Discriminating anisometropic amblyopia from myopia based on interocular inhibition.
Amblyopia screening during childhood is critical for early detection and successful treatment. In the current study, we develop and evaluate a screening method that exploits the imbalanced interocular inhibition between amblyopic and fellow eyes. In nineteen subjects with anisometropic amblyopia and twenty-two age-matched subjects with myopia, we measured the area under the contrast sensitivity functions (AUCSFs) in eight monocular conditions defined by the tested eye (left, right), patching of the untested eye (translucent, opaque), and refractive status (corrected, uncorrected). For each tested eye, we defined the inhibition index as the ratio between the AUCSF values obtained in the translucent and opaque patching conditions of the untested eye. To evaluate the screening potential of the inhibition index, we compared results from patients with amblyopia and myopia. With and without optical correction, the index was significantly lower in the amblyopic eye than in the fellow eye of the amblyopic subjects and both eyes of the myopic subjects. No significant difference was found among the two eyes of the myopic subjects and the fellow eyes of the amblyopic subjects. With the inhibition index as the predictor, a logistic regression model successfully discriminated amblyopic eyes from myopic eyes with 100% accuracy in the uncorrected condition. In the corrected condition, with the inhibition index and interocular visual acuity difference as predictors, amblyopic eyes were likewise discriminated from myopic eyes with 100% accuracy. This pattern of CSF changes, caused by the different patching modes of the untested eye, provides a potential CSF signature to discriminate anisometropic amblyopia from myopia.


Nematode parasites of two anuran species Rhinella schneideri (Bufonidae) and Scinax acuminatus (Hylidae) from Corrientes, Argentina.
The nematological fauna of most anuran species from Corrientes province, north of Argentina; has not been studied. We report for the first time the nematode species found in Rhinella schneideri and Scinax acuminatus. Forty four amphibians representing two species (R. schneideri--six males, three females and two juveniles--and S. acuminatus--fifteen males and eighteen females) were collected near the city of Corrientes, between January 2002 and December 2003 and searched for nematodes. R. schneideri contained eight species of nematodes (adults: Rhabdias füelleborni, R. elegans, Oswaldocruzia proencai, Cosmocerca podicipinus, C. parva and Falcaustra mascula; larvae: Porrocaecum sp. and Physaloptera sp.), and S. acuminatus contained three (adults: Cosmocerca parva and Oxyascaris caudacutus; larvae: Physaloptera sp.). We present morphology (scanning electron microscope) and metric information, range extensions, and new host records for these nematode species.


The benefits of risk factor prevention in Americans aged 51 years and older.
We assessed the potential health and economic benefits of reducing common risk factors in older Americans. A dynamic simulation model tracked a national cohort of persons 51 and 52 years of age to project their health and medical spending in prevention scenarios for diabetes, hypertension, obesity, and smoking. The gain in life span from successful treatment of a person aged 51 or 52 years for obesity would be 0.85 years; for hypertension, 2.05 years; and for diabetes, 3.17 years. A 51- or 52-year-old person who quit smoking would gain 3.44 years. Despite living longer, those successfully treated for obesity, hypertension, or diabetes would have lower lifetime medical spending, exclusive of prevention costs. Smoking cessation would lead to increased lifetime spending. We used traditional valuations for a life-year to calculate that successful treatments would be worth, per capita, $198,018 (diabetes), $137,964 (hypertension), $118,946 (smoking), and $51,750 (obesity). Effective prevention could substantially improve the health of older Americans, and--despite increases in longevity--such benefits could be achieved with little or no additional lifetime medical spending.


Incidence of Endemic Entomopathogenic Nematodes Following Application of Steinernema riobrave for Control of Diaprepes abbreviatus.
Control of Diaprepes abbreviatus by endemic and exotic entomopathogenic nematodes (EPN) was monitored during 2000-2001 in two citrus orchards in central Florida (Bartow and Poinciana). Caged sentinel insect larvae were buried beneath citrus trees for 7 days at 1 to 2-month intervals from April to October each year. At Bartow, the survey occurred in experimental plots that were (i) not treated with commercial EPN, (ii) treated twice annually since 1998 with commercially formulated Steinernema riobrave, or (iii) treated twice annually with S. riobrave and liquid fertilization (15 times/year) occurred in place of dry fertilizer (3 times/year) used in the other treatments. Four endemic EPN species, in addition to S. riobrave, were recovered from the sandy soil at Bartow: S. diaprepesi, Heterorhabditis zealandica, H. indica, and H. bacteriophora. Mean insect mortality in control plots was 39.4% (range = 13% to 74%), with seasonal maxima in May to July each year. Endemic EPN were recovered from 55% (range = 22% to 81%) of the cadavers each month. Total numbers of endemic EPN recovered in all plots during 2 years were directly related to the numbers of adult weevils (D. abbreviatus and Pachnaeus litus) captured in modified Tedder's traps and inversely related to recovery of S. riobrave. Insect mortality was higher and cadavers containing endemic EPN were more numerous in untreated control plots than in S. riobrave-treated plots, except during months in which S. riobrave was applied. In treated plots, endemic EPN were recovered from cadavers at twice the rate of S. riobrave. Suppression of endemic EPN in plots treated with S. riobrave, combined with inferior persistence by the introduced species, may have attenuated the net efficacy of S. riobrave against D. abbreviatus. In contrast, H. indica was the only endemic nematode recovered from the sandy clay loam soil at Poinciana, where the average mortality of D. abbreviatus was 12% (range 3% to 20%) and incidence of H. indica did not exceed 8%. Results of these surveys suggest that the regional patterns in the abundance and damage to citrus caused by D. abbreviatus in Florida are regulated by endemic EPN and other soilborne enemies of the weevil.


Dopamine-modulated potassium channels on rat striatal neurons: specific activation and cellular expression.
We have used cell-attached patch-clamp electrophysiology to characterize the activation and distribution of an 85 pS K+ channel on freshly dissociated rat striatal (caudate-putamen) neurons. In recordings from 643 cells, openings of this channel showed an absolute dependence on the presence of dopamine or the D2-like dopamine receptor agonist quinpirole in the cell-attached patch pipette, but were never seen when the D2 antagonist domperidone was applied along with quinpirole, or in the absence of drug. This channel displayed inward rectification at depolarized membrane potentials, but its activation was otherwise voltage insensitive. It was largely restricted to a subset of dissociated cells with diameters > or = 10 microns, with channel openings seen in about 25% of patches. When present, there were typically multiple channels per patch. Cells of this size were immunocytochemically stained for neuron-specific enolase but not glial fibrillary acidic protein; about 40% were also labeled for gamma-amino butyric acid (GABA) and about 60% for NADPH diaphorase, with GABAergic cells displaying a shape most similar to that of cells expressing the channel. A large number of distinct types of other channels were also present, comprising inwardly rectifying channels of 5-35 pS conductance and voltage-activated channels of 100-250 pS, but the frequencies of occurrence and fractional open times of these channels were independent of the presence or absence of dopaminergic agonists. Thus, the 85 pS K+ channel uniquely requires activation by a D2-like dopamine receptor on rat striatal neurons, and is selectively expressed by a subset of these cells, which are most likely to be GABAergic neurons.


Does Motivation Matter? Analysis of a Randomized Trial of Proactive Outreach to VA Smokers.
Current guidelines advise providers to assess smokers' readiness to quit, then offer cessation therapies to smokers planning to quit and motivational interventions to smokers not planning to quit. We examined the relationship between baseline stage of change (SOC), treatment utilization, and smoking cessation to determine whether the effect of a proactive smoking cessation intervention was dependent on smokers' level of motivation to quit. Secondary analysis of a multicenter randomized controlled trial. A total of 3006 current smokers, aged 18-80 years, at four Veterans Affairs (VA) medical centers. Proactive care included proactive outreach (mailed invitation followed by telephone outreach), offer of smoking cessation services (telephone or face-to-face), and access to pharmacotherapy. Usual care participants had access to VA smoking cessation services and state telephone quitlines. Baseline SOC measured with Readiness to Quit Ladder, and 6-month prolonged abstinence self-reported at 1 year. At baseline, 35.8 % of smokers were in preparation, 38.2 % in contemplation, and 26.0 % in precontemplation. The overall interaction between SOC and treatment arm was not statistically significant (p = 0.30). Among smokers in preparation, 21.1 % of proactive care participants achieved 6-month prolonged abstinence, compared to 13.1 % of usual care participants (OR, 1.8 [95 % CI, 1.2-2.6]). Similarly, proactive care increased abstinence among smokers in contemplation (11.0 % vs. 6.5 %; OR, 1.8 [95 % CI, 1.1-2.8]). Smokers in precontemplation quit smoking at similar rates (5.3 % vs. 5.6 %; OR, 0.9 [95 % CI, 0.5-1.9]). Within each stage, uptake of smoking cessation treatments increased with higher SOC and with proactive care as compared with usual care. Mostly male participants limits generalizability. Randomization was not stratified by SOC. Proactive care increased treatment uptake compared to usual care across all SOC. Proactive care increased smoking cessation among smokers in preparation and contemplation but not in precontemplation. Proactively offering cessation therapies to smokers at all SOC will increase treatment utilization and population-level smoking cessation.


The neck after vertical hemilaryngectomy: computed tomographic study.
Computed tomographic scans in 22 postoperative vertical hemilaryngectomy patients were analyzed retrospectively to determine the normal postoperative appearance and to evaluate the role of CT in assessing recurrent neoplasm. Twelve patients without clinical evidence of recurrence illustrated the normal postoperative changes: loss of the preepiglottic space fat and the aryepiglottic fold on the operated side, convexity of the residual true vocal cord, and regeneration of the resected thyroid cartilage ala. In the six patients with recurrent neoplasm, the CT manifestations included increased width of the remaining true vocal cord, convexity of the surgically formed pseudocord at glottic level, subglottic tumor, and extralaryngeal neck masses. Recurrence was mimicked in four patients by bulky soft tissue at the endolaryngeal operative site at both CT and laryngoscopy; this was due to hyperkeratosis or granulation tissue in three cases and an inclusion cyst in one case. CT supplemented the physical examination and indirect laryngoscopy, providing information regarding the presence and extent of tumor that was useful in planning the mode or scope of subsequent therapy.


