Preventive effect of a chicken extract on the development of hypertension in stroke-prone spontaneously hypertensive rats.
The antihypertensive effect of Brand's Essence of Chicken (BEC), a popular chicken extract used as a traditional health food, was examined with stroke-prone spontaneously hypertensive rats (SHRSPs). The animals were maintained from 6 to 25 weeks of age on drinking water with or without BEC. The BEC-fed group showed a significant reduction in the development of hypertension when compared with the control animals. The levels of blood urea nitrogen and plasma creatinine in the BEC-fed group were significantly lower than those in the control group, suggesting that the renal glomerular function had been improved by the daily administration of BEC. It thus seems likely that BEC would be useful as a prophylactic treatment against the development of hypertension and renal injury.


"Waiting in Araf" research without consent: a Turkish mother's experience.
In this article, a nurse author from Turkey relates the anxiety and struggle that she experienced with the birth of her first baby when, for unknown reasons, the baby experienced acute rectal bleeding after birth. Unsatisfactory doctor-patient relations, abolishment of patient rights, suspicion of research without permission, and clinical iatrogenesis are discussed. The mother describes the 10 days she spent with her child in the hospital as "waiting in Araf." According to Middle Eastern culture, "Araf" is defined in the Koran as a place between Eden and Hell where people who have sinned are required to wait. Though anticipating acceptance into Eden, they wait with fear as they watch Hell on one side, and with hope while watching the happiness of Eden on the other side. The author's story depicts such an experience.


Treatment of severe mandibular fractures using AO reconstruction plates.
The goal of this study was to retrospectively evaluate the use of 2.4-mm AO titanium reconstruction plates for mandibular fractures. We analyzed the clinical and radiologic data of 63 patients with 63 single fractures (53 comminuted, 5 dislocated, and 5 with bone loss) and 2 patients with double fractures. Fracture location was symphysis in 37 patients (56.9%), body in 13 (20%), and angle in 15 (23.1%). We recorded the mechanism of injury, time between injury and surgery, gender and age, temporary maxillomandibular fixation (MMF) and its duration, and surgical approach. Follow-up examinations were performed at 1, 3, 6, and 12 months, at which time we noted the status of healing and any complications. Fifty patients (77%) had a successful treatment outcome without complications; 13 patients (20%) developed minor complications; and 2 patients (3%) developed nonunion with infection requiring hardware removal and reosteosynthesis with bone graft. We found that 2.4-mm AO titanium reconstruction plates can be used to treat severe mandibular fractures with a low rate of major complications (3%) and a high success rate.


Augmented GNSS differential corrections minimum mean square error estimation sensitivity to spatial correlation modeling errors.
Railway signaling is a safety system that has evolved over the last couple of centuries towards autonomous functionality. Recently, great effort is being devoted in this field, towards the use and exploitation of Global Navigation Satellite System (GNSS) signals and GNSS augmentation systems in view of lower railway track equipments and maintenance costs, that is a priority to sustain the investments for modernizing the local and regional lines most of which lack automatic train protection systems and are still manually operated. The objective of this paper is to assess the sensitivity of the Linear Minimum Mean Square Error (LMMSE) algorithm to modeling errors in the spatial correlation function that characterizes true pseudorange Differential Corrections (DCs). This study is inspired by the railway application; however, it applies to all transportation systems, including the road sector, that need to be complemented by an augmentation system in order to deliver accurate and reliable positioning with integrity specifications. A vector of noisy pseudorange DC measurements are simulated, assuming a Gauss-Markov model with a decay rate parameter inversely proportional to the correlation distance that exists between two points of a certain environment. The LMMSE algorithm is applied on this vector to estimate the true DC, and the estimation error is compared to the noise added during simulation. The results show that for large enough correlation distance to Reference Stations (RSs) distance separation ratio values, the LMMSE brings considerable advantage in terms of estimation error accuracy and precision. Conversely, the LMMSE algorithm may deteriorate the quality of the DC measurements whenever the ratio falls below a certain threshold.


Should we worry about the eyes of celiac patients?
In this article, we evaluate subfoveal choroidal thickness in celiac patients with respect to adherence to the gluten-free diet and nonadherence to the gluten-free diet, comparing with age and sex matched healthy controls using spectral-domain optical coherence tomography. A case-control study among 42 celiac patients and 42 healthy participants was conducted in the Department of Pediatric Gastroenterology. Celiac patients of our policlinics compliant with spectral-domain optical coherence tomography examination enrolled in the study. Celiac patients had been asked verbally about their adherence to gluten-free diet, were evaluated according to negative or positive EmA and anti-TG2 for defining adherence, and were divided into two groups (adherence to gluten-free diet and nonadherence to gluten-free diet). Subfoveal choroidal thickness was thinner in EmA (+) or anti-TG2 (+) eyes than EmA(-) or anti-TG2 (-) eyes in celiac patients, but it was not statistically significant. The mean subfoveal choroidal thickness values in eyes with celiac disease, whose diagnosis time was longer than 60 months, were thinner than shorter group. Longer duration of gluten-free diet was associated with adherence difficulty and thinner choroidal thickness (r = -0.15, p = 0.34). Adherence to gluten-free diet was 88.2% for children below the age of 60 months and 57.1% for children older than 60 months. In conclusion, in addition to other extraintestinal manifestations of celiac disease, diagnosis time longer than 60 months in pediatric celiac patients, nonadherence to the gluten-free diet, and antibody positivity should be focused on during ophthalmologic examination and choroid measurement.


The temporal course of T- and B-cell responses to vaccination with BNT162b2 and mRNA-1273.
To investigate the response of the immune system (and its influencing factors) to vaccination with BNT162b2 or mRNA-1273. 531 vaccinees, recruited from healthcare professionals, donated samples before, in between, and after the administration of the two doses of the vaccine. T- and B-cell responses were examined via interferon-γ (IFN-γ) release assay, and antibodies against different epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (S1 and NCP) were detected via ELISA and surrogate neutralization assay. Results were correlated with influencing factors such as age, sex, prior infection, vaccine received (BNT162b2 or mRNA-1273), and immunosuppression. Furthermore, antinuclear antibodies (ANAs) were measured to screen for autoimmune responses following vaccination with an mRNA vaccine. No markers of immunity against SARS-CoV-2 were found before the first vaccination. Two weeks after it, specific responses against SARS-CoV-2 were already measurable (median ± median absolute deviation (MAD): anti-S1 IgG 195.5 ± 172.7 BAU/mL; IgA 6.7 ± 4.9 OD; surrogate neutralization 39 ± 23.7%), and were significantly increased two weeks after the second dose (anti-S1 IgG 3744 ± 2571.4 BAU/mL; IgA 12 ± 0 OD; surrogate neutralization 100 ± 0%, IFN-γ 1897.2 ± 886.7 mIU/mL). Responses were stronger for younger participants (this difference decreasing after the second dose). Further influences were previous infection with SARS-CoV-2 (causing significantly stronger responses after the first dose compared to unexposed individuals (p ≤ 0.0001)) and the vaccine received (significantly stronger reactions for recipients of mRNA-1273 after both doses, p < 0.05-0.0001). Some forms of immunosuppression significantly impeded the immune response to the vaccination (with no observable immune response in three immunosuppressed participants). There was no significant induction of ANAs by the vaccination (no change in qualitative ANA results (p 0.2592) nor ANA titres (p 0.08) from pre-to post-vaccination. Both vaccines elicit strong and specific immune responses against SARS-CoV-2 which become detectable one week (T-cell response) or two weeks (B-cell response) after the first dose.


Nonlinear signal-processing model for scalar diffraction in optical recording.
A nonlinear signal-processing model is derived for the optical recording channel based on scalar diffraction theory. In this model, the signal waveform is written in closed form as an explicit function of the channel bits that are stored on an optical disk, thereby comprising both linear and nonlinear terms. Its explicit dependence on the channel bits makes this model well suited for signal-processing purposes. With the model it is also convenient to assess the importance of nonlinear contributions to the signal waveform. The model is applied for one-dimensional optical storage as well as for two-dimensional (2D) optical storage in which bits are arranged on a 2D hexagonal lattice. Signal folding is addressed as a typical nonlinear issue in 2D optical storage and can be eliminated by recording of pit marks of sizes considerably smaller than the size of the hexagonal bit cell. Further simplifications of the model with only a limited number of channel parameters are also derived.


Autism according to diagnostic and statistical manual of mental disorders 5(th) edition: The need for further improvements.
The fifth edition of the diagnostic and statistical manual of mental disorders (DSM-5) introduced significant changes in the classification of autism spectrum disorders (ASD), including the abolition of the diagnostic subcategories proposed by DSM-IV-Text Revision. DSM-5 describes three levels of increasing severity of ASD. The authors report two explanatory cases with ASD (verbal boys, aged about 7 and a half years, without intellectual disability). According to DSM-5, both cases fall into the lowest severity level of ASD. However, their neuropsychological and neurobehavioral profile varies significantly. While the first boy showed a prevalent impairment of visuoconstructional and visuoperceptual abilities, the second one presented a predominant involvement of verbal functions, with qualitative impairments in communication. A further step forward in the definition and classification of ASD, taking into account both intensity and quality of symptoms, is recommended in order to formulate a reliable prognosis, plan an individualized treatment and monitor the clinical course over time.


Two-dimensional movement control using electrocorticographic signals in humans.
We show here that a brain-computer interface (BCI) using electrocorticographic activity (ECoG) and imagined or overt motor tasks enables humans to control a computer cursor in two dimensions. Over a brief training period of 12-36 min, each of five human subjects acquired substantial control of particular ECoG features recorded from several locations over the same hemisphere, and achieved average success rates of 53-73% in a two-dimensional four-target center-out task in which chance accuracy was 25%. Our results support the expectation that ECoG-based BCIs can combine high performance with technical and clinical practicality, and also indicate promising directions for further research.


