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Atorvastatin (ATV) is frequently prescribed and generally well tolerated, but can lead to myotoxicity, especially at higher doses. A genome-wide association study of circulating levels of ATV, 2-hydroxy (2-OH) ATV, ATV lactone (ATV L), and 2-OH ATV L was performed in 590 patients who had been hospitalized with a non-ST elevation acute coronary syndrome 1 month earlier and were on high-dose ATV (80 mg or 40 mg daily). The UGT1A locus (lead single nucleotide polymorphism, rs887829) was strongly associated with both increased 2-OH ATV/ATV (P = 7.25 × 10-16 ) and 2-OH ATV L/ATV L (P = 3.95 × 10-15 ) metabolic ratios. Moreover, rs45446698, which tags CYP3A7*1C, was nominally associated with increased 2-OH ATV/ATV (P = 6.18 × 10-7 ), and SLCO1B1 rs4149056 with increased ATV (P = 2.21 × 10-6 ) and 2-OH ATV (P = 1.09 × 10-6 ) levels. In a subset of these patients whose levels of ATV and metabolites had also been measured at 12 months after hospitalization (n = 149), all of these associations remained, except for 2-OH ATV and rs4149056 (P = 0.057). Clinically, rs4149056 was associated with increased muscular symptoms (odds ratio (OR) 3.97; 95% confidence interval (CI) 1.29-12.27; P = 0.016) and ATV intolerance (OR 1.55; 95% CI 1.09-2.19; P = 0.014) in patients (n = 870) primarily discharged on high-dose ATV. In summary, both novel and recognized genetic associations have been identified with circulating levels of ATV and its major metabolites. Further study is warranted to determine the clinical utility of genotyping rs4149056 in patients on high-dose ATV.

Given their established analgesic properties, nonsteroidal anti‐inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl‐β‐cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD‐diclofenac; and (2) the PK of HPβCD following administration of HPβCD‐diclofenac and intravenous itraconazole formulated with HPβCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half‐life, t½) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½. There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD‐diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (

The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting., “Amyloid‐beta accumulation cycle”. Amyloid‐beta accumulation occurs in early latent phase of Alzheimer's disease, triggering its pathology development, yet the mechanism has been elusive. This integrated hypothesis explains that amyloid‐beta accumulation occurs as a vicious cycle and offers insights on how the cycle may be interfered by cell cycle‐ or mitosis‐targeting drugs.

Objective:\ud \ud Many different gene families are currently being investigated for their potential role in epilepsy and in the response to antiepileptic drugs. A common research challenge is identifying the members of a gene family that are most significantly dysregulated within the human epileptic focus, before taking them forward for resource‐intensive functional studies. Published data about transcriptomic changes within the human epileptic focus remains incomplete. A need exists for an accurate in silico system for the prediction of dysregulated genes within the epileptic focus. We present such a bioinformatic system. We demonstrate the validity of our approach by applying it to the solute carrier (SLC) gene family. There are >400 known SLCs. SLCs have never been systematically studied in epilepsy.\ud Methods:\ud \ud Using our in silico system, we predicted the SLCs likely to be dysregulated in the epileptic focus. We validated our in silico predictions by identifying ex vivo the SLCs dysregulated in epileptic foci, and determining the overlap between our in silico and ex vivo results. For the ex vivo analysis, we used a custom oligonucleotide microarray containing exon probes for all known SLCs to analyze 24 hippocampal samples obtained from surgery for pharmacoresistant mesial temporal lobe epilepsy and 24 hippocampal samples from normal postmortem controls.\ud Results:\ud \ud There was a highly significant (p < 9.99 × 10−7) overlap between the genes identified by our in silico and ex vivo strategies. The SLCs identified were either metal ion exchangers or neurotransmitter transporters, which are likely to play a part in epilepsy by influencing neuronal excitability.\ud Significance:\ud \ud The identified SLCs are most likely to mediate pharmacoresistance in epilepsy by enhancing the intrinsic severity of epilepsy, but further functional work will be needed to fully evaluate their role. Our successful in silico strategy can be adapted in order to prioritize genes relevant to epilepsy from other gene families.

AIM: The aim was to evaluate clinical risk factors associated with myotoxicity in statin users. METHODS: This was a cohort study of patients prescribed a statin in UK primary care practices contributing to the Clinical Practice Research Datalink. Outcomes of interest were creatine phosphokinase (CPK) concentrations and clinical records of rhabdomyolysis. RESULTS: The cohort comprised 641,703 statin users. Simvastatin was most frequently prescribed (66.3%), followed by atorvastatin (24.4%). CPK was measured in 127,209 patients: 81.4% within normal range and 0.7% above four times ULN CPK compared with normal CPK (OR 1.28, 95% CI 1.01, 1.60). Rosuvastatin users had higher risk of >four times ULN CPK (OR 1.62, 95% CI 1.22, 2.15) as did patients with larger daily doses of other statin types. A recent clinical record of myalgia was associated with an increased OR of >four times ULN CPK (OR 1.73, 95% CI 1.37, 2.18). In patients who were rechallenged to statins and had repeat CPK measurements after >four times ULN CPK abnormalities, 54.8% of the repeat CPK values were within normal range, 32.1% between one to three times and 13.0% >four times ULN. CONCLUSIONS: The frequencies of substantive CPK increases and rhabdomyolysis during statin treatment were low, with highest risks seen in those on large daily doses or interacting drugs and on rosuvastatin. CPK measurements appeared to have been done in a haphazard manner and better guidance is needed.

