Development and testing of a patient-derived questionnaire for treatment of neovascular age-related macular degeneration: dimensions of importance in treatment of neovascular age-related macular degeneration.
Studies reporting on patient perspectives during treatment of neovascular age-related macular degeneration (nAMD) are limited. Thus, the aim of this study was to develop and test psychometric performance of a patient-derived questionnaire to capture important experiences during intravitreal treatment. Patients (n = 44) with at least 3-month experience of intravitreal injection treatment for nAMD identified the dimensions of priority and also performed a weighting procedure to develop a score for comparison. The questionnaire comprised two versions: one focusing on the relative importance' of the dimensions and one on the experience of the 'management' during treatment. The questionnaire was then tested for psychometric performance in a longitudinal design in newly diagnosed patients at baseline (n = 197), after three (n = 184) and six (n = 150) months of treatment. Of the 15 included dimensions, the following were most frequently reported: 'receive treatment to preserve vision', 'information', 'waiting time', 'trust' and 'accommodating staff. The psychometric testing showed moderate reliability (intraclass correlation coefficient: 0.65-0.67) for the two versions and high level of face validity (8.3). The dimensions, 'preserving vision', 'early access to treatment', 'pain relief', 'information about the treatment/diagnosis' and 'visual aids' were consistently reported higher in 'importance' than in 'management', at both 3 and 6 months, indicating a potential for improvement in clinical practice for these dimensions. This study provides a brief patient-derived questionnaire, expressed with a score with good psychometric performance that can be used for monitoring during intravitreal injection treatment of nAMD patients.


Real-Time Measurements of Oral Mucosal Carbon Dioxide (POMCO2) Reveals an Inverse Correlation With Blood Pressure in a Porcine Model of Coagulopathic Junctional Hemorrhage.
Shock states that occur during, for example, profound hemorrhage can cause global tissue hypoperfusion leading to organ failure. There is an unmet need for a reliable marker of tissue perfusion during hemorrhage that can be followed longitudinally. Herein, we investigated whether longitudinal POMCO2 tracks changes in hemodynamics in a swine model of coagulopathic uncontrolled junctional hemorrhage. Female Yorkshire-crossbreed swine (n = 7, 68.1 ± 0.7 kg) were anesthetized and instrumented for continuous measurement of mean arterial pressure (MAP). Coagulopathy was induced by the exchange of 50 to 60% of blood volume with 6% Hetastarch over 30 minutes to target a hematocrit of <15%. A 4.5-mm arteriotomy was made in the right common femoral artery with 30 seconds of free bleeding. POMCO2 was continuously measured from baseline through hemodilution, hemorrhage, and a subsequent 3-h intensive care unit period. Rotational thromboelastometry and blood gases were measured. POMCO2 and MAP showed no significant changes during the hemodilution phase of the experiment, which produced coagulopathy evidenced by prolonged clot formation times. However, POMCO2 increased because of the uncontrolled hemorrhage by 11.3 ± 3.1 mmHg and was inversely correlated with the drop (17.9 ± 5.9 mmHg) in MAP (Y = -0.4122*X + 2.649, P = .02, r2 = 0.686). In contrast, lactate did not significantly correlate with the changes in MAP (P = .35) or POMCO2 (P = .37). Despite the logical appeal of measuring noninvasive tissue CO2 measurement as a surrogate for gastrointestinal perfusion, prior studies have only reported snapshots of this readout. The present investigation shows real-time longitudinal measurement of POMCO2 to confirm that MAP inversely correlates to POMCO2 in the face of coagulopathy. The simplicity of measuring POMCO2 in real time can provide an additional practical option for military or civilian medics to monitor trends in hypoperfusion during hemorrhagic shock.


Historic trophic decline in New England's coastal marine ecosystem.
Overfishing is a worldwide occurrence that simplifies marine food webs, changes trophic patterns, and alters community structure, affecting not only the density of harvested species but also their trophic function. The northwestern Atlantic has a history of heavy fishing, and over the past century has also experienced destructive bottom fishing and harmful mobile fishing gear. After confirming that preservation solvent did not alter the nitrogen stable isotopes of preserved samples, we used museum specimens and modern samples to analyze nitrogen stable isotopes in tissues of two common demersal fishes pre-1950 (1850 to 1950) compared to 2021 to assess changes in trophic positions of coastal New England consumers over this time period. Both the mesopredator Centropristis striata (black sea bass) and the benthivore Stenotomus chrysops (scup) experienced significant declines in trophic position during this time. C. striata declined almost a full trophic level, S. chrysops declined half a trophic level, and these species are now occupying almost the same trophic position. Heavy fishing activities potentially shorten food chains, simplify trophic complexity, lessen the separation of trophic niches, and generally flatten food webs. The consequences of these within-species shifts are poorly investigated but could generate underappreciated cascading impacts on community structure and function. Archived natural-history collections are an invaluable resource for investigating ecological changes in natural communities through time. The evaluation of changing trophic positions via stable isotope analysis may allow fisheries managers to quantify large-scale effects of fishing on ecosystems and food webs over time.


The relationship between the weight-adjusted-waist index and left ventricular hypertrophy in Chinese hypertension adults.
Left ventricular hypertrophy (LVH) is a major cardiac complication of hypertension. Weight-adjusted-waist index (WWI) is a new obesity index that has been found to be positively associated with cardiovascular disease mortality. We aimed to investigate the relationship between the WWI and LVH in Chinese hypertension adults. The study is a community-based cross-sectional study that included 4715 patients with hypertension and integrated clinical and echocardiographic data. LVH was diagnosed by transthoracic echocardiography in these patients based on a criterion of left ventricular mass index (LVMI) over 49.2 g/m2.7 in men and 46.7 g/m2.7 in women. The independent association between the WWI quartiles and LVH prevalence was analyzed by logistic regression models. The prevalence of LVH in the first quartile of WWI (Q1: <10.16), second (Q2: 10.16 ~ 10.67), the third (Q3: 10.68~11.19), and the highest quartile (Q4: ≥11.20) was 34.1%, 38.4%, 42.4%, 51.5%, respectively. Logistic regression analysis suggested that the WWI was independently correlated with LVH with adjustment of confounding factors, and increased across the quartile of WWI. Compared to the first quartile of WWI (Q1), the odds ratios (ORs) and their 95% confidence intervals (CIs) for LVH in the increasing quartiles (Q2-Q4) were 1.33(1.08-1.63), 1.50 (1.19-1.89) and 2.28(1.74-2.99), respectively. In stratified analyses, the relationship between WWI and LVH risk persisted. The WWI may be an independent determinant of LVH in Chinese hypertension adults.


Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion.
Many human cancers manifest the capability to circumvent attack by the adaptive immune system. In this work, we identified a component of immune evasion that involves frequent up-regulation of fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses immune attack, as revealed by cancer cells engineered to lack its expression. FMRP-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, FMRP's immunosuppression was multifactorial, involving repression of the chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with up-regulation of three immunomodulators-interleukin-33 (IL-33), tumor-secreted protein S (PROS1), and extracellular vesicles. Gene signatures associate FMRP's cancer network with poor prognosis and response to therapy in cancer patients. Collectively, FMRP is implicated as a regulator that orchestrates a multifaceted barrier to antitumor immune responses.


Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon.
The pathophysiology of constipation is not clearly identified as yet, and the interstital cells of Cajal (ICC), known to generate the slow wave activity and to be involved in intestinal neurotransmission and the enteric nervous system (ENS), are suspected to play an important role. The aims of the present study were to assess the distribution of ICC and neuronal cells of ENS in patients with slow-transit constipation and acquired megacolon. Sigmoid colon specimens were obtained from patients who underwent colectomy due to slow-transit constipation (n = 10), acquired megacolon (n = 9) and non-obstructive colon cancer (n = 10) as a control group. The ICC were visualized by c-Kit immunohistochemistry and neuronal cells of the ENS were demonstrated by protein gene product (PGP) 9.5. Density of cells stained by c-Kit and PGP 9.5 was calculated as percent area (area stained/area of X-Y plane) x 100, when images were collected at a magnification of x40 objective, with maximum area examined in the horizontal X-Y plane of 400 microm x 400 microm using an image analyzer. The densities of ICC and PGP 9.5 reactive neuronal structures were significantly decreased in all layers of sigmoid colon specimens in patients with slow-transit constipation and acquired megacolon, compared with that of the control group. However, there was no statistically significant difference in either the density of ICC or that of neuronal structures between the patients with slow-transit constipation and acquired megacolon. Slow-transit constipation and acquired megacolon were associated with alteration of ICC and neuronal cells of ENS in the sigmoid colon.


Blood pressure and heart rate immediately after termination of short-term ventricular fibrillation.
Implantable cardioverter/defibrillators (ICDs) can detect ventricular fibrillation (VF) and terminate it. For determining the optimal defibrillation threshold, ventricular fibrillation is repetitively induced and terminated with DC shocks. Depending on the protocol, several fibrillation/defibrillation sequences are mandatory before the final implantation of an ICD. This procedure provides an elegant human model of circulatory arrest and resuscitation. In anesthetized 73 patients (15 females) of on the average 60+/-11 years, the end-expiratory pressure was set to zero. Left ventricular pressure (LVP) was monitored with a microtip-catheter, central venous pressure (CVP) through a cannula which was advanced into the superior V. cava. ECG was recorded. After testing, a monoexponential function was found to best fit the time courses of LVP, CVP and heart rate. Data are mean+/-S.D. After termination of circulatory arrest, peak LVP increased with a time constant tau of 9.2+/-4.2 beats, CVP decreased with tau=2.8+/-1.5 beats, and RR-intervals decreased with tau=4.3+/-3.5 beats. Correlations between prefibrillatory values and steady-state values after termination of fibrillation were high: peak LVP: r=0.78; CVP: r=0.95; RRI: r=0.82. After DC termination of VF, the heart 'finds' relatively quickly a steady-state rhythm at the prefibrillatory level (22 beats), thereby normalizing CVP almost in parallel (14 beats). Peak LVP plateaus only after about 40 beats, although reasonable arterial pressures are reached within the first beats. Our data are limited to periods of ventricular fibrillation of no longer than 60s, which limits the generalisability to the setting of clinical cardiac arrest.


