The value of bedside teaching in undergraduate medical education: a literature review.
This article was migrated. The article was marked as recommended. Background: Bedside teaching used to be an integral component of undergraduate medical education. In recent times, however, there has been a steady decline in the use of bedside teaching. This has occurred despite students, clinicians and patients viewing bedside teaching as valuable. Aims: This review aims to appraise the current literature surrounding the perspectives in bedside teaching and evaluate its role within modern medical education. Methods: A literature search was conducted in PubMed, Cochrane Library, and Ovid to identify appropriate studies. The journal articles were obtained by conducting sensitive and appropriate searches using keywords. All studies were examined comprehensively by the authors for suitability for inclusion. Results: 2,770 records were identified from the initial search. An additional 3 records were identified after discussion with experts in the field. 583 duplicates were identified in the pool of records initially sourced. Of the remaining 2,190 records, 1,930 were excluded after inclusion and exclusion criteria were applied to their titles and abstracts. A further 252 records were excluded from the remaining 260 records after inclusion and exclusion criteria were applied to their full-texts. The remaining eight articles were reviewed by both authors and were deemed suitable for inclusion to the review. Conclusion: The review showed that there is evidence in the literature to show that students, clinicians, and patients regard bedside teaching as beneficial. Discussions highlighted that bedside teaching can aid competency-based education models and cannot be replaced by simulation-based education. These results illustrate that, while there is evidence to show that bedside teaching holds value in medical education today, further studies should be conducted aiming to display long-term outcomes of bedside teaching.


Delayed shrinkage of the brain after ischemic stroke: preliminary observations with voxel-guided morphometry.
The most important effect of cerebral ischemia is brain infarction. In this magnetic resonance imaging (MRI) study, the authors aimed at assessing postischemic brain atrophy. Ten patients suffering from their first acute cerebral ischemia in the territory of the middle cerebral artery were studied retrospectively. Three-dimensional MRI volume scans were recorded in the acute and chronic stage after infarction and analyzed voxel by voxel intraindividually with the newly developed voxel-guided morphometry. Shrinkage of brain tissue was detected in all patients, not only in the perilesional cortical structures but also in contralateral homolog cortex areas and subcortically in the striatum and thalamus. This secondary shrinkage was not related to the size of the infarcts or to the clinical outcome of patients. Our study suggests that delayed brain atrophy after acute ischemic stroke involved areas anatomically connected with the ischemic brain lesion but nevertheless was accompanied by a simultaneous improvement of the neurological deficit.


[Extragenital diseases in geriatric-gynecological surgical cases].
Of the surgical cases accumulated in 18 departments of Obstetrics and Gynecology in West Berlin from 1960 through 1969 6662 major procedures were performed on women of at least 60 years of age. In 282 cases (4,2%) surgery was carried out for primarily extragenital gynecological disorders: 119 malignant tumors, 16 benign tumors, and 147 other diseases of extragenital orgin. The postoperative mortality of these patients (89 deaths; 29,8%) was markedly higher than that observed for the whole group (7,7%). This difference may have been caused by the greater extensiveness of the underlying disease in the former group as well as the unsatisfactory utilization of preoperative diagnostic procedures found in some instances. The cooperation with surgeons prior to and during surgery may still be improved upon. In 98 patients (1,5%) operative procedures for additional surgical disorders were performed simultaneously. Especially in those cases where additional appendectomies were carried out, it appears that total abdominal hysterectomy and bilateral salpingo-oophorectomy might have been the treatment of choice for the underlying disease.


Concomitant occurrence of subchondral cyst and ruptured anterior crucial ligament at knee joint: new findings by MRI.
The magnetic resonance imaging (MRI) in 4 cases of subchondral cyst at the knee joint region, were acquired from a 1.5 Tesla imager. We found a high incidence of concomitant occurrence of subchondral cysts with a ruptured anterior cruciate ligament (ACL) in all of these cases. The 2 men and 2 women, had an average age of 35. Clinically, they complained of dull knee pain and mild instability. Conventional radiography detected subchondral cysts in 3 of them, while MRI disclosed that all of the subchondral cysts were at the tibial plateau, close to the intercondyloid eminence. To date, MRI is the only imaging modality which can depict the concomitant occurrence of a subchondral cyst and a ruptured anterior cruciate ligament at the knee joint. Whether these subchondral cysts were the consequences of the ruptured anterior cruciate ligaments as one of the causes in addition to synovial fluid intrusion and bony contusion, need further clinical observation and investigation.


COVID-19 vaccination implementation in 52 African countries: trajectory and implications for future pandemic preparedness.
To end the COVID-19 pandemic, the WHO set a goal in 2021 to fully vaccinate 70% of the global population by mid-2022. We projected the COVID-19 vaccination trajectory in 52 African countries and compared the projected to the 'actual' or 'observed' coverage as of December 2022. We also estimated the required vaccination speed needed to have attained the WHO 70% coverage target by December 2022. We obtained publicly available, country-reported daily COVID-19 vaccination data, covering the initial 9 months following the deployment of vaccines. We used a deterministic compartmental Susceptible-Exposed-Infectious-Recovered-type model and fit the model to the number of COVID-19 cases and vaccination coverage in each African country using a Markov chain Monte Carlo approach within a Bayesian framework. Only nine of the 52 African countries (Tunisia, Cabo Verde, Lesotho, Mozambique, Rwanda, Seychelles, Morocco, Botswana and Mauritius) were on track to achieve full COVID-19 vaccination coverage rates ranging from 72% to 97% by the end of December 2022, based on their progress after 9 months of vaccine deployment. Of the 52 countries, 26 (50%) achieved 'actual' or 'observed' vaccination coverage rates within ±10 percentage points of their projected vaccination coverage. Among the countries projected to achieve <30% by December 2022, nine of them (Chad, Niger, Nigeria, South Sudan, Tanzania, Somalia, Zambia, Sierra Leone and Côte d'Ivoire) achieved a higher observed coverage than the projected coverage, ranging from 12.3 percentage points in South Sudan to 35.7 percentage points above the projected coverage in Tanzania. Among the 52 countries, 83% (43 out of 52) needed to at least double their vaccination trajectory after 9 months of deployment to reach the 70% target by December 2022. Our findings can guide countries in planning strategies for future global health emergencies and learning from each other, especially those that exceeded expectations and made significant progress towards the WHO's 2022 COVID-19 vaccination target despite projected poor coverage rates.


Characterization of durum wheat resistance against leaf rust under climate change conditions of increasing temperature and [CO2].
Durum wheat cultivation in Mediterranean regions is threatened by abiotic factors, mainly related to the effects of climate change, and biotic factors such as the leaf rust disease. This situation requires an in-depth knowledge of how predicted elevated temperatures and [CO2] will affect durum wheat-leaf rust interactions. Therefore, we have characterised the response of one susceptible and two resistant durum wheat accessions against leaf rust under different environments in greenhouse assays, simulating the predicted conditions of elevated temperature and [CO2] in the far future period of 2070-2099 for the wheat growing region of Cordoba, Spain. Interestingly, high temperature alone or in combination with high [CO2] did not alter the external appearance of the rust lesions. However, through macro and microscopic evaluation, we found some host physiological and molecular responses to infection that would quantitatively reduce not only pustule formation and subsequent infection cycles of this pathogen, but also the host photosynthetic area under these predicted weather conditions, mainly expressed in the susceptible accession. Moreover, our results suggest that durum wheat responses to infection are mainly driven by temperature, being considered the most hampering abiotic stress. In contrast, leaf rust infection was greatly reduced when these weather conditions were also conducted during the inoculation process, resembling the effects of possible heat waves not only in disease development, but also in fungal germination and penetration success. Considering this lack of knowledge in plant-pathogen interactions combined with abiotic stresses, the present study is, to the best of our knowledge, the first to include the effects of the expected diurnal variation of maximum temperature and continuous elevated [CO2] in the durum wheat-leaf rust pathosystem.


Glutathione, carbohydrate and other metabolites of Larix olgensis A. Henry reponse to polyethylene glycol-simulated drought stress.
Drought stress in trees limits their growth, survival, and productivity and it negatively affects the afforestation survival rate. Our study focused on the molecular responses to drought stress in a coniferous species Larix olgensis A. Henry. Drought stress was simulated in one-year-old seedlings using 25% polyethylene glycol 6000. The drought stress response in these seedlings was assessed by analyzing select biochemical parameters, along with gene expression and metabolite profiles. The soluble protein content, peroxidase activity, and malondialdehyde content of L. olgensis were significantly changed during drought stress. Quantitative gene expression analysis identified a total of 8172 differentially expressed genes in seedlings processed after 24 h, 48 h, and 96 h of drought stress treatment. Compared with the gene expression profile of the untreated control, the number of up-regulated genes was higher than that of down-regulated genes, indicating that L. olgensis mainly responded to drought stress through positive regulation. Metabolite analysis of the control and stress-treated samples showed that under drought stress, the increased abundance of linoleic acid was the highest among up-regulated metabolites, which also included some saccharides. A combined analysis of the transcriptome and metabolome revealed that genes dominating the differential expression profile were involved in glutathione metabolism, galactose metabolism, and starch and sucrose metabolism. Moreover, the relative abundance of specific metabolites of these pathways was also altered. Thus, our results indicated that L. olgensis prevented free radical-induced damage through glutathione metabolism and responded to drought through sugar accumulation.


Vitamin D insufficiency among children and adolescents living in Tehran, Iran.
Vitamin D is important for calcium absorption and skeletal growth. Vitamin D insufficiency (VDI) is a prevalent health problem in children. A study was performed to determine the prevalence of VDI in healthy children living in Tehran, Iran. In a cross-sectional study, 963 students (424 boys and 539 girls) aged 7-18 years were selected by random sampling. Serum 25-hydroxyvitamin D (25-OHD), calcium, alkaline phosphatase and phosphorus were measured. VDI was defined as serum 25-OHD <20 ng/ml. Prevalence of VDI was 53.6% in girls and 11.3% in boys. VDI in female students was about five times more common than males (p < 0.000001). VDI in children and adolescent girls is a health problem not only for these age-groups but also for the next generation to come. Encouraging girls to have more sun exposure, fortification of foods and prescription of supplemental vitamin D are recommended.


MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer.
The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment.Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 205-15. ©2017 AACR.


Comparative renal tubular toxicity of chemotherapy regimens including ifosfamide in patients with newly diagnosed sarcomas.
The aim of this study was to assess renal tubular toxicity (RTT) of ifosfamide-containing regimens (ICR) in patients with newly diagnosed sarcomas at St. Jude Children's Research Hospital. The authors reviewed the records of 199 patients receiving ICR at St. Jude between June 1986 and December 31, 1994 for evidence of RTT. Their median age was 13.3 years (range 1.2-24.8); 150 patients were white and 112 were male patients. Diagnoses included osteosarcoma (n = 82), Ewing sarcoma (n = 82), rhabdomyosarcoma (n = 28), and a group of other tumors (n = 7). The authors estimated the proportion of patients with severe RTT during the first five cycles of ICR and within 1 year after therapy for three groups of patients receiving ifosfamide (IFOS, n = 110), ifosfamide/cisplatin (IFOS/CDDP, n = 51), and ifosfamide/carboplatin (IFOS/CARBO, n = 38). The IFOS/CDDP patients received three cycles of IFOS before receiving CDDP and received only 200 mg/m2 by cycle 5, whereas the IFOS/CARBO patients received both agents simultaneously. The authors compared the probability of severe RTT among treatment groups using a generalized linear model for the first five cycles of ICR, as well as the probability of severe RTT within 1 year after therapy among treatment groups for patients receiving all prescribed IFOS using an exact chi-square test with pairwise comparisons when the three-way P value was less than 0.10. The proportion of patients with severe RTT during the first three cycles of ICR was significantly greater in the IFOS/CARBO group than in the other two. Although the proportion of patients with severe RTT in the IFOS/CDDP group increased during cycles 4/5, the proportion of patients with severe RTT remained significantly greater in the IFOS/ CARBO group. Within 1 year after therapy, the proportion of patients with severe RTT differed among the three groups, and pairwise comparisons revealed a significant difference between the IFOS and the IFOS/CDDP group. Severe RTT developed in four IFOS/CDDP patients more than 1 year after therapy, suggesting a long-term effect of CDDP on tubular function. Chemotherapy regimens including IFOS/ CARBO produce severe acute RTT more frequently than regimens including IFOS or IFOS/CDDP. Patients receiving IFOS/ CDDP appear at risk for delayed RTT. Long-term follow-up of these patients is essential to assess whether the number of patients receiving IFOS/CDDP with severe RTT continues to increase over time and to evaluate the long-term significance of these abnormalities.


The features of muscle activity during chair standing and sitting motion in submerged condition.
This study aimed to measure muscle activity and motion kinematics during chair-based exercises under submerged and non-submerged conditions. Twelve healthy men performed chair-based standing and sitting movements. Surface electrodes were attached at the tibialis anterior, gastrocnemius, rectus femoris, biceps femoris, rectus abdominis, and erector spinae. The ankle, knee, and hip joint angles and forward inclination angle of the trunk segment in the sagittal plane were calculated. The mean muscle activities during both movements in the submerged condition for the entire motion were lower than those in the non-submerged condition except in the tibialis anterior and biceps femoris during the sitting movement (in the standing exercise, rectus femoris: 14.1% and 5.2%; and erector spinae: 18.3% and 13.6% in non-submerged and submerged conditions, respectively; and in the sitting exercise, rectus femoris: 12.1% and 4.5% and erector spinae: 12.9% and 9.9% in the non-submerged and submerged conditions, respectively). However, the integrated muscle activity in submerged conditions was similar or higher to that in non-submerged conditions during both movements, except for the rectus femoris. This was mainly due to the increased duration of motion (44.3% and 39.9% longer for standing and sitting exercises in submerged conditions, respectively, compared with non-submerged conditions). The hip joint flexion at the beginning and end of movement and forward inclination angles of the trunk segment at the beginning of the movement in the submerged condition were larger than those in the non-submerged condition during both movements (hip: 126.1° and 111.5° at the beginning, 182.3° and 178.4° at the end and trunk: 2.7° and 17.4° at the beginning in non-submerged and submerged conditions for the standing exercise, respectively; hip: 182.4° and 178.0° at the beginning, 125.9° and 111.1° at the end and trunk: 2.2° and 16.9° at the end in non-submerged and submerged conditions for the sitting exercise, respectively). Reduced or similar muscle activity but similar or higher muscular effort was observed in the submerged condition for all the muscles except the rectus femoris, with the upper body inclined forward. These findings could have beneficial implications for the prescription of exercise and rehabilitation regimens.


Determination of urinary 8-hydroxy-2'-deoxyguanosine by a combination of on-line molecularly imprinted monolithic solid phase microextraction with high performance liquid chromatography-ultraviolet detection.
8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a sensitive biomarker for DNA oxidative damage. However, its determination in human urine is confounded by trace level and complex matrix. In this study, a new configuration of on-line solid phase microextraction coupled to high performance liquid chromatography-ultraviolet detection was established with molecularly imprinted monolithic column as extraction sorbent. The tailor made monolith exhibited high extraction efficiency with the enrichment factor 101.84 for 8-OHdG owing to its special porous structure and inherent selectivity. Under optimal condition, appreciable sensitivity had been achieved for this incorporation with limit of detection 2.04 nmol/L (S/N = 3) and limit of quantification 7.12 nmol/L (S/N = 10), respectively. Precise determination with wide range linearity (0.007-5.00 μmol/L) afforded a practical alternative in urinary 8-OHdG analysis and 107 different subjects had been successfully analyzed. This newly developed method embodied useful prospect for the investigation of DNA oxidative damage with less expense, convenient maintenance and ease of operation.


The efficiency of contact lens care regimens on protein removal from hydrogel and silicone hydrogel lenses.
To investigate the efficiency of lysozyme and albumin removal from silicone hydrogel and conventional contact lenses, using a polyhexamethylene biguanide multipurpose solution (MPS) in a soaking or rubbing/soaking application and a hydrogen peroxide system (H(2)O(2)). Etafilcon A, lotrafilcon B and balafilcon A materials were incubated in protein solutions for up to 14 days. Lenses were either placed in radiolabeled protein to quantify the amount deposited or in fluorescent-conjugated protein to identify its location, using confocal laser scanning microscopy (CLSM). Lenses were either rinsed with PBS or soaked overnight in H(2)O(2) or MPS with and without lens rubbing. After 14 days lysozyme was highest on etafilcon A (2,200 mug) >balafilcon A (50 microg) >lotrafilcon B (9.7 microg) and albumin was highest on balafilcon A (1.9 microg) =lotrafilcon B (1.8 microg) >etafilcon A (0.2 microg). Lysozyme removal was greatest for balafilcon A >etafilcon A >lotrafilcon B, with etafilcon A showing the most change in protein distribution. Albumin removal was highest from etafilcon A >balafilcon A >lotrafilcon B. H(2)O(2) exhibited greater lysozyme removal from etafilcon A compared to both MPS procedures (p<0.001) but performed similarly for lotrafilcon B and balafilcon A lenses (p>0.62). Albumin removal was solely material specific, while all care regimens performed to a similar degree (p>0.69). Protein removal efficiency for the regimens evaluated depended on the lens material and protein type. Overall, lens rubbing with MPS before soaking did not reduce the protein content on the lenses compared to nonrubbed lenses (p=0.89).


Acute subdural hematoma. Spontaneous forms of arterial origin.
3 cases of acute subdural hematoma associated with bleeding from cortical arteries are described. There was no history of trauma. Referred cases in the literature and the possible mechanisms are discussed.


Low kV versus dual-energy virtual monoenergetic CT imaging for proven liver lesions: what are the advantages and trade-offs in conspicuity and image quality? A pilot study.
Single-energy low tube potential (SE-LTP) and dual-energy virtual monoenergetic (DE-VM) CT images both increase the conspicuity of hepatic lesions by increasing iodine signal. Our purpose was to compare the conspicuity of proven liver lesions, artifacts, and radiologist preferences in dose-matched SE-LTP and DE-VM images. Thirty-one patients with 72 proven liver lesions (21 benign, 51 malignant) underwent full-dose contrast-enhanced dual-energy CT (DECT). Half-dose images were obtained using single tube reconstruction of the dual-source SE-LTP projection data (80 or 100 kV), and by inserting noise into dual-energy projection data, with DE-VM images reconstructed from 40 to 70 keV. Three blinded gastrointestinal radiologists evaluated half-dose SE-LTP and DE-VM images, ranking and grading liver lesion conspicuity and diagnostic confidence (4-point scale) on a per-lesion basis. Image quality (noise, artifacts, sharpness) was evaluated, and overall image preference was ranked on per-patient basis. Lesion-to-liver contrast-to-noise ratio (CNR) was compared between techniques. Mean lesion size was 1.5 ± 1.2 cm. Across the readers, the mean conspicuity ratings for 40, 45, and 50 keV half-dose DE-VM images were superior compared to other half-dose image sets (p < 0.0001). Per-lesion diagnostic confidence was similar between half-dose SE-LTP compared to half-dose DE-VM images (p ≥ 0.05; 1.19 vs. 1.24-1.32). However, SE-LTP images had less noise and artifacts and were sharper compared to DE-VM images less than 70 keV (p < 0.05). On a per-patient basis, radiologists preferred SE-LTP images the most and preferred 40-50 keV the least (p < 0.0001). Lesion CNR was also higher in SE-LTP images than DE-VM images (p < 0.01). For the same applied dose level, liver lesions were more conspicuous using DE-VM compared to SE-LTP; however, SE-LTP images were preferred more than any single DE-VM energy level, likely due to lower noise and artifacts.


