Fixed-dose combination therapy for type 2 diabetes: sitagliptin plus pioglitazone

Importance of the field: Type 2 diabetes is typically associated with insulin resistance and dysfunction of insulin-secreting pancreatic beta-cells. Addressing these defects often requires therapy with a combination of differently acting antidiabetic agents. A potential novel combination in development brings together the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin with the thiazolidinedione pioglitazone into a fixed-dose single-tablet combination. The former component acts mainly to increase prandial insulin secretion; the latter improves insulin sensitivity.

Decadence in the Forest: Smyth's Der Wald in its Critical Context

Ethel Smyth’s opera, Der Wald, met with mixed reactions at its premiere in Berlin in 1902. Many factors contributed to this, not least, as Smyth herself observed, anti-British sentiment in Germany following the second Boer War. One might have expected that the reception of the opera at its British premiere on 18 July at Covent Garden might have been more positive, but even here critical opinion was divided. Even positive reviews were not free from gender discrimination, and other reviews condemned the opera for being too German or Wagnerian. What was meant by ‘Wagnerian’? This article answers the question in three ways. Firstly, I argue that ‘Wagnerian’ meant not a leitmotif-filled, through-composed work (as distinct from a number opera), but simply a lyrical drama; for British audiences the model for this was Tannhäuser or Lohengrin, not the Ring or Tristan. Secondly, taking this definition on board, I analyse the musical language of the opera, in particular the key structure. The central duet sung by the doomed lovers, Heinrich and Röschen, is in F major, almost the furthest possible distance from the home key of the opera (E major), which characterizes the forest and ‘nature’ in general; by contrast, the next scene, where the Kundry-like Iolanthe attempts to seduce Heinrich (a crucial reversal of the more conventional power relations of the love duet), sees a return to the home key. Thirdly, I set the hermeneutical implications of this reversal in the context of the decadent movement, with which late nineteenth-century Wagnerism was associated, and which, following the conviction of Oscar Wilde in 1895, was discredited. Der Wald thus failed because of its ‘guilt by association’ with an aesthetic that had fallen into disrepute.

Future Directions in Treating Cough

Cough is a common and troublesome symptom that can be difficult to treat. New therapeutic options that are safe and more effective than those currently available are needed. In this article, the authors offer opinion on future directions in the treatment of cough, with a particular emphasis on the clinical syndrome associated with cough reflex hypersensitivity. In addition, the article provides an overview of some of the diagnostic technologies and promising drug targets likely to emerge from current clinical and scientific endeavor.

Impact of ATP-binding cassette, subfamily B, member 1 pharmacogenetics on tacrolimus-associated nephrotoxicity and dosage requirements in paediatric patients with liver transplant

Importance of the field: Tacrolimus is the most commonly used immunosuppressive agent following solid-organ transplantation in children. Its clinical use, however, is complicated by side effects (mainly nephrotoxicity), narrow therapeutic index and pharmacokinetic variability which can result in an increased risk of treatment failure or toxicity. Studies examining inter-individual differences in the expression of the ABCB1 (ATP-binding cassette, subfamily B, member 1) gene (which encodes the drug transporter, P-gp) and its genetic polymorphisms have attempted to elucidate variations in tacrolimus response and disposition in children.

Safe Therapeutic Economic Pharmaceutical Selection (STEPS): development, introduction and use in Northern Ireland

A number of medicine selection methods have been used worldwide for formulary purposes. In Northern Ireland, integrated medicines management is being developed, and related projects have been carried out. This paper deals with the description of the STEPS (Safe Therapeutic Economic Pharmaceutical Selection) programme. The paper outlines the development of STEPS and its application as an element of a cost-effective medicines-management process in Northern Ireland.

Malignant pleural mesothelioma: current treatments and emerging drugs

Background: Malignant pleural mesothelioma (MPM) is an uncommon disease whose incidence is increasing worldwide over the past 30 years. Surgical resection and radiotherapy represent the standard treatment in patient with resectable MPM. Chemotherapy is also necessary to reduce incidence of distant metastases, but the optimal setting of treatment (neoadjuvant, adjuvant and intrapleural) is not clarified. For the patients with unresectable MPM, the combination cisplatin and pemetrexed or ralitrexed is the standard treatment as supported by a Phase III study. Better understanding of molecular pathways involved in MPM has enabled inclusion of new drugs targeted against pathways responsible for proliferation, cell survival and angiogenesis. Objective: This review discusses the current treatment option, the specific signal pathways activated in MPM and the novel agents under evaluation in clinical trials. Methods: We use for this article abstracts, papers, oral presentations from ASCO and the website http://www.clinical-trials.gov. Results/conclusion: This review summarizes the activity of chemotherapy and of new agents under evaluation in clinical trials. The better understanding of molecular pathways activated in MPM will hopefully provide new therapeutic options for these patients in the future.

