Will a heavy sediment load affect responses of phytoplankton functional groups to aquatic environmental changes in different water body types?
Sediment, as a natural component of rivers, directly affects the abundance and function of phytoplankton by altering water physicochemical properties. Despite mounting evidence for the sensitivity of phytoplankton to environmental factors, the responses of phytoplankton functional groups to complex environmental changes in rivers with a heavy sediment load are still poorly understood. Herein, the effectiveness of phytoplankton functional groups was evaluated as an indicator of aquatic environmental changes in a heavily sediment-laden river. Samples were collected from 44 sites (22 free-flowing river sections and 22 man-made reservoir sections) with a mean annual sediment concentration of 4.69 kg m-3 in the Yellow River, China. A total of 31 phytoplankton functional groups were classified during spring (April-May) and autumn (September-October) in 2019. Groups C, MP, and D, which are well adapted to strong water disturbances and turbid habitats, showed distinct advantages over other groups. Despite no significant differences in many environmental variables between the river and reservoir sections, these variables (especially nitrogen nutrients) had remarkable effects on the phytoplankton community structure. The phytoplankton functional groups were sensitive to environmental changes even under sediment interference, although geo-climatic variables also exhibited non-trivial effects. The mean niche breadth of the abundant taxa (river: 11.16; reservoir: 7.93) was higher than that of the rare taxa (river: 5.64; reservoir: 4.86) in different water bodies. Thus, growth and diffusion of the abundant taxa played paramount roles in maintaining ecosystem stability. The results indicate that, in a large-scale sediment-laden river, phytoplankton functional groups can effectively indicate changes in the aquatic environment of either a free-flowing river or a man-made reservoir.


[Time-course of plasma testosterone in patients with prostate cancer treated by endocrine therapy].
To assess the time-course of plasma testosterone in patients with prostate cancer treated by endocrine therapy. A PubMed review of the literature on plasma testosterone and the various endocrine therapies for prostate cancer was performed. The time-course of plasma testosterone varies according to the type of endocrine therapy. The effective castration level, classically considered to be 50 ng/dl, is currently tending to be replaced by 20 ng/dl. Following surgical castration, plasma testosterone reaches effective castration levels within several hours, while with LH-RH agonist therapy, plasma testosterone reaches its trough value after three to four weeks, and remains low for six months after stopping treatment. However, about 15% of patients treated with LH-RH agonists do not achieve effective castration levels. Plasma testosterone remains unchanged or even increases in response to anti-androgens. Plasma testosterone assay is of limited value in routine clinical practice in patients receiving endocrine therapy for prostate cancer, but should be performed in the case of elevation of PSA to ensure that the patient has achieved effective castration levels. The correlation between plasma testosterone and progression of prostate cancer is unclear. Other studies are therefore necessary to define the value of plasma testosterone assay in patients treated for prostate cancer.


A systematic review on the guidelines for nutritional assessment for head and neck cancer patients managed by surgery.
There are a number of guidelines to assess the nutrition status of cancer cases. None of these guidelines are specifically head and neck cancer related; except for the European guidelines. This article reviews the different guidelines in nutrition for cancer cases and also their drawbacks.


Role of copper in photochemical damage to hair.
The objective of this work was to identify whether low levels of redox metals such as copper will accelerate damage to hair on exposure to UV irradiation and whether this damage can be prevented. The methods used were proteomics to measure the protein damage via protein loss after different periods of exposure and mass spectroscopy methods to identify specific marker peptides that are specifically created by this type of damage. In this work, we have developed new insights into the mechanism of UV damage using these proteomic methods. A marker fragment in the hair protein loss extract was identified (m/z = 1279) that is unique to UV exposure and increases with time of UV exposure. We have also identified for the first time in hair the role of exogenous copper in increasing UV damage both in terms of total protein degradation and also increased formation of the marker fragment and proposed a mechanism of action. It has been demonstrated that shampoo treatment containing a chelant such as N,N'-ethylenediamine disuccinic acid (EDDS) reduced copper accumulation in hair. This work provides evidence for the role of copper in UV-induced damage to hair and strategies to reduce copper levels in hair using a chelant such as EDDS.


