Contribution of Noncanonical Antigens to Virulence and Adaptive Immunity in Human Infection with Enterotoxigenic E. coli.

Enterotoxigenic Escherichia coli (ETEC) contributes significantly to the substantial burden of infectious diarrhea among children living in low- and middle-income countries. In the absence of a vaccine for ETEC, children succumb to acute dehydration as well as nondiarrheal sequelae related to these infections, including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches defined by a subset of ETEC pathovar-specific antigens known as colonization factors (CFs). To identify additional conserved immunogens unique to this pathovar, we employed an "open-aperture" approach to capture all potential conserved ETEC surface antigens, in which we mined the genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (n = 118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (n = 52) and toxin subunits. These arrays were then used to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this approach, we found that immune responses were largely constrained to a small number of antigens, including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children <2 years of age, both EtpA and a second antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing either etpA or eatA genes were significantly more likely to develop symptomatic disease. These studies support a role for antigens not presently targeted by vaccines (noncanonical) in virulence and the development of adaptive immune responses during ETEC infections. These findings may inform vaccine design efforts to complement existing approaches.

Strong hydroclimatic controls on vulnerability to subsurface nitrate contamination across Europe.

Subsurface contamination due to excessive nutrient surpluses is a persistent and widespread problem in agricultural areas across Europe. The vulnerability of a particular location to pollution from reactive solutes, such as nitrate, is determined by the interplay between hydrologic transport and biogeochemical transformations. Current studies on the controls of subsurface vulnerability do not consider the transient behaviour of transport dynamics in the root zone. Here, using state-of-the-art hydrologic simulations driven by observed hydroclimatic forcing, we demonstrate the strong spatiotemporal heterogeneity of hydrologic transport dynamics and reveal that these dynamics are primarily controlled by the hydroclimatic gradient of the aridity index across Europe. Contrasting the space-time dynamics of transport times with reactive timescales of denitrification in soil indicate that ~75% of the cultivated areas across Europe are potentially vulnerable to nitrate leaching for at least one-third of the year. We find that neglecting the transient nature of transport and reaction timescale results in a great underestimation of the extent of vulnerable regions by almost 50%. Therefore, future vulnerability and risk assessment studies must account for the transient behaviour of transport and biogeochemical transformation processes.

Field Diagnostics and Seasonality of Ophidiomyces ophiodiicola in Wild Snake Populations.

Snake fungal disease (SFD) is an emerging disease caused by the fungal pathogen, Ophidiomyces ophiodiicola. Clinical signs of SFD include dermal lesions, including regional and local edema, crusts, and ulcers. Snake fungal disease is widespread in the Eastern United States, yet there are limited data on how clinical signs of SFD compare with laboratory diagnostics. We compared two sampling methods for O. ophiodiicola, scale clip collection and swabbing, to evaluate whether collection method impacted the results of polymerase chain reaction (PCR). In addition, we evaluated the use of clinical signs to predict the presence of O. ophiodiicola across seasons, snake habitat affiliation (aquatic or terrestrial) and study sites. We found no significant difference in PCR results between sampling methods. Clinical signs were a strong predictor of O. ophiodiicola presence in spring and summer seasons. Snakes occupying terrestrial environments had a lower overall probability of testing positive for O. ophiodiicola compared to snakes occupying aquatic environments. Although our study indicates that both clinical signs of SFD and prevalence of O. ophiodiicola vary seasonally and based on habitat preferences of the host, our analysis suggests that clinical signs can serve as a reliable indicator of O. ophiodiicola presence, especially during spring and summer.

Acupuncture reduces the time from extubation to 'ready for discharge' from the post anaesthesia care unit: results from the randomised controlled AcuARP trial.