AIMS: Electronic healthcare records (EHRs) are increasingly used to store clinical information. A secondary benefit of EHRs is their use, in an anonymized form, for observational research. The Clinical Practice Research Datalink (CPRD) contains EHRs from primary care in the UK and, despite 1083 peer-reviewed research publications, has never been used to obtain pharmacogenetic samples. Using a statin-induced myopathy paradigm, we evaluated using the CPRD to obtain patient samples for a pharmacogenetic study targeting 250 cases and 500 controls from UK general practitioner (GP) practices. METHODS: The CPRD identified potential patients fitting specific case-definition criteria (active rhabdomyolysis or creatine phosphokinase > four times the upper limit of normal), and corresponding GP practices were asked to invite patient participation. Consenting patients were requested to provide either saliva or blood samples and to complete an ethnicity questionnaire. Control subjects were recruited from the same GP practice (saliva) or a small number of practices (blood). Samples were forwarded for DNA extraction. RESULTS: Thirty-six months of recruitment yielded DNA samples from 149 statin-induced myopathy cases and 587 tolerant controls. Data show that contacting patients through their GP is a reliable method for obtaining samples without compromising anonymity. Saliva collection directly from patients was considerably less effective than blood sampling. After 10 months of recruitment, saliva sampling was suspended in favour of blood sampling. CONCLUSIONS: We demonstrate the potential of EHRs for identifying accurately phenotyped cases and controls for pharmacogenetic studies. Recruitment was successful only because of the willingness of GP practices to participate and the existence of strong doctor-patient relationships. The present study provides a model that can be implemented in future genetic analyses using EHRs.

Study Objective To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. Design Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. Setting Clinical research center. Subjects Healthy adult volunteers. Intervention Study 1: Subjects received HPβCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPβCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. Measurements and Main Results Study 1: IV HPβCD-diclofenac had a higher peak plasma concentration (Cmax) and earlier time to reach maximum plasma concentration (Tmax), but equivalent plasma exposure (area under the curve from time zero to t [AUC0–t]) to IV Voltarol. The geometric mean ratio of HPβCD-diclofenac (IV) to Voltarol (IV) for AUC0–t was 106.27%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IM) for AUC0–t was 110.91%. The geometric mean ratio of HPβCD-diclofenac (IV) to HPβCD-diclofenac (IM) for AUC0–t was 101.25%. The geometric mean ratio of HPβCD-diclofenac (IM) to Voltarol (IV) for AUC0–t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPβCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPβCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml). Conclusions Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPβCD-diclofenac compared with Voltarol and after IM administration of HPβCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPβCD-diclofenac was equivalent to IV administration of HPβCD-diclofenac and IV administration of Voltarol. Study 2: HPβCD-diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPβCD-diclofenac. HPβCD-diclofenac was safe and well tolerated following IV and IM administration.