Pancreatic ductal adenocarcinoma cell secreted extracellular vesicles containing ceramide-1-phosphate promote pancreatic cancer stem cell motility.
The high mortality rate associated with pancreatic ductal adenocarcinoma (PDAC) is in part due to lack of effective therapy for this highly chemoresistant tumor. Cancer stem cells, a subset of cancer cells responsible for tumor initiation and metastasis, are not targeted by conventional cytotoxic agents, which renders the identification of factors that facilitate cancer stem cell activation useful in defining targetable mechanisms. We determined that bioactive sphingolipid induced migration of pancreatic cancer stem cells (PCSC) and signaling was specific to ceramide-1-phosphate (C1P). Furthermore, PDAC cells were identified as a rich source of C1P. Importantly, PDAC cells express the C1P converting enzyme ceramide kinase (CerK), secrete C1P-containing extracellular vesicles that mediate PCSC migration, and when co-injected with PCSC reduce animal survival in a PDAC peritoneal dissemination model. Our findings suggest that PDAC secrete C1P-containing extracellular vesicles as a means of recruiting PCSC to sustain tumor growth therefore making C1P release a mechanism that could facilitate tumor progression.


Innovations in first episode psychosis interventions: The case for a "RAISE-Plus" approach.
Several papers in the current issue of Schizophrenia Research show evidence supporting interventions that are not yet grouped with standard care practices in FEP. Taken together, these studies make the case for a more inclusive approach for early psychosis care than what is embodied in RAISE. Although providing all interventions to all patients, however, will be impractical and expensive, a personalized approach to such interventions, whereby the appropriate interventions are implemented in a phase specific and individually tailored manner after a careful assessment of each person's core deficits within a coordinated specialty care model, is likely to improve lives and be cost-effective.


Assessment of atrial septal defect size and residual rim using real-time 3D transesophageal echocardiography.
Accurate preoperative determination of defect location and size is important for successful transcatheter closure of atrial septal defects (ASD). Real-time 3D transesophageal echocardiography (3DTEE) has the potential to delineate the shape of ASD in 3D space. Full volume and 3D zoom datasets by 3DTEE were acquired in 17 ASD patients. Using quantitative software, maximal/minimal diameter, defect area and residual rim length were measured and compared to the standard 2D measurements. Real-time 3DTEE allowed delineation of the en-face view of the ASDs. The defect typically had an oval shape, and its size changed dynamically, having its minimal size at end-diastole and maximal at end-systole. A good correlation was noted between the maximal defect area by 3DTEE and 2DTEE (r = 0.93, p < 0.001). Successful delineation of rim length to the specific cardiac structure was 100% by 3DTEE and 88% by 2DTEE. There was a fair correlation of residual rim length between 3DTEE and 2DTEE (r = 0.69, p < 0.001). Eight patients underwent transcatheter closure of the ASD. Excellent correlation was noted between 3D-derived maximal defect diameter and device diameter (r = 0.97, p < 0.001). Real-time 3DTEE allows measurements of the temporal and spatial changes of ASD size and shape. This methodology provides detailed information on defect dynamics.


Real-world efficacy and tolerability of fremanezumab in adults with chronic migraine: a 3-month, single-center, prospective, observational study.
Following the promising pre-marketing placebo-controlled randomized clinical trials of fremanezumab, post-marketing studies are necessary to verify efficacy and tolerability in various real-world settings. The present study assessed real-world efficacy and safety of fremanezumab. A 3-month, single-center, prospective, observation study of adults with chronic migraine who were treated with monthly subcutaneous injections of 225 mg fremanezumab in Denmark. The primary outcome was defined as proportion of patients who achieved ≥30% reduction in monthly migraine days (MMDs) from baseline to weeks 9-12. Among secondary outcomes were ≥50 and ≥75% responder rates and the proportion of patients reporting adverse events. A total of 91 patients with chronic migraine were enrolled and received at least one dose of fremanezumab of whom 89 patients (98%) completed the 3-months treatment period. At baseline, the mean (SD) number of monthly headache days was 24.3 ± 5.8 and mean number of MMDs was 18.5 ± 7.4. The number of patients who achieved ≥30% reduction in MMDs from baseline to weeks 9-12 was 58 (65%), while 45 (51%) and 21 (24%) had ≥50 and 75% reduction in MMD, respectively. Twenty-one patients (23%) reported adverse event, in which the most common were constipation (4.4%), fatigue (4.4%) and dizziness (3.3%). No serious adverse events were reported. In adult chronic migraine patients with previous failure of conventional oral migraine preventives, fremanezumab was found to be effective and well-tolerated.


