroskin Tricot + an adhesive silicone gel sheet versus Gecko Nanoplast (silicone gel bandage)) We included one study (60 participants). The evidence is very uncertain on the effect of Caroskin Tricot versus Gecko Nanoplast on the POSAS, pain, pruritus, and adverse events. The study did not use the VSS or assess quality of life or adherence. Different types of pressure garments (Jobst versus Tubigrip) We included one study (110 participants). The evidence is very uncertain on the adherence to either Jobst or Tubigrip. This study did not report any other outcomes. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend using either PGT or an alternative for preventing hypertrophic scarring after burn injury. PGT is already commonly used in practice and it is possible that continuing to do so may provide some benefit to some people. However, until more evidence becomes available, it may be appropriate to allow patient preference to guide therapy.

Measuring Inflammation in the Vitreous and Retina: A Narrative Review.

Uveitis consists of a group of syndromes characterised by intraocular inflammation, accounting for up to 15% of visual loss in the western world and 10% worldwide. Assessment of intraocular inflammation has been limited to clinician-dependent, subjective grading. Developments in imaging technology, such as optical coherence tomography (OCT), have enabled the development of objective, quantitative measures of inflammatory activity. Important quantitative metrics including central macular thickness and vitreous signal intensity allow longitudinal monitoring of disease activity and can be used in conjunction with other imaging modalities enabling holistic assessment of ocular inflammation. Ongoing work into the validation of instrument-based measures alongside development of core outcome sets is crucial for standardisation of clinical trial endpoints and developing guidance for quantitative multi-modal imaging approaches. This review outlines methods of grading inflammation in the vitreous and retina, with a focus on the use of OCT as an objective measure of disease activity.

Higher religiosity and spirituality are associated with ethnic group membership among middle-aged and older adults living with HIV.

Background: HIV is a chronic illness that impacts the lives of more than 1 million people in the United States. As persons living with HIV (PWH) are living longer, it is important to understand the influence that religiosity/spirituality has among middle-aged and older PWH.Objective: Compare the degree of religiosity/spirituality among middle-aged and older PWH and HIV-negative individuals, and to identify demographic, clinical, and psychosocial factors associated with religiosity/spirituality among PWH.Method: Baseline data on 122 PWH and 92 HIV-negative individuals (ages 36-65 years; 61.1% Non-Hispanic White) from a longitudinal study were analyzed for the current study. Recruitment occurred through HIV treatment clinics and community organizations in San Diego. Participants completed questionnaires on religiosity, spirituality, and psychosocial functioning. Independent samples t-tests, Pearson correlations, and multiple linear regression analyses were conducted to test the study objective.Results: No significant differences in religiosity/spirituality were found between PWH and HIV-negative individuals. Demographic and psychosocial variables were unrelated to religiously/spirituality among HIV-negative individuals. Among PWH, multiple linear regression models indicated higher daily spirituality was significantly associated with racial/ethnic minority membership (Hispanic/Latino, African American/Black, or Other), fewer years of estimated duration of HIV, greater social support, and higher grit. Greater engagement in private religious practices was significantly associated with racial/ethnic minority membership and higher social support.Conclusions: For PWH, being a racial/ethnic minority and having higher social support was associated with greater engagement in religious/spiritual practices. Future longitudinal studies should examine whether religion/spirituality impacts well-being across the lifespan among racial/ethnic minority groups of PWH.

Influence of humectants on the thermotropic behaviour and nanostructure of fully hydrated lecithin bilayers.