Determination of chlorpheniramine and its binding with human serum albumin by capillary electrophoresis with tris(2,2'-bipyridyl)ruthenium(II) electrochemiluminescence detection.
Tris(2,2'-bipyridyl)ruthenium(II) electrochemiluminescence (ECL) detection in a capillary electrophoresis separation system was used for the determination of chlorpheniramine (CPM). The experimental conditions, such as the applied potential, separation voltage, injection voltage, injection time and the pH of the separation buffer were considered in detail. The ECL intensity showed two linear responses to CPM, i.e., from 15 microM to 1 mM and from 0.8 microM to 15 microM with a detection limit of 0.5 microM. The binding of CPM with human serum albumin was also monitored using this method and the binding constant was estimated to be 4.1 x 103 M(-1).


Membrane characterization of cultured human keratinocytes by freeze-fracture electron microscopy.
Human skin explants obtained from 2 to 5-year-old patients with harelips were cultured in NCTC 168 medium at 37 degrees C, in a humidified atmosphere of 5% CO2 in air. After a 2-week incubation period, plasma membranes of the newly grown cells were characterized by freeze-fracture electron microscopy. Desmosomal diameter in cultured keratinocytes was much smaller, ranging from 0.08 to 0.19 micron, than that in vivo, where it ranged from 0.3 to 0.7 micron in diameter. On the E-face of the plasma membranes, attached to the bottom of the culture dish, small particle aggregations were observed. These were thought to be half-desmosomes, each consisting of 10 to 30 particles. Small gap junctions were also observed. These ranged in size from 0.05 to 0.1 micron in diameter. Membranous structures were found adhering to the plasma membrane from the intercellular spaces. These membranous structures may be lipid vesicles, since they are similar in freeze-fracture electron-microscopic features to lamellar lipid structures seen in the intercellular spaces of horny cells in vivo.


The influence of perinatal risk factors on the incidence of atypical coagulation factor VII during the first days of life.
The correlation between the appearance of functionally-atypical factor VII and perinatal complications was investigated in 66 newborn infants. The presence of an abnormal clotting factor was assumed if the ratio between clotting activity and antigen-related factor VII material exceeded the normal range for adult plasma. The newborns were divided into a risk group of infants threatened by adverse conditions of labour or post-natal adaptation, and a control group of newborns without perinatal complications. The findings were as follows: The incidence of atypical factor VII was significantly higher in the risk group. There was no difference between prenatal and postnatal complications in this respect. Infants born by caesarian section or with cord complications, as well as those with delayed respiratory adaptation, showed a higher incidence of atypical factor VII than the risk group as a whole. Atypical factor VII was not detected until the third day of life, irrespective of the prenatal or postnatal complications. These findings suggest that perinatal risk factors are associated with an alteration of factor VII synthesis.


Diapause and diapause dynamics of Colias alexandra (Lepidoptera: Pieridae).
The mechanisms and adaptations involved in the "obligate" third instar larval diapause of Colias alexandra, a native Rocky Mountain and intermountain region butterfly, are examined. Generally univoltine throughout its distribution, scattered, isolated bivoltine populations occur. Factors influencing continuous development were investigated under laboratory conditions on a single generation of offspring from a univoltine population each year from 1976-1979. If exposed to mean temperatures >24°C during the second instar, a significant number of larvae fail to diapause. These results are interpreted in the context of the actual environmental conditions experienced by the univoltine source population and a bivoltine population. A high degree of individual variability in response to continuous development conditions is shown. Variation in certainty of diapause, within an originally univoltine population, could be the evolutionary starting point for evolving a genuine multivoltine cueing system and provide the mechanism for ecological range expansion.


Procaine has opposite effects on passive Na and K permeabilities in frog skin.
Procaine has opposite effects on the active transport of Na+ when applied on the mucosal side of the frog skin [where it produces a stimulation of the short-circuit current (Isc)] or when added on the serosal side (where it produces an inhibition of Isc). In an attempt to reveal and localize the primary effect of procaine on either the apical or latero-basal membranes of the epithelial cells, we have tried to "chemically dissect" both membrane functions with inhibitors and ionophores. When applied on the apical side of the latero-basally depolarized epithelium, 25 mmol/l procaine increases Isc and Voc (transepithelial open-circuit potential), while decreasing the transepithelial resistance. The E1-E2 linearity domain of the I-V curves is narrowed. On the serosal side of the depolarized epithelium, the same concentration of procaine does not affect Isc and Voc (which are already inhibited) but it produces an increase in the transepithelial resistance (Rt). Procaine influence on the passive K+ permeability was studied by using the ionophore nystatin, which is assumed to form channels permeable to K+, when applied on the amiloride blocked apical membrane. In nystatin-treated epithelia, 25 mmol/l procaine on the apical side decreased Isc, Voc and Rt. In parallel experiments during Cl- substitution by SO2-(4), the procaine effects on Isc and Voc are no longer maintained, but transient.(ABSTRACT TRUNCATED AT 250 WORDS)


Co-composting of poultry manure mixtures amended with biochar - The effect of biochar on temperature and C-CO2 emission.
Biochar as an amendment could have an impact on composting dynamics. This study investigated the effect of the addition of biochar (B) to poultry manure (P) mixed with wheat straw (S) (i.e. P:S, P:S+5%B and P:S+10%B) on temperature and carbon dioxide emission. For temperature studies a modified equation for net degree-hour parameter DHnet (°Chday(-1)) was proposed. The modified equation takes into account ambient temperature. The highest daily temperatures DHnet were observed on day 2 and the mixture with the highest addition of biochar (P:S+10%) reached the max temperature. The period of thermophilic temperatures (40°C>) was shorter for mixtures amended with biochar. The addition of biochar increased C-CO2 emission and the total C-CO2 emission were higher about 6.9% and 7.4% for P:S+5%B and P:S+10%B, respectively.


Systemic fibrinolytic activity and inhibitor levels during treatment of deep vein thrombosis with urokinase and streptokinase.
In a prospective, randomized trial 33 patients with deep vein thrombosis were treated either with 2,200 or 1,100 IU/kg/h urokinase or with 100,000 IU/h streptokinase for at least 6 days. While streptokinase was given continuously, urokinase was administered intermittently (12 hr urokinase alternating with 12 hr heparin). Urokinase treatment resulted in a dose-dependent fibrinolytic state with shortening of the euglobulin clot lysis time, easily demonstrable amidolytic activity and moderate decrease of plasminogen. At the end of each urokinase-free interval the fibrinolytic activity had mostly faded, but was reproducibly elicited again by each new urokinase administration. Streptokinase immediately evoked the customary, intense fibrinolytic state, which progressively tapered off as plasminogen fell to 1% of its pretreatment concentration. In all treatment groups alpha-2-antiplasmin dropped to approximately 40% of its initial value during the first 12 hr with a further decrease to about 20% after 6 days. alpha-2-macroglobulin fell only moderately with either urokinase regimen, whereas it decreased progressively to 45% under streptokinase. While the fibrinolytic activity decreased under streptokinase over the 6-day infusion period, it appeared to increase with each successive urokinase infusion particularly with 1100 IU/kg/h. Thus the final euglobulin clot lysis times and the final fibrinogen concentrations were similar in all three treatment groups on the sixth day.


What do medical students actually need to know about artificial intelligence?
With emerging innovations in artificial intelligence (AI) poised to substantially impact medical practice, interest in training current and future physicians about the technology is growing. Alongside comes the question of what, precisely, should medical students be taught. While competencies for the clinical usage of AI are broadly similar to those for any other novel technology, there are qualitative differences of critical importance to concerns regarding explainability, health equity, and data security. Drawing on experiences at the University of Toronto Faculty of Medicine and MIT Critical Data's "datathons", the authors advocate for a dual-focused approach: combining robust data science-focused additions to baseline health research curricula and extracurricular programs to cultivate leadership in this space.


The effects of acute infection on indices of zinc status.
Various indices of zinc status were assessed in 12 patients with acute urinary tract or chest infections on Day 1 and Day 7 of the infection. Leucocyte counts were raised on Day 1 but had returned to near normal by Day 7. Plasma zinc was decreased on Day 1 in conjunction with depressed plasma albumin concentrations (r = 0.71, p < 0.001) but both had returned to normal by Day 7. Mononuclear cell zinc was raised in all patients on Day 1 compared to Day 7 and control values, but polymorphonuclear cell zinc remained unchanged. However, polymorphonuclear cell alkaline phosphatase activity was grossly increased on Day 1 and correlated with leucocyte count (r = 0.61, p < 0.01). Plasma alkaline phosphatase activity was variable. These results indicate that in patients with infections measurement of plasma mononuclear cell zinc concentration and alkaline phosphatase activity are misleading indicators of zinc status. Polymorphonuclear cell zinc is unaffected by leucocytosis, inflammation and stress and may therefore provide a more reliable index of zinc status in such patients.


Metastatic melanoma of unknown origin mimicking neurofibromatosis.
We present an unusual case of metastatic melanoma in a young patient with imaging appearance resembling neurofibromatosis. A 36-year-old-man with a history of cervical radiculopathy presented with cauda equina syndrome. An MRI was performed for further evaluation demonstrating multiple intradural, extramedullary enhancing lesions in the thoracic and lumbar spine, as well as extra-axial enhancing lesions with involvement of the lateral ventricles and posterior fossa. Bilateral pulmonary masses were found on chest CT. Lung lesions were biopsied and positive for metastatic melanoma. Melanoma is the third most common primary neoplasm to produce brain metastasis and should be considered on the differential as a cause of newly detected intracranial and intraspinal masses in young patients.


Application of different methods to formulate PEG-liposomes of oxaliplatin: evaluation in vitro and in vivo.
In this work, the Film Method (FM), Reverse-Phase Evaporation (REV), and the Heating Method (HM) were applied to prepare PEG-coated liposomes of oxaliplatin with natural neutral and cationic lipids, respectively. The formulations developed with the three methods, showed similar physicochemical characteristics, except in the loading of oxaliplatin, which was statistically lower (P<0.05) using the HM. The incorporation of a semi-synthetic lipid in the formulation developed by FM, provided liposomes with a particle size of 115 nm associated with the lowest polydispersity index and the highest drug loading, 35%, compared with the other two lipids, suggesting an increase in the membrane stability. That stability was also evaluated according to the presence of cholesterol, the impact of the temperature, and the application of different cryoprotectants during the lyophilization. The results indicated long-term stability of the developed formulation, because after its intravenous in vivo administration to HT-29 tumor bearing mice was able to induce an inhibition of tumor growth statistically higher (P<0.05) than the inhibition caused by the free drug. In conclusion, the FM was the simplest method in comparison with REV and HM to develop in vivo stable and efficient PEG-coated liposomes of oxaliplatin with a loading higher than those reported for REV.


