Experience-dependent neural plasticity, learning, and memory in the era of epitranscriptomics.

In this short review, we highlight recent findings in the emerging field of epitranscriptomic mechanisms and discuss their potential role in neural plasticity, learning and memory. These include the influence of RNA modifications on activity-induced RNA structure states, RNA editing and RNA localization, and how qualitative state changes in RNA increase the functional diversity and information-carrying capacity of RNA molecules. We predict that RNA modifications may be just as important for synaptic plasticity and memory as quantitative changes in transcript and protein abundance, but with the added advantage of not being required to signal back to the nucleus, and therefore better suited to be coordinated with the temporal dynamics of learning.

In vitro analysis of the effect of supplementation with activated charcoal on the equine hindgut.

The present study uses in vitro analytical techniques to investigate the effect of activated charcoal on the microbial community of the equine hindgut and the metabolites they produce. Incubations were performed in Wheaton bottles using a 50 ml incubation of a high-energy feed or a low-energy feed, plus bottles with no added food source, together with five levels of activated charcoal (0, 10, 25, 50 or 100 mg per bottle) and fecal samples as a bacterial inoculum. Using this method the rate of gas production, volatile fatty acid and ammonia concentrations, and pH values were analyzed and found to vary depending on the addition of feed, but the activated charcoal had no effect (P>0.05) on any of these. It is already believed that the effect of activated charcoal as a control for toxic substances is at its highest in the foregut or midgut of animals, and therefore should have little impact on the hindgut. The data presented here suggest that if any of the activated charcoal does reach the hindgut, then it has no significant impact on the microbial community present, nor on the major metabolites produced, and so should not have a detrimental effect on the principal site of fermentation in the horse.

Proton therapy for prostate cancer: why and what orthopaedic surgeons need to know about it.

Most orthopaedic surgeons are unfamiliar with proton therapy or the difference between proton radiation and photon (X-ray) radiation. After they perform a total hip replacement or metallic hip implant, their patient cannot have proton therapy for prostate cancer because the protons must pass exclusively through the hips and are blocked by metal. Proton therapy is a sophisticated and expensive technology with growing demand and limited supply. In proton therapy, heavy protons are accelerated to almost the speed of light in a synchrotron (particle accelerator) down a magnetic beam the length of a football field to radiate cancers. Proton therapy is a remarkably safe and effective treatment for prostate cancer, the most common cancer in men, although treatment superiority has yet to be proved in randomized studies. There are currently only 10 proton centers in the United States.

Polydactyly of the hand.

Polydactyly is considered either the most or second most (after syndactyly) common congenital hand abnormality. Polydactyly is not simply a duplication; the anatomy is abnormal with hypoplastic structures, abnormally contoured joints, and anomalous tendon and ligament insertions. There are many ways to classify polydactyly, and surgical options range from simple excision to complicated bone, ligament, and tendon realignments. The prevalence of polydactyly makes it important for orthopedic surgeons to understand the basic tenets of the abnormality.

Web-based participatory surveillance of infectious diseases: the Influenzanet participatory surveillance experience.

To overcome the limitations of the state-of-the-art influenza surveillance systems in Europe, we established in 2008 a European-wide consortium aimed at introducing an innovative information and communication technology approach for a web-based surveillance system across different European countries, called Influenzanet. The system, based on earlier efforts in The Netherlands and Portugal, works with the participation of the population in each country to collect real-time information on the distribution of influenza-like illness cases through web surveys administered to volunteers reporting their symptoms (or lack of symptoms) every week during the influenza season. Such a large European-wide web-based monitoring infrastructure is intended to rapidly identify public health emergencies, contribute to understanding global trends, inform data-driven forecast models to assess the impact on the population, optimize the allocation of resources, and help in devising mitigation and containment measures. In this article, we describe the scientific and technological issues faced during the development and deployment of a flexible and readily deployable web tool capable of coping with the requirements of different countries for data collection, during either a public health emergency or an ordinary influenza season. Even though the system is based on previous successful experience, the implementation in each new country represented a separate scientific challenge. Only after more than 5 years of development are the existing platforms based on a plug-and-play tool that can be promptly deployed in any country wishing to be part of the Influenzanet network, now composed of The Netherlands, Belgium, Portugal, Italy, the UK, France, Sweden, Spain, Ireland, and Denmark.

Current concepts of the anatomy of the thumb trapeziometacarpal joint.

This review article describes the anatomy of the thumb trapeziometacarpal joint. In the final phase of opposition screw home torque rotation of the volar beak of the thumb metacarpal in the pivot area of the trapezium recess and tension on the dorsal ligament complex create stability for power pinch and power grip. The resulting compressive shear forces can lead over time to trapeziometacarpal joint osteoarthritis.