This is the peer reviewed version of the following article: The Cochrane database of systematic reviews, which has been published in final form at https://doi.org/10.1002/14651858.CD004598.pub4. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Background: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews, 2005, Issue 4 (and last updated in the Cochrane Database of Systematic Reviews, 2013 issue 8), on local anaesthetic blockade (LASB) of the sympathetic chain to treat people with complex regional pain syndrome (CRPS). Objectives: To assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure. Search methods: For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE (Ovid), EMBASE (Ovid), LILACS (Birme), conference abstracts of the World Congresses of the International Association for the Study of Pain, and various clinical trial registers up to September 2015. We also searched bibliographies from retrieved articles for additional studies. Selection criteria: We considered randomised controlled trials (RCTs) that evaluated the effect of sympathetic blockade with local anaesthetics in children or adults with CRPS compared to placebo, no treatment, or alternative treatments. Data collection and analysis: We used standard methodological procedures expected by Cochrane. The outcomes of interest were reduction in pain intensity, the proportion who achieved moderate or substantial pain relief, the duration of pain relief, and the presence of adverse effects in each treatment arm. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table. Main results: We included an additional four studies (N = 154) in this update. For this update, we excluded studies that did not follow up patients for more than 48 hours. As a result, we excluded four studies from the previous review in this update. Overall we included 12 studies (N = 461), all of which we judged to be at high or unclear risk of bias. Overall, the quality of evidence was low to very low, downgraded due to limitations, inconsistency, imprecision, indirectness, or a combination of these. Two small studies compared LASB to placebo/sham (N = 32). They did not demonstrate significant short-term benefit for LASB for pain intensity (moderate quality evidence). One small study (N = 36) at high risk of bias compared thoracic sympathetic block with corticosteroid and local anaesthetic versus injection of the same agents into the subcutaneous space, reporting statistically significant and clinically important differences in pain intensity at one-year follow-up but not at short term follow-up (very low quality evidence). Of two studies that investigated LASB as an addition to rehabilitation treatment, the only study that reported pain outcomes demonstrated no additional benefit from LASB (very low quality evidence). Eight small randomised studies compared sympathetic blockade to various other active interventions. Most studies found no difference in pain outcomes between sympathetic block versus other active treatments (low to very low quality evidence). One small study compared ultrasound-guided LASB with non-guided LASB and found no clinically important difference in pain outcomes (very low quality evidence). Six studies reported adverse events, all with minor effects reported. Authors' conclusions: This update's results are similar to the previous versions of this systematic review, and the main conclusions are unchanged. There remains a scarcity of published evidence and a lack of high quality evidence to support or refute the use of local anaesthetic sympathetic blockade for CRPS. From the existing evidence, it is not possible to draw firm conclusions regarding the efficacy or safety of this intervention, but the limited data available do not suggest that LASB is effective for reducing pain in CRPS.

Summary Although environmental stress likely plays a significant role in promoting aging, the relationship remains poorly understood. To characterize this interaction in a more comprehensive manner, we examined the stress response profiles for 46 long-lived yeast mutant strains across four different stress conditions (oxidative, ER, DNA damage, and thermal), grouping genes based on their associated stress response profiles. Unexpectedly, cells lacking the mitochondrial AAA protease gene AFG3 clustered strongly with long-lived strains lacking cytosolic ribosomal proteins of the large subunit. Similar to these ribosomal protein mutants, afg3Δ cells show reduced cytoplasmic mRNA translation, enhanced resistance to tunicamycin that is independent of the ER unfolded protein response, and Sir2-independent but Gcn4-dependent lifespan extension. These data demonstrate an unexpected link between a mitochondrial protease, cytoplasmic mRNA translation, and aging.

To reevaluate and update evidence-based best practice recommendations published in 2004 for anesthetic perioperative care and pain management in weight loss surgery (WLS), we performed a systematic search of English-language literature on anesthetic perioperative care and pain management in WLS published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. We identified relevant abstracts by using key words, retrieved full text articles, and stratified the resulting evidence according to systems used in established evidence-based models. We updated prior evidence-based best practice recommendations based upon interim literature. In instances of controversial or inadequate scientific evidence, the task force reached consensus recommendations following evaluation of the best available information and expert opinion. The search yielded 1,788 abstracts, with 162 potentially relevant titles; 45 were reviewed in detail. Despite more information on perioperative management of patients with obstructive sleep apnea (OSA), evidence to support preoperative testing and treatment or to guide perioperative monitoring is scarce. New evidence on appropriate intraoperative dosing of muscle relaxants allows for greater precision in their use during WLS. A novel application of alpha-2 agonists for perioperative anesthetic care is emerging. Key elements that may enhance patient safety include integration of the latest evidence on WLS, obesity, and collaborative multidisciplinary care into clinical care. However, large gaps remain in the evidence base.

Polymeric networks and the ensuing hydrogels of MAA and NVP were successfully synthesized using a UV-initiated free radical polymerization and characterized to assess their applicability as carriers for directed drug delivery. FT-IR spectroscopy revealed shifts in peak absorbances that indicated the presence of hydrogen bonding complexes between functional groups, while SEM imaging showed that the different comonomers affect the surface morphology of the microparticles. Dynamic pH swelling studies demonstrated the pH responsiveness of the carriers in gastric and intestinal conditions and revealed that systems containing higher concentrations of MAA experienced the highest degree of hydrogen bonding complexation in gastric conditions. The presence of NVP in the systems enhanced swelling. Equilibrium swelling studies revealed that the mesh size was sufficiently large to allow drug diffusion across the networks.

Biphalin is an opioid peptide analogue that currently is under clinical development as a new type of site-directed analgesic. In rats, the intrathecal (i.t.) analgesic potency of biphalin is 1000-fold greater than morphine. Such a high activity may reflect this compound's activation of three types of opioid receptors (mu, delta and kappa). NMDA receptors also play an important role in nociceptive processing. Therefore, we investigated in rats whether an NMDA antagonist may influence biphalin-induced antinociception. In the present study, ketamine was chosen because of the widespread safe use of this drug in clinical practice. I.t. application of ketamine alone had relatively little analgesic effect and its excitatory effects limited possible doses of the drug. Co-administration of ketamine with biphalin or morphine produced markedly greater antinociception than biphalin or morphine alone in acute, thermal tail flick testing. These results suggest that NMDA antagonists may be useful potentiators of biphalin analgesia. Thus, to obtain the same spinal antinociceptive effect, lower doses of biphalin or morphine are required when ketamine is co-administered.

