bluuebunny/crossref_metadata_2025 huggingface dataset:
Alteration of mitochondrial efficiency affects oxidative balance, development and growth in frog (Rana temporaria) tadpoles
Authors: Salin Karine , Luquet Emilien , Rey Benjamin , Roussel Damien , Voituron Yann
Published: February 2012

Mitochondria are known to play a central role in life history processes, being the main source of reactive oxygen species (ROS), which promote oxidative constraint. Surprisingly, although the main role of the mitochondria is to produce ATP, the plasticity of mitochondrial ATP generation has received little attention in life history studies. Yet, mitochondrial energy transduction represents the physiological link between environmental resources and energy allocated to animal performance. Studying both facets of mitochondrial functioning (ATP and ROS production) would allow better understanding of the proximate mechanisms underlying life history. We have experimentally modulated the mitochondrial capacity to generate ROS and ATP during larval development of Rana temporaria tadpoles, via chronic exposure (34 days) to a mitochondrial uncoupler (2,4-dinitrophenol, dNP). The aim was to better understand the impact of mitochondrial uncoupling on both responses in terms of oxidative balance, energy input (oxygen and feeding consumption) and energy output (growth and development of the tadpole). Exposure to 2,4-dNP reduced mitochondrial ROS generation, total antioxidant defences and oxidative damage in treated tadpoles compared with controls. Despite the beneficial effect of dNP on oxidative status, development and growth rates of treated tadpoles were lower than those in the control group. Treatment of tadpoles with 2,4-dNP promoted a mild mitochondrial uncoupling and enhanced metabolic rate. These tadpoles did not increase their food consumption, and thus failed to compensate for the energy loss elicited by the decrease in the efficiency of ATP production. These data suggest that the cost of ATP production, rather than the oxidative balance, is the parameter that constrains growth/development of tadpoles, highlighting the central role of energy transduction in larval performance.
Dietary protein quality differentially regulates trypsin enzymes at the secretion and transcription level in Panulirus argus by distinct signaling pathways
Authors: Perera Erick , Rodríguez-Viera Leandro , Rodríguez-Casariego Javier , Fraga Iliana , Carrillo Olimpia , Martínez-Rodríguez Gonzalo , Mancera Juan M.
Published: February 2012

The effects of pelleted diets with different protein composition (fish, squid or soybean meals as main protein sources) on trypsin secretion and expression were studied in the lobster Panulirus argus. Trypsin secretion was shown to be maximal 4 h after ingestion. At this time, fish- and squid-based diets induced trypsin secretion, as well as up-regulation of the major trypsin isoform at the transcription level. While fish- and squid-based diets elicited a prandial response, soybean-based diet failed to stimulate the digestive gland to secrete trypsin into the gastric fluid or induce trypsin expression above the levels observed in fasting lobsters. In vitro assays showed that intact proteins rather than protein hydrolysates stimulate trypsin secretion in the lobster. However, the signal for trypsin transcription appears to be different to that for secretion and is probably mediated by the appearance of free amino acids in the digestive gland, suggesting a stepwise regulation of trypsin enzymes during digestion. We conclude that trypsin enzymes in P. argus are regulated at the transcription and secretion level by the quality of dietary proteins through two distinct signaling pathways. Our results indicate that protein digestion efficiency in spiny lobsters can be improved by selecting appropriated protein sources. However, other factors like the poor solubility of dietary proteins in dry diets could hamper further enhancement of digestion efficiency.
Aging modulates cuticular hydrocarbons and sexual attractiveness inDrosophila melanogaster
Authors: Kuo Tsung-Han , Yew Joanne Y. , Fedina Tatyana Y. , Dreisewerd Klaus , Dierick Herman A. , Pletcher Scott D.
Published: February 2012

Attractiveness is a major component of sexual selection that is dependent on sexual characteristics, such as pheromone production, which often reflect an individual’s fitness and reproductive potential. Aging is a process that results in a steady decline in survival and reproductive output, yet little is known about its effect on specific aspects of attractiveness. In this report we asked how aging impacts pheromone production and sexual attractiveness in Drosophila melanogaster. Evidence suggests that key pheromones in Drosophila are produced as cuticular hydrocarbons (CHC), whose functions in attracting mates and influencing behavior have been widely studied. We employed gas chromatography/mass spectrometry and laser desorption/ionization mass spectrometry to show that the composition of D. melanogaster CHC is significantly affected by aging in both sexes and that these changes are robust to different genetic backgrounds. Aging affected the relative levels of many individual CHC, and it shifted overall hydrocarbon profiles to favor compounds with longer chain lengths. We also show that the observed aging-related changes in CHC profiles are responsible for a significant reduction in sexual attractiveness. These studies illuminate causal links among pheromones, aging and attractiveness and suggest that CHC production may be an honest indicator of animal health and fertility.
The Environment and Directed Technical Change
Authors: Acemoglu Daron , Aghion Philippe , Bursztyn Leonardo , Hemous David
Published: February 2012