Deep learning in vivo catheter tip locations for photoacoustic-guided cardiac interventions.
Interventional cardiac procedures often require ionizing radiation to guide cardiac catheters to the heart. To reduce the associated risks of ionizing radiation, photoacoustic imaging can potentially be combined with robotic visual servoing, with initial demonstrations requiring segmentation of catheter tips. However, typical segmentation algorithms applied to conventional image formation methods are susceptible to problematic reflection artifacts, which compromise the required detectability and localization of the catheter tip. We describe a convolutional neural network and the associated customizations required to successfully detect and localize in vivo photoacoustic signals from a catheter tip received by a phased array transducer, which is a common transducer for transthoracic cardiac imaging applications. We trained a network with simulated photoacoustic channel data to identify point sources, which appropriately model photoacoustic signals from the tip of an optical fiber inserted in a cardiac catheter. The network was validated with an independent simulated dataset, then tested on data from the tips of cardiac catheters housing optical fibers and inserted into ex vivo and in vivo swine hearts. When validated with simulated data, the network achieved an F1 score of 98.3% and Euclidean errors (mean ± one standard deviation) of 1.02±0.84 mm for target depths of 20 to 100 mm. When tested on ex vivo and in vivo data, the network achieved F1 scores as large as 100.0%. In addition, for target depths of 40 to 90 mm in the ex vivo and in vivo data, up to 86.7% of axial and 100.0% of lateral position errors were lower than the axial and lateral resolution, respectively, of the phased array transducer. These results demonstrate the promise of the proposed method to identify photoacoustic sources in future interventional cardiology and cardiac electrophysiology applications.


Lead and zinc dust depositions from ore trains characterised using lead isotopic compositions.
This study investigates an unusual source of environmental lead contamination - the emission and deposition of lead and zinc concentrates along train lines into and out of Australia's oldest silver-lead-zinc mine at Broken Hill, Australia. Transport of lead and zinc ore concentrates from the Broken Hill mines has occurred for more than 125 years, during which time the majority was moved in uncovered rail wagons. A significant amount of ore was lost to the adjoining environments, resulting in soil immediately adjacent to train lines elevated with concentrations of lead (695 mg kg(-1)) and zinc (2230 mg kg(-1)). Concentrations of lead and zinc decreased away from the train line and also with depth shown in soil profiles. Lead isotopic compositions demonstrated the soil lead contained Broken Hill ore in increasing percentages closer to the train line, with up to 97% apportioned to the mined Broken Hill ore body. SEM examination showed ceiling dusts collected from houses along the train line were composed of unweathered galena particles, characteristic of the concentrate transported in the rail wagons. The loss of ore from the uncovered wagons has significantly extended the environmental footprint of contamination from local mining operations over an area extending hundreds of kilometres along each of the three train lines.


Patterns of treatment seeking behavior for mental illnesses in Southwest Ethiopia: a hospital based study.
Early recognition of the signs and symptoms of mental health disorders is important because early intervention is critical to restoring the mental as well as the physical and the social health of an individual. This study sought to investigate patterns of treatment seeking behavior and associated factors for mental illness. A quantitative, institution-based cross sectional study was conducted among 384 psychiatric patients at Jimma University Specialized Hospital (JUSH) located in Jimma, Ethiopia from March to April 2010. Data was collected using a pretested WHO encounter format by trained psychiatric nurses. Data was analyzed using SPSS V.16. Major depression disorder 186 (48.4%), schizophrenia 55 (14.3%) and other psychotic disorders 47 (12.2%) were the most common diagnoses given to the respondents. The median duration of symptoms of mental illness before contact to modern mental health service was 52.1 weeks. The main sources of information for the help sought by the patients were found to be family 126 (32.8%) and other patients 75 (19.5%). Over a third of the patients 135 (35.2%), came directly to JUSH. Half of the patients sought traditional treatment from either a religious healer 116 (30.2%) or an herbalist 77 (20.1%) before they came to the hospital. The most common explanations given for the cause of the mental illness were spiritual possession 198 (51.6%) and evil eye 61 (15.9%), whereas 73 (19.0%) of the respondents said they did not know the cause of mental illnesses. Nearly all of the respondents 379 (98.7%) believed that mental illness can be cured with modern treatment. Individuals who presented with abdominal pain and headache were more likely to seek care earlier. Being in the age group 31-40 years had significant statistical association with delayed treatment seeking behavior. There is significant delay in modern psychiatric treatment seeking in the majority of the cases. Traditional healers were the first place where help was sought for mental illness in this population. Most of the respondents claimed that mental illnesses were caused by supernatural factors. In contrast to their thoughts about the causes of mental illnesses however, most of the respondents believed that mental illnesses could be cured with biomedical treatment. Interventions targeted at improving public awareness about the causes and treatment of mental illness could reduce the delay in treatment seeking and improve treatment outcomes.


Controls on Fe(II)-activated trace element release from goethite and hematite.
Electron transfer and atom exchange (ETAE) between aqueous Fe(II) and Fe(III) oxides induces surface growth and dissolution that affects trace element fate and transport. We have recently demonstrated Ni(II) cycling through goethite and hematite (adsorbed Ni incorporates into the mineral structure and preincorporated Ni releases to solution) during Fe(II)-Fe(III) ETAE. However, the chemical parameters affecting net trace element release remain unknown. Here, we examine the chemical controls on Ni(II) and Zn(II) release from Ni- and Zn-substituted goethite and hematite during reaction with Fe(II). Release follows a rate law consistent with surface reaction limited mineral dissolution and suggests that release occurs near sites of Fe(III) reductive dissolution during Fe(II)-Fe(III) ETAE. Metal substituent type affects reactivity; Zn release is more pronounced from hematite than goethite, whereas the opposite trend occurs for Ni. Buildup of Ni or Zn in solution inhibits further release but this resumes upon fluid exchange, suggesting that sustained release is possible under flow conditions. Mineral and aqueous Fe(II) concentrations as well as pH strongly affect sorbed Fe(II) concentrations, which directly control the reaction rates and final metal concentrations. Our results demonstrate that structurally incorporated trace elements are mobilized from iron oxides into fluids without abiotic or microbial net iron reduction. Such release may affect micronutrient availability, contaminant transport, and the distribution of redox-inactive trace elements in natural and engineered systems.


Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2).
The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors.


Effect of attenuation correction on lesion detection using a hybrid PET system.
The purpose of this study was to investigate the effect of attenuation correction (AC) on lesion detection for a hybrid PET system. Experimental list-mode data were acquired from hot spheres inside a uniform cylindrical phantom with an elliptical cross-section using a Siemens E. CAM+ dual-camera hybrid PET system. Spheres with inner diameters of 0.8- and 1-cm and the cylindrical phantom were filled with F-18 to simulate lesions with lesion-to-background (L/B) ratios of 14:1 and 8:1, respectively, found in clinical PET studies. The list-mode data of each sphere size were regrouped into sinograms with peak-to-peak energy window settings at 30% and 20% for the 0.8- and 1-cm diameter lesion, respectively. They were then rebinned using the single slice rebinning method. Attenuation correction was applied assuming uniform attenuation. The sinograms with and without AC were reconstructed using 5 iterations of OS-EM algorithm with 8 angles/ subset and postfiltered with a Butterworth filter with n = 5 and fc = 0.52 cycles/cm. Human observer performance study and localization receiver operating characteristic (LROC) analysis were used to evaluate the reconstructed images for maximum lesion detection. Average areas under the LROC curves (A(LROC)) across 8 observers obtained with and without AC were determined. The null hypothesis that there was no difference between with AC and without AC was tested using a two-tailed t-test with 95% confidence interval. The results indicated that for the 0. 8-cm lesion with 14:1 L/B ratio, the A(LROC) decreases from 0.66 to 0.62 when AC is applied as compared to without AC andfrom 0.69 to 0.63 for the 1.0-cm lesion with 8:1 L/ B ratio, but no statistical significant difference (p > 0. 05). The authors conclude that for a phantom with hot lesions embedded in a uniform background, AC decreases lesion detectability compared to without AC using a hybrid PET system for small lesion sizes.


Corneal change accompanying orthokeratology. Plastic or elastic? Results of a randomized controlled clinical trial.
Effects of orthokeratology on refractive error, visual acuity, and corneal curvature were monitored on two randomized comparison groups for 364 days of lens wear and 95 days of follow-up after lens wear was discontinued. Approximately 36% of the treatment group compared with 13% of the control group had 1 diopter or more change in refractive error; however, after lens wear was discontinued, there was substantial remission and differences between the groups were small. Although there was a positive correlation between the amount of change during lens wear and the persistence of change after discontinuation, neither the magnitude of persistence nor differences between groups were clinically important. The lack of persistence indicates that the cornea is either highly elastic or has some other memory mechanism. We conclude that orthokeratology produces modest reductions in myopia; however, the effect will not persist without continued lens wear and therefore is of limited clinical value in permanently reducing myopia.


Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity.
MIM (Missing-in-Metastasis), also known as MTSS1 (metastasis suppressor 1), is a scaffold protein that is down-regulated in multiple metastatic cancer cell lines compared with non-metastatic counterparts. MIM regulates cytoskeletal dynamics and actin polymerization, and has been implicated in the control of cell motility and invasion. MIM has also been shown to bind to a receptor PTP (protein tyrosine phosphatase), PTPδ, an interaction that may provide a link between tyrosine-phosphorylation-dependent signalling and metastasis. We used shRNA-mediated gene silencing to investigate the consequences of loss of MIM on the migration and invasion of the MCF10A mammary epithelial cell model of breast cancer. We observed that suppression of MIM by RNAi enhanced migration and invasion of MCF10A cells, effects that were associated with increased levels of PTPδ. Furthermore, analysis of human clinical data indicated that PTPδ was elevated in breast cancer samples when compared with normal tissue. We demonstrated that the SRC protein tyrosine kinase is a direct substrate of PTPδ and, upon suppression of MIM, we observed changes in the phosphorylation status of SRC; in particular, the inhibitory site (Tyr527) was hypophosphorylated, whereas the activating autophosphorylation site (Tyr416) was hyperphosphorylated. Thus the absence of MIM led to PTPδ-mediated activation of SRC. Finally, the SRC inhibitor SU6656 counteracted the effects of MIM suppression on cell motility and invasion. The present study illustrates that both SRC and PTPδ have the potential to be therapeutic targets for metastatic tumours associated with loss of MIM.