Acupuncture may improve peri-operative care as it reduces post-operative symptoms, such as pain, nausea and vomiting, or sedation. This patient-assessor blinded, randomised trial in 75 women undergoing gynaecologic laparoscopy evaluated the effects of acupuncture combined with a standardised anaesthetic regimen (ACU) on post-anaesthetic recovery, when compared to acupressure (APU) or standard anaesthesia alone (CON). Main outcome measure was the time from extubation to 'ready for discharge' from recovery as assessed by validated questionnaires. The main outcome differed significantly between groups (p = 0.013). Median time to ready for discharge in the ACU group (30 (IQR: 24-41) min) was 16 minutes (35%) shorter than in the CON group (46 (36-64) min; p = 0.015) and tended to be shorter than in the APU group (43 (31-58) min; p = 0.08). Compared to CON (p = 0.029), median time to extubation was approximately 7 minutes shorter in both, the ACU and the APU group. No acupuncture or acupressure-related side-effects could be observed. A difference in time to recovery of 16 minutes compared to standard alone can be considered clinically relevant. Thus, results of this study encourage the application of acupuncture in gynaecological laparoscopy as it improves post-anaesthetic recovery.

Correction to: Neural therapy of an athlete's chronic plantar fasciitis: a case report and review of the literature.

In the publication of this article [1], there are reference errors in four positions the respective references are missing since reference Fischer [26] was omitted.

Neural therapy of an athlete's chronic plantar fasciitis: a case report and review of the literature.

BACKGROUND: The focus of this case report is on the role of inflammation as a contributor to pain in plantar fasciitis and its cure by the injection of local anesthetics. CASE PRESENTATION: This is a case report on a 24-year-old white man, a middle-distance runner, with chronic unilateral plantar fasciitis and perceived heel pain for almost 1.5 years. He was treated with neural therapy (that is, injection of < 1 ml procaine 1% which is a local anesthetic with strong anti-inflammatory properties) of the surgical scar and along the surgical puncture channel. The follow-up period from the time of first presentation until publication was 2.5 years. At admission, pain intensity (visual analog scale) in the affected leg was severe (10 cm, visual analog scale; range 0-10 cm) when walking and moderate (5 cm, visual analog scale) when standing. After the first session of injections he could stand pain-free and pain when walking was markedly reduced (- 90%). After the third session, he reported no pain in the affected leg and could return to sports at his former level (no difference in training load compared to non-injured state). There was no recurrence of inflammatory signs or heel pain despite intense athletics training up to the date of publication. CONCLUSIONS: In prolonged cases of plantar fasciitis, inflammation is an important component in the development of persistent pain. The results of our case describe the effects of three neural therapy sessions that abolished inflammation and associated heel pain. Neural therapy might be an effective and time-efficient approach in the treatment of plantar fasciitis, enabling an early return to sports.

Effects of aerobic exercise on brain metabolism and grey matter volume in older adults: results of the randomised controlled SMART trial.

There is mounting evidence that aerobic exercise has a positive effect on cognitive functions in older adults. To date, little is known about the neurometabolic and molecular mechanisms underlying this positive effect. The present study used magnetic resonance spectroscopy and quantitative MRI to systematically explore the effects of physical activity on human brain metabolism and grey matter (GM) volume in healthy aging. This is a randomised controlled assessor-blinded two-armed trial (n=53) to explore exercise-induced neuroprotective and metabolic effects on the brain in cognitively healthy older adults. Participants (age >65) were allocated to a 12-week individualised aerobic exercise programme intervention (n=29) or a 12-week waiting control group (n=24). The main outcomes were the change in cerebral metabolism and its association to brain-derived neurotrophic factor (BDNF) levels as well as changes in GM volume. We found that cerebral choline concentrations remained stable after 12 weeks of aerobic exercise in the intervention group, whereas they increased in the waiting control group. No effect of training was seen on cerebral N-acetyl-aspartate concentrations, nor on markers of neuronal energy reserve or BDNF levels. Further, we observed no change in cortical GM volume in response to aerobic exercise. The finding of stable choline concentrations in the intervention group over the 3 month period might indicate a neuroprotective effect of aerobic exercise. Choline might constitute a valid marker for an effect of aerobic exercise on cerebral metabolism in healthy aging.

Range of motion and cervical myofascial pain.

