Phosphatidylserine Translocation after Radiosurgery in an Animal Model of Arteriovenous Malformation.
Phosphatidylserine (PS) is asymmetrically distributed across the plasma membrane, located predominantly on the inner leaflet in healthy cells. Translocation of PS to the outer leaflet makes it available as a target for biological therapies. We examined PS translocation after radiosurgery in an animal model of brain arteriovenous malformation (AVM). An arteriovenous fistula was created by end-to-side anastomosis of the left external jugular vein to the common carotid artery in 6-week-old, male Sprague Dawley rats. Six weeks after AVM creation, 15 rats underwent Gamma Knife stereotactic radiosurgery receiving a single 15 Gy dose to the margin of the fistula; 15 rats received sham treatment. Externalization of PS was examined by intravenous injection of a PS-specific near-infrared probe, PSVue-794, and in vivo fluorescence optical imaging at 1, 7, 21, 42, 63 and 84 days postirradiation. Fluorescent signaling indicative of PS translocation to the luminal cell surface accumulated in the AVM region, in both irradiated and nonirradiated animals, at all time points. Fluorescence was localized specifically to the AVM region and was not present in any other anatomical sites. Translocated PS increased over time in irradiated rats (P < 0.001) but not in sham-irradiated rats and this difference reached statistical significance at day 84 (P < 0.05). In summary, vessels within the mature rat AVM demonstrate elevated PS externalization compared to normal vessels. A single dose of ionizing radiation can increase PS externalization in a time-dependent manner. Strict localization of PS externalization within the AVM region suggests that stereotactic radiosurgery can serve as an effective priming agent and PS may be a suitable candidate for vascular-targeting approaches to AVM treatment.


Development of the Cambridge Contextual Reading Test for improving the estimation of premorbid verbal intelligence in older persons with dementia.
The Cambridge Contextual Reading Test (CCRT), which sets the NART words within semantic and syntactic context, has been shown to yield a higher prediction of premorbid intelligence than the National Adult Reading Test (NART) for patients with mild/moderate dementia (Beardsall & Huppert, 1994). This study validates and standardizes the CCRT in a sample of healthy older persons. The CCRT was validated against WAIS-R verbal IQ (VIQ) and the Mill Hill Vocabulary Test (MHVT). Regression equations were used to compare predictions of WAIS-R VIQ from CCRT and demographic variables. A conversion table was constructed for predicted VIQ from the equation derived from CCRT scores. Seventy-three healthy British older persons aged over 70 years completed the CCRT, NART, WAIS-R verbal subtests and MHVT. The benefit of context was greatest for those with lowest word reading ability. The CCRT was satisfactorily correlated with VIQ and the MHVT. Whereas the regression equation predicting VIQ using CCRT alone accounted for 61 per cent of the variance, 68 per cent was accounted for when demographic variables were included. The CCRT is a valid measure of verbal ability for older persons. When accurate information about years of full-time education is available, prediction of verbal intelligence should be made combining CCRT with demographic variables. Otherwise, prediction should be made using CCRT alone. The CCRT may be used in preference to NART in neuropsychological batteries with older persons provided caution is exercised when language difficulties are indicated.


Review of naltrexone, a long-acting opiate antagonist.
The basis for using narcotic antagonists for the treatment of opiate addiction is discussed briefly, and the chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of naltrexone hydrochloride, an opiate antagonist drug, are reviewed. Naltrexone is rapidly and completely absorbed after oral administration but undergoes substantial first-pass extraction and metabolism by the liver. Naltrexone has a half-life of 3.9-10.3 hours and a slow terminal elimination-phase half-life of 96 hours. The major metabolite of naltrexone is 6-beta-naltrexol, which is present in plasma in greater concentrations than the parent drug. Problems in study design and patient adherence to treatment have made assessment of naltrexone's clinical efficacy difficult; however, studies have consistently demonstrated that patients who remained off opiates longer were those who took naltrexone longer. Factors associated with successful treatment outcomes include sustained therapy with naltrexone, participation in multidisciplinary programs of behavioral therapy and psychotherapy, and good family and social support systems. Gastrointestinal irritation and, in some studies, clinically insignificant increases in blood pressure, have been the most common adverse effects. Currently available data suggest that naltrexone is a very safe drug. The usual dosage of naltrexone hydrochloride is 50 mg orally once daily or 350 mg orally per week in three divided doses. Patients should be detoxified and opiate free for two to five days before initiation of naltrexone therapy. Naltrexone appears to be a useful adjunct to therapy in opiate addicts who are well motivated and who have strong psychological support systems.


Change in Physical Activity, Sleep Quality, and Psychosocial Variables during COVID-19 Lockdown: Evidence from the Lothian Birth Cohort 1936.
(1) Objectives: The COVID-19 pandemic has disproportionately affected the lives of older people. In this study, we examine changes in physical activity, sleep quality, and psychosocial variables among older people during COVID-19 lockdown. We build on cross-sectional studies on this topic by assessing change longitudinally. We also examined whether participant characteristics including demographic, cognitive, personality, and health variables were related to more positive or negative changes during lockdown. (2) Methods: 137 older participants (mean age 84 years) from the Lothian Birth Cohort 1936 study were included in the analysis. They completed the same questionnaires assessing physical activity, sleep quality, mental wellbeing, social support, loneliness, neighbourhood cohesion, and memory problems before (mostly 2 years earlier) and again during national lockdown. (3) Results: On average, levels of physical activity were reduced (those doing minimal physical activity increased from 10% to 19%) and perceived social support increased during lockdown (effect size drm = 0.178). More positive change in the psychosocial and behavioural outcome variables during lockdown was associated with personality traits (greater intellect, emotional stability, and extraversion) and having a higher general cognitive ability. Participants with a history of cardiovascular disease, more symptoms of anxiety, or who lived alone were more likely to experience negative changes in the outcome variables during lockdown. (4) Discussion: These results provide further insight into the experiences of older people during the COVID-19 pandemic and could help to identify those at greatest risk of negative psychosocial or behavioural changes during this time.


Associations of serum 25-hydroxyvitamin D with overall and breast cancer-specific mortality in a multiethnic cohort of breast cancer survivors.
Despite limited evidence on the association of vitamin D with outcomes in breast cancer survivors, some clinicians advise breast cancer patients to use vitamin D supplements. More evidence is needed to inform these recommendations. In the Health, Eating, Activity, and Lifestyle study, we examined associations of post-treatment serum concentrations of 25-hydroxyvitamin D (25(OH)D) on overall and breast cancer-specific mortality in 585 breast cancer survivors from western Washington State, New Mexico, and Los Angeles County. 25(OH)D was measured in stored blood collected 2 years post-enrollment. Outcomes were ascertained from the Surveillance, Epidemiology, and End Results registries and medical records. Cox proportional hazards models were fit to assess associations of serum 25(OH)D with overall and breast cancer-specific mortality. After a median follow-up of 9.2 years; 110 women died, including 48 from breast cancer. Standard cut points classified 211 (31.6 %) women as serum 25(OH)D deficient (<20 ng/mL), 189 (32.2 %) as insufficient (20-30 ng/mL), and 185 (36.2 %) as sufficient (>30 ng/mL). Compared to women with deficient 25(OH)D, those in the sufficient ranges had a decreased risk of overall mortality (age-adjusted HR = 0.58; 95 % CI 0.36-0.96); however, multivariate adjustments attenuated the association (HR = 0.90; 95 % CI 0.50-1.61). No association was found between serum 25(OH)D and breast cancer-specific mortality (sufficient: HR = 1.21; 95 % CI 0.52-2.80) in multivariate models. In this breast cancer cohort, higher serum 25(OH)D may be associated with improved survival, but results were not statistically significant and must be interpreted with caution. The potential prognostic effect of vitamin D from diet, supplements, or both should be evaluated in future larger studies with additional endpoints from breast cancer patients.


Drug-eluting stents versus bare-metal stents in patients with decreased GFR: a meta-analysis.
Decreased estimated glomerular filtration rate (eGFR) is a strong predictor of both mortality and subsequent cardiac events after percutaneous coronary intervention. The safety and efficacy of drug-eluting (DESs) versus bare-metal stents (BMSs) in this population have not been evaluated adequately. A systematic review and meta-analysis. Studies involving the comparison of clinical outcomes between DESs and BMSs in patients with eGFR <60 mL/min/1.73 m(2). Studies exclusively involving patients with ST-segment elevation myocardial infarction were excluded. MEDLINE (on Ovid), EMBASE, and the Cochrane Library databases from 2002-2013 were searched for studies comparing DESs with BMSs in patients with eGFR <60 mL/min/1.73 m(2). DES versus BMS implantation. Mortality, repeat revascularization, myocardial infarction, and stent thrombosis. Data from 26 comparative studies with 66,840 patients were included. Compared with BMSs, DESs were associated with significant reductions in repeat revascularization (OR, 0.61; 95% CI, 0.50-0.74; P < 0.001) and myocardial infarction (OR, 0.85; 95% CI, 0.79-0.92; P < 0.001), with no detectable difference in stent thrombosis (OR, 0.72; 95% CI, 0.46-1.12; P = 0.1). The superiority of DESs over BMSs in decreasing mortality also was documented (OR, 0.77; 95% CI, 0.65-0.90; P = 0.01). This survival benefit of DESs over BMSs was attenuated in randomized controlled trials or adjusted observational studies versus unadjusted observational studies. Most studies were observational studies. Meta-analysis was not performed on individual patient data. DES use in patients with eGFR <60 mL/min/1.73 m(2) is associated with a reduced rate of repeat revascularization and myocardial infarction without increased risk of stent thrombosis. The true effect of DESs versus BMSs on mortality needs to be confirmed by randomized controlled trials.