Meta-analysis: The value of clinical assessment in the diagnosis of deep venous thrombosis.
Clinical assessment of suspected deep venous thrombosis (DVT) should be based on systematically evaluated evidence. To determine whether clinical findings, risk scores, and physicians' empirical judgments affect the likelihood of detecting DVT on definitive testing. MEDLINE, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, ACP Journal Club, and citation lists (1966 to January 2005). Cohort studies published in English, French, Spanish, or Italian that compared clinical assessment with a reference standard. The authors extracted standardized data, including setting, exclusions, population characteristics, reference standard, and results, and assessed quality against validated criteria. The authors combined data by using random-effects meta-analysis and, if appropriate, used meta-regression to identify covariates that predicted diagnostic accuracy. Only malignancy (likelihood ratio [LR], 2.71), previous DVT (LR, 2.25), recent immobilization (LR, 1.98), difference in calf diameter (LR, 1.80), and recent surgery (LR, 1.76) were useful for ruling in DVT, while only absence of calf swelling (LR, 0.67) or difference in calf diameter (LR, 0.57) was useful for ruling out DVT. The Wells clinical score was more valuable than the individual characteristics; it stratified patients into groups with high (LR, 5.2), intermediate, and low (LR, 0.25) probability of DVT. The Wells score seemed able to stratify patients by risk only for proximal DVT, and it performed better in cohorts that were younger or excluded patients with previous thromboembolism. Pooled estimates were subject to substantial heterogeneity. This may limit extrapolation between observers and settings. Only published studies were included, so findings may be subject to publication bias. Individual clinical features are of limited value in diagnosing DVT. Overall assessment of clinical probability by using the Wells score is more useful.


Acute treatment of hypertensive intracerebral hemorrhage.
Hypertensive intracerebral hemorrhage remains an entity in search of definitive treatment. It requires management in a specialized unit, where hypertension, hyperglycemia, seizures, and elevated intracranial pressure can be expertly managed. However, the exact target range of hypertensive therapy is uncertain. Extraventricular drainage and surgery for cerebellar hemorrhage can both be life-saving. The role of craniotomy for hematoma resection remains unclear. Surgery for deep or pontine hemorrhages has questionable value. The reduction of clot expansion acutely may lead to improved outcomes. One option to this end, the tight control of hypertension acutely, may be difficult to prove effective. Another, the use of factor VIIa, eluded validation in one trial. Efforts are under way to reduce intraventricular hemorrhage, and with it, hydrocephalus. The role of clot evacuation in the subset of individuals with lobar hemorrhage is also being studied. In all likelihood, the key to acute treatment of this condition will be early intervention, with implementation of blood pressure control, administration of clotting factors in the emergency department, or both. This treatment will be followed by transfer to a specialized unit, with appropriate interventions in selected patients. However, morbidity and mortality will remain high, pointing out the importance of prevention through management of hypertension.


Liver function assessment according to the Albumin-Bilirubin (ALBI) grade in sorafenib-treated patients with advanced hepatocellular carcinoma.
The Albumin-Bilirubin (ALBI) grade has been proposed as a new, simple, and objective method of assessing liver function. However, there is lack of data in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC). We evaluated the correlations between the ALBI grade and Child-Pugh score, adverse events, and survival in 89 patients with advanced HCC who were prospectively treated with sorafenib. Majority of patients with ALBI grade 1 (14/15 patients, 93%) had a Child-Pugh score of 5. Patients with ALBI grade 2 had a wide range of liver function according to the Child-Pugh scores, with scores of 5, 6, 7, and ≥ 8. We divided ALBI grade 2 patients into ALBI grade 2A and 2B groups according to the median ALBI score among patients with ALBI grade 2. Although no significant difference was observed, the incidence of liver dysfunction in sorafenib-treated patients with ALBI grades 1, 2A, and 2B was 7%, 19%, and 35%, respectively. Overall survival in the ALBI grade 2B group was significantly shorter than that in the ALBI grade 1 and 2A groups. Thus, ALBI grade 2B was an independent predictor of poor prognosis in addition to elevated serum aspartate aminotransferase levels, increased serum alpha-fetoprotein level, and macrovascular invasion. Sorafenib may be indicated for all patients with advanced HCC and ALBI grade 1 and for some with ALBI grade 2. The subdivision of patients with ALBI grade 2 increases the utility of ALBI in identifying patients indicated for sorafenib therapy.


A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours.
This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles. Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. NCT02316197.


An augmented reality C-arm for intraoperative assessment of the mechanical axis: a preclinical study.
Determination of lower limb alignment is a prerequisite for successful orthopedic surgical treatment. Traditional methods include the electrocautery cord, alignment rod, or axis board which rely solely on C-arm fluoroscopy navigation and are radiation intensive. To assess a new augmented reality technology in determining lower limb alignment. A camera-augmented mobile C-arm (CamC) technology was used to create a panorama image consisting of hip, knee, and ankle X-rays. Twenty-five human cadaver legs were used for validation with random varus or valgus deformations. Five clinicians performed experiments that consisted in achieving acceptable mechanical axis deviation. The applicability of the CamC technology was assessed with direct comparison to ground-truth CT. A t test, Pearson's correlation, and ANOVA were used to determine statistical significance. The value of Pearson's correlation coefficient R was 0.979 which demonstrates a strong positive correlation between the CamC and ground-truth CT data. The analysis of variance produced a p value equal to 0.911 signifying that clinician expertise differences were not significant with regard to the type of system used to assess mechanical axis deviation. All described measurements demonstrated valid measurement of lower limb alignment. With minimal effort, clinicians required only 3 X-ray image acquisitions using the augmented reality technology to achieve reliable mechanical axis deviation.


PHEA-g-PMMA Well-Defined Graft Copolymer: ATRP Synthesis, Self-Assembly, and Synchronous Encapsulation of Both Hydrophobic and Hydrophilic Guest Molecules.
A series of well-defined amphiphilic graft copolymer bearing a hydrophilic poly(2-hydroxyethyl acrylate) (PHEA) backbone and hydrophobic poly(methyl methacrylate) (PMMA) side chains was synthesized by successive reversible addition-fragmentation chain transfer (RAFT) polymerization and atom transfer radical polymerization (ATRP) through the grafting-from strategy. A well-defined PHEA-based backbone with Cl-containing ATRP initiating group in every repeated unit (M w/M n = 1.08), poly(2-hydroxyethyl 2-((2-chloropropanoyloxy)methyl)acrylate) (PHECPMA), was first prepared by RAFT homopolymerization of 2-hydroxyethyl 2-((2-chloropropanoyloxy)methyl)acrylate (HECPMA), a Cl-containing trifunctional acrylate. ATRP of methyl methacrylate was subsequently initiated by PHECPMA homopolymer to afford the target well-defined poly(2-hydroxyethyl acrylate)-graft-poly(methyl methacrylate) (PHEA-g-PMMA) graft copolymers (M w/M n ≤ 1.36) with 34 PMMA side chains and 34 pendant hydroxyls in PHEA backbone using CuCl/dHbpy as catalytic system. The critical micelle concentration (cmc) of the obtained graft copolymer was determined by fluorescence spectroscopy using N-phenyl-1-naphthylamine as probe while micellar morphologies in aqueous media were visualized by transmission electron microscopy. Interestingly, PHEA-g-PMMA graft copolymer could self-assemble into large compound micelles rather than common spherical micelles, which can encapsulate hydrophilic rhodamine 6 G and hydrophobic pyrene separately or simultaneously.


Effects of phosphorus stress on the growth and secondary metabolism of Artemisia argyi.
Phosphorus is essential in critical plant processes such as signaling, photosynthesis, energy metabolism, and enzyme activity during respiration. Phosphorus stress therefore has a significant impact on plant growth and metabolism. Here, we characterized the biochemical responses of Artemisia argyi Level. et Vant to low phosphorus (LP) and high phosphorus (HP) stress. Plants were treated with 0 g (LP), 1.5 g (control), or 3 g (HP) P per 10 kg of soil. The results demonstrated that CK encouraged the most plant growth, as quantified by leaf size and plant biomass. We also found that the total amounts of phenolic and flavonoid compounds (such as chlorogenic acid, isochlorogenic acid A, isochlorogenic acid B, isochlorogenic acid C, cryptochlorogenic acid, neochlorogenic acid, hispidulin, jaceosidin, eupatilin, and casticin) were increased in the leaves of A. argyi plants exposed to LP stress compared to those raised under CK conditions. The levels of these compounds were inversely related to the amount of phosphorus added, and therefore peaked in plants treated with LP stress. Levels of terpenoids were also found to fluctuate under LP and HP stress compared to CK conditions. Furthermore, transcriptomic analyses showed up-regulation of several genes encoding key enzymes in the flavonoid and phenolic acid metabolic pathways under LP stress. There were also alterations in the expression levels of genes in the methylerythritol 4-phosphate and mevalonate pathways of terpene synthesis. This study contributes to a deeper understanding of the physiological and molecular mechanisms underlying phosphorus stress responses and their impacts on the growth and quality of the economically important species A. argyi.


Dietary administration of PVC and PE microplastics produces histological damage, oxidative stress and immunoregulation in European sea bass (Dicentrarchus labrax L.).
Worldwide, plastic waste is increasingly being discharged into the oceans, where it breaks down into smaller particles. Of these particles, the ingestion of microplastics (MPs; particles smaller than 5 mm) have been documented in some aquatic animals, including fish, whose health and welfare suffer as a consequence. However, their precise effects are not completely understood. To shed light on this issue, European sea bass (Dicentrarchus labrax L.) specimens were fed diets containing 0 (control), 100 or 500 mg polyvinylchloride (PVC) or polyethylene (PE) MPs kg-1 diet for three weeks, after which samples of liver, intestine, skin mucus and head kidney (HK) were obtained. A histological study of the liver and intestine revealed important alterations in the fish fed the MP diets, compared with control fish. At a functional level, PE-MPs, but not PVC-MPs, decreased the activity of antioxidant enzymes, suggesting a certain level of oxidative stress. As regards immunity, the intake of PVC-MPs increased the phagocytic and respiratory burst activities of HK leucocytes whilst the intake of PE-MPs increased skin mucus immunoglobulin M levels and the respiratory burst activity of leucocytes. The results suggest that the short-medium term intake of PVC- or PE-MPs by fish slightly depresses their immunity and produces oxidative stress. However, based on the histological alterations found, it seems that longer exposure times might lead to irreversible damage that could compromise fish health and welfare.