FDG PET in the differential diagnosis of parkinsonian disorders.
The differential diagnosis of parkinsonian disorders can be challenging, especially early in the disease course. PET imaging with [(18)F]-fluorodeoxyglucose (FDG) has been used to identify characteristic patterns of regional glucose metabolism in patient cohorts with idiopathic Parkinson's disease (PD), as well as variant forms of parkinsonism such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBGD). In this study, we assessed the utility of FDG PET in the differential diagnosis of individual patients with clinical parkinsonism. 135 parkinsonian patients were referred for FDG PET to determine whether their diagnosis could be made accurately based upon their scans. Imaging-based diagnosis was obtained by visual assessment of the individual scans and also by computer-assisted interpretation. The results were compared with 2-year follow-up clinical assessments made by independent movement disorders specialists who were blinded to the original PET findings. We found that blinded computer assessment agreed with clinical diagnosis in 92.4% of all subjects (97.7% early PD, 91.6% late PD, 96% MSA, 85% PSP, 90.1% CBGD, 86.5% healthy control subjects). Concordance of visual inspection with clinical diagnosis was achieved in 85.4% of the patients scanned (88.4% early PD, 97.2% late PD, 76% MSA, 60% PSP, 90.9% CBGD, 90.9% healthy control subjects). This study demonstrates that FDG PET performed at the time of initial referral for parkinsonism accurately predicted the clinical diagnosis of individual patients made at subsequent follow-up. Computer-assisted methodologies may be particularly helpful in situations where experienced readers of FDG PET images are not readily available.


Speed-dependent contribution of callosal pathways to ipsilateral movements.
Transcallosal inhibitory interactions between primary motor cortices are important to suppress unintended movements in a resting limb during voluntary activation of the contralateral limb. The functional contribution of transcallosal inhibition targeting the voluntary active limb remains unknown. Using transcranial magnetic stimulation, we examined transcallosal inhibition [by measuring interhemispheric inhibition (IHI) and the ipsilateral silent period (iSP)] in the preparatory and execution phases of isotonic slower self-paced and ballistic movements performed by the ipsilateral index finger into abduction and the elbow into flexion in intact humans. We demonstrate decreased IHI in the preparatory phase of self-paced and ballistic index finger and elbow movements compared to rest; the decrease in IHI was larger during ballistic than self-paced movements. In contrast, in the execution phase, IHI and the iSP increased during ballistic compared to self-paced movements. Transcallosal inhibition was negatively correlated with reaction times in the preparatory phase and positively correlated with movement amplitude in the execution phase. Together, our results demonstrate a widespread contribution of transcallosal inhibition to ipsilateral movements of different speeds with a functional role during rapid movements; at faster speeds, decreased transcallosal inhibition in the preparatory phase may contribute to start movements rapidly, while the increase in the execution phase may contribute to stop the movement. We argue that transcallosal pathways enable signaling of the time of discrete behavioral events during ipsilateral movements, which is amplified by the speed of a movement.


Junin virus infection of Callithrix jacchus: pathologic features.
Infection of Callithrix jacchus, a New World primate, with the prototype strain of Junin virus produced a severe disease. The animals developed multifocal hemorrhages and characteristic microscopic lesions such as meningoencephalitis, interstitial pneumonia, lymphocytic depletion of lymphatic tissue, hepatocytic necrosis, and a variable decrease in bone marrow cellularity. High virus concentrations correlated with lesions, and with the presence of viral antigenic determinants as revealed by immunofluorescent methods. With the exception of central nervous system damage, the morphological features and immunohistochemical and viral findings were similar to those recorded in human Argentine hemorrhagic fever.


Development of a Bioimpedance and sEMG Fusion Sensor for Gait Phase Detection: Validation with a Transtibial Amputee.
Accurate gait phase detection is crucial for safe and efficient robotic prosthesis control in lower limb amputees. Several sensing modalities, including mechanical and biological signals, have been proposed to improve the accuracy of gait phase detection. In this paper, we propose a bioimpedance and sEMG fusion sensor for high-accuracy gait phase detection. We fabricated a wearable band-type sensor for multichannel bioimpedance and sEMG measurement, and we conducted gait experiments with a transtibial amputee to obtain biosignal data. Finally, we trained a deep-learning-based gait phase detection algorithm and evaluated its detection performance. Our results showed that using both bioimpedance and sEMG yielded the highest accuracy of 95.1%. Using only sEMG yielded a higher accuracy (90.9%) than that using only bioimpedance (85.1%). Therefore, we conclude that using both signals simultaneously is beneficial for improving the accuracy of gait phase detection. In addition, the proposed sensor can be applied to several applications by improving the accuracy of motion intention detection.


Adaptive Design Practice at the Center for Devices and Radiological Health (CDRH), January 2007 to May 2013.
Adaptive designs have generated great interest in the clinical trial community as a result of their versatility and efficiency. Recently, the Center for Devices and Radiological Health (CDRH) at the US Food and Drug Administration (FDA) surveyed all adaptive design applications submitted between 2007 and May 2013 for regulatory review. In this paper, we discuss the overall results and findings that emerged from an in-depth examination of the submissions. We summarize the current status of adaptive designs used in medical device studies. We also identify some of the lessons learned and common pitfalls that we encountered in our review of the designs.


Tyrosine motions in relation to the ferric spin equilibrium of cytochrome P-450cam.
Second derivative spectroscopy was used to determine the percentage of tyrosine residues that are exposed to solvent in cytochrome P-450cam isolated from Pseudomonas putida. The ratio between two peak to trough second derivative absorbance differences has been shown to be dependent on the polarity of the microenvironment surrounding tyrosine residues [Ragone, R., Colonana, G., Balestrieri, C., Servillo, L., & Irace, G. (1984) Biochemistry 23, 1871]. With a number of camphor analogues that independently vary the spin equilibrium of the ferric cytochrome P-450 cam, experiments have demonstrated that the percentage of tyrosine residues exposed to solvent is linearly dependent on the percentage of ferric high-spin species present. This is not simply a function of the extent of substrate binding since in all cases the substrate concentration was sufficient to ensure saturation of the cytochrome. The local microenvironment of approximately one tyrosine residue appears to be linearly correlated with the percentage of ferric high-spin cytochrome. Structural studies of cytochrome P-450cam using small-angle X-ray scattering [Lewis, B. A., & Sligar, S. G. (1983) J. Biol. Chem. 258, 3599] and high-pressure difference spectroscopy [Fisher, M. T., Scarlata, S. F., & Sligar, S. G. (1985) Arch. Biochem. Biophys. 240, 456] imply that global conformational changes linked to the spin equilibria are small. Together with the data reported herein, these results suggest that one tyrosine residue is involved in a conformational change that is directly linked with the spin equilibrium.


Association of maternal genital and reproductive infections with verbal memory and motor deficits in adult schizophrenia.
Maternal exposure to genital and reproductive infections has been associated with schizophrenia in previous studies. Impairments in several neuropsychological functions, including verbal memory, working memory, executive function, and fine-motor coordination occur prominently in patients with schizophrenia. The etiologies of these deficits, however, remain largely unknown. We aimed to assess whether prospectively documented maternal exposure to genital/reproductive (G/R) infections was related to these neuropsychological deficits in offspring with schizophrenia and other schizophrenia spectrum disorders. The cases were derived from a population-based birth cohort; all cohort members belonged to a prepaid health plan. Cases were assessed for verbal memory, working memory, executive function, and fine-motor coordination. Compared to unexposed cases, patients exposed to maternal genital/reproductive infection performed more poorly on verbal memory, fine-motor coordination, and working memory. Stratification by race revealed associations between maternal G/R infection and verbal memory and fine-motor coordination for case offspring of African-American mothers, but not for case offspring of White mothers. Significant infection-by-race interactions were also observed. Although independent replications are warranted, maternal G/R infections were associated with verbal memory and motor function deficits in African-American patients with schizophrenia.


Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities.
Breast cancer is the most frequent cancer among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early-stage breast cancer. Cancer stem-like cells (CSCs) that are endowed with high plasticity and self-renewal properties have been shown to play a key role in breast cancer development, progression, and metastasis. A subpopulation of CSCs that combines tumor-initiating capacity and a dormant/quiescent/slow cycling status is present throughout the clinical history of breast cancer patients. Dormant/quiescent/slow cycling CSCs are a key component of tumor heterogeneity and they are responsible for chemoresistance, tumor migration, and metastatic dormancy, defined as the ability of CSCs to survive in target organs and generate metastasis up to two decades after diagnosis. Understanding the strategies that are used by CSCs to resist conventional and targeted therapies, to interact with their niche, to escape immune surveillance, and finally to awaken from dormancy is of key importance to prevent and treat metastatic cancer. This review summarizes the current understanding of mechanisms involved in CSCs chemoresistance, dissemination, and metastasis in breast cancer, with a particular focus on dormant cells. Finally, we discuss how advancements in the detection, molecular understanding, and targeting of dormant CSCs will likely open new therapeutic avenues for breast cancer treatment.


Three-dimensional motion analysis of lumbopelvic rhythm during lateral trunk bending.
[Purpose] To examine the variations in the lumbopelvic rhythm and lumbar-hip ratio in the frontal plane. [Subjects and Methods] Markers were placed on the T10 and T12 spinous processes, bilateral paravertebral muscles at the T11 level, the pelvis, and the femur. Lumbar spine and hip angles were measured during lateral trunk bending using three-dimensional motion analysis. Data from the trunk lateral bending movement were categorized into descending (start of hip movement to when the hip angle reached its maximum value) and ascending (from the maximum hip angle to the end of movement) phases. The lumbar-hip ratio was calculated as the ratio of the lumbar spine angle to the hip angle. [Results] The lumbar-hip ratio decreased from 5.9 to 3.6 in the descending phase, indicating lumbar spinal movement was less than hip movement. In the ascending phase, the lumbar-hip ratio was reversed. The lumbopelvic rhythm was better expressed by a cubic or quadratic function rather than a linear function. These functions indicate that when the hip inclines by 1° that the lumbar spine bends laterally by 2.4°. [Conclusion] The lumbopelvic rhythm and lumbar-hip ratio indicate lumbar lateral bending instead of a limitation of hip inclination.