Effect of Chloroquine and Hydroxychloroquine on Cytokine Release Syndrome in Patients with COVID-19.
Objective: To assess the effect of chloroquine and hydroxychloroquine on cytokine release syndrome (CRS) in adult patients with coronavirus disease 2019 (COVID-19) having mild to moderate symptoms.Methods: This blinded, placebo-controlled, randomized study was conducted in the Department of Medicine, Pak Emirates Military Hospital Rawalpindi, from June 1-15, 2020. A total of 150 hospitalized patients were enrolled after diagnoses with COVID-19 through reverse transcription polymerase chain reaction (RT-PCR). They were divided into three groups: hydroxychloroquine plus general care (HGC, n=50), chloroquine plus general care (CGC, n=50); and only general care (OGC, n=50). The HGC group received treatment with hydroxychloroquine 400 mg every 12 hours for day one and 200 mg for the next 4 days. The CGC group received treatment with chloroquine 250 mg every 12 hours for 7 days. The OGC group was kept as a control with only general care. After 12 days, the patients were screened for development of CRS through detection of interleukin 6 (IL-6) in serum samples by using Roche cobas e411 electrochemiluminescence immunoassay analyzer.Results: The mean duration from onset of symptoms to randomization was 7.65 days (SD = 3.287 days; range, 2-15 days). The mean age of patients was 37.57 (range 19-63) years. Results showed that out of a total 150 patients, only 10 patients (6%, mean=1.93; CI=1.89-1.97, P=0.651) developed CRS in all study groups. Four patients (8%) developed CRS in the HGC group, 2 patients (4%) in the CGC group, and 4 patients (8%) in the OGC group. There was no significant difference in the mean level of CRS among study groups.Conclusion: Administration of hydroxychloroquine and chloroquine has no effect in reducing the development of CRS in patients with COVID-19 having mild to moderate symptoms.


Interventional approaches to acute venous thromboembolism.
During the last decade, advances in minimally invasive technologies have spurred a renaissance in the aggressive treatment of venous thromboembolism (VTE) using percutaneous techniques. In this article, we outline the relative risks and benefits of endovascular VTE therapies, highlight clinical situations in which the benefits of endovascular treatment are likely to outweigh its risks, and provide an update regarding the specific new modalities that may be applied to VTE. Pharmacomechanical thrombolysis represents the most promising currently available method to treat VTE. However, pending demonstration that it actually improves VTE outcomes in randomized trials with long-term follow-up, a highly individualized approach to patient selection is recommended. At present, highly compromised patients with pulmonary emboli (PE) in whom systemic thrombolytic therapy has failed or is contraindicated are reasonable candidates for catheter-based PE interventions. Adjunctive pharmacomechanical catheter-directed deep venous thrombosis (DVT) thrombolysis is best indicated for the first-line treatment of patients with phlegmasia cerulea dolens, acute inferior vena cava (IVC) occlusion, and acute iliofemoral DVT after careful clinical assessment and a balanced discussion with the patient. It is hoped that multidisciplinary clinical trials with involvement by both interventionalists and pulmonary physicians will validate these techniques in the near future.


Transcranial Doppler Remote Positioning System with Virtual Reality Integration for Vestibular Studies.
Transcranial doppler (TCD) ultrasound probes are an invaluable tool in cerebral blood flow (CBF) studies. Their operation demands maintaining consistent pose on the subject throughout the experimental protocol. However, the displacement of the TCD probe during vestibular studies is common and substantially prolongs the experiment or even terminates it. This is a significant challenge for integrating motion-based vestibular studies with CBF investigations. In response, a mechatronics system is designed to allow remote repositioning of the TCD probe during data collection experiments while the subject is wearing a head mounted virtual reality (VR) display and seated in a vestibular disorientation device. This paper presents the design, prototype, and operation of this mechatronics apparatus.Clinical Relevance- The mechatronics apparatus of this paper can enable motion-based vestibular studies that entail the use of CBF velocity measurement and head-mounted virtual reality display.


Tuning the Chiroptical Properties of Elongated Nano-objects via Hierarchical Organization.
Chiral materials appear as excellent candidates to control and manipulate the polarization of light in optical devices. In nanophotonics, the self-assembly of colloidal plasmonic nanoparticles gives rise to strong resonances in the visible range, and when such organizations are chiral, a strong chiroplasmonic effect can be observed. In the present work, we describe the optical properties of chiral artificial nanophotonic materials, Goldhelices, which are hierarchically organized by grazing incidence spraying. These Goldhelices are made by plasmonic nanoparticles (gold) grafted onto helical templates made from silica nanohelices. A comparison of oriented versus non-oriented surfaces has been performed by Mueller matrix polarimetry, showing the importance of the organization of the Goldhelices regarding their interaction with light. Moreover, mono- versus multilayer photonic films are created, and the measured optical properties are discussed and compared to simulations.


Long-Term Outcome After Surgical Resection of a Spinal Choroid Plexus Tumor in a Dog.
A 6 yr old castrated male Clumber spaniel was referred for evaluation of acute paraplegia. MRI of the thoracolumbar spine demonstrated an intradural-extramedullary mass lesion at the level of T12 and extradural spinal cord compression at L1-L2. A hemilaminectomy was performed to achieve gross total resection of the mass lesion and removal of extruded disc material. A diagnosis of spinal choroid plexus tumor (CPT) and intervertebral disc extrusion was made. At 4 mo postoperatively, MRI demonstrated a mass lesion at the right lateral aperture of the fourth ventricle. Spinal drop metastasis from a primary intracranial CPT was suspected. The dog was ambulating independently and neurologically normal at that time. At 17 mo postoperatively, a third MRI was performed owing to decreased postural reactions in both hind limbs and vision loss in the right eye, and it demonstrated an increase in size of the intracranial mass lesion. These two additional MRI studies of the entire central nervous system showed no other metastatic lesions nor any evidence of local recurrence. At 25 mo postoperatively, the dog died at home. This is the first case report of surgical intervention and antemortem histopathological diagnosis of a spinal CPT in a dog.


Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer.
Tamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen. A case-control study was conducted among 34 Cancer and Leukemia Group B (CALGB) institutions. We matched each of 124 women who had experienced a documented TE while taking adjuvant tamoxifen for breast cancer (but who were not necessarily on a CALGB treatment trial) to two control subjects (women who took adjuvant tamoxifen but did not experience TE) by age at diagnosis (+/-5 years). DNA from blood was analyzed for FVL mutations. Conditional logistic regression was used to estimate odds ratios (ORs) and to evaluate other potential factors associated with TE and tamoxifen use. All P values are based on two-sided tests. FVL mutations were identified in 23 (18.5%) case and 12 (4.8%) control subjects (OR = 4.66, 95% confidence interval = 2.14 to 10.14, P < .001). In the multivariable model, FVL mutation was associated with TE (OR = 4.73, 95% confidence interval = 2.10 to 10.68, P < .001). Other statistically significant factors associated with TE risk were personal history of TE and smoking. Among women taking adjuvant tamoxifen for early-stage breast cancer, those who had a TE were nearly five times more likely to carry a FVL mutation than those who did not have a TE. Postmenopausal women should be evaluated for the FVL mutation before prescription of adjuvant tamoxifen if a positive test would alter therapeutic decision making.


Treatment of allergic rhinitis during pregnancy.
Allergic rhinitis is a frequent problem during pregnancy. In addition, physiological changes associated with pregnancy can affect the upper airways. Evidence-based guidelines on the management of allergic rhinitis have recently been published, the most recent being the Allergic Rhinitis and its Impact on Asthma (ARIA)--World Health Organization consensus. Many pregnant women experience allergic rhinitis and particular attention is required when prescribing drugs to these patients. Medication can be prescribed during pregnancy when the apparent benefit of the drug is greater than the apparent risk. Usually, there is at least one drug from each major class that can be safely utilised to control symptoms. All glucocorticosteroids are teratogenic in animals but, when the indication is clear (for diseases possibly associated, such as severe asthma exacerbation), the benefit of the drug is far greater than the risk. Inhaled glucocorticosteroids (e.g. beclomethasone or budesonide) have not been incriminated as teratogens in humans and are used by pregnant women who have asthma. A few histamine H(1)-receptor antagonists (H(1)-antihistamines) can safely be used as well. Most oral decongestants (except pseudoephedrine) are teratogenic in animals. There are no such data available for intra-nasal decongestants. Finally, pregnancy is not considered as a contraindication for the continuation of allergen specific immunotherapy.


Use of antibacterial agents in renal failure.
This article provides background information on the pharmacokinetics of antibacterial agents in patients with normal and impaired renal function. Tables are provided to allow quick determination of appropriate dosages for varying degrees of renal failure. The use of serum levels, newer strategies for cefazolin, vancomycin, and aminoglycoside dosing, methods of dialysis and associated antibiotics dosage adjustments, and antibiotic toxicity in renal failure are reviewed.


Management of diaphragmatic injury during transperitoneal laparoscopic urological procedures.
Carbon dioxide pneumothorax is a rare complication in laparoscopic urology, but with the widespread use of laparoscopy and the increasing surgical pathologies managed by this technique this infrequent complication has become a potential risk. A total of 786 laparoscopic transperitoneal urologic operations were reviewed at our institution. All procedures were performed by the same surgeon and included 213 adrenalectomies, 181 simple nephrectomies, 143 lymphadenectomies, 118 radical nephrectomies, 107 partial nephrectomies and 24 nephroureterectomies. Mean patient age was 53.2 years (range 24 to 70). Mean BMI was 28.15 Kg/m2 (range 20 to 48.9). A total of 6 cases (0.7%) of diaphragmatic injury were found. All reported patients had additional factors that may have contributed to diaphragmatic injury. Diaphragmatic repair was always carried out by intracorporeal suturing and only one case required chest tube placement. All patients evolved uneventfully. Repair of diaphragmatic injuries should always be attempted with intracorporeal suture since this is a feasible, reproducible and reliable technique.


Hyperspectral Imaging for Glioblastoma Surgery: Improving Tumor Identification Using a Deep Spectral-Spatial Approach.
The primary treatment for malignant brain tumors is surgical resection. While gross total resection improves the prognosis, a supratotal resection may result in neurological deficits. On the other hand, accurate intraoperative identification of the tumor boundaries may be very difficult, resulting in subtotal resections. Histological examination of biopsies can be used repeatedly to help achieve gross total resection but this is not practically feasible due to the turn-around time of the tissue analysis. Therefore, intraoperative techniques to recognize tissue types are investigated to expedite the clinical workflow for tumor resection and improve outcome by aiding in the identification and removal of the malignant lesion. Hyperspectral imaging (HSI) is an optical imaging technique with the power of extracting additional information from the imaged tissue. Because HSI images cannot be visually assessed by human observers, we instead exploit artificial intelligence techniques and leverage a Convolutional Neural Network (CNN) to investigate the potential of HSI in twelve in vivo specimens. The proposed framework consists of a 3D-2D hybrid CNN-based approach to create a joint extraction of spectral and spatial information from hyperspectral images. A comparison study was conducted exploiting a 2D CNN, a 1D DNN and two conventional classification methods (SVM, and the SVM classifier combined with the 3D-2D hybrid CNN) to validate the proposed network. An overall accuracy of 80% was found when tumor, healthy tissue and blood vessels were classified, clearly outperforming the state-of-the-art approaches. These results can serve as a basis for brain tumor classification using HSI, and may open future avenues for image-guided neurosurgical applications.