Several studies investigating myofascial pain syndrome include assessments of range of motion (ROM) as a diagnostic criterion. However, the value of ROM in this context has not yet been evaluated in controlled clinical studies. We aimed to examine whether patients with myofascial pain syndrome display alterations of ROM when compared to healthy subjects. Twenty-two individuals (13 females, 9 males; aged 33.4 ± 13.9 yrs) afflicted with active myofascial trigger points in the upper trapezius muscle as well as 22 age and sex matched healthy controls were included. All subjects underwent an examination of maximal active cervical ROM in flexion/extension assessed by means of a 3D ultrasonic movement analysis system (30 Hz; Zebris CMS 70). In the patients group, pressure pain threshold (PPT) of the trigger points was determined using a pressure algometer. Maximum range of motion in the sagittal plane did not differ between individuals with MTrP (125.9 ± 23.2°, 95% CI: 116.2-135.6°) and asymptomatic subjects (128.2 ± 20.4°, 95% CI: 119.7-136.7°; p > .05). In patients, PPT (1.7 ± .6, 95% CI: 1.5-1.9) was not correlated with cervical mobility (r = -.13; p > .05). Based on these pilot data, range of motion in flexion/extension is not a valid criterion for the detection of myofascial trigger points. Additional research incorporating movement amplitudes in other anatomical planes and additional afflicted muscles should be conducted in order to further delineate the relative impact of MTrP on range of motion.

No effect of the cyclooxygenase-2 inhibitor etoricoxib on pre-emptive and post-operative analgesia in visceral surgery: results of a randomized controlled trial.

BACKGROUND: Pre-emptive analgesia in perioperative care has potential benefits for patients. The pre-emptive and postoperative analgesic effects of the cyclooxygenase-2 inhibitor etoricoxib have been investigated using a 2 × 2 factorial trial design. METHODS: According to the 2 × 2 factorial study design, 103 patients scheduled for visceral surgery, were randomly allocated to two groups prior to surgery. Patients could receive either etoricoxib or placebo (to investigate pre-emptive analgesia). Subsequent to surgery, patients randomly received either etoricoxib or placebo, again. It follows, that four treatment modalities (continuous or replaced intervention) result, to investigate postoperative analgesia. Main Outcome Measure was the cumulative morphine use 48 h post-surgery. Other outcomes included pain intensities, pain thresholds and sensory detection. RESULTS: Eighty-six patients (female n = 42; mean age 53.82 ± 13.61 years) were evaluated on the basis of an intention to treat analysis. Pre-emptive administration of 120 mg etoricoxib did not significantly reduce the cumulative morphine dose within the first 48 h after surgery, when compared to the administration of placebo. The analysis of the post-operative treatment groups showed a non-significant 8% reduction in morphine dose during the continuous administration of etoricoxib. There were no changes in sensory perception as detected with QST before and after surgery or between groups. CONCLUSIONS: The effect of administering etoricoxib was not superior to placebo in reducing the morphine dose required for postoperative analgesia. The lack of changes in peripheral nociception suggests that central algetic mechanisms are of higher impact in the development of postoperative pain following abdominal or thoracic surgery.

[Gender differences in acute and chronic pain conditions. Implications for diagnosis and therapy]. / Geschlechtsspezifische Aspekte bei akuten und chronischen Schmerzen. Implikationen für Diagnose und Therapie.

Gender differences can influence incidence and outcome of acute and chronic pain conditions. The reasons are to be found in genetic factors, hormonal effects and differences in anatomy and physiology. Furthermore differences relating to psychiatric comorbidities (i.e. depression) and psychosocial factors (roles, coping strategies) have been demonstrated. Men and women differ in the response to drugs and other treatments. They are differently affected by side effects of drugs. There is a gender bias in diagnosis and therapy. There is a need to study the influence of gender, age and race in order to optimize treatment towards a more individualized therapy. This article highlights already identified differences.

Clinical relevance of different dose calculation strategies for mediastinal IMRT in Hodgkin's disease.

