Building a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects.

The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK1) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK1 antagonist compound [Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF3)2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain.

Routine use of PICO dressings may reduce overall groin wound complication rates following peripheral vascular surgery.

BACKGROUND: Approximately 19% of morbidity in peripheral vascular surgery is attributable to wound complications, which can result in delayed healing, and also arterial or graft infection leading to limb loss and even mortality in extreme cases. AIM: To determine whether groin wound complications were reduced following the routine introduction of PICO negative pressure wound therapy dressings in patients who underwent peripheral vascular surgery. METHODS: Patients who underwent peripheral vascular surgery from 2011 to 2016 were identified and divided into PICO and non-PICO groups. Patient, procedure and wound characteristics were tabulated and analysed. Patients were followed-up for at least six weeks postoperatively. Wound complication rates, infection confirmed by microbiology, and requirement for re-admission due to wound complications were noted. Basic cost analysis was performed. FINDINGS: In total, 151 patients were analysed (N = 73 PICO, N = 78 non-PICO). No difference in age (P = 0.862), body mass index (P = 0.673), diabetes (P = 0.339), pre-operative albumin (P = 0.196), use of drain (P = 0.343) and history of meticillin-resistant Staphylococcus aureus (P = 0.281) was observed between groups. The PICO group contained more smokers than the non-PICO group (45% vs 29%, P = 0.034). Wound complications were seen in 8% (N = 6) of the PICO group and 19% (N = 15) of the non-PICO group (P = 0.042). No significant difference in infection was found between the two groups (3% vs 6%, P = 0.249), but fewer seromas were observed when PICO dressings were used (1.4% vs 7.7%, P = 0.069). Haematoma (2.7% vs 3.8%, P = 0.531) and dehiscence rates (1.4% vs 1.3%, P = 0.735) were similar between the two groups. CONCLUSIONS: Routine use of PICO dressings is associated with a reduction in wound complication rates following peripheral vascular surgery, and is cost-effective.

Post-war development of emergency medicine in Kosovo.

OBJECTIVES: To (1) investigate emergency medical care priorities in Kosovo, (2) assess Kosovo's post-war development of emergency medical services and (3) identify expectations. METHODS: An instrument with seven open-ended questions, approved by the institutional review board, was designed for in-person interviews (preferred) or written survey. The survey was administered in October 2003 at the Kosovo University Clinical Center, Pristina, Kosovo, and one regional hospital. Targeted participants were emergency care providers, clinical consultants and health policy consultants. Surveys were conducted by interview with simultaneous interpretation by a native Albanian speaker, an orthopaedic surgeon or in written Albanian form. The responses were evaluated quantitatively and qualitatively. RESULTS: 13 respondents participated in the study: 10 gave interviews and 3 provided written response; 7 were emergency care providers, 4 were emergency care consultants and 2 were health policy consultants. Emergency care priorities were defined as trauma, cardiac disease and suicide. Most respondents believed that emergency medicine as a specialised field was a post-war development. The international community was credited with the provision of infrastructure, supplies and training. Most respondents denied any harm from international assistance. However, some respondents described instances of inappropriate international investment. Ongoing needs are training of providers and equipping of facilities and vehicles. Improved hospital management, political administration and international involvement are thought to be necessary for continued development. CONCLUSIONS: Survey respondents agreed on priorities in emergency care, credited the international community with development to date, and identified administrative structures and international training support as the keys to ongoing development.

Toward More Patient-Centered and Prevention-Oriented Oral Health Care: The ADVOCATE Project.

ADVOCATE (Added Value for Oral Care) is a project funded by the European Commission's Horizon 2020 program, which aims to develop strategies for a system transition toward more patient-centered and prevention-oriented oral health care delivery within health care systems. This system should balance the restorative and preventive approaches in dental and oral health care. ADVOCATE is a partnership among 6 European Union member states, which involves collaboration among universities, state-funded health care providers, and private insurance companies in Denmark, Germany, Hungary, Ireland, the Netherlands, the United Kingdom, and Aridhia, a biomedical informatics company based in Scotland. There are 6 interrelated work packages, which aim to address the following objectives: 1) in-depth evaluation of oral health care systems in European Union member states to identify best system designs for oral disease prevention, 2) development of a set of measures to provide information on oral care delivery and oral health outcomes, 3) evaluation of a feedback approach in dental practice that aims to facilitate a change toward preventive oral health care delivery, and 4) economic evaluation of strategies to promote preventive oral health care and development of policy recommendations for oral health care systems. The project is novel in its use of data that are routinely collected by health insurance organizations, as well as the engagement of key stakeholders from dental teams, insurers, patients, and policy makers in guiding the development and progress of the project. This article outlines in detail the objectives and research methodology of the ADVOCATE project and its anticipated impact. Knowledge Transfer Statement: This commentary describes the development of policy options to promote a greater focus on disease prevention in general dental practice. The approach builds on identifying the comparative effectiveness of alternative incentive schemes, as well as methods to monitor clinical and patient-derived measures of success in creating health for patients. The article describes the development and application of the measures and the evaluation of their success in orienting clinical practice more toward disease prevention.