Liposome and multiple emulsion formulations augment the anticalcifying efficacy of phosphocitrate in a cutaneous calcergy model.
The anticalcifying agent phosphocitrate was incorporated into phosphatidylcholine/cholesterol liposomes by reverse-phase evaporation. The compound was entrapped to the extent of 11.6% (mol mol-1 of lipid) and the liposomes exhibited prolonged retention of the compound when incubated with rat plasma. Phosphocitrate's ionic contribution in solution adversely influenced the encapsulation efficiency but improvements were made through ion-pairing with the quaternary ammonium detergent centrimide, or with the inclusion of stearylamine in the lipid phase. The liposomal dose that could be practically administered in-vivo was restricted to 2.5 mg phosphocitrate kg-1 day-1. The formulation of a multiple emulsion preparation of phosphocitrate, however, offered an alternative delivery mode permitting infrequent dosing to be successfully investigated. In a rat calcergy model, both vehicles effectively reduced the formation of induced subcutaneous calcified plaques at doses for which the phosphocitrate salt alone was inactive. The current formulations demonstrate that the therapeutic efficacy of phosphocitrate can be markedly improved through an appropriately designed drug delivery system, signalling a new approach for the future therapeutic application of this compound.


Ceramide-mediated insulin resistance and impairment of cognitive-motor functions.
Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) are associated with cognitive impairment, brain insulin resistance, and neurodegeneration. Recent studies linked these effects to increased pro-ceramide gene expression in liver and increased ceramide levels in serum. Since ceramides are neurotoxic and cause insulin resistance, we directly examined the role of ceramides as mediators of impaired signaling and central nervous system function using an in vivo model. Long Evans rat pups were administered C2Cer:N-acetylsphinganine or its inactive dihydroceramide analog (C2DCer) by i.p. injection. Rats were subjected to rotarod and Morris water maze tests of motor and cognitive function, and livers and brains were examined for histopathology and integrity of insulin/IGF signaling. C2Cer treatment caused hyperglycemia, hyperlipidemia, and mild steatohepatitis, reduced brain lipid content, and increased ceramide levels in liver, brain, and serum. Quantitative RT-PCR analysis revealed significant alterations in expression of several genes needed for insulin and IGF-I signaling, and multiplex ELISAs demonstrated inhibition of signaling through the insulin or IGF-1 receptors, IRS-1, and Akt in both liver and brain. Ultimately, the toxic ceramides generated in peripheral sources such as liver or adipose tissue caused sustained impairments in neuro-cognitive function and insulin/IGF signaling needed for neuronal survival, plasticity, and myelin maintenance in the brain. These findings support our hypothesis that a liver/peripheral tissue-brain axis of neurodegeneration, effectuated by increased toxic lipid/ceramide production and transport across the blood-brain barrier, could mediate cognitive impairment in T2DM and NASH.


Topography and morphometry of the subarcuate canal.
The current study shows in a close-up view anatomical relationship between the subarcuate canal and the osseous labyrinth. For this purpose we used micro-computed tomography which allowed performing three-dimensional reconstruction of the subarcuate canal and gave adequate data for estimation its diameter across its course. The diameter of the middle part (the most uniform) of the subarcuate canal varied from 0.28 mm to 0.46 mm. Hence, we calculated the centre of mass for each cross-section of the separated subarcuate canal. This procedure helped us to visualise trajectory of the subarcuate canal and its spatial orientation within the petrous bone. From our data we concluded that subarcuate canals revealed not well defined trajectories and their spatial orientation varied across the studied temporal bones.


Multireader Study on the Diagnostic Accuracy of Ultrafast Breast Magnetic Resonance Imaging for Breast Cancer Screening.
Breast cancer screening using magnetic resonance imaging (MRI) has limited accessibility due to high costs of breast MRI. Ultrafast dynamic contrast-enhanced breast MRI can be acquired within 2 minutes. We aimed to assess whether screening performance of breast radiologist using an ultrafast breast MRI-only screening protocol is as good as performance using a full multiparametric diagnostic MRI protocol (FDP). The institutional review board approved this study, and waived the need for informed consent. Between January 2012 and June 2014, 1791 consecutive breast cancer screening examinations from 954 women with a lifetime risk of more than 20% were prospectively collected. All women were scanned using a 3 T protocol interleaving ultrafast breast MRI acquisitions in a full multiparametric diagnostic MRI protocol consisting of standard dynamic contrast-enhanced sequences, diffusion-weighted imaging, and T2-weighted imaging. Subsequently, a case set was created including all biopsied screen-detected lesions in this period (31 malignant and 54 benign) and 116 randomly selected normal cases with more than 2 years of follow-up. Prior examinations were included when available. Seven dedicated breast radiologists read all 201 examinations and 153 available priors once using the FDP and once using ultrafast breast MRI only in 2 counterbalanced and crossed-over reading sessions. For reading the FDP versus ultrafast breast MRI alone, sensitivity was 0.86 (95% confidence interval [CI], 0.81-0.90) versus 0.84 (95% CI, 0.78-0.88) (P = 0.50), specificity was 0.76 (95% CI, 0.74-0.79) versus 0.82 (95% CI, 0.79-0.84) (P = 0.002), positive predictive value was 0.40 (95% CI, 0.36-0.45) versus 0.45 (95% CI, 0.41-0.50) (P = 0.14), and area under the receiver operating characteristics curve was 0.89 (95% CI, 0.82-0.96) versus 0.89 (95% CI, 0.82-0.96) (P = 0.83). Ultrafast breast MRI reading was 22.8% faster than reading FDP (P < 0.001). Interreader agreement is significantly better for ultrafast breast MRI (κ = 0.730; 95% CI, 0.699-0.761) than for the FDP (κ = 0.665; 95% CI, 0.633-0.696). Breast MRI screening using only an ultrafast breast MRI protocol is noninferior to screening with an FDP and may result in significantly higher screening specificity and shorter reading time.


Determinants of Bacterial Morphology: From Fundamentals to Possibilities for Antimicrobial Targeting.
Bacterial morphology is extremely diverse. Specific shapes are the consequence of adaptive pressures optimizing bacterial fitness. Shape affects critical biological functions, including nutrient acquisition, motility, dispersion, stress resistance and interactions with other organisms. Although the characteristic shape of a bacterial species remains unchanged for vast numbers of generations, periodical variations occur throughout the cell (division) and life cycles, and these variations can be influenced by environmental conditions. Bacterial morphology is ultimately dictated by the net-like peptidoglycan (PG) sacculus. The species-specific shape of the PG sacculus at any time in the cell cycle is the product of multiple determinants. Some morphological determinants act as a cytoskeleton to guide biosynthetic complexes spatiotemporally, whereas others modify the PG sacculus after biosynthesis. Accumulating evidence supports critical roles of morphogenetic processes in bacteria-host interactions, including pathogenesis. Here, we review the molecular determinants underlying morphology, discuss the evidence linking bacterial morphology to niche adaptation and pathogenesis, and examine the potential of morphological determinants as antimicrobial targets.


Proposed chromosomal phylogeny for the South American primates of the Callitrichidae family (Platyrrhini).
Cytogenetic and cytotaxonomic studies (G, C, sequential G/C, and NOR banding) were performed on 110 specimens representing the four genera of South American primates of the family Callitrichidae: Cebuella (C. pygmaea), Callithrix, groups argentata (C. argentata, C. emiliae, C. chrysoleuca, C. humeralifera, C. mauesi), and jacchus (C. aurita, C. geoffroyi, C. jacchus, C. kuhli, C. penicillata), Leontopithecus (L. chrysomelas, L. rosalia), and Saguinus (S. midas midas, S. m. niger). Mitotic chromosomes are characterized, and the rearrangements distinguishing the karyotypes of the taxa are inferred from arm homologies. The results were then converted into numerical data and submitted to cladistic analysis. The following conclusions were achieved: 1) Five karyotypic classes were observed, which correspond to the five taxa studied. Differences between them are as follows: a) Cebuella (2n = 44, 10 acrocentrics, A + 32 bi-armed autosomes, bi) and the argentata group (2n = 44, 10A + 32bi) are different from each other due to a reciprocal translocation; b) both can be distinguished from the jacchus group (2n = 46, 14A + 30bi) by a centric fusion/fission rearrangement and a paracentric inversion; c) Leontopithecus (2n = 46, 14A + 30bi) and Saguinus (2n = 46, 14A + 30bi) differ from the jacchus group by a reciprocal translocation and three paracentric inversions; and d) Saguinus is different from the others by one paracentric inversion and pericentric inversions in at least four pairs of acrocentric autosomes. 2) The cladistic analysis separates Cebus (used as an outgroup) from the Callitrichidae groups, which forms a clade. Among the Callitrichidae, marmosets (Cebuella and Callithrix) form a sub-clade, Cebuella and the argentata group being more closely related to each other than both are to the jacchus group. Tamarins (Leontopithecus and Saguinus) are also quite close, so that if one was not derived from the other, they with the marmosets share a common ancestor. Among the tamarins, Leontopithecus is karyotypically closest to the marmosets, specifically to the jacchus group. 3) Based on the chromosome information and considering the possible direction of the evolutionary changes (primitivity or phyletic dwarfism hypothesis, previously advanced by other authors), it was possible to propose the ancestral karyotypes and to develop two alternatives for the origin, differentiation and dispersion of the callitrichid. Both proposals are plausible, but when the geographical distribution is considered, the phyletic dwarfism hypothesis seems to be the most probable.