[A method of hermetic sealing of glass tubes to be filled with polyacrylamide gel].
A reliable and simple system is suggested for hermetic sealing of glass tubes to be filled with polyacrylamide gel. It consists of a disk made of hydrophobic material (teflon, capronyl), whose diameter corresponds to that of the tube and rubber sleeve with an inner diameter of 1 mm less than that of the tube and disk. In assembly the disk closes the bottom end of the tube and is fixed with the rubber sleeve.


Brief Report: Sexual Attraction and Relationships in Adolescents with Autism.
Past research suggests more variation in sexual attraction in Autism Spectrum Disorder (ASD) using clinical samples. This study utilised a population representative group of 14/15 year olds from the Longitudinal Study of Australian Children. Ninety-four adolescents (73 males, 21 females) with ASD and 3454 (1685 males, 1675 females) without self-reported on sexual attraction and past sexual relationships. Females with ASD reported lower rates of heterosexual preference (adjusted odds ratio: 0.14, p < .001), higher rates of bisexuality (adjusted odds ratio: 6.05, p < .001) and uncertainty in attraction (adjusted odds ratio: 10.44, p < .001) compared with non-ASD females. ASD males reported fewer prior boyfriends/girlfriends. Findings confirm female adolescents with ASD have differences in sexual attraction compared with non-ASD females.


Observing Dissipative Topological Defects with Coupled Lasers.
Topological defects have been observed and studied in a wide range of systems, such as cosmology, spin systems, cold atoms, and optics, as they are quenched across a phase transition into an ordered state. These defects limit the coherence of the system and its ability to approach a fully ordered state, so revealing their origin and control is becoming an increasingly important field of research. We observe dissipative topological defects in a one-dimensional ring of phased-locked lasers, and show how their formation is related to the Kibble-Zurek mechanism and is governed in a universal manner by two competing time scales. The ratio between these two time scales depends on the system parameters, and thus offers the possibility of enabling the system to dissipate to a fully ordered, defect-free state that can be exploited for solving hard computational problems in various fields.


[Primary lipodystrophies].
Primary lipodystrophies represent a heterogeneous group of very rare diseases with a prevalence of less than 1 case for 100.000, inherited or acquired, caracterized by a loss of body fat either generalized or localized (lipoatrophy). In some forms, lipoatrophy is associated with a selective hypertrophy of other fat depots. Clinical signs of insulin resistance are often present: acanthosis nigricans, signs of hyperandrogenism. All lipodystrophies are associated with dysmetabolic alterations with insulin resistance, altered glucose tolerance or diabetes and hypertriglyceridemia leading to a risk of acute pancreatitis. Chronic complications are those resulting from diabetes involving the retina, kidney and nerves, cardiovascular complications and steatotic liver lesions that could result in cirrhosis. Genetic forms of generalized lipodystrophy (or Berardinelli-Seip syndrome) result, in most cases, from recessive mutations in one of two genes: either BSCL2 coding seipin or BSCL1 coding AGPAT2, an acyl-transferase involved in triglyceride synthesis. Acquired generalized lipodystrophy (Lawrence syndrome) is of unknown origin but is sometimes associated with signs of autoimmunity. Partial lipodystrophies can be familial with dominant transmission. Heterozygous mutations have been identified in the LMNA gene encoding nuclear lamin A/C belonging to the nuclear lamina, or in PPARG encoding the adipogenic transcription factor PPARgamma. Some less typical lipodystrophies, associated with signs of premature aging, have been linked to mutations in LMNA or in the ZMPSTE24 gene encoding the protease responsible for the maturation of prelamin A into lamin A. Acquired partial lipodystrophy (Barraquer-Simons syndrome) is characterized by cephalothoracic fat loss. Its aetiology is unknown but mutations in LMNB2, encoding the lamina protein lamin B2, could represent susceptibility factors. Highly active antiretroviral treatments for HIV infection are currently the most frequent cause of acquired secondary lipodystrophic syndromes. The genetic diagnosis is performed in specialized laboratories and, in the most severe forms, antenatal diagnosis could be proposed. Treatment of diabetes, dyslipidemia and complications involves the classical intervention strategies. Insulino-sensitizing drugs are useful. Therapeutic trials with recombinant human leptin in patients with very low leptin levels reported good results with respect to the metabolic and liver alterations. The prognosis is linked to the precocity and severity of the diabetic, cardiovascular and liver complications.


Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Novel biomarkers are required to aid treatment decisions and improve patient outcomes. MicroRNAs (miRNAs) are potentially ideal diagnostic biomarkers, as they are stable molecules, and tumour and tissue specific. Logistic regression analysis revealed an endoscopic-ultrasound fine-needle aspiration (EUS-FNA) 2-miRNA classifier (miR-21 + miR-155) capable of distinguishing benign from malignant pancreatic lesions with a sensitivity of 81.5% and a specificity of 85.7% (AUC 0.930). Validation FNA cohorts confirmed both miRNAs were overexpressed in malignant disease, while circulating miRNAs performed poorly. Fifty-five patients with a suspicious pancreatic lesion on cross-sectional imaging were evaluated by EUS-FNA. At echo-endoscopy, the first part of the FNA was sent for cytological assessment and the second part was used for total RNA extraction. Candidate miRNAs were selected after careful review of the literature and expression was quantified by qRT-PCR. Validation was performed on an independent cohort of EUS-FNAs, as well as formalin-fixed paraffin embedded (FFPE) and plasma samples. We provide further evidence for using miRNAs as diagnostic biomarkers for pancreatic malignancy. We demonstrate the feasibility of using fresh EUS-FNAs to establish miRNA-based signatures unique to pancreatic malignant transformation and the potential to enhance risk stratification and selection for surgery.


The role of adult bone marrow-derived stem cells in choroidal neovascularization.
Age-related macular degeneration (ARMD) is the primary cause of blindness in people aged of 50 years or more. The wet form leads to severe loss of central vision. Recent evidence supports that adult hematopoietic stem cells (HSCs) contribute to preretinal neovascularization. In the current study, it was determined whether HSCs, by producing both blood and blood vessels, provide functional hemangioblast activity during choroidal neovascularization (CNV) in mice. Gfp chimeric mice were developed by bone marrow ablation of C57BL/6J mice and reconstitution with donor tissue from gfp(+/+) transgenic mice. Gfp chimeric mice underwent laser rupture of Bruch's membrane and were killed and eyes enucleated at 1, 2, 3, and 4 weeks after laser injury. CNV was examined by confocal microscopy of retinal flatmounts. Because endothelial progenitor cells (EPCs) derive from HSCs, immunocytochemistry was used to quantify relative the EPC contribution to CNV. Laser injury alone was sufficient to induce stem cell recruitment and subsequent CNV. Gfp+ cells formed part of the functional vasculature in the choroid as early as 1 week after injury and were present for the duration of the study. The relative EPC contribution to CNV remained fairly constant throughout the study and constituted almost 50% of the total vasculature. Adult stem cells are recruited to the choroid in a model of CNV, where they contribute to forming aberrant new vessels. This observation suggests that targeting stem cell recruitment to the eye may offer a novel therapeutic strategy for ARMD.


Novel viral sequences related to human T-cell leukemia virus in T cells of a seropositive baboon.
Antibodies reactive with proteins of human T-cell leukemia virus (HTLV) can be found in Old World monkeys. A T-lymphocyte cell line established from a seropositive baboon (Papio cynocephalus) was analyzed for the presence of viral DNA sequences. The provirus found in these cells was related to but distinct from HTLV subgroup I. These results add to recent evidence from human studies that HTLV represents a spectrum of infectious T-lymphotropic retroviruses that includes closely and distantly related members.


Integration of proviral DNA into the PDGF beta-receptor gene in HTLV-I-infected T-cells results in a novel tyrosine kinase product with transforming activity.
We have previously shown that noninfected human T-cell lines express the canonical 5.7 kb mRNA coding for the type beta platelet-derived growth factor-receptor (PDGF beta-receptor), whereas HTLV-I-infected T-cell lines express a novel PDGF beta-receptor mRNA of 3.8 kb. In this report, we have extended those studies to molecularly characterize the 3.8 kb PDGF beta-receptor mRNA and show that it has resulted from integration of an apparently undeleted HTLV-I provirus into the PDGF beta-receptor gene in an orientation enabling expression of a truncated PDGF beta-receptor mRNA using the 3' HTLV-I long terminal repeat as a promoter. Further, NIH3T3 cells transfected with a plasmid containing the truncated PDGF beta-receptor ORF plasmid generate colonies in soft agar with more cells per colony than untransfected cells, or cells transfected with the Tax 1 or PDGF-B (c-sis) plasmids. These results indicate that the truncated PDGF beta-receptor protein acquires transforming capability and that HTLV-I-induced truncation of PDGF beta-receptor may correlate with HTLV-I-associated neoplasia of human T-cells.


Normal keratinocytes suppress early stages of neoplastic progression in stratified epithelium.
The importance of interactions between potentially neoplastic cells and their normal neighbors on malignant progression of precancerous lesions is not well understood. In this study, we have established novel human tissue models that simulate intraepithelial neoplasia in stratified epithelia to investigate the fate and phenotype of neoplastic keratinocyte clones in normal cell context during clonal expansion and early malignant progression. This was accomplished by mixing genetically marked keratinocytes with malignant potential (II-4) with normal keratinocytes at ratios of 1:1, 4:1, 12:1, and 64:1 (normal:II-4) to visualize nests of marked, dysplastic cells in organotypic cultures and in cultures transplanted to nude mice. Four weeks after transplantation of 4:1 mixtures, grafts were normal and demonstrated no beta-galactosidase (beta-gal)-positive cells, suggesting that cells with malignant potential were eliminated from the tissue at this mixing ratio. However, grafted 1:1 mixtures demonstrated persistence of expanded foci of dysplastic cells (4 weeks) and invasion (8 weeks). This demonstrated that the capacity of a keratinocyte clone with neoplastic potential to persist and invade is directly related to the threshold number of such keratinocytes present in the tissue. To explain the failure of II-4 to persist in vivo, the intraepithelial dynamics between the two populations were studied before grafting. Double-stain immunofluorescence for bromodeoxyuridine/beta-gal and filaggrin/beta-gal of mixtures grown in organotypic cultures for 7 days demonstrated that when increasing numbers of normal cells were added (12:1), II-4 ceased to proliferate and expressed filaggrin. This suggests a novel mechanism of tumor suppression wherein contact with normal cells induces cell cycle withdrawal and terminal differentiation of potentially malignant cells. These findings support the view that normal tissue architecture acts as a dominant suppressor of early neoplastic progression in stratified epithelium.