Cystathionine γ lyase S-sulfhydrates Drp1 to ameliorate heart dysfunction.
Hydrogen sulfide (H2S), produced by cystathionine γ lyase (CSE), is an important endogenous gasotransmitter to maintain heart function. However, the molecular mechanism for how H2S influences the mitochondrial morphology during heart failure remains poorly understood. Here, we found that CSE/H2S pathway mediated cardiac function and mitochondrial morphology through regulating dynamin related protein 1 (Drp1) activity and translocation. Mechanistically, elevation of H2S levels by CSE overexpression declined protein level, phosphorylation (Ser 616), oligomerization and GTPase activity of Drp1 by S-sulfhydration in mouse hearts. Interestingly, Drp1 S-sulfhydration directly competed with S-nitrosylation by nitric oxide at the specific cysteine 607. The non-S-sulfhydration of Drp1 mutation (C607A) attenuated the regulatory effect of H2S on Drp1 activation, mitochondrial fission and heart function. Moreover, the non-canonical role of Drp1 mediated isoprenaline-induced mitochondrial dysfunction and cardiomyocyte death through interaction with voltage-dependent anion channel 1. These results uncover that a novel mechanism that H2S S-sulfhydrated Drp1 at cysteine 607 to prevent heart failure through modulating its activity and mitochondrial translocation. Our findings also provide initial evidence demonstrating that Drp1 may be a critical regulator as well as an effective strategy for heart dysfunction.


Hydrolytic and transglucosylation activities of a purified calf spleen beta-glucosidase.
Certain properties of the transglucosylitic activity and the hydrolytic activity of a purified calf spleen beta-glucosidase (beta-D-glucoside glucohydrolase EC 220.127.116.11) were investigated. There was a stimulation of both activities by sodium taurocholate and "Gaucher's factor". The K-m values for 4-methylumbelliferyl-beta-D-glucoside and glucosylceramide as donors in the transglucosylation reaction were 2 mM and 0.075 mM, respectively. The K-m for ceramide as acceptor was 0.149 mM with both of these compounds. The ability of several glucoside to act as donors was examined. The capacity to catalyze this "transglucosylation" reaction is greatly diminished in spleen tissue samples from Gaucher's patients. The enzyme possesses the capacity to hyrolyze 4-methylumbellifery-beta-D-glucoside, p-nitrophenyl-beta-D-glucoside, glucosylsphingosine, glucosylceramide and deoxycorticosterol-beta-D-glucoside. It is postulated that a single enzyme protein may be responsible for both the hydrolytic and the transglucosylitic activities.


Evaluation of the immunogenic properties of the recombinant Histophilus somni outer membrane protein 40 kDa (rOMP40).
Gram-negative bacterial infections are a serious problem in beef and dairy cattle. Bacterial outer membrane proteins (OMPs) play a pivotal role in cellular survival and the host-bacterium interaction. Histophilus somni OMP40 was identified as a porin with homology between its N-terminal amino acid sequence and the sequences of porins of other gram-negative bacteria The aim of this study was to produce recombinant H. somni OMP40 (rOMP40), optimize its production and evaluate its immunogenic properties in calves. The cross-reactivity of anti-rOMP40 antibodies were also checked. The highest overexpression of rOMP40 was demonstrated by Escherichia coli C41 using the autoinduction process. Double immunization of calves (20 μg rOMP40 per animal) induced a significant increase of anti-rOMP40 antibodies in the IgG1 (P ≤ 0.01) and IgG2 (P ≤ 0.01, after first immunization only) subclasses, but not IgM. ELISA revealed increased reactivity of the IgG against surface antigens of E. coli and Pasteurella multocida after the second immunization (P < 0.01). Cross reactivity of anti-rOMP40 antibodies with ~ 40 kDa antigens of most common gram-negative pathogens was shown by Western blotting. Immunization with H. somni rOMP40 induced a humoral response in cattle with broad cross-reactivity with similar antigens of other species of Pasteurellaceae and Enterobacteriaceae families and the delayed-type hypersensitivity reaction. The obtained results encourage further study to evaluate the protective effect of the produced protein as a subunit vaccine in cattle.