Comparative study between prostatic carcinoma G1-G3 and Gleason grading systems.
The need of an accurate and prognostically valuable method for grading the prostatic carcinoma resulted in, in the last decades, a large number of systems, none of them succeeding in being unanimously accepted by the pathologists family. The authors selected and reassessed using Gleason system a group of 221 cases with prostatic adenocarcinoma previously diagnosed using a combined G1-G3 system. The results were converted from Gleason system to G1-G3 system and then compared with the initial diagnostics. The group was divided, following the type of surgical procedure used for drawing the tissue, into three groups: transvesical prostatectomies (TVP), transurethral resections (TUR) and needle biopsies (B). The concordance between the two systems was good, even the number of TUR and B specimens was significant (85% of the studied group) showing that any of them can be successfully used in current practice, depending only on pathologist's experience.


Prevalence and incidence of hyperplastic polyps and adenomas in familial colorectal cancer: correlation between the two types of colon polyps.
Colorectal adenomas are recognised as precursors of colorectal carcinomas. The significance of hyperplastic (metaplastic) colorectal polyps is unknown. The relationship between hyperplastic polyps and adenomas, and the prevalence and incidence of these lesions were evaluated in individuals predisposed to familial colorectal cancer. A total of 299 individuals participating in our surveillance programme during 1990-2000 were retrospectively evaluated. Subjects were classified into three groups: hereditary non-polyposis syndrome (HNPCC) (n=108), hereditary colorectal cancer (HCRC) (n=127), and individuals with empirical risk estimates-two close relatives (TCR) (n=64). Findings from 780 colonoscopies were evaluated regarding prevalence and incidence of hyperplastic polyps and adenomas. Correlations between hyperplastic polyps and adenomas were calculated by Pearson correlation. In total, 292 hyperplastic polyps and 186 adenomas were observed in 98 and 90 individuals, respectively. A positive correlation was found between the numbers of hyperplastic polyps and adenomas (r=0.40; p<0.001). Correlations between adenomas and hyperplastic polyps were similar in the three groups. The risk of detecting new hyperplastic polyps (odds ratio 5.41) or adenomas (OR 2.56) increased significantly when there was a positive finding at first colonoscopy. Hyperplastic polyps as well as adenomas may identify individuals with a high risk of colorectal cancer. This information is important when these individuals are selected and included in tailored surveillance programmes.


Frequency dependent intermittency and ionic basis of impulse conduction in postganglionic sympathetic fibres of guinea-pig vas deferens.
Some characteristic features of the functional innervation of guinea-pig vas deferens have been determined. Both ganglionic transmission from the hypogastric nerves and impulse propagation in proximal regions (main branch bundles within about 15 mm from the prostatic end of the organ) of the majority of single postganglionic sympathetic fibres of vas deferens nerve, had a high safety factor. Failure at these levels cannot account for the intermittent pattern of electrically-evoked secretion of transmitter from the individual varicosity of the terminals of vas deferens nerves, observed under identical experimental conditions. The shape of the extracellular single fibre action potential recorded by small calibre suction electrodes remained constant in proximal regions of vas deferens nerve, when the frequency of stimulation was varied between 0.5 and 8 Hz. Therefore, frequency-dependent facilitation of transmitter secretion in this tissue cannot be explained by frequency-dependent growth in the amplitude of nerve action potentials, as earlier assumed. However, when recordings were made in distal regions of vas deferens nerve (in small axon bundles, close to their points of insertion into the substance of the epididymal end of the organ), on two occasions fibres were found in which the safety factor for impulse conduction was low and frequency-dependent. The possibility is discussed that this feature, which was an exception in these non-terminal regions of vas deferens nerve, may be shared by the majority of fibres as they proceed distally towards the terminals. Clearly, if this is the case, intermittent failure of transmitter secretion from the individual varicosity may be due, at least in part, to intermittent failure of conduction of the nerve impulse to the terminals. Some useful qualitative information on the ionic basis of the extracellular nerve action potential, that might underlie a proximo-distal decline in the safety factor for impulse conduction in these nerves, was obtained by determining the effects on the shape of the signal, caused by varying the ionic composition of the medium (sodium, calcium), and by local addition of agents with known actions on sodium (tetrodotoxin), potassium (tetra-ethyl ammonium, 4-aminopyridine, rubidium, barium) and calcium channels (cobalt, manganese, lanthanum, nickel, D-600). By these criteria, the action potential that was shown to be a "normal" sodium-potassium spike, in proximal regions of vas deferens nerve, was found to have a different "pharmacological profile", in distal regions of the nerve, in a manner suggesting that here nerve impulse conduction had become somehow "calcium-dependent".(ABSTRACT TRUNCATED AT 400 WORDS)


Physiological evaluation of liquid-barrier, vapor-permeable protective clothing ensembles for work in hot environments.
Work clothes using fabrics with vapor-transmitting characteristics are in limited use in various industrial applications, and there is a growing interest in their purported ability to help reduce heat stress. This study was performed to compare two vapor-transmitting ensembles with other clothing ensembles previously tested. The evaluation was based on an established experimental protocol that determines the critical values of air temperature and water-vapor pressure so that an individual maintains thermal balance, while controlling other factors that contribute to worker heat stress (e.g., air motion and metabolism). There were no differences between the two vapor-transmitting garments in their effects on worker heat stress. When compared to the results of other studies, the two vapor-transmitting garments had critical environmental characteristics similar to two layers of cotton coveralls and they performed better from a heat stress standpoint than a disposable vapor-barrier suit worn over cloth coveralls.


Cell cycle effects of fatty acid derivatives of cytarabine, CP-4055, and of gemcitabine, CP-4126, as basis for the interaction with oxaliplatin and docetaxel.
To bypass resistance due to limited entry into the cell derivatives of cytarabine (CP-4055, elacytarabine) and gemcitabine (CP-4126) containing a fatty acid chain at the 5' position of the nucleoside were developed. CP-4055 showed an increased retention of the active metabolite, the triphosphate. This characteristic was supposed to favor combinations, such as with the tubulin antagonist docetaxel, the platinum oxaliplatin and the antifolate pemetrexed. The role of the cell cycle effects of CP-4055 and CP-4126 on the efficacy of the combination with docetaxel or pemetrexed was determined. The combination of CP-4055 with oxaliplatin and docetaxel was also evaluated in a mouse xenograft model. CP-4055 induced a G2/M and S phase accumulation and CP-4126 an S phase accumulation. Both analogs induced a dose-dependent cell kill (apoptosis and necrosis). None of the docetaxel combinations induced a synergistic effect. The combination of docetaxel with CP-4055 or CP-4126 induced a G2/M accumulation in the A549 (lung cancer) cell line, but a G0/G1 accumulation in the WiDR (colon cancer) cell line. Preincubation with docetaxel induced an increased cell kill in both cell lines. The combination with oxaliplatin showed a synergistic effect in both cell lines. Combinations with pemetrexed were antagonistic in both cell lines. In the A549 cell line pemetrexed with CP-4055 led to an increase of the G0/G1 phase and the S phase. In WiDR the combination of pemetrexed with CP-4055 increased the G0/G1 phase and increased the cell kill. Pemetrexed with CP-4126 induced an increase in the G0/G1 phase and the S phase in the A549 cell line. In the xenograft study, on a colon cancer and a lung metastasis model, the combination of CP-4055 with docetaxel showed the best results. Treatment with CP-4055 followed by docetaxel after 4 h resulted in a reduction in metastasis in a lung metastasis model, and a favorable toxicity profile was observed. In conclusion, the combinations with oxaliplatin showed a synergistic effect in the combination studies. Although the combinations with docetaxel did not show an enhanced effect in the in vitro studies, this combination revealed an increased effect in the xenograft model.


Monocyte-T lymphocyte interaction for regulation of insulin receptors of the activated T lymphocyte.
During activation the lymphocyte attains functional insulin receptors with precise regulation, a consequence of insulin concentration manipulations. These studies test the hypothesis that insulin receptor (+) monocytes monitor insulin concentrations, so instructing the T lymphocytes. Monocyte-enriched populations were incubated with insulin (0-10(-6) M) followed by co-culture with T lymphocytes and an activating stimulus. A dose-related fall in T lymphocyte insulin receptor binding was observed that was specific for the monocyte as the signalling cell and for insulin as the signal received. Monocytes from normal volunteers during a euglycemic, hyperinsulinemic clamp were cultured with T lymphocytes and an activating stimulus. A decline in specific insulin receptor binding on T lymphocytes was observed, which Scatchard analysis demonstrated to be a consequence of reduction in receptor numbers. These studies demonstrate that the receptor (+) monocyte perceives the concentration of insulin and passes this information to T lymphocytes regulating the number of activation-induced insulin receptors. The interplay between the monocyte and T lymphocyte parallels the interaction of these cell types for recognition of antigen.


A spontaneous prothrombotic disorder resembling heparin-induced thrombocytopenia.
Antibodies against the "self" protein, platelet factor 4 (PF4), bound to heparin-the cause of immune heparin-induced thrombocytopenia-are believed invariably to be triggered by preceding heparin therapy. We describe a novel syndrome, spontaneous heparin-induced thrombocytopenia, in which clinical and serologic features characteristic of this adverse drug reaction develop in patients despite the absence of preceding heparin therapy. Three patients met the study criteria (clinical and serologic features of heparin-induced thrombocytopenia without preceding heparin exposure), of whom 2 patients were identified among 225 patients (0.89%, 95% confidence interval, 0.11%-3.17%) with serologically confirmed heparin-induced thrombocytopenia recognized during an 18-year period at 1 hospital. The platelet serotonin-release assay was used to detect heparin-dependent immunoglobulin G-induced platelet activation, and 2 enzyme immunoassays were used to detect antibodies against PF4/heparin. Two patients presented with thrombocytopenia and multiple arterial thrombosis, and 1 patient presented with anaphylactoid reactions after 2 subcutaneous injections of low-molecular-weight heparin. All 3 patients had high levels of platelet-activating anti-PF4/heparin antibodies of immunoglobulin G class at presentation despite the absence of previous heparin exposure. However, each patient did have a preceding infectious or inflammatory event; 1 patient had concomitant antiphospholipid antibodies. Circumstances other than heparin use can trigger a spontaneous disorder that closely mimics heparin-induced thrombocytopenia, further supporting the autoimmune nature of this adverse drug reaction.