Dietary restriction increases lifespan and slows the onset of age-associated disease in organisms from yeast to mammals. In humans, several age-related diseases are associated with aberrant protein folding or aggregation, including neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. We report here that dietary restriction dramatically suppresses age-associated paralysis in three nematode models of proteotoxicity. Similar to its longevity-enhancing properties, dietary restriction protects against proteotoxicity by a mechanism distinct from reduced insulin/IGF-1-like signaling. Instead, the heat shock transcription factor, hsf-1, is required for enhanced thermotolerance, suppression of proteotoxicity, and lifespan extension by dietary restriction. These findings demonstrate that dietary restriction confers a general protective effect against proteotoxicity and promotes longevity by a mechanism involving hsf-1.

Summary Background: Pediatric sedation is of paramount importance but can be challenging. Fear and anticipatory anxiety before invasive procedures often lead to uncooperativeness. A novel device (PediSedate®) provides sedation through a combination of inhaled nitrous oxide and distraction (video game). We evaluated the acceptability and safety of the PediSedate® device in children. Methods: We enrolled children between 3 and 9 years old who were scheduled to undergo surgical procedures that required general inhalational anesthesia. After the device was applied, he/she played a video game while listening to the audio portion of the game through the earphones. Nitrous oxide in oxygen was administered via the nasal piece of the headset starting at 50% and increasing to 70%, in 10% increments every 8 min. Treatment failures, vital signs, arterial oxygen saturation, depth of sedation, airway patency, side effects, acceptance of the device and parental satisfaction were all evaluated. Results: Of 100 children included, treatment failure occurred in 18% mainly because of poor tolerance of the device. At least 96% of the children who completed the study exhibited an excellent degree of sedation, 22% had side effects, and none experienced serious airway obstruction. Nausea and vomiting were the most common side effects and no patients had hemodynamic instability. Conclusions: The PediSedate® device combines nonpharmacologic with pharmacologic methods of sedation. Most of the children we evaluated were able to tolerate the PediSedate® device and achieved an adequate degree of sedation.

Objective The sympathetic nervous system (SNS) seems to play a proinflammatory role in the early asymptomatic phase of arthritis, but its role in the late stages of chronic arthritis is not well known. The purpose of this study was to examine the effects of the SNS on late-stage chronic arthritis in mice with type II collagen–induced arthritis (CIA). Methods We tested the effects of the SNS by ablating sympathetic nerves at different time points in mice with CIA. Early sympathectomy was performed 7 days before immunization. Late sympathectomy was performed on day 56. Cytokine stimulation assays were performed on local lymph node cells and spleen cells, and levels of interleukin-10 (IL-10), IL-4, tumor necrosis factor α (TNFα), and interferon-γ (IFNγ) were determined. Results Animals with CIA that underwent early sympathectomy showed significantly lower arthritis scores than the controls. In contrast, animals that underwent late sympathectomy had significantly increased arthritis scores compared with controls. On day 0, lymph node cells from animals subjected to early sympathectomy had increased levels of IL-10 and IL-4 and unchanged levels of TNFα and IFNγ compared with those from untreated animals. This indicates an immune-stimulating property of the SNS in draining lymph nodes. On day 80, lymph node cells and spleen cells from animals subjected to late sympathectomy showed increased levels of TNFα and IFNγ compared with those from nonsympathectomized controls with CIA. This indicates an immune-depressing property of the SNS in draining lymph nodes and spleen. Arthritis per se largely diminished sympathetic nerve fiber density in synovium on day 80 (P < 0.01). Conclusion The effect of the SNS is bimodal, enhancing or depressing levels of proinflammatory and antiinflammatory cytokines. This feature is dependent on the time point of immune system activation and the respective compartment. The SNS supports inflammation during the asymptomatic phase of CIA, whereas it inhibits inflammation during the chronic symptomatic phase.

To reevaluate and update evidence-based best practice recommendations published in 2004 for anesthetic perioperative care and pain management in weight loss surgery (WLS), we performed a systematic search of English-language literature on anesthetic perioperative care and pain management in WLS published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. We identified relevant abstracts by using key words, retrieved full text articles, and stratified the resulting evidence according to systems used in established evidence-based models. We updated prior evidence-based best practice recommendations based upon interim literature. In instances of controversial or inadequate scientific evidence, the task force reached consensus recommendations following evaluation of the best available information and expert opinion. The search yielded 1,788 abstracts, with 162 potentially relevant titles; 45 were reviewed in detail. Despite more information on perioperative management of patients with obstructive sleep apnea (OSA), evidence to support preoperative testing and treatment or to guide perioperative monitoring is scarce. New evidence on appropriate intraoperative dosing of muscle relaxants allows for greater precision in their use during WLS. A novel application of α-2 agonists for perioperative anesthetic care is emerging. Key elements that may enhance patient safety include integration of the latest evidence on WLS, obesity, and collaborative multidisciplinary care into clinical care. However, large gaps remain in the evidence base.