[Unilateral extended medialization thyroplasty. Treatment for total aspiration after laser surgery and radiotherapy of laryngeal cancer].
Total aspiration is a rare complication after extended laser surgery for laryngeal cancer with adjuvant radiotherapy. Two patients with long-standing total aspiration after laser surgery with radiotherapy despite intensified swallowing therapy were treated with an extended medialization thyroplasty. Postoperatively, both patients were able to swallow food and liquids without aspiration. One patient no longer has a gastrostomy tube and has been free from aspiration with normal oral food intake for 3 years. The second patient, with a tiny mucosal scar perforation, developed an abscess 2 months after surgery and needed revision surgery, with a subsequent return of aspiration. The second patient's complication stresses the significance of an intact endolaryngeal scar because of the well-known prolonged healing of mucosa in the irradiated larynx. In our opinion, the potential benefits of medialization thyroplasty outweigh the risk of significant complications, especially after irradiation.


Hydrodynamics with heated microelectrodes.
Voltammetry with continuously heated microelectrodes yields well-defined sigmoidal current-voltage curves. Unlike hydrodynamic electrodes, the surface temperature of a heated electrode can be adjusted arbitrarily within a certain range. Inside a thermal layer, a virtually stagnant diffusion layer of constant thickness delta(diff) exists. delta(diff )is independent of temperature within a certain range. On the basis of this theory, equations are derived which play a similar role to, for instance, the Levich equation for the rotating disk electrode. Reasonable agreement of the derived relationship with the results from voltammetric experiments is obtained.


Arsonoliposomes, a novel class of arsenic-containing liposomes: effect of palmitoyl-arsonolipid-containing liposomes on the viability of cancer and normal cells in culture.
Arsonolipid-containing liposomes have been recently prepared. The demonstrated antileukemic action of arsenic trioxide prompted us to study their effect on the viability of several types of cancer cells to investigate the possibility of relevant applications. Five different cell types, three malignant (HL-60, C6. and GH3) and two non-malignant (HUVEC and RAME), were used. Liposomes containing the palmitoyl side chain arsonolipid (with different lipid compositions) were incubated with a given number of cells. Cell viability was estimated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-dimethyltetrazolium bromide assay. Morphologic studies were also performed. Our results reveal that arsonoliposomes cause a dose (initiated at 10(-6) M)- and time-dependent inhibition of survival in all three malignant cell lines studied. No significant effect on the survival of the normal cells studied was observed at these, as well as at 10-fold higher. concentrations, although arsenic trioxide was toxic to HUVEC cells at equivalent arsenic concentrations. Microscopy studies reveal that although morphologic changes were initiated in HL-60 and C6 cells after incubation with arsonoliposomes, no changes in HUVEC and RAME cells were observed. Considering the numerous advantages of liposomal systems in therapeutics, it is concluded that the arsonoliposome system is very interesting and future applications should be exploited by further studies.


Target training: a technique for assessing self-regulation of skin temperature.
The determination of the achievement of self-regulation of hand temperature can be difficult, even with adequate baseline and control procedures. Although bidirectional training is often mentioned as a technique for thorough learning and for a convincing demonstration of temperature control, patients are sometimes unwilling or unable to lower hand temperature volitionally. This case report describes a patient who, due to failure at lowering her hand temperature, developed the target training method to convince herself of her self-regulation skill. The method may be useful in both clinical and research settings.