Humectants are used widely in topical formulations as they provide cosmetic and health benefits to skin. Of particular interest to our laboratories is the interaction of humectants in phospholipid based topical skin care formulations. This study probed the effects of three exemplary humectants on a fully hydrated lecithin system (DPPC) by use of X-ray scattering and differential scanning calorimetry. While the three humectants affected the nanostructure of 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC, bilayers in a similar manner, leading to an increased membrane order, differences in the effect on the thermal behaviour of DPPC suggest that betaine and sarcosine interacted via a different mechanism compared to acetic monoethanolamide, AMEA. At concentrations above 0.4 M, betaine and sarcosine stabilised the gel phase by depletion of the interfacial water via the preferential exclusion mechanism. At the same time, a slight increase in the rigidity of the membrane was observed with an increase in the membrane thickness. Overall, the addition of betaine or sarcosine resulted in an increase in the pre- and main transition temperatures of DPPC. AMEA, on the other hand, decreases both transition temperatures, and although the interlamellar water layer was also decreased, there was evidence from the altered lipid chain packing, that AMEA molecules are present also at the bilayer interface, at least at high concentrations. Above the melting point in the fluid lamellar phase, none of the humectants induced significant structural changes, neither concerning the bilayer stacking order nor its overall membrane fluidity. An humectant-induced increase in the Hamaker constant is the most plausible explanation for the observed reduction of the inter-bilayer distances, both in the gel and fluid phase.

A series of in vitro and human studies of a novel lip cream formulation for protecting against environmental triggers of recurrent herpes labialis.

PURPOSE: These studies describe the testing of a novel, daily-use lip cream designed for individuals with lips prone to recurrent herpes labialis (RHL) that protects against environmental triggers. SUBJECTS AND METHODS: In vitro occlusive and in vitro and in vivo photoprotection analyses, a characterization of normal vs dry lips, and a randomized, evaluator-blinded, clinical trial that assessed the lip cream in healthy subjects with dry lips were conducted. In the clinical trial, subjects applied the lip cream or were untreated and evaluated using transepidermal water loss (TEWL), corneometry, visual assessments of lip dryness, expert photographic evaluations, and subject-rated outcomes. RESULTS: The lip cream's in vitro water vapor transmission rate (84.1 g/(m2 h)) indicated moderate occlusivity. The lip cream, but not placebo or control (water), reduced ultraviolet A (UVA)- and UVB-induced DNA damage, and tumor necrosis factor-α (EpiDermFT) and pros-taglandin E2 release (EpiDermFT and EpiGingival™). The lip cream's in vivo sun protection factor (SPF) was 12.2 (lower confidence limit, 11.3) and SPF/UVA protection factor ratio was 0.9. The characterization of dry vs normal lips identified differences in moisturization. In the clinical trial, the lip cream significantly decreased TEWL (difference: -7.19 [95% CI: -11.41, -2.98]; P<0.01), increased corneometry (difference: 4.62 [95% CI: 1.05, 8.19]; P<0.05), and reduced visual dryness (difference: -1.48 [95% CI: 2.24, -0.71]; P<0.001) compared to untreated subjects. Significant benefits were also observed on expert photographic assessments of scaling (difference: -0.89 [95% CI: -1.75, -0.03]; P< 0.05), cupping (difference: -1.50 [95% CI: -2.30, -0.70]; P<0.001), and healthy appearance (difference: -1.44 [95% CI: -2.29, -0.58]; P<0.01); differences in overall healthy appearance were not significant (P=0.51). Subject-rated assessments indicated improvements in cracking, dryness, and flaking in the lip cream group but worsening in untreated subjects. CONCLUSION: These studies indicate that this novel, daily-use lip cream protects against UV radiation, drying, and chapping, which are established environmental RHL triggers.

Effects of acute dietary nitrate supplementation on aortic blood pressures and pulse wave characteristics in post-menopausal women.