A decoherence-free quantum memory using trapped ions.
We demonstrate a decoherence-free quantum memory of one qubit. By encoding the qubit into the decoherence-free subspace (DFS) of a pair of trapped 9Be+ ions, we protect the qubit from environment-induced dephasing that limits the storage time of a qubit composed of a single ion. We measured the storage time under ambient conditions and under interaction with an engineered noisy environment and observed that encoding into the DFS increases the storage time by up to an order of magnitude. The encoding reversibly transfers an arbitrary qubit stored in a single ion to the DFS of two ions.


Unveiling the Power of Gabapentin-Loaded Nanoceria with Multiple Therapeutic Capabilities for the Treatment of Dry Eye Disease.
Dry eye (DE) disease, which is primarily linked to aqueous deficiency, is an escalating health issue worldwide, mainly due to the widespread use of electronic devices. The major obstacles in DE pharmacotherapy include insufficient therapeutic efficacy and low ocular bioavailability. This study presents the development of a ceria-based nanosystem to carry gabapentin (GBT), aiming to offer comprehensive relief from DE symptoms. We prepared multifunctional nanoceria capped with thiolated gelatin followed by cross-linking with glutaraldehyde, yielding a nanocarrier with desirable biocompatibility and antioxidant, anti-inflammatory, antiangiogenic, antiapoptotic, and neuronal protective activities. Specifically, the highly abundant thiol groups on gelatin increased the cellular uptake of the nanocarrier by 2.3-fold and its mucin-binding efficiency by 10-fold, thereby extending ocular retention and amplifying therapeutic activity. Moderate cross-linking of the thiolated gelatin not only enhanced the ocular bioavailability of the nanoceria but also provided slow, degradation-controlled release of GBT to promote the lacrimal stimulation to restore the tear film. In a rabbit model of DE, topical administration of our GBT/nanoceria nanoformulation resulted in comprehensive alleviation of symptoms, including repairing corneal epithelial damage, preserving corneal nerve density, and stimulating tear secretion, demonstrating superior performance in comparison to the free drug. These results underscore the safety and potential of this innovative nanoformulation for DE pharmacotherapy.


Collagen balls in cervica-vaginal smears.
To dewribe the recent detection of collagen balls in cervical-vaginal specimens from 7 women within the previous 2 years. Papaniolaou-stained cervical-vaginal specimens, 3 conventional and 4 ThinPreps (Cytyc Corp., Boxborgugh, Massachusetts, U.S.A.), were reviewed due to the presence of structures indistinguishable from collagen balls. The structures displayed 3-dimensionality, a hyalinized core and a covering of benign-appearing cells,fratures identical to those seen in collagen balls from serous cavity fluids. Averaging 94 x 60 microm, they were similar in size to a human oocyte at ovulation. Their presence did not correlate with any concurrent Pap smear findings or previous medical history. Since collagen balls have previously been reported to occur only in serous cavity fluids, they are thought to arise at those locations. We propose that collagen balls are transported via the fallopian tube and uterine fundus to the cervix, much in the same way that an ovum is transported to the uterine flindus for implantation. The likelihood of such an event is most probably quite low. The recent finding of 7 cases of collagen balls may correlate with an increased prevalence of collagen balls in peritonealfl uids, thus increasing the probability of their transport to the cervix.


A critical study of the student interns' practice activities in a chiropractic college teaching clinic.
The diagnoses and treatment provided for 2000 patients attending a chiropractic college teaching clinic are described. The relationship between presenting complaint and the diagnostic and treatment procedures used is examined. Inconsistencies were noted with regard to interns' practice activities. Certain therapeutic modalities were clearly underutilized. Interns rarely sought advice or help in diagnosis or treatment, and they were generally unable to successfully predict the number of treatments that would be required. Support is given that links these findings to the fact that patients are not truly representative of patients seen by chiropractors in the field; they are relatively young, with mild complaints. The study concludes that students' clinical training and experience may not reach the level at which they will be tested by patient problems in active practice after graduation. Three alternatives to the current clinical teaching model are presented.


Antegrade vs Crossover Femoral Artery Access in the Endovascular Treatment of Isolated Below-the-Knee Lesions in Patients With Critical Limb Ischemia.
To evaluate the safety and effectiveness of antegrade vs crossover femoral artery access in the endovascular treatment of isolated below-the-knee (BTK) lesions in patients with critical limb ischemia (CLI). Between January 2014 and December 2015, 224 high-risk patients (mean age 75.8±9.8 years; 151 men) with CLI underwent infragenicular interventions on 292 crural vessels in 3 European vascular centers. All patients had isolated TransAtlantic Inter-Society Consensus (TASC) C (n=26) or D (n=198) BTK lesions. Primary endpoints were freedom from access-related complications and technical success comparing the antegrade vs crossover access groups. Balloon angioplasty was the most used treatment modality (169 vessels, 75.4%). The technical success rate was 88.4% in the entire cohort and 88.0% in the antegrade group vs 90.4% in the crossover group (p>0.99). In all patients, the technical success rate was higher for stenotic lesions (100%) vs occlusions (85.5%, p=0.002) and in patients with TASC C BTK lesions (100%) vs TASC D (86.9%, p=0.033). The overall freedom from access-related complications was 97.8%: 99% in the antegrade group and 90.6% in the crossover group (p=0.022). Larger sheath size (5/6-F vs 4-F) was associated with a significantly higher risk for access-related complications (7.1% vs 1.1%, respectively; p=0.047). The present multicenter study showed high technical success and a low incidence of access-related complications in the treatment of isolated BTK lesions using either antegrade or crossover femoral access. The antegrade approach with the use of a 4-F system seems to have a significantly lower rate of access-related complications.


Use of cytological preparations for the intraoperative diagnosis of stereotactically obtained brain biopsies: a 19-year experience and survey of neuropathologists.
The goals of this study were to analyze the accuracy of cytological techniques, consisting of touch and smear preparations, for the intraoperative diagnosis of stereotactically obtained brain biopsy samples, and to determine the prevalence of the use of these methods among neuropathologists. A survey regarding preferred methods for intraoperative diagnosis of stereotactically obtained brain biopsy samples was completed by 92 (62%) of 148 neuropathologists. Twenty-three percent of respondents chose frozen-section examination alone; 13% chose one or more cytological methods alone; and the remainder (64%) chose a combination of frozen-section examination and cytology. At the University of Pittsburgh, the neuropathology records for all stereotactic brain biopsies performed from May 1979 through May 1998 were retrospectively reviewed. Of the 946 stereotactic brain biopsies, 316 cases were excluded because the intraoperative neuropathological consultation was not recorded. Thirty-five cases were excluded because frozen-section examinations were performed. Therefore, a total of 595 cases were suitable for analysis. Intraoperative cytological investigation correlated with the final diagnosis in 90% of cases (52% complete correlation and 38% partial correlation). In 11% of cases there was no correlation between the intraoperative and final diagnoses. Intraoperative diagnoses were most accurate in cases of abscess, germinoma, lymphoma, metastasis, and malignant glioma. Overall, 91% of biopsy specimens were diagnostic when examined using the paraffin-embedded section technique. The sensitivity of cytological preparations in detecting a diagnostic specimen was 96% and the specificity in detecting a nondiagnostic specimen was 75%. Intraoperative cytological preparations correlated with the final diagnoses in 90% of stereotactic biopsies and had a 96% sensitivity in detecting diagnostic specimens. The highest rate of correlation was noted in cases of abscess, germinoma, lymphoma, metastasis, and malignant glial tumor.


Urologic considerations and complications in kidney transplant recipients.
Urologic considerations during the kidney transplantation process, starting with initial recipient evaluation and continuing through the post-transplant, long-term follow-up, are critical for minimizing urologic complications and improving graft survival. Appropriate, targeted, preoperative urologic evaluation of the recipient allows for an optimized urinary tract to accept the graft, whereas post-transplant urologic follow-up and monitoring decrease the risk of graft lost secondary to a urologic cause, particularly in patients with a urologic reason for their kidney failure and in those patients with concomitant urologic diagnoses. Urologic complications comprise the second most common adverse post-transplant event, occurring in 2.5% to 14% of patients and are associated with high morbidity, graft loss, and mortality. Early and late urologic complications, including hematuria, hematoma, lymphocele, urine leak, ureteral stricture, nephrolithiasis, and vesicoureteral reflux, and their causes and treatment options are explored. A multidisciplinary team approach to kidney transplantation, including transplant surgery, urology, and nephrology, optimizes outcomes and graft survival. Although the current role of the urologist in kidney transplantation varies greatly by institution, appropriate consultation, participation, and monitoring in select patients is essential.


Periocular and intra-articular injection of canine adipose-derived mesenchymal stem cells: an in vivo imaging and migration study.
Immune-mediated diseases affect millions of people worldwide with an economic impact measured in the billions of dollars. Mesenchymal stem cells (MSCs) are being investigated in the treatment of certain immune mediated diseases, but their application in the treatment of the majority of these disorders remains largely unexplored. Keratoconjunctivitis sicca can occur as a result of progressive immune-mediated destruction of lacrimal tissue in dogs and humans, and immune-mediated joint disease is common to both species. In dogs, allogeneic MSC engraftment and migration have yet to be investigated in vivo in the context of repeated injections. With these aims in mind, the engraftment of allogeneic canine MSCs after an injection into the periocular and intra-articular regions was followed in vivo using magnetic resonance and fluorescent imaging. The cells were shown to be resident near the site of the injection for a minimum of 2 weeks. Analysis of 61 tissues demonstrated preferential migration and subsequent engraftment of MSCs in the thymus as well as the gastrointestinal tract. These results also detail a novel in vivo imaging technique and demonstrate the differential spatial distribution of MSCs after migration away from the sites of local delivery. The active engraftment of the MSCs in combination with their previously documented immunomodulatory capabilities suggests the potential for therapeutic benefit in using MSCs for the treatment of periocular and joint diseases with immune involvement.