Three-dimensional rotational angiography of the inferior vena cava as an adjunct to inferior vena cava filter retrieval.

The objective of this study was to explore the role of three-dimensional (3-D) rotational angiography (RA) of the inferior vena cava (IVC; 3-D CV) before filter retrieval and its impact on treatment planning compared with standard anteroposterior cavography (sCV). Thirty patients underwent sCV and 3-D CV before IVC filter retrieval. Parameters assessed were: projection of filter arms or legs beyond the caval lumen, thrombus burden within the filter and IVC, and orientation of the filter within IVC. Skin and effective radiation doses were calculated. Statistical analysis was performed using paired Student t test and nonparametric McNemar's test. Standard anteroposterior cavography detected 49 filter arms or legs projecting beyond the caval lumen in 25 patients. Three-dimensional CV demonstrated 89 filter arms or legs projecting beyond the caval lumen in 28 patients. Twenty-two patients had additional filter arms or legs projecting beyond the caval lumen detected on 3-D CV that were not detected on sCV (p < 0.001). Filter apex tilt detection differed significantly (p < 0.001) between sCV and 3-D CV, with 3-D CV being more accurate. The filter apex abutted the IVC wall in 10 patients (33%) on 3-D CV, but this was diagnosed in only 3 patients (10%) with sCV. Thrombus was detected in 8 patients (27%), 1 thrombus of which was seen only on 3-D CV, and treatment was changed in this patient because of thrombus size. Mean effective radiation doses for 3-D CV were approximately two times higher than for sCV (1.68 vs. 0.86 mSv), whereas skin doses were three times lower (12.87 vs. 35.86 mGy). Compared with sCV, performing 3-D CV before optional IVC filter retrieval has the potential to improve assessment of filter arms or legs projecting beyond the caval lumen, filter orientation, and thrombus burden.

Traumatic dislocations and instability of the trapeziometacarpal joint of the thumb.

The surgeon treating traumatic injuries to the TMC joint should be aware of the fundamental misconceptions and pervasive axiomatic myths perpetuated in the medical literature: namely that the volar beak ligament is the prime stabilizer, that the dorsal ligament complex plays no significant role in TMC joint function, and that the APL is a deforming force in Bennett fractures. On the contrary, stability of the TMC joint in power pinch and power grasp depends on the TMC joint's two prime stabilizers, the volar beak of the thumb metacarpal and the dorsal radial ligament complex; and the APL is not a deforming force in a Bennett fracture. Screw-home-torque occurs in the final phase of opposition; the acute Bennett fracture can be treated closed and percutaneously fixed if the screw-home-torque technique is used to anatomically reduce the fracture. After soft tissue interposition, if a semi-acute Bennett fracture is diagnosed late, it should be treated open with a volar approach, the screw-home-torque reduction technique, and screw or pin fixation. Rolando multipart fractures of the thumb metacarpal into the TMC joint are best treated closed, with traction in opposition with pin fixation; pure dislocations of the TMC joint that tear the dorsal ligament complex and Bennett fractures with an associated dorsal ligament complex tear (as diagnosed by the screw-home-torque technique) require open reduction and dorsal ligament complex repair. The current literature is so replete with myths and folklore regarding the anatomy that a conscientious surgeon treating a traumatic dislocation or in-stability of the TMC joint should return to the cadaver room and carefully review and understand TMC joint anatomy.

A randomised controlled crossover trial of nurse practitioner versus doctor led outpatient care in a bronchiectasis clinic.

BACKGROUND: With the decrease in junior doctor hours, the advent of specialist registrars, and the availability of highly trained and experienced nursing personnel, the service needs of patients with chronic respiratory diseases attending routine outpatient clinics may be better provided by appropriately trained nurse practitioners. METHODS: A randomised controlled crossover trial was used to compare nurse practitioner led care with doctor led care in a bronchiectasis outpatient clinic. Eighty patients were recruited and randomised to receive 1 year of nurse led care and 1 year of doctor led care in random order. Patients were followed up for 2 years to ensure patient safety and acceptability and to assess differences in lung function. Outcome measures were forced expiratory volume in 1 second (FEV(1)), 12 minute walk test, health related quality of life, and resource use. RESULTS: The mean difference in FEV(1) was 0.2% predicted (95% confidence interval -1.6 to 2.0%, p=0.83). There were no significant differences in the other clinical or health related quality of life measures. Nurse led care resulted in significantly increased resource use compared with doctor led care (mean difference pound 1497, 95% confidence interval pound 688 to pound 2674, p<0.001), a large part of which resulted from the number and duration of hospital admissions. The mean difference in resource use was greater in the first year ( pound 2625) than in the second year ( pound 411). CONCLUSIONS: Nurse practitioner led care for stable patients within a chronic chest clinic is safe and is as effective as doctor led care, but may use more resources.