PURPOSE: Consumption of nitrate-rich beetroot juice can lower blood pressure in peripheral as well as central arteries and may exert additional hemodynamic benefits (e.g. reduced aortic wave reflections). The specific influence of nitrate supplementation on arterial pressures and aortic wave properties in postmenopausal women, a group that experiences accelerated increases in these variables with age, is unknown. Accordingly, the primary aim of this study was to determine the effect of consuming nitrate-rich beetroot juice on resting brachial and aortic blood pressures (BP) and pulse wave characteristics in a group of healthy postmenopausal women, in comparison to a true (nitrate-free beetroot juice) placebo. METHODS: Brachial (oscillometric cuff) and radial (SphygmoCor) pressures and derived-aortic waveforms were measured during supine rest in thirteen healthy postmenopausal women (63 ±â€¯1 yr) before and 100 min after consumption of 140 ml of either nitrate-rich (9.7 mmol, 0.6 gm NO3-) or nitrate-depleted beetroot juice on randomized visits approximately 10 days apart (cross-over design). Ten young premenopausal women (22 ±â€¯1 yr) served as a reference (non-supplemented) cohort. RESULTS: Brachial and derived-aortic variables showed the expected age-associated differences in these women (all p < 0.05). In post-menopausal women, nitrate supplementation reduced (p < 0.05 vs. placebo visit) brachial systolic BP (BRnitrate -4.9 ±â€¯2.1 mmHg vs BRplacebo +1.1 ± 1.8 mmHg), brachial mean BP (BRnitrate -4.1 ±â€¯1.7 mmHg vs BRplacebo +0.9 ± 1.3 mmHg), aortic systolic BP (BRnitrate -6.3 ±â€¯2.0 mmHg vs BRplacebo +0.5 ± 1.7 mmHg) and aortic mean BP (BRnitrate -4.1 ±â€¯1.7 mmHg vs BRplacebo +0.9 ± 1.3 mmHg), and increased pulse pressure amplification (BRnitrate +4.6 ± 2.0% vs BRplacebo +0.7 ± 2.5%, p = 0.04), but did not alter aortic pulse wave velocity or any other derived-aortic variables (e.g., augmentation pressure or index). CONCLUSIONS: Dietary nitrate supplementation favorably modifies aortic systolic and mean blood pressure under resting conditions in healthy postmenopausal women. Acute supplementation of nitrate does not, however, appear to restore indices of aortic stiffness in this group. Future work should evaluate chronic, long-term effects of this non-pharmacological supplement.

Effect of rectal douching/enema on rectal gonorrhoea and chlamydia among a cohort of men who have sex with men on HIV pre-exposure prophylaxis.

OBJECTIVES: Rectal douching/enema (RD) is a common practice among men who have sex with men (MSM) in preparation for sex. RD can break down the rectal mucosal barrier and potentially affect the rectal microbiome. The objective of this study was to understand if RD is associated with acquiring rectal infections (RI) with rectal gonorrhoea (NG) and/or chlamydia (CT). METHODS: From 2013 to 2015, 395 adult HIV-uninfected MSM were enrolled in a randomised controlled study for pre-exposure prophylaxis (PrEP) adherence with routine sexual risk survey and testing. Using data from this cohort, baseline differences by RI were assessed using Pearson's χ² and Wilcoxon-Mann-Whitney test. Association between RD and RI was modelled using multivariable logistic regression adjusted for potential confounders (sexual behaviour, substance use and age) selected a priori. Effect modification by number of male partners and sensitivity analysis to rule out reverse causality were also conducted. RESULTS: Of 395 participants, 261 (66%) performed RD and 133 (33%) had at least one NG/CT RI over 48 weeks. Number of condomless anal receptive sex (med: 4, p<0.001), male partners (med:6, p<0.001) and substance use (any of methamphetamine/hallucinogens/dissociative/poppers) (p<0.001) were associated with increased odds of RI. Controlling for potential confounders, odds of prevalent RI were 3.59 (p<0.001, 95% CI 1.90 to 6.78) and incident RI 3.87 (p=0.001, 95% CI 1.78 to 8.39) when douching weekly or more compared with not douching. MSM with more than six male partners had 5.34 (p=0.002, 95% CI 1.87 to 15.31) increased odds of RI when douching weekly or more compared with not douching. CONCLUSION: Rectal hygiene with RD is a common practice (66%) among HIV-uninfected MSM on PrEP in this study, which increases the odds of acquiring rectal NG and/or CT independent of sexual risk behaviour, substance use and other factors. This suggests interventional approaches targeting rectal hygiene products and practices could reduce sexually transmitted infections.