Emergency medical vehicle collisions in an urban system.
Emergency medical services collisions (EMVCs) are a largely unexplored area of emergency medical services (EMS) research. Factors that might contribute to an EMVC are numerous and include use of warning lights and siren (WL&S). Few of these factors have been evaluated scientifically. Similarly, the incidence and severity of EMVCs is poorly documented in the literature. This study sought to define the incidence and severity of, and where possible, identify any contributing factors to EMVCs in a large urban system. Retrospective study of all collisions involving vehicles assigned to the EMS Division of the Houston Fire Department in calendar year 1993. Fifty-one ambulances were operational 24 hours per day during calendar year 1993. Houston EMS received 150,000 requests for assistance, made 180,000 vehicular responses, and accrued 2,651,760 miles in 1993. Eighty-six EMVCs were identified during the study period. The gross incidence rate was therefore 3.2 EMVC/100,000 miles driven or 4.8 collisions/10,000 responses. Of the 86 EMVCs, 74 (86%) files were complete and available for evaluation. Major collisions, determined according to injuries or vehicular damage, accounted for 10.8% of all EMVCs. There were 17 persons transported to hospitals from EMS collisions, yielding an injury incidence of 0.64 injuries/100,000 miles driven or 0.94 injuries/10,000 responses. There were no fatalities. The majority of collisions (85.1%) occurred at some site other than an intersection. There was no statistical association between occurrence at an intersection and severity, day versus night, weekend versus weekday, presence or absence of precipitation, or use of WL & S versus severity of collision. Drivers with a history of previous EMVCs were involved in 33% of all collisions. The presence of prior EMVCs was associated (p < 0.001) with the number of persons transported from the collision to a local hospital. Five drivers, all with previous EMVCs, accounted for 88.2% (15/17) of all injuries. A few drivers with previous EMVCs account for a disproportionate number of EMVCs and nearly 90% of all injuries. This risk factor--history of previous EMVC--has not been reported in the EMS literature. It is postulated that this factor ultimately will prove to be the major determinant of EMVCs. Data collection of EMS collisions needs to be standardized and a proposed collection tool is provided.


Little therapy, little physical activity: rehabilitation within the first 14 days of organized stroke unit care.
To examine rehabilitation interventions and resulting physical activity patterns of patients managed in acute stroke units to help inform development of a randomized controlled trial of very early rehabilitation. An open observational study of patient activity and therapist report of patient interventions. A survey of stroke unit resources. Patients less than 14 days post-stroke from 5 metropolitan stroke units were observed over 2 consecutive weekdays at 10-minute intervals between 08.00 h and 17.00 h. Physical activity, location and person(s) present were ascertained at each observation. Therapists completed treatment records. Senior staff completed stroke unit surveys. Patients after stroke (n=58) were with therapists 5.2% of the observed day. Few patients (17.1%) received daily therapy by more than one therapist. When patients received therapy, average session times were 24 minutes of physiotherapy, 23 minutes of occupational therapy and 33 minutes of speech pathology. The more time that family members were present, the longer the treatment time. Four to 11 min of upper-limb therapy was provided. Muscle weakness and left hemiparesis were associated with less upper-limb activity. These acute stroke care units were resourced according to recommended staff-patient ratios. Patients received little therapy and had low levels of physical activity.


Herbal extracts modulate the amplitude and frequency of slow waves in circular smooth muscle of mouse small intestine.
Herbal preparations like STW 5 (Iberogast) are widely used drugs in the treatment of dyspepsia and motility-related disorders of the gastrointestinal tract. STW 5 is a phytotherapeutic agent consisting of a fixed mixture of 9 individual plant extracts. The electrophysiological mechanisms of action of STW 5 remain obscure. The aim of the present study was to investigate whether herbal extracts influence electrophysiological parameters of the small intestine. For this purpose, the resting membrane potential (RMP) and the slow wave rhythmicity of smooth muscle cells of mouse small intestine were observed. Intracellular recordings of smooth muscle cells of the circular muscle layer of mouse small intestine were performed using standard microelectrode techniques. After dissection of the mucosa, the small intestine was placed in an organ bath and a microelectrode was applied on a circular smooth muscle cell. The RMP and the amplitude of slow waves were measured in millivolts. The RMP of smooth muscle cells was -59 +/- 1.3 mV. This RMP was significantly depolarized by STW 5 (9.6 +/- 1.6 mV); the depolarizing effects can be mainly attributed to the constituents of matricariae flos, angelicae radix and chelidonii herba. The basal frequency of small intestinal slow waves was 39.5 +/- 1.4 min(-1) and the amplitude was 23.1 +/- 0.9 mV. STW 5 significantly reduced the amplitude and frequency of the slow waves (11.7 +/- 0.8 mV; 33.5 +/- 3.4 min(-1)). This effect on slow waves represents the sum of the effects of the 9 phytoextracts. Whereas angelicae radix and matricariae flos completely blocked slow wave activity, Iberis amara increased the frequency and amplitude, chelidonii herba reduced the frequency and amplitude of the slow waves, mentae piperitae folium reduced the frequency and left amplitude unchanged and liquiritae radix, carvi fructus and melissae folium had no effects. Herbal extracts cause changes in smooth muscle RMP and slow wave rhythmicity, up to reversible abolition, by blockade of large conductance Ca2+ channels and other not yet identified mechanisms. In herbal preparations like STW 5 these effects add up to a total effect and this study indicates that herbal preparations which are widely used in dyspepsia and motility-related disorders have characteristic, reproducible, reversible effects on small intestinal electrophysiology.


Ca2+ release induced by cyclic ADP ribose in mice lacking type 3 ryanodine receptor.
The action of cyclic-ADP-ribose was studied on calcium release from sarcoplasmic reticulum of skeletal muscles of neonatal and adult wild-type and RyR3-deficient mice. cADPR increased calcium efflux from microsomes, enhanced caffeine-induced calcium release, and, in 20% of the tests, triggered calcium release in single muscle fibers. These responses occurred only in the diaphragm of adult RyR3-deficient mice. cADPR action was abolished by ryanodine, ruthenium red, and 8-brome-cADPR. These results strongly favor a specific action of cADPR on RyR1. The responsiveness of RyR1 appears in adult muscles when RyR3 is lacking.


Subpixel image registration with reduced bias.
A backward linear digital image correlation algorithm was introduced to obtain subpixel image registration without noise-induced bias for an image set consisting of a noise-free reference image and a number of noisy current images. Furthermore, a correction procedure using additional reference images (generated by offsetting the original image to displacement increments of either half-pixels or even quarter-pixels) was proposed to reduce subpixel approximation bias in the analysis. Numerical results of six sets of synthetic images showed that the proposed algorithm was effective in improving the accuracy of subpixel image registration.


Near-infrared fluorescence imaging using a protease-specific probe for the detection of colon tumors.
Early tumor detection is crucial for the prevention of colon cancer. Near-infrared fluorescence (NIRF) imaging using a target-activatable probe may permit earlier disease detection. Matrix metalloproteinases (MMPs) participate in tumorigenesis and tumor growth. The aim of this study was to determine whether NIRF imaging using an MMP-activatable probe can detect colon tumors at early stages. WE UTILIZED TWO MURINE COLON CANCER MODELS: a sporadic colon cancer model induced by azoxymethane (AOM), and a colitis-associated cancer model induced by a combination of AOM and dextran sodium sulfate (DSS). Colonic lesions were analyzed by histologic examination, Western blotting, immunohistochemical staining, and NIRF imaging using an MMP-activatable probe. Multiple variable-sized tumors developed in both models and progressed from adenomas to adenocarcinomas over time. At the early stage of the AOM/DSS model, diffuse inflammation was observed within the tumors. MMP expression increased progressively through normal, inflammation, adenoma, and adenocarcionoma stages. NIRF signal intensities were strongly correlated with each tumor stage from adenoma to adenocarcinoma. NIRF imaging also distinguished tumors from inflamed mucosa. NIRF imaging using a protease-activatable probe may be a useful tool for early tumor detection. This approach could translate to improve the endoscopic detection of colon tumors, especially in patients with inflammatory bowel disease.


The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46.
The destruction of viral-infected and tumor cells is mediated in part via the lysis receptor of natural killer (NK) cells, NKp46. The nature, however, of its lysis ligands expressed on target cells is poorly defined. Recently, we have identified a novel functional interaction between the lysis receptors NKp46 and NKp44 and the hemagglutinin of influenza and hemagglutinin-neuroaminidase of Sendai viruses. This recognition depends on the sialylation of NKp46 and NKp44 receptors. In this study, we expand the significance of these observations by demonstrating a conserved pattern of NKp46 and NKp44 recognition by various hemagglutinins derived from different viral strains. We further establish that this recognition is direct and mainly mediated via alpha2,6-linked sialic acid carried by NKp46. In addition, we demonstrate that the ability of NKp46 to recognize target cells is confined to the membrane proximal domain, and largely relies on the highly conserved sugar-carrying residue, Thr 225. This residue plays a critical dual role in NKp46 interactions with both viral hemagglutinins and the unknown tumor ligands via different mechanisms. These results may explain the ability of NK cells to kill such a broad spectrum of viral-infected and tumor cells.


Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.
We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.


Intraosseous vascular access through the anterior mandible--a cadaver model pilot study.
Several insertion sites have been described for intraosseous puncture in cases of emergencies when a conventional vascular access cannot be established. This pilot study has been designed to evaluate the feasibility of the mandibular bone for the use of an intraosseous vascular access in a cadaver model. 17 dentistry and 16 medical students participating in a voluntary course received a short introduction into the method and subsequently used the battery powered EZ-IO system with a 15 mm cannula for a puncture of the anterior mandible in 33 cadavers. The time needed to perform each procedure was evaluated. India ink was injected into the accesses and during the anatomy course cadavers were dissected to retrace the success or failure of the puncture. Dental students needed 25.5±18.9(mean±standard deviation)s and medical students 33±20.4 s for the procedure (p = 0.18). Floor of mouth extravasation occurred in both groups in 3 cases. Success rates were 82 and 75% (p = 0.93). Despite floor of mouth extravasation of injected fluid into a mandibular intraosseous access might severely complicate this procedure, the anterior mandible may be helpful as an alternative to other intraosseous and intravenous insertion sites when these are not available in medical emergencies.


