In Pursuit of an Allosteric Human Tropomyosin Kinase A (hTrkA) Inhibitor for Chronic Pain.

Human ß-nerve growth factor (ß-NGF) and its associated receptor, human tropomyosin receptor kinase A (hTrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located hTrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective hTrkA allosteric inhibitor, 1. 1 was shown to be active against the full length hTrkA, showing preferential binding for the inactive kinase, and was confirmed through the X-ray of hTrkA···1 bound complex. 1 was also found to inhibit ß-NGF induced neurite outgrowth in rat PC12 cells. Daily oral administration of 1 improved the joint compression threshold of rats injected intra-articularly with monoiodoacetate over a 14-day period. The efficacy of 1 in a relevant chronic pain model of osteoarthritis coupled with in vitro confirmation of target mediation makes allosteric hTrkA inhibitors potential candidates for modulating pain.

Serotonin-Modulating Antidepressants and Risk of Bleeding after Trauma.

Serotonin-modulating antidepressants have been associated with increased risk of gastrointestinal bleeding and increased blood loss during elective surgery. This study sought to investigate the effect of preinjury selective-serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) use on transfusion requirements after trauma, and to evaluate whether resumption of SSRI/SNRI after trauma may worsen bleeding risk. This was a retrospective matched-cohort study evaluating patients with solid organ injury. Preinjury SSRI/SNRI users were matched to non-SSRI/SNRI users based on age, preinjury aspirin use, Injury Severity Score, and abdominal Abbreviated Injury Severity Score. The primary endpoint was transfusion requirement during hospitalization. The absolute need for transfusion was higher in SSRI/SNRI users throughout hospitalization (50.9% vs 37.3%, P = 0.02). After logistic multivariate analysis, SSRI/SNRI users were more likely to require transfusion at 24 hours (odds ratio (95% confidence interval): 2.73 (1.41, 5.29), P = 0.003), but this difference did not persist for overall hospitalization (odds ratio (95% confidence interval): 1.32 (0.74, 2.36), P = 0.35). Fewer patients restarted on SSRI/SNRI therapy within 72 hours required packed red blood cell transfusion compared with those who were restarted later or not at all (43.2% vs 60.3%; P = 0.04). Preinjury use of serotonin-modulating antidepressants led to an increased requirement of blood transfusions after solid organ injury. Although clinicians should weigh bleeding risk before reinitiation of SSRI/SNRI, the results of this study indicate that reasonable efforts to restart these medications after stabilization do not result in further risk for transfusion.

Efficacy of alvimopan following bowel resection: a comparison of two dosing strategies.

BACKGROUND: Alvimopan is indicated to accelerate the time to gastrointestinal recovery following partial bowel resection with primary anastomosis. The approved dosing regimen includes an initial dose prior to surgery and 12 mg twice daily after surgery for up to 7 days; however, there are no human studies evaluating the need for the preoperative dose. We report our experience with gastrointestinal recovery when the preoperative dose is omitted. OBJECTIVE: To evaluate the efficacy of alvimopan therapy when the preoperative dose is not administered. METHODS: This retrospective study included elective surgery patients who underwent bowel resection with primary anastomosis without colostomy or ileostomy. The study compared (a) patients who received alvimopan and received a dose preoperatively, (b) patients who received alvimopan but did not receive a dose preoperatively, and (c) matched control patients who did not receive alvimopan. Length of stay following bowel resection, direct hospital costs, time to first bowel movement, and time to oral diet were evaluated. RESULTS: Of 50 patients who received alvimopan, 27 received the preoperative dose and 23 did not. These 50 patients were matched to similar control patients who received no alvimopan during their admission for resection. Compared with controls, time to discharge was significantly shorter in patients who received alvimopan, regardless of whether the preoperative dose was administered (P < .001) or omitted (P = .03). Patients who did not receive the preoperative dose still experienced faster time to first bowel movement (71 vs 97 hours; P = .006) and faster time to first diet (17 vs 54 hours; P < .001) than non-alvimopan users. CONCLUSION: Patients receiving the approved alvimopan dosing regimen experienced the most rapid recovery of gastrointestinal function. However, administering alvimopan only postoperatively (if the preoperative dose is omitted) may still reduce the severity of postoperative ileus.

Evaluating contemporary antibiotics as a risk factor for Clostridium difficile infection in surgical trauma patients.