New rat model for attention deficit hyperactive disorder (ADHD).
In a strain of the Long-Evans Cinnamon (LEC) rats, we found spontaneously hyperactive animals designated as "wiggling," and established a congenic wiggling (Wig) rat by transferring the gene from the LEC to the Wistar King-Aptekman/Hokkaido (WKAH) strain. We evaluated the feasibility of the Wig rat for an animal model of human attention deficit hyperactive disorder (ADHD). Mode of inheritance was examined by use of linkage analyses. Motor activity, behavior, and working memory were assessed by use of electric digital counters, open field test, and Y-maze and water-maze tests. The abnormal behavior, including hyperactivity, was transmitted in autosomal recessive mode. Diurnal and nocturnal motor activity of 12- to 14-week-old Wig rats was markedly higher than that of controls, and this hyperactivity was more prominent during nighttime than daytime. Ambulation in the open-field test was significantly increased in Wig rats, but rearing was decreased in Wig rats, compared with controls. Results of the Y-maze tests indicated that spontaneous alternation behavior was significantly impaired in Wig rats, although there was no difference in the total arm entries. The water-maze test could not be performed because, when exposed to water, Wig rats panicked and almost drowned. Wig rats are hyperactive and have impaired working memory and impulsive behavior, as assessed by the motor activity and open-field tests and the Y-maze test, and these abnormalities are transmitted by a single gene with Mendelian pattern. Wig rats represent an excellent animal model of human ADHD.


Dental caries in the permanent teeth of the people of Gulbarga, Karnataka.
In a sample of 2,096 randomly selected individuals of both sexes (male, 1,097., female, 999) in Gulbarga, Karnataka, dental caries was observed in about 20% individuals. The inter-sex difference in the prevalence of caries was statistically insignificant. People of the upper income group (23.2%) were affected more than the middle (20.0%) and lower income groups (17.0%). Christians (23.4%) were affected more than Hindus (20.0%) and Muslims (15.8%). Nearly one-third affected cases were in the age group 20-24 years. First molars of either jaw were more often affected than second and third molars. Mandibular first molars were affected maximum, followed by mandibular second, maxillary first and maxillary second molars. A toothwise study of caries-attack, by age, revealed increase in the frequency of carious teeth with increasing age.


Risperidone therapy in two successive pregnancies.
There is very limited information available on the use of psychotropic drugs in consecutive pregnancies. The authors report a case of a woman with schizophrenia wherein risperidone was used successfully in two consecutive pregnancies. This is only the second known report in the existing literature in which atypical antipsychotic was used successfully in two successive pregnancies.


Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans.
Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.


Mast cell heterogeneity and anti-inflammatory annexin A1 expression in leprosy skin lesions.
Mast cells (MCs) have important immunoregulatory roles in skin inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory protein that can be expressed by mast cells, neutrophils, eosinophils, monocytes, epithelial and T cells. This study investigated MCs heterogeneity and ANXA1 expression in human dermatoses with special emphasis in leprosy. Sixty one skin biopsies from 2 groups were investigated: 40 newly diagnosed untreated leprosy patients (18 reaction-free, 11 type 1 reaction/T1R, 11 type 2 reaction/T2R); 21 patients with other dermatoses. Tryptase/try+ and chymase/chy + phenotypic markers and toluidine blue stained intact/degranulated MC counts/mm2 were evaluated. Try+/chy+ MCs and ANXA1 were identified by streptavidin-biotin-peroxidase immunostaining and density was reported. In leprosy, degranulated MCs outnumbered intact ones regardless of the leprosy form (from tuberculoid/TT to lepromatous/LL), leprosy reactions (reactional/reaction-free) and type of reaction (T1R/T2R). Compared to other dermatoses, leprosy skin lesions showed lower numbers of degranulated and intact MCs. Try+ MCs outnumbered chy+ in leprosy lesions (reaction-free/reactional, particularly in T2R), but not in other dermatoses. Compared to other dermatoses, ANXA1 expression, which is also expressed in mast cells, was higher in the epidermis of leprosy skin lesions, independently of reactional episode. In leprosy, higher MC degranulation and differential expression of try+/chy+ subsets independent of leprosy type and reaction suggest that the Mycobacterium leprae infection itself dictates the inflammatory MCs activation in skin lesions. Higher expression of ANXA1 in leprosy suggests its potential anti-inflammatory role to maintain homeostasis preventing tissue and nerve damage.


Selective digestive tract decontamination and vancomycin-resistant enterococcus isolation in the surgical intensive care unit.
Vancomycin-resistant Enterococcus (VRE) has emerged as a significant nosocomial pathogen in the surgical intensive care unit (SICU). We wished to test the hypothesis that the use of selective digestive tract decontamination (SDD) in the SICU affects the frequency of VRE isolation. A retrospective review of hospital records and the SICU database was performed using patients admitted to the SICU service for three or more days from January 1, 1996 to December 31, 1999 at our large tertiary-care teaching hospital. During this time use of SDD in selected patient populations decreased due to physician preference. Information gathered included length of SICU stay, presence of VRE infection or colonization, and use and duration of SDD protocol, vancomycin, and ceftazidime. There were 110 newly diagnosed VRE cases in the SICU during this time period. During the same time period 54 patients received SDD. Eight patients who received SDD had positive VRE cultures and seven had the initial positive culture after receiving SDD. Overall, 9.1% of eligible SICU patients received SDD, 18.5% of patients in the SICU for over 3 days had VRE, 7.3% of VRE patients received SDD, and 13.0% of the SICU patients who received SDD subsequently developed VRE. SDD use was not associated with VRE in univariate analysis. Logistic regression analysis showed higher odds ratios for SDD use in combination with vancomycin than for vancomycin use alone (OR=4.3 vs. 10.9). Odds ratios were over three times higher for SDD plus vancomycin plus ceftazidime use when compared to vancomycin plus ceftazidime use alone (OR=70.5 vs. 19.8). We conclude that administration of SDD alone did not correlate with increased VRE isolation, but that SDD use in conjunction with vancomycin and ceftazidime was associated with VRE isolation.


How Business Interests and Government Inaction Led to the Humidifier Disinfectant Disaster in South Korea: Implications for Better Risk Governance.
Humidifier sterilizers were regarded as innovative and health-promoting products; they were widespread in South Korea until 2011. However, hospitals reported mysterious deaths, and a legal investigation in April 2016 found that hundreds of people have died due to use of the sterilizing disinfectant. This article takes up that topic, discussing the government's role in dealing with the risk regarding the humidifier disinfectant. We pay particular attention to the unequal nature of the uncertainty produced by the distorted socioeconomic structure. Through in-depth interviews with key informants and an examination of relevant documents from the government, civic groups, and newspapers, we find that the government had increasingly acknowledged the risk, yet their inaction failed to stop the high number of casualties, and they have only recently responded proactively. The uncertainty of the risk was unevenly distributed between companies, the government, experts, and citizens. We argue that the proactive and transparent role of the government with the precautionary principle could fix the unequal structure of knowledge production and preserve public health.


[Thalidomide, cereblon and multiple myeloma].
Cereblon was identified as a direct target of thalidomide by Prof. H. Handa, and this pioneering work triggered active research on IMiDs (immunomodulatory drugs), which include thalidomide-derivatives, such as lenalidomide and pomalidomide. These small molecules have been shown to bind to cereblon (CRBN) to modulate its activity as a substrate receptor. In addition, structural analyses on CRBN have revealed unique actions of these small agents, by which degradation of transcription factors is controlled in a specific and unique way. I summarize recent progress on CRBN-CRLA ubiquitin ligase and IMiDs, focusing on the therapeutic application of these drugs for treatment of multiple myeloma.


[Use of cinacalcet in secondary hyperparathyroidism: assessment of nutritional, lipid and inflammatory status in chronic kidney disease].
Introduction: observations in cell lines suggest that the use of cinacalcet could be associated with increase in body fat, inflammatory state, and alteration in lipid metabolism. However, when scaling the model to the clinical level, the occurrence of these effects is unknown. Objectives: to analyze the effect of cinacalcet therapy on anthropometric, inflammatory and lipid parameters in renal patients with secondary hyperparathyroidism (SHPT). Methods: observational study with two approaches. The retrospective study included 89 patients who started cinacalcet treatment since 2018 with a maximum follow-up of 36 months. Body mass index (BMI) variables, waist circumference, tricipital skinfold, parathyroid hormone (PTH), and biochemical profile were analyzed. The prospective study included 52 patients who started cinacalcet treatment since 2020 with a 12-month follow-up. BMI, PTH, lipid profile, and PCR variables were analyzed. Results: in the retrospective study, BMI was 27 kg/m2, with 62 % overweight and 65 % of patients with high cardiovascular risk. Cinacalcet reduced PTH by 12 % after six months (p < 0.01) and serum calcium decreased by 3.4 % at the end of follow-up (p = 0.04). According to the prospective study, BMI was 26.8 kg/m2, with 60 % overweight. PTH decreased by 8.4 % after six months. Total cholesterol, LDL cholesterol, and triglycerides decreased by 6.8 %, 12.5 %, and 5.5 %, respectively, at the end of follow-up. Conclusions: the prevalent nutritional status is excess weight. In patients with SHPT, cinacalcet improves PTH control without causing changes in anthropometric, lipid, and inflammatory parameters.


Facial carbuncle - a new method of conservative surgical management plus irrigation with antibiotic-containing solution.
This paper reports on a non-conventional method for the management of facial carbuncles, highlighting its superiority over conventional surgical treatment in terms of cosmetic outcome and shorter duration of wound healing. The mainstay of treatment for carbuncles involves the early administration of antibiotics in combination with surgical intervention. The conventional saucerisation, or incision and drainage, under normal circumstances results in moderate to large wounds, which may need secondary surgery such as skin grafting, resulting in a longer duration of wound healing and jeopardising cosmetic outcome. The reported three cases presented with extensive carbuncles over the chin, face and lips region. In addition to early commencement of intravenous antibiotics, the pus was drained, with minimal incision and conservative wound debridement, with the aim of maximal skin conservation. This was followed by thrice-daily irrigation with antibiotic-containing solution for a minimum of 2 consecutive days. The wounds healed within two to four weeks, without major cosmetic compromise. The new method showed superior cosmetic outcomes, with a shorter duration of wound healing. Conservative surgical management can be performed under regional anaesthesia, which may reduce morbidity and mortality; patients with facial carbuncles often have higher risks with general anaesthesia.