Lifetime methamphetamine dependence is associated with cerebral microgliosis in HIV-1-infected adults.

Methamphetamine (Meth) use is common among HIV-infected persons. It remains unclear whether Meth dependence is associated with long-lasting degenerative changes in the brain parenchyma and microvasculature of HIV-infected individuals. We examined the postmortem brains of 78 HIV-infected adults, twenty of whom were diagnosed with lifetime Meth dependence (18 past and two current at the final follow-up visit). Using logistic regression models, we analyzed associations of Meth with cerebral gliosis (immunohistochemistry for ionized calcium-binding adapter molecule-1 (Iba1) and glial fibrillary acidic protein (GFAP) in frontal, temporo-parietal, and putamen-internal capsule regions), synaptodendritic loss (confocal microscopy for synaptophysin (SYP) and microtubule-associated protein-2 (MAP2) in frontal cortex), ß-amyloid plaque deposition (immunohistochemistry in frontal and temporo-parietal cortex and putamen), and arteriolosclerosis (histopathology in forebrain white matter). We found that Meth was associated with marked Iba1 gliosis in the temporo-parietal region (odds ratio, 4.42 (95 % confidence interval, 1.36, 14.39), p = 0.014, n = 62), which remained statistically significant after adjusting for HIV encephalitis, white matter lesions, and opportunistic diseases (n = 61); hepatitis C virus seropositivity (n = 54); and lifetime dependence on alcohol, opiates, and cannabis (n = 62). There was no significant association of Meth with GFAP gliosis, SYP or MAP2 loss, ß-amyloid plaque deposition, or arteriolosclerosis. In conclusion, we found lifetime Meth dependence to be associated with focal cerebral microgliosis among HIV-infected adults, but not with other brain degenerative changes examined. Some of the changes in select brain regions might be reversible following extended Meth abstinence or, alternatively, might have not been induced by Meth initially.

Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV.

The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) remains puzzling. We interrogated several levels of data (host genetic, histopathology, brain viral load, and neurocognitive) to identify histopathological changes most relevant to HAND. The design of the study is a clinicopathological study employing genetic association analyses. Data and brain tissue from 80 HIV-infected adults were used. Markers in monocyte chemoattractant protein-1 (MCP-1), interleukin 1-alpha (IL1-α), macrophage inflammatory protein 1-alpha (MIP1-α), DRD3, DRD2, and apolipoprotein E (ApoE) were genotyped. Microtubule associated protein 2 (MAP2), synaptophysin (SYP), human leukocyte antigen-DR (HLA-DR), glial fibrillary acidic protein (GFAP), amyloid beta (A-Beta), and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactivity were quantified in the frontal cortex, putamen, and hippocampus. A composite score for each marker (mean of the three brain regions) was used. Neurocognitive functioning and other clinical variables were determined within 1 year of death. Brain HIV RNA viral load was available for a subset of cases. MAP2 and SYP proved most relevant to neurocognitive functioning. Immunoreactivity of these markers, as well as A-Beta and Iba-1, was correlated with brain HIV RNA viral load. Several genetic markers in combination with other factors predicted histopathology: HIV blood viral load, MIP1-α genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-α genotype predicted GFAP immunoreactivity; ApoE genotype and age at death predicted A-Beta immunoreactivity. These data indicate that HIV replication in the brain is the primary driving force leading to neuroinflammation and dysfunctional protein clearance, as reflected by A-Beta and Iba-1. Downstream to these changes are synaptodendritic degeneration, which is the immediate histopathological substrate of the neurocognitive impairment characteristic of HAND. These intermediate histopathological phenotypes are influenced by host genetic polymorphisms in genes encoding cytokines/chemokines, neuronal protein clearance pathways, and dopaminergic factors.

Changes in soil biogeochemistry following disturbance by girdling and mountain pine beetles in subalpine forests.