This paper introduces endogenous and directed technical change in a growth model with environmental constraints. The final good is produced from “dirty” and “clean” inputs. We show that: (i) when inputs are sufficiently substitutable, sustainable growth can be achieved with temporary taxes/subsidies that redirect innovation toward clean inputs; (ii) optimal policy involves both “carbon taxes” and research subsidies, avoiding excessive use of carbon taxes; (iii) delay in intervention is costly, as it later necessitates a longer transition phase with slow growth; and (iv) use of an exhaustible resource in dirty input production helps the switch to clean innovation under laissez-faire. (JEL O33, O44, Q30, Q54, Q56, Q58)
Americans Do IT Better: US Multinationals and the Productivity Miracle
Authors: Bloom Nicholas , Sadun Raffaella , Reenen John Van
Published: February 2012

US productivity growth accelerated after 1995 (unlike Europe's), particularly in sectors that intensively use information technologies (IT). Using two new micro panel datasets we show that US multinationals operating in Europe also experienced a “productivity miracle.” US multinationals obtained higher productivity from IT than non-US multinationals, particularly in the same sectors responsible for the US productivity acceleration. Furthermore, establishments taken over by US multinationals (but not by non-US multinationals) increased the productivity of their IT. Combining pan-European firm-level IT data with our management practices survey, we find that the US IT related productivity advantage is primarily due to its tougher “people management” practices. (JEL D24, E23, F23, M10, M16, O30)
Macroeconomic Effects of Financial Shocks
Authors: Jermann Urban , Quadrini Vincenzo
Published: February 2012

We document the cyclical properties of US firms' financial flows and show that equity payout is procyclical and debt payout is countercyclical. We then develop a model with debt and equity financing to explore how the dynamics of real and financial variables are affected by “financial shocks.” We find that financial shocks contributed significantly to the observed dynamics of real and financial variables. The recent events in the financial sector show up as a tightening of firms' financing conditions which contributed to the 2008–2009 recession. The downturns in 1990–1991 and 2001 were also influenced by changes in credit conditions. (JEL E23, E32, E44, G01, G32)
A Continuous Dilemma
Authors: Friedman Daniel , Oprea Ryan
Published: February 2012

We study prisoners' dilemmas played in continuous time with flow payoffs accumulated over 60 seconds. In most cases, the median rate of mutual cooperation is about 90 percent. Control sessions with repeated matchings over eight subperiods achieve less than half as much cooperation, and cooperation rates approach zero in one-shot sessions. In follow-up sessions with a variable number of subperiods, cooperation rates increase nearly linearly as the grid size decreases, and, with one-second subperiods, they approach continuous levels. Our data support a strand of theory that explains how capacity to respond rapidly stabilizes cooperation and destabilizes defection in the prisoner's dilemma. (JEL C72, C78, C91)
Why Don't We See Poverty Convergence?
Authors: Ravallion Martin
Published: February 2012

Average living standards are converging among developing countries and faster growing economies see more progress against poverty. Yet we do not find poverty convergence; countries starting with higher poverty rates do not see higher proportionate rates of poverty reduction. The paper tries to explain why. Analysis of a new dataset suggests that, at given mean consumption, high initial poverty has an adverse effect on consumption growth and also makes growth less poverty-reducing. Thus, for many poor countries, the growth advantage of starting out with a low mean is lost due to a high incidence of poverty. JEL: D63, I31, I32, O15
The Internet and Local Wages: A Puzzle
Authors: Forman Chris , Goldfarb Avi , Greenstein Shane
Published: February 2012

How did the diffusion of the internet affect regional wage inequality? We examine the relationship between business investment in advanced internet technology and local variation in US wage growth between 1995 and 2000. We identify a puzzle. The internet is widespread, but the economic payoffs are not. Advanced internet technology is only associated with substantial wage growth in the 6 percent of counties that were already highly wealthy, educated, and populated and had IT-intensive industry. Advanced internet and wage growth appear unrelated elsewhere. Overall, advanced internet explains over half the difference in wage growth between already well-off counties and all others. JEL: J31, L86, O33, R11, R23
The Impact of Shrouded Fees: Evidence from a Natural Experiment in the Indian Mutual Funds Market
Authors: Anagol Santosh , Kim Hugh Hoikwang
Published: February 2012

We study a natural experiment in the Indian mutual funds sector that created a 22-month period in which closed-end funds were allowed to charge an arguably shrouded fee, whereas open-end funds were forced to charge entry loads. Forty-five new closed-end funds were started during this period, collecting $7.6 billion US, whereas only two closed-end funds were started in the 66 months prior to this period, collecting $42 billion US, and no closed-end funds were started in the 20 months after this period. We estimate that investors lost and fund firms gained approximately $350 million US due to this shrouding. JEL: D14, G23, G28, O16
Contracts versus Salaries in Matching
Authors: Echenique Federico
Published: February 2012

Firms and workers may sign complex contracts that govern many aspects of their interactions. I show that when firms regard contracts as substitutes, bargaining over contracts can be understood as bargaining only over wages. Substitutes is the assumption commonly used to guarantee the existence of stable matchings of workers and firms. JEL: C78, D86, J31, J41
Efficient Pollution Regulation: Getting the Prices Right: Reply
Authors: Muller Nicholas Z , Mendelsohn Robert
Published: February 2012

Fraas and Lutter raise two important points in their comment on Muller and Mendelsohn (2009): How to design policies for sources that yield negative marginal damages? How does statistical uncertainty in the marginal damages affect the trading ratios across emitters? We address both issues in this response. JEL: H53, Q53, Q58
Cancelled Surgeries and Payment by Results in the English National Health Service
Authors: McIntosh Bryan , Cookson Graham , Jones Simon
Published: February 2012

Objectives

To model the frequency of ‘last minute’ cancellations of planned elective procedures in the English NHS with respect to the patient and provider factors that led to these cancellations.