[Why and how to modify standard cystectomy].
To improve quality of life in postcystectomy patients, we made 150 radical cystectomies with recovery of urethral voiding. Cystectomy was performed by a modified technique in 87 of 135 operated men: transprostatic cystvesiculectomy (n = 11), transprostatic cystectomy (n = 53), supraprostatic cystectomy (n = 23). Indication for this modification was the absence of extravesicular growth of the primary tumor and prostatic cancer. Monitoring of radicalism was carried out by intraoperative urgent histological investigation of the resection line. 74 patients have undergone retrograde cystectomy. Postoperative lethality was 2.3%. 9 month and longer follow up results were studied.


Fighting Assessment Triggers Rapid Changes in Activity of the Brain Social Decision-Making Network of Cichlid Fish.
Social living animals have to adjust their behavior to rapid changes in the social environment. It has been hypothesized that the expression of social behavior is better explained by the activity pattern of a diffuse social decision-making network (SDMN) in the brain than by the activity of a single brain region. In this study, we tested the hypothesis that it is the assessment that individuals make of the outcome of the fights, rather than the expression of aggressive behavior per se, that triggers changes in the pattern of activation of the SDMN which are reflected in socially driven behavioral profiles (e.g., dominant vs. subordinate specific behaviors). For this purpose, we manipulated the perception of the outcome of an agonistic interaction in an African cichlid fish (Oreochromis mossambicus) and assessed if either the perception of outcome or fighting by itself was sufficient to trigger rapid changes in the activity of the SDMN. We have used the expression of immediate early genes (c-fos and egr-1) as a proxy to measure the neuronal activity in the brain. Fish fought their own image on a mirror for 15 min after which they were allocated to one of three conditions for the two last minutes of the trial: (1) they remained fighting the mirror image (no outcome treatment); (2) the mirror was lifted and a dominant male that had just won a fight was presented behind a transparent partition (perception of defeat treatment); and (3) the mirror was lifted and a subordinate male that had just lost a fight was presented behind a transparent partition (perception of victory treatment). Results show that these short-term social interactions elicit distinct patterns in the SDMN and that the perception of the outcome was not a necessary condition to trigger a SDMN response as evidenced in the second treatment (perception of defeat treatment). We suggest that the mutual assessment of relative fighting behavior drives these acute changes in the state of the SDMN.


Interaction of salicylate and a terpenoid plant extract with model membranes: reconciling experiments and simulations.
We investigate the effects of two structurally similar small cyclic molecules: salicylic acid and perillic acid on a zwitterionic model lipid bilayer, and show that both molecules might have biological activity related to membrane thinning. Salicylic acid is a nonsteroidal antiinflammatory drug, some of the pharmacological properties of which arise from its interaction with the lipid bilayer component of the plasma membrane. Prior simulations show that salicylate orders zwitterionic lipid membranes. However, this is in conflict with Raman scattering and vesicle fluctuation analysis data, which suggest the opposite. We show using extensive molecular dynamics simulations, cumulatively >2.5 μs, that salicylic acid indeed disorders membranes with concomitant membrane thinning and that the conflict arose because prior simulations suffered from artifacts related to the sodium-ion induced condensation of zwitterionic lipids modeled by the Berger force field. Perillic acid is a terpenoid plant extract that has antiinfective and anticancer properties, and is extensively used in eastern medicine. We found that perillic acid causes large-scale membrane thinning and could therefore exert its antimicrobial properties via a membrane-lytic mechanism reminiscent of antimicrobial peptides. Being more amphipathic, perillic acid is more potent in disrupting lipid headgroup packing, and significantly modifies headgroup dipole orientation. Like salicylate, the membrane thinning effect of perillic acid is masked by the presence of sodium ions. As an alternative to sodium cations, we advocate the straightforward solution of using larger countercations like potassium or tetra-methyl-ammonium that will maintain electroneutrality but not interact strongly with, and thus not condense, the lipid bilayer.


Endopeptidase O promotes Streptococcus suis immune evasion by cleaving the host- defence peptide cathelicidins.
Streptococcus suis is a zoonotic Gram-positive bacterium that causes invasive infections such as sepsis and meningitis, threatening public health worldwide. For successful establishment of infection, the bacterium should subvert the innate effectors of immune defence, including the cathelicidin family of host-defence peptides that combat pathogenic bacteria by directly disrupting cell membranes and coordinating immune responses. Here, our study shows that an extracellular endopeptidase O (PepO) of S. suis contributes to assisting the bacterium to resist cathelicidin-mediated killing, as the deletion of the pepO gene makes S. suis more sensitive to the human cathelicidin LL-37, as well as its mouse equivalent, mCRAMP. This protease targets and cleaves both LL-37 and mCRAMP, degrading them into shorter peptides with only a few amino acids, thereby abrogating their ability to kill S. suis. By cleaving LL-37 and mCRAMP, PepO impairs their chemotactic properties for neutrophil migration and undermines their anti-apoptosis activity, which is required for prolonging neutrophil lifespan. Also, PepO inhibits the ability of LL-37 and mCRAMP to promote lysosome development in macrophages. Moreover, the loss of PepO attenuates organ injury and decreases bacterial burdens in a murine model of S. suis bacteraemia. Taken together, these data provide novel insights into the role of the intrinsic proteolytic characteristics of PepO in S. suis-host interaction. Our findings demonstrate that S. suis utilizes the PepO protease to cleave cathelicidins, which is an immunosuppressive strategy adopted by this bacterium to facilitate pathogenesis.


Excision Versus Fixation of the Radial Head: A Comparative Study of the Functional Outcomes of the Two Techniques.
The management of displaced and comminuted radial head fractures has been a matter of debate amongst surgeons for many years. Radial head excision formed the mainstay of surgical management of these injuries. Over the years, there have been improvements in the surgical techniques and availability of better implants and instrumentation techniques, hence, open reduction and internal fixation of these fractures is gaining popularity. To compare the outcome of elbow function between radial head excision and open reduction and internal fixation of the radial head with mini screws of Mason Type II and Type III radial head fractures and to assess the complications that occur in both techniques. A prospective study was conducted in the Department of Orthopaedic Surgery of Justice K.S.Hegde Charitable hospital. A total of 40 patients between the age group of 30-50 years with Mason Type II and Type III fresh closed radial head fractures were included in the study. Group I consisted of 20 patients who underwent radial head excision and Group II consisted of 20 patients who underwent open reduction and internal fixation with mini screws. Patients were reviewed at postoperative week 3, 6 and 24. Radiographs were taken and functional outcome assessment of the elbow was done during all the follow ups. Elbow physiotherapy was started on postoperative week three. Scoring of elbow function was done as per the Disabilities of the Arm, Shoulder and Hand (DASH) scoring system. Results were tabulated, compared and analysed statistically using the 'chi-square test'. At the end of six months, the patients of the open reduction and internal fixation group had lower DASH scores (4.82±2.73 points) than the radial head excision group (14.23±5.60 points). This inferred that patients who underwent open reduction and internal fixation had better functional outcomes than the excision group. Complications of proximal radial migration was noted in three patients, elbow osteoarthritis was noted in two and periarticular ossification was noted in six patients who underwent radial head excision. Open reduction and internal fixation of Mason Type II and Type III radial head fractures is a better management technique as compared to radial head excision for management of Mason Type II and III radial head fractures.


Standardized out-patient diagnosis and treatment process for osteoporosis clinics during the COVID-19 pandemic.
Since the end of 2019, China and other regions around the world have been facing a pandemic of novel coronavirus pneumonia (COVID-19). The virus is highly transmissible, and the human population is generally susceptible. Most patients with osteoporosis are postmenopausal women or elderly people with hypoimmunity, so the osteoporosis clinic has become a new hotspot for corona virus infection. During the COVID-19 pandemic, it is necessary to establish standardized out-patient protocols to provide safe and effective treatment for osteoporosis patients and medical staff. In an osteoporosis clinic, we advocate the following suggestions to prevent and control osteoporosis during the pandemic period: (1) specialized diagnosis and treatment techniques for osteoporosis patients in the outpatient care, including enhancing the prevention for outpatient medical staff, strengthening awareness of COVID-19 prevention, strictly screening outpatients with COVID-19 infection, and insistent administration of anti-osteoporosis drugs during outbreaks; (2) home prevention for osteoporosis patients including keeping windows open, exposing them to sunlight, supplementing them with enough protein, exercising regularly, and administrating calcium supplements; and (3) simplifying the follow-up and evaluation of osteoporosis using online platforms.


Distribution of Plant-Parasitic Nematodes in Michigan Corn Fields.
Plant-parasitic nematodes (PPNs) can cause substantial economic yield losses to many agronomic crops in the United States. A regional-scale survey was completed across 20 counties to determine PPNs prevalence in Michigan corn and how factors such as soil type, tillage, irrigation, and cropping systems influence their distribution. Ten different major genera of PPNs were identified in Michigan corn fields: Longidorus (needle), Helicotylenchus (spiral), Pratylenchus (lesion), Meloidogyne (root-knot), Heterodera (cyst), Hoplolaimus (lance), Tylenchorhynchus or Merlinius (stunt), Paratylenchus (pin), Criconemella (ring), and Xiphinema (dagger). No significant differences among different categories of tillage for lesion, stunt, or needle nematode prevalence was detected. Lesion nematodes were most prevalent in muck soil, while stunt nematode prevalence was significantly affected by the soil type. Needle nematodes were least abundant in irrigated soils and in contrast, stunt nematodes were higher in non-irrigated soils. Spiral nematodes were the most common PPNs in Michigan corn in all cropping systems. These findings will be helpful in planning future nematode studies in Michigan and in developing and evaluating corn nematode management strategies.