BACKGROUND: With most Clostridium difficile infections (CDI) occurring after exposure to antimicrobial treatment, specific antibiotics and duration of exposure were evaluated independently for increased risk of CDI in surgical patients. METHODS: A retrospective, case-control design was used to study surgical inpatients. The case group had a positive Clostridium difficile toxin assay, whereas the control group did not. RESULTS: Four antibiotics had a risk that was statistically significant for causing CDI in surgical patients: cefepime (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.7-19.1; p = 0.0044), imipenem/cilastatin (OR, 3.2; 95% CI, 1.2-8.9; p = 0.0388), piperacillin/tazobactam (OR, 2.4; 95% CI, 1.3-4.5; p = 0.0067), and vancomycin (OR, 1.9; 95% CI, 1.0-3.5; p = 0.0439). Exposure longer than 7 days to cefepime (p = 0.0006), piperacillin/tazobactam (p = 0.0021), and imipenem/cilastatin (p = 0.0171) also increased risk for development of CDI. CONCLUSION: The use of cefepime, imipenem/cilastatin, piperacillin/tazobactam, and vancomycin and the use of multiple classes of antibiotics for at least 7 days significantly increased the risk of CDI in surgical inpatients.

Lead Diversification 2: application to P38, gMTP and lead compounds.

Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C-H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.

A high-fidelity simulation mannequin to introduce pharmacy students to advanced cardiovascular life support.

OBJECTIVE: To design and implement an advanced cardiac life support (ACLS) workshop featuring a human patient simulator (HPS) for third-year pharmacy students. DESIGN: The ACLS workshop consisted of a pre-session lecture, a calculation exercise, and a 40-minute ACLS session using an HPS. Twenty-four 5-member teams of students were assigned roles on a code team and participated in a ventricular fibrillation/pulseless ventricular tachycardia case. ASSESSMENT: Students completed an anonymous postactivity survey instrument and knowledge quiz. Most students who completed the ACLS workshop agreed they would like to participate in additional simulation activities and that the HPS experience enhanced their understanding of ACLS and the pharmacist responsibilities during an ACLS event (99.2% and 98.3%, respectively). However, the median score on the knowledge-based questions was 25%. CONCLUSION: Pharmacy students agreed HPS enhanced their learning experience; however, their retention of the knowledge learned was not consistent with the perceived benefits of HPS to education.

Efficient Constrained Local Model Fitting for Non-Rigid Face Alignment.

Active appearance models (AAMs) have demonstrated great utility when being employed for non-rigid face alignment/tracking. The "simultaneous" algorithm for fitting an AAM achieves good non-rigid face registration performance, but has poor real time performance (2-3 fps). The "project-out" algorithm for fitting an AAM achieves faster than real time performance (> 200 fps) but suffers from poor generic alignment performance. In this paper we introduce an extension to a discriminative method for non-rigid face registration/tracking referred to as a constrained local model (CLM). Our proposed method is able to achieve superior performance to the "simultaneous" AAM algorithm along with real time fitting speeds (35 fps). We improve upon the canonical CLM formulation, to gain this performance, in a number of ways by employing: (i) linear SVMs as patch-experts, (ii) a simplified optimization criteria, and (iii) a composite rather than additive warp update step. Most notably, our simplified optimization criteria for fitting the CLM divides the problem of finding a single complex registration/warp displacement into that of finding N simple warp displacements. From these N simple warp displacements, a single complex warp displacement is estimated using a weighted least-squares constraint. Another major advantage of this simplified optimization lends from its ability to be parallelized, a step which we also theoretically explore in this paper. We refer to our approach for fitting the CLM as the "exhaustive local search" (ELS) algorithm. Experiments were conducted on the CMU Multi-PIE database.

BRCA1 and BRCA2 mutation prevalence and clinical characteristics of a population-based series of ovarian cancer cases from Denmark.