Editorial Commentary: Two Fixation Points Are Better for Medial Patellofemoral Ligament Reconstruction-To Minimize Complications, Bone Tunnels Should Be Avoided.
Medial patellofemoral ligament (MPFL) reconstruction has gained in popularity over the past 15 years, with most studies showing a clear advantage over techniques such as MPFL repair or medial imbrication for the treatment of patellar instability. A debate continues as to the type of fixation on the patella, tunnel versus suture anchor, as well as the number of fixation points. In fact, some senior patellofemoral surgeons have opted away from patellar bony fixation altogether to avoid complications associated with patellar fixation such as fracture or penetration of the articular cartilage. In my practice, I prefer to use 2 all-suture suture anchors for patellar fixation as there is minimal risk of fracture or significant cartilage damage compared with tunnel drilling or placement of larger suture anchors. The graft choice for MPFL reconstruction has been shown to be relatively unimportant, and for this reason, I typically choose gracilis allograft to avoid graft-site morbidity and hamstring weakness.


Laparoscopic treatment of appendicovesical fistula.
A 23-year-old man had a history of intermittent episodes of urinary tract infection with associated low abdominal pain for 15 years. Persistent bacteriuria even with prolonged antibiotics was the reason why he was referred to our hospital. Laboratory tests were normal except pyuria and growth of Escherichia coli in the urinary samples. Cystoscopy revealed a small slit-like opening on the right lateral wall of bladder dome. We found some air within the bladder and a suspicious communicating tract between the appendix and bladder on a CT scan. With a strong impression of appendicovesical fistula, a laparoscopy was performed to confirm a diagnosis and to remove the appendicovesical fistula resulting in a satisfactory result without any complication.


Site-specific management of nematodes pitfalls and practicalities.
The greatest constraint to potato production in the United Kingdom (UK) is damage by the potato cyst nematodes (PCN) Globodera pallida and G. rostochiensis. Management of PCN depends heavily on nematicides, which are costly. Of all the inputs in UK agriculture, nematicides offer the largest potential cost savings from spatially variable application, and these savings would be accompanied by environmental benefits. We mapped PCN infestations in potato fields and monitored the changes in population density and distribution that occurred when susceptible potato crops were grown. The inverse relationship between population density before planting and multiplication rate of PCN makes it difficult to devise reliable spatial nematicide application procedures, especially when the pre-planting population density is just less than the detection threshold. Also, the spatial dependence found suggests that the coarse sampling grids used commercially are likely to produce misleading distribution maps.


Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.
Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy. We randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n = 231) or BSC alone (n = 232). Tumor assessments by blinded central review were scheduled from week 8 until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included objective response, overall survival (OS), and safety. BSC patients who progressed could receive panitumumab in a cross-over study. Panitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76% of BSC patients entered the cross-over study. Panitumumab was well tolerated. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed. No patients had grade 3/4 infusion reactions. Panitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer.


Evaluation of the Q16 questionnaire on neurotoxic symptoms and a review of its use.
The questionnaire 16 (Q16) is commonly used to study prevalences of neurotoxic symptoms among workers exposed to organic solvents. It has also been recommended that exposed workers reporting more than six symptoms should be referred for further examination of possible chronic toxic encephalopathy. It would be useful to know whether symptoms reported in the questionnaire also reflect impairment of similar functions measured with objective or semiobjective methods in a formerly highly exposed group. 135 painters and 71 carpenters answered the Q16, were interviewed about symptoms compatible with an organic brain damage, and took a battery of psychometric tests. A subsample of 52 painters and 45 carpenters were interviewed for psychiatric diagnosis according to Diagnostic and Statistical Manual for Mental Disorders, 3rd version (DSM III) and their vibration thresholds in hands and feet were measured. The entire group was followed up in the register of diagnoses at early retirement 1971-93. The lifetime exposure to organic solvents was assessed. Current exposure to organic solvents was found to be low or none. The prevalence of people with more than six symptoms in the Q16 rose with increasing cumulative exposure to solvents. The sensitivity of the questionnaire (more than six symptoms) to detect people who were assessed to exhibit symptoms compatible with an organic brain damage was only 38%. One of seven people who had retired early with a diagnosis compatible with a chronic toxic encephalopathy, and two of five people with a psychiatric diagnosis compatible with this condition, had more than six symptoms in the Q16. The agreement between Q16 replies and psychometric test results, as well as other examinations, was low. The notable exposure-response relation indicates that the questionnaire is useful for comparison of groups with different exposures to organic solvents. There was low agreement between the number of symptoms on the questionnaire and the assessment of symptoms compatible with organic brain damage, as well as psychiatric, or early retirement diagnoses compatible with chronic toxic encephalopathy. The questionnaire does not seem useful for screening of patients with chronic toxic encephalopathy in groups without ongoing exposure to organic solvents.


The Oral Bacterial Communities of Children with Well-Controlled HIV Infection and without HIV Infection.
The oral microbial community (microbiota) plays a critical role in human health and disease. Alterations in the oral microbiota may be associated with disorders such as gingivitis, periodontitis, childhood caries, alveolar osteitis, oral candidiasis and endodontic infections. In the immunosuppressed population, the spectrum of potential oral disease is even broader, encompassing candidiasis, necrotizing gingivitis, parotid gland enlargement, Kaposi's sarcoma, oral warts and other diseases. Here, we used 454 pyrosequencing of bacterial 16S rRNA genes to examine the oral microbiome of saliva, mucosal and tooth samples from HIV-positive and negative children. Patient demographics and clinical characteristics were collected from a cross-section of patients undergoing routine dental care. Multiple specimens from different sampling sites in the mouth were collected for each patient. The goal of the study was to observe the potential diversity of the oral microbiota among individual patients, sample locations, HIV status and various dental characteristics. We found that there were significant differences in the microbiome among the enrolled patients, and between sampling locations. The analysis was complicated by uneven enrollment in the patient cohorts, with only five HIV-negative patients enrolled in the study and by the rapid improvement in the health of HIV-infected children between the time the study was conceived and completed. The generally good oral health of the HIV-negative patients limited the number of dental plaque samples that could be collected. We did not identify significant differences between well-controlled HIV-positive patients and HIV-negative controls, suggesting that well-controlled HIV-positive patients essentially harbor similar oral flora compared to patients without HIV. Nor were significant differences in the oral microbiota identified between different teeth or with different dental characteristics. Additional studies are needed to better characterize the oral microbiome in children and those with poorly-controlled HIV infections.


Mediastinal micro-vessels clipping during lymph node dissection may contribute to reduce postoperative pleural drainage.
Postoperative pleural drainage markedly influences the length of postoperative stay and financial costs of medical care. The aim of this study is to retrospectively investigate potentially predisposing factors related to pleural drainage after curative thoracic surgery and to explore the impact of mediastinal micro-vessels clipping on pleural drainage control after lymph node dissection. From February 2012 to November 2013, 322 consecutive cases of operable non-small cell lung cancers (NSCLC) undergoing lobectomy and mediastinal lymph node dissection with or without application of clipping were collected. Total and daily postoperative pleural drainage were recorded. Propensity score matching (1:2) was applied to balance variables potentially impacting pleural drainage between group clip and group control. Analyses were performed to compare drainage volume, duration of chest tube and postoperative hospital stay between the two groups. Variables linked with pleural drainage in whole cohort were assessed using multivariable logistic regression analysis. Propensity score matching resulted in 197 patients (matched cohort). Baseline patient characteristics were matched between two groups. Group clip showed less cumulative drainage volume (P=0.020), shorter duration of chest tube (P=0.031) and postoperative hospital stay (P=0.022) compared with group control. Risk factors significantly associated with high-output drainage in multivariable logistic regression analysis were being male, age >60 years, bilobectomy/sleeve lobectomy, pleural adhesion, the application of clip applier, duration of operation ≥220 minutes and chylothorax (P<0.05). This study suggests that mediastinal micro-vessels clipping during lymph node dissection may reduce postoperative pleural drainage and thus shorten hospital stay.


The role of the extra-framework cations in the adsorption of CO(2) on faujasite Y.
A purely electrostatic picture predicts that small, more polarizing cations adsorb more strongly than the large ones. In the case of the adsorption of CO(2) on faujasite Y, however, the inverse order is found at low pressure: CsY and KY adsorb stronger than NaY and LiY. This trend cannot be explained by a simple monopole-dipole or monopole-quadrupole interaction of CO(2) with a single cation. Therefore, we have conducted a combined adsorption, IR and DFT study in order to shed light on this phenomenon. Our results show that a simultaneous interaction of CO(2) with the cations (located in the hexagonal window between supercage and sodalite cage) and framework oxygen atoms (in the 12-ring connecting two supercages) can explain the strong adsorption of CO(2) on CsY and KY. We also discuss the effect of van der Waals interactions. Although there is a redistribution of the charge of three framework oxygen atoms in the 12-ring towards the carbon atom of CO(2), the geometry of CO(2) remains almost linear. The adsorption mode can, therefore, be interpreted as a carbonate precursor. In zeolite Y, this acid-base like interaction is more important than polarization of CO(2) by the cation only. Furthermore, evidence for an adsorption mode where CO(2) binds simultaneously to two cations in the supercage was detected by DFT, as already reported for Na-ferrierite. This adsorption mode is, however, strongly dependant on the distance between two cations in the supercage and is only favorable in the case of KY.