Clonal evolution and tumor progression in 2 human colorectal adenoma-derived cell-lines invitro - the involvement of chromosome-1 abnormalities.

Two human colorectal adenoma cell lines, S/RG and S/AN, have been continuously passaged in vitro to determine whether they would immortalize and if specific cytogenetic changes were involved in immortalization and tumor progression. At passage 7, S/RG was highly aneuploid, but had no abnormalities of chromosome 1 (Paraskeva et al, Cancer Res 49: 1282-1286, 1989). With continued passage under two independent sets of growth conditions an isochromosome Iq and derivatives of this isochromosome occurred as specific abnormalities. S/AN was near-diploid at passage 10, with a deletion in lp and monosomy 18. The karyotype at passage 44 showed no change. The cell lines are stable in that they have remained anchorage-dependent and non-tumorigenic after several years in culture and S/AN has retained a near diploid karyotype. These cell lines are therefore highly valuable for further studies of tumor progression in human colorectal carcinogenesis.

The significance of pulmonary changes associated with cerebral perfusion with hypoxic blood in monkeys.

Parameters of cerebral and pulmonary function were studied in ten animals whose brains were perfused with hypoxic right atrial blood according to the Moss method. All animals died as a result of cerebral hypoxia at about 95 minutes after the onset of perfusion. Gross pulmonary congestion, edema, and leukocyte plugs occurred in the seven animals breathing spontaneously, but positive pressure ventilation prevented these changes in three. The resumption of cerebral perfusion with oxygenated blood after 30 minutes of the Moss procedure did not prevent the pulmonary changes and, of more importance, did not prevent cerebral swelling and death at about the same time as that of all the other animals. There were no changes in oxygen uptake or in arterial oxygen tension to indicate that progressive pulmonary failure contributed to death. It is concluded that this model produces brain swelling and brain death with incidental pulmonary pathological changes indistinguishable from early findings in hemorrhagic shock models and that the cerebral hypoxic perfusion model in monkeys is not suitable for studying the effects of "shock lung" therapy.

Hypokalemic periodic paralysis with unusual responses to acetazolamide and sympathomimetics.

Five members in three generations of a family were affected by an illness that had many clinical features of the hypokalemic form of periodic paralysis (HPP). The serum potassium was either moderately reduced or normal during attacks, and there was no evidence of myotonia or cold-intolerance. All of the patients improved to a variable degree with oral potassium supplements, and 3 responded favorably to triamterene. The usually beneficial drug acetazolamide, however, invariably caused weakness in these patients, an effect previously described in only one other family with HPP. In addition, amphetamine-like sympathomimetic drugs effectively aborted or prevented paralysis in several members. Muscle biopsy in two patients revealed some unusual features, and electromyography showed myopathic potentials. There was no evidence of diabetes. The urine electrolyte concentrations during glucose tolerance tests, however, were different from those previously reported in HPP. This family may represent a variant form of HPP.

Management of 136 consecutive supratentorial berry aneurysms.

A series of 103 consecutive cases admitted to the University of Chicago Hospitals with a recently ruptured supratentorial aneurysm were medically managed by antifibrinolytic medication, and, when applicable, by hypotension, intracranial pressure control, and respiratory support. Nine patients deteriorated and died, and six rebled and died before they were judged fit for surgical treatment. Four were treated by carotid occlusion. Nine, because of refusal or medical judgment, did not have surgical treatment. Sixty-nine of these patients and a further 33, electively admitted, underwent craniotomy. In these 102 patients, there was no mortality. Seven developed postoperative hemiparesis or hemiplegia. Six recovered. One has a residual monoparesis.

Treatment of aneurysmal hemiplegia with dopamine and mannitol.

Three patients with severe postoperative hemiplegia and one with hemiplegia following a subarachnoid hemorrhage are presented. None had hematomas. All were treated with dopamine-induced hypertension, mannitol, and large quantities of intravascular fluids. All showed a remarkable degree of clinical improvement, presumably secondary to an increase in cerebral blood flow.

Obesity and non-insulin dependent diabetes mellitus. 22-23 April 1998, The Royal Society, London, UK.

This two-day meeting provided researchers with an overview of the broad range of targets for possible drug development by highlighting a range of receptor molecules and factors controlling food intake. The direct or indirect role various proteins play in the development of non-insulin dependent diabetes mellitus (NIDDM) or obesity were discussed. Mutations resulting in NIDDM or obesity in animal models were highlighted, although these mapped mutations have not as yet been shown to be the main cause of NIDDM in humans. This further highlights the complexity of these diseases resulting in a broad spectrum phenotype. The importance of NIDDM and obesity research was stressed in the global forecast contributing to social and economic problems in both developed and developing countries. The management and early detection of NIDDM was proposed as the best means of reducing therapeutic costs and the severity of the diseases.

New drugs in cancer therapy.

Approximately 2000 academic and industry researchers, and medical doctors attended this symposium on new drugs in cancer. The Netherlands (land of water) its control and its victory in water management was compared to cancer research, and the fight against the disease. The meeting was officially opened by the major of Amsterdam, S Patijn, who highlighted the multicultural characteristics of Amsterdam. Cancer is an international problem and it was very encouraging to see representatives from both developing and developed countries attending the meeting. The conference organizers stressed that the NCI, EORTC, pharmaceutical industries and researchers must strive together to advance cancer research.