Efficient Inner-to-Outer Wall Energy Transfer in Highly Pure Double-Wall Carbon Nanotubes Revealed by Detailed Spectroscopy.
The coaxial stacking of two single-wall carbon nanotubes (SWCNTs) into a double-wall carbon nanotube (DWCNT), forming a so-called one-dimensional van der Waals structure, leads to synergetic effects that dramatically affect the optical and electronic properties of both layers. In this work, we explore these effects in purified DWCNT samples by combining absorption, wavelength-dependent infrared fluorescence-excitation (PLE), and wavelength-dependent resonant Raman scattering (RRS) spectroscopy. Purified DWCNTs are obtained by careful solubilization that strictly avoids ultrasonication or by electronic-type sorting, both followed by a density gradient ultracentrifugation to remove unwanted SWCNTs that could obscure the DWCNT characterization. Chirality-dependent shifts of the radial breathing mode vibrational frequencies and transition energies of the inner and outer DWCNT walls with respect to their SWCNT analogues are determined by advanced two-dimensional fitting of RRS and PLE data of DWCNT and their reference SWCNT samples. This exhaustive data set verifies that fluorescence from the inner DWCNT walls of well-purified samples is severely quenched through efficient energy transfer from the inner to the outer DWCNT walls. Combined analysis of the PLE and RRS results further reveals that this transfer is dependent on the inner and outer wall chirality, and we identify the specific combinations dominant in our DWCNT samples. These obtained results demonstrate the necessity and value of a combined structural characterization approach including PLE and RRS spectroscopy for bulk DWCNT samples.


Strategic planning with multitype libraries in the community: a model with extra funding as the main goal.
Medical libraries are discovering that ongoing collaboration in fundraising with other types of community libraries is mutually beneficial. Such partnerships may lead to joint grants, increase library visibility and access to decision makers, allow participation in community information networks, and provide leverage in additional fundraising projects. These partnerships have the potential to raise the profile of libraries. The accompanying community recognition for the parent organization may create a positive image, draw patients to the health center, and position the library and institution for future success in fundraising. Within institutions, development officers may become allies, mentors, and beneficiaries of the medical librarian's efforts. For a planned approach to community outreach with extra funding as the major objective, busy medical library administrators need guidelines. Standard participative techniques were applied to strategic planning by Indianapolis libraries to help achieve successful community outreach and to write joint statements of mission, vision, goals, and objectives.


Legal "rites": criminalizing the mentally ill.
1. Because of more stringent civil commitment criteria, persons formerly hospitalized on a civil commitment now enter the system on criminal observation orders, having been arrested, booked, and often jailed for minor offenses such as vagrancy, shoplifting, or disorderly conduct. This represents a criminalization of the mentally ill. 2. In a single forensic system (Wisconsin) there was an increase of 73% in such commitments following court decisions and legislative revisions setting forth new commitment criteria. This increase was principally in criminal observations, although this rise was evident as well in "unable to stand trial" commitments. It was not present in "not guilty by reason of insanity" adjudications. 3. Aside from the obvious untoward effects per se of criminalizing mentally ill persons, other untoward effects occur in terms of prolonging hospitalization, depriving those persons of prompt treatment, and putting unnecessary and inhumane pressures on the family and the community, as well as on the mentally ill person himself. 4. The "freedom" to the penniless, helpless, ill, and finally arrested, jailed and criminally committed is not freedom at all--it's abandonment. The "right" to be demented, agonized and terrorized in the face of treatment which cannot, because of legal prohibition, be applied is no right at all--it's a new form of imprisonment. The "liberty" to be naked in a padded cell, hallucinating, delusional, and tormented, is not liberty--it is a folie à deux between pseudo-sophisticated liberals and an unrealizing public. The delusion is that if one changes the name of something to something else, or if one substitutes a jail for a hospital or a preoccupation with legal rites for honest concern over patients' rights, he has done something significant, useful and important, or at least something.


Bioactivity of androgens within the testes and serum of normal men.
Little is known about how human spermatogenesis is regulated, so it is not surprising that there have been few breakthroughs in the treatment of male infertility resulting from abnormalities of spermatogenesis. Testosterone is the predominant intratesticular steroid in both the rat and man. Previous studies have shown that the testosterone concentration within the rat testis that is required for the quantitative maintenance of spermatogenesis is far higher than the total testosterone concentration in rat blood, indicating that much of the testosterone within the testis might be biologically inactive. In contrast to the rat, little is known about the androgen requirements for human spermatogenesis, in part because, until recently, a minimally invasive method suitable for obtaining intratesticular fluids from the human testis has not been available. Percutaneous aspiration now makes it feasible to do so. A major objective of the present study was to assay the bioactive androgen concentration within the testes of normal, fertile men. Percutaneous aspiration was used to obtain intratesticular fluid from such men, and we adapted a highly sensitive recombinant protein mammalian cell-based bioassay to measure androgen bioactivity. Total intratesticular testosterone concentration, which we define as immunoreactive testosterone as measured by radioimmunoassay, was well in excess of that in serum (1236 +/- 86 nM vs 11.7 +/- 0.7 nM). The concentration of bioactive androgens within the normal human testis was found to be about two thirds that of the total testosterone concentration. Interestingly, the concentration of the major, known binding proteins for testosterone within the testis, serum hormone-binding globulin (SHBG)/ABP (52.4 +/- 9.7 nM), was insufficient to account for the difference between total testosterone and bioactive androgens. This indicates that, in addition to its binding to SHBG/ABP, androgens may also be bound by unknown molecules, and that this contributes to reducing androgen bioactivity. These observations could have relevance for understanding the relationship between spermatogenesis and intratesticular androgens in normal men and in men diagnosed with infertility.


Reconstruction of the bile duct with transanastomotic U tubes.
Thirty-one adult patients have undergone reconstruction of the bile duct using a transanastomotic U tube to stent biliary-enteric anastomoses. The U tube is brought through the substance of the liver into the proximal part of the bile duct, threaded through the anastomosis, usually to a Roux-en-Y limb of jejunum and then withdrawn from the jejunum through a separate enterotomy. Both ends of the Silastic (silicone rubber) catheter are then brought out the abdominal wall through separate stab incisions and secured to the abdominal wall. In 21 patients, the procedure was performed for benign disease. There were no operative deaths. Recurrent strictures developed in two patients (9.5 per cent). There were seven infectious complications, none of which were life-threatening. Preoperative bilirubin levels averaged 9.5 milligrams per cent; postoperative bilirubin levels averaged 2.6 milligrams per cent. Recurrent stricture developed in two patients at 20 and 19 months after removal of the U tubes. In ten patients, the obstruction of the biliary tract was secondary to malignant disease--seven primary tumors of the biliary tract and three metastatic tumors. Operative mortality was 20 per cent. Among the patients who survived the operation, the average bilirubin level was 6.6 milligrams per cent as compared with the average preoperative level of 14.4 milligrams per cent.


Jumping translocations in spontaneous abortions.
Chromosome translocations involving one donor chromosome and multiple recipient chromosomes have been referred to as jumping translocations (JTs). Acquired JTs are commonly observed in cancer patients, mainly involving chromosome 1. Constitutional forms of JTs mostly involve the acrocentric chromosomes and their satellites and have been reported in patients with clinical abnormalities. Recognizable phenotypes resulting from these events have included Down, Prader-Willi, and DiGeorge syndromes. The presence of JTs in spontaneous abortions has not been previously described. The breakpoints of all JTs occur in areas rich in repetitive DNA (telomeric, centromeric, and nucleolus organizing regions). We report two different unstable chromosome rearrangements in samples derived from spontaneous abortions. The first case involved a chromosome 15 donor. The recipient chromosomes were 1, 9, 15, and 21, and the respective breakpoints were in either the heterochromatic regions or the centromeres. FISH studies confirmed that the breakpoints of the jumping 15 rearrangement did not involve the Prader-Willi region but originated at the centromere or in the proximal short arm. A second case of instability was observed with a rearrangement resulting from a presumed de novo 8;21 translocation. Three JT cell lines were observed. They consisted of a deleted 8p chromosome, a dicentric 8;21 translocation, and an 8q isochromosome. The instability regions appeared to be at the pericentromeric region of chromosome 8 and the satellite region of chromosome 21. Both cases proved to be de novo events. The unstable nature of the JT resulting in chromosomal imbalance most likely contributed to the fetal loss. It appears that JT events may predispose to chromosomal imbalance via nondisjunction and chromosomal rearrangement and, therefore, may be an unrecognized cause of fetal loss.


Association between plasminogen activator inhibitor gene polymorphisms and osteonecrosis of the femoral head susceptibility: A case-control study.
This study aimed to analyze the correlation of the plasminogen activator inhibitor (PAI-1) gene polymorphisms (rs6092 and rs7242) with susceptibility of osteonecrosis of the femoral head (ONFH).This case-control study included 106 ONFH patients and 151 healthy controls. PAI-1 polymorphisms were genotyped by polymerase chain reaction (PCR) with direct sequencing. The genotype distribution of polymorphism in the control group was checked with the status of Hardy-Weinberg equilibrium (HWE). The χ test was applied to compare the genotypes of polymorphisms between the case and control groups. The association intensity between PAI-1 polymorphisms and ONFH risk was estimated by odds ratios (ORs) and 95% confidence intervals (95% CI). The linkage disequilibrium of PAI-1 polymorphisms was analyzed by Haploview.We found that the genotypes and alleles of PAI-1 rs6092 and rs7242 polymorphisms had no obvious association with the risk of ONFH (P >.05). But the strong linkage disequilibrium existed between rs6092 and rs7242 polymorphisms and haplotype G-T was significantly associated with the decreased risk of ONFH occurrence (OR = 0.666, 95%CI = 0.445-0.998).PAI-1 rs6092 and rs7242 polymorphisms are not associated with ONFH development, but haplotype G-T may be a protective factor of ONFH.