Combining two or more longevity-altering interventions and determining the resulting effect on lifespan is a common method for examining the relationship between such interventions. An important subset of this type of analysis occurs when one of the factors under study promotes longevity, such as daf-16 in Caenorhabditis elegans or SIR2 in Saccharomyces cerevisiae. For both of these genes, several studies have combined a lifespan shortening null allele with an intervention that extends lifespan. A resulting lifespan similar to that of the short-lived single mutant has generally been interpreted as suggesting that the factors act in the same pathway. In contrast, an intervention extending the lifespan of the short-lived mutant has been interpreted as suggesting that the factors act in genetically distinct pathways. Specific examples of this type of comparison are studies in which DR fails to extend lifespan in yeast (Lin et al. 2000), invertebrates (Rogina & Helfand 2004; Wang & Tissenbaum 2006), and mice (Li et al. 2008) when Sir2-orthologs are mutated. These data have been, and continue to be, interpreted by some to support a model in which DR promotes longevity and healthspan through activation of sirtuins (Baur et al. 2010). It has been previously reported that deletion of SIR2 blocks RLS extension from DR by reduction of glucose and in strains lacking GPA2 or HXK2, two genetic mimics of DR, but not in a strain lacking the rDNA replication fork block protein, FOB1 (Kaeberlein et al. 2004). In order to examine the influence of deleting SIR2 on RLS extension more generally, we generated 30 additional double mutant strains in which a RLS extending deletion was combined with deletion of SIR2. We also tested three additional methods of DR involving growth on alternative carbon sources (ethanol, glycerol, or raffinose). Strikingly, none of these interventions resulted in a significant RLS extension relative to sir2Δ cells (Figure 1; Figure S2; Table S1). Figure 1 Single-gene deletions that extend RLS in wild-type cells do not extend RLS of sir2Δ cells One possible interpretation of these data is that each of the RLS-extending interventions acts upstream of Sir2, perhaps by promoting Sir2 activity. Two observations are inconsistent with this model. First, at least eight single-gene deletions that increase wild type RLS, and all four forms of DR, significantly extend the RLS of sir2Δ fob1Δ cells (Figure S1A; Figure S2; Table S1), demonstrating that SIR2 is not absolutely required for RLS extension in these cases. Second, at least five long-lived deletion mutants show no indication of enhanced Sir2 activity in vivo, as measured by rDNA recombination or rDNA silencing (Figure S3). A similar lack of increased Sir2 activity has been previously reported in cells subjected to DR (Kaeberlein et al. 2005; Riesen & Morgan 2009; Smith et al. 2009). Interestingly, deletion of TOR1 caused a significant decrease in rDNA recombination, but this effect was independent of SIR2 (Figure S3A). An alternative explanation for these data is that loss of SIR2 alters aging such that molecular processes that do not limit RLS in wild-type cells become limiting in sir2Δ cells. Sir2 has multiple functions, including repression of extrachromosomal rDNA circle formation (Kaeberlein et al. 1999), enhancing global rDNA stability and silencing (Gottlieb & Esposito 1989; Smith & Boeke 1997), promoting asymmetric inheritance of damaged proteins (Aguilaniu et al. 2003), and maintaining telomeric chromatin during aging (Dang et al. 2009). Our observation that only deletion of FOB1 is sufficient to suppress the short RLS of sir2Δ cells suggests that (1) the primary RLS-limiting defect in sir2Δ cells is likely related to rDNA instability and (2) none of the 32 deletions tested that slow aging in wild-type cells is able to overcome this defect. One prior study reported that overexpression of Hsp104 could also suppress the short RLS of sir2Δ cells (Erjavec et al. 2007), raising the possibility that accumulation of damaged proteins in sir2Δ mother cells may also contribute to the reduced longevity. While it is likely that many of the genes examined in this study do not require Sir2 for their effect on RLS, we do not believe that all of the 32 long-lived single gene deletion mutants examined here necessarily act via Sir2-independent mechanisms. For example, deletion of SAS2, a histone acetyltransferase known to antagonize Sir2 effects on chromatin (Dang et al. 2009), extends wild-type RLS but fails to extend the RLS of sir2Δ fob1Δ cells (FigureS2b). Thus, both functional and genetic evidence suggest that Sas1 likely acts in the same longevity pathway as Sir2. This study provides a clear demonstration of the challenges associated with interpreting longevity epistasis data. In particular, the failure of a longevity-intervention to extend lifespan in a short-lived background may not be informative regarding the mechanism of lifespan extension in the wild-type context. In the absence of strong evidence indicating that the lifespan shortening is caused by acceleration of the wild-type aging process, caution is warranted when interpreting these types of data.