Estrogen-producing endometrioid adenocarcinoma resembling sex cord-stromal tumor of the ovary: a review of four postmenopausal cases.
The 4 present cases with endometrioid adenocarcinoma (EMA) of the ovary were characterized by estrogen overproduction and resemblance to sex cord-stromal tumor (SCST). The patients were all postmenopausal, at ages ranging from 60 to 79 years (av. 67.5), who complained of abdominal discomfort or distention and also atypical genital bleeding. Cytologically, maturation of the cervicovaginal squamous epithelium and active endometrial proliferation were detected. The serum estrogen (estradiol, E2) value was preoperatively found to be elevated, ranging from 48.7 to 83.0 pg/mL (av. 58.4). In contrast, follicle stimulating hormone was suppressed to below the normal value. MR imaging diagnoses included SCSTs such as granulosa cell tumor or thecoma for 3 cases because of predominantly solid growth, and epithelial malignancy for one case because of cystic and solid structure. Grossly, the solid part of 3 cases was homogeneously yellow in color. Histologically, varying amounts of tumor components were arranged in solid nests, hollow tubules, cord-like strands and cribriform-like nests in addition to the conventional EMA histology. In summary, postmenopausal ovarian solid tumors with the estrogenic manifestations tend to be preoperatively diagnosed as SCST. Due to this, in the histological diagnosis, this variant of ovarian EMA may be challenging and misdiagnosed as SCST because of its wide range in morphology.


NANOG priming before full reprogramming may generate germ cell tumours.
Reprogramming somatic cells into a pluripotent state brings patient-tailored, ethical controversy-free cellular therapy closer to reality. However, stem cells and cancer cells share many common characteristics; therefore, it is crucial to be able to discriminate between them. We generated two induced pluripotent stem cell (iPSC) lines, with NANOG pre-transduction followed by OCT3/4, SOX2, and LIN28 overexpression. One of the cell lines, CHiPS W, showed normal pluripotent stem cell characteristics, while the other, CHiPS A, though expressing pluripotency markers, failed to differentiate and gave rise to germ cell-like tumours in vivo. Comparative genomic hybridisation analysis of the generated iPS lines revealed that they were genetically more stable than human embryonic stem cell counterparts. This analysis proved to be predictive for the differentiation potential of analysed cells. Moreover, the CHiPS A line expressed a lower ratio of p53/p21 when compared to CHiPS W. NANOG pre-induction followed by OCT3/4, SOX2, MYC, and KLF4 induction resulted in the same tumour-inducing phenotype. These results underline the importance of a re-examination of the role of NANOG during reprogramming. Moreover, this reprogramming method may provide insights into primordial cell tumour formation and cancer stem cell transformation.


Predictors of children's secondhand smoke exposure at home: a systematic review and narrative synthesis of the evidence.
Children's exposure to secondhand smoke (SHS) has been causally linked to a number of childhood morbidities and mortalities. Over 50% of UK children whose parents are smokers are regularly exposed to SHS at home. No previous review has identified the factors associated with children's SHS exposure in the home. To identify by systematic review, the factors which are associated with children's SHS exposure in the home, determined by parent or child reports and/or biochemically validated measures including cotinine, carbon monoxide or home air particulate matter. Electronic searches of MEDLINE, EMBASE, PsychINFO, CINAHL and Web of Knowledge to July 2014, and hand searches of reference lists from publications included in the review were conducted. Forty one studies were included in the review. Parental smoking, low socioeconomic status and being less educated were all frequently and consistently found to be independently associated with children's SHS exposure in the home. Children whose parents held more negative attitudes towards SHS were less likely to be exposed. Associations were strongest for parental cigarette smoking status; compared to children of non-smokers, those whose mothers or both parents smoked were between two and 13 times more likely to be exposed to SHS. Multiple factors are associated with child SHS exposure in the home; the best way to reduce child SHS exposure in the home is for smoking parents to quit. If parents are unable or unwilling to stop smoking, they should instigate smoke-free homes. Interventions targeted towards the socially disadvantaged parents aiming to change attitudes to smoking in the presence of children and providing practical support to help parents smoke outside the home may be beneficial.


Phylogenomic analyses data of the avian phylogenomics project.
Determining the evolutionary relationships among the major lineages of extant birds has been one of the biggest challenges in systematic biology. To address this challenge, we assembled or collected the genomes of 48 avian species spanning most orders of birds, including all Neognathae and two of the five Palaeognathae orders. We used these genomes to construct a genome-scale avian phylogenetic tree and perform comparative genomic analyses. Here we present the datasets associated with the phylogenomic analyses, which include sequence alignment files consisting of nucleotides, amino acids, indels, and transposable elements, as well as tree files containing gene trees and species trees. Inferring an accurate phylogeny required generating: 1) A well annotated data set across species based on genome synteny; 2) Alignments with unaligned or incorrectly overaligned sequences filtered out; and 3) Diverse data sets, including genes and their inferred trees, indels, and transposable elements. Our total evidence nucleotide tree (TENT) data set (consisting of exons, introns, and UCEs) gave what we consider our most reliable species tree when using the concatenation-based ExaML algorithm or when using statistical binning with the coalescence-based MP-EST algorithm (which we refer to as MP-EST*). Other data sets, such as the coding sequence of some exons, revealed other properties of genome evolution, namely convergence. The Avian Phylogenomics Project is the largest vertebrate phylogenomics project to date that we are aware of. The sequence, alignment, and tree data are expected to accelerate analyses in phylogenomics and other related areas.


Multilevel Examination of Health Disparity: The Role of Policy Implementation in Neighborhood Context, in Patient Resources, and in Healthcare Facilities on Later Stage of Breast Cancer Diagnosis.
There is a substantial racial/ethnic disparity in female breast cancer mortality in Chicago between non-Hispanic black (NHblack) and Hispanic patients compared with their non-Hispanic white (NHwhite) counterparts. This observation prompted a multilevel examination of factors that might account for the disparity, with the goal of identifying potential policy interventions that might meaningfully address it METHODS: In the Breast Cancer Care in Chicago study, 411 NHblack, 397 NHwhite, and 181 Hispanic patients diagnosed between the ages of 30 and 79 were interviewed, and medical records were abstracted for information on screening and diagnostic follow-up. We conducted a multilevel analysis to assess the role of neighborhood context, patient resources, facility characteristics, and mode of detection in determining the disparity in later stage at diagnosis. After adjustment for neighborhood context, mode of detection, and facility accreditation/resources, there was no significant disparity in later stage breast cancer diagnosis between NHblack or Hispanic patients compared with NHwhite patients. The results suggest that racial/ethnic differences in mode of detection and facility accreditation/resources account for most of the disparity in stage at diagnosis. Understanding the causes of differential screen detection and access to highly accredited facilities could inform interventions to meaningfully address this disparity. Multilevel approaches to studying health disparities are becoming the research standard for understanding and addressing health disparities. Optimal design of multilevel interventions addressing disparities in later stage diagnosis would benefit from enhanced understanding of pathways to detection and diagnosis available to patients in medically underserved communities.


Increased Intrinsic Activity of Medial-Temporal Lobe Subregions is Associated with Decreased Cortical Thickness of Medial-Parietal Areas in Patients with Alzheimer's Disease Dementia.
In Alzheimer's disease (AD), disrupted connectivity between medial-parietal cortices and medial-temporal lobes (MTL) is linked with increased MTL local functional connectivity, and parietal atrophy is associated with increased MTL memory activation. We hypothesized that intrinsic activity in MTL subregions is increased and associated with medial-parietal degeneration and impaired memory in AD. To test this hypothesis, resting-state-functional and structural-MRI was assessed in 22 healthy controls, 22 mild cognitive impairment patients, and 21 AD-dementia patients. Intrinsic activity was measured by power-spectrum density of blood-oxygenation-level-dependent signal, medial-parietal degeneration by cortical thinning. In AD-dementia patients, intrinsic activity was increased for several right MTL subregions. Raised intrinsic activity in dentate gyrus and cornu ammonis 1 was associated with cortical thinning in posterior cingulate cortices, and at-trend with impaired delayed recall. Critically, increased intrinsic activity in the right entorhinal cortex was associated with ipsilateral posterior cingulate degeneration. Our results provide evidence that in AD, intrinsic activity in MTL subregions is increased and associated with medial-parietal atrophy. Results fit a model in which medial-parietal degeneration contributes to MTL dysconnectivity from medial-parietal cortices, potentially underpinning disinhibition-like changes in MTL activity.


The pox in the North American backyard: Volepox virus pathogenesis in California mice (Peromyscus californicus).
Volepox virus (VPXV) was first isolated in 1985 from a hind foot scab of an otherwise healthy California vole (Microtus californicus). Subsequent surveys in San Mateo County, CA, revealed serological evidence suggesting that VPXV is endemic to this area, and a second viral isolate from a Pinyon mouse (Peromyscus truei) was collected in 1988. Since then, few studies have been conducted regarding the ecology, pathology, and pathogenicity of VPXV, and its prevalence and role as a potential zoonotic agent remain unknown. To increase our understanding of VPXV disease progression, we challenged 24 California mice (Peromyscus californicus) intranasally with 1.6 × 10(3) PFU of purified VPXV. By day five post infection (pi) we observed decreased activity level, conjunctivitis, ruffled hair, skin lesions, facial edema, and crusty noses. A mortality rate of 54% was noted by day eight pi. In addition, internal organ necrosis and hemorrhages were observed during necropsy of deceased or euthanized animals. Viral loads in tissues (brain, gonad, kidney, liver, lung, spleen, submandibular lymph node, and adrenal gland), bodily secretions (saliva, and tears), and excretions (urine, and/or feces) were evaluated and compared using real time-PCR and tissue culture. Viral loads measured as high as 2 × 10(9) PFU/mL in some organs. Our results suggest that VPXV can cause extreme morbidity and mortality within rodent populations sympatric with the known VPXV reservoirs.