The deficiencies of current medical therapy for the management of angina pectoris.
The prime management need in angina pectoris is to abolish or to minimize pain. Nitrates, calcium antagonists and beta-blockers are indicated for this purpose but they are not a complete answer to the problem. Selection of therapy for individual patients is not guided scientifically and, at present, treatment of angina follows general protocols rather than a personalized approach based on the underlying patho-anatomy and physiology. Medical therapy offers palliation of the disease rather than a cure, although recent evidence raises possibilities that some anti-anginal therapy, notably the calcium antagonists, may favourably affect disease progression. Tachyphylaxis, dosing, unwanted effects, and optimal sequences and combinations of medical therapy are important clinical problems about which remarkably little is known. The greatest deficiency of current medical therapy, however, is that, despite the amelioration of angina, beneficial effects on mortality have not been established. Thus, for the foreseeable future non-pharmacological therapy in the form of surgery or angioplasty will dominate management of high-risk anginal patients. At present, it is only in unstable angina that there is evidence of prognostic benefit from medical therapy with aspirin and anticoagulants. In more stable forms of angina, medical versus surgical comparisons reflect 'old' drugs and strategies. The prospects of reducing death and infarction by medical therapy in anginal patients should be re-examined.


The impact of an additional copy of chromosome 21 in B-cell precursor acute lymphoblastic leukemia.
A common finding in pediatric B-cell precursor acute lymphoblastic leukemia (BCPALL) is that chromosome 21 is never lost and an extra chromosome 21 is often gained. This implies an important role for chromosome 21 in the pathobiology of BCPALL, emphasized by the increased risk of BCPALL in children with Down syndrome. However, model systems of chromosome 21 gain are lacking. We therefore developed a BCPALL cell line (Nalm-6, DUX4-rearranged) with an additional chromosome 21 by means of microcell-mediated chromosome transfer. FISH, PCR, multiplex ligation-dependent probe amplification, and whole exome sequencing showed that an additional chromosome 21 was successfully transferred to the recipient cells. Transcription of some but not all genes on chromosome 21 was increased, indicating tight transcriptional regulation. Nalm-6 cells with an additional chromosome 21 proliferated slightly slower compared with parental Nalm-6 and sensitivity to induction chemotherapeutics was mildly increased. The extra copy of chromosome 21 did not confer sensitivity to targeted signaling inhibitors. In conclusion, a BCPALL cell line with an additional human chromosome 21 was developed, validated, and subjected to functional studies, which showed a minor but potentially relevant effect in vitro. This cell line offers the possibility to study further the role of chromosome 21 in ALL.


Circulatory and humoral responses of sympathectomized fetal sheep to hypoxemia.
In fetal sheep, hypoxemia causes arterial hypertension, bradycardia, a redistribution of blood flow, and an increase in plasma vasopressin and catecholamine concentrations. To assess the role of the sympathetic nervous system in mediating these responses, we administered 6-hydroxydopamine to 11 chronically catheterized fetal sheep. Some of the responses to acute hypoxemia, achieved by administration of a low-O2 gas mixture to the ewe, were similar to those in intact fetal sheep. Fetal arterial O2 tension decreased from 22 +/- 3 to 12 +/- 3 (SD) Torr; fetal heart rate decreased transiently; combined ventricular output and umbilical-placental blood flow, as measured by the radionuclide-labeled microsphere technique, were maintained; cerebral, myocardial, and adrenal blood flow increased, and pulmonary blood flow decreased. However, there was no significant change in arterial pressure or blood flow to the peripheral, renal, and splanchnic circulations in the chemically sympathectomized fetuses in response to hypoxemia. The sympathetic nervous system is important in certain fetal vascular responses to hypoxemia but is not necessary for vascular responses in certain critical organs and thus is not crucial for fetal survival during hypoxia.


Analysis of antigens targeted by circulating IgG and IgA antibodies in patients with mucous membrane pemphigoid predominantly affecting the oral cavity.
Mucous membrane pemphigoid (MMP) includes a range of variants frequently having oral, particularly gingival, lesions. It has been suggested that MMP exclusively involving the oral cavity could be a distinct subset, but the immunological status of patients with predominantly oral lesions has received little attention. Indirect immunofluorescence (IIF) on normal human skin and normal human salt-split skin (SSS) as a substrate and immunoblotting on extracts of human keratinocyte cultures and normal human skin were carried out in 28 consecutive patients with MMP predominantly affecting the gingiva. There was no significant difference between frequency of positive SSS-IIF among patients with exclusive oral lesions (42%) and with MMP not restricted to the oral cavity (78%) (P = 0.114). By immunoblotting, IgG of 13 sera (46%) reacted with the 180 kD bullous pemphigoid antigen (BPAg2), six (21%) reacted with the 230 kD bullous pemphigoid antigen (BPAg1), and two (7%) reacted with an antigen of 200 kD. IgA of three sera (11%) reacted with BPAg2 and three (11%) reacted with BPAg1. There was no significant difference between frequency of positive immunoblotting among patients with exclusive oral lesions (68%) and with MMP not restricted to the oral cavity (67%) (P = 1.00). Most of the MMP sera contain IgG and IgA antibodies to the two major bullous pemphigoid antigens, independent of clinical presentation. Thus, in the majority of cases, patients with exclusively gingival pemphigoid lesions do not appear to have a distinct variety of mucous membrane pemphigoid.


Early identification and assessment of new and emerging health technologies: actions, progress, and the future direction of an international collaboration--EuroScan.
To report on a workshop, and subsequent discussions, that reviewed the achievements and progress of the EuroScan collaboration since its establishment in 1999 to share information on the methods and results of early identification and assessment of new and emerging health technologies; considered challenges to the collaboration; and discussed its possible future direction. A workshop was held in Stockholm in September 2006, with thirty-two participants from ten countries and representatives from EuroScan member agencies, policy makers involved in policy or decision making relating to new technologies, and invited external commentators from international HTA networks. The workshop used a mix of presentations, panel and audience discussions, and small group work to consider the achievements and challenges put forward. EuroScan has developed as a sustainable network, and has made progress on all tasks in its initial action plan, with the EuroScan information sharing database on new and emerging technologies being one of the collaboration's key achievements. Identified immediate concerns for the network included consideration of the impact of its current name and membership model; acknowledgement and publication of the full range of benefits of membership; contribution to and development of the database to encourage increased information sharing; and EuroScan's ongoing interaction with the wider HTA world. The workshop was a useful mechanism for reviewing the work of EuroScan and for creating a platform to take the collaboration forward. The workshop affirmed the benefits of the network to individual members; posed some significant challenges to the network to consider; and acted as a stimulus for an interim name change to better represent the global membership, and a major review of the EuroScan database of identified and assessed emerging health technologies.


Surface free energy and microarray deposition technology.
Microarray techniques use a combinatorial approach to assess complex biochemical interactions. The fundamental goal is simultaneous, large-scale experimentation analogous to the automation achieved in the semiconductor industry. However, microarray deposition inherently involves liquids contacting solid substrates. Liquid droplet shapes are determined by surface and interfacial tension forces, and flows during drying. This article looks at how surface free energy and wetting considerations may influence the accuracy and reliability of spotted microarray experiments.


Production and characterization of monoclonal antibodies against nucleoprotein of avian influenza virus.
The present study was carried out with an aim to develop anti-nucleoprotein (anti-NP) monoclonal antibodies (MAbs) for use in immunodiagnostic testing for detection of avian influenza virus (AIV) antigen or antibodies. The NP gene of AIV, cloned in pET vector, was expressed in Escherichia coli BL 21 strain to produce a 6x-His tagged recombinant NP (rNP) antigen of ∼61 kDa molecular weight as soluble fraction. The rNP antigen was detected in soluble fraction of bacterial cell lysate with anti-His HRPO conjugate and reacted with the reference AIV antibody positive serum in immunoblotting. The rNP was used to immunize BALB/c mice to produce hybridoma secreting anti-NP MAbs. Out of 11 anti-NP MAbs produced, 8D2-H5, 8D2-H9, and 6D11-A7 were of IgM isotype and 5D10-C9 and 5D10-F11 were of IgG2b type, while 3F3-D2, 7D2-C9, 7D2-G7, and 7D2-G8 were of IgG1 isotype. The MAbs 3F3-D2 and 7D2-G8 showed high intensity positive reaction with rNP and a low intensity reaction with H5N1 virus in Western blot analysis. The anti-NP MAbs produced in the present work may be valuable in developing a competitive ELISA or immunochromatographic strip test-based assays for the rapid diagnosis of avian influenza.


Stress, hormonal changes, alcohol, food constituents and drugs: factors that advance the incidence of tobacco smoke-related cancer?
The genotoxicity of the most potent carcinogen in cigarette smoke [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)] is dependent on the relationship between its activation by cytochrome P450 enzymes and its detoxification by carbonyl reduction to NNK alcohol (NNAL) followed by glucuronidation. Recently, '11 beta-hydroxysteroid dehydrogenase' (11 beta-HSD 1) was identified to be responsible for NNK carbonyl reduction. It is now speculated that differences in tissue expression of 11 beta-HSD 1, as well as genetic polymorphisms, may have profound influences on the organospecificity and potency of NNK-induced cancerogenesis. Moreover, endogenous and exogenous substrates or inhibitors of 11 beta-HSD 1 may shift the NNK/NNAL equilibrium and favour NNK toxification in a variety of physiological and therapeutic situations. These issues are discussed here by Edmund Maser, who also describes how recent observations could provide the experimental base for epidemiological or clinical studies, which focus on polymorphisms in 11 beta-HSD 1 enzyme expression, as well as on implications of exposure to 11 beta-HSD 1 modulators and concurrent smoking.


Expression of B cell and immunoglobulin transcripts is a feature of inflammation in late allografts.
To assess the significance of B-cell and plasma cell infiltrates in renal allografts, we compared expression of B-cell-associated transcripts (BATs) and immunoglobulin transcripts (IGTs) to histopathology and function in 177 renal allograft biopsies for clinical indications. BAT and IGT expression correlated with immunostaining for B cells and plasma cells and with expression of B-cell and plasma cell transcription factors. BATs and IGTs were increased in both T-cell-mediated and antibody-mediated rejection. BAT and IGT scores were strongly related to time posttransplant: biopsies <5 months expressed less BATs and did not express increased IGTs. In contrast, T-cell-associated transcripts were independent of time posttransplant. In biopsies > or =5 months, BAT and IGT scores correlated with interstitial inflammation, tubular atrophy and interstitial fibrosis. By regression tree analysis, the only variables independently correlated with BATs and IGTs were time and inflammation. Expression of BATs and IGTs correlated with renal function, but this relationship was due to differences in early versus late biopsies: BATs and IGTs were not related to function or future function after correcting for time.