Methods

A dataset of 5,288,604 elective patients spell in the English NHS from January 1st, 2007 to December 31st, 2007 was extracted from the Hospital Episode Statistics. A binary dependent variable indicating whether or not a patient had a Health Resource Group coded as S22 - ‘Planned elective procedure not carried out’ - was modeled using a probit regession estimated via maximum likelihood including patient, case and hospital level covariates.

Results

Longer waiting times and being admitted on a Monday were associated with a greater rate of cancelled procedures. Male patients, patients from lower socioeconomic groups and older patients had higher rates of cancelled procedures. There was significant variation in cancellation rates between hospitals; Foundation Trusts and private facilities had the lowest cancellation rates.

Conclusions

Further research is needed on why Foundation Trusts exhibit lower cancellation rates. Hospitals with relatively high cancellation rates should be encouraged to tackle this problem. Further evidence is needed on whether hospitals are more likely to cancel operations where the procedure tariff is lower than the S22 tariff as this creates a perverse incentive to cancel. Understanding the underlying causes of why male, older and patients from lower socioeconomic groups are more likely to have their operations cancelled is important to inform the appropriate policy response. This research suggests that interventions designed to reduce cancellation rates should be targeted to high-cancellation groups.
Philibert Joseph Roux (1780–1854)
Authors: Perdicoyianni-Paléologou Hélène
Published: February 2012

Philibert Joseph Roux (1780–1854), a French surgeon, was a student and friend of Marie Xavier François Bichat, the father of modern pathology and histology. He was assigned as a surgeon to the Hôpital Beaujon (1806), the Hôpital de la Charité (1810) and to Hôtel-Dieu de Paris (1835), where he succeeded to Guillaume Dupuyrten, a French anatomist, as a Chief Surgeon. Roux is best known for having performed the surgical repair of a cleft palate and for having been the first surgeon to stitch a ruptured female perineum. His contribution to surgery has also included the publication of Quarante années de pratique chirurgicale. Roux was awarded the grade of Chevalier of the National Order of the legion of Honor and that of Officer. He also served as a President of the Academy of Sciences. He died of a stroke on 3 March 1854.
The other Dr Hooker: William Dawson Hooker (1816–40)
Authors: Lambert Harold
Published: February 2012

William Hooker and his son Joseph were famous as botanists and as the creators of the Royal Botanic Gardens in Kew. Joseph was famous also as the friend and mentor of Charles Darwin. But there was another brother, a little older than Joseph, also a doctor and naturalist. He went to Jamaica in the interests of his health and soon died there of yellow fever. His life was short and tragic with a medical conundrum at its end but its story also illustrates many of the beliefs and concerns that preoccupied doctors in this early Victorian era. It also illustrates the close relationship between medicine and botany that prevailed then.
Medicine in Dr Samuel Johnson's Dictionary of the English Language
Authors: Sharma Om P
Published: February 2012

When compiling the Dictionary of the English Language, Johnson read and annotated over two hundred thousand passages from innumerable English authors of various disciplines across four centuries. Most of the literary anecdotes came from Shakespeare, Milton, Dryden and Pope. The medical and scientific anecdotes came from 31 scientists, physicians, pharmacologists and surgeons. This reflects Johnson's admiration for science and its benefit to the public. He told Boswell, ‘Why Sir, if you have but one book with you upon a journey let it be a book of science. When you read through a book of entertainment, you know it, and it can do no more for you, but a book of science is inexhaustible’.
Father of the modern hip replacement: Professor Sir John Charnley (1911–82)
Authors: Jackson John
Published: February 2012

Professor Sir John Charnley was a British orthopaedic surgeon, inventor and skilled craftsman. He is best known for his development of the first truly successful operation for total arthroplasty of the hip, the low-friction arthroplasty. As well as publishing significant works on closed fracture management and compression arthrodesis, he can also be accredited with pioneering work in the development of clean-air operating conditions and body-exhaust suits.
Imprudent blow, catastrophic consequence: a case of commotio cordis associated with violence
Authors: Zheng Na , Liang Man , Liu Yan , Ren Liang , Zhu Shao Hua , Liu Liang
Published: February 2012