Biological nitrogen fixation in non-legume plants.
Nitrogen is an essential nutrient in plant growth. The ability of a plant to supply all or part of its requirements from biological nitrogen fixation (BNF) thanks to interactions with endosymbiotic, associative and endophytic symbionts, confers a great competitive advantage over non-nitrogen-fixing plants. Because BNF in legumes is well documented, this review focuses on BNF in non-legume plants. Despite the phylogenic and ecological diversity among diazotrophic bacteria and their hosts, tightly regulated communication is always necessary between the microorganisms and the host plant to achieve a successful interaction. Ongoing research efforts to improve knowledge of the molecular mechanisms underlying these original relationships and some common strategies leading to a successful relationship between the nitrogen-fixing microorganisms and their hosts are presented. Understanding the molecular mechanism of BNF outside the legume-rhizobium symbiosis could have important agronomic implications and enable the use of N-fertilizers to be reduced or even avoided. Indeed, in the short term, improved understanding could lead to more sustainable exploitation of the biodiversity of nitrogen-fixing organisms and, in the longer term, to the transfer of endosymbiotic nitrogen-fixation capacities to major non-legume crops.


A Temperature Sensitive Variant of p53 Drives p53-Dependent MicroRNA Expression without Evidence of Widespread Post-Transcriptional Gene Silencing.
The p53 tumour suppressor is a transcription factor that can regulate the expression of numerous genes including many encoding proteins and microRNAs (miRNAs). The predominant outcomes of a typical p53 response are the initiation of apoptotic cascades and the activation of cell cycle checkpoints. HT29-tsp53 cells express a temperature sensitive variant of p53 and in the absence of exogenous DNA damage, these cells preferentially undergo G1 phase cell cycle arrest at the permissive temperature that correlates with increased expression of the cyclin-dependent kinase inhibitor p21WAF1. Recent evidence also suggests that a variety of miRNAs can induce G1 arrest by inhibiting the expression of proteins like CDK4 and CDK6. Here we used oligonucleotide microarrays to identify p53-regulated miRNAs that are induced in these cells undergoing G1 arrest. At the permissive temperature, the expression of several miRNAs was increased through a combination of either transcriptional or post-transcriptional regulation. In particular, miR-34a-5p, miR-143-3p and miR-145-5p were strongly induced and they reached levels comparable to that of reference miRNAs (miR-191 and miR-103). Importantly, miR-34a-5p and miR-145-5p are known to silence the Cdk4 and/or Cdk6 G1 cyclin-dependent kinases (cdks). Surprisingly, there was no p53-dependent decrease in the expression of either of these G1 cdks. To search for other potential targets of p53-regulated miRNAs, p53-downregulated mRNAs were identified through parallel microarray analysis of mRNA expression. Once again, there was no clear effect of p53 on the repression of mRNAs under these conditions despite a remarkable increase in p53-induced mRNA expression. Therefore, despite a strong p53 transcriptional response, there was no clear evidence that p53-responsive miRNA contributed to gene silencing. Taken together, the changes in cell cycle distribution in this cell line at the permissive temperature is likely attributable to transcriptional upregulation of the CDKN1A mRNA and p21WAF1 protein and not to the down regulation of CDK4 or CDK6 by p53-regulated miRNAs.


An ancient push-pull pollination mechanism in cycads.
Most cycads engage in brood-site pollination mutualisms, yet the mechanism by which the Cycadales entice pollination services from diverse insect mutualists remains unknown. Here, we characterize a push-pull pollination mechanism between a New World cycad and its weevil pollinators that mirrors the mechanism between a distantly related Old World cycad and its thrips pollinators. The behavioral convergence between weevils and thrips, combined with molecular phylogenetic dating and a meta-analysis of thermogenesis and coordinated patterns of volatile attraction and repulsion suggest that a push-pull pollination mutualism strategy is ancestral in this ancient, dioecious plant group. Hence, it may represent one of the earliest insect/plant pollination mechanisms, arising long before the evolution of visual floral signaling commonly used by flowering plants.


Co-localization of Reelin and proteolytic AbetaPP fragments in hippocampal plaques in aged wild-type mice.
Reelin is a large extracellular glycoprotein required for proper neuronal positioning during development. In the adult brain, Reelin plays a crucial modulatory role in the induction of synaptic plasticity and successful formation of long-term memory. Recently, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). We previously reported that aging in several species is characterized by a decline in Reelin-expressing interneurons and concomitant accumulation in amyloid-like plaques in the hippocampal formation, significantly correlating with cognitive impairments. In transgenic AD mice, we detected Reelin in oligomeric amyloid-beta aggregates and in tight association with fibrillary plaques. Here, we used immunohistochemistry at the light and electron microscopy level to characterize further the morphology, temporal and spatial progression, as well as the potential of Reelin-positive plaques to sequester murine amyloid-beta peptides in wild-type mice. We developed a new immunohistochemical protocol involving a stringent protease pretreatment which markedly enhanced Reelin-immunoreactivity and allowed specific detection of variable shapes of murine anti-amyloid-beta protein precursor-immunoreactivity in plaques in the hippocampus, likely representing N-terminal fragments and amyloid-beta species. Ultrastructural investigations confirmed the presence of Reelin in extracellular space, somata of interneurons in young and aged wild-type mice. In aged mice, Reelin- and amyloid-beta-immunoreactivity was detected in extracellular, spherical deposits, likely representing small intermediates or fragments of amyloid fibrils. Our results suggest that Reelin itself aggregates into abnormal oligomeric or protofibrillary deposits during aging, potentially creating a precursor condition for fibrillary amyloid-beta plaque formation.


Generation of an algorithm based on minimal gene sets to clinically subtype triple negative breast cancer patients.
Recently, a gene expression algorithm, TNBCtype, was developed that can divide triple-negative breast cancer (TNBC) into molecularly-defined subtypes. The algorithm has potential to provide predictive value for TNBC subtype-specific response to various treatments. TNBCtype used in a retrospective analysis of neoadjuvant clinical trial data of TNBC patients demonstrated that TNBC subtype and pathological complete response to neoadjuvant chemotherapy were significantly associated. Herein we describe an expression algorithm reduced to 101 genes with the power to subtype TNBC tumors similar to the original 2188-gene expression algorithm and predict patient outcomes. The new classification model was built using the same expression data sets used for the original TNBCtype algorithm. Gene set enrichment followed by shrunken centroid analysis were used for feature reduction, then elastic-net regularized linear modeling was used to identify genes for a centroid model classifying all subtypes, comprised of 101 genes. The predictive capability of both this new "lean" algorithm and the original 2188-gene model were applied to an independent clinical trial cohort of 139 TNBC patients treated initially with neoadjuvant doxorubicin/cyclophosphamide and then randomized to receive either paclitaxel or ixabepilone to determine association of pathologic complete response within the subtypes. The new 101-gene expression model reproduced the classification provided by the 2188-gene algorithm and was highly concordant in the same set of seven TNBC cohorts used to generate the TNBCtype algorithm (87%), as well as in the independent clinical trial cohort (88%), when cases with significant correlations to multiple subtypes were excluded. Clinical responses to both neoadjuvant treatment arms, found BL2 to be significantly associated with poor response (Odds Ratio (OR) =0.12, p=0.03 for the 2188-gene model; OR = 0.23, p < 0.03 for the 101-gene model). Additionally, while the BL1 subtype trended towards significance in the 2188-gene model (OR = 1.91, p = 0.14), the 101-gene model demonstrated significant association with improved response in patients with the BL1 subtype (OR = 3.59, p = 0.02). These results demonstrate that a model using small gene sets can recapitulate the TNBC subtypes identified by the original 2188-gene model and in the case of standard chemotherapy, the ability to predict therapeutic response.


Specific inhibition of the reverse transcriptase of human immunodeficiency virus type 1 and the chimeric enzymes of human immunodeficiency virus type 1 and type 2 by nonnucleoside inhibitors.
We have studied the effects of four nonnucleoside inhibitors, including the novel natural product inhibitor calanolide A, on molecular chimeras containing complementary segments of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptases (RTs). All four compounds specifically inhibited the DNA polymerase activity of HIV-1 RT but had no apparent effect on the RNase H activity of this enzyme or on the DNA polymerase or RNase H activity of HIV-2 RT. Three of these compounds showed the generally expected patterns of resistance and susceptibility with the various chimeric RTs. However, the inhibition patterns of the chimeric RTs by calanolide A provided evidence that there is a segment between residues 94 and 157 in HIV-1 RT that is critical for inhibition. However, the data also suggest that there may be a second segment located between amino acids 225 and 427 in HIV-1 RT that is also important for specifying susceptibility to the drug.


A sensitive array for microRNA expression profiling (miChip) based on locked nucleic acids (LNA).
MicroRNAs represent a class of short (approximately 22 nt), noncoding regulatory RNAs involved in development, differentiation, and metabolism. We describe a novel microarray platform for genome-wide profiling of mature miRNAs (miChip) using locked nucleic acid (LNA)-modified capture probes. The biophysical properties of LNA were exploited to design probe sets for uniform, high-affinity hybridizations yielding highly accurate signals able to discriminate between single nucleotide differences and, hence, between closely related miRNA family members. The superior detection sensitivity eliminates the need for RNA size selection and/or amplification. MiChip will greatly simplify miRNA expression profiling of biological and clinical samples.


A rare case of cutaneous metastasis of postpartum choriocarcinoma.
Gestational trophoblastic disease has been reported to be responsive to chemotherapy, with a 90% cure rate. Several factors place patients at high risk of experiencing treatment failure with single agent chemotherapy. Choriocarcinoma following term pregnancy is very rare and associated with a poor prognosis and a mortality rate of 33-40%. We present a rare case of cutaneous metastasis of choriocarcinoma to the left third digit.


Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia.
Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. Relative to matched controls, schizophrenia patients show (1) a global and regional reduction in the integrity of the brain's white matter (WM), assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA), and (2) accelerated age-related decline in FA values. In the largest mega-analysis to date, we tested if differences in the trajectories of WM tract development influenced patient-control differences in FA. We also assessed if specific tracts showed exacerbated decline with aging. Three cohorts of schizophrenia patients (total n = 177) and controls (total n = 249; age = 18-61 years) were ascertained with three 3T Siemens MRI scanners. Whole-brain and regional FA values were extracted using ENIGMA-DTI protocols. Statistics were evaluated using mega- and meta-analyses to detect effects of diagnosis and age-by-diagnosis interactions. In mega-analysis of whole-brain averaged FA, schizophrenia patients had lower FA (P = 10-11 ) and faster age-related decline in FA (P = 0.02) compared with controls. Tract-specific heterochronicity measures, that is, abnormal rates of adolescent maturation and aging explained approximately 50% of the regional variance effects of diagnosis and age-by-diagnosis interaction in patients. Interactive, three-dimensional visualization of the results is available at www.enigma-viewer.org. WM tracts that mature later in life appeared more sensitive to the pathophysiology of schizophrenia and were more susceptible to faster age-related decline in FA values. Hum Brain Mapp 37:4673-4688, 2016. © 2016 Wiley Periodicals, Inc.