SKDCPM algorithm can improve the single-trial decoding performance of very similar error-related potentials.
Error related potential (ErrP) is an effective control signal for the brain-computer interface (BCI). Current ErrP decoding methods can only distinguish right and wrong mental states. However, in real scenarios, error conditions often contain more detailed information, such as the degree of error, which would induce very similar ErrPs. Distinguishing such ErrPs effectively is of vital importance to provide more detailed information for optimizing BCIs. Hereto, a major challenge is the EEG differences of very similar ErrPs are very small. Thus, it is necessary to develop new efficient method for decoding very similar ErrPs. This study newly proposed an algorithm named shrinkage discriminant canonical pattern matching (SKDCPM), and compared its decoding results with the linear discriminant analysis (LDA), shrinkage LDA (SKLDA), stepwise LDA (SWLDA), Bayesian LDA (BLDA) and the DCPM, which were algorithms commonly used for ErrP decoding. A data set of 18 subjects was built, it had four conditions, i.e., right (0°), errors with varying degrees, i.e., 45°, 90°, 180° deviation from the predicted direction. As a result, the SKDCPM had high balanced accuracy (BACC) in right-wrong classification (0° vs. others). More importantly, it achieved a grand averaged BACC of 69.54% with the highest up to 74.25%, which outperformed all the other algorithms in very similar ErrPs decoding (45° vs. 90° vs. 180°) significantly. This study could provide new decoding methods for developing the ErrP-based BCI system.


Langerhans cells in organ-cultured corneas.
We examined the effect of corneal preservation in organ culture at 34 degrees C on Langerhans cells in murine and human corneas. The presence of Langerhans cells was demonstrated by an adenosine triphosphatase stain. Langerhans cells were identified on fresh corneas and on corneas that had been in organ culture for one week or less. However, Langerhans cells were not found on most corneas after the second to third week in culture. The absence of Langerhans cells was found to be directly related to the condition of the corneal epithelium. During the second and occasionally as late as the third week in culture, the superficial layers of epithelium are sloughed. Examination of the corneas lacking Langerhans cells disclosed Langerhans cells in the sloughed epithelium. The results demonstrate that most corneas preserved in organ culture at 34 degrees C do not contain Langerhans cells at the time of transplantation.


ERK5 positively regulates cigarette smoke-induced urocystic epithelial-mesenchymal transition in SV‑40 immortalized human urothelial cells.
Bladder cancer is universally acknowledged as a significant public health issue. Abundant evidence shows that cigarette smoke (CS) is the primary risk factor for bladder cancer. However, the mechanism of CS-induced bladder cancer has not been fully elucidated. CS-induced epithelial-mesenchymal transition (EMT) is critically involved in cell malignant transformation. The role of ERK5, the lesser studied member of the MAPK family, in regulating CS-triggered EMT has not yet been investigated. The objective of the present study was to investigate the regulatory role of ERK5 in CS-induced urocystic EMT. SV-40 immortalized normal human urothelial cells (SV-HUC-1) were used as in vitro CS exposure models. EMT phenotypic alterations were assessed by changes in cell morphology, invasive capacity, as well as expression of epithelial and mesenchymal markers. Protein and mRNA expression levels were analyzed by western blotting and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). ERK5 inhibition studies were performed with a specific inhibitor. Exposure of SV-HUC-1 cells to CS induced morphological change, enhanced invasive capacity, reduced epithelial marker expression and increased mesenchymal marker expression. Importantly, we demonstrated for the first time that ERK5 positively regulated CS-mediated EMT in urothelial cells, as evidenced by the findings that CS promoted ERK5 activation, and that the CS-triggered alteration in the EMT phenotype was reversed by ERK5 inhibition.


Circulating and intra-articular immune complexes in patients with rheumatoid arthritis. Correlation of 125I-Clq binding activity with clinical and biological features of the disease.
The correlation between the incidence and level of immune complexes in serum and synovial fluid and the various clinical and biological manifestations of rheumatoid arthritis has been studied. Immune complexes were quantitated using a sensitive radioimmunoassay, the 125I-Clq binding test, in unheated native sera and synovial fluids from 50 patients with seropositive (RA +) and 45 with seronegative (RA -) rheumatoid arthritis, 17 with other inflammatory arthritis, and 37 with degenerative and post-traumatic joint disease. The following observations were made: (a) when compared to the results from patients with degenerative and post-traumatic joint diseases, the 125I-Clq binding activity (Clq-BA) in synovial fluid was found to be increased (by more than 2 SD) in most of the patients with RA + (80%) and RA - (71%) and in 29% of patients with other inflammatory arthritis; the serum Clq-BA was also frequently increased in both RA + (76%) and RA - (49%) patients, but only exceptionally in patients with other inflammatory arthritis (6%); (b) a significant negative correlation existed between the Clq-BA and the immunochemical C4 level in synovial fluids from patients with RA + and RA -; (c) neither the serum nor the synovial fluid Clq-BA in rheumatoid arthritis significantly correlated with the erythrocyte sedimentation rate, the clinical stage of the disease, or the IgM rheumatoid factor titer; and (d) the serum Clq-BA in patients with rheumatoid arthritis and extra-articular disease manifestations (40 +/- 34% in those with RA +,32 +/- 29% in those with RA -) was significantly increased as compared to the serum Clq-BA in patients with joint disease alone (24 +/- 30% in those with RA +, 10 +/- 13% in those with RA -). Experimental studies were carried out in order to characterize the Clq binding material in rheumatoid arthritis. This material had properties similar to immune complexes: it sedimented in a high molecular weight range on sucrose density gradients (10-30S) and lost the ability to bind Clq after reduction and alkylation, or after acid dissociation at pH 3.8, or after passage through an anti-IgG immunoabsorbant. DNase did not affect the Clq BA. These results support the hypothesis that circulating as well as intra-articular immune complexes may play an important role in some pathogenetic aspects of rheumatoid arthritis. The 125I-Clq binding test may also be of some practical clinical value in detecting patients who have a higher risk of developing vasculitis.


Neonicotinoid insecticide residues in surface water and soil associated with commercial maize (corn) fields in southwestern Ontario.
Neonicotinoid insecticides have come under scrutiny for their potential unintended effects on non-target organisms, particularly pollinators in agro-ecosystems. As part of a larger study of neonicotinoid residues associated with maize (corn) production, 76 water samples within or around the perimeter of 18 commercial maize fields and neighbouring apiaries were collected in 5 maize-producing counties of southwestern Ontario. Residues of clothianidin (mean = 2.28, max. = 43.60 ng/mL) and thiamethoxam (mean = 1.12, max. = 16.50 ng/mL) were detected in 100 and 98.7% of the water samples tested, respectively. The concentration of total neonicotinoid residues in water within maize fields increased six-fold during the first five weeks after planting, and returned to pre-plant levels seven weeks after planting. However, concentrations in water sampled from outside the fields were similar throughout the sampling period. Soil samples from the top 5 cm of the soil profile were also collected in these fields before and immediately following planting. The mean total neonicotinoid residue was 4.02 (range 0.07 to 20.30) ng/g, for samples taken before planting, and 9.94 (range 0.53 to 38.98) ng/g, for those taken immediately after planting. Two soil samples collected from within an conservation area contained detectable (0.03 and 0.11 ng/g) concentrations of clothianidin. Of three drifted snow samples taken, the drift stratum containing the most wind-scoured soil had 0.16 and 0.20 ng/mL mainly clothianidin in the melted snow. The concentration was at the limit of detection (0.02 ng/mL) taken across the entire vertical profile. With the exception of one sample, water samples tested had concentrations below those reported to have acute, chronic or sublethal effects to honey bees. Our results suggest that neonicotinoids may move off-target by wind erosion of contaminated soil. These results are informative to risk assessment models for other non-target species in maize agro-ecosytems.


Cochlear implants in young children.
The cochlear implant is best characterized as a device that provides access to the sound environment. The device enables the hearing pathway to respond to environmental and speech sounds, providing informational cues from the surroundings and from others that may escape visual detection. As the developmental effects of a profound hearing loss are multiple, cochlear implants have been applied to ever younger children in an attempt to promote a more normal level of developmental learning through audition. In deafness, transducer elements of the inner ear fail to trigger auditory nerve afferent nerves in the presence of sound input. However, large reserves of afferent fibers exist even in the auditory nerve of a profoundly deaf patient. Furthermore, these nerve fibers retain the ability to respond to prosthetic activation. Through developmental learning in the early, formative years, auditory centers of the brain appear capable of processing information from the implant to provide speech comprehension and oral language development. Multichannel implants have replaced original single channel designs. multichannel devices enable larger percentages of recipients to recognize the spoken word without visual cues because they provide spectral information in addition to temporal and intensity cues. Testing under conditions of auditory (implant)-only input reveals significant open-set speech understanding capabilities in more than 75% of children after three years of device use. The benefit provided by implants may vary with a number of conditions including: hearing history, age of deafness onset, age at implantation, etiology of deafness, linguistic abilities, and the presence of a motivated system of support of oral language development. Patient variables should be given individual consideration in judging candidacy for a cochlear implant and in planning rehabilitative and education services after surgery and activation of the device.


Government health care spending and child mortality.
Government health care spending (GHS) is of increasing importance to child health. Our study determined the relationship between reductions in GHS and child mortality rates in high- and low-income countries. The authors used comparative country-level data for 176 countries covering the years 1981 to 2010, obtained from the World Bank and the Institute for Health Metrics and Evaluation. Multivariate regression analysis was used to determine the association between changes in GHS and child mortality, controlling for differences in infrastructure and demographics. Data were available for 176 countries, equating to a population of ∼ 5.8 billion as of 2010. A 1% decrease in GHS was associated with a significant increase in 4 child mortality measures: neonatal (regression coefficient [R] 0.0899, P = .0001, 95% confidence interval [CI] 0.0440-0.1358), postneonatal (R = 0.1354, P = .0001, 95% CI 0.0678-0.2030), 1- to 5-year (R = 0.3501, P < .0001, 95% CI 0.2318-0.4685), and under 5-year (R = 0.5207, P < .0001, 95% CI 0.3168-0.7247) mortality rates. The effect was evident up to 5 years after the reduction in GHS (P < .0001). Compared with high-income countries, low-income countries experienced greater deteriorations of ∼ 1.31 times neonatal mortality, 2.81 times postneonatal mortality, 8.08 times 1- to 5-year child mortality, and 2.85 times under 5-year mortality. Reductions in GHS are associated with significant increases in child mortality, with the largest increases occurring in low-income countries.