Commotio cordis is a rare and catastrophic mechano-electric feedback syndrome, and it is especially apt to occur in male children, adolescents and youths during sports activities. The authors present a case of unexpected sudden death due to commotio cordis associated with violence. In a house of detention, a 19-year-old boy was punched and kicked in the face, neck and chest during a fight with another suspect in their ward. Unfortunately, his precordium was the major injured region. The victim turned pale, then lost the ability to resist and lost consciousness immediately. When the emergency medical personnel arrived, the victim was found in a condition of cardiac and respiratory arrest and he was pronounced dead at the scene without cardiopulmonary resuscitation. Both autopsy signs and forensic morphology were in accord with the criteria for commotio cordis diagnosis, showing no cardiac or other organic fatal lesions and no underlying cardiac diseases; moreover, the toxicological screening was negative for alcohol, drug and common toxicants. In the present case, the whole fight was seen by some witnesses in their ward, and it was recorded by the monitoring unit. Based on the statements of the witnesses and the monitoring videotape, combined with the forensic pathological and toxicological examinations, all the testimonies supported the conclusion that the cause of death was commotio cordis.
Application of sonoelastography to regional anaesthesia: a descriptive study with the Thiel embalmed cadaver model
Authors: Munirama S , McLeod G A , Eisma R , Schwab A , Corner G , Soames R , Cochran S
Published: February 2012

Introduction

Ultrasound-guided regional anaesthesia (UGRA) is being used increasingly in patients but varying patient characteristics make it difficult to visualize needles and spread of local anaesthetic fluid.

Methods

To evaluate the use of elastography for UGRA by performing ultrasound-guided nerve blocks in Thiel embalmed cadavers. Both upper limb and lower limb blocks were performed on cadavers with ultrasound guidance. B-mode and elastography images obtained on split screen were analysed.

Results

The B-mode images were superior compared with the ultrasound elastography images with respect to the anatomical details; however, dynamic changes such as fluid spread were visualized better with elastography.

Conclusion

The elastography images also had good dose response to the volume of the injectate implying its usefulness in detecting local anaesthetic spread when low volumes are used as test doses.
Acceleration of tendon–bone healing in anterior cruciate ligament reconstruction using an enamel matrix derivative in a rat model
Authors: Kadonishi Y. , Deie M. , Takata T. , Ochi M.
Published: February 2012

We examined whether enamel matrix derivative (EMD) could improve healing of the tendon–bone interface following reconstruction of the anterior cruciate ligament (ACL) using a hamstring tendon in a rat model. ACL reconstruction was performed in both knees of 30 Sprague-Dawley rats using the flexor digitorum tendon. The effect of commercially available EMD (EMDOGAIN), a preparation of matrix proteins from developing porcine teeth, was evaluated. In the left knee joint the space around the tendon–bone interface was filled with 40 µl of EMD mixed with propylene glycol alginate (PGA). In the right knee joint PGA alone was used. The ligament reconstructions were evaluated histologically and biomechanically at four, eight and 12 weeks (n = 5 at each time point). At eight weeks, EMD had induced a significant increase in collagen fibres connecting to bone at the tendon–bone interface (p = 0.047), whereas the control group had few fibres and the tendon–bone interface was composed of cellular and vascular fibrous tissues. At both eight and 12 weeks, the mean load to failure in the treated specimens was higher than in the controls (p = 0.009). EMD improved histological tendon–bone healing at eight weeks and biomechanical healing at both eight and 12 weeks. EMD might therefore have a human application to enhance tendon–bone repair in ACL reconstruction.
Multiple fractures in the elderly
Authors: Clement N. D. , Aitken S. , Duckworth A. D. , McQueen M. M. , Court-Brown C. M.
Published: February 2012

We present the prevalence of multiple fractures in the elderly in a single catchment population of 780 000 treated over a 12-month period and describe the mechanisms of injury, common patterns of occurrence, management, and the associated mortality rate. A total of 2335 patients, aged ≥ 65 years of age, were prospectively assessed and of these 119 patients (5.1%) presented with multiple fractures. Distal radial (odds ratio (OR) 5.1, p <  0.0001), proximal humeral (OR 2.2, p < 0.0001) and pelvic (OR 4.9, p < 0.0001) fractures were associated with an increased risk of sustaining associated fractures. Only 4.5% of patients sustained multiple fractures after a simple fall, but due to the frequency of falls in the elderly this mechanism resulted in 80.7% of all multiple fractures. Most patients required admission (> 80%), of whom 42% did not need an operation but more than half needed an increased level of care before discharge (54%). The standardised mortality rate at one year was significantly greater after sustaining multiple fractures that included fractures of the pelvis, proximal humerus or proximal femur (p < 0.001). This mortality risk increased further if patients were < 80 years of age, indicating that the existence of multiple fractures after low-energy trauma is a marker of mortality.
Early results of a non-invasive extendible prosthesis for limb-salvage surgery in children with bone tumours
Authors: Hwang N. , Grimer R. J. , Carter S. R. , Tillman R. M. , Abudu A. , Jeys L. M.
Published: February 2012

We reviewed our initial seven-year experience with a non-invasive extendible prosthesis in 34 children with primary bone tumours. The distal femur was replaced in 25 cases, total femur in five, proximal femur in one and proximal tibia in three. The mean follow-up was 44 months (15 to 86) and 27 patients (79%) remain alive. The prostheses were lengthened by an electromagnetic induction mechanism in an outpatient setting and a mean extension of 32 mm (4 to 80) was achieved without anaesthesia. There were lengthening complications in two children: failed lengthening in one and the formation of scar tissue in the other. Deep infection developed in six patients (18%) and local recurrence in three. A total of 11 patients required further surgery to the leg. Amputation was necessary in five patients (20%) and a two-stage revision in another. There were no cases of loosening, but two patients had implant breakage and required revision. The mean Musculoskeletal Tumor Society functional score was 85% (60% to 100%) at last known follow-up. These early results demonstrate that the non-invasive extendible prosthesis allows successful lengthening without surgical intervention, but the high incidence of infection is a cause for concern.
Do forced air patient-warming devices disrupt unidirectional downward airflow?
Authors: Legg A. J. , Cannon T. , Hamer A. J.
Published: February 2012