Dirofilaria immitis: further characterization of the transglutaminase enzyme and its role in larval molting.
We recently reported the cDNA cloning and functional characterization of a novel transglutaminase (TGase) from the dog filarial parasite Dirofilaria immitis. D. immitis TGase (DiTG) has no sequence similarity with any other known TGase, but has significant similarity to protein disulfide isomerase (PDI)-related endoplasmic reticulum protein ERp60. In the present study. we further characterized the recombinant DiTG (rDiTG) and studied its role in the molting process of third-stage larvae. The enzymatic activity of rDiTG requires Ca2+, and the maximum activity was observed at a calcium concentration of 4 mM. Interestingly, the rDiTG was highly thermostable, with optimal activity observed at 55 degrees C, similar to that seen with the native enzyme. Dithiothreitol (DTT) was not essential for enzyme activity. In fact, rDiTG was more active in the absence of DTT. The known inhibitors of TGase, such as monodansylcadaverine (MDC), cystamine and iodoacetamide, inhibited the TGase activity, but not the PDI activity, of rDiTG, demonstrating the dual activity of rDiTG. The TGase-specific pseudosubstrate, MDC, completely inhibited the molting of D. immitis L3 to L4 if present during the first 24-48 h of the molting process. Electron microscopic studies revealed that MDC-treated infective larvae failed to show separation between the L3 and L4 cuticles. The L4 cuticle and accompanying hypodermis were much thinner in MDC-treated worms than in controls. Using anti-rDiTG antiserum, the native DiTG antigen was localized in the hypodermis, afibrillar muscle cells and gut epithelium in adult male and female worms as well as developing embryos in the females.


Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells.
A. oxyphylla extract is known to possess a wide range of pharmacological activites. However, the molecular mechanism of A. oxyphylla and its bioactive compound nootkatone in colorectal cancer is unknown. Our study aims to examine the role of A. oxyphylla and its bioactive compound nootkatone, in tumor suppression using several in vitro assays. Both A. oxyphylla extract and nootkatone exhibited antiproliferative activity in colorectal cancer cells. A. oxyphylla displayed antioxidant activity in colorectal cancer cells, likely mediated via induction of HO-1. Furthermore, expression of pro-apoptotic protein NAG-1 and cell proliferative protein cyclin D1 were increased and decreased respectively in the presence of A. oxyphylla. When examined for anticancer activity, nootkatone treatment resulted in the reduction of colony and spheroid formation. Correspondingly, nootkatone also led to increased NAG-1 expression and decreased cyclin D1 expression. The mechanism by which nootkatone suppresses cyclin D1 involves protein level regulation, whereas nootkatone increases NAG-1 expression at the transcriptional level. In addition to having PPARγ binding activity, nootkatone also increases EGR-1 expression which ultimately results in enhanced NAG-1 promoter activity. In summary, our findings suggest that nootkatone is an anti-tumorigenic compound harboring antiproliferative and pro-apoptotic activity.


Time-calibrated phylogeny of the woody Australian genus Hakea (Proteaceae) supports multiple origins of insect-pollination among bird-pollinated ancestors.
A past study based on morphological data alone showed that the means by which plants of the Australian genus Hakea reduce florivory is related to the evolution of bird pollination. For example, bird pollination was shown to have arisen only in insect-pollinated lineages that already produced greater amounts of floral cyanide, a feature that reduces florivory. We examine a central conclusion of that study, and a common assumption in the literature, that bird pollination arose in insect-pollinated lineages, rather than the reverse. We combined morphological and DNA data to infer the phylogeny and age of the Australian genus Hakea, using 9.2 kilobases of plastid and nuclear DNA and 46 morphological characters from a taxonomically even sampling of 55 of the 149 species. Hakea is rooted confidently in a position that has not been suggested before. The phylogeny implies that bird pollination is primitive in Hakea and that multiple shifts to insect pollination have occurred. The unexpectedly young age of Hakea (a crown age of ca. 10 Ma) makes it coincident with its primary bird pollinators (honeyeaters) throughout its history. Our study demonstrates that Hakea is an exception to the more commonly described shift from insect to bird pollination. However, we note that only one previous phylogenetic study involved Australian plants and their honeyeater pollinators and that our finding might prove to be more common on that continent.