A recent unprecedented epidemic of beetle-induced tree mortality has occurred in the lodgepole pine forests of Western North America. Here, we present the results of studies in two subalpine forests in the Rocky Mountains, one that experienced natural pine beetle disturbance and one that experienced simulated disturbance imposed through bole girdling. We assessed changes to soil microclimate and biogeochemical pools in plots representing different post-disturbance chronosequences. High plot tree mortality, whether due to girdling or beetle infestation, caused similar alterations in soil nutrient pools. During the first 4 years after disturbance, sharp declines were observed in the soil dissolved organic carbon (DOC) concentration (45-51 %), microbial biomass carbon concentration (33-39 %), dissolved organic nitrogen (DON) concentration (31-42%), and inorganic phosphorus (PO4(3-)) concentration (53-55%). Five to six years after disturbance, concentrations of DOC, DON, and PO4(3-) recovered to 71-140 % of those measured in undisturbed plots. Recovery was coincident with observed increases in litter depth and the sublitter, soil O-horizon. During the 4 years following disturbance, soil ammonium, but not nitrate, increased to 2-3 times the levels measured in undisturbed plots. Microbial biomass N increased in plots where increased ammonium was available. Our results show that previously observed declines in soil respiration following beetle-induced disturbance are accompanied by losses in key soil nutrients. Recovery of the soil nutrient pool occurs only after several years following disturbance, and is correlated with progressive mineralization of dead tree litter.

Acute dietary nitrate supplementation does not augment submaximal forearm exercise hyperemia in healthy young men.

Despite the popularity of dietary nitrate supplementation and the growing evidence base of its potential ergogenic and vascular health benefits, there is no direct information about its effects on exercising limb blood flow in humans. We hypothesized that acute dietary nitrate supplementation from beetroot juice would augment the increases in forearm blood flow, as well as the progressive dilation of the brachial artery, during graded handgrip exercise in healthy young men. In a randomized, double-blind, placebo-controlled crossover study, 12 young (22 ± 2 years) healthy men consumed a beetroot juice (140 mL Beet-It Sport, James White Juice Company) that provided 12.9 mmol (0.8 g) of nitrate or placebo (nitrate-depleted Beet-It Sport) on 2 study visits. At 3 h postconsumption, brachial artery diameter, flow, and blood velocity were measured (Doppler ultrasound) at rest and during 6 exercise intensities. Nitrate supplementation raised plasma nitrate (19.5-fold) and nitrite (1.6-fold) concentrations, and lowered resting arterial pulse wave velocity (PWV) versus placebo (all p < 0.05), indicating absorption, conversion, and a biological effect of this supplement. The supplement-associated lowering of PWV was also negatively correlated with plasma nitrite (r = -0.72, p = 0.0127). Despite these systemic effects, nitrate supplementation had no effect on brachial artery diameter, flow, or shear rates at rest (all p ≥ 0.28) or during any exercise workload (all p ≥ 0.18). These findings suggest that acute dietary nitrate supplementation favorably modifies arterial PWV, but does not augment blood flow or brachial artery vasodilation during nonfatiguing forearm exercise in healthy young men.

Metabolic activation of the indoloquinazoline alkaloids evodiamine and rutaecarpine by human liver microsomes: dehydrogenation and inactivation of cytochrome P450 3A4.

