Positive allosteric modulation of TRPV1 as a novel analgesic mechanism.

BACKGROUND: The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C- and lightly-myelinated Aδ-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment. RESULTS: Withdrawal responses of the capsaicin-only or MRS1477-only treated paws were not significantly different from the untreated, contralateral paws. However, rats treated with the combination of capsaicin and MRS1477 exhibited increased withdrawal latency and decreased response intensity consistent with agonist potentiation and inactivation or lesion of TRPV1-containing nerve terminals. The loss of nerve endings was manifested by an increase in levels of axotomy markers assessed by qRT-PCR and colocalization of ATF3 in TRPV1+ cells visualized via immunohistochemistry. CONCLUSIONS: The present observations suggest a novel, non-narcotic, selective, long-lasting TRPV1-based approach for analgesia that may be effective in acute, persistent, or chronic pain disorders.

Economic considerations in abdominal transplantation.

Care for end-stage organ failure through transplant is one of the landmark accomplishments of the modern medicine. At the same time, organ transplant is a resource-intensive service that has been under increasing scrutiny in this era of cost containment. A detailed understanding of the economic implications of organ quality, recipient characteristics, and allocation policy is vital for the transplant professionals. Prior studies of kidney transplant economics demonstrate significant cost savings achieved by eliminating the need for long-term dialysis. However, transplant providers are experiencing higher financial costs because of changes in recipient characteristics. Liver transplantation economics are also more challenging because of organ allocation based on the severity of illness. Furthermore, the broader use of marginal organs has been demonstrated to increase costs. Novel strategies are vital to reduce the financial burden faced by the centers that perform transplantations on elevated risk patients and utilize lower quality organs.

Measuring Clinical Productivity.

Productivity measurements have been used to evaluate and compare physicians and physician practices. Anesthesiology is unique in that factors outside anesthesiologist control impact opportunity for revenue generation and make comparisons between providers and facilities challenging. This article uses data from the multicenter University of Pittsburgh Physicians Department of Anesthesiology to demonstrate factors influencing productivity opportunity by surgical facility, between department divisions and subspecialties within multispecialty divisions, and by individuals within divisions. The complexities of benchmarking anesthesiology productivity are demonstrated, and the potential value of creating a productivity profile for facilities and groups is illustrated.

Preoperative risk factors for unexpected postoperative intensive care unit admission: A retrospective case analysis.

INTRODUCTION: The purpose of this retrospective case-control study was to investigate preoperative risk factors for unexpected postoperative intensive care unit (ICU) admissions in patients undergoing non-emergent surgical procedures in a tertiary medical centre. METHODS: A medical record review of adult patients undergoing elective non-cardiac and non-transplant major surgical procedures during the period of January 2011 through December 2015 in the operating rooms of a large university hospital was carried out. The primary outcome assessed was unexpected ICU admission, with mortality as a secondary outcome. Demographic data, length of hospital and ICU stay and preoperative comorbidities were also obtained as exposure variables. Propensity score matching was then employed to yield a study and control group. RESULTS: The group of patients who met inclusion criteria in the study and the control group that did not require ICU admission were obtained, each containing 1191 patients after propensity matching. Patients with acute and/or chronic kidney injury (odds ratio (OR) 2.20 [1.75-2.76]), valvular heart disease (OR: 1.94 [1.33-2.85]), peripheral vascular disease (PVD) (OR: 1.41 [1.02-1.94]) and congestive heart failure (CHF) (OR: 1.80 [1.31-2.46]) were all associated with increased unexpected ICU admission. History of cerebrovascular accident (CVA) (OR: 3.03 [1.31-7.01]) and acute and/or chronic kidney injury (OR: 1.62 [1.12-2.35]) were associated with increased mortality in all patients; CVA was also associated with increased mortality (OR: 3.15 [1.21-8.20]) specifically in the ICU population. CONCLUSIONS: CHF, acute/chronic kidney injury, PVD and valve disease were significantly associated with increased unexpected ICU admission; patients with CVA suffered increased mortality when admitted to the ICU.

The benefits of ultrasound-guided continuous sensory nerve blockade in the setting of burn injury: a case report of bilateral continuous superficial peroneal nerve blockade in a patient with severe sleep apnea.