Identification of the active site of human mitochondrial malonyl-coenzyme a decarboxylase: A combined computational study.
Malonyl-CoA decarboxylase (MCD) can control the level of malonyl-CoA in cell through the decarboxylation of malonyl-CoA to acetyl-CoA, and plays an essential role in regulating fatty acid metabolism, thus it is a potential target for drug discovery. However, the interactions of MCD with CoA derivatives are not well understood owing to unavailable crystal structure with a complete occupancy in the active site. To identify the active site of MCD, molecular docking and molecular dynamics simulations were performed to explore the interactions of human mitochondrial MCD (HmMCD) and CoA derivatives. The findings reveal that the active site of HmMCD indeed resides in the prominent groove which resembles that of CurA. However, the binding modes are slightly different from the one observed in CurA due to the occupancy of the side chain of Lys183 from the N-terminal helical domain instead of the adenine ring of CoA. The residues 300 - 305 play an essential role in maintaining the stability of complex mainly through hydrogen bond interactions with the pyrophosphate moiety of acetyl-CoA. Principle component analysis elucidates the conformational distribution and dominant concerted motions of HmMCD. MM_PBSA calculations present the crucial residues and the major driving force responsible for the binding of acetyl-CoA. These results provide useful information for understanding the interactions of HmMCD with CoA derivatives. Proteins 2016; 84:792-802. © 2016 Wiley Periodicals, Inc.


The influence of membrane composition on the solubilizing effects of Triton X-100.
Multilamellar liposomes containing pure phosphatidylcholine (PC) or mixtures of PC with cholesterol, cholesteryl palmitate, beta-carotene, cardiolipin, phosphatidylethanolamine or gramicidin A have been treated with the detergent Triton X-100. Solubilization has been monitored as a decrease in turbidity of the liposome suspension, and also by determination of bilayer components in the solubilized fraction. The same solubilization pattern is found for unsaturated (egg yolk) or saturated (dimyristoyl) PC. Similar results are also found when dimyristoyl PC is solubilized above or below its gel-to-fluid transition temperature. Cholesterol solubilizes in parallel with PC; gramicidin A is solubilized preferentially to this phospholipid and the non-polar lipids cholesteryl palmitate or beta-carotene remain insoluble at detergent concentrations producing complete PC solubilization. Addition of cardiolipin or phosphatidylethanolamine does not seem to alter the general pattern of PC solubilization. Phosphatidylethanolamine is less soluble than PC, while cardiolipin solubilizes at the same detergent concentrations than PC. These results are considered in relation to previous studies with natural membranes.


Di-rhamnolipids improve effect of trehalose on both hypothermic preservation and cryopreservation of rat hepatocytes.
Trehalose, a disaccharide of glucose, is a highly hydrophilic small molecule (MW = 342D) and a bioprotectant normally impermeable to the membrane phospholipid bilayer. Di-rhamnolipids, a major component of rhamnolipids, were applied to increase the effect of trehalose in cryopreservation and hypothermic preservation. We found that di-rhamnolipids (10 mg/L) increased the survival of hepatocytes after cryopreservation or hypothermic preservation as indicated by cell viability using trypan blue exclusion and methyl thiazolyl tetrazolium assay. Correspondingly, after hepatocytes were preserved in the presence of di-rhamnolipids, their hepatospecific functions were comparable to those of freshly cultured cells in terms of intracellular glutathione level, albumin secretion, urea production, and metabolic activities of cytochrome P450 isoforms. Measurement of trehalose intracellular concentration showed that its accumulation increased in the presence of di-rhamnolipids (10 mg/L) but was not altered by two other well-known surfactants, Tween-80, and Pluronic 127. Hence, di-rhamnolipids, which are non-toxic, effective, and commercially available, could be a promising protectant by potentiating the function of trehalose against hypothermic or cryopreservation cell damage.