BACKGROUND AND PURPOSE: Conventional algorithms show uncertainties in dose calculation already for three-dimensional conformal radiotherapy (3D-CRT). Intensity-modulated radiotherapy (IMRT) might even increase these. We wanted to assess differences in dose distribution for pencil beam (PB), collapsed cone (CC), and Monte Carlo (MC) algorithm for both 3D-CRT and IMRT in patients with mediastinal Hodgkin lymphoma. PATIENTS AND METHODS: Based on 20 computed tomograph (CT) datasets of patients with mediastinal Hodgkin lymphoma, we created treatment plans according to the guidelines of the German Hodgkin Study Group (GHSG) with PB and CC algorithm for 3D-CRT and with PB and MC algorithm for IMRT. Doses were compared for planning target volume (PTV) and organs at risk. RESULTS: For 3D-CRT, PB overestimated PTV(95) and V(20) of the lung by 6.9% and 3.3% and underestimated V(10) of the lung by 5.8%, compared to the CC algorithm. For IMRT, PB overestimated PTV(95), V(20) of the lung, V(25) of the heart and V(10) of the female left/right breast by 8.1%, 25.8%, 14.0% and 43.6%/189.1%, and underestimated V(10) of the lung, V(4) of the heart and V(4) of the female left/right breast by 6.3%, 6.8% and 23.2%/15.6%, compared to MC. CONCLUSION: The PB algorithm underestimates low doses to the organs at risk and overestimates dose to PTV and high doses to the organs at risk. For 3D-CRT, a well-modeled PB algorithm is clinically acceptable; for IMRT planning, however, an advanced algorithm such as CC or MC should be used at least for part of the plan optimization.

[Gender aspects in anesthesia : modified approach in research and treatment?]. / Gender-Aspekte in der Anästhesie : Modifiziertes Vorgehen in Forschung und Versorgung?

Gender differences can have a relevant influence on the perioperative outcome as male and female patients are affected differently by adverse events, e.g. side effects of drugs. Furthermore, differences relating to specific drug effects, comorbidities and outcome after anesthesia or intensive care have been demonstrated. There seems to be a gender bias in diagnosis and therapy. While the knowledge regarding this field is still growing certain aspects have already been integrated into clinical practice: prevention of postoperative nausea and vomiting (PONV), target controlled infusion (TCI) model and male only policy with production of blood products. There is a need to study the influence of gender, age and race in order to optimize treatment towards a more individualized therapy. This article highlights already identified differences and discusses potential underlying mechanisms.

[Acupuncture in emergency medicine : results of a case series]. / Akupunktur in der Notfallmedizin : Ergebnisse einer Fallserie.

BACKGROUND: Acupuncture (AP) might be indicated in emergency medicine. This case series was performed to demonstrate the practicability and possible effects of AP in emergency medical services (EMS) as a basis for randomized controlled trials (RCT). SUBJECTS AND METHODS: A total of 60 patients (average age 55.4±23.0 years, 57% female) treated by the EMS received AP if applicable. Main outcome parameter was to rate the symptom alleviating effect of acupuncture treatment on a 4-point scale or by VAS. RESULTS: Of the 60 patients 35 (58%) reported considerable improvement, 15 patients (25%) reported complete relief and 10 patients (17%) reported no changes in the cardinal symptom. The predominant symptoms alleviated by AP were nausea (n=31) and vomiting (n=21). Pericardium 3 and 6 (27%) and Spleen 6 and 9 were the most commonly used AP points. CONCLUSION: This case series demonstrates that AP can alleviate certain symptoms in emergency patients. The results of the study provide data as a basis to perform clinical controlled trials on the effectiveness of AP in emergency medicine.

Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve.

BACKGROUND AND PURPOSE: Amitriptyline is often prescribed as a first-line treatment for neuropathic pain but its precise mode of analgesic action remains uncertain. Amitriptyline is known to inhibit voltage-dependent ion channels and also to act as an antagonist at ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). In the present study, we tested the effect of amitriptyline on nicotinic responses of unmyelinated axons in isolated segments of human peripheral nerve. In particular, a comparison was made between the concentrations of amitriptyline necessary for inhibition of nAChRs and those required for inhibition of the compound C-fibre action potential. EXPERIMENTAL APPROACH: Isolated axon fascicles were prepared from short segments of human sural nerve, and multiple measures of axonal excitability were recorded using computer-controlled threshold tracking software. KEY RESULTS: Amitriptyline (EC(50) 2.6 microM) reduced the nicotine-induced increase in C-fibre excitability but only slightly altered the amplitude and latency to onset of the compound action potential. In contrast, tetrodotoxin produced a clear reduction in the amplitude and a prolongation of action potential onset latency but was without effect on the nicotine-induced increase in axonal excitability. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that low concentrations of amitriptyline suppress the response of human peripheral C-type axons to nicotine by directly inhibiting nAChRs. Blockade of tetrodotoxin-sensitive, voltage-dependent sodium channels does not contribute to this effect. An inhibitory action of amitriptyline on nAChRs in unmyelinated nociceptive axons may be an important component of amitriptyline's therapeutic effect in the treatment of neuropathic pain.