The Placement of Children in Need of Out-of-Home Care: Forms of Care and Differences in Attachment Security and Behavioral Problems in the Italian Context.
The current paper investigated differences in secure attachment levels and behavioral problems among four groups of children in out-of-home care in Italy: closed adoption (child and birth parents not in contact following adoption), open adoption (child and birth parents still in contact after placement), foster care (child living temporarily with relatives or unrelated foster parents) and institutional care (child in residential care for large groups of children). One hundred and thirty children aged 10-19 were included in this study. The Attachment Interview for Childhood and Adolescence and the Achenbach Youth Self-Report were employed to measure participants' secure attachment levels and behavioral problems. Both a multivariate analysis of covariance and measured variable path analysis were performed. Age, gender and time elapsed between the request for child protection and placement on out-of-home care were used as covariates. The results showed that adolescents in closed adoption had higher secure attachment scores than those in foster care and institutional care, while adolescents in open adoption scored significantly higher on problem behaviors than those in the other out-of-home care groups. Findings were discussed in terms of limitations and implications for future research.


RSF governs silent chromatin formation via histone H2Av replacement.
Human remodeling and spacing factor (RSF) consists of a heterodimer of Rsf-1 and hSNF2H, a counterpart of Drosophila ISWI. RSF possesses not only chromatin remodeling activity but also chromatin assembly activity in vitro. While no other single factor can execute the same activities as RSF, the biological significance of RSF remained unknown. To investigate the in vivo function of RSF, we generated a mutant allele of Drosophila Rsf-1 (dRsf-1). The dRsf-1 mutant behaved as a dominant suppressor of position effect variegation. In dRsf-1 mutant, the levels of histone H3K9 dimethylation and histone H2A variant H2Av were significantly reduced in an euchromatic region juxtaposed with heterochromatin. Furthermore, using both genetic and biochemical approaches, we demonstrate that dRsf-1 interacts with H2Av and the H2Av-exchanging machinery Tip60 complex. These results suggest that RSF contributes to histone H2Av replacement in the pathway of silent chromatin formation.


Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide.
To evaluate the effect of treatment with a combination of nitric oxide synthase inhibitors and inhaled nitric oxide on systemic hypotension during sepsis. Prospective, randomized, controlled study on anesthetized animals. A cardiopulmonary research laboratory. Forty-seven male adult Sprague-Dawley rats. Animals were anesthetized, mechanically ventilated with room air, and randomized into six groups: a) the control group (C, n=6) received normal saline infusion; b) the endotoxin-treated group received 100 mg/kg i.v. of Escherichia coli lipopolysaccharide (LPS, n=9); c) the third group received LPS, and 1 hr later the animals were treated with 100 mg/kg i.v. Nw-nitro-L-arginine (LNA, n=9); d) the fourth group received LPS, and after 1 hr, the animals were treated with 100 mg/kg i.v. aminoguanidine (AG, n=9); e) the fifth group received LPS and 1 hr later was treated with LNA plus 1 ppm inhaled nitric oxide (LNA+NO, n=7); f) the sixth group received LPS and 1 hr later was treated with aminoguanidine plus inhaled NO (AG+NO, n=7). Inhaled NO was administered continuously until the end of the experiment. Systemic mean blood pressure (MAP) was monitored through a catheter in the carotid artery. Mean exhaled NO (ENO) was measured before LPS (T0) and every 30 mins thereafter for 5 hrs. Arterial blood gases and pH were measured every 30 mins for the first 2 hrs and then every hour. No attempt was made to regulate the animal body temperature. All the rats became equally hypothermic (28.9+/-1.2 degrees C [SEM]) at the end of the experiment. In the control group, blood pressure and pH remained stable for the duration of the experiment, however, ENO increased gradually from 1.3+/-0.7 to 17.6+/-3.1 ppb after 5 hrs (p< .05). In the LPS treated rats, MAP decreased in the first 30 mins and then remained stable for 5 hrs. The decrease in MAP was associated with a gradual increase in ENO, which was significant after 180 mins (58.9+/-16.6 ppb) and reached 95.3+/-27.5 ppb after 5 hrs (p< .05). LNA and AG prevented the increase in ENO after LPS to the level in the control group. AG caused a partial reversal of systemic hypotension, which lasted for the duration of the experiment. LNA reversed systemic hypotension almost completely but only transiently for 1 hr, and caused severe metabolic acidosis in all animals. The co-administration of NO with AG had no added benefits on MAP and pH. In contrast, NO inhalation increased the duration of the reversal in MAP after LNA, alleviated the degree of acidosis, and decreased the mortality rate (from 55% to 29%). In this animal model, LPS-induced hypotension was alleviated slightly and durably after AG, but only transiently after LNA. Furthermore, co-administration of NO with AG had no added benefits but alleviated the severity of metabolic acidosis and mortality after LNA. We conclude that nitric oxide synthase (NOS) inhibitors, given as a single large bolus in the early phase of sepsis, can exhibit some beneficial effects. Administration of inhaled NO with NOS inhibitors provided more benefits in some conditions and therefore may be a useful therapeutic combination in sepsis. NO production in sepsis does not seem to be a primary cause of systemic hypotension. Other factors are likely to have a major role.


SOP conservative (medical and mechanical) treatment of erectile dysfunction.
Erectile dysfunction (ED) is the most frequently treated male sexual dysfunction worldwide. ED is a chronic condition that exerts a negative impact on male self-esteem and nearly all life domains including interpersonal, family, and business relationships. The aim of this study is to provide an updated overview on currently used and available conservative treatment options for ED with a special focus on their efficacy, tolerability, safety, merits, and limitations including the role of combination therapies for monotherapy failures. The methods used were PubMed and MEDLINE searches using the following keywords: ED, phosphodiesterase type 5 (PDE5) inhibitors, oral drug therapy, intracavernosal injection therapy, transurethral therapy, topical therapy, and vacuum-erection therapy/constriction devices. Additionally, expert opinions by the authors of this article are included. Level 1 evidence exists that changes in sedentary lifestyle with weight loss and optimal treatment of concomitant diseases/risk factors (e.g., diabetes, hypertension, and dyslipidemia) can either improve ED or add to the efficacy of ED-specific therapies, e.g., PDE5 inhibitors. Level 1 evidence also exists that treatment of hypogonadism with total testosterone < 300 ng/dL (10.4 nmol/L) can either improve ED or add to the efficacy of PDE5 inhibitors. There is level 1 evidence regarding the efficacy and safety of the following monotherapies in a spectrum-wide range of ED populations: PDE5 inhibitors, intracavernosal injection therapy with prostaglandin E1 (PGE1, synonymous alprostadil) or vasoactive intestinal peptide (VIP)/phentolamine, and transurethral PGE1 therapy. There is level 2 evidence regarding the efficacy and safety of the following ED treatments: vacuum-erection therapy in a wide range of ED populations, oral L-arginine (3-5 g), topical PGE1 in special ED populations, intracavernosal injection therapy with papaverine/phentolamine (bimix), or papaverine/phentolamine/PGE1 (trimix) combination mixtures. There is level 3 evidence regarding the efficacy and safety of oral yohimbine in nonorganic ED. There is level 3 evidence that combination therapies of PDE5 inhibitors + either transurethral or intracavernosal injection therapy generate better efficacy rates than either monotherapy alone. There is level 4 evidence showing enhanced efficacy with the combination of vacuum-erection therapy + either PDE5 inhibitor or transurethral PGE1 or intracavernosal injection therapy. There is level 5 evidence (expert opinion) that combination therapy of PDE5 inhibitors + L-arginine or daily dosing of tadalafil + short-acting PDE5 inhibitors pro re nata may rescue PDE5 inhibitor monotherapy failures. There is level 5 evidence (expert opinion) that adding either PDE5 inhibitors or transurethral PGE1 may improve outcome of penile prosthetic surgery regarding soft (cold) glans syndrome. There is level 5 evidence (expert opinion) that the combination of PDE5 inhibitors and dapoxetine is effective and safe in patients suffering from both ED and premature ejaculation.


The Effects of Photobiomodulation of 808 nm Diode Laser Therapy at Higher Fluence on the in Vitro Osteogenic Differentiation of Bone Marrow Stromal Cells.
The literature has supported the concept of mesenchymal stromal cells (MSCs) in bone regeneration as one of the most important applications in oro-maxillofacial reconstructions. However, the fate of the transplanted cells and their effects on the clinical outcome is still uncertain. Photobiomodulation (PBM) plays an important role in the acceleration of tissue regeneration and potential repair. The aim of this in vitro study is to evaluate the effectiveness of PBM with 808 nm diode laser therapy, using a flat-top hand-piece delivery system at a higher-fluence (64 J/cm2) irradiation (1 W, continuous-wave) on bone marrow stromal cells (BMSCs). The BMSCs of 3 old female Balb-c mice were analyzed. The cells were divided into two groups: irradiated group and control group. In the former the cells were irradiated every 24 h during 0 day (T0), 5 (T1), 10 (T2), and 15 (T3) days, whereas the control group was non-irradiated. The results have shown that the 64 J/cm2 laser irradiation has increased the Runt-related transcription factor 2 (Runx2). Runx2 is the most important early marker of osteoblast differentiation. The higher-fluence suppressed the synthesis of adipogenic transcription factor (PPARγ), the pivotal transcription factor in adipogenic differentiation. Also, the osteogenic markers such as Osterix (Osx) and alkaline phosphatase (ALP) were upregulated with an increase in the matrix mineralization. Furthermore, western blotting data demonstrated that the laser therapy has induced a statistically valid increase in the synthesis of transforming growth factor β1 (TGF-β1) but had no effects on the tumor necrosis factor α (TNFα) production. The data has statistically validated the down-regulation of the important pro-inflammatory cytokines such as interleukin IL-6, and IL-17 after 808 nm PBM exposition. An increase in anti-inflammatory cytokines such as IL-1rα and IL-10 was observed. These in vitro studies provide for first time the initial proof that the PBM of the 808 nm diode laser therapy with flat-top hand-piece delivery system at a higher-fluence irradiation of 64 J/cm2 (1 W/cm2) can modulate BMSCs differentiation in enhancing osteogenesis.