Applied proteomics--analyzing protein structure and function for drug discovery. 27-28 January 1999, London, UK.

This two-day meeting, attended by approximately 60 delegates, was aimed at researchers in the proteomics field. The proteome is defined as the entire protein content of the cell. Proteomics is the analysis of the end-product of gene expression and all regulations governing gene expression are taken into account, ie, transcriptional and translational. The three stages involved in proteomic analysis are: a separation phase, ie, two dimensional (2D) gel electrophoresis; a characterization phase, ie, mass spectrometry; and, a data analysis phase, ie, bioinformatics.

Effect of sodium nitroprusside on cerebral blood flow in conscious human beings.

Hemispheric cerebral blood flow was measured in 14 patients prior to and after the injection of sodium nitroprusside. The intracarotid method of Xenon was utilized, and flow was calculated by the flow initial technique. With a small reduction in blood pressure during the administration of sodium nitroprusside, the cerebral blood flow fell significantly by 15.9+/- 5.6%.

Intracranial pressure gradients in a patient with a thalamic tumor.

The clinical history and intracranial pressure records of a patient with a thalamic tumor obstructing the ventricular system is presented. There were sustained differences in pressure between the anterior and posterior parts of the obstructed lateral ventricle. Brain compliance was markedly reduced and there were numerous pressure waves. It is believed that these supratentorial pressure gradients are most marked when there is a loss of brain compliance, and that they contribute to the mechanisms of brain shifts and spreading edema. Thus, they must be taken into account in the management of patients with intracranial mass lesions.

Description and uses of intracranial pressure monitoring.

Today, ICP monitoring is used to facilitate the diagnosis, treatment, and prognosis of abnormal ICP profiles. The level of ICP is made readily available and impending ICP abnormalities can be detected by evaluation of compensation mechanisms. ICP monitoring can also be used to evaluate methods of ICP reduction as shown in Fig 5. It can also aid in determining the prognosis. A poor prognosis is indicated by a CPP of less than 30 mm. Hg, rising ICP in spite of treatment, and loss of compliance. ICP monitoring is useful only in the experienced hands of a neurosurgical team which is better qualified to interpret data in association with the clinical picture and determine a plan of treatment. They are also fully aware of and can guard against possible infection, CSF leakage, hematoma, and its consequences.

Utility of bronchoalveolar lavage in the diagnosis of pulmonary infection in children with haematological malignancies.

BACKGROUND: Fibre-optic bronchoscopy with bronchoalveolar lavage (BAL) is a safe procedure and is associated with low morbidity and mortality in immunocompromised children. Although many studies have highlighted the advantages of positive BAL results in the diagnosis of pulmonary infections, there have been few reports examining the impact of a negative BAL result on clinical management in immunocompromised children on empiric broad-spectrum antimicrobial therapy. AIM: The aim of this study was to evaluate BAL in the diagnosis of pulmonary infections in children with haematological malignancies who develop pneumonia unresponsive to empiric antimicrobial therapy, and also to determine whether a negative BAL result contributed to the clinical management of these patients. MATERIALS AND METHODS: A retrospective review of 44 BAL procedures performed in 33 children with haematological malignancy diagnosed and treated at Our Lady's Children Hospital, Crumlin, Dublin 12, Ireland, over a 10-year period was carried out. RESULTS: We identified a pathogen causing pneumonia in 24 of 44 BAL procedures (54.5 %). The BAL procedure resulted in modification of antimicrobial treatment after 20 of 24 procedures with positive results (83.3 %) in 16 of 20 patients (80 %). Management was changed after 8 of 20 procedures with negative results (40 %) in 8 of 18 patients (44.4 %). The procedure was well tolerated in all patients. CONCLUSIONS: Our study supports the use of bronchoscopy with BAL as a diagnostic intervention in this patient population. We consider BAL a safe procedure from which both positive and negative results contribute to the patient's clinical management.

Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.

Investigating barriers to implementation of the NICE Guidelines for Depression: a staff survey with Community Mental Health Teams.

Clinical guidelines have been designed to lead to significant and consistent improvements in health care but are rarely fully implemented within healthcare services. The study involved a survey of staff at four Community Mental Health Teams, which aimed to assess their knowledge and use of both the psychological recommendations of the National Institute for Health and Clinical Excellence (NICE) guidelines for Depression and specifically of cognitive-behavioural therapy (CBT) based interventions. It also aimed to assess team members' clinical assessment skills and decision-making patterns when making recommendations about services for patients with depression. The results indicated that while over 90% of staff said they were using the NICE guidelines for Depression, less than 20% were very confident in using them. Most staff had knowledge about CBT and most (88%) would be very willing to refer to CBT but mentioned problems such as lack of resources and/or social problems affecting service delivery. Most staff were generally able to correctly identify the severity and type of depression. Despite this, some staff were making decisions that were not in accordance with the NICE recommendations. Reasons for these patterns are discussed.