Examining the Attitudes and Knowledge of Social Work and Nursing Students on Later-Life Sexuality.
ABSTRACTWe examined ageist beliefs, attitudes, and knowledge towards sexuality in later life among 148 nursing students and 137 social work students in their first year of studies. The students completed the Fraboni Scale of Ageism, the Attitudes and Knowledge towards Older Adults' Sexuality Scale, and questionnaires regarding contact with older adults, prior sexual education, and socio-demographics. The results indicated that nursing students have more conservative attitudes towards older adults' sexuality. Ageist beliefs correlated positively with more conservative attitudes towards older adults' sexuality. These conservative attitudes 'were negatively correlated with knowledge about sexuality in later life. Older students have more knowledge about sexuality in later life and more permissive attitudes towards older adults' sexuality. Religious students have less knowledge, and more conservative attitudes, towards older adults' sexuality. Previous sexual education was not associated with the students' attitudes and knowledge towards older adults' sexuality. Implications for designing continuing education programs are discussed.


Globally deimmunized lysostaphin evades human immune surveillance and enables highly efficacious repeat dosing.
There is a critical need for novel therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) and other drug-resistant pathogens, and lysins are among the vanguard of innovative antibiotics under development. Unfortunately, lysins' own microbial origins can elicit detrimental antidrug antibodies (ADAs) that undermine efficacy and threaten patient safety. To create an enhanced anti-MRSA lysin, a novel variant of lysostaphin was engineered by T cell epitope deletion. This "deimmunized" lysostaphin dampened human T cell activation, mitigated ADA responses in human HLA transgenic mice, and enabled safe and efficacious repeated dosing during a 6-week longitudinal infection study. Furthermore, the deimmunized lysostaphin evaded established anti-wild-type immunity, thereby providing significant anti-MRSA protection for animals that were immune experienced to the wild-type enzyme. Last, the enzyme synergized with daptomycin to clear a stringent model of MRSA endocarditis. By mitigating T cell-driven antidrug immunity, deimmunized lysostaphin may enable safe, repeated dosing to treat refractory MRSA infections.


Dual pattern recognition receptor ligands CL401, CL413, and CL429 as adjuvants for inactivated chikungunya virus.
Chikungunya virus (CHIKV) is responsible for incapacitating joint pains and is a significant health hazard in many countries. Though a definite need for a CHIKV vaccine is felt, long disappearance of CHIKV from circulation in humans has been a concern for vaccine development. Use of two separate pattern recognition receptor ligands has been shown to enhance immune response to the administered antigen. In addition, intradermal delivery of vaccine tends to mimic the natural mode of CHIKV infection. Therefore, in this study, we explored whether intradermal and intramuscular immunization with inactivated CHIKV (I-CHIKV) supplemented with dual pattern-recognition receptor ligands, CL401, CL413, and CL429, is an effective approach to enhancing antibody response to CHIKV. Our in vivo data show that I-CHIKV supplemented with these chimeric PRR ligands induces enhanced neutralizing antibody response after intradermal delivery, but is less efficient after intramuscular immunization. These results suggest that intradermal delivery of I-CHIKV with chimeric adjuvants is a possible way to elicited a better antibody response.


Comparing the Detection Performance Between Multiparametric Magnetic Resonance Imaging and Prostate-Specific Membrane Antigen PET/CT in Patients With Localized Prostate Cancer: A Systematic Review and Meta-analysis.
Multiparametric MRI (mpMRI) has been promoted as an auxiliary diagnostic tool for prostate biopsy. However, prostate-specific membrane antigen (PSMA) including 68 Ga-PSMA-11, 18 F-DCFPyL, and 18 F-PSMA-1007 applied PET/CT imaging was an emerging diagnostic tool in prostate cancer patients for staging or posttreatment follow-up, even early detecting. Many studies have used PSMA PET for comparison with mpMRI to test the diagnostic ability for early prostate cancer. Unfortunately, these studies have shown conflicting results. This meta-analysis aimed to compare the differences in diagnostic performance between PSMA PET and mpMRI for detecting and T staging localized prostatic tumors. This meta-analysis involved a systematic literature search of PubMed/MEDLINE and Cochrane Library databases. The pooling sensitivity and specificity of PSMA and mpMRI verified by pathological analysis were calculated and used to compare the differences between the 2 imaging tools. Overall, 39 studies were included (3630 patients in total) from 2016 to 2022 in the current meta-analysis and found that the pooling sensitivity values for localized prostatic tumors and T staging T3a and T3b of PSMA PET were 0.84 (95% confidence interval [CI], 0.83-0.86), 0.61 (95% CI, 0.39-0.79), and 0.62 (95% CI, 0.46-0.76), respectively, whereas those of mpMRI were found to be 0.84 (95% 0.78-0.89), 0.67 (95% CI, 0.52-0.80), and 0.60 (95% CI, 0.45-0.73), respectively, without significant differences ( P > 0.05). However, in a subgroup analysis of radiotracer, the pooling sensitivity of 18 F-DCFPyL PET was higher than mpMRI (relative risk, 1.10; 95% CI, 1.03-1.17; P < 0.01). This meta-analysis found that whereas 18 F-DCFPyL PET was superior to mpMRI at detecting localized prostatic tumors, the detection performance of PSMA PET for localized prostatic tumors and T staging was comparable to that of mpMRI.


[Relationship between GSTM1 genotype and susceptibility to senile cataract].
To study the relationship between the glutathione s-transferase gene deletion and cataract formation. Blood cells of total of 77 cases with senile cataract and 76 controls were detected for GSTM1 gene, and the subcapsular epithelial cells of 22 cataract lenses were also detected for GSTM1 gene. The GSTM1 gene deletion rate in cataract group was 53.25% and that in the control group was 46.05%, they being not significantly different statistically (chi(2) = 0.750, P > 0.05, OR = 0.75). GSTM1 gene deletion rate in the subcapsular epithelial cells of 20 cases was basically consistent with that in blood cells. GSTM1 gene deletion is not related to senile cataract formation.


MicroRNA-146a modulates TGF-β1-induced phenotypic differentiation in human dermal fibroblasts by targeting SMAD4.
During wound healing and tissue repair the dermal fibroblast-to-myofibroblast transdifferentiation plays an important role, transforming growth factor-β1 (TGF-β1) is considered to be the main stimuli factor of transdifferentiation. MicroRNAs (miRNAs) have recently emerged as key post-transcriptional regulators of gene expression. The involvement of miRNAs and their roles in TGF-β1-induced myofibroblast transdifferentiation remains to be determined in detail. The current study found that the expression of miR-146a was upregulated in human dermal fibroblasts cells in response to TGF-β1 stimulation in dose-dependent manner by quantitative RT-PCR. Bioinformatic analyses predict that signaling effectors mothers against decapentaplegic protein 4 (SMAD4) is a miR-146a target gene. Luciferase assay demonstrated that miR-146a mimics suppressed SMAD4 3'-UTR reporter construct activity. Furthermore, miR-146a overexpression in dermal fibroblast did not decrease target mRNA levels, but significantly reduced target protein expression. In addition, dermal fibroblasts transfected with miR-146a mimics exhibited attenuated TGF-β1 -induced α-smooth muscle actin (α-SMA) expression compared with the control. This study demonstrated that miR-146a may function as a novel negative regulator to modulate myofibroblast transdifferentiation during TGF-β1 induction by targeting SMAD4.


[Weekly cyclophosphamide pulse therapy combined with corticosteroids in the treatment of pemphigus].
To investigate the better regimen of combined cyclophosphamide pulse therapy with corticosteroids in the treatment of Pemphigus. Intravenous cyclophosphamide was given weekly in a dosage of 600 mg to those Pemphigus patients whose conditions couldn't be improved by corticosteroids (oral prednisone 1.2-1.5 mg/kg/d) alone. Ten patients with Pemphigus received weekly cyclophosphamide therapy in addition to corticosteroid. Patients conditions improved quickly, without side effects. Cyclophosphamide weekly pulse therapy combined with corticosteroids is a good regimen in the treatment of Pemphigus.


Contrast Induced Nephropathy and Long-term Renal Decline After Percutaneous Transluminal Angioplasty for Symptomatic Peripheral Arterial Disease.
Administration of iodinated contrast media during endovascular procedures for peripheral arterial disease (PAD) may cause contrast induced nephropathy (CIN). The aim of the present study was to establish the incidence of CIN after these procedures and to study its association with long-term loss of kidney function, cardiovascular events, and death. Consecutive patients first presenting with symptomatic PAD (Rutherford classification II-VI) who were treated with an endovascular procedure were included in this prospective observational cohort study. CIN was defined as >25% increase of serum creatinine concentration from baseline at 5 days after the intervention. Some 337 patients were included with a mean estimated glomerular filtration rate (eGFR) of 67 mL/minute. Thirteen percent (95% confidence interval [CI] 9-16) of these patients developed CIN after endovascular interventions for PAD. One year after treatment, eGFR was reduced by 12.4 mL/minute (95% CI 8.6-16.2) in patients with CIN compared with 6.2 mL/minute (95% CI 4.9-7.0) in patients without acute kidney injury (p < .01). After correction for potential confounders, CIN was associated with a 7.8 mL/minute (95% CI 4.5-11.0) reduction of eGFR at 1 year after endovascular intervention (p < .01). Furthermore, patients with CIN were at increased risk of long-term cardiovascular events and mortality. Exposure to iodinated contrast media during endovascular procedures for symptomatic PAD frequently results in CIN. Patients with CIN are at increased risk of long-term loss of renal function, cardiovascular events, and death.