The non-nucleoside reverse transcriptase inhibitor nevirapine is used in the treatment of HIV in many developing countries. Its use is associated with occurrence of hypersensitivity in 6-10% of patients. This hypersensitivity can manifest as a number of phenotypes which include the severe skin blistering reactions Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The aim was to undertake a genome wide association study (GWAS) in order to identify genetic variants associated with predisposition to nevirapine-induced hypersensitivity. A total of 333 nevirapine-exposed (151 hypersensitive and 182 tolerant) , HIV-infected Malawian adults were genotyped for 826,551 genotyped SNPs using the Illumina HumanOmni1-Quad_v1 chip. A replication cohort of 62 hypersensitive and 59 tolerant patients from Malawi and Uganda was genotyped for 40 SNPs statistically significantly associated with a hypersensitive phenotype in the main cohort (p

Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in human immunodeficiency virus (HIV) treatment can cause hypersensitivity reactions in 6-10% of patients, which in the most serious cases (1.3%) can manifest as Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). A total of 209 patients with NVP hypersensitivity (57 from a prospective cohort and 152 clinic patients) were compared with 463 control patients on NVP without any hypersensitivity. The case group included 70 patients with serious blistering reactions (SJS or TEN). All individuals were genotyped for 2 SNPs in the CYP2B6 gene (c.516G>T [CYP2B6*9] and c.983T>C [CYP2B6*18]) using the TaqMan real-time genotyping platform. A replication cohort of 29 controls and 31 nevirapine hypersensitive patients, including 8 SJS/TEN cases, was subsequently typed. An association between the CYP2B6*18 polymorphism and NVP-induced SJS/TEN was observed (p=0.013). In the SJS/TEN group, 30% of individuals possessed at least one *18 allele vs. 16% in the tolerant group (p=0.006; OR (95% CI) 2.24(1.27-3.94)). This association was also borderline significant in the replication cohort (p=0.075). Combined analysis resulted in an odds ratio of 2.52 (95% CI 1.48-4.20; p=0.0005) for the association of SJS/TEN with CYP2B6*18. This association was not observed for other hypersensitivity phenotypes. Data show a putative association between the CYP2B6*18 polymorphism and nevirapine-induced SJS/TEN. CYP2B6*18 has a frequency of around 5-10% in African populations but is not observed in Caucasians, and this may therefore represent an ethnicity-specific predisposing factor.

The specificity of intracellular signaling events is controlled, in part, by compartmentalization of protein kinases and phosphatases. The subcellular localization of these enzymes is often maintained by protein- protein interactions. A prototypic example is the compartmentalization of the cAMP-dependent protein kinase (PKA) through its association with A-kinase anchoring proteins (AKAPs). A docking and dimerization domain (D/D) located within the first 45 residues of each regulatory (R) subunit protomer forms a high affinity binding site for its anchoring partner. We now report the structures of two D/D-AKAP peptide complexes obtained by solution NMR methods, one with Ht31(493-515) and the other with AKAP79(392-413). We present the first direct structural data demonstrating the helical nature of the peptides. The structures reveal conserved hydrophobic interaction surfaces on the helical AKAP peptides and the PKA R subunit, which are responsible for mediating the high affinity association in the complexes. In a departure from the dimer-dimer interactions seen in other X-type four-helix bundle dimeric proteins, our structures reveal a novel hydrophobic groove that accommodates one AKAP per RIIalpha D/D.

This paper describes the design of linked micromap plots for showing county estimates on a state by state basis. The linked micromap template was specifically developed to represent spatially indexed statistical summaries. Each plot shows regional names, spatial patterns and statistical patterns while linking them all together. Thus the design is useful for communicating summaries from a host of health and environmental studies. The specific design challenge in this paper is to create one-page plots for the states with 60 to 120 counties. While the county names and micromaps take up substantial space, the three examples demonstrate that there is sufficient space to represent two variables. The basic design has the potential for showing more. Consequently the new designs are suitable for presenting sophisticated summaries.

This paper describes two interactive templates for representing spatially indexed estimates. Both templates use a matrix layout of small panels. The first template, called linked micromap plots, can represent multivariate estimates associated with each spatially indexed study unit. The second template, called conditioned choropleth maps, shows the connection between a dependent variable, as represented in a classed choropleth map, and two explanatory variables. The paper describes the cognitive considerations that motivate the layouts and representation details. The discussion also addresses topics of data quality and access, hypothesis generation, and interactive features such as pan and zoom and dynamic conditioning via sliders. The examples show epidemiological (mortality rates) and environmental (toxic concentrations) applications.