Retigabine reduces the excitability of unmyelinated peripheral human axons.

Enhancement of membrane K(+) conductance may reduce the abnormal excitability of primary afferent nociceptive neurons in neuropathic pain. It has been shown that retigabine, a novel anticonvulsant, activates Kv7 (KCNQ/M) channels in the axonal/nodal membrane of peripheral myelinated axons. In this study, we have tested the effects of retigabine on excitability parameters of C-type nerve fibers in isolated fascicles of human sural nerve. Application of retigabine (3-10 microM) produced an increase in membrane threshold. This effect was pronounced in depolarized axons and small in hyperpolarized axons. This finding indicates that retigabine produces a membrane hyperpolarization which is limited by the K(+) equilibrium potential. The retigabine-induced reduction in excitability was accompanied by modifications of the post-spike recovery cycle. Most notable is the development of a late subexcitability at 250-400 ms following a short burst of action potentials. All effects of retigabine were blocked in the presence of XE991 (10 microM). The data show that Kv7 channels are present on axons of unmyelinated, including nociceptive, peripheral human nerve fibers. It is likely that activation of these channels by retigabine may reduce the ectopic generation of action potentials in neuropathic pain.

Evaluation of impedance spectroscopy for the characterization of small biological samples in tissue-based test systems.

Marker free techniques are needed for the construction of efficient tissue-based test and sensor systems. In principle biological tissue can be characterized by impedance spectroscopy. In this paper we investigate by simulation how sensitive parameters of small biological tissue samples can be determined by impedance spectroscopy under optimal measurement conditions. Further, we experimentally evaluate whether the effects of different clinical relevant radio therapy variants on 3D in vitro tumor models are determinable and distinguishable by impedance spectroscopy using a tissue-based test system. The simulations demonstrate that changes in tissue parameters related to the extracellular space are determinable with a high sensitivity. The experiments show that the effect of different radiation dose levels on 3D in vitro tumor models can be determined and distinguished by using a capillary measurement system and impedance spectroscopy. These results are relevant for the development of tissue-based test and sensor systems using impedance spectroscopy to evaluate personalized therapy variants or new therapy approaches.

MRI characteristics of the MLF in MS patients with chronic internuclear ophthalmoparesis.

OBJECTIVE: The authors imaged the medial longitudinal fasciculus (MLF) in 58 patients with MS and chronic internuclear ophthalmoparesis (INO) to determine which MRI technique best shows the characteristic lesion associated with this ocular motor syndrome. METHODS: Using quantitative infrared oculography, the authors determined the ratios of abduction to adduction for velocity and acceleration, to confirm the presence of INO and to determine the severity of MLF dysfunction in 58 patients with MS and INO. Conventional MRI techniques, including proton density imaging (PDI), T2-weighted imaging, and fluid-attenuated inversion recovery (FLAIR) imaging, were used to ascertain which technique best shows MLF lesions within the brainstem tegmentum. T1-weighted imaging was performed to determine the frequency of brainstem tegmentum hypointensities. RESULTS: All patients studied had evidence of an MLF lesion hyperintensity on PDI, whereas T2-weighted imaging and FLAIR imaging showed these lesions in 88% and 48% of patients, respectively. With PDI, dorsomedial tegmentum lesions were seen in the pons in 93% of patients and in the midbrain of 66% of patients. Lesions were observed at both locations in 59% of patients. One patient had an MLF lesion with a corresponding T1 hypointensity. CONCLUSIONS: PDI best shows the MLF lesion in patients with MS and INO.