The distinction between unipolar and bipolar depression: a cognitive theory perspective.
There is very limited data about the cognitive structure of bipolar depression when compared to unipolar depression. The aim of the study was to look into the differences between unipolar and bipolar depressed patients regarding their cognitive structure in view of Beck's cognitive theory. In this study, 70 bipolar patients during a depressive episode, 189 unipolar depressed patients and 120 healthy subjects were recruited. The participants were interviewed by using a structured clinical diagnostic scale. To evaluate the cognitive structure differences, the Automatic Thoughts Questionnaire (ATQ) and the Dysfunctional Attitude Scale (DAS) were used. We found that on the mean ATQ total score, the unipolar depressed patients scored significantly higher (92.9±22.7) than both the bipolar depressed patients (73.2±24.7) and the healthy subjects (47.1±19.6), even after controlling for all confounding factors, e.g. gender, marital status, depressive symptom severity (F = 157.872, p<0.001). The bipolar depressed patients also scored significantly higher on the mean ATQ total score than the healthy controls. On the mean DAS total score, and on the mean score of its subscale of need for approval, the bipolar depressed patients scored (152.8±21.2 and 48.2±7.4, respectively) significantly higher than both the unipolar depressed patients (160.9±29.0 and 51.9±9.7, respectively) and the healthy subjects (127.9±32.8 and 40.2±12.2, respectively), even after controlling for any confounding factor (F=45.803 [p<0.001] and F=43.206 [p<0.001], respectively). On the mean score of the perfectionistic attitude subscale of the DAS, the depressed groups scored significantly higher than the healthy subjects, but they did not seem to separate from each other (F=41.599, p<0.001). These results may help enhance the understanding of the potentially unique psychotherapeutic targets and the underlying cognitive theory of bipolar depression.


Ray theory-based compounded plane wave ultrasound imaging for aberration corrected transcranial imaging: Phantom experiments and simulations.
Compounded plane wave imaging (CPWI) allows high-frame-rate measurement and has been one of the most promising modalities for real-time brain imaging. However, ultrasonic brain imaging using the CPWI modality is usually performed with a worn thin or removal of the skull layer. Otherwise, the skull layer is expected to distort the ultrasonic wavefronts and significantly decrease intracranial imaging quality. The motivation of this study is to investigate a CPWI method for transcranial brain imaging with the skull layer. A coordinate transformation ray-tracing (CTRT) approach was proposed to track the distorted ultrasonic wavefronts and calculate the time delays for the ultrasound plane wave passing through the skull layer. With an accurate correction for the time delays in beamforming, the CTRT-based CPWI could achieve high-quality intracranial images with the presence of skulls. The proposed CTRT-based CPWI method was verified using a simplified three-layer transcranial model. The full-wave simulation demonstrated that CTRT could accurately (i.e., relative percentage error less than0.18%) track the distorted transmitting wavefront through skull. Compared with the CPWI without aberration correction, the CTRT-based CPWI provided high-quality intracranial imaging and could accurately localize intracranial point scatterers; specifically, positioning error decreases from 0.5 mm to 0.1 mm on average in the axial direction and from 0.7 mm to 0.1 mm on average in the lateral direction. As the compounded angles increased in the CTRT-based CPWI, the contrast improved by 16.2 dB on average for the region of interest, and the array performance indicator (representing resolution) decreased by 4.0 on average for the intracranial point scatterers. The CTRT is of low computational cost compared with full wave simulation. This study suggested that the proposed CTRT-based CPWI might have the potential for real-time and non-invasive transcranial aberration-corrected imaging.


An uncommon presentation for a severe invasive infection due to methicillin-resistant Staphylococcus aureus clone USA300 in Italy: a case report.
Methicillin resistant Staphylococcus aureus (MRSA) has been considered for many years a typical nosocomial pathogen. Recently MRSA has emerged as a frequent cause of infections in the community. More commonly, community-acquired (CA)-MRSA is a cause of infections of the skin and soft-tissues, but life-threatening infections such as necrotizing pneumonia and sepsis can occasionally occur. This report describes an uncommon presentation of invasive CA-MRSA infection in an adolescent without known risk factors. The presentation was typical for bacterial meningitis, but the clinical findings also revealed necrotizing pneumonia. Following the development of deep venous thrombosis, the presence of an inherited thrombophilic defect (factor V Leiden) was detected. The patient was successfully treated with an antibiotic combination including linezolid and with anticoagulant therapy. CA-MRSA was isolated from both cerebrospinal fluid and blood. The isolates were resistant to oxacillin and other beta-lactam antibiotics and susceptible to the other antibiotics tested including erythromycin. Molecular typing revealed that the strains contained the Panton-Valentine leukocidin genes and type IV SCCmec, and were ST8, spa type t008, and agr type 1. This genetic background is identical to that of the USA300 clone. This report highlights that meningitis can be a new serious presentation of CA-MRSA infection. CA-MRSA strains with the genetic background of the USA300 clone are circulating in Italy and are able to cause severe infections.


Personality and patient adherence: correlates of the five-factor model in renal dialysis.
The five-factor taxonomy of personality traits has received increasing attention in the literature regarding personality correlates of health outcomes and behaviors. We examined the association of the five NEO Five-Factor Inventory dimensions to medical regimen adherence in a sample of 72 renal dialysis patients. Results indicated that Conscientiousness (Dimension III) is a five-factor trait significantly associated with adherence to the medication regimen. No other NEO-FFI dimension was significantly associated with patient adherence.


Human Wharton's jelly mesenchymal stem cells derived-exosomes enriched by miR-124 promote an anti-fibrotic response in an experimental model of liver fibrosis.
Liver fibrosis is a significant challenge to global health that results in organ failure through inflammation and the release of fibrotic biomarkers. Due to the lack of effective treatments for liver fibrosis, anti-fibrotic and anti-inflammatory therapies are being developed. Since there has been an association between aberrant expression of miR-124 and liver disease progression, we investigated whether delivery of miR-124 through human Wharton's jelly mesenchymal stem cells derived-exosomes (hWJMSC-Exo) can improve liver fibrosis. We established a 6-week carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis, then we administered hWJMSC-Exo and miR-124-3p-enriched exosomes (ExomiR-124) for three weeks. The extent of fibrosis and inflammation was assessed by histology, biochemistry, Real-time PCR, immunohistochemistry, and Enzyme-linked immunoassays (ELISA). The inflammatory status of the spleen was also investigated using flow cytometry. Based on the gene and protein expression measurement of IL-6, IL-17, TGF-β, STAT3, α-SMA, and COL1, In vivo administration of Exo and ExomiR-124 effectively reduce collagen accumulation and inhibition of inflammation. Regarding histopathology findings, the therapeutic effect of ExomiR-124 against liver fibrosis was significantly greater than hWJMSC-Exo. In addition, we found that Exo and ExomiR-124 was capable of phenotype switching of splenic monocytes from inflammatory Ly6Chi to restorative Ly6Clo. MSC-derived exosomes demonstrated anti-inflammatory effect via different aspects. Aside from the therapeutic approach, enrichment of exosomes as a nanocarrier by miR-124 revealed the down-regulation of STAT3, which plays a crucial role in liver fibrosis. The anti-inflammatory and anti-fibrotic properties of ExomiR-124 could be a promising option in liver fibrosis combination therapies.


Prevention of recurrent ulcer bleeding, a multicentre study of the effect of ranitidine and trimipramine over one year.
Short term studies of the prevention of bleedings from peptic ulcers and erosions have been reported by a number of authors following treatment with antacids (1), H2-receptor blockers, cimetidine (2-15), a combination of cimetidine and tranexamic acid (16), cimetidine and somatostatin (17), cimetidine and sucralfate or secretion (18, 19, 20), cimetidine compared to antacid (21), and cimetidine compared to antacid and pirenzepine (22). The H2-blocker rantitidine has been compared to placebo (24, 25, 26). An uncontrolled study has been performed using proglumide (27), a controlled study with vasopressin (28) and with secretin versus somatostatin (28). In the studies with H2-receptor antagonists conflicting results have been obtained. No report has been published concerning the effect over more than a few days or weeks.


Regulation of neuronal input transformations by tunable dendritic inhibition.
Transforming synaptic input into action potential output is a fundamental function of neurons. The pattern of action potential output from principal cells of the mammalian hippocampus encodes spatial and nonspatial information, but the cellular and circuit mechanisms by which neurons transform their synaptic input into a given output are unknown. Using a combination of optical activation and cell type-specific pharmacogenetic silencing in vitro, we found that dendritic inhibition is the primary regulator of input-output transformations in mouse hippocampal CA1 pyramidal cells, and acts by gating the dendritic electrogenesis driving burst spiking. Dendrite-targeting interneurons are themselves modulated by interneurons targeting pyramidal cell somata, providing a synaptic substrate for tuning pyramidal cell output through interactions in the local inhibitory network. These results provide evidence for a division of labor in cortical circuits, where distinct computational functions are implemented by subtypes of local inhibitory neurons.


A new pre-test probability score for diagnosis of deep vein thrombosis in patients before surgery.
Venous thromboembolism is a serious perioperative complication. We developed a new pre-test probability score for predicting deep vein thrombosis (DVT) before surgery. Whole leg ultrasonography was performed on 973 inpatients and outpatients with suspected DVT based on a preoperative D-dimer cut-off value of ≥ 1 μg/ml. We allocated two-thirds (n = 651) of the study participants to a derivation cohort and one-third (n = 322) to a validation cohort. The pre-test probability model was developed from the derivation cohort data. The pre-test probability model for DVT assigned 2 points to D-dimer ≥ 1.5 μg/mL and 1 point each to age ≥ 60 years, female sex, ongoing glucocorticoid therapy, prolonged immobility, and cancer with high risk of DVT. The area under the curve of the pre-test probability score was 0.72 and 0.70 in the derivation and validation cohorts, respectively. The rates of DVT according to pre-test probability scores in the derivation and validation cohorts were 7% and 6% in the low (score = 0-2), 23% and 22% in the intermediate (score = 3-4), and 47% and 50% in the high probability group (score ≥ 5), respectively (p < 0.0001). The pre-test probability score (Kagoshima-DVT score) was helpful in detecting preoperative DVT in both inpatients and outpatients. We identified low probability group to reduce whole-leg ultrasonography and high probability group to detect more DVT before surgery.


Fc gamma receptor is not required for in vivo processing of radio- and drug-conjugates of the dead tumor cell-targeting monoclonal antibody, APOMAB®.
The Fc region of a monoclonal antibody (mAb) can play a crucial role in its biodistribution and therapeutic activity. The chimeric mAb, chDAB4 (APOMAB®), which binds to dead tumor cells after DNA-damaging anticancer treatment, has been studied pre-clinically in both diagnostic and therapeutic applications in cancer. Given that macrophages contribute to the tumor accumulation of chDAB4 and its potency as an antibody drug conjugate in vivo, we next wanted to determine whether the Fc region of the chDAB4 mAb also contributed. We found that, regardless of prior labeling with chDAB4, dead EL4 lymphoma or Lewis Lung (LL2) tumor cells were phagocytosed equally by wild-type or Fcγ knock-down macrophage cell lines. A similar result was seen with bone marrow-derived macrophages from wild-type, Fcγ knock-out (KO) and NOTAM mice that express Fcγ but lack immunoreceptor tyrosine-based activation motif (ITAM) signaling. Among EL4 tumor-bearing wild-type, Fcγ KO or NOTAM mice, no differences were observed in post-chemotherapy uptake of 89Zr-labeled chDAB4. Similarly, no differences were observed between LL2 tumor-bearing wild-type and Fcγ KO mice in post-chemotherapy uptake of 89Zr-chDAB4. Also, the post-chemotherapy activity of a chDAB4-antibody drug conjugate (ADC) directed against LL2 tumors did not differ among tumor-bearing wild-type, Fcγ KO and NOTAM mice, nor did the proportions and characteristics of the LL2 tumor immune cell infiltrates differ significantly among these mice. In conclusion, Fc-FcγR interactions are not essential for the diagnostic or therapeutic applications of chDAB4 conjugates because the tumor-associated macrophages, which engulf the chDAB4-labelled dead cells, respond to endogenous 'eat me' signals rather than depend on functional FcγR expression for phagocytosis.