The authors studied all patients with serologic evidence of human immunodeficiency virus (HIV) infection and malignant non-Hodgkin's lymphoma (NHL) that presented at a single hospital from 1982 to 1989. Sixteen patients were identified, all white homosexual men with a mean age of 38.2 years. Lymphoma was the initial presentation of HIV infection in 37.5%. Sixty-two percent of the cases had a high-grade NHL, 31% had intermediate-grade, and 6% (one patient) had a low-grade lymphoplasmacytoid lymphoma. Extranodal involvement was present in 43.7%, with the gastrointestinal tract and liver being the most common sites. Actuarial survival was increased by treatment with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B). Colorimetric in situ hybridization identified Epstein-Barr virus (EBV) in nine of the 14 cases hybridized. A statistically significant association of EBV with diffuse small noncleaved type (i.e., Burkitt's-like) (six of six) compared with other morphologic types (three of eight) was found (P = 0.025).

Opioids and Arrhythmias. Evidence is provided indicating that the action of opioids on cardiac electrical stability is contingent on the nature of the stress that impinges on the myocardium. This concept is illustrated by the studies of three clinically relevant conditions, namely, acute behavioral stress, hemorrhage, and myocardial ischemia. During aversive conditioning in dogs, morphine sulfate has been found to prevent the stress-induced reduction in cardiac electrical stability. This protective effect is significantly blunted by administration of atropine, indicating that enhanced vagal activity plays a major role. However, there is a remaining component of morphine's action, which is probably due to reduced perception of the aversive stress. In the context of hemorrhage, the mu-selective agonist fentanyl substantially reduces the profibrillatory effect of this physiological stress. The main mechanism involved in this condition is amplification of baroreceptor sensitivity leading to inhibition of cardiac sympathetic drive. Full activation of mu receptors with fentanyl is also effective in reducing vulnerability to fibrillation during acute coronary artery occlusion. This effect was due to vagal efferent activation and not to enhanced baroreceptor responsiveness as in the case of hemorrhage. Administration of the partial mu-agonist buprenorphine does not exert an antifibrillatory action. Collectively, these results not only demonstrate the potent stabilizing influence of opioids on cardiac rhythm but also the stress specificity of the intermediary mechanisms.

Common Opioid Actions in Pain and Cardiovascular Stress Responses. This overview describes three parallel aspects of the architecture and function of opioid action in nociceptive and cardiovascular spheres. First, in both circumstances, opioid secretion and receptor activation are essentially dormant during basal conditions and assume physiological importance only during stress. Second, in either context, opioids produce their responses by activating complementary mechanisms centrally and in the periphery. Third, endorphins act as “neuromodulators” of either type of response through a typical cellular architecture in which they diminish underlying excitatory neurotransmission.

Background Opioid-induced bowel dysfunction (OBD) is characterized by constipation, incomplete evacuation, bloating, and increased gastric reflux. OBD occurs both acutely and chronically, in multiple disease states, resulting in increased morbidity and reduced quality of life. Objectives To compare the efficacy and safety of traditional and peripherally active opioid antagonists versus conventional interventions for OBD. Search methods We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in January 2007. Additional reports were identified from the reference lists of retrieved papers. Selection criteria Studies were included if they were randomized controlled trials that investigated the efficacy of mu-opioid antagonists for OBD. Data collection and analysis Data were extracted by two independent review authors and included demographic variables, diagnoses, interventions, efficacy, and adverse events. Main results Twenty-three studies met inclusion criteria and provided data on 2871 opioid antagonist-treated patients. The opioid antagonists investigated were alvimopan (nine studies), methylnaltrexone (six), naloxone (seven), and nalbuphine (one). Meta-analysis demonstrated that methylnaltrexone and alvimopan were better than placebo in reversing opioid-induced increased gastrointestinal transit time and constipation, and that alvimopan appears to be safe and efficacious in treating postoperative ileus. The incidence of adverse events with opioid antagonists was similar to placebo and generally reported as mild-to-moderate. Authors' conclusions Insufficient evidence exists for the safety or efficacy of naloxone or nalbuphine in the treatment of OBD. Long-term efficacy and safety of any of the opioid antagonists is unknown, as is the incidence or nature of rare adverse events. Alvimopan and methylnaltrexone both show promise in treating OBD, but further data will be required to fully assess their place in therapy.