Novel bicyclic lactam inhibitors of thrombin: potency and selectivity optimization through P1 residues.

Peptidomimetic inhibitors of thrombin lacking the important Ser195-carbonyl interaction have been prepared. The binding energy lost after the removal of the activated carbonyl was recaptured through a series of modifications of the P1 residues of the bicyclic lactam inhibitors. Selected substituted compounds displayed useful pharmacological profiles both in vitro and in vivo.

The reprofessionalisation of community pharmacy? An exploration of attitudes to extended roles for community pharmacists amongst pharmacists and General Practioners in the United Kingdom.

In the light of recent developments within the British National Health Service some sociologists have suggested that the medical profession's status is under threat. They have specified a range of factors contributing to this state of affairs, such as the new consumerism; however, it is thought that attempts by other, related occupations at reprofessionalisation are particularly significant in this trend. It may be possible to understand recent initiatives at extending community pharmacists' role within this framework. This paper suggests that while community pharmacy is developing strategies to enhance its professional status, it is not so much an attempt at usurping general practitioners'(GPs) (primary care doctors') role as a bid for survival, especially on the part of the rank and file. However, GPs do not necessarily see the initiatives in this light. Although many GPs are accommodating some changes in community pharmacy, they also perceive some of the initiatives as a threat to their autonomy and control, this was especially evident in representative bodies such as the Local Medical Committee. Doctors' accommodating attitudes were qualified with traditional attitudes of dominance such as 'limitation' and 'exclusion'. Such attitudes could prevent community pharmacy from achieving professional status. However, there is also evidence that pharmacists themselves contribute to this situation because many of them also attribute ultimate authority to doctors. Moreover, they are held back by internal occupational divisions particularly between retail pharmacists and employee pharmacists, with the former being the most insecure.

Potent and selective bicyclic lactam inhibitors of thrombin. Part 4: transition state inhibitors.

Bicyclic piperazinone based thrombin inhibitors of general structure 2 were prepared and evaluated in vitro and in vivo. These inhibitors, having in common an electrophilic basic trans-cyclohexylamine P1 residue, displayed high thrombin affinity, high selectivity against trypsin and good in vivo efficacy in the rat arterial thrombosis model.

Creatine supplementation increases renal disease progression in Han:SPRD-cy rats.

The growing use of creatine as a potential ergogenic aid among active individuals has raised concern regarding its effects on the kidney, particularly among those individuals with compromised renal function. The object of this study is to investigate the effects of oral creatine supplementation in an accepted animal model of renal cystic disease. Han:Sprague-Dawley (SPRD)-cy rats with cystic kidney disease were administered a creatine supplement at a loading dose of 2.0 g/kg of diet for 1 week, followed by 5 weeks during which the dose was one fifth this amount, mimicking typical human consumption on a body-weight basis. Cystic kidney disease progression was assessed by measuring kidney size and fluid content and determining cyst scores. Renal function was assessed by measuring serum urea and creatinine concentrations and creatinine clearance. Creatine supplementation resulted in greater cyst growth and worsened renal function in the Han:SPRD-cy rat, evidenced by greater kidney weights (2.87 +/- 0.08 versus 2.61 +/- 0.09 g/100 g of body weight; P: = 0.0365), renal fluid contents (89.22 +/- 0.41 versus 87.38 +/- 0.48 g/100 g of kidney weight; P: = 0.0057), cyst scores (0.49 +/- 0.02 versus 0.40 +/- 0.03; P: = 0.0167) and serum urea concentrations (23.96 +/- 0.92 versus 20.65 +/- 1.06 mmol/L; P: = 0.0230), and lower creatinine clearances (0.125 +/- 0.098 versus 0.162 +/- 0.011 mL/min/100 g of body weight; P: = 0.0159). These results indicate that creatine supplements may exacerbate disease progression in an animal model of cystic renal disease. Although systematic research of the effects of creatine supplementation in humans with compromised renal function is awaited, it follows that creatine should be used with particular caution in individuals with or at risk for renal disease.

Rational design, synthesis, and biological activity of benzoxazinones as novel factor Xa inhibitors.

Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1, 4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC(50) of 27 microM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC(50) of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.