Enhancing osteogenic differentiation of mouse embryonic stem cells by nanofibers.
Controlled differentiation of embryonic stem cells (ESC) is necessary to their use as a cell source for tissue engineering or regeneration. To date, most studies have concentrated on chemical cues to direct ESC differentiation. However, during normal embryonic development, multiple factors beyond chemical cues play a role, including the extracellular matrix (ECM) in bone development. In this study, we use nanofibrous (NF) matrices to mimic the morphology of the ECM to examine the contribution of the ECM morphology to the differentiation of mouse ESC. After 12 h of differentiation culture, mouse ESC form protrusions interacting with NF matrices, while they appear not to interact with flat films. Immunofluorescence staining after 26 days of differentiation culture indicates a greater degree of differentiation for mouse ESC on NF matrices compared to flat films. Polymerase chain reaction results, also, show greater degree of osteogenic differentiation on NF matrices compared to flat films when osteogenic supplements are added to the culture. Overall, these results demonstrate that NF morphology contributes to the controlled differentiation of mouse ESC.


Human cells and cell cultures: availability, authentication and future prospects.
The availability of well characterized, viable human cells, tissues and cell lines along with pertinent data on the specific patient donors is a prerequisite for much current transplantation and biomedical research. In the USA, institutional and multi-center networks have been established for provision of primary human cells and tissues to qualified clinicians and research scientists. Monetary support derives from government, university, institutional and fee sources. Problems involved include concern for the rights and privacy of tissue donors, cultural reservations relating to tissue provision, the need for safe and expeditious transport, short term survival and limited supply, adequate correlation of patient data with samples provided, presence of infectious viruses and microorganisms, as well as state or government regulations regarding national or international shipping. The use of human cell lines with continuous or even somewhat limited doubling potentials overcomes many of the above difficulties. National cell banks have been established to provide reference lines for use by multiple investigators. Use of such cell lines assures improved research comparability both geographically and with time. Authentication procedures are critically important for all of these programs. Verification of tissue types and conditions is required through histological, biochemical and immunological assays. Tests for microbial and viral contaminants must be applied. In addition to such procedures utilized for tissues, with cell lines the banking agency must also verify species and where possible identity, properties and functions. The literature is replete with descriptions documenting incorrect identifications and infections of proliferating cell strains used for research. The availability of viable tissue through local sources and distribution agencies in the USA is becoming more commonplace even including full family participation and collection of related, detailed histories. Increased support for this developmental activity is needed, coupled with provision of blood and normal cells and cell lines from family members in many disease categories. Modern techniques, new and improved culture ware, serum-free media, reagents such as growth, adherence and transfer factors will permit isolation, propagation and wide spread distribution not only of human tumor cells but also normal and functional human cells of most renewing and expanding tissue types. Hybridization and immortalization techniques are enhancing this capability such that virtually all human cell types should be available for short or longer-term propagation and study in the foreseeable future.


Grey and white matter changes in children with monocular amblyopia: voxel-based morphometry and diffusion tensor imaging study.
To investigate the potential morphological alterations of grey and white matter in monocular amblyopic children using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). A total of 20 monocular amblyopic children and 20 age-matched controls were recruited. Whole-brain MRI scans were performed after a series of ophthalmologic exams. The imaging data were processed and two-sample t-tests were employed to identify group differences in grey matter volume (GMV), white matter volume (WMV) and fractional anisotropy (FA). After image screening, there were 12 amblyopic participants and 15 normal controls qualified for the VBM analyses. For DTI analysis, 14 amblyopes and 14 controls were included. Compared to the normal controls, reduced GMVs were observed in the left inferior occipital gyrus, the bilateral parahippocampal gyrus and the left supramarginal/postcentral gyrus in the monocular amblyopic group, with the lingual gyrus presenting augmented GMV. Meanwhile, WMVs reduced in the left calcarine, the bilateral inferior frontal and the right precuneus areas, and growth in the WMVs was seen in the right cuneus, right middle occipital and left orbital frontal areas. Diminished FA values in optic radiation and increased FA in the left middle occipital area and right precuneus were detected in amblyopic patients. In monocular amblyopia, cortices related to spatial vision underwent volume loss, which provided neuroanatomical evidence of stereoscopic defects. Additionally, white matter development was also hindered due to visual defects in amblyopes. Growth in the GMVs, WMVs and FA in the occipital lobe and precuneus may reflect a compensation effect by the unaffected eye in monocular amblyopia.


Tanshinone IIA inhibits HIF-1α and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway.
Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) play important roles in angiogenesis and tumor growth. Tanshinone IIA (T2A) is a novel antiangiogenic agent with promising antitumor effects; however, the molecular mechanism underlying the antiangiogenic effects of T2A remains unclear. In the present study, we provided evidence showing that T2A inhibited angiogenesis and breast cancer growth by down-regulating VEGF expression. Specifically, T2A repressed HIF-1α expression at the translational level and inhibited the transcriptional activity of HIF-1α, which led to the down-regulation of VEGF expression. Suppression of HIF-1α synthesis by T2A correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway regulating HIF-1α expression at the translational level. In addition, we also found that T2A inhibited the angiogenesis and growth of human breast cancer xenografts in nude mice through suppression of HIF-1α and VEGF. Our study provides novel perspectives and potential targets for the treatment of human breast cancer.


Natural products from the termite Nasutitermes corniger lowers aminoglycoside minimum inhibitory concentrations.
Bacterial infectious agents present a risk to populations, as they are responsible for high morbidity and mortality. For combating these pathogens, our main line of defense is the use of antibiotics. However, indiscriminate use of these drugs develops resistant strains to these same drugs. The present study has tested the antibacterial and modifying antibiotic activity of natural products from Nasutitermes corniger (Termitidae) (Motschulsky), a termite used in folk medicine in Northeast Brazil, by the microdilution and checkerboard methods, respectively. In this study, the aqueous extract from the nest of N. corniger (ANCE) was prepared and tested with chlorpromazine (CPZ) for its antimicrobial activity, using the microdilution method. CPZ and ANCE were used independently and also in combination with aminoglycosides, against a strain of Escherichia coli resistant to these antibiotics, to determine the participation of efflux systems in resistance mechanisms. The fractional inhibitory concentration (FIC) index was calculated and evaluated for the occurrence of synergism, using the checkerboard method. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) values were >/= 2048 mug/mL for both strains of E. coli assayed, indicating low antibacterial activity. However, synergism was observed with kanamycin when the decoction was used, but when chlorpromazine was used, synergism was observed with kanamycin, amikacin, and neomycin. This synergism with CPZ indicated the involvement of an efflux system in the resistance to these aminoglycosides. Therefore, it was suggested that the natural products from N. corniger could be used as a source of zoo-derived natural products with kanamycin-modifying activity, resulting in a new approach against bacterial resistance to antibiotics.


Trichomonas vaginalis flavin reductase 1 and its role in metronidazole resistance.
The enzyme flavin reductase 1 (FR1) from Trichomonas vaginalis, formerly known as NADPH oxidase, was isolated and identified. Flavin reductase is part of the antioxidative defence in T. vaginalis and indirectly reduces molecular oxygen to hydrogen peroxide via free flavins. Importantly, a reduced or absent flavin reductase activity has been reported in metronidazole-resistant T. vaginalis, resulting in elevated intracellular oxygen levels and futile cycling of metronidazole. Interestingly, FR1 has no close homologue in any other sequenced genome, but seven full-length and three truncated isoforms exist in the T. vaginalis genome. However, out of these, only FR1 has an affinity for flavins, i.e. FMN, FAD and riboflavin, which is high enough to be of physiological relevance. Although there are no relevant changes in the gene sequence or any alterations of the predicted FR1-mRNA structure in any of the strains studied, FR1 is not expressed in highly metronidazole-resistant strains. Transfection of a metronidazole-resistant clinical isolate (B7268), which does not express any detectable amounts of FR, with a plasmid bearing a functional FR1 gene nearly completely restored metronidazole sensitivity. Our results indicate that FR1 has a significant role in the emergence of metronidazole resistance in T. vaginalis.


Interaction with objects by group-living Saimiri sciureus.
We have studied the spontaneous interaction with small, inedible objects by group-living Saimiri. Twenty-one animals living in a large outdoor enclosure were presented with a set of 10 novel objects of diverse materials, colors, sizes, and shapes. We have used a sampling technique to record the number of monkeys interacting with each object; qualitative observations complemented these measurements. Next day the same objects were presented again and the observations continued. This experiment was repeated with some variations three times over a period of six months. The highest score for novel objects was obtained immediately upon objects presentation; afterwards the score sharply decreased for that day. On second presentation of the same objects the scores were more evenly distributed during the day, the cumulative total resembling that of day one. Objects' characteristics influenced the amount of interaction with them. The important factors seemed to be the material the objects were made of and their complexity. The objects that were contacted most frequently elicited intense investigative behavior and social play. These results differ from some previous works in which Saimiri were observed to interact only rarely with novel objects.


Vulvar Darier-Ferrand dermatofibrosarcoma: unusual localization of a rare tumor.
Dermatofibrosarcoma protuberans (DFSP) is a low-to-intermediate grade sarcoma of dermal origin that rarely presents in the vulva, typically occurring on the trunk of young to middle-aged adults. Even though it has a low potential for distant metastases, it often recurs locally. Therefore, surgical excision is the treatment of choice. We report a case of DFSP with fibrosarcoma transformation involving the vulva treated by large excision with tumor free margins followed by plastic reconstruction. Our aim is to highlight this rare disease and through literature evaluate the safety and efficacy of surgical treatment. Early recognition of this rare entity whose localization and the aggressive nature of the fibrosarcomatous component will be an issue in the surgical management.