No reflow leading to catastrophic hemodynamic collapse in a patient with severe aortic stenosis and its management.
We report a case of an 87-year-old female who underwent percutaneous coronary intervention (PCI) for non-ST elevation myocardial infarction while she was being worked up for transcatheter aortic valve procedure. Hemodynamic compromise occurred during the PCI, which could only be mitigated by doing a balloon aortic valvuloplasty and Impella™ insertion. This case report will help in preparedness for any untoward events in patients with aortic stenosis and undergoing percutaneous coronary intervention.


Spermatogenesis, fertility and sexual behavior in a hypospadiac mouse model.
Administering of flutamide to pregnant mice causes hypospadias in male offspring. We investigated spermatogenesis, fertility and sexual behavior in this hypospadiac mouse model. Male offspring exposed to flutamide during the embryonic period were divided into hypospadiac group 1 and normal external genitalia group 2. Control group 3 consisted of male offspring not exposed to flutamide. We analyzed the spermatogenesis, epididymides sperm motility, in vitro fertilization rate and sexual behavior of each mouse. There were no significant differences in the weight of the testes or mean seminiferous tubular diameter in the groups. The number of apoptotic germ cells per unit area was not significantly different in the 3 groups. In groups 1 to 3 there were no significant differences in the mean epididymides sperm motility rate plus or minus standard deviation (62.6% +/- 10.0%, 57.2% +/- 7.0% and 67.0 +/- 7.6%) or in the in vitro fertilization rate (52%, 48% and 48%, respectively). However, there were significant differences in groups 1 to 3 in mean mounting frequency (0, 29 +/- 4.0 and 12.4 +/- 4.5 times per hour) and mean intromission frequency (0, 24.4 +/- 3.5 and 3.8 +/- 1.5 times per hour, respectively). Females coupled with group 1 or 2 male mice did not achieve pregnancy. These results suggest that spermatogenesis, sperm motility and fertilization in vitro were unaffected in hypospadiac mice but sexual motivation and arousal were deficient.


Current Perspectives on Aerobic Exercise in People with Parkinson's Disease.
Parkinson's disease (PD) is a progressive neurological disorder characterized by motor and non-motor symptoms for which only symptomatic treatments exist. Exercise is a widely studied complementary treatment option. Aerobic exercise, defined as continuous movement of the body's large muscles in a rhythmic manner for a sustained period that increases caloric requirements and aims at maintaining or improving physical fitness, appears promising. We performed both a scoping review and a systematic review on the generic and disease-specific health benefits of aerobic exercise for people with PD. We support this by a meta-analysis on the effects on physical fitness (VO2max), motor symptoms (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor section), and health-related quality of life (39-item Parkinson's disease Questionnaire (PDQ-39)). Aerobic exercise has generic health benefits for people with PD, including a reduced incidence of cardiovascular disease, a lower mortality, and an improved bone health. Additionally, there is level 1 evidence that aerobic exercise improves physical fitness (VO2max) and attenuates motor symptoms (MDS-UPDRS motor section) in the off-medication state, although the long-term effects (beyond 6 months) remain unclear. Dosing the exercise matters: improvements appear to be greater after training at higher intensities compared with moderate intensities. We found insufficient evidence for a beneficial effect of aerobic exercise on health-related quality of life (PDQ-39) and conflicting results regarding non-motor symptoms. Compliance to exercise regimes is challenging for PD patients but may be improved by adding exergaming elements to the training program. Aerobic exercise seems a safe intervention for people with PD, although care must be taken to avoid falls in at-risk individuals. Further studies are needed to establish the long term of aerobic exercise, including a focus on non-motor symptoms and health-related quality of life.


Neuroblastoma.
Neuroblastoma is a heterogeneous disease; tumors can spontaneously regress or mature, or display an aggressive, therapy-resistant phenotype. Increasing evidence indicates that the biological and molecular features of neuroblastoma significantly influence and are highly predictive of clinical behavior. Because of this, neuroblastoma has served as a paradigm for biological risk assessment and treatment assignment. Most current clinical studies of neuroblastoma base therapy and its intensity on a risk stratification that takes into account both clinical and biological variables predictive of relapse. For example, surgery alone offers definitive therapy with excellent outcome for patients with low-risk disease, whereas patients at high risk for disease relapse are treated with intensive multimodality therapy. In this review recent advances in the understanding of the molecular genetic events involved in neuroblastoma pathogenesis are discussed, and how they are impacting the current risk stratification and providing potential targets for new therapeutic approaches for children with neuroblastoma. In addition, the results of significant recent clinical trials for the treatment of neuroblastoma are reviewed.


Carbon dioxide gas as a perfusion medium for the sapphire probe in laser ablation of human atheromatous plaques: comparison study with saline.
The effectiveness of CO2 gas as a perfusion medium was compared to that of saline in laser ablation of human atheromatous plaque. In an experimental circulation-occlusion model using flowing whole blood, human cadaveric arterial samples were irradiated by a sapphire probe with the Nd-YAG laser. The following experiments were performed: 1) lasing without perfusion, 2) lasing with saline perfusion of the probe, and 3) lasing with CO2 perfusion. Different perfusion flow rates of saline and CO2 were used. Results showed that the mean ablation area was 1.6-fold larger with CO2 than with saline perfusion (P less than 0.05, Student's t test). The mean lateral injury at the site adjacent to the ablation crater and at the area directly facing the probe was not significantly different with either perfusion medium. The larger ablation area with CO2 was probably due to the fact that CO2 is a good insulator for maintaining a higher probe temperature and keeps the probe free of blood debris. In conclusion, our results show that CO2 perfusion facilitates more effective laser ablation of atheromatous plaque than saline perfusion by the sapphire probe with the continuous wave Nd-YAG laser.


Pharmacognosy, phytochemistry, and molecular studies of an important medicinal herb Achillea millefolium L.
Achillea millefolium L. is traditionally important medicinal herb used for the treatment of various ailments from the centuries. Recent studies showed its biological activities on hay fever, hepato-biliary disorders, and as appetite enhancing drug. It is also reported to be used for the treatments of skin inflammations, wounds, cuts, and abrasions. To investigate preliminary pharmacognostical, phytochemical, and molecular parameters of aerial parts of the drug. A. millefolium was identified and collected from the Himalaya region. The material is properly dried, macro-and microscopic evaluation, phytochemical and molecular studies as per the standard quality control and WHO guidelines. The leaves are pinnately lobed, inflorescence compound corymbose. Nonglandular trichomes are uni-seriate, multicellular, and smooth walled; glandular trichomes are bicellular, present throughout the aerial parts. The endodermis is evident in the stem and leaf mesophyll is equifacial. The partial genome sequence analysis showed similarity toward studied species, which can clearly distinguish it from other species of the genus Achillea. The best chromatographic separation was observed with ascentis express C18, 2.7 μm, 100 mm × 4.6 mm. The flavonoids and phenolic acids have shown maximum absorbance at 330 nm. The system suitability parameters such as theoretical plate, tailing factor, and resolution met the acceptance criteria with United States pharmacopeia (USP). The findings of this study will be helpful for the precise identification of the raw drug of A. millefolium from its closely allied species.


Outcomes after breast conservation treatment with radiation in women with prior nonbreast malignancy and subsequent invasive breast carcinoma.
Little information has been reported regarding outcomes after treatment for patients with early-stage invasive breast cancer and a prior nonbreast malignancy. This report analyzes the outcomes in patients with Stage I and II breast cancer after breast conservation treatment (BCT) with a prior nonbreast malignancy. The study cohort comprised 66 women with invasive breast cancer and a prior nonbreast malignancy. All patients were treated with breast conservation surgery followed by definitive breast irradiation between 1978 and 2003. Median ages at diagnosis of invasive breast cancer and prior malignancy were 57 and 50 years, respectively. The median interval between the prior malignancy and breast cancer was 7.0 years. Median and mean follow-up times after BCT were 5.3 and 7.0 years. The 5-year and 10-year overall survival rates were 94% (95% confidence interval [CI], 82-98%) and 78% (95% CI, 59-89%), respectively. There were 4 patients (6%) with local failure and 10 patients (15%) with distant metastases. The 10-year rate of local failure rate was 5% (95% CI, 2-16%) and freedom from distant metastases was 78% (95% CI, 61-88%). No obvious differences in survival or local control were noted compared with the reported results in the literature for patients with invasive breast cancer alone. Both overall survival and local control at 5 and 10 years were comparable to rates observed in early-stage breast cancer patients without a prior malignancy. Prior nonbreast malignancy is not a contraindication to BCT, if the primary cancer is effectively controlled.


Comparison of the effectiveness of high-flow and conventional nasal cannula oxygen therapy in pulmonary embolism patients with acute hypoxemic respiratory failure.
The leading cause of mortality in pulmonary embolism (PE) is hypoxemic respiratory failure. The aim of this study was to compare the efficacy of high-flow nasal cannula (HFNC) and conventional nasal cannula (CNC) oxygen therapy in PE patients with hypoxemia. Fifty-eight patients with a PaO2/FIO2 ratio below 300 who were admitted to the emergency department with acute respiratory distress and followed up in our intensive care unit due to PE between March and October 2019 were included in the study. One group (n= 29) received HFNC oxygen therapy and the other group (n= 29) received CNC oxygen therapy. Arterial blood gas analysis showed no significant differences in baseline SpO2 and PaO2 between the HFNC and CNC groups, whereas both values were significantly higher in the HFNC group starting at 1 hour (PaO2: p= .01, p= .001, p= .001; SpO2: p= .009, p= .005, p= .002). Among massive PE patients with contraindications for thrombolytic therapy, there was no significant difference between the HFNC and CNC groups in baseline SpO2, PaO2, or respiratory rate, but those who received HFNC therapy had significant higher SpO2 starting at 15 minutes (p= .004 for all), significantly higher PaO2 starting at 1 hour (p= .01, p= .001, p= .001), and significantly lower respiratory rate starting at 30 minutes (p= .003, p= .001, p= .001, p= .002, p= .002). In patients presenting with PE and hypoxemic respiratory failure, HFNC oxygen therapy was more effective on both vital signs and arterial blood gas parameters compared to conventional oxygen therapy and can be used safely as primary treatment.