Patient warming significantly decreases the risk of surgical site infection. Recently there have been concerns that forced air warming may interfere with unidirectional airflow, potentially posing an increased risk of infection. Our null hypothesis was that forced air and radiant warming devices do not increase the temperature and the number of particles over the surgical site when compared with no warming device. A forced air warming device was compared with a radiant warming device and no warming device as a control. The temperature and number of particles were measured over the surgical site. The theatre was prepared as for a routine lower-limb arthroplasty operation, and the same volunteer was used throughout the study.

Forced air warming resulted in a significant mean increase in the temperature (1.1°C vs 0.4°C, p < 0.0001) and number of particles (1038.2 vs 274.8, p = 0.0087) over the surgical site when compared with radiant warming, which raises concern as bacteria are known to require particles for transport.
Responsiveness of the Manchester–Oxford foot questionnaire (MOXFQ) compared with AOFAS, SF-36 and EQ-5D assessments following foot or ankle surgery
Authors: Dawson J. , Boller I. , Doll H. , Lavis G. , Sharp R. , Cooke P. , Jenkinson C.
Published: February 2012

The responsiveness of the Manchester–Oxford Foot Questionnaire (MOXFQ) was compared with foot/ankle-specific and generic outcome measures used to assess all surgery of the foot and ankle. We recruited 671 consecutive adult patients awaiting foot or ankle surgery, of whom 427 (63.6%) were female, with a mean age of 52.8 years (18 to 89). They independently completed the MOXFQ, Short-Form 36 (SF-36) and EuroQol (EQ-5D) questionnaires pre-operatively and at a mean of nine months (3.8 to 14.4) post-operatively. Foot/ankle surgeons assessed American Orthopaedic Foot and Ankle Society (AOFAS) scores corresponding to four foot/ankle regions. A transition item measured perceived changes in foot/ankle problems post-surgery. Of 628 eligible patients proceeding to surgery, 491 (78%) completed questionnaires and 262 (42%) received clinical assessments both pre- and post-operatively. The regions receiving surgery were: multiple/whole foot in eight (1.3%), ankle/hindfoot in 292 (46.5%), mid-foot in 21 (3.3%), hallux in 196 (31.2%), and lesser toes in 111 (17.7%). Foot/ankle-specific MOXFQ, AOFAS and EQ-5D domains produced larger effect sizes (> 0.8) than any SF-36 domains, suggesting superior responsiveness. In analyses that anchored change in scores and effect sizes to patients’ responses to a transition item about their foot/ankle problems, the MOXFQ performed well. The SF-36 and EQ-5D performed poorly. Similar analyses, conducted within foot-region based sub-groups of patients, found that the responsiveness of the MOXFQ was good compared with the AOFAS.

This evidence supports the MOXFQ’s suitability for assessing all foot and ankle surgery.
The effects of an injury to the brain on bone healing and callus formation in young adults with fractures of the femoral shaft
Authors: Yang T-Y. , Wang T-C. , Tsai Y-H. , Huang K-C.
Published: February 2012

In patients with traumatic brain injury and fractures of long bones, it is often clinically observed that the rate of bone healing and extent of callus formation are increased. However, the evidence has been unconvincing and an association between such an injury and enhanced fracture healing remains unclear. We performed a retrospective cohort study of 74 young adult patients with a mean age of 24.2 years (16 to 40) who sustained a femoral shaft fracture (AO/OTA type 32A or 32B) with or without a brain injury. All the fractures were treated with closed intramedullary nailing. The main outcome measures included the time required for bridging callus formation (BCF) and the mean callus thickness (MCT) at the final follow-up. Comparative analyses were made between the 20 patients with a brain injury and the 54 without brain injury. Subgroup comparisons were performed among the patients with a brain injury in terms of the severity of head injury, the types of intracranial haemorrhage and gender. Patients with a brain injury had an earlier appearance of BCF (p < 0.001) and a greater final MCT value (p < 0.001) than those without. There were no significant differences with respect to the time required for BCF and final MCT values in terms of the severity of head injury (p = 0.521 and p = 0.153, respectively), the types of intracranial haemorrhage (p = 0.308 and p = 0.189, respectively) and gender (p = 0.383 and p = 0.662, respectively).

These results confirm that an injury to the brain may be associated with accelerated fracture healing and enhanced callus formation. However, the severity of the injury to the brain, the type of intracranial haemorrhage and gender were not statistically significant factors in predicting the rate of bone healing and extent of final callus formation.
Exam Corner – February 2012
Authors: Khanduja V.
Published: February 2012

The FRCS (Tr & Orth) examination has three components: MCQs, Vivas and Clinical Examination. The Vivas are further divided into four sections comprising Basic Science, Adult Pathology, Hands and Children’s Orthopaedics and Trauma. The Clinical Examination section is divided into Upper and Lower limb cases. The aim of this section in the Journal is to focus specifically on the trainees preparing for the exam and to cater to all the sections of the exam. The vision is to complete the cycle of all relevant exam topics (as per the syllabus) in four years.
Pharmacology, Efficacy, and Safety of Linagliptin for the Treatment of Type 2 Diabetes Mellitus
Authors: Neumiller Joshua J
Published: February 2012

Objective:

To review the pharmacology, pharmacokinetics, and clinical efficacy and safety of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor recently approved in the US for use as a treatment for type 2 diabetes mellitus.