Non-markovian model of photon-assisted dephasing by electron-phonon interactions in a coupled quantum-dot-cavity system.
We investigate the influence of electron-phonon interactions on the dynamical properties of a quantum-dot-cavity QED system. We show that non-markovian effects in the phonon reservoir lead to strong changes in the dynamics, arising from photon-assisted dephasing processes, not present in markovian treatments. A pronounced consequence is the emergence of a phonon induced spectral asymmetry when detuning the cavity from the quantum-dot resonance. The asymmetry can only be explained when considering the polaritonic quasiparticle nature of the quantum-dot-cavity system. Furthermore, a temperature induced reduction of the light-matter coupling strength is found to be relevant in interpreting experimental data, especially in the strong coupling regime.


Water-stable Eu-MOF fluorescent sensors for trivalent metal ions and nitrobenzene.
Two novel Eu metal-organic frameworks (MOFs), namely {[Eu2(pdba)3(H2O)3]·2H2O}n (1) and {[Eu3(pdba)4(H2O)4]·5H2O}n (2), were prepared with 4'-(1H-pyrazol-3-yl)-[1,1'-biphenyl]-3,5-dicarboxylic acid (H2pdba) under hydrothermal conditions. MOF 1 exhibits a 3D supramolecular structure assembled from the ππ interactions between the benzene rings of the ligands, whereas 2 comprises a 3D structure through coordination connection between nitrogen atom and Eu3+. It is worth noting that the two MOFs showed good luminescence performance and high-sensitivity fluorescence quenching behavior toward Fe3+ (Cr3+) and nitrobenzene. Furthermore, the experimental results for stability in water and cycle test show that these two MOFs can be used as potential fluorescent probes.


Lesion size correlates with Leishmania antigen-stimulated TNF-levels in human cutaneous leishmaniasis.
Cutaneous leishmaniasis (CL) is a worldwide disease endemic in several regions of the globe. The hallmark of CL is skin ulcers likely driven by efforts of the immune system to control Leishmania growth. Cytokines, such as tumor necrosis factor (TNF) and interferon-gamma can control disease progression in animal models. Nevertheless, the impact of these cytokines in CL ulcer outcome is not well established in humans. In this study, 96 CL patients from an endemic area of Leishmania braziliensis were enrolled for a follow-up study that consisted of clinical and immunological evaluations in a 2-year period. Statistical analysis revealed that healing time (P = 0.029), age (P = 0.002), and TNF levels (P = 0.0002) positively correlate with ulcer size at the time of the first clinical evaluation. Our findings suggest that ulcer size correlates with healing time and TNF levels support the use of TNF inhibitors combined with standard therapy to improve healing in CL patients with severe lesions.


Mass Spectrometry-Based Techniques to Elucidate the Sugar Code.
Cells encode information in the sequence of biopolymers, such as nucleic acids, proteins, and glycans. Although glycans are essential to all living organisms, surprisingly little is known about the "sugar code" and the biological roles of these molecules. The reason glycobiology lags behind its counterparts dealing with nucleic acids and proteins lies in the complexity of carbohydrate structures, which renders their analysis extremely challenging. Building blocks that may differ only in the configuration of a single stereocenter, combined with the vast possibilities to connect monosaccharide units, lead to an immense variety of isomers, which poses a formidable challenge to conventional mass spectrometry. In recent years, however, a combination of innovative ion activation methods, commercialization of ion mobility-mass spectrometry, progress in gas-phase ion spectroscopy, and advances in computational chemistry have led to a revolution in mass spectrometry-based glycan analysis. The present review focuses on the above techniques that expanded the traditional glycomics toolkit and provided spectacular insight into the structure of these fascinating biomolecules. To emphasize the specific challenges associated with them, major classes of mammalian glycans are discussed in separate sections. By doing so, we aim to put the spotlight on the most important element of glycobiology: the glycans themselves.


High Baseline Lipoprotein(a) Level as a Risk Factor for Coronary Artery Calcification Progression: Sub-analysis of a Prospective Multicenter Trial.
Lipoprotein(a), or Lp(a), is a low-density lipoprotein-like particle largely independent of known risk factors for, and predictive of, cardiovascular disease (CVD). We investigated the association between baseline Lp(a) levels and the progression of coronary artery calcification (CAC) in patients with hypercholesterolemia undergoing statin therapy. This study was a sub-analysis of a multicenter prospective study that evaluated the annual progression of CAC under intensive and standard pitavastatin treatment with or without eicosapentaenoic acid in patients with an Agatston score of 1 to 999, and hypercholesterolemia treated with statins. We classified the patients into 3 groups according to CAC progression. A total of 147 patients (mean age, 67 years; men, 54%) were analyzed. The proportion of patients with Lp(a) > 30 mg/dL significantly increased as CAC progressed (non-progression; 5.4%, 0<CAC progression ≦100; 7.7%, and CAC progression >100; 23.6%). Logistic regression analysis showed that Lp(a) > 30 mg/dL was an independent predictor of the annual change in Agatston score > 100 (OR: 5.51; 95% CI: 1.28-23.68; p=0.02), even after adjusting for age, sex, hypertension, diabetes mellitus, current smoking, body mass index, and lipid-lowering medications. Baseline Lp(a) >30 mg/dL was a predictor of CAC progression in this population of patients with hypercholesterolemia undergoing statin therapy.


Breastfeeding reduces risk of respiratory illness in infants.
Breastfeeding has long been believed to protect against infection in infants, but protection against respiratory illnesses has not been consistently demonstrated in studies in developed countries. Between 1988 and 1992, the authors assessed the effect of breastfeeding on incidence and duration of respiratory illnesses during the first 6 months of life in a prospective study that actively tracked breastfeeding and respiratory illnesses. A cohort of 1,202 healthy infants, born in Albuquerque, New Mexico, between January 1, 1988 and June 30, 1990, from homes without smokers was enrolled. The daily occurrences of respiratory symptoms and breastfeeding status were reported by the mothers every 2 weeks. Illnesses were classified as lower respiratory illness (LRI) if wheezing or wet cough was reported; the remaining illnesses were classified as upper respiratory. The annualized incidence rates for LRI were 2.8, 2.6, and 2.1 during follow-up time with no, partial, or full breastfeeding, respectively, but the incidence rates for upper respiratory illness and lower respiratory illness combined were similar in the three categories. After adjustment for potential confounding factors, full breastfeeding was associated with a reduction in lower respiratory illness risk (odds ratio=0.81, 95% confidence interval 0.68-0.96). Median duration of all respiratory illnesses was 5 days for the fully breastfed infants during the first 6 months of life compared with a median of 6 days for not breastfed and partially breastfed infants. Multivariate analysis confirmed that breastfeeding significantly reduced the duration of respiratory illness. This pattern of reduced incidence of LRI and shorter duration of all respiratory illnesses suggests that breastfeeding reduces the severity of infant respiratory illnesses during the first 6 months of life.


The influence of distance and quality on utilisation of birthing services at health facilities in Eastern Region, Ghana.
Skilled birth attendance is the single most important intervention to reduce maternal mortality. However, studies have not used routinely collected health service birth data at named health facilities to understand the influence of distance and quality of care on childbirth service utilisation. Thus, this paper aims to quantify the influence of distance and quality of healthcare on utilisation of birthing services using routine health data in Eastern Region, Ghana. We used a spatial interaction model (a model that predicts movement from one place to another) drawing on routine birth data, emergency obstetric care surveys, gridded estimates of number of pregnancies and health facility location. We compared travel distances by sociodemographic characteristics and mapped movement patterns. A kilometre increase in distance significantly reduced the prevalence rate of the number of women giving birth in health facilities by 6.7%. Although quality care increased the number of women giving birth in health facilities, its association was insignificant. Women travelled further than expected to give birth at facilities, on average journeying 4.7 km beyond the nearest facility with a recorded birth. Women in rural areas travelled 4 km more than urban women to reach a hospital. We also observed that 56% of women bypassed the nearest hospital to their community. This analysis provides substantial opportunities for health planners and managers to understand further patterns of skilled birth service utilisation, and demonstrates the value of routine health data. Also, it provides evidence-based information for improving maternal health service provision by targeting specific communities and health facilities.


Vastus medialis motor unit properties in knee osteoarthritis.
Maximal isometric quadriceps strength deficits have been widely reported in studies of knee osteoarthritis (OA), however little is known about the effect of osteoarthritis knee pain on submaximal quadriceps neuromuscular function. The purpose of this study was to measure vastus medialis motor unit (MU) properties in participants with knee OA, during submaximal isometric contractions. Vastus medialis motor unit potential (MUP) parameters were assessed in 8 patients with knee OA and 8 healthy, sex and age-matched controls during submaximal isometric contractions (20% of maximum isometric torque). Unpaired t-tests were used to compare groups for demographic and muscle parameters. Maximum knee extension torque was ~22% lower in the OA group, a difference that was not statistically significantly (p = 0.11). During submaximal contractions, size related parameters of the needle MUPs (e.g. negative peak duration and amplitude-to-area ratio) were greater in the OA group (p < 0.05), with a rightward shift in the frequency distribution of surface MUP negative peak amplitude. MUP firing rates were significantly lower in the OA group (p < 0.05). Changes in MU recruitment and rate coding strategies in OA may reflect a chronic reinnervation process or a compensatory strategy in the presence of chronic knee pain associated with OA.