Roles of the middle domain-specific WUSCHEL-RELATED HOMEOBOX genes in early development of leaves in Arabidopsis.
During leaf development in flowering plants, adaxial (upper) and abaxial (lower) side-specific genes are responsible for blade outgrowth, which takes places predominantly in the lateral direction, and for margin development as well as differentiation of adaxial and abaxial tissues. However, the underlying mechanisms are poorly understood. Here, we show that two WUSCHEL-RELATED HOMEOBOX (WOX) genes, PRESSED FLOWER (PRS)/WOX3 and WOX1, encoding homeobox transcription factors, act in blade outgrowth and margin development downstream of adaxial/abaxial polarity establishment. The expression of PRS and WOX1 defines a hitherto undescribed middle domain, including two middle mesophyll layers and the margin, as a center that organizes the outgrowth of leaf blades. The expression of PRS and WOX1 is repressed in the abaxial leaf domain by the abaxial-specific transcription factor KANADI. Furthermore, PRS and WOX1 coordinate adaxial/abaxial patterning together with adaxial- and abaxial-specific genes. Our data suggest a model of blade outgrowth and adaxial/abaxial patterning via the middle domain-specific WOX genes in Arabidopsis thaliana leaves.


Follow-up after transanal endoscopic microsurgery or transanal excision of large benign rectal polyps.
Between January 1986 and December 1995, 238 patients with benign rectal polyps underwent either transanal endoscopic microsurgery (n = 226) or transanal excision (n = 12) at the Clinic of General and Abdominal Surgery, Johannes Gutenberg-University, Mainz. Mean polyp size was 4.2 cm; 89.1% of polyps measured more than 2 cm in diameter. In 89.1% of cases, histological analysis revealed polyps containing tubulovillous or villous adenomas. Synchronous colonic polyps were detected in 12.5% of patients. Follow-up data are available on 222 patients (94%). At follow-up examination, 169 of the 193 surviving patients (87.6%) were recurrence free. Seven of 193 patients (3.6%) had developed neoplastic colonic polyps and, in 17 patients (8.8%), metachronous polyps were detected. Transanal endoscopic microsurgical polypectomy was furthermore demonstrated to be a low-risk procedure with a low recurrence rate for the complete resection of large rectal polyps. At a follow-up rate of 61.1 %, the incidence of metachronous carcinoma ranged at 3.1%, which is markedly below the rate of 8-18% for tubulovillous or villous adenomas larger than 1 cm in diameter cited in the literature.


The effects of different knowledge-dissemination interventions on the mastitis knowledge of Tanzanian smallholder dairy farmers.
We developed three different knowledge-dissemination methods for educating Tanzanian smallholder farmers about mastitis in their dairy cattle. The effectiveness of these methods (and their combinations) was evaluated and quantified using a randomised controlled trial and multilevel statistical modelling. To our knowledge, this is the first study that has used such techniques to evaluate the effectiveness of different knowledge-dissemination interventions for adult learning in developing countries. Five different combinations of knowledge-dissemination method were compared: 'diagrammatic handout' ('HO'), 'village meeting' ('VM'), 'village meeting and video' ('VM+V'), 'village meeting and diagrammatic handout' ('VM+HO') and 'village meeting, video and diagrammatic handout' ('VM+V+HO'). Smallholder dairy farmers were exposed to only one of these interventions, and the effectiveness of each was compared to a control ('C') group, who received no intervention. The mastitis knowledge of each farmer (n=256) was evaluated by questionnaire both pre- and post-dissemination. Generalised linear mixed models were used to evaluate the effectiveness of the different interventions. The outcome variable considered was the probability of volunteering correct responses to mastitis questions post-dissemination, with 'village' and 'farmer' considered as random effects in the model. Results showed that all five interventions, 'HO' (odds ratio (OR)=3.50, 95% confidence intervals (CI)=3.10, 3.96), 'VM+V+HO' (OR=3.34, 95% CI=2.94, 3.78), 'VM+HO' (OR=3.28, 95% CI=2.90, 3.71), 'VM+V' (OR=3.22, 95% CI=2.84, 3.64) and 'VM' (OR=2.61, 95% CI=2.31, 2.95), were significantly (p<0.0001) more effective at disseminating mastitis knowledge than no intervention. In addition, the 'VM' method was less effective at disseminating mastitis knowledge than other interventions. Combinations of methods showed no advantage over the diagrammatic handout alone. Other explanatory variables with significant positive associations on mastitis knowledge included education to secondary school level or higher, and having previously learned about mastitis by reading pamphlets or attendance at an animal-health course.


Altered drug binding due to the use of indwelling heparinized cannulas (heparin lock) for sampling.
The effect of the use of the so-called heparin lock for blood sampling on the binding of propranolol has been studied and a cumulative dose-response curve to heparin constructed. The use of this method of blood sampling introduced considerable artifactual changes into the measurement of propranolol's plasma binding. The free fraction rose from 9.9% to 13.4% after only 50 U of heparin was used to flush the cannula. The increase in the free fraction of propranolol showed excellent correlation with the increase in free fatty acid levels (p less than 0.001, r = 0.996). The importance of ensuring that sampling techniques do not introduce artifactual changes in pharmacokinetic studies is emphasized.


Situational factors and behavioral self-predictions in the identification of clients at high risk to drop out of psychotherapy.
Two hundred and eight adults who requested outpatient treatment at a community mental health center were asked to complete brief questionnaires immediately prior to and after their first therapy session. Questionnaires contained items that pertained to self-predicted length of stay in psychotherapy, situational barriers to regular attendance, and past behavior in similar situations (e.g., appointment-keeping with other health care professionals). Therapists also were asked to make predictions with regard to client length of stay. Questionnaire data were analyzed via a series of double cross-validated multiple regression and discriminant function equations, and results indicated that client and therapist predictions of length of stay in therapy were the most stable and consistent correlates of attendance behavior.


Prognostic factors in bone marrow transplantation for beta thalassemia major: experiences from Iran.
This study concerns the effects of several pre-transplant features on outcome for patients with beta thalassemia major who underwent bone marrow transplantation (BMT). Seventy patients with beta thalassemia major underwent bone marrow transplantation during the period 1991-1997 in Shariati Hospital in Tehran, Iran. The survival and rejection curves levelled off at 8 and 18 months after transplantation at 82.6% and 11.4%, respectively. Pre-transplant clinical features (age, serum ferritin, portal fibrosis, hepatomegaly and quality of chelation therapy) were examined for their effects on survival and recurrence of thalassemia in this group of patients who were less than 16 years old. Increasing age, presence of portal fibrosis and increasing serum ferritin were significantly associated with reduced probability of survival (P = 0.0047, P = 0.016 and P = 0.024, respectively). Hepatomegaly and inadequate pre-transplant chelation therapy which were documented as poor prognostic factors in previous studies, were not evaluable in this study. We also showed the benefits of transplanting more than 5.5 x 10(8)/kg cells in this group of patients with no increase in complications.


Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABA(C) receptors.
The effects of the enantiomers of a number of flexible and cis-constrained GABA analogues were tested on GABA(C) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (1S,2R)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((+)-CAMP), a potent and full agonist at the rho1 (EC(50) approximately 40 microM, I(max) approximately 100%) and rho 2 (EC(50) approximately 17 microM, I(max) approximately 100%) receptor subtypes, was found to be a potent partial agonist at rho3 (EC(50) approximately 28 microM, I(max) approximately 70%). (1R,2S)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((-)-CAMP), a weak antagonist at human rho1 (IC(50) approximately 890 microM) and rho2 (IC(50) approximately 400 microM) receptor subtypes, was also found to be a moderately potent antagonist at rat rho3 (IC(50) approximately 180 microM). Similarly, (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid ((+)-ACPECA) was a full agonist at rho1 (EC(50) approximately 135 microM, I(max) approximately 100%) and rho2 (EC(50) approximately 60 microM, I(max) approximately 100%), but only a partial agonist at rho3 (EC(50) approximately 112 microM, I(max) approximately 37%), while (1S,4R)-4-aminocyclopent-2-ene-1-carboxylic acid ((-)-ACPECA) was a weak antagonist at all three receptor subtypes (IC(50)>>300 microM). 4-Amino-(S)-2-methylbutanoic acid ((S)-2MeGABA) and 4-amino-(R)-2-methylbutanoic acid ((R)-2MeGABA) followed the same trend, with (S)-2MeGABA acting as a full agonist at the rho1 (EC(50) approximately 65 microM, I(max) approximately 100%), and rho2 (EC(50) approximately 20 microM, I(max) approximately 100%) receptor subtypes, and a partial agonist at rho3 (EC(50) approximately 25 microM, I(max) approximately 90%). (R)-2MeGABA, however, was a moderately potent antagonist at all three receptor subtypes (IC(50) approximately 16 microM at rho1, 125 microM at rho2 and 35 microM at rho3). On the basis of these expanded biological activity data and the solution-phase molecular structures obtained at the MP2/6-31+G* level of ab initio theory, a rationale is proposed for the genesis of this stereoselectivity effect.


Microbial diversity and activity in hypersaline high Arctic spring channels.
Lost Hammer (LH) spring is a unique hypersaline, subzero, perennial high Arctic spring arising through thick permafrost. In the present study, the microbial and geochemical characteristics of the LH outflow channels, which remain unfrozen at ≥-18°C and are more aerobic/less reducing than the spring source were examined and compared to the previously characterized spring source environment. LH channel sediments contained greater microbial biomass (~100-fold) and greater microbial diversity reflected by the 16S rRNA clone libraries. Phylotypes related to methanogenesis, methanotrophy, sulfur reduction and oxidation were detected in the bacterial clone libraries while the archaeal community was dominated by phylotypes most closely related to THE ammonia-oxidizing Thaumarchaeota. The cumulative percent recovery of (14)C-acetate mineralization in channel sediment microcosms exceeded ~30% and ~10% at 5 and -5°C, respectively, but sharply decreased at -10°C (≤1%). Most bacterial isolates (Marinobacter, Planococcus, and Nesterenkonia spp.) were psychrotrophic, halotolerant, and capable of growth at -5°C. Overall, the hypersaline, subzero LH spring channel has higher microbial diversity and activity than the source, and supports a variety of niches reflecting the more dynamic and heterogeneous channel environment.