PURPOSE: To evaluate the prevalence of BRCA1 and BRCA2 mutations and associations with clinical correlates of disease in a population-based series of ovarian cancer cases from Denmark. METHODS: DNA sequencing and multiplex ligation-dependent probe amplification analysis were used to analyze the BRCA1 and BRCA2 genes for coding sequence mutations and large genomic rearrangements in 445 confirmed cases of ovarian cancer. We evaluated associations between mutation status and clinical characteristics, including cancer risks for first-degree relatives and clinicopathologic features of tumors. RESULTS: Deleterious BRCA1 or BRCA2 mutations were identified in 26 cases; thus, mutations in these genes are responsible for at least 5.8% of ovarian cancer cases in this population. Five different mutations were identified in more than one individual, suggesting that they may be founder mutations in Denmark. We identified several differences between mutation carriers and noncarriers: mutation carriers were diagnosed at a significantly early age (median, 49 and 61 years, respectively; P = 0.0001); the frequency of BRCA1 mutation carriers was 23% for women diagnosed <40 years, 15% for 40 to 49 years, 4% for 50 to 59 years, and 2% for > or =60 years (P = 0.00002); ovarian cancer in carriers was diagnosed at a later stage (P = 0.002) and tumors were of poorer grade (P = 0.0001); and first-degree relatives of mutation carriers had greater relative risks of both ovarian cancer [10.6 (95% confidence interval, 4.2-26.6); P < 0.0001] and breast cancer <60 years [8.7 (95% confidence interval, 3.0-25.0); P < 0.0001]. CONCLUSION: These data may have a significant effect on risk assessment and clinical management of individuals from Denmark who are predisposed to ovarian cancer because they carry a BRCA1 or BRCA2 mutation.

Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model.

STUDY DESIGN: The effects of a low, local dose of a tumor necrosis factor-alpha (TNF-alpha) inhibitor on neuropathic pain behaviors in a rat chronic constriction injury model were evaluated. OBJECTIVE: To investigate whether a peripherally implanted polymer drug depot can deliver a dose of etanercept sufficient to reduce thermal hyperalgesia and mechanical allodynia in a rat model of neuropathic pain. SUMMARY OF BACKGROUND DATA: TNF-alpha inhibitors reduce pain-associated behavior in experimental models of neuropathic pain. Moreover, systemic injections of TNF-alpha inhibitors have suggested some efficacy in treating sciatic pain in limited, off-label clinical studies. Improvements in these results may be obtained by optimal dosing via targeted, sustained delivery at the site of disc-induced inflammation. METHODS: Unilateral chronic constriction injury was applied to the sciatic nerve of 56 male, Wistar rats. Four groups of animals (n = 7) received 0.5 mL phosphate-buffered saline every 3 days, 0.3 or 3 mg/kg etanercept every 3 days, or gabapentin (60 mg/kg) 1 hour before each behavioral test all via subcutaneous injection. Two groups of animals received 1.5 or 3.0 microg/h etanercept delivered by poly(lactic-co-glycolic acid) (PLGA) millicylinders (1 mm diameter x 10 mm long) implanted near the injured sciatic nerve. One group received a PLGA millicylinder implanted near the injured sciatic nerve. The final group received 3.0 microg/h etanercept via PLGA millicylinder implanted next to the uninjured, contralateral sciatic nerve. RESULTS: A low, local dose of etanercept (approximately 3 microg/h) delivered by a polymer depot significantly reduced (P < 0.05) thermal hyperalgesia for 57 days as compared to polymer depot without drug or an etanercept-loaded depot implanted near the contralateral sciatic nerve, and equivalent to a 10-fold higher dose delivered by repeat subcutaneous injection. CONCLUSION: This preclinical study indicates that delivering TNF-alpha inhibitors by means of a locally administered polymeric formulation provides long-lasting analgesia in an inflammatory neuropathic pain model.

Comparing Object Alignment Algorithms with Appearance Variation: Forward-Additive vs Inverse-Composition.

A common problem that affects object alignment algorithms is when they have to deal with objects with unseen intra-class appearance variation. Several variants based on gradient-decent algorithms, such as the Lucas-Kanade (or forward-additive) and inverse-compositional algorithms, have been proposed to deal with this issue by solving for both alignment and appearance simultaneously. In [1], Baker and Matthews showed that without appearance variation, the inverse-compositional (IC) algorithm was theoretically and empirically equivalent to the forward-additive (FA) algorithm, whilst achieving significant improvement in computational efficiency. With appearance variation, it would be intuitive that a similar benefit of the IC algorithm would be experienced over the FA counterpart. However, to date no such comparison has been performed. In this paper we remedy this situation by performing such a comparison. In this comparison we show that the two algorithms are not equivalent due to the inclusion of the appearance variation parameters. Through a number of experiments on the MultiPIE face database, we show that we can gain greater refinement using the FA algorithm due to it being a truer solution than the IC approach.

