Neuromodulation for the management of chronic pelvic pain syndromes: A systematic review.

BACKGROUND: Chronic pelvic pain is a burdensome condition that involves multiple medical sub-specialties and is often difficult to treat. Sacral stimulation for functional bladder disease has been well established, but little large-scale evidence exists regarding utilization of other neuromodulation techniques to treat chronic pelvic pain. Emerging evidence does suggest that neuromodulation is a promising treatment, and we aim to characterize the use and efficacy of such techniques for treating chronic pelvic pain syndromes. MATERIALS AND METHODS: A systematic review of the literature demonstrating the treatment of chronic pelvic pain syndromes with neuromodulation. Abstracts were reviewed and selected for inclusion, including case series, prospective studies, and randomized controlled trials (RCTs). Case studies and publications in abstract only were not included. The reporting for this systematic review follows Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The literature search was performed using MEDLINE, Embase, Cochrane Library, PubMed, CINAHL, and Scopus. RESULTS: A total of 50 studies were included in this review, three of which were randomized controlled trials, and the remaining were prospective and retrospective case series. The range of pelvic pain conditions treated included interstitial cystitis, peripheral neuralgia, pudendal neuralgia, gastrointestinal pain, urogenital pain, sacroiliac joint pain, and visceral chronic pelvic pain. We reported on outcomes involving pain, functionality, psychosocial improvement, and medication reduction. CONCLUSIONS: Neuromodulation is a growing treatment for various chronic pain syndromes. Peripheral nerve stimulation was the least studied form of stimulation. Posterior tibial nerve stimulation appears to offer short-term benefit, but long-term results are challenging. Sacral nerve stimulation is established for use in functional bladder syndromes and appears to offer pain improvement in these patients as well. Dorsal root ganglion stimulation and spinal cord stimulation have been used for a variety of conditions with promising results. Further studies of homogeneous patient populations are necessary before strong recommendations can be made at this time, although pooled analysis may also be impactful.

Diabetic peripheral neuropathy: advances in diagnosis and strategies for screening and early intervention.

Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 and 2 diabetes. It is a leading cause of lower-limb amputation and disabling neuropathic pain. Amputations in patients with diabetes have a devastating effect on quality of life and are associated with an alarmingly low life expectancy (on average only 2 years from the amputation). Amputation also places a substantial financial burden on health-care systems and society in general. With the introduction of national diabetes eye screening programmes, the prevalence of blindness in working-age adults is falling. This is not the case, however, with diabetes related amputations. In this Review, we appraise innovative point-of-care devices that enable the early diagnosis of DPN and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN. We also propose a framework for screening and early multifactorial interventions as the best prospect for preventing or halting DPN and its devastating sequelae.

Intrapulmonary Autoantibodies to HSP72 Are Associated with Improved Outcomes in IPF.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease, with high mortality. Currently, the aetiology and the pathology of IPF are poorly understood, with both innate and adaptive responses previously being implicated in the disease pathogenesis. Heat shock proteins (Hsp) and antibodies to Hsp in patients with IPF have been suggested as therapeutic targets and prognostic biomarkers, respectively. We aimed to study the relationship between the expression of Hsp72 and anti-Hsp72 antibodies in the BAL fluid and serum Aw disease progression in patients with IPF. METHODS: A novel indirect ELISA to measure anti-Hsp72 IgG was developed and together with commercially available ELISAs used to detect Hsp72 IgG, Hsp72 IgGAM, and Hsp72 antigen, in the serum and BALf of a cohort of IPF (n = 107) and other interstitial lung disease (ILD) patients (n = 66). Immunohistochemistry was used to detect Hsp72 in lung tissue. The cytokine expression from monocyte-derived macrophages was measured by ELISA. RESULTS: Anti-Hsp72 IgG was detectable in the serum and BALf of IPF (n = 107) and other ILDs (n = 66). Total immunoglobulin concentrations in the BALf showed an excessive adaptive response in IPF compared to other ILDs and healthy controls (p = 0.026). Immunohistochemistry detection of C4d and Hsp72 showed that these antibodies may be targeting high expressing Hsp72 type II alveolar epithelial cells. However, detection of anti-Hsp72 antibodies in the BALf revealed that increasing concentrations were associated with improved patient survival (adjusted HR 0.62, 95% CI 0.45-0.85; p = 0.003). In vitro experiments demonstrate that anti-Hsp72 complexes stimulate macrophages to secrete CXCL8 and CCL18. CONCLUSION: Our results indicate that intrapulmonary anti-Hsp72 antibodies are associated with improved outcomes in IPF. These may represent natural autoantibodies, and anti-Hsp72 IgM and IgA may provide a beneficial role in disease pathogenesis, though the mechanism of action for this has yet to be determined.