Long-term control of petroclival meningiomas through radiosurgery Clinical article

Because of their critical location adjacent to brain, cranial nerve, and vascular structures, petroclival meningiomas remain a clinical challenge. As first author, I evaluated outcomes in 168 patients with petroclival meningiomas who underwent Gamma Knife surgery (GKS) during a 21-year interval at the University of Pittsburgh.

Gamma Knife stereotactic radiosurgery for idiopathic trigeminal neuralgia. Clinical article

Object
Trigeminal neuralgia pain causes severe disability. Stereotactic radiosurgery is the least invasive surgical option for patients with trigeminal neuralgia. Since different medical and surgical options have different rates of pain relief and morbidity, it is important to evaluate longer-term outcomes.

Methods
The authors retrospectively reviewed outcomes in 503 medically refractory patients with trigeminal neuralgia who underwent Gamma Knife surgery (GKS). The median patient age was 72 years (range 26–95 years). Prior surgery had failed in 205 patients (43%). The GKS typically was performed using MR imaging guidance, a single 4-mm isocenter, and a maximum dose of 80 Gy.

Results
Patients were evaluated for up to 16 years after GKS; 107 patients had > 5 years of follow-up. Eighty-nine percent of patients achieved initial pain relief that was adequate or better, with or without medications (Barrow Neurological Institute [BNI] Scores I–IIIb). Significant pain relief (BNI Scores I–IIIa) was achieved in 73% at 1 year, 65% at 2 years, and 41% at 5 years. Including Score IIIb (pain adequately controlled with medication), a BNI score of I–IIIb was found in 80% at 1 year, 71% at 3 years, 46% at 5 years, and 30% at 10 years. A faster initial pain response including adequate and some pain relief was seen in patients with trigeminal neuralgia without additional symptoms, patients without prior surgery, and patients with a pain duration of = 3 years. One hundred ninety-three (43%) of 450 patients who achieved initial pain relief reported some recurrent pain 3–144 months after initial relief (median 50 months). Factors associated with earlier pain recurrence that failed to maintain adequate or some pain relief were trigeminal neuralgia with additional symptoms and = 3 prior failed surgical procedures. Fifty-three patients (10.5%) developed new or increased subjective facial paresthesias or numbness and 1 developed deafferentation pain; these symptoms resolved in 17 patients. Those who developed sensory loss had better long-term pain control (78% at 5 years).

Conclusions
Gamma Knife surgery proved to be safe and effective in the treatment of medically refractory trigeminal neuralgia and is of value for initial or recurrent pain management. Despite the goal of minimizing sensory loss with this procedure, some sensory loss may improve long-term outcomes. Pain relapse is amenable to additional GKS or another procedure.

Boost radiosurgery as a strategy after failure of initial management of pediatric primitive neuroectodermal tumors Clinical article

The aim in this study was to determine the outcomes of boost stereotactic radiosurgery, specifically Gamma Knife surgery (GKS), for recurrent primitive neuroectodermal tumors (PNETs) in children in whom initial multimodality management had failed.

E-Participation and E-Participants: solving the patent ‘crisis’

One of the major planks of some visions for E-Gov is that there is a willing participatory group who are more than happy to be involved in new forms of democracy and will be active and useful suppliers of input to e-consultation or e-participation processes. This group is different from that which goes online to the government site web and signs a petition asking the prime minister to resign. It is becoming clear, though, that the commitment to e-participation may well be there in theory, but difficult to access in practice. Further, the participation which is most welcome can frequently require training and expertise which is not widely available or there may be differences in opinion as to the point of participation. In this paper I will look to the attempts to encourage participation in the patent system. The UK is about to initiate a trial system utilising New York Law School’s Peer To Patent project, but has also attempted to involve participants in previous consultation exercises. I will use these as demonstrations of the sorts of problems which e-participation has met, and consider whether this new form of E-Gov is perhaps being oversold. The interesting question is whether participation is a growing tool which can ensure better public services from the State. My conclusion is that consultation and participatory projects can demonstrate involvement and are certainly educative but e-participatory projects are most likely incapable of achieving the goals set by their more optimistic advocates. The paper emphasises the patents field, but the lessons from it can – I suggest – be viewed as indicators having wider governance relevance. The primary point being made is that the technocratic view is always over-optimistic.