Child and adolescent suicide deaths in New Mexico, 1990-1994.
The suicide death rate in New Mexico is consistently higher than the national rate. Among adolescents, suicide is the third leading cause of death nationally, but in New Mexico it is the second leading cause of death. This study describes the pattern of adolescent suicide deaths in New Mexico. We conducted a retrospective review of all medical examiner autopsies for adolescent suicides (ages 20 years and younger) in New Mexico from 1990-1994. Records were reviewed for demographics and possible contributing factors such as depression, previous attempts, and alcohol and drug use. We identified 184 suicide deaths among children and adolescents ages 9-20 years for an overall rate of 12.9 per 100,000. Our rates for ages 5-9 years (0.2), 10-14 years (3.8), and 15-19 years (22.3) are over twice the U. S. rates. Suicide deaths resulted primarily from firearms (67%), hanging (16%), poisoning (6%), inhalation (4%), and other methods (7%). Method varied by ethnicity (p = .01) and gender (p = .03); males and non-Hispanic Whites were overrepresented among firearm deaths. Firearm ownership was known in 60 (48%) of the firearm deaths. Of these, 53% of the firearms belonged to a family member, 25% to the decedent, and 22% to a friend. Over one-third of decedents (41%) experienced mental disorders, primarily depressed mood and clinical depression. Previous suicide attempts were noted for 15% of the decedents. Some 50% of the decedents had alcohol or drugs present at the time of death; among American Indians/Alaska Natives, 74% had drugs or alcohol present (p = .003). Targeted interventions are needed to reduce adolescent suicide in New Mexico. We suggest raising awareness about acute and chronic contributing factors to suicide; training physicians to look for behavioral manifestations of depression; and involving physicians, teachers, and youth activity leaders in efforts to limit firearm accessibility, such as advising parents to remove firearms from their households.


Number of ovulations in the marmoset monkey (Callithrix jacchus): relation to body weight, age and repeatability.
The relation between number of ovulations and body weight, age or maternal identity was examined in 69 ovarian cycles from 29 captive-born common marmoset monkeys (Callithrix jacchus). Specifically, we addressed the following questions: was there high repeatability of ovulation number? Most of the variation in ovulation number was within, rather than between subjects. Repeatability in number of ovulations was 0.081 (n = 20 females with 2-6 ovulatory cycles per female); was age related to number of ovulations? There was no relation between age and number of ovulations, either within or between subjects; and was weight related to number of ovulations? Weight was related to number of ovulations. When the relation between number of ovulations (1-2 versus 3-4) and weight was examined through a logistic regression, there was a significant relation. Also, of the 11 subjects which had a variable number of ovulations across cycles, 90.9% were heavier when ovulating 3-4 than when ovulating 2. These results are discussed as the basis for the proposal that callitrichid primates may have been selected for potential variation in reproductive output and that this variation may be related to energy availability.


Temporary occlusion of the middle cerebral artery in intracranial aneurysm surgery: time limitation and advantage of brain protection.
The risk of focal infarction secondary to the induced reversible arrest of local arterial flow during microsurgical dissection of middle cerebral artery (MCA) aneurysms was evaluated further to define the optimal approach to temporary arterial occlusion. To compare the effectiveness of potential brain-protection anesthetics, a group of patients treated with the intravenous agents propofol, etomidate, and pentobarbital, administered individually or in combination, was compared to a group treated with the inhalational agent isoflurane. Forty-nine consecutive MCA aneurysm surgeries involving the temporary clipping of the parent vessel were retrospectively reviewed. Thirty-eight patients received intravenous brain-protection (IVBP) anesthesia. Groups of patients with and without infarctions, and receiving and not receiving IVBP anesthesia, were compared based on the duration and nature of temporary arterial occlusion. Postoperative radiographic evidence of new infarction was used as the threshold for failure of occlusion tolerance. The overall infarction rate was 22.4% (11 of 49 patients), including 15.8% (six of 38 patients) in the IVBP group versus 45.5% (five of 11 patients) in the group that did not receive brain protection (NBP). In the NBP group, the mean duration of temporary occlusion was 3.9 +/- 2.2 minutes for patients without infarction versus 12.2 +/- 4.3 minutes for patients with focal infarction (p < 0.01). In contrast, the mean duration was 13.6 +/- 10.6 minutes for patients without infarction and 18.5 +/- 9.9 minutes for patients with infarction in the IVBP group. All patients (four of four) in the NBP group who underwent occlusion lasting 10 minutes or longer suffered an infarction versus five of 23 patients in the IVBP group (p < 0.0001). Patients with multiple aneurysms were found to be at increased risk of developing focal infarction, whereas those treated with intermittent temporary clip application were at decreased risk. It is concluded that patients in whom focal iatrogenic ischemia is induced during MCA aneurysm clip ligation have a significant advantage compared with those receiving isoflurane when they are given pentobarbital as the primary neuroprotective agent or when they receive propofol or etomidate titrated to achieve electroencephalographic burst suppression, particularly if more than 10 minutes of occlusion time is required. It is also concluded that 10 minutes is a general guideline for safe, temporary occlusion of the MCA. The use of intermittent temporary arterial occlusion and its use in patients with multiple aneurysms need further evaluation before specific recommendations can be made.


Heuristic-systematic information processing and risk judgment.
The heuristic-systematic information processing model (HSM) holds that individuals will use one or both of these modes of information processing when attempting to evaluate information in order to arrive at a judgment. Systematic processing is defined by effortful scrutiny and comparison of information, whereas heuristic processing is defined by the use of cues to arrive more easily at a judgment. Antecedents to the two processing modes include information sufficiency, motivation, and self-efficacy. Structural equation modeling is used to examine competing configuration of this model and to evaluate the model as appropriate for predicting risk judgment. The model also is evaluated across three groups that vary with respect to their level of concern. These analyses are executed within a case study involving an epidemiological investigation of a suspected cancer cluster. The analysis confirms the HSM's theoretically proposed structure and shows it to be a useful vehicle for evaluating risk judgment. In the overall analysis, antecedent variables generally function as specified by theory. Systematic processing is predicted by greater motivation. Heuristic processing is predicted by information sufficiency. Self-efficacy is a significant predictor of both processing modes. And heuristic processing is shown to be associated with judgment of less risk. However, when the analysis is contrasted across three groups (those concerned about cancer, not concerned and uncertain) it is shown that the model is significantly more robust for the uncertain group. This finding may have implications for the use of the HSM in risk research specifically, and in field research generally.


Blue blood.
In a world of increasing immigration of a diverse range of nationalities, hereditary hemoglobin variants will be increasingly encountered, and should be considered in infants and children presenting with low saturations. We present a case report of an infant presenting with low oxygen saturations, who was extensively investigated before the correct diagnosis became apparent. Initial haemoglobin electrophoresis was normal, but subsequently abnormal on repeat testing. With further screening, a number of affected family members have since been identified.


Intracerebral hemorrhage: clinical overview and pathophysiologic concepts.
Intracerebral hemorrhage is by far the most destructive form of stroke. Apart from the management in a specialized stroke or neurological intensive care unit (NICU), no specific therapies have been shown to consistently improve outcomes after ICH. Current guidelines endorse early aggressive optimization of physiologic derangements with ventilatory support when indicated, blood pressure control, reversal of any preexisting coagulopathy, intracranial pressure monitoring for certain cases, osmotherapy, temperature modulation, seizure prophylaxis, treatment of hyerglycemia, and nutritional support in the stroke unit or NICU. Ventriculostomy is the cornerstone of therapy for control of intracranial pressure patients with intraventricular hemorrhage. Surgical hematoma evacuation does not improve outcome for more patients, but is a reasonable option for patients with early worsening due to mass effect due to large cerebellar or lobar hemorrhages. Promising experimental treatments currently include ultra-early hemostatic therapy, intraventricular clot lysis with thrombolytics, pioglitazone, temperature modulation, and deferoxamine to reduce iron-mediated perihematomal inflammation and tissue injury.


Racial/Ethnic Disparities in Triage Scores Among Pediatric Emergency Department Fever Patients.
Emergency department (ED) triage scores are assigned to patients in a short period based on assessment of need for lifesaving measures, risk and pain levels, resource needs, and vital signs. Racial/ethnic disparities have been found across a number of outcomes but are not consistent across all studies. This study examines pediatric ED cases reporting fever, a commonly reported triage symptom, to explore racial/ethnic and age disparities in triage score assignment. This study uses the 2009-2015 National Hospital Ambulatory Medical Care Survey, an annual national sample of ED visits in the United States. Pediatric cases where fever is the sole reported reason for visit are analyzed for racial/ethnic disparities, controlling for sex, age, insurance status, body temperature, region, and hospital type. Among all pediatric fever cases, temperature is the sole significant predictor of triage scores. However, non-Hispanic (NH) black pediatric patients older than 1 year have approximately 22% greater risk of being given a less urgent triage score relative to NH white patients. Findings suggest racial disparities in the triage of NH black pediatric patients older than 1 year for fever. Although fever is a single and often non-life-threatening condition, especially after infancy, findings of racial disparities in triage scores suggests a need for further evaluation of the assignment of patient urgency in emergency medicine.


[Neurogenic changes in filtration-absorptive ratios in skeletal muscle vessels].
In cats, the volumometry of extracorporeally circulating blood revealed that the character of changes of the capillary hydrostatic pressure in the hindlimb skeletal muscles occurring in response to stimulation of the lumbar sympathetic string, virtually depends on the mode of perfusion: under constant blood flow the capillary pressure increased while in perfusion under constant pressure it decreased. The capillary filtration coefficient (CFC) increased in response to stimulation of sympathetic efferents irrespective of the mode of vascular bed perfusion. The mechanisms of the above changes of the capillary hydrostatic pressure are considered from the standpoint of participation of hemodynamic factors and active shifts of pre-and postcapillary pressure. Possible role of the change of the vascular bed permeability and activation of beta-adrenoreceptors in the mechanism of the capillary filtration coefficient increase, is discussed.


Aspirator-Assisted Endoscopic Third Ventriculostomy in an Infant: 2-Dimensional Operative Video.
Endoscopic third ventriculostomy (ETV) is an effective treatment for hydrocephalus in carefully selected patients.1 Studies have shown that larger ostomy size may be associated with higher ETV success and reduced ostomy closure in pediatric and adult patients.2-5 Therefore dilation of the ostomy is a key step in this procedure, which is traditionally accomplished with a balloon catheter, leaving behind loose redundant tissue at the ostomy site. In this 2-dimensional endoscopic operation (Video 1), we demonstrate the technique of using an aspiration device to enlarge the ETV ostomy in a controlled and efficient manner while eliminating redundant tissue. The patient is a 6-month-old girl with newly developed triventricular hydrocephalus seen on head ultrasound, manifested as upward gaze palsy, fontanelle fullness, and rapidly increasing head circumference. We chose to treat her with an ETV, given an ETV success score of 70.6,7 She underwent an ETV augmented with the NICO Myriad aspirator (NICO Corporation, Indianapolis, Indiana, USA) and achieved excellent clinical outcome. No intraoperative or postoperative complication occurred. Postoperative magnetic resonance imaging demonstrated an 8.4-mm ostomy on the third ventricular floor, nearly twice the size of a typical ETV ostomy.5 The key considerations in using this device include setting a low aspiration limit to avoid oversuction and using only mediolateral motion to avoid damage to the basilar artery. Future comparative studies are needed to investigate the efficacy, safety, and long-term outcome in aspirator-assisted ETV versus traditional techniques, as well as to evaluate ostomy size as an independent variable for long-term ETV success.