Evodiamine and rutaecarpine are the main active indoloquinazoline alkaloids of the herbal medicine Evodia rutaecarpa, which is widely used for the treatment of hypertension, abdominal pain, angina pectoris, gastrointestinal disorder, and headache. Immunosuppressive effects and acute toxicity were reported in mice treated with evodiamine and rutaecarpine. Although the mechanism remains unknown, it is proposed that metabolic activation of the indoloquinazoline alkaloids and subsequent covalent binding of reactive metabolites to cellular proteins play a causative role. Liquid chromatography-tandem mass spectrometry analysis of incubations containing evodiamine and NADPH-supplemented microsomes in the presence of glutathione (GSH) revealed formation of a major GSH conjugate which was subsequently indentified as a benzylic thioether adduct on the C-8 position of evodiamine by NMR analysis. Several other GSH conjugates were also detected, including conjugates of oxidized and demethylated metabolites of evodiamine. Similar GSH conjugates were formed in incubations with rutaecarpine. These findings are consistent with a bioactivation sequence involving initial cytochrome P450-catalyzed dehydrogenation of the 3-alkylindole moiety in evodiamine and rutaecarpine to an electrophile 3-methyleneindolenine. Formation of the evodiamine and rutaecarpine GSH conjugates was primarily catalyzed by heterologously expressed recombinant CYP3A4 and, to a lesser extent, CYP1A2 and CYP2D6, respectively. It was found that the 3-methyleneindolenine or another reactive intermediate was a mechanism-based inactivator of CYP3A4, with inactivation parameters KI = 29 µM and kinact = 0.029 minute(-1), respectively. In summary, these findings are of significance in understanding the bioactivation mechanisms of indoloquinazoline alkaloids, and dehydrogenation of evodiamine and rutaecarpine may cause toxicities through formation of electrophilic intermediates and lead to drug-drug interactions mainly via CYP3A4 inactivation.

Radiolabeled mass-balance excretion and metabolism studies in laboratory animals: a commentary on why they are still necessary.

The necessity of conducting traditional radiolabeled absorption, distribution, metabolism and excretion (ADME) studies in animals during development of new investigative agents has been questioned in a recent review. We present a compilation of the benefits of such studies in the understanding of the in vivo pharmacological activity and disposition of new drug candidates, including interpretation of preclinical toxicology findings, characterization of circulating metabolites, and determination of principal pathways of clearance. This understanding is valuable in anticipating the human disposition of the drugs and the planning of the clinical development program. Because of new technologies, evolving regulatory expectations, and increased scientific understanding of the disposition of drugs, the traditional design and timing of both animal and human ADME studies should be reviewed. Innovative "fit-for-purpose" studies may well be a better choice in a particular drug development program than a standard animal ADME "package". However, we submit that, at this time, radiolabeled animal ADME studies still provide a definitive and irreplaceable component of our understanding of the in vivo actions and behaviors of drugs and should continue to be performed prior to the exposure of large numbers of human subjects to investigative drugs.

A guide for considering performance-based assessments when determining a patient's capacity for safe, independent living.

Clinicians treating older adults are often asked to evaluate the everyday functioning capabilities of their patients. Difficulties with daily functioning are part of the diagnostic criteria for most neuropsychiatric disorders, including dementia. Many methods of assessing daily functioning exist, including self- or collateral reports (through clinical interview or structured rating scales), direct home- or community-based observations, and performance-based measures conducted within the clinic or laboratory. Performance-based measures use simulated or role-play functioning scenarios and have the key advantage of decreasing reporter bias; these instruments may provide complementary information to subjective reports and/or field observations. Thus, treating clinicians should consider incorporating performance-based assessments as part of the diagnostic process to establish (or rule out) presence of functioning impairments and when developing recommendations about a patient's capacity for safe independent living.

The need to decide if all estrogens are intrinsically similar.

We used gene expression profiling to investigate whether the molecular effects induced by estrogens of different provenance are intrinsically similar. In this article we show that the physiologic estrogen 17-beta-estradiol, the phytoestrogen genistein, and the synthetic estrogen diethylstilbestrol alter the expression of the same 179 genes in the intact immature mouse uterus under conditions where each chemical has produced an equivalent gravimetric and histologic uterotrophic effect, using the standard 3-day assay protocol. Data are also presented indicating the limitations associated with comparison of gene expression profiles for different chemicals at times before the uterotrophic effects are fully realized. We conclude that the case has yet to be made for regarding synthetic estrogens as presenting a unique human hazard compared with phytoestrogens and physiologic estrogens. Key words: diethylstilbestrol, estrogen, gene expression, genistein, microarray, phytoestrogen, toxicogenomics, uterus.