Cardiovascular Disease, Cancer, and Mortality Among People With Type 2 Diabetes and Alcoholic or Nonalcoholic Fatty Liver Disease Hospital Admission.

OBJECTIVE: To describe associations between alcoholic liver disease (ALD) or nonalcoholic fatty liver disease (NAFLD) hospital admission and cardiovascular disease (CVD), cancer, and mortality in people with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We performed a retrospective cohort study by using linked population-based routine data from diabetes registry, hospital, cancer, and death records for people aged 40-89 years diagnosed with T2DM in Scotland between 2004 and 2013 who had one or more hospital admission records. Liver disease and outcomes were identified by using ICD-9 and ICD-10 codes. We estimated hazard ratios (HRs) from Cox proportional hazards regression models, adjusting for key risk factors. RESULTS: A total of 134,368 people with T2DM (1,707 with ALD and 1,452 with NAFLD) were studied, with a mean follow-up of 4.3 years for CVD and 4.7 years for mortality. Among those with ALD, NAFLD, or without liver disease hospital records 378, 320, and 21,873 CVD events; 268, 176, and 15,101 cancers; and 724, 221, and 16,203 deaths were reported, respectively. For ALD and NAFLD, respectively, adjusted HRs (95% CIs) compared with the group with no record of liver disease were 1.59 (1.43, 1.76) and 1.70 (1.52, 1.90) for CVD, 40.3 (28.8, 56.5) and 19.12 (11.71, 31.2) for hepatocellular carcinoma (HCC), 1.28 (1.12, 1.47) and 1.10 (0.94, 1.29) for non-HCC cancer, and 4.86 (4.50, 5.24) and 1.60 (1.40, 1.83) for all-cause mortality. CONCLUSIONS: Hospital records of ALD or NAFLD are associated to varying degrees with an increased risk of CVD, cancer, and mortality among people with T2DM.

Metformin and survival of people with type 2 diabetes and pleural mesothelioma: A population-based retrospective cohort study.

OBJECTIVES: This study aimed to investigate the effect of metformin on survival of people with type 2 diabetes and pleural mesothelioma. MATERIALS AND METHODS: We conducted a retrospective cohort study of people with type 2 diabetes diagnosed with pleural or unspecified mesothelioma between 1993 and 2014 using linked Scottish population-based diabetes and cancer datasets. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models were used to describe the association between use of metformin and all-cause mortality following diagnosis of pleural mesothelioma. RESULTS: There were 300 people with type 2 diabetes and pleural or unspecified mesothelioma of whom 148 had ever used metformin and 290 died during follow up. The median survival time was 8.8 months and 6.5 months for metformin users and non-users respectively (p=0.37, log-rank test). After adjusting for age, sex, diabetes duration, socio-economic status, and other anti-diabetic medications the hazard ratio for mortality associated with metformin was 0.99 (95% confidence intervals: 0.76-1.28; p=0.92). Similar non-statistically significant associations were obtained in sensitivity analyses based on metformin use in year prior to diagnosis of mesothelioma, use of metformin for more than one year, in people below the mean age at diagnosis of mesothelioma (74 years) and 74 years of age or older, limitation to pleural mesothelioma and following further adjustment for body mass index and smoking. CONCLUSION: There was no evidence that metformin improved survival among people with type 2 diabetes and pleural mesothelioma or to support trials of metformin in people with mesothelioma.