Data Sources:

English-language articles in the PubMed database to October 2011 (selected using the search terms linagliptin, alogliptin, sitagliptin, saxagliptin, vildagliptin, and pharmacokinetics, pharmacodynamics, or diabetes) were identified for review. Reference lists from identified articles were reviewed for additional references of interest. Abstracts published at relevant meetings were also evaluated, and information was obtained from the manufacturer.

Study Selection and Data Extraction:

Publications reporting the pharmacology, pharmacokinetics, and clinical efficacy and safety of linagliptin were reviewed.

Data Synthesis:

Linagliptin therapy results in clinically meaningful reductions in hemoglobin A1c, as well as fasting and postprandial plasma glucose levels in patients with type 2 diabetes mellitus. It contrasts with other agents in its class by not requiring dosage adjustment in patients with renal or hepatic impairment. Oral doses of linagliptin 5 mg once daily have been shown to be clinically effective, well tolerated, and weight-neutral. An increased rate of hypoglycemia when linagliptin was used in combination with an insulin secretagogue compared to placebo was noted in clinical trials.

Conclusions:

Linagliptin provides an additional therapeutic option for type 2 diabetes mellitus and, in contrast to other agents in the DPP-4 class, can be used without dose adjustment in patients with any degree of declining renal function.
Warfarin Genotyping in a Single PCR Reaction for Microchip Electrophoresis
Authors: Poe Brian L , Haverstick Doris M , Landers James P
Published: February 2012

BACKGROUND

Warfarin is the most commonly prescribed oral anticoagulant medication but also is the second leading cause of emergency room visits for adverse drug reactions. Genetic testing for warfarin sensitivity may reduce hospitalization rates, but prospective genotyping is impeded in part by the turnaround time and costs of genotyping. Microfluidics-based assays can reduce reagent consumption and analysis time; however, no current assay has integrated multiplexed allele-specific PCR for warfarin genotyping with electrophoretic microfluidics hardware. Ideally, such an assay would use a single PCR reaction and, without further processing, a single microchip electrophoresis (ME) run to determine the 3 single-nucleotide polymorphisms (SNPs) affecting warfarin sensitivity [i.e., CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) *2, CYP2C9 *3, and the VKORC1 (vitamin K epoxide reductase complex 1) A/B haplotype].

METHODS

We designed and optimized primers for a fully multiplexed assay to examine 3 biallelic SNPs with the tetraprimer amplification refractory mutation system (T-ARMS). The assay was developed with conventional PCR equipment and demonstrated for microfluidic infrared-mediated PCR. Genotypes were determined by ME on the basis of the pattern of PCR products.

RESULTS

Thirty-five samples of human genomic DNA were analyzed with this multiplex T-ARMS assay, and 100% of the genotype determinations agreed with the results obtained by other validated methods. The sample population included several genotypes conferring warfarin sensitivity, with both homozygous and heterozygous genotypes for each SNP. Total analysis times for the PCR and ME were approximately 75 min (1-sample run) and 90 min (12-sample run).

CONCLUSIONS

This multiplexed T-ARMS assay coupled with microfluidics hardware constitutes a promising avenue for an inexpensive and rapid platform for warfarin genotyping.
Dealing with Institutional Distances in International Marketing Channels: Governance Strategies that Engender Legitimacy and Efficiency
Authors: Yang Zhilin , Su Chenting , Fam Kim-Shyan
Published: February 2012

Firms doing business in foreign institutional environments face pressures to gain social acceptance (commonly referred to as legitimacy) and difficulty in evaluating market information, both of which undercut firm performance. In this article, the authors argue that firms can design governance strategies to deal with foreign institutions to secure both social acceptance and firm performance. Using a Chinese sample of manufacturers that export products to various foreign markets through local distributors, the authors develop and test a model that bridges the effects of institutional environments and governance strategy on channel performance. Specifically, they find that firms can use two governance strategies, contract customization and relational governance, to deal with both legitimacy and efficiency issues and to safeguard channel performance. Thus, international channel managers are advised to maintain an integrated management of legitimacy and efficiency in foreign marketing channels.
Impact of the NGF Maturation and Degradation Pathway on the Cortical Cholinergic System Phenotype
Authors: Allard Simon , Leon Wanda C. , Pakavathkumar Prateep , Bruno Martin A. , Ribeiro-da-Silva Alfredo , Cuello A. Claudio
Published: February 2012