Ultrasound in the Study of Thoracic Diseases: Innovative Aspects.
Thoracic ultrasound (TU) has rapidly gained popularity over the past 10 years. This is in part because ultrasound equipment is available in many settings, more training programmes are educating trainees in this technique, and ultrasound can be done rapidly without exposure to radiation. The aim of this review is to present the most interesting and innovative aspects of the use of TU in the study of thoracic diseases. In pleural diseases, TU has been a real revolution. It helps to differentiate between different types of pleural effusions, guides the performance of pleural biopsies when necessary and is more cost-effective under these conditions, and assists in the decision to remove thoracic drainage after talc pleurodesis. With the advent of COVID19, the use of TU has increased for the study of lung involvement. Nowadays it helps in the diagnosis of pneumonias, tumours and interstitial diseases, and its use is becoming more and more widespread in the Pneumology ward. In recent years, TU guided biopsies have been shown to be highly cost-effective, with other advantages such as the absence of radiation and the possibility of being performed at bedside. The use of contrast in ultrasound to increase the cost-effectiveness of these biopsies is very promising. In the study of the mediastinum and peripheral pulmonary nodules, the introduction of echobronchoscopy has brought about a radical change. It is a fully established technique in the study of lung cancer patients. The introduction of elastography may help to further improve its cost-effectiveness. In critically-ill patients, diaphragmatic ultrasound helps in the assessment of withdrawal of mechanical ventilation, and is now an indispensable tool in the management of these patients. In neuromuscular patients, ultrasound is a good predictor of impaired lung function. Currently, in Neuromuscular Disease Units, TU is an indispensable tool. Ultrasound study of the intercostal musculature is also effective in the study of respiratory function, and is widely used in Respiratory Rehabilitation. In Intermediate Care Units, thoracic ultrasound is indispensable for patient management. In these units there are ultrasound protocols for the management of patients with acute dyspnoea that have proven to be very effective.


Long Noncoding RNA PVT1 Promotes Melanoma Progression via Endogenous Sponging miR-26b.
Melanoma is an extremely aggressive malignant skin tumor with a high mortality. Various long noncoding RNAs (lncRNAs) have been reported to be associated with the oncogenesis of melanoma. The purposes of this study were to investigate the potential role of lncRNA PVT1 in melanoma progression and to explore its possible mechanisms. A total of 35 patients who were diagnosed with malignant melanoma were enrolled in this study. Expression of PVT1 was significantly upregulated in melanoma tissue and was associated with a poor prognosis. Loss-of-function experiments showed that PVT1 knockdown markedly suppressed the proliferation activity, induced cell cycle arrest at the G0/G1 phase, and enhanced the apoptosis of melanoma cell lines. Bioinformatics analysis and dual-luciferase reporter assay revealed that PVT1 directly bound to miR-26b, which had been verified to be a tumor suppressor in melanoma. Moreover, further functional rescue experiments revealed that PVT1 knockdown could observably reverse the tumor-promoting role of the miR-26b inhibitor. Overall, our study demonstrates the oncogenic role of PVT1 as a miR-26b sponge, possibly providing a novel therapeutic target for melanoma.


Wolbachia enhances insect-specific flavivirus infection in Aedes aegypti mosquitoes.
Mosquitoes transmit a diverse group of human flaviviruses including West Nile, dengue, yellow fever, and Zika viruses. Mosquitoes are also naturally infected with insect-specific flaviviruses (ISFs), a subgroup of the family not capable of infecting vertebrates. Although ISFs are not medically important, they are capable of altering the mosquito's susceptibility to flaviviruses and may alter host fitness. Wolbachia is an endosymbiotic bacterium of insects that when present in mosquitoes limits the replication of co-infecting pathogens, including flaviviruses. Artificially created Wolbachia-infected Aedes aegypti mosquitoes are being released into the wild in a series of trials around the globe with the hope of interrupting dengue and Zika virus transmission from mosquitoes to humans. Our work investigated the effect of Wolbachia on ISF infection in wild-caught Ae. aegypti mosquitoes from field release zones. All field mosquitoes were screened for the presence of ISFs using general degenerate flavivirus primers and their PCR amplicons sequenced. ISFs were found to be common and widely distributed in Ae. aegypti populations. Field mosquitoes consistently had higher ISF infection rates and viral loads compared to laboratory colony material indicating that environmental conditions may modulate ISF infection in Ae. aegypti. Surprisingly, higher ISF infection rates and loads were found in Wolbachia-infected mosquitoes compared to the Wolbachia-free mosquitoes. Our findings demonstrate that the symbiont is capable of manipulating the mosquito virome and that Wolbachia-mediated viral inhibition is not universal for flaviviruses. This may have implications for the Wolbachia-based DENV control strategy if ISFs confer fitness effects or alter mosquito susceptibility to other flaviviruses.


Hispolon inhibits TPA-induced invasion by reducing MMP-9 expression through the NF-κB signaling pathway in MDA-MB-231 human breast cancer cells.
Hispolon has been demonstrated to possess analgesic, anti-inflammatory and anticancer activities. However, whether hispolon prevents the invasion of breast carcinoma cells and the underlying mechanisms of its action remain unknown. In the present study, various assays, including a matrigel-based Transwell invasion assay and electrophoretic mobility shift assay, were used to investigate the anti-invasion effect of hispolon and explore its mechanism of action. The results revealed that hispolon inhibited the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced migration and invasion of MDA-MB-231 human breast cancer cells at non-toxic concentrations. Hispolon also prevented the TPA-induced secretion of matrix metalloproteinase-9 (MMP-9) and reduced its expression at the transcriptional and translational levels. Furthermore, the phosphorylation of IκBα was reduced by hispolon, which resulted in the suppression of nuclear factor-κB (NF-κB), and p65 phosphorylation and nuclear translocation. An electrophoretic mobility shift assay demonstrated that NF-κB DNA-binding activity was induced by TPA and inhibited by hispolon. In addition, Bay 11-7082, which is a specific inhibitor of NF-κB, functioned in a similar manner as hispolon and blocked the secretion and expression of MMP-9. In conclusion, the results of the present study indicated that hispolon inhibited TPA-induced migration and invasion of MDA-MB-231 cells by reducing the secretion and expression of MMP-9 through the NF-κB signaling pathway.


Characterization of Polyamidoamino (PAMAM) Dendrimers Using In-Line Reversed Phase LC Electrospray Ionization Mass Spectrometry.
Generation 3 (G3) PAMAM dendrimers are symmetrical, highly branched polymers widely reported in the scientific literature as therapeutic agents themselves or as carrier scaffolds for various therapeutic agents. A large number of analytical techniques have been applied to study PAMAM dendrimers, but one that has been missing is in-line reversed phase LC electrospray ionization mass spectrometry (RP/LC/ESI/MS). To translate PAMAM dendrimers into therapeutic agents, a better understanding of their purity, stability and structure is required, and in-line RP/LC/ESI/MS is widely applied to all three of these analytical questions. In this study, we developed a robust in-line RP/LC/ESI/MS method for assessing stability, purity and structure of the G3 PAMAM dendrimers, and we also examined the reasons why previous attempts at method development failed. Using the RP/LC/ESI/MS method we uncovered several unique aspects of the chemistry of G3 PAMAM dendrimers. They are interconverted between two isomeric forms by dialysis, and under higher concentration levels there is an inter-molecular displacement reaction resulting, which degrades PAMAM dendrimers. Purification of G3 dendrimers by RP/LC was also previously unreported; so we slightly modified the LC/MS method for isolating individual components from a complex dendrimer mixture. Thus, we have developed a robust, comprehensive method for characterizing PAMAM dendrimers and their degradation.


The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men.
The observation that dehydroepiandrosterone (DHEA) concentrations decrease markedly with age has led to the hypothesis that declining DHEA concentrations may contribute to age-related changes in cognition. In the United States, DHEA is widely available as an over-the-counter supplement that individuals are using in an effort to ameliorate age-related cognitive and physical changes. To investigate the relationship between age-associated decreases in endogenous DHEA sulfate (DHEA-S) concentrations and declines in neuropsychological performance in a prospective, longitudinal study. The subjects were 883 men from a community-dwelling volunteer sample in the Baltimore Longitudinal Study of Aging. The men were aged 22 to 91 years at the initial visit, and they were followed up for as long as 31 years (mean, 11. 55 years), with biennial reassessments of multiple cognitive domains and contemporaneous measurement of serum DHEA-S concentrations. Outcome measures were the results of cognitive tests of verbal and visual memory, 2 tests of mental status, phonemic and semantic word fluency tests, and measures of visuomotor scanning and attention. Serum DHEA-S concentrations were determined by standard radioimmunoassay. Neither the rates of decline in mean DHEA-S concentrations nor the mean DHEA-S concentrations within individuals were related to cognitive status or cognitive decline. A comparison between the highest and lowest DHEA-S quartiles revealed no cognitive differences, despite the fact that these groups differed in endogenous DHEA-S concentration by more than a factor of 4 for a mean duration of 12 years. Our longitudinal results augment those of previous prospective studies by suggesting that the decline in endogenous DHEA-S concentration is independent of cognitive status and cognitive decline in healthy aging men.


[Chronic interstitial lung diseases in childhood--an overview].
The spectrum of chronic interstitial lung disease in children includes a large and heterogeneous group of rare disorders. This paper reviews these disorders by focussing on basic pathophysiological mechanisms, and by discussing the difficulties in the classification of these diseases. Diagnostic and therapeutic approaches are also listed. The overall prognosis is dubious and mortality remains high.