A dynamic classification approach for nursing.
Nursing has a long tradition of classification, stretching back at least 150 years. The introduction of computers into health care towards the end of the 20(th) Century helped to focus efforts, culminating in the development of a range of standardized classifications. Many of these classifications are still in use today and, while content is periodically updated, the underlying classification structures remain relatively static. In this paper an approach to classification that is relatively new to nursing is presented; an approach that uses formal Web Ontology Language definitions for classes, and computer-based reasoning on those classes, to determine automatically classification structures that more flexibly meet the needs of users. A new proposed classification structure for the International Classification for Nursing Practice is derived under the new approach to provide a new view on the next release of the classification and to contribute to broader quality improvement processes.


[Ultrastructure of the proximal neurosecretory contact region in a sturgeon].
The proximal neurosecretory contact region (PCR), a homologue of the tetrapoda median eminence occupies the rostral and chiefly the ventral surfaces of the hypothalamic tuber cinereum. Three types of granule-containing neurosecretory fibres and their terminals have been found in the PCR with the electron microscope. Peptidergic, A1 and A2 type fibres contain granules of 120--300 nm and 100--170 nm in diameter, correspondingly, and monoaminergic B fibres have granules of 80--100 nm in diameter. Neurosecretory terminals and tanycyte vascular "endfeet" make contacts with a 70 nm thick outer basement membrane of the primary portal capillaries. Some thin horizontally oriented tanycyte branches form a multiserial layer bordering the external zone of the PCR from the preoptico-hypophyseal tract. Few neuroglial cells with pale cytoplasm and numerous lysosomes and lipofuscin granules are seen there. It is hypothesized that, like in other vertebrates, in the PCR of Acipenseridae both peptide and monoamine hypophysiotropic neurohormones may be discharged in the portal circulation to affect the functional activity of glandular cells of the pars distalis.


Clinical relevance of gene mutations and rearrangements in advanced differentiated thyroid cancer.
Tumor genotyping is becoming crucial to optimize the clinical management of patients with advanced differentiated thyroid cancer (DTC); however, its implementation in clinical practice remains undefined. We herein report our single-center experience on molecular advanced DTC testing by next-generation sequencing approach, to better define how and when tumor genotyping can assist clinical decision making. We retrospectively collected data on all adult patients with advanced DTC who received molecular profiling at the IRCSS Sant'Orsola-Malpighi Hospital from 2008 to 2022. The genetic alterations were correlated with radioactive iodide refractory (RAI-R), RAI uptake/disease status, and time to RAI resistance (TTRR) development. A significant correlation was found between RAI-R development and genetic alterations (P = 0.0001). About 48.7% of RAI-R cases were positive for TERT/TP53 mutations (as both a single event and comutations with other driver gene alterations, such as BRAF mutations, RAS mutations, or gene fusions), while the great majority of RAI-sensitive cases carried gene fusions (41.9%) or were wild type (WT; 41.9%). RAI uptake/disease status and time to TTRR were significantly associated with genetic alterations (P = 0.0001). In particular, DTC with TERT/TP53 mutations as a single event or as comutations displayed a shorter median TTRR of 35.4 months (range 15.0-55.8 months), in comparison to the other molecular subgroups. TERT/TP53 mutations as a single event or as comutations remained independently associated with RAI-R after Cox multivariate analysis (hazard ratio 4.14, 95% CI 1.51-11.32; P = 0.006). Routine testing for genetic alterations should be included as part of the clinical workup, for identifying both the subset of more aggressive tumors and the subset of tumors harboring actionable gene fusions, thus ensuring the appropriate management for all patients with advanced DTC.


Effects of bromocriptine on human subjects depend on working memory capacity.
Pharmacological manipulation of brain dopamine concentration affects visuospatial working memory in humans and in animals, the latter effects localized to the prefrontal cortex. However, the effects of dopamine agonists on humans are poorly understood. We hypothesized that bromocriptine would have an effect on cognitive functions associated with the prefrontal cortex via its effects on cortical dopamine receptors and on subcortical receptors in areas that project to the neocortex. We found that the effect of bromocriptine on young normal subjects depended on the subjects' working memory capacity. High-capacity subjects performed more poorly on the drug, while low-capacity subjects improved. These results demonstrate an empirical link between a dopamine-mediated working memory system and higher cognitive function in humans.


Incidence of Listeria monocytogenes in nature.
During a research project on the occurrence of Listeria monocytogenes 194 strains were isolated in southern West Germany during the years 1972 to 1974:154 from soil and plant samples (20.3%), 16 from feces of deer and stag (15.7%), 9 from old moldy fodder and wildlife feeding grounds (27.2%), and 8 from birds (17.3%). The highest number of isolates was obtained from uncultivated fields. The beta-hemolytic serovars 1/2b and 4b were were predominant; other serovars (some of them identified for the first time), including nonhemolyzing strains, have been encountered frequently. It is suggested that Listeria monocytogenes is a saprophytic organism which lives in a plant-soil environment and therefore can be contracted by humans and animals via many possible routes from many sources.


Relationships between big-five personality factors and Alzheimer's disease pathology in autosomal dominant Alzheimer's disease.
Changes in personality characteristics are associated with the onset of symptoms in Alzheimer's disease (AD) and may even precede clinical diagnosis. However, personality changes caused by disease progression can be difficult to separate from changes that occur with normal aging. The Dominantly Inherited Alzheimer Network (DIAN) provides a unique cohort in which to relate measures of personality traits to in vivo markers of disease in a much younger sample than in typical late onset AD. Personality traits measured with the International Personality Item Pool at baseline from DIAN participants were analyzed as a function of estimated years to onset of clinical symptoms and well-established AD biomarkers. Both neuroticism and conscientiousness were correlated with years to symptom onset and markers of tau pathology in the cerebrospinal fluid. Self-reported conscientiousness and both neuroticism and conscientiousness ratings from a collateral source were correlated with longitudinal rates of cognitive decline such that participants who were rated as higher on neuroticism and lower on conscientiousness exhibited accelerated rates of cognitive decline. Personality traits are correlated with the accumulation of AD pathology and time to symptom onset, suggesting that AD progression can influence an individual's personality characteristics. Together these findings suggest that measuring neuroticism and conscientiousness may hold utility in tracking disease progression in AD.


Relationship between weathered coal deposits and the etiology of Balkan endemic nephropathy.
Field studies in epidemiology and environmental geochemistry in areas in Yugoslavia containing villages with a high incidence of Balkan endemic nephropathy (BEN), indicate a possible relationship between the presence of low-rank coal deposits and the etiology of BEN. Preliminary results from qualitative chemical analyses of drinking water from shallow farm wells indicate the presence of soluble polar aromatic and polynuclear aromatic hydrocarbons. These compounds may be derived from weathering of low-rank coals occurring in the vicinity of the endemic villages. All of the endemic villages are in alluvial valleys of tributaries to the Danube River. All except one of the clusters of endemic villages are located in the vicinity of known Pliocene age coals. Detailed sampling of the drinking waters and the nearby coals are being undertaken to identify a possible etiologic factor.


Design and performance of a multiprocessor system employing board-to-board free-space optical interconnections: COSINE-1.
A practical thirty-six processor computer system employing manually reconfigurable board-to-board free-space optical interconnections has been built. The free-space optical interconnection section employs collimated beams that have 90 cm of transmission length at the maximum. It acts as a reconfigurable optical backplane that accommodates 144 input/output ports. The processors applied to the system are Transputers, each of which has four bidirectional links to communicate with other Transputers. This paper describes the design concept and the optical interconnection performances of the optical interconnection section employed in the constructed system.


Increasing body mass index negatively impacts outcomes following robotic radical prostatectomy.
To clarify the impact of increasing body mass index (BMI) on outcomes following robotic radical prostatectomy. From January 2003 to May 2005, 132 patients with clinically localized prostate cancer underwent a robotic radical prostatectomy. Patients were divided into 3 cohorts based on BMI: 38 normal (range, 18 to 24.9), 60 overweight (range, 25 to 29.9), and 34 obese (BMI>30). The operative time was significantly longer in obese (304 min) men compared with overweight (235 min) and normal (238 min) BMI patients (P<0.001). Estimated blood loss was significantly greater in both the obese (316 mL) and overweight (318 mL) groups compared with men with normal BMI (234 mL) (P<0.005). Three patients (1 obese and 2 overweight) required conversion to open surgery. Twenty-three of 132 men (17%) had a positive surgical margin, with obese (21%) and overweight (20%) men at a greater risk compared with normal BMI men (11%). No significant differences existed between groups with regard to final pathologic stage, Gleason score, biochemical recurrence at 1-year, and postoperative complication rate. Overweight and obese men had a longer operative duration, greater blood loss, longer hospital duration, and higher positive surgical margin rate. Robotic prostatectomy in men with elevated BMI is technically more challenging and is associated with more operative morbidity.


Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin.
Pharmacological activation of the adaptive response to hypoxia is a therapeutic strategy of growing interest for neurological conditions, including stroke, Huntington's disease, and Parkinson's disease. We screened a drug library with known safety in humans using a hippocampal neuroblast line expressing a reporter of hypoxia-inducible factor (HIF)-dependent transcription. Our screen identified more than 40 compounds with the ability to induce hypoxia response element-driven luciferase activity as well or better than deferoxamine, a canonical activator of hypoxic adaptation. Among the chemical entities identified, the antihelminthic benzimidazoles represented one pharmacophore that appeared multiple times in our screen. Secondary assays confirmed that antihelminthics stabilized the transcriptional activator HIF-1α and induced expression of a known HIF target gene, p21(cip1/waf1), in post-mitotic cortical neurons. The on-target effect of these agents in stimulating hypoxic signaling was binding to free tubulin. Moreover, antihelminthic benzimidazoles also abrogated oxidative stress-induced death in vitro, and this on-target effect also involves binding to free tubulin. These studies demonstrate that tubulin-binding drugs can activate a component of the hypoxic adaptive response, specifically the stabilization of HIF-1α and its downstream targets. Tubulin-binding drugs, including antihelminthic benzimidazoles, also abrogate oxidative neuronal death in primary neurons. Given their safety in humans and known ability to penetrate into the central nervous system, antihelminthic benzimidazoles may be considered viable candidates for treating diseases associated with oxidative neuronal death, including stroke.