Least Squares Congealing for Unsupervised Alignment of Images.

In this paper, we present an approach we refer to as "least squares congealing" which provides a solution to the problem of aligning an ensemble of images in an unsupervised manner. Our approach circumvents many of the limitations existing in the canonical "congealing" algorithm. Specifically, we present an algorithm that:- (i) is able to simultaneously, rather than sequentially, estimate warp parameter updates, (ii) exhibits fast convergence and (iii) requires no pre-defined step size. We present alignment results which show an improvement in performance for the removal of unwanted spatial variation when compared with the related work of Learned-Miller on two datasets, the MNIST hand written digit database and the MultiPIE face database.

Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer.

A total of 283 epithelial ovarian cancer families from the United Kingdom (UK) and the United States (US) were screened for coding sequence changes and large genomic alterations (rearrangements and deletions) in the BRCA1 and BRCA2 genes. Deleterious BRCA1 mutations were identified in 104 families (37%) and BRCA2 mutations in 25 families (9%). Of the 104 BRCA1 mutations, 12 were large genomic alterations; thus this type of change represented 12% of all BRCA1 mutations. Six families carried a previously described exon 13 duplication, known to be a UK founder mutation. The remaining six BRCA1 genomic alterations were previously unreported and comprised five deletions and an amplification of exon 15. One of the 25 BRCA2 mutations identified was a large genomic deletion of exons 19-20. The prevalence of BRCA1/2 mutations correlated with the extent of ovarian and breast cancer in families. Of 37 families containing more than two ovarian cancer cases and at least one breast cancer case with diagnosis at less than 60 years of age, 30 (81%) had a BRCA1/2 mutation. The mutation prevalence was appreciably less in families without breast cancer; mutations were found in only 38 out of 141 families (27%) containing two ovarian cancer cases only, and in 37 out of 59 families (63%) containing three or more ovarian cancer cases. These data indicate that BRCA1 and BRCA2 are the major susceptibility genes for ovarian cancer but that other susceptibility genes may exist. Finally, it is likely that these data will be of clinical importance for individuals in families with a history of epithelial ovarian cancer, in providing accurate estimates of their disease risks.

Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis. Mutation in brief #964. Online.

Misdiagnosis of a germline mutation associated with an inherited disease syndrome can have serious implications for the clinical management of patients. A false negative diagnosis (mutation missed by genetic screening) limits decision making about intervention strategies within families. More serious is the consequence of a false positive diagnosis (genetic test suggesting a mutation is present when it is not). This could lead to an individual, falsely diagnosed as a mutation carrier, undergoing unnecessary clinical intervention, possibly involving risk-reducing surgery. As part of screening 283 ovarian cancer families for BRCA1 mutations, we used two different methods (mutation specific PCR and multiplex ligation-dependent probe amplification) to screen for a known rearrangement mutation L78833.1:g.44369_50449dup (ins6kbEx13). We found false positive and false negative results in several families. We then tested 61 known carriers or non-carriers from an epidemiological study of BRCA1 and BRCA2 mutation carriers (the EMBRACE study). These data highlight the need for caution when interpreting analyses of the ins6kbEx13 mutation and similar mutations, where characterising the exact sequence alteration for a deleterious mutation is not a part of the routine genetic test.

Increased gastric-end tidal P(CO2) gap during exercise at high altitude measured by gastric tonometry.

Using automated air gastric tonometry, the hypothesis that gastric perfusion is reduced while exercising at high altitude was explored. This prospective observational study of 5 well acclimatized healthy volunteers was performed during a medical research expedition to Chamlang base camp (5000 m), Hongu valley, Nepal. We used gastric tonometry at rest and during graded submaximal exercise. The end tidal partial pressure of carbon dioxide was subtracted from the gastric mucosal partial pressure of carbon dioxide to calculate the P(CO2) gradient, which is a marker of gastric mucosal perfusion. When compared with rest, there was no increase in the mean P(CO2) gradient at the lower work rate (0.22 vs. 0.18, p 0.10), but an increase was seen between rest and the higher work rate (0.22 vs. 0.77, p = 0.04). We conclude that exercising while at high altitude can lead to a raised P(CO2) gradient when gastric tonometry is performed, indicating reduced perfusion. This may represent reduced gastric mucosal perfusion under these conditions.

Resuscitation from hemorrhagic shock using rectally administered fluids in a wilderness environment.