Cortical cholinergic atrophy plays a significant role in the cognitive loss seen with aging and in Alzheimer's disease (AD), but the mechanisms leading to it remain unresolved. Nerve growth factor (NGF) is the neurotrophin responsible for the phenotypic maintenance of basal forebrain cholinergic neurons in the mature and fully differentiated CNS. In consequence, its implication in cholinergic atrophy has been suspected; however, no mechanistic explanation has been provided. We have previously shown that the precursor of NGF (proNGF) is cleaved extracellularly by plasmin to form mature NGF (mNGF) and that mNGF is degraded by matrix metalloproteinase 9. Using cognitive-behavioral tests, Western blotting, and confocal and electron microscopy, this study demonstrates that a pharmacologically induced chronic failure in extracellular NGF maturation leads to a reduction in mNGF levels, proNGF accumulation, cholinergic degeneration, and cognitive impairment in rats. It also shows that inhibiting NGF degradation increases endogenous levels of the mature neurotrophin and increases the density of cortical cholinergic boutons. Together, the data point to a mechanism explaining cholinergic loss in neurodegenerative conditions such as AD and provide a potential therapeutic target for the protection or restoration of this CNS transmitter system in aging and AD.
Cracking Down on Inhibition: Selective Removal of GABAergic Interneurons from Hippocampal Networks
Authors: Antonucci Flavia , Alpár Alán , Kacza Johannes , Caleo Matteo , Verderio Claudia , Giani Alice , Martens Henrik , Chaudhry Farrukh A. , Allegra Manuela , Grosche Jens , Michalski Dominik , Erck Christian , Hoffmann Anke , Harkany Tibor , Matteoli Michela , Härtig Wolfgang
Published: February 2012

Inhibitory (GABAergic) interneurons entrain assemblies of excitatory principal neurons to orchestrate information processing in the hippocampus. Disrupting the dynamic recruitment as well as the temporally precise activity of interneurons in hippocampal circuitries can manifest in epileptiform seizures, and impact specific behavioral traits. Despite the importance of GABAergic interneurons during information encoding in the brain, experimental tools to selectively manipulate GABAergic neurotransmission are limited. Here, we report the selective elimination of GABAergic interneurons by a ribosome inactivation approach through delivery of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs)in vitroas well as in the mouse and rat hippocampusin vivo. We demonstrate the selective loss of GABAergic—but not glutamatergic—synapses, reduced GABA release, and a shift in excitation/inhibition balance in mixed cultures of hippocampal neurons exposed to SAVAs. We also show the focal and indiscriminate loss of calbindin+, calretinin+, parvalbumin/system A transporter 1+, somatostatin+, vesicular glutamate transporter 3 (VGLUT3)/cholecystokinin/CB1cannabinoid receptor+and neuropeptide Y+local-circuit interneurons upon SAVA microlesions to the CA1 subfield of the rodent hippocampus, with interneuron debris phagocytosed by infiltrating microglia. SAVA microlesions did not affect VGLUT1+excitatory afferents. Yet SAVA-induced rearrangement of the hippocampal circuitry triggered network hyperexcitability associated with the progressive loss of CA1 pyramidal cells and the dispersion of dentate granule cells. Overall, our data identify SAVAs as an effective tool to eliminate GABAergic neurons from neuronal circuits underpinning high-order behaviors and cognition, and whose manipulation can recapitulate pathogenic cascades of epilepsy and other neuropsychiatric illnesses.
No Dissociation between Perception and Action in Patient DF When Haptic Feedback is Withdrawn
Authors: Schenk Thomas
Published: February 2012

Goodale et al. (1991) reported a striking dissociation between vision for perception and action. They examined DF, a human patient who had damage to her ventral visual stream and suffered from visual form agnosia. She was unable to perceive an object's size but could match the opening of her hand to the object's size during grasping. It was concluded that grasping relied on a separate representation of visual size in the dorsal stream and required no visual input from the ventral stream. This observation inspired the influential perception–action model, which claimed separate visual streams for perception and action. However, in grasping (but not in corresponding perceptual tasks), participants receive haptic feedback after each trial. Using this feedback, DF might compensate for her impaired size-vision. I reexamined DF's grasping behavior using a mirror apparatus to dissociate the image of an object from its physical presence. DF's grasping was only normal when she received haptic feedback. Thus, in grasping, DF can rely on haptic feedback to compensate for her deficit in size-perception. This can explain why her grasping is significantly better than her perceptual performance. The findings emphasize the extent of early interstream interactions and highlight the multimodal nature of sensory processing in the dorsal stream.
Posttraining Transcranial Magnetic Stimulation of Striate Cortex Disrupts Consolidation Early in Visual Skill Learning
Authors: De Weerd Peter , Reithler Joel , van de Ven Vincent , Been Marin , Jacobs Christianne , Sack Alexander T.
Published: February 2012