Actual versus Forecast Burden of Primary Hip and Knee Replacement Surgery in Australia: Analysis of Data from the Australian Orthopaedic Association National Joint Replacement Registry.
National projections of future joint replacement use can help us understand the changing burden of severe osteoarthritis. This study aimed to compare actual utilisation rates for primary total hip replacement (THR) and total knee replacement (TKR) to previously forecast estimates for Australia. Data from the Australian Orthopaedic Association National Joint Replacement Registry and Australian Bureau of Statistics were used to calculate 'actual' THR and TKR utilisation rates for the years 2014-2019, by sex and age group. 'Forecast' utilisation rates for 2014-2019 were derived from an earlier study that modelled two alternate scenarios for THR and TKR in Australia: Scenario 1 assumed a constant rate of surgery; Scenario 2 assumed continued growth in surgery rates. Actual utilisation rates were compared descriptively to forecast rates for females and males (overall and by age group). Rate ratios were calculated to indicate the association between actual and forecast THR and TKR rates, with a rate ratio of 1.00 reflecting perfect alignment. Over the study period, 191,996 THRs (53% in females) and 312,203 TKRs (55% in females) were performed. For both sexes, actual rates lay clearly between the Scenario 1 and 2 forecast estimates. In 2019, actual THR utilisation rates were 179 per 100,000 females (Scenario 1: 156; Scenario 2: 200) and 158 per 100,000 males (Scenario 1: 139; Scenario 2: 191). Actual TKR utilisation rates in 2019 were 289 per 100,000 females (Scenario 1: 275; Scenario 2: 387) and 249 per 100,000 males (Scenario 1: 216; Scenario 2: 312). Age-specific rate ratios were close to 1.00 for all age groups, indicating good alignment between forecast and actual joint replacement rates. These validation analyses showed that linear plus exponential growth forecasting scenarios provided an efficient approximation of actual joint replacement utilisation. This indicates our modelling techniques can be used to judiciously predict future surgery demand, including for age groups with high surgery rates.


Prevalence and Risk Factor Analysis of Post-Intensive Care Syndrome in Patients with COVID-19 Requiring Mechanical Ventilation: A Multicenter Prospective Observational Study.
Post-intensive care syndrome (PICS) is an emerging problem in critically ill patients and the prevalence and risk factors are unclear in patients with severe coronavirus disease 2019 (COVID-19). This multicenter prospective observational study aimed to investigate the prevalence and risk factors of PICS in ventilated patients with COVID-19 after ICU discharge. Questionnaires were administered twice in surviving patients with COVID-19 who had required mechanical ventilation, concerning Barthel Index, Short-Memory Questionnaire, and Hospital Anxiety and Depression Scale scores. The risk factors for PICS were examined using a multivariate logistic regression analysis. The first and second PICS surveys were obtained at 5.5 and 13.5 months (mean) after ICU discharge, with 251 and 209 patients completing the questionnaires and with a prevalence of PICS of 58.6% and 60.8%, respectively, along with the highest percentages of cognitive impairment. Delirium (with an odds ratio of (OR) 2.34, 95% CI 1.1-4.9, and p = 0.03) and the duration of mechanical ventilation (with an OR of 1.29, 95% CI 1.05-1.58, and p = 0.02) were independently identified as the risk factors for PICS in the first PICS survey. Approximately 60% of the ventilated patients with COVID-19 experienced persistent PICS, especially delirium, and required longer mechanical ventilation.


Large-area molecular patterning with polymer pen lithography.
The challenge of constructing surfaces with nanostructured chemical functionality is central to many areas of biology and biotechnology. This protocol describes the steps required for performing molecular printing using polymer pen lithography (PPL), a cantilever-free scanning probe-based technique that can generate sub-100-nm molecular features in a massively parallel fashion. To illustrate how such molecular printing can be used for a variety of biologically relevant applications, we detail the fabrication of the lithographic apparatus and the deposition of two materials, an alkanethiol and a polymer onto a gold and silicon surface, respectively, and show how the present approach can be used to generate nanostructures composed of proteins and metals. Finally, we describe how PPL enables researchers to easily create combinatorial arrays of nanostructures, a powerful approach for high-throughput screening. A typical protocol for fabricating PPL arrays and printing with the arrays takes 48-72 h to complete, including two overnight waiting steps.


The genome-linked protein of picornaviruses. VIII. Complete amino acid sequence of poliovirus VPg and carboxy-terminal analysis of its precursor, P3-9.
VPg, the genome-linked protein of poliovirus, and its putative precursor P3-9, were radiolabelled and subjected to carboxypeptidase-A digestion. The release of amino acids was followed by identification and quantification on an amino acid analyser. Both proteins were found to be co-terminal with a sequence of -valyl-glutamine-COOH, an observation that provides further evidence that host cell trimming of virus-specific peptides does not play a role in poliovirus protein processing. Radiolabelled VPg was subjected to automated Edman degradation. The combined results complete the structural analysis of VPg, a polypeptide 22 amino acids in length with a molecular weight of 2354. Only one form of VPg has been found linked to virion RNA and it originates by a cleavage at glutaminyl-glycine pairs at both termini. The observation is consistent with other cleavages found in the virus processing scheme.


An age-dependent fitness cost of migration? Old trans-Saharan migrating spoonbills breed later than those staying in Europe, and late breeders have lower recruitment.
Migration is a widespread phenomenon in the animal kingdom. On the basis of the considerable variation that exists between and within species, and even within populations, we may be able to infer the (age- and sex-specific) ecological trade-offs and constraints moulding migration systems from assessments of fitness associated with migration and wintering in different areas. During three consecutive breeding seasons, we compared the reproductive performance (timing of breeding, breeding success, chick body condition and post-fledging survival) of Eurasian spoonbills Platalea leucorodia that breed at a single breeding site in The Netherlands, but migrate different distances (c. 4,500 vs. 2,000 km, either or not crossing the Sahara) to and from wintering areas in southern Europe and West Africa. Using mark-recapture analysis, we further investigated whether survival until adulthood (recruitment probability) of chicks hatched between 2006 and 2010 was related to their hatch date and body condition. Long-distance migrants bred later, particularly the males, and raised chicks of poorer body condition than short-distance migrants. Hatch dates strongly advanced with increasing age in short-distance migrants, but hardly advanced in long-distance migrants, causing the difference in timing of breeding between long- and short-distance migrants to be more pronounced among older birds. Breeding success and chick body condition decreased over the season, and chicks that fledged late in the season or in poor condition were less likely to survive until adulthood. As a result, long-distance migrants-particularly the males and older birds-likely recruit fewer offspring into the breeding population than short-distance migrants. This inference is important for predicting the population-level consequences of changes in winter habitat suitability throughout the wintering range. Assuming that the long-distance migrants-being the birds that occupy the traditional wintering areas-are not the poorer quality birds, and that the observed age-dependent patterns in timing of breeding are driven by within-individual effects and not by selective disappearance, our results suggest that the strategy of long-distance migration, involving the crossing of the Sahara to winter in West Africa, incurred a cost by reducing reproductive output, albeit a cost paid only later in life.


A novel kinase inhibitor of FADD phosphorylation chemosensitizes through the inhibition of NF-κB.
Fas-associated protein with death domain (FADD) is a cytosolic adapter protein essential for mediating death receptor-induced apoptosis. It has also been implicated in a number of nonapoptotic activities including embryogenesis, cell-cycle progression, cell proliferation, and tumorigenesis. Our recent studies have shown that high levels of phosphorylated FADD (p-FADD) in tumor cells correlate with increased activation of the antiapoptotic transcription factor NF-κB and is a biomarker for aggressive disease and poor clinical outcome. These findings suggest that inhibition of FADD phosphorylation is a viable target for cancer therapy. A high-throughput screen using a cell-based assay for monitoring FADD-kinase activity identified NSC 47147 as a small molecule inhibitor of FADD phosphorylation. The compound was evaluated in live cells and mouse tumors for its efficacy as an inhibitor of FADD-kinase activity through the inhibition of casein kinase 1α. NSC 47147 was shown to decrease levels of p-FADD and NF-κB activity such that combination therapy leads to greater induction of apoptosis and enhanced tumor control than either agent alone. The studies described here show the utility of bioluminescent cell-based assays for the identification of active compounds and the validation of drug-target interaction in a living subject. In addition, the presented results provide proof-of-principle studies as to the validity of targeting FADD-kinase activity as a novel cancer therapy strategy.


Aging effects on the sorption-desorption characteristics of anthropogenic organic compounds in soil.
Field studies have demonstrated that prolonged pesticide-soil contact times (aging) may lead to unexpected persistence of these compounds in the environment. Although this phenomenon is well documented in the field, there have been very few controlled laboratory studies that have tested the effects of long-term aging and the role of differing sorbates on contaminant sorption-desorption behavior and fate in soils. This study examines the sorption-desorption behavior of chlorobenzene, ethylene dibromide (1,2-dibromomethane), atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine), and 2, 4-D (2,4-dichlorophenoxyacetic acid) on one soil type after 1 d, 30 d, and 14 mo of aging. Sorption isotherms were evaluated after each aging period to observe changes in the uptake of each compound by soil. Desorption kinetic data were generated after each aging period to observe changes in release from soil, and desorption parameters were evaluated using a three-site desorption model that includes equilibrium, nonequilibrium, and nondesorption sites. The data indicate no statistically significant increase in sorption for ethylene dibromide or chlorobenzene from 1 to 30 d, although sorption of 2,4-D increased slightly, and sorption of atrazine decreased slightly. Statistically significant increases in linear sorption coefficients (Kd), from 1 d to 14 mo of aging, were apparent for ethylene dibromide and 2,4-D. The Kd values for chlorobenzene, measured after 1 d, 30 d, and 14 mo of aging, were statistically indistinguishable. Aging affected the distribution of chemicals within sorption sites. With aging, the desorbable fraction decreased and the nondesorbable fraction, which was apparent after only 1 d of pesticide-soil contact, increased for all chemicals studied.