Blood levels of cadmium and lead in relation to breast cancer risk in three prospective cohorts.
Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in the environment and ubiquitous human exposure. We examined associations of circulating levels of cadmium and lead with breast cancer risk in three case-control studies nested within the Cancer Prevention Study-II (CPS-II) LifeLink Cohort, European Prospective Investigation into Cancer and Nutrition - Italy (EPIC-Italy) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Metal levels were measured in stored erythrocytes from 1,435 cases and 1,433 controls using inductively coupled plasma-mass spectrometry. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models with each study result weighted by the within- and between-study variances. I2 values were calculated to estimate proportion of between study variation. Using common cut-points, cadmium levels were not associated with breast cancer risk in the CPS-II cohort (continuous RR = 1.01, 95% CI 0.76-1.34), but were inversely associated with risk in the EPIC- Italy (continuous RR = 0.80, 95% CI 0.61-1.03) and NSHDS cohorts (continuous RR = 0.73, 95% CI 0.54-0.97). The inverse association was also evident in the meta-analysis (continuous RR = 0.84, 95% CI 0.69-1.01) with low between-study heterogeneity. Large differences in lead level distributions precluded a meta-analysis of their association with breast cancer risk; no associations were found in the three studies. Adult cadmium and lead levels were not associated with higher risk of breast cancer in our large meta-analysis.


Feasibility of targeted drug delivery to selective areas of the retina.
A new method was developed to deliver locally a bolus dose of a drug to the retinal vasculature. The targeted delivery system was based on encapsulating the drug in heat-sensitive liposomes, which are injected intravenously and lysed in the retinal vessels by a heat pulse generated by a laser. To test if substances delivered in the vessels could also penetrate into the surrounding tissue, 6-carboxyfluorescein was encapsulated in liposomes and used as a marker for drug penetration. Moderate argon laser pulses were applied to the retinal vessels of Dutch pigmented rabbits to induce breakdown of the blood-retinal barrier (BRB). A suspension of liposomes at a dose of 2 ml/kg body weight, corresponding to a carboxyfluorescein dose of 12 mg/kg, was injected into the ear vein. The dye was released from the liposomes proximal to the damaged portion of the vessel. Fundus fluorescein angiograms were recorded with a video camera and digitized for subsequent image analysis. The penetration of carboxyfluorescein into the retinal tissue was evaluated by comparing the fluorescence intensity of the area around the damaged vessel with that of an adjacent control area. The dye penetration increased with the numbers of laser applications (P less than 0.001). The leakage was localized distally to the released site and was restricted to areas with a disrupted BRB. The mass of carboxyfluorescein that penetrated gradually spread with time. Both veins and arteries could be used for the targeted delivery. These results indicated that this delivery system, which is fully controllable by laser through the pupil, can deliver drugs inside the vasculature and into the retinal tissue wherever the BRB is disrupted.


Evidence for an electrostatic mechanism of force generation by the bacteriophage T4 DNA packaging motor.
How viral packaging motors generate enormous forces to translocate DNA into viral capsids remains unknown. Recent structural studies of the bacteriophage T4 packaging motor have led to a proposed mechanism wherein the gp17 motor protein translocates DNA by transitioning between extended and compact states, orchestrated by electrostatic interactions between complimentarily charged residues across the interface between the N- and C-terminal subdomains. Here we show that site-directed alterations in these residues cause force dependent impairments of motor function including lower translocation velocity, lower stall force and higher frequency of pauses and slips. We further show that the measured impairments correlate with computed changes in free-energy differences between the two states. These findings support the proposed structural mechanism and further suggest an energy landscape model of motor activity that couples the free-energy profile of motor conformational states with that of the ATP hydrolysis cycle.


Effects of oral administration of Echinacea purpurea (American herb) on incidence of spontaneous leukemia caused by recombinant leukemia viruses in AKR/J mice.
Four-week-old female AKR/J mice were given oral doses of powdered leaves from Echinacea purpurea three times weekly for 8 weeks (7.5 mg/mouse/week): controls received phosphate-buffered saline. Mean survival age of experimental AKR/J mice treated with the E. purpurea preparation was significantly prolonged and enlargement of thymic lymphoma in experimental mice was significantly suppressed compared with controls. In normal 3-week-old female AKR/J mice, mortality from thymic lymphoma was delayed markedly after injection into the thymus of cell-free extract of thymus from the experimental 28-week-old female AKR/J mice that received the oral E. purpurea preparation was injected directly into the thymus. Proliferation of endogenous recombinant murine leukemia viruses (MuLV) in the thymus was markedly inhibited after the first oral administration of the E. purpurea preparation as compared with untreated controls (final age, 28 weeks). Production of endogenous interferon (IFN)-gamma in AKR/J mice was also effectively augmented by the oral treatment with the E. purpurea preparation, however, the production of other cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 was minimal. These results suggest that this suppressive effects on spontaneously occurring leukemia caused by endogenous recombinant MuLV in female AKR/J mice may depend on enhancement of nonspecific immune or cellular immune systems (or of both) by the E. purpurea preparation.


Are anti-ganglioside antibodies associated with proventricular dilatation disease in birds?
The identification of Parrot bornaviruses (PaBV) in psittacine birds with proventricular dilatation disease (PDD) has not been sufficient to explain the pathogenesis of this fatal disease, since not all infected birds develop clinical signs. Although the most accepted theory indicates that PaBV directly triggers an inflammatory response in this disease, another hypothesis suggests the disease is triggered by autoantibodies targeting neuronal gangliosides, and PDD might therefore resemble Guillain-Barré Syndrome (GBS) in its pathogenesis. Experimental inoculation of pure gangliosides and brain-derived ganglioside extracts were used in two different immunization studies. The first study was performed on 17 healthy chickens (Gallus gallus domesticus): 11 chickens were inoculated with a brain ganglioside extract in Freund's complete adjuvant (FCA) and six chickens inoculated with phosphate-buffered saline. A second study was performed five healthy quaker parrots (Myiopsitta monachus) that were divided into three groups: Two quaker parrots received purified gangliosides in FCA, two received a crude brain extract in FCA, and one control quaker parrot received FCA alone. One chicken developed difficult in walking. Histologically, only a mild perivascular and perineural lymphocytic infiltrate in the proventriculus. Two quaker parrots (one from each treatment group) had mild lymphoplasmacytic encephalitis and myelitis. However, none of the quaker parrots developed myenteric ganglioneuritis, suggesting that autoantibodies against gangliosides in birds are not associated with a condition resembling PDD.


Approach to acute febrile illness during the COVID-19 pandemic.
Coronavirus disease 2019 (COVID-19) is a febrile respiratory illness that has spread rampantly across the globe and has emerged as one of the biggest pandemics of all time. Besides the direct effects of COVID-19 on mortality, collateral impacts on diagnosis and management of acute febrile illnesses (AFI) is a matter of great concern. The overlap in presentation, shunting of available resources and infection control precautions in patients with suspected COVID-19 result in a significant delay in diagnoses and management of AFI. This review highlights the challenges in the management of acute febrile illness during COVID pandemic and possible solutions for the same.


Association of clinic vascular access monitoring practices with clinical outcomes in hemodialysis patients.
Early identification of access dysfunctions may be associated with improved patient outcomes. We examined whether patient outcomes were associated with vascular access monitoring practices in an incident dialysis cohort. We conducted a national prospective cohort study and analyzed 363 hemodialysis patients who had a first permanent vascular access (arteriovenous fistula or graft) by 6 months after the start of dialysis. Multivariate methods were used to examine associations between monitoring practices and 6-month Kt/V (reaching Kt/V >/=1.2), access intervention, access failure, and 2-year septicemia and all-cause hospitalization and mortality. Patients who received monitoring weekly or more often (49%) were more likely to have an access intervention (adjusted RH = 1.40, 95% CI, 1.07-1.84) than those who received monitoring less frequently. Additionally, patients treated at clinics that reported performing regular access monitoring (80% of patients) were less likely to be hospitalized for septicemia (IRR = 0.35, 95% CI, 0.21-0.61) or for any cause (IRR = 0.77, 95% CI, 0.60-0.99). There were no statistically significant differences between patients exposed to different vascular access monitoring practices in access failure, achievement of Kt/V, or survival. Frequent monitoring of dialysis access may initially increase the number of interventions but is beneficial to longer-term outcomes, including septicemia-related and all-cause hospitalization.


Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging.
Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. Individuals with DS exhibit changes in neurochemistry and neuroanatomy that worsen with age, neurological delay in learning and memory, and predisposition to Alzheimer's disease. The Ts65Dn mouse is the best characterized model of DS and has many features reminiscent of DS, including developmental anomalies and age-related neurodegeneration. The mouse carries a partial triplication of mouse chromosome 16 containing roughly 100 genes syntenic to human chromosome 21 genes. We hypothesized that there would be differences in brain metabolites with trisomy and age, and that long-term treatment with rapamycin, mechanistic target of rapamycin (mTOR) inhibitor and immunosuppressant, would correct these differences. Using HPLC coupled with electrochemical detection, we identified differences in levels of metabolites involved in dopaminergic, serotonergic, and kynurenine pathways in trisomic mice that are exacerbated with age. These include homovanillic acid, norepinephrine, and kynurenine. In addition, we demonstrate that prolonged treatment with rapamycin reduces accumulation of toxic metabolites (such as 6-hydroxymelatonin and 3-hydroxykynurenine) in aged mice.


Genome Sequence of Arenibacter algicola Strain SMS7, Found in Association with the Marine Diatom Skeletonema marinoi.
Arenibacter algicola strain SMS7 was isolated from a culture of the marine diatom Skeletonema marinoi strain ST54, sampled from top-layer sediments in Kosterfjord, Sweden. Here, we present its 5,857,781-bp genome, consisting of a circular chromosome and one circular plasmid, in all containing 4,932 coding sequences.


[Post-basic training of intensive care nurses. International scene].
The aim of this report is describe the international scenery of post-basic training of nurses in critical care units. There is an emphasis in the necessity of post-graduation training and so support different authors when they declare that the basic training of nurses does not make them able to develop their professional activity in critical care units. The second part, using an exhaustive bibliographical review, explains which is the situation at an international level, pointing out the fact that specialized training is not a compulsory requirement for professionals and nurses who get to work in CCUs. Finally, some relevant activities which SEEIUC is performing to impulse the traning of nurses in critical care units are reported.