Attitudes of experiential education directors regarding tobacco sales in pharmacies in the USA.
Accreditation guidelines in the USA suggest that experiential sites for pharmacy students should demonstrate 'a strong commitment to health promotion and illness prevention'; however, most community pharmacies sell tobacco products. This study aimed to determine the proportion of students rotating through advanced pharmacy practice experience (APPE) sites where tobacco is sold and experiential education directors' perception regarding the sales of tobacco in APPE sites. A brief survey was distributed by mail to experiential education directors at US pharmacy schools. The survey characterized the proportion of students who rotate at practice sites where tobacco is sold, directors' perceptions of tobacco sales in experiential sites, and the number of hours of tobacco education in their pharmacy curricula. Directors (n = 81; 63%) estimated that 69% of students rotate through sites where tobacco is sold. If given the opportunity to choose between two potential sites, where one sells tobacco and the other does not, 40% of directors would be unlikely to choose a site that sold tobacco. With respect to tobacco sales, pharmacy schools are largely noncompliant with guidelines and resolutions of professional organizations.


Characterization of the estrogenicity of Swiss midland rivers using a recombinant yeast bioassay and plasma vitellogenin concentrations in feral male brown trout.
In our study, we aim to characterize the estrogenicity of 18 independent rivers that receive effluent from sewage treatment works. During the winter and summer of 2003, we collected multiple water samples and measured environmental estrogens with an in vitro yeast-based reporter gene assay; estrogenicity was expressed as ng 17beta-estradiol equivalents (EEQ) per L of water. Estradiol equivalents values in winter ranged from 0.3 to 2.0 ng/L and, in summer, from 0.4 to 7.0 ng/L. Winter and summer EEQ values were not correlated with each other or with the dilution factor of the effluent in the river. Variation in EEQ values was large and correlated from winter to summer. Part of this variation in estrogenicity is explained by water flow rates; variation is larger at reduced flow rates. We measured plasma vitellogenin concentrations in immature male brown trout. At five sites, vitellogenin concentrations exceeded 1 microg/ml; however, at the majority of the sites, plasma vitellogenin concentrations were below 0.5 microg/ml. Our data indicate that the exposure of brown trout to environmental estrogens in Swiss midland rivers is low. However, some sites show reoccurring higher EEQ values and, at some sites, plasma vitellogenin concentrations in male fish clearly are elevated.


Compliance to empirical contact precautions for multidrug-resistant microorganisms.
Health care-associated infections impact patient morbidity and mortality, and institutions adopt evidence-based measures to prevent and control such infections. In this study, professionals were observed during patient care under empirical contact precautions. A total of 243 observations were performed in which 39.5% complied with all measures. The positivity rate of surveillance cultures was 38.36%, and adherence to the measures in patients with colonization was 43.1%.


Mitochondrial respiration during recirculation after prolonged ischemia in cat brain.
Mitochondrial function was examined in cats after 1 h of complete cerebral ischemia and subsequent recirculation periods from 15 min to 56 h. During ischemia the NAD-linked respiratory control ratio and the maximal phosphorylation capacity of "free" and synaptosomal mitochondria decreased to 53% to 76% of control values. During postischemic reperfusion to 6 h, mitochondrial function was restored to 80%, remaining less than control throughout the entire investigated recirculation period with a tendency of secondary deterioration from 12 h of reperfusion onward. ADP: O ratios were unaffected during ischemia, but decreased significantly during early recirculation (15 to 30 min), and were completely restored from 45 min reperfusion onward. Correlation with electrophysiologic recordings revealed that mitochondrial dysfunction was not a limiting factor for neurophysiologic recovery during early recirculation (15 to 90 min). When the recirculation period was extended (greater than 3 h), good neurophysiologic recovery was associated with a return of mitochondrial function to control levels; inversely, poor mitochondrial function was correlated with poor neurophysiologic recovery.


Plant temperatures and heat flux in a Sonoran Desert ecosystem.
In the extreme desert environment the potential energy load is high, consequently high temperatures might be a limiting factor for plant survival. Field measurements of plant temperatures in a Sonoran Desert ecosystem were made using fine thermocouples. Temperatures of six desert species were measured: Opuntia engelmannii, Opuntia bigelovii, Opuntia acanthocarpa, Echinocereus engelmannii, Larrea tridentata and Franseria deltoidea. Daily temperature profiles were used to compare the different responses of cacti and shrubs to the desert heat load and also to compare spring and summer responses. Leaf temperature of shrubs was at or near air temperature during both the mild, spring season and the hotter dry season. The cacti, on the other hand, absorbed and stored heat, thus temperatures were often above air temperature. The energy absorbed is determined largely by plant orientation and surface area exposed to the sun. Actual energy absorbed by the plants was estimated from energy diagrams.The flat stem pads of Opuntia engelmannii plants are oriented to receive maximum sunlight without long periods of continuous heating. Opuntia bigelovii spines reflect and absorb much of the environmental energy load, thereby protecting the thick, succulent stems from overheating. The smaller stems of Opuntia acanthocarpa dissipate heat more effectively by their large surface area exposed to convective air currents. Leaves on desert shrubs remain nearer to air temperature than do succulent stems of cacti, because their very large surface to volume ratio allows them to dissipate much heat by convection.


Screening the phytoremediation potential of desert broom (Baccharis sarothroides Gray) growing on mine tailings in Arizona, USA.
The metal concentrations in a copper mine tailings and desert broom (Baccharis sarothroides Gray) plants were investigated. The metal concentrations in plants, soil cover, and tailings were determined using ICP-OES. The concentration of copper, lead, molybdenum, chromium, zinc, arsenic, nickel, and cobalt in tailings was 526.4, 207.4, 89.1, 84.5, 51.7, 49.6, 39.7, and 35.6mgkg(-1), respectively. The concentration of all elements in soil cover was 10-15% higher than that of the tailings, except for molybdenum. The concentration of copper, lead, molybdenum, chromium, zinc, arsenic, nickel, and cobalt in roots was 818.3, 151.9, 73.9, 57.1, 40.1, 44.6, 96.8, and 26.7mgkg(-1) and 1214.1, 107.3, 105.8, 105.5, 55.2, 36.9, 30.9, and 10.9mgkg(-1) for shoots, respectively. Considering the translocation factor, enrichment coefficient, and the accumulation factor, desert broom could be a potential hyperaccumulator of Cu, Pb, Cr, Zn, As, and Ni.


[Role of injury in the appearance of "activated" smooth muscle cells].
The ultrastructure of the smooth muscle tissue was studied in the posterior vena cava in rats after the disturbance of blood outflow, in the stomach following resection of half of its fundus and cecum after constriction of its ascending limb. "Activation" of the smooth muscle was found to reflect the stage of the cell ultrastructure injury, and then the processes of intracellular regeneration. Analysis of the correlation between the DNP-synthesizing and the "activated" cells showed the latter to be of local origin, from the differentiated myocytes.


Burst release of encapsulated annexin A5 in tumours boosts cytotoxic T-cell responses by blocking the phagocytosis of apoptotic cells.
Cancer immunotherapies, particularly therapeutic vaccination, do not typically generate robust anti-tumour immune responses. Here, we show that the intratumoral burst release of the protein annexin A5 from intravenously injected hollow mesoporous nanoparticles made of diselenide-bridged organosilica generates robust anti-tumour immunity by exploiting the capacity of primary tumours to act as antigen depots. Annexin A5 blocks immunosuppressive apoptosis and promotes immunostimulatory secondary necrosis by binding to the phagocytic marker phosphatidylserine on dying tumour cells. In mice bearing large established tumours, the burst release of annexin A5 owing to diselenide-bond cleavage under the oxidizing conditions of the tumour microenvironment and the reducing intracellular conditions of tumour cells induced systemic cytotoxic T-cell responses and immunological memory associated with tumour regression and the prevention of relapse, and led to complete tumour eradication in about 50% of mice with orthotopic breast tumours. Reducing apoptosis signalling via in situ vaccination could be a versatile strategy for the generation of adaptive anti-tumour immune responses.


Brief communication: The prevalence of high intake of vitamin E from the use of supplements among U.S. adults.
People who consume at least 400 IU of vitamin E per day from supplements may be at slightly increased risk for premature mortality. To estimate the percentage of U.S. adults age 20 years or older who consume at least 400 IU of vitamin E per day through the use of vitamins, minerals, or other dietary supplements. Cross-sectional analysis. The 1999-2000 National Health and Nutrition Examination Survey. Representative sample of the civilian, noninstitutionalized U.S. population. Participants answered questions about the use of vitamins, minerals, or other dietary supplements. Among 4609 adults, 11.3% (95% CI, 9.7% to 13.1%) consumed at least 400 IU of vitamin E per day from supplements. Such intake increased with age, was about equal for men and women, and was more common among white persons (14.1%; CI, 11.9% to 16.7%) than African-American (3.7% [CI, 2.6% to 5.2%]) or Mexican-American persons (3.9% [CI, 2.8% to 5.4%]). The median dietary intake of vitamin E was 8.8 IU per day. Information about vitamin E intake was self-reported. The use of vitamin E supplements in dosages of at least 400 IU per day is common among U.S. adults.


Target Deconvolution by Limited Proteolysis Coupled to Mass Spectrometry.
Limited proteolysis coupled to mass spectrometry (LiP-MS) is a recent proteomics technique that allows structure-based target engagement profiling on a proteome-wide level. To achieve this, native lysates are first incubated with a compound, followed by a short incubation with a nonspecific protease. Binding of a compound can change accessibility at the binding site or induce other structural changes in the target. This leads to treatment-specific proteolytic fingerprints upon limited proteolysis, which can be analyzed by standard bottom-up MS-based proteomics. Here, we describe a basic LiP-MS protocol using the natural product rapamycin as an example compound. Along with the provided LiP-MS reference data available via ProteomeXchange with identifier PXD035183, this enables the straightforward implementation of the method by scientists with a basic biochemistry and mass spectrometry background. We describe how the procedure can easily be adapted to other protein samples and small molecules.