We report the successful use in a wilderness environment of rectally administered oral rehydation fluid to resuscitate a patient who was in shock. The subject was a 21-year-old Nepali man who had experienced a major upper gastrointestinal hemorrhage.

Barrett's surveillance is worthwhile and detects curable cancers. A prospective cohort study addressing cancer incidence, treatment outcome and survival.

OBJECTIVES: To establish whether Barrett's surveillance is worthwhile in terms of incident cancers and whether outcomes are favourable. METHODS: A prospective non-randomized single centre Barrett's surveillance programme commencing 1 January 1992 through 1 April 2001 (112 months). Oesophagectomy recommended for high-grade dysplasia or carcinoma. RESULTS: Of 23 725 patients, 506 were diagnosed as Barrett's oesophagus and 24 (5%) had carcinoma at diagnosis (prevalence cancers). One hundred and twenty-six patients had at least one surveillance endoscopy; 248 surveillance endoscopies were performed spanning 338 patient years. Thirteen surveillance (incidence) cancers were detected. In the prevalence cancer group 12 of the 24 patients underwent oesophagectomy. Lymph nodes showed evidence of metastases in 10 of the 12 resections. In the surveillance group 10 patients underwent oesophagectomy. Lymph nodes showed evidence of metastases in one of the 10 resections. One patient in the prevalence cancer group (4% of group; 8% of those operated) and seven patients in the surveillance cancer group (54% of group; 70% of those operated) remain disease-free more than 2 years post-oesophagectomy. The cost per cancer cured is 7546 pounds. One curable cancer was detected per 48 patient years of surveillance. CONCLUSIONS: Few Barrett's surveillance studies have addressed treatment outcomes and survival. In our study 5% of Barrett's patients undergoing endoscopy have prevalent cancers. If surveillance is performed, 4% per year develop cancer and 2% per year are cured of their cancers. Most surveillance cancers are operable and of those undergoing surgery 70% are cured. Barrett's surveillance is cost-effective compared with other cancer screening or surveillance initiatives.

Mycobacteria other than Mycobacterium tuberculosis are not present in erythema induratum/nodular vasculitis: a case series and literature review of the clinical and histologic findings.

Erythema induratum (EI)/nodular vasculitis (NV) is characterized by recurrent crops of tender oedematous nodules on the lower legs. A lobular panniculitis with granulomatous inflammation, vasculitis, focal necrosis and septal fibrosis is present. Mycobacterium tuberculosis DNA has been detected in some lesions by means of polymerase chain reaction (PCR). Ten cases of EI/NV were found. H&E slides were reviewed. PCR assays for M. tuberculosis and mycobacteria other than M. tuberculosis (MOTT) were performed. PCR did not reveal M. tuberculosis (0%) or MOTT (0%) DNA, with positive controls, indicating the reliability of the assays. Among the MOTT, cutaneous infections are most commonly caused by M. marinum. Subcutaneous tuberculoid granulomas may be seen with M. kansasii, M. marinum, M. scrofulaceum and M. avium complex. M. gordonae, M. szulgai and M. malmoense rarely cause cutaneous infections. M. simiae, M. gastri and M. asiaticum are probably not cutaneous pathogens. M. tuberculosis and MOTT DNA was not found in EI/NV. EI/NV has diverse aetiologies with varying pathogeneses leading to similar histologic changes. The cases analysed may not have had an infectious aetiology. However, in EI/NV, performance of PCR for MOTT as well as M. tuberculosis complex may still be beneficial, particularly in cases from immunocompromised hosts.

Economic and demographic factors affecting mangrove loss in the coastal provinces of Thailand, 1979-1996.

The following paper analyzes the economic and demographic factors determining the conversion of mangroves in the coastal provinces of Thailand to commercial shrimp farming. Mangrove conversion therefore is determined by the returns to shrimp farmers, (i.e. the price of shrimp), the input costs to farming shrimp (e.g. feed price and wages) and the "accessibility" of mangrove areas. Additional exogenous influences, such as income per capita, population growth, and in-migration (i.e. the number of shrimp farms) also are important. Both a mangrove conversion and a shrimp farm expansion relationship are estimated empirically through a panel analysis across 21 coastal provinces of Thailand between 1979-1996. Results show that the price of shrimp, minimum wage, distance from market, feed price, population growth, income per capita, and shrimp-farm density all have important influences on mangrove loss due to shrimp farming in Thailand.