Effect of a clinical pharmacist-managed lipid clinic on achieving National Cholesterol Education Program low-density lipoprotein goals.

Despite national guidelines for treatment of hyperlipidemia, significant numbers of individuals with coronary artery disease are not treated to their National Cholesterol Education Program (NCEP) low-density lipoprotein (LDL) goals. The potential benefits of a clinical pharmacist-managed lipid clinic would be to improve rates of success in achieving these goals, improve drug adherence and compliance with therapy, and reduce cardiovascular events. All patients who had a documented history of coronary artery disease and were under the care of one cardiologist were treated in the pharmacist-managed lipid clinic. A second cardiologist provided usual care to a group of patients with coronary artery disease who served as controls. Patients in each arm were followed for a minimum of 6 months. A protocol for therapy changes in clinic patients was developed by the clinical pharmacist and approved by the cardiologist. At the end of 6 months, 69% of patients in the pharmacist-managed clinic achieved their LDL goal, compared with 50% of controls. Compliance with laboratory tests and drug regimens also improved in clinic patients. Compliance with lipid panels went from 8% 2 months before to 89% 2 months after the start of the study. At the end of 6 months compliance with laboratory work and refills was 80%. Thus the clinical pharmacist-managed clinic was highly successful in achieving NCEP goals for secondary prevention.

High dietary fat intake increases renal cyst disease progression in Han:SPRD-cy rats.

The effect of a high level of dietary fat on renal cyst disease was examined in the Han:SPRD-cy rat model of polycystic kidney disease. Control and diseased rats at 4 wk of age were fed either a low fat or high fat diet (5 or 20 g/100 g diet) for 6 wk. In rats with kidney disease fed the high fat rather than the low fat diet, kidneys were 17% larger, renal fluid content was 19% higher and cyst scores were 30% higher, indicating greater disease progression. In diseased rats fed the high fat diet, serum urea was 25% higher, indicating worsened renal function. Serum creatinine was 49% higher only in males. To examine whether high dietary fat worsened renal cyst disease by altering sex hormone concentrations, serum testosterone and estrogen concentrations were determined. In normal compared with diseased male rats, serum testosterone concentrations were one to three times higher. Serum testosterone concentrations were higher in normal male rats fed the high compared with the low fat diet, but were not affected by diet in diseased rats. Serum estrogen concentrations were unaffected by dietary fat levels or by disease state. Although it remains to be elucidated how dietary fat influences sex hormone concentrations in this disease, the current study demonstrates that a high dietary fat intake increases kidney disease progression in Han:SPRD-cy rats.

Permanent and functional male-to-female sex reversal in d-rR strain medaka (Oryzias latipes) following egg microinjection of o,p'-DDT.

Complete sex reversal of fish is accomplished routinely in aquaculture practices by exposing fish to exogenous sex steroids during gonadal differentiation. A variety of environmental chemicals are also active at sex steroid receptors and theoretically possess the potential to alter normal sexual differentiation in fish. However, in controlled environmental chemical exposures to date, only partial alterations of fish sexual phenotype have been observed. Here we report complete, permanent, and functional male-to-female sex reversal in the Japanese medaka (Oryzias latipes, d-rR strain) after a onetime embryonic exposure to the xenoestrogen o, p'-DDT. d-rR strain medaka are strict gonochorists that possesses both sex-linked pigmentation, which distinguishes genotypic sex, and sexually dimorphic external secondary sexual characteristics, which distinguish phenotypic sex. We directly microinjected the xenoestrogen o, p'-DDT into the egg yolks of medaka at fertilization to parallel the maternal transfer of lipophilic contaminants to the embryo. At 10 weeks of age, microinjected medaka were examined for mortality and sex reversal. A calculated embryonic dose of 511 +/- 22 ng/egg o, p'-DDT (mean +/- standard error) resulted in 50% mortality. An embryonic exposure of 227 +/- 22 ng/egg o, p'-DDT resulted in 86% (6 of 7) sex reversal of genetic males to a female phenotype (XY females). XY females were distinguished by sex-linked male pigmentation accompanying female secondary sexual characteristics. Histologic examination of the gonads confirmed active ovaries in 100% of the XY females. In 10-day breeding trials in which XY females were paired with normal XY males, 50% of the XY females produced fertilized embryos; this represents a comparable breeding success rate to normal XX females. Fertilized eggs produced from XY females hatched to viable larvae. These results clearly indicate that a weakly estrogenic pesticide, o, p'-DDT, when presented during the critical period of gonadal development, can profoundly alter sexual differentiation.