Several reviews of randomized controlled trials (RCTs) have shown the efficacy of mu-opioids in reducing spontaneous neuropathic pain (NP). However, relatively little is known about their specific efficacy for evoked pain, which is a significant problem for many patients with NP. The present systematic review assesses the efficacy of opioid agonists for the treatment of evoked NP based upon published RCTs. We searched articles in any language using the MEDLINE database (1966 to December 2004), the Cochrane Central Register of Controlled Trials (4th quarter, 2004) and the reference lists of retrieved papers, employing search terms for RCTs, opioids and NP. Only RCTs in which opioid agonists were given to treat NP of any etiology, and evoked pain was assessed were included. Data were extracted by two independent investigators. Nine articles met inclusion criteria and were classified as short-term (less than 24 h; n = 7) or intermediate-term trials (4 weeks; n = 2). Although the scarcity of retrieved data precluded formal meta-analysis of short-term trials, we found that the intensity of dynamic mechanical allodynia was significantly attenuated by opioids relative to placebo in all studies. In contrast, no consistent effects on the magnitude of static allodynia, the threshold for mechanical allodynia or the threshold or magnitude of heat allodynia were found. The threshold and magnitude of cold-induced allodynia generally responded positively to opioid treatments in patients with peripheral pain syndromes, but not central pain syndromes. Evoked pain was studied in only two intermediate-term trials, in both of which oxycodone was significantly superior to placebo. The results of the two trials were combinable for a meta-analysis that showed an overall 24 points difference in endpoint pain intensities between patients given opioids and those treated with placebo (95% CI −33 to −15; p < 0.00001). In conclusion: short-term studies show that opioids can reduce the intensity of dynamic mechanical allodynia and perhaps of cold allodynia in peripheral NP. Insufficient evidence precludes drawing conclusions regarding the effect of opioids on other forms of evoked NP. A meta-analysis of intermediate-term studies demonstrates the efficacy of opioids over placebo for evoked NP. These findings are clinically relevant because dynamic mechanical allodynia and cold allodynia are the most prevalent types of evoked pain in NP.

Oral trimethoprim-sulfamethoxazole (Bactrim) plus erythromycin (TMZ-E) was tested versus placebo (P) as prophylaxis for bacterial infection in a randomized, double-blind trial in adult cancer patients receiving cytotoxic chemotherapy expected to result in significant neutropenia. The incidence of adverse reactions attributable to TMZ and/or E was higher in drug-treated episodes (18 of 28 vs 3 of 29 for P, P less than 0.0005) resulting in poorer compliance. The incidence of fever was not significantly different between episodes treated with TMZ-E (18/27) and those treated with P (17/29), nor was there a significant difference in the median interval between the onset of neutropenia and the onset of fever. However, 14 of 18 fevers in TMZ-E recipients were without a documented infectious source compared with only 6 of 17 in P recipients (P less than 0.05). The same patterns were apparent even when episodes in which compliance with the regimen was either excellent or good were considered separately. There was no significant difference in the number of deaths from infection between TMZ-E and P recipients (3/27 vs 1/29). It is concluded that TMZ-E prophylaxis is of no practical benefit, may mask the cause of infection in febrile neutropenic cancer patients, and is associated with substantial toxicity.

Experiments were performed to evalute reproductive and developmental toxicology in rats and rabbits exposed to styrene oxide by inhalation. Female rats were exposed to 100 or 300 ppm styrene oxide or to filtered air for 7 h/day, 5 days/week for 3 weeks. Extensive mortality occurred in rats that received prolonged exposure to 100 ppm styrene oxide while 300 ppm was rapidly lethal. As a result exposures were terminated in this latter group and the group was eliminated from further study. The rats of the 0 and 100 ppm groups were then mated and exposed to 0 or 100 ppm styrene oxide daily through 18 days of gestation (dg). Female rabbits were artificially inseminated and exposed for 7 h daily to 0, 15, or 50 ppm styrene oxide through 24 dg. Both of these lower concentrations used for exposure of the rabbits produced mortality of does. The rats were killed at 20 dg and the rabbits at 30 dg. Pregnant animals were examined for toxic changes including altered tissue weights and histopathologic effects. Litters were evaluated using several measures of embryotoxicity, and live fetuses were examined for external, visceral, and skeletal malformations. Exposure during gestatation appeared to increase preimplantation loss in rats, and tended to increase the incidence of resorptions in rabbits. In both species, fetal weights and crown-rump lengths were reduced by gestational exposure. The incidences of ossification defects of the sternebrae aned occipital bones were increased by gestational exposure of rats to styrene oxide. These results indicate that inhalation exposures at these concentrations produce reproductive and development toxicity, as well as maternal toxicity.

A 36-year-old man had one year of periodic symptoms suggestive of episodic hypothalamic dysfunction: hypersomnia, thirst, ravenous hunger and gorging behavior, pallor, and irritability. However, neuroendocrine testing proved normal. A mild transient acidosis at the onset of his attacks and a history of bowel bypass five years earlier prompted metabolic screening. Markedly increased urinary D-lactic and phenolic acids were present, as were intermittent elevations of plasma D-lactic acid during two symptomatic episodes. Prompt and sustained clinical remission coincided with disappearance of abnormal organic acid excretion during oral antibiotic therapy. D-Lactic acidosis must be considered in the differential diagnosis of otherwise unexplained neurological syndromes, particularly in patients with altered bowel anatomy.