A highly stable minimally processed plant-derived recombinant acetylcholinesterase for nerve agent detection in adverse conditions.

Although recent innovations in transient plant systems have enabled gram quantities of proteins in 1-2 weeks, very few have been translated into applications due to technical challenges and high downstream processing costs. Here we report high-level production, using a Nicotiana benthamiana/p19 system, of an engineered recombinant human acetylcholinesterase (rAChE) that is highly stable in a minimally processed leaf extract. Lyophylized clarified extracts withstand prolonged storage at 70 °C and, upon reconstitution, can be used in several devices to detect organophosphate (OP) nerve agents and pesticides on surfaces ranging from 0 °C to 50 °C. The recent use of sarin in Syria highlights the urgent need for nerve agent detection and countermeasures necessary for preparedness and emergency responses. Bypassing cumbersome and expensive downstream processes has enabled us to fully exploit the speed, low cost and scalability of transient production systems resulting in the first successful implementation of plant-produced rAChE into a commercial biotechnology product.

Association between BMI measured within a year after diagnosis of type 2 diabetes and mortality.

OBJECTIVE: To describe the association of BMI with mortality in patients diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using records of 106,640 patients in Scotland, we investigated the association between BMI recorded around the diagnosis of type 2 diabetes mellitus (T2DM) and mortality using Cox proportional hazards regression adjusted for age and smoking status, with BMI 25 to <30 kg/m(2) as a referent group. Deaths within 2 years of BMI determination were excluded. Mean follow-up to death or the end of 2007 was 4.7 years. RESULTS: A total of 9,631 deaths occurred between 2001 and 2007. Compared with the reference group, mortality risk was higher in patients with BMI 20 to <25 kg/m(2) (hazard ratio 1.22 [95% CI 1.13-1.32] in men, 1.32 [1.22-1.44] in women) and patients with BMI ≥35 kg/m(2) (for example, 1.70 [1.24-2.34] in men and 1.81 [1.46-2.24] in women for BMI 45 to <50 kg/m(2)). Vascular mortality was higher for each 5-kg/m(2) increase in BMI >30 kg/m(2) by 24% (15-35%) in men and 23% (14-32%) in women, but was lower below this threshold. The results were similar after further adjustment for HbA1c, year of diagnosis, lipids, blood pressure, and socioeconomic status. CONCLUSIONS: Patients categorized as normal weight or obese with T2DM within a year of diagnosis of T2DM exhibit variably higher mortality outcomes compared with the overweight group, confirming a U-shaped association of BMI with mortality. Whether weight loss interventions reduce mortality in all T2DM patients requires study.

Diabetes treatments and cancer risk: the importance of considering aspects of drug exposure.

Investigations of the association between diabetes, diabetes treatments, and cancer risk have raised several epidemiological challenges. In particular, a patient's exposure to glucose-lowering drugs needs to be represented accurately to allow unbiased assessment of the link between the treatments and cancer risk. Many studies have used a simple binary contrast (exposure to a specific drug vs no exposure), which has potentially serious drawbacks. In addition, methods used to determine the duration and cumulative dose of drug exposure differ widely between studies. In this Review, we discuss representation of drug exposure in pharmacoepidemiological investigations of the connection between diabetes drugs and cancer risk. We identify principles that might improve future research (particularly in observational studies), and consider issues related to reverse causation and detection bias.

Neuregulin-1ß regulation of embryonic endothelial progenitor cell survival.

Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3ß, and Erk1/2 and the nuclear accumulation and transcriptional activation of ß-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.

Sol-gel-derived iron oxide thin films on silicon: surface properties and interfacial chemistry.

Uniform high-quality iron oxide thin films can be formed from the spin coating of iron oxide/hydroxide sol-gels on a silicon substrate. Thermal processing of the films at temperatures of approximately 300 degrees C results in the transformation of films into a ternary layered structure with iron oxide, Fe(2)O(3), at the surface, characterized by Mossbauer spectroscopy, and reduced, metallic iron characterized by depth profiling of the surface by X-ray photoelectron spectroscopy as a function of Ar(+) etching. Imaging of the etched surface by scanning electron microscopy reveals two distinct regions at the interface, nanoparticles that are very iron-rich separated by an unstructured region that is somewhat less iron-rich. The results demonstrate a synthetic protocol for the spontaneous formaton of a ternary layered structure from a simple one-step preparation.