Practice-induced improvements in skilled performance reflect “offline ” consolidation processes extending beyond daily training sessions. According to visual learning theories, an early, fast learning phase driven by high-level areas is followed by a late, asymptotic learning phase driven by low-level, retinotopic areas when higher resolution is required. Thus, low-level areas would not contribute to learning and offline consolidation until late learning. Recent studies have challenged this notion, demonstrating modified responses to trained stimuli in primary visual cortex (V1) and offline activity after very limited training. However, the behavioral relevance of modified V1 activity for offline consolidation of visual skill memory in V1 after early training sessions remains unclear. Here, we used neuronavigated transcranial magnetic stimulation (TMS) directed to a trained retinotopic V1 location to test for behaviorally relevant consolidation in human low-level visual cortex. Applying TMS to the trained V1 location within 45 min of the first or second training session strongly interfered with learning, as measured by impaired performance the next day. The interference was conditional on task context and occurred only when training in the location targeted by TMS was followed by training in a second location before TMS. In this condition, high-level areas may become coupled to the second location and uncoupled from the previously trained low-level representation, thereby rendering consolidation vulnerable to interference. Our data show that, during the earliest phases of skill learning in the lowest-level visual areas, a behaviorally relevant form of consolidation exists of which the robustness is controlled by high-level, contextual factors.
Weak and Nondiscriminative Responses to Conspecifics in the Rat Hippocampus
Authors: von Heimendahl Moritz , Rao Rajnish P. , Brecht Michael
Published: February 2012

Little is known about how hippocampal neurons in rodents respond to and represent conspecifics. To address this question, we let rats interact while quantifying hippocampal neuronal activation patterns with extracellular recordings and immediate-early gene (c-Fos) expression. A total of 319 single putative pyramidal neurons was recorded in dorsal hippocampus. In sessions with multiple stimulus rats, no cell responded differentially to individual rats (N= 267 cells). We did find, however, that the presence of other rats induced a significant enhancement or suppression of firing in a fraction of neurons (n= 22 of 319; 7%). As expected, a large fraction of neurons (n= 170; 53%) had place fields. There was no evidence for place-independent responses to rats. Rather, the modulations were linked to the spatial responses. While neurons did not discriminate between individual rats, they did discriminate between rats and inanimate objects. Surprisingly, neuronal responses were more strongly modulated by objects than by rats, even though subjects spent more time near their conspecifics. Consistent with the low fraction of rat-modulated cells, social encounters did not induce c-Fos expression in the hippocampus, while there was a social interaction-specific expression in the basolateral amygdala. In both interacting and non-interacting rats, the fraction of c-Fos-expressing cells in the hippocampus was very low. Our investigation of social coding in the rat hippocampus, along with other recent work, showed that social responses were rare and lacked individual specificity, altogether speaking against a role of rodent dorsal hippocampus in social memory.
Remembering to Learn: Independent Place and Journey Coding Mechanisms Contribute to Memory Transfer
Authors: Bahar Amir S. , Shapiro Matthew L.
Published: February 2012

The neural mechanisms that integrate new episodes with established memories are unknown. When rats explore an environment, CA1 cells fire in place fields that indicate locations. In goal-directed spatial memory tasks, some place fields differentiate behavioral histories (“journey-dependent” place fields) while others do not (“journey-independent” place fields). To investigate how these signals inform learning and memory for new and familiar episodes, we recorded CA1 and CA3 activity in rats trained to perform a “standard” spatial memory task in a plus maze and in two new task variants. A “switch” task exchanged the start and goal locations in the same environment; an “altered environment” task contained unfamiliar local and distal cues. In the switch task, performance was mildly impaired, new firing maps were stable, but the proportion and stability of journey-dependent place fields declined. In the altered environment, overall performance was strongly impaired, new firing maps were unstable, and stable proportions of journey-dependent place fields were maintained. In both tasks, memory errors were accompanied by a decline in journey codes. The different dynamics of place and journey coding suggest that they reflect separate mechanisms and contribute to distinct memory computations. Stable place fields may represent familiar relationships among environmental features that are required for consistent memory performance. Journey-dependent activity may correspond with goal-directed behavioral sequences that reflect expectancies that generalize across environments. The complementary signals could help link current events with established memories, so that familiarity with either a behavioral strategy or an environment can inform goal-directed learning.
Neural Broadening or Neural Attenuation? Investigating Age-Related Dedifferentiation in the Face Network in a Large Lifespan Sample
Authors: Park Joonkoo , Carp Joshua , Kennedy Kristen M. , Rodrigue Karen M. , Bischof Gerard N. , Huang Chih-Mao , Rieck Jennifer R. , Polk Thad A. , Park Denise C.
Published: February 2012

Previous studies have found that cortical responses to different stimuli become less distinctive as people get older. This age-related dedifferentiation may reflect the broadening of the tuning curves of category-selective neurons (broadening hypothesis) or it may be due to decreased activation of category-selective neurons (attenuation hypothesis). In this study, we evaluated these hypotheses in the context of the face-selective neural network. Over 300 participants, ranging in age from 20 to 89 years, viewed images of faces, houses, and control stimuli in a functional magnetic resonance imaging session. Regions within the core face network and extended face network were identified in individual subjects. Activation in many of these regions became significantly less face-selective with age, confirming previous reports of age-related dedifferentiation. Consistent with the broadening hypothesis, this dedifferentiation in the fusiform face area (FFA) was driven by increased activation to houses. In contrast, dedifferentiation in the extended face network was driven by decreased activation to faces, consistent with the attenuation hypothesis. These results suggest that age-related dedifferentiation reflects distinct processes in different brain areas. More specifically, dedifferentiation in FFA activity may be due to broadening of the tuning curves for face-selective neurons, while dedifferentiation in the extended face network reflects reduced face- or emotion-selective activity.