Optimization of ERK activity biosensors for both ratiometric and lifetime FRET measurements.
Among biosensors, genetically-encoded FRET-based biosensors are widely used to localize and measure enzymatic activities. Kinases activities are of particular interest as their spatiotemporal regulation has become crucial for the deep understanding of cell fate decisions. This is especially the case for ERK, whose activity is a key node in signal transduction pathways and can direct the cell into various processes. There is a constant need for better tools to analyze kinases in vivo, and to detect even the slightest variations of their activities. Here we report the optimization of the previous ERK activity reporters, EKAR and EKAREV. Those tools are constituted by two fluorophores adapted for FRET experiments, which are flanking a specific substrate of ERK, and a domain able to recognize and bind this substrate when phosphorylated. The latter phosphorylation allows a conformational change of the biosensor and thus a FRET signal. We improved those biosensors with modifications of: (i) fluorophores and (ii) linkers between substrate and binding domain, resulting in new versions that exhibit broader dynamic ranges upon EGF stimulation when FRET experiments are carried out by fluorescence lifetime and ratiometric measurements. Herein, we characterize those new biosensors and discuss their observed differences that depend on their fluorescence properties.


FOXA1 Suppresses SATB1 Transcription and Inactivates the Wnt/β-Catenin Pathway to Alleviate Diabetic Nephropathy in a Mouse Model.
Diabetic nephropathy (DN) represents the most common diabetic complication that may lead to end-stage renal disease. This work focused on the effect of FOXA1 on the DN development and the molecular mechanism. A mouse model of DN was induced by high-fat diets and streptozotocin. The concentrations of blood glucose and urinary protein in mice, and the pathological changes in mouse kidney tissues were determined. A podocyte cell line MPC-5 was treated with high glucose (HG) to mimic a DN-like condition in vitro. FOXA1 and SATB1 were overexpressed in HG-treated MPC-5 cells and in DN mice to explore their effects on cell proliferation and apoptosis, and on pathological changes in mouse kidney tissues. The binding relationship between FOXA1 and STAB1 was predicted and validated. Activation of the Wnt/β-catenin pathway was detected. FOXA1 was poorly expressed in the kidney tissues of DN mice. Overexpression of FOXA1 reduced the concentrations of fasting blood glucose and 24-h urinary protein in mice. It also suppressed the accumulation of glomerular mesangial matrix and hyperplasia of glomerular basement membrane, and reduced collagen deposition and interstitial fibrosis in mouse kidney. Also, FOXA1 reduced HG-induced apoptosis of MPC-5 cells. FOXA1 bound to the promoter region of SATB1 for transcription suppression. Overexpression of SATB1 activated the Wnt/β-catenin pathway and blocked the protective roles of FOXA1 in DN mice and in HG-treated MPC-5 cells. This study demonstrated that FOXA1 transcriptionally suppresses SATB1 expression and inactivates the Wnt/β-catenin signaling pathway, thereby inhibiting podocyte apoptosis and DN progression.


Diagnostic problems of von Willebrand's disease in a general hospital laboratory.
The expression of variant types of von Willebrand's disease can present an elusive diagnostic problem. Bleeding history of patients can vary greatly, as can the results of tests for the components of the Factor VIII complex. Recent advances in characterizing and measuring the factor VIII complex have greatly improved the diagnosis of the variant forms of von Willebrand's disease. However, some of the less sophisticated procedures, which are more readily available, can still be utilized by the routine general hospital laboratory to identify or suspect the occasional case of von Willebrand's disease. These points are exemplified in this report of seven family members who were studied.


Degenerative spondylolisthesis. Developmental or acquired?
Degenerative spondylolisthesis is four times more common in women than in men. Although this gender difference has long been recognised there has been no explanation for it. We have examined the radiographs and CT scans of 118 patients over the age of 55 years and of a control group under the age of 46 years. Our findings confirmed the presence of more sagittally-orientated facet joints in patients with degenerative spondylolisthesis but did not show that the gender difference can be explained by the morphology of the facet joint. Furthermore, we conclude that the increased angle of the facet joint is the result of arthritic remodelling and not the primary cause of degenerative spondylolisthesis. It is more likely to be due to loss of soft-tissue resilience with subsequent failure of the facet joints which are acting as the last restraints to subluxation.


Ultrasound measurements at the proximal phalanges in healthy women and patients with hip fractures.
Measurements of bone mineral density (BMD) are useful for the assessment of fracture risk in osteoporosis. First prospective studies showed that quantitative ultrasound as measured at the calcaneus also predicts future hip fracture risk, independently of BMD and as accurately as BMD. The aim of this study was to compile a reference population for a new ultrasound device that determines amplitude-dependent speed of sound (AD-SOS) through the proximal phalanges of the hand and to prove its ability to distinguish between health volunteers and osteoporotic patients. In a case-control study we examined 139 healthy women aged 21-94 years and a group of 24 female patients aged 69-94 years with recent hip fractures. In the healthy reference population additional BMD measurements were performed with dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound measurements at the calcaneus were carried out. In vivo precision of AD-SOS measurements through the phalanges was 0.52% CV. Simple regression analyses showed a negative correlation with age (r = -0.73, p < 0.001); modest significant correlations with BMD of the lumbar spine (r = 0.36, p < 0.001) and BMD of the femoral neck (r = 0.37, p = 0.002) as measured with DXA were shown. The comparison with another ultrasound device measuring SOS and broadband ultrasound attenuation (BUA) through the calcaneus showed correlation with SOS (r = 0.50, p < 0.001); no significant correlation was found with BUA measurements. Furthermore a dependency of AD-SOS values in anthropometric factors such as body mass index (r = 0.37, p < 0.001), height (r = 0.40, p < 0.001) and weight (r = 0.23, p < 0.05) was shown. First study results on 24 clinically diagnosed osteoporotic patients, defined as patients with recent (< 1 week) pertrochanteric or femoral neck fractures, showed a good separation between age- and sex-matched controls and osteoporotic patients (Z = -2.0 SD). Receiver operating characteristic (ROC) curves showed an area under the fitted curve of 0.83 +/- 0.06. These results are powerful for a device measuring AD-SOS through the proximal phalanges of the hand, and further prospective studies have proven the capability of phalangeal ultrasound in fracture risk assessment.


Biochemical characterization of the soluble form of tumor antigen MUC1 isolated from sera and ascites fluid of breast and pancreatic cancer patients.
Transmembrane glycoprotein tumor antigen MUC1 that is overexpressed on pancreatic and breast tumor cells can be found in large amounts in soluble form in serum and ascites fluid. MUC1 has been identified as a target of human antitumor antibody and CTL responses that are generated in the absence of helper T cells. The soluble form of MUC1 should support generation of helper T cells, but we have found recently that this form, although effectively endocytosed by dendritic cells, remains trapped in early endosomes and is not trafficked to antigen-processing compartments. The exact biochemical structure of this form of MUC1 has not been elucidated to date, and it is thus not clear what structural characteristics may be responsible for its retention in early endosomes. We have purified soluble MUC1 from ascites fluid of breast/pancreatic cancer patients (ASC-MUC1) and quantitated O-linked carbohydrates. We have altered ASC-MUC1 by enzymatic treatment: trypsin or clostripain digestion, desialylation, and further in vitro glycosylation. We have found that desialylated ASC-MUC1 was further glycosylated by peptidyl N-acetylgalactosamine transferases and was not when sialic acid was present. These alterations created new forms of ASC-MUC1 that might be handled more efficiently by antigen-presenting cells to generate better tumor-specific immunity and used to identify structures that are directly involved in retention of this antigen in early endosomes.


Missed Central Venous Guide Wires: A Systematic Analysis of Published Case Reports.
The inadvertent loss of an entire guide wire during central venous catheterization can lead to serious patient harm and require additional investigations as well as retrieval procedures. We aimed to analyze globally published reports of lost wires during central venous catheterization to understand its possible etiology, presentation, treatment, and outcomes with an objective of finding solutions to make the procedure safer. MEDLINE, Scopus, and CINAHL, supplemented by scanning the reference lists of relevant publications. All reports describing an inadvertent intravascular loss of a complete guide wire during placement of central venous catheters published up to December 2014 were included. Reports exclusively describing the 1) retrieval method, 2) partially retained guide wires, and 3) entrapped guide wires during withdrawal were excluded. In each instance, we collected data about the method of the missed guide wire detection, the time interval between the procedure and detection, the supplementary investigations performed to confirm the diagnosis, and the risk factors associated with such events as well as the complications, the final outcome, and the wire retrieval methods used. A systematic analysis of the accessed publications was performed. Over the last decade, the number of reported instances of lost guide wires during central venous catheterization has increased rapidly. Unsupervised or improperly supervised insertions of the central catheters by trainees, distractions during insertions, and high workload are the main risk factors. A retained guide wire increases the risk and cost of additional diagnostic and therapeutic interventions, as well as imposing many minor-to-serious life-threatening complications. Continuing education along with simulator-based skill development, vigilant supervision, and a shared workload during out of hours working are likely to prevent such occurrences.


Effects of aging and reduced relative frequency of knowledge of results on learning a motor skill.
Although there is evidence for age-related changes in both cognition and motor control, very little is known about the effect of age on learning of new motor skills. The present experiment addressed the interaction between aging and the role of knowledge of results (KR) on a motor learning task. Using a three-segment task on which each segment had specific timing goals, three different manipulations of relative frequency of information about performance were compared in younger and older adults. The three conditions were (a) 100% KR in which information about performance on each segment was provided after every trial, (b) 67% KR in which the performance information was faded over trials, and (c) 67% KR in which the performance information was faded over the segments within each trial. Following 90 acquisition trials, all subjects performed retention, transfer, and reacquisition tests. There were age-related differences for movement accuracy and consistency on acquisition and on the retention tests but not on the transfer test. However, none of these differences interacted with the frequency of KR manipulations. Surprisingly, there was no effect due to the fading schedules of KR. In general, these results indicated that younger and older adults use KR in a similar way to learn a motor skill.