Foot massage. A nursing intervention to modify the distressing symptoms of pain and nausea in patients hospitalized with cancer.
This article describes the findings of an empirical study on the use of foot massage as a nursing intervention in patients hospitalized with cancer. The study was developed from the earlier work of Ferrell-Torry and Glick (1992). In a sample of 87 subjects, a 10-minute foot massage (5 minutes per foot) was found to have a significant immediate effect on the perceptions of pain, nausea, and relaxation when measured with a visual analog scale. The use of foot massage as a complementary method is recommended as a relatively simple nursing intervention for patients experiencing nausea or pain related to the cancer experience. Further research into its effectiveness in the management of these symptoms by the family at home is warranted.


Exaggerated sympathetic responses to bradykinin in spontaneously hypertensive rats.
Possible defects in blood pressure (BP) regulation were studied by recording responses to centrally-administered bradykinin. Pressor effects accompanied by increased sympathetic nerve activity were elicited by intracerebroventricular injections in intact rats, but significant differences between Kyoto-Wistar normotensive (KNR) and spontaneously hypertensive rats (SHR) were not detected. By contrast, intracarotid injections into cross-perfused head preparations consistently produced more prominent systemic effects in SHR than in KNR, and these differences became even more pronounced following carotid denervation. After destruction of central noradrenergic neurons in KNR by intracerebroventricular injection of 6-hydroxydopamine (6-OHDA), responses to bradykinin became the same as those in SHR. These results are in accord with the interpretation that alpha-adrenergic mechanisms for blood pressure regulation in supramedullary brain areas no longer function normally in SHR and that a similar dysfunction can be induced in KNR by pretreatment with 6-OHDA.


Development and pilot of an interprofessional pediatric resuscitation program for non-acute care inpatient providers.
Multiprofessional ward healthcare providers are generally unprepared to assemble and engage in the initial resuscitation of pediatric inpatients. This is important as the performance of these first-responders, in the several minutes prior to the arrival of acute care support, may have significant effects on overall patient outcome. Accordingly, we aimed to develop and pilot a training program intended for non-acute care inpatient providers, relevant to their working context. Using the latest theory and evidence in medical education, we created an interprofessional, entirely in-situ, simulation-based small-group activity. The activity was then piloted for four months with the goals of assessing perceived usefulness, as well as implementation factors such as participant accessibility and overall resource requirements. A total of 37 interprofessional (physician and nursing) staff were trained in 16 small group sessions over four months. Post-participation questionnaires revealed that the activity was perceived to be highly useful for their practice; especially the rapid cycle deliberate practice instructional method, and the increased focus on crisis resource management. Resource requirements were comparable to, and perhaps less than, existing acute care training programs. This project describes the preliminary steps taken in creating a curriculum intended to improve interprofessional resuscitation performance across an institution.


Interaction between emergency medical dispatcher and caller in suspected out-of-hospital cardiac arrest calls with focus on agonal breathing. A review of 100 tape recordings of true cardiac arrest cases.
One of the objectives of this study was to assess the emergency medical dispatchers (EMDs) ability for the identification and prioritisation of cardiac arrest (CA) cases, and offering and achievements of dispatcher-assisted bystander cardiopulmonary resuscitation (CPR). The other objective was to give an account of the frequency of agonal respiration in cardiac arrest calls and the caller's descriptions of breathing. Prospective study evaluating 100 tape recordings of the EMD calls of emergency medical service (EMS)-provided advanced life support- (ALS) cases, of out-of-hospital cardiac arrest. The quality of EMD-performed interviews was highly commended in 63% of cases, but insufficient or unapproved in the remaining 37%. The caller's state of mind was not a major problem for co-operation. Among the 100 cases, 24 were suspected to be unconscious and in respiratory arrest. A further 38 cases were presented as unconscious with abnormal breathing. In only 14 cases dispatcher-assisted bystander CPR was offered by the EMD, and in 11 of these it was attempted, and completed in eight. Only four of the cases were unconscious patients with abnormal breathing. The incidence of suspected agonal breathing was estimated to be approximately 30% and the descriptions were; difficulty, poorly, gasping, wheezing, impaired, occasional breathing. Among suspected cardiac arrest cases, EMDs offer CPR instruction to only a small fraction of callers. A major obstacle was the presentation of agonal breathing. Patients with a combination of unconsciousness and agonal breathing should be offered dispatcher-assisted CPR instruction. This might improve survival in out-of hospital cardiac arrest.


The cytoplasmic domain of rhesus cytomegalovirus Rh178 interrupts translation of major histocompatibility class I leader peptide-containing proteins prior to translocation.
Cytomegalovirus (CMV) efficiently evades many host immune defenses and encodes a number of proteins that prevent antigen presentation by major histocompatibility complex class I (MHC-I) molecules in order to evade recognition and killing of infected cells by cytotoxic CD8(+) T cells. We recently showed that rhesus CMV-specific Rh178 intercepts MHC-I protein translation before interference of MHC-I maturation by homologues of the human CMV US6 family. Here, we demonstrate that Rh178 localizes to the membrane of the endoplasmic reticulum, displaying a short luminal and large cytosolic domain, and that the membrane-proximal cytosolic portion is essential for inhibition of MHC-I expression. We further observed that Rh178 does not require synthesis of full-length MHC-I heavy chains but is capable of inhibiting the translation of short, unstable amino-terminal fragments of MHC-I. Moreover, the transfer of amino-terminal fragments containing the MHC-I signal peptide renders recipient proteins susceptible to targeting by Rh178. The cytosolic orientation of Rh178 and its ability to target protein fragments carrying the MHC-I signal peptide are consistent with Rh178 intercepting partially translated MHC-I heavy chains after signal recognition particle-dependent transfer to the endoplasmic reticulum membrane. However, interference with MHC-I translation by Rh178 seems to occur prior to SEC61-dependent protein translocation, since inhibition of MHC-I translocation by eeyarestatin 1 resulted in a full-length degradation intermediate that can be stabilized by proteasome inhibitors. These data are consistent with Rh178 blocking protein translation of MHC-I heavy chains at a step prior to the start of translocation, thereby downregulating MHC-I at a very early stage of translation.


Remdesivir: First Approval.
The antiviral agent remdesivir (Veklury®; Gilead Sciences), nucleotide analogue prodrug, has broad-spectrum activity against viruses from several families. Having demonstrated potent antiviral activity against coronaviruses in preclinical studies, remdesivir emerged as a candidate drug for the treatment of the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, during the current global pandemic. Phase III evaluation of remdesivir in the treatment of COVID-19 commenced in early 2020 and has thus far yielded promising results. In late May 2020, Taiwan conditionally approved the use of remdesivir in patients with severe COVID-19. This was followed by a rapid succession of conditional approvals in various countries/regions including the EU and Canada. Preceding these conditional approvals, an emergency use authorization for remdesivir had been granted in the USA (on 1 May 2020) and a special approval for emergency use was granted in Japan (on 7 May 2020). This article summarizes the milestones in the development of remdesivir leading to its first conditional approval for the treatment of COVID-19.


Restoration of insulin receptor improves diabetic phenotype in T2DM mice.
Type 2 diabetes mellitus (T2DM), also known as adult-onset diabetes, is characterized by ineffective insulin action due to insulin resistance in key metabolic tissues. Insulin receptor (IR) plays an important role in insulin signal transduction, defect of which has been considered the fundamental cause of T2DM. IR content reduction in diabetes is one key contributor to the defective insulin signaling and diabetes progression. Rescuing IR levels by transgenic complementation has not been considered as a treatment option because it is limited by uncontrollable expression level, tissue selectivity, or developmental defects. In the current study, we demonstrated that single-dose adeno-associated virus (AAV) vector delivered expression of human IR (hIR) in the liver of inducible IR-knockout mice and significantly improved the diabetic phenotype caused by IR deletion during adulthood. Such an approach was also applied, for the first time to our knowledge, to treating ob/ob mice, a model of severe T2DM attributed to superfluous calorie intake and insulin resistance. Interestingly, similar treatment with AAV-hIR had no obvious effect in healthy animals, indicative of low hypoglycemic risk as a consequence of potential excessive insulin action. The results described here support restoration of IR expression as a safe and effective T2DM therapeutic with a long-lasting profile.


Effect of preoperative vitreous status on visual outcomes following vitrectomy for epiretinal membrane repair.
To determine the correlation between clinically observed posterior vitreous detachment (PVD) and both surgical status of the hyaloid and the visual outcome following epiretinal membrane (ERM) surgery. Retrospective chart review. One hundred and nine eyes of 109 consecutive patients who underwent vitrectomy and repair of idiopathic ERM between January 2006 and September 2008. Preoperative exam notes from selected charts were reviewed for the presence or absence of a PVD. Operative notes were queried to whether the hyaloid was attached or detached at the onset of surgery. The postoperative visual acuity (VA) was correlated with the intraoperative status of the hyaloid. Preoperative observation of PVD was correlated with the hyaloid status at the time of vitrectomy. Hyaloid status did not impact postoperative VA. Eyes with an attached hyaloid at the onset of surgery had an average postoperative best corrected visual acuity (BCVA) of 20/60 and eyes with PVDs found during surgery had an average BCVA of 20/60(+1) (p < 0.66). Of the 109 patients, 72 had a preoperative fundoscopic examination whose results positively correlated with the intraoperative status of the hyaloid. Having an attached hyaloid did not have a significant impact on postoperative visual outcomes in eyes undergoing ERM when compared with outcomes for eyes having a detached hyaloids prior to surgery. Detection of a PVD on preoperative fundoscopic examination was highly sensitive for a "true" PVD, i.e., actual detachment of the posterior hyaloidmembrane as confirmed during surgery.