Impact of UK colorectal cancer screening pilot on primary care.

BACKGROUND: The UK Colorectal Cancer Screening Pilot has recently been completed to evaluate the feasibility of screening using the faecal occult blood test. Screening will be phased in over the next several years, and it is important to consider the impact on the NHS workforce. AIM: To determine the impact of the UK Colorectal Cancer Screening Pilot on primary care workload. DESIGN OF STUDY: A retrospective survey and prospective audit of general practice staff. SETTING: General practice. METHOD: Workload impact was assessed using a postal questionnaire and a prospective audit of activity in participating practices. Questionnaires were sent to practices that had been involved in the Pilot between 6 weeks and 1 year previously. They were sent to a random sample of 59 practices in Scotland and 60 practices in England between February 2001 and March 2002. Audit forms were sent prospectively to 60 practices involved in the Pilot between May 2001 and September 2002. RESULTS: Sixty-seven per cent of GPs, 82% of practice managers, 69% of practice nurses, and 70% of receptionists responded to the questionnaire. Of 60 practices contacted to take part in the workload audit, 38 returned completed 'workload impact audit' forms. Most practice staff indicated they spent 2% or less of their time during the screening period on Pilot-related activities. Forty per cent of GPs thought that a national colorectal cancer screening programme would substantially impact on the workload in primary care. However, there were variations by country: practice staff in Scotland were more likely to think that it would substantially impact on workload than practice staff in England (44.7% versus 26.6%). CONCLUSIONS: The surveys and audit demonstrate that the Pilot has had a discernible, albeit modest, impact on workload in primary care. Workload of particular significance to primary care personnel includes increases in paperwork, administration, and information provision to patients. The majority of primary care staff support the introduction of a colorectal cancer screening programme. However, there is a strong perception, particularly among GPs, that a national programme of faecal occult blood test screening will impact significantly on workload in primary care, and that primary care-based activities generated through screening should be adequately resourced and remunerated.

Telephone consultations to manage requests for same-day appointments: a randomised controlled trial in two practices.

BACKGROUND: General practitioners (GPs) in the United Kingdom have recently begun to adopt the use of telephone consultation during daytime surgery as a means of managing demand, particularly requests for same-day appointments. However, it is not known whether the strategy actually reduces GP workload. AIM: To investigate how the use of telephone consultations impacts on the management of requests for same-day appointments, on resource use, indicators of clinical care, and patient perceptions of consultations. DESIGN OF STUDY: Randomised controlled trial. SETTING: All patients (n = 388) seeking same-day appointments in each surgery in two urban practices (total population = 10,420) over a four-week period. METHOD: The primary outcome measure was use of doctor time for the index telephone or face-to-face consultation. Secondary outcomes were subsequent use of investigations and of services in the two-week period following consultation, frequency of blood pressure measurement and antibiotic prescriptions, and number of problems considered at consultation. Patient perceptions were measured by the Patient Enablement Instrument (PEI) and reported willingness to use telephone consultations in the future. RESULTS: Telephone consultations took less time (8.2 minutes versus 6.7 minutes; diff = 1.5, 95% confidence interval [CI] = 0.6 to 2.4, P = 0.002). Patients consulting by telephone reconsulted the GP more frequently in the two weeks that followed (0.6 consultations versus 0.4 consultations; diff = 0.2, 95% CI = 0.0 to 0.3, P = 0.01). Blood pressure was measured more often in the group of patients managed face-to-face (25/188 [13.3%] versus 12/181 [6.6%]; diff = 6.7%, 95% CI = 0.6% to 12.7%). There was no significant difference in patient perceptions or other secondary outcomes. CONCLUSION: Use of telephone consultations for same-day appointments was associated with time saving, and did not result in lower PEI scores. Possibly, however, this short-term saving was offset by higher re-consultation and less use of opportunistic health promotion.