The management of pain after burn injuries is a clinical challenge magnified in patients with significant comorbidities. Presently, burn pain is treated via a wide variety of modalities, including systemic pharmacotherapy and regional analgesia. Although the latter can provide effective pain control in patients with burn injuries, it is relatively underused. Furthermore, the development of ultrasound guidance has allowed for novel approaches and sparing of motor nerve blockade with preference toward sensory-specific analgesia that has not been possible previously. This can result in decreased opiate use and shorter latency to initiation of rehabilitation. In this report, we describe a patient with chronic pain, morbid obesity, and severe sleep apnea who presented with uncontrolled pain resulting from a burn injury to the dorsum of his feet. The treatment consisted of multimodal analgesia and placement of bilateral continuous superficial peroneal nerve catheters, as he underwent skin grafting and postprocedural hydrotherapy. This novel approach allowed for sparing of postprocedural opiates with positive clinical results.

Luciferase immunoprecipitation systems for measuring antibodies in autoimmune and infectious diseases.

Antibody profiles have the potential to revolutionize personalized medicine by providing important information related to autoimmunity against self-proteins and exposure to infectious agents. One immunoassay technology, luciferase immunoprecipitation systems (LIPS), harnesses light-emitting recombinant proteins to generate robust, high-quality antibody data often spanning a large dynamic range of detection. Here, we describe the general format of LIPS and discuss studies using the technology to measure autoantibodies in several human autoimmune diseases including type 1 diabetes, Sjögren's syndrome, systemic lupus erythematosus, and immunodeficiencies secondary to anticytokine autoantibodies. We also describe the usefulness of evaluating antibodies against single or multiple antigens from infectious agents for diagnosis, pathogen discovery, and for obtaining individual exposure profiles. These diverse findings support the notion that the LIPS is a useful technology for generating antibody profiles for personalized diagnosis and monitoring of human health.

Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion.

TRPV1 is expressed in a subpopulation of myelinated Aδ and unmyelinated C-fibers. TRPV1+ fibers are essential for the transmission of nociceptive thermal stimuli and for the establishment and maintenance of inflammatory hyperalgesia. We have previously shown that high-power, short-duration pulses from an infrared diode laser are capable of predominantly activating cutaneous TRPV1+ Aδ-fibers. Here we show that stimulating either subtype of TRPV1+ fiber in the paw during carrageenan-induced inflammation or following hind-paw incision elicits pronounced hyperalgesic responses, including prolonged paw guarding. The ultrapotent TRPV1 agonist resiniferatoxin (RTX) dose-dependently deactivates TRPV1+ fibers and blocks thermal nociceptive responses in baseline or inflamed conditions. Injecting sufficient doses of RTX peripherally renders animals unresponsive to laser stimulation even at the point of acute thermal skin damage. In contrast, Trpv1-/- mice, which are generally unresponsive to noxious thermal stimuli at lower power settings, exhibit withdrawal responses and inflammation-induced sensitization using high-power, short duration Aδ stimuli. In rats, systemic morphine suppresses paw withdrawal, inflammatory guarding, and hyperalgesia in a dose-dependent fashion using the same Aδ stimuli. The qualitative intensity of Aδ responses, the leftward shift of the stimulus-response curve, the increased guarding behaviors during carrageenan inflammation or after incision, and the reduction of Aδ responses with morphine suggest multiple roles for TRPV1+ Aδ fibers in nociceptive processes and their modulation of pathological pain conditions.

Commercial multiplex technologies for the microbiological diagnosis of sepsis.

In patients with suspected sepsis, rapid and accurate diagnosis of the causative infectious agent is critical. Although clinicians often use empiric antimicrobial therapy until the blood cultures are available to potentially adjust treatment, this approach is often not optimum for patient care. Recently, several commercial molecular multiplex technologies have shown promise for fast and comprehensive diagnosis of microorganisms and their antimicrobial resistance signatures. While one class of multiplex technologies is directed at improving the speed and diagnostic information obtained from positive blood cultures, the other identifies the causative microorganisms directly from clinical blood samples. This review provides an overview of these molecular technologies and describes their performance capabilities compared to standard blood cultures and in some cases to each other. We discuss the current clinical impact, limitations, and likely futures advances these multiplex technologies may have in guiding the management of patients with sepsis.

Extrapancreatic autoantibody profiles in type I diabetes.

Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing ß-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-ß. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-ß (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D.