Evaluating the effects of a single copy of a mutation in the myostatin gene (c.*1232G>A) on carcass traits in crossbred lambs.
This study evaluated the effects of the ovine c.*1232G>A myostatin mutation (MM) on carcass traits in heterozygous crossbred lambs sired by Texel and Poll Dorset rams using ultrasound, CT scanning, carcass classification and VIA. In experiment 1, MM was associated with increased loin depth (+2.8%) and area (+3.2%). MM-carriers had significantly higher CT-estimated lean weight and proportion (2 to 4%) and muscle to bone ratio (by ~3%), in both experiments, and muscle to fat ratio (28%) in experiment 2. Muscle areas in three cross-sectional CT scans, were higher (2 to 5%) in MM-carriers. In experiment 2, fat-related measurements were significantly lower in MM-carrier lambs but this was not seen in experiment 1. A significant increase in muscle density, indicative of lower intramuscular fat, in MM-carriers shows that meat quality characteristics need attention. Carrying MM significantly decreased carcass fat scores. VIA did not detect any significant MM effects.


Influence of tablet splitting on content uniformity of lisinopril/hydrochlorthiazide tablets.
Dose-related adverse effects of medications are a major problem in modern medical practice. The "correct" dose, based on drug company guidelines in package inserts, may not be correct for many patients. Tablet splitting or dividing has been an accepted practice for many years as a means of obtaining the prescribed dose of medication. As model tablets for this investigation, two batches of lisinopril- hydrochlorothiazide scored tablets labeled to contain 20/12.5 mg were used. The aim of this study was to establish possible influence of tablet splitting on content uniformity of lisinopril/hydrochlorthiazide tablets. Determination of the content uniformity of lisinopril and hydrochlorthiazide in our batches, was carried out by HPLC method. The results of content uniformity studies for halves of tablets containing combination of lisinopril-hydrochlorthiazide (supposed to contain 50% of stated 20/12.5 mg in the whole tablet) were: 49.60 +/-3.29% and 49.29+/-0.60 % (lisinopril); 50.33+/-3.50% and 50.69+/-1.95% (hydrochlorthiazide) for batch I and II, respectively. We can conclude that the results obtained in this study support an option of tablet splitting, which is very important for obtaining the required dosage when a dosage form of the required strength is unavailable, and for better individualization of the therapy.


Understanding the normalization of telemedicine services through qualitative evaluation.
Qualitative studies can help us understand the "successes" and "failures" of telemedicine to normalize within clinical service provision. This report presents the development of a robust conceptual model of normalization processes in the implementation and development of telemedicine services. Retrospective and cumulative analysis of longitudinal qualitative data from three studies was undertaken between 1997 and 2002. Observation and semistructured interviews produced a substantial body of data relating to approximately 582 discrete data collection episodes. Data were analyzed separately in each of three studies. Cumulative analysis was conducted by constant comparison. (1) Implementation of telemedicine services depends on a positive link with a (local or national) policy level sponsor. (2) Adoption of telemedicine systems in service depends on successful structural integration so that development of organizational structures takes place. (3) Translation of telemedicine technologies into clinical practice depends on the enrollment of cohesive, cooperative groups. (4) Stabilization of telemedicine systems in practice depends on integration at the level of professional knowledge and practice, where clinicians are able to accommodate telemedicine through the development of new procedures and protocols. A rationalized linear diffusion model of "telehealthcare" is inadequate in assessing the potential for normalization, and the political, organizational, and "ownership" problems that govern the process of development, implementation, and normalization need to be accounted for. This report presents a model for assessing the potential for successful implementation of telehealthcare services. This model defines the requirements for the successful normalization of telemedicine systems in clinical practice.


Carnivorous fungi from Cretaceous amber.
Carnivorous fungi dating back to the age of the dinosaurs have been found fossilized in circa-100-million-year-old amber. The fossil fungi used hyphal rings as trapping devices and are preserved together with their prey, small nematodes. The excellent preservation in amber allowed comparison with extant groups: On the basis of the mode of ring formation and the dimorphic mode of life, the fossils cannot be assigned to any recent carnivorous fungus, providing evidence that different groups occupied this ecological niche in the Cretaceous and that trapping devices were developed independently multiple times in the course of Earth history.


Pseudohypertension in the elderly.
1. Direct intra-arterial blood pressure (radial artery) has been compared with indirect blood pressures using a regular sized adult cuff and a thigh cuff, with a mercury sphygmomanometer, in 24 hypertensive patients aged 62--84 years, and in 16 hypertensive patients aged 29--59 years. 2. The patients were studied because they were suspected of having a false elevation of their indirect blood pressure, since they had diastolic pressures over 100 mmHg, without hypertensive retinopathy, cardiac hypertrophy, or nephropathy. 3. Indirect diastolic pressure was falsely elevated by 30 mmHg or more in 12 out of 24 of the subjects over age 60, and in four of the 16 of those under age 60. Pseudohypertension (indirect diastolic greater than 100 mmHg, direct diastolic greater than 90 mmHg) was present in 12 subjects over age 60 and 5 under age 60. 4. Errors in indirect measurement of blood pressure are a serious problem, particularly in the elderly. Direct intra-arterial measurement may be useful in the management of hypertension.


Single-cell assessment of transcriptome alterations induced by Scriptaid in early differentiated human haematopoietic progenitors during ex vivo expansion.
Priming haematopoietic stem/progenitor cells (HSPCs) in vitro with specific chromatin modifying agents and cytokines under serum-free-conditions significantly enhances engraftable HSC numbers. We extend these studies by culturing human CD133+ HSPCs on nanofibre scaffolds to mimic the niche for 5-days with the HDAC inhibitor Scriptaid and cytokines. Scriptaid increases absolute Lin-CD34+CD38-CD45RA-CD90+CD49f+ HSPC numbers, while concomitantly decreasing the Lin-CD38-CD34+CD45RA-CD90- subset. Hypothesising that Scriptaid plus cytokines expands the CD90+ subset without differentiation and upregulates CD90 on CD90- cells, we sorted, then cultured Lin-CD34+CD38-CD45RA-CD90- cells with Scriptaid and cytokines. Within 2-days and for at least 5-days, most CD90- cells became CD90+. There was no significant difference in the transcriptomic profile, by RNAsequencing, between cytokine-expanded and purified Lin-CD34+CD38-CD45RA-CD49f+CD90+ cells in the presence or absence of Scriptaid, suggesting that Scriptaid maintains stem cell gene expression programs despite expansion in HSC numbers. Supporting this, 50 genes were significantly differentially expressed between CD90+ and CD90- Lin-CD34+CD38-CD45RA-CD49f+ subsets in Scriptaid-cytokine- and cytokine only-expansion conditions. Thus, Scriptaid treatment of CD133+ cells may be a useful approach to expanding the absolute number of CD90+ HSC, without losing their stem cell characteristics, both through direct effects on HSC and potentially also conversion of their immediate CD90- progeny into CD90+ HSC.


Probabilities in implicit learning.
The visual system possesses a remarkable ability in learning regularities from the environment. In the case of contextual cuing, predictive visual contexts such as spatial configurations are implicitly learned, retained, and used to facilitate visual search-all without one's subjective awareness and conscious effort. Here we investigated whether implicit learning and its facilitatory effects are sensitive to the statistical property of such implicit knowledge. In other words, are highly probable events learned better than less probable ones even when such learning is implicit? We systematically varied the frequencies of context repetition to alter the degrees of learning. Our results showed that search efficiency increased consistently as contextual probabilities increased. Thus, the visual contexts, along with their probability of occurrences, were both picked up by the visual system. Furthermore, even when the total number of exposures was held constant between each probability, the highest probability still enjoyed a greater cuing effect, suggesting that the temporal aspect of implicit learning is also an important factor to consider in addition to the effect of mere frequency. Together, these findings suggest that implicit learning, although bypassing observers' conscious encoding and retrieval effort, behaves much like explicit learning in the sense that its facilitatory effect also varies as a function of its associative strengths.


Mapping the evolution of adsorption of water in nanoporous silica by in situ solid-state 1H NMR spectroscopy.
A recently developed technique for carrying out in situ solid-state NMR studies of adsorption processes in nanoporous materials is applied to map the evolution of the adsorption of water on the widely used siliceous nanoporous host material MCM-41. The technique allows the very earliest stages of the adsorption process to be probed, and using solid-state 1H NMR, the time resolution is of the order of a few hundred seconds. This work reveals that different water environments are populated at different stages of the adsorption process and reveals insights regarding both the sequence in which these different environments become populated and the exchange of water molecules between these environments. The results also provide access to information on the kinetics of the adsorption process, revealing an initial regime of rapid water adsorption up to ca. 1 wt % water, followed by a regime of slower water adsorption. In both regimes, the amount of water adsorbed increases linearly with time. As demonstrated by these results, the approach employed in this work creates new opportunities for investigating, in unprecedented detail, adsorption processes in nanoporous materials.


Moderate Traumatic Brain Injury: Clinical Characteristics and a Prognostic Model of 12-Month Outcome.
Patients with moderate traumatic brain injury (TBI) often are studied together with patients with severe TBI, even though the expected outcome of the former is better. Therefore, we aimed to describe patient characteristics and 12-month outcomes, and to develop a prognostic model based on admission data, specifically for patients with moderate TBI. Patients with Glasgow Coma Scale scores of 9-13 and age ≥16 years were prospectively enrolled in 2 level I trauma centers in Europe. Glasgow Outcome Scale Extended (GOSE) score was assessed at 12 months. A prognostic model predicting moderate disability or worse (GOSE score ≤6), as opposed to a good recovery, was fitted by penalized regression. Model performance was evaluated by area under the curve of the receiver operating characteristics curves. Of the 395 enrolled patients, 81% had intracranial lesions on head computed tomography, and 71% were admitted to an intensive care unit. At 12 months, 44% were moderately disabled or worse (GOSE score ≤6), whereas 8% were severely disabled and 6% died (GOSE score ≤4). Older age, lower Glasgow Coma Scale score, no day-of-injury alcohol intoxication, presence of a subdural hematoma, occurrence of hypoxia and/or hypotension, and preinjury disability were significant predictors of GOSE score ≤6 (area under the curve = 0.80). Patients with moderate TBI exhibit characteristics of significant brain injury. Although few patients died or experienced severe disability, 44% did not experience good recovery, indicating that follow-up is needed. The model is a first step in development of prognostic models for moderate TBI that are valid across centers.