A validation study of three anxiety and depression self-assessment scales.
All measuring instruments require further validation both in the setting for which they were designed and in other fields. The Hospital Anxiety and Depression Scale was designed for detection and assessment of those mood disorders in the setting of hospital medical and surgical clinics. Reasons are given for supposing it has advantages over other similar scales. The present study undertakes a further validation of the scale in a general hospital setting. The opportunity is taken to assess the usefulness, in this setting of the Irritability Depression and Anxiety Scale and also of two subscales of the General Health Questionnaire, the one relating to the concept of depression and the other to the concept of anxiety. Score ranges of the latter two subscales are suggested and will require replication for confirmation of their usefulness.


Effect of Cornus mas L. fruit extract on blood pressure, anthropometric and body composition indices in patients with non-alcoholic fatty liver disease: A double-blind randomized controlled trial.
Obesity is linked to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD are at increased risk for hypertension. Some investigations have hypothesized that Cornus mas L. fruit can improve obesity and hypertension. We investigated the effect of C. mas L. fruit extract on blood pressure, anthropometric and body composition indices in patients with NAFLD. This 12-week double-blind randomized controlled trial was conducted on fifty patients with NAFLD. Patients received 20 cc/d C. mas L. fruit extract or placebo. We measured diastolic blood pressure (DBP), systolic blood pressure (SBP), weight, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), body fat mass (BFM), body fat percent (BFP) and fat free mass (FFM) before and after intervention. Treatment group compared to control group showed a significant reduction in DBP (-8.62 ± 11.86 mmHg vs. 0.53 ± 8.53 mmHg; Pcrude = 0.003; Padjucted = 0.03) and SBP (-8.63 ± 14.37 mmHg vs. 0.0 ± 12.67 mmHg; Pcrude = 0.02; Padjucted = 0.02). We found no difference between groups in weight, WC, HC, WHR, BFM, BFP and FFM (P > 0.05). After adjusting for confounding factors, a significant reduction was observed in treatment group compared to control group in BFM (-0.2 ± 3.9 kg vs. 0.7 ± 2.4 kg; P = 0.01) and BFP (-0.2 ± 4.9% vs. 0.8 ± 2.8%; P = 0.02). C. mas L. fruit extract statistically reduced blood pressure and body fat. However, it had no effect on other anthropometric and body composition indices. Studies with larger sample sizes and higher dosages of extract are needed. Registered on 30/9/2018 at Iranian Registry of Clinical Trials IRCT20180419039359N1 (https://www.irct.ir/trial/30707).


Within and between species variation in response to environmental gradients in Polygonum pensylvanicum and Polygonum virginianum.
The responses of Polygonum pensylvanicum L., an early successional annual, and of Polygonum virginianum L., a late successional perennial, were examined along discontinuous gradients of soil moisture, light and nutrient availability. In the case of P. virginianum both individuals grown from seed and individuals grown from rhizomes were examined. The results show that variation in the response of individuals of a species of different age to environmental variation is as great as that found between the two congeneric species of different successional habitats. In general, individuals of the two species were more similar to one another in response to the resource gradients when both were started from seed, than were individuals of P. virginianum grown from seed and from rhizomes. Potential differences in stored reserves (starting capital) between rhizomes and seeds appeared to have little effect upon responses to resource availability. A number of plant characters were found to vary along the gradients in ways that were unique to the character, the gradient, and the age of the individual. These characters included aspects of leaf size, shape, and orientation, as well as whole plant architecture. Many if not all of these characters are likely to have significant effects upon the functioning of plants. The origin of this difference in response to the gradients of individuals of P. virginianum of differing age may be ontogenetic or may reflect differences in genetic composition created by recombination.


Behavioural topography in the striatum: differential effects of quinpirole and D-amphetamine microinjections.
Behavioural evidence has accumulated that supports the hypothesis that specific territories of the striatum contribute differentially to the control of motor behaviours. The present experiments compare the behavioural effects of microinjections of amphetamine (20 microg/0.5 microl) with those elicited by the D2-class dopamine receptor agonist quinpirole (3 microg/0.5 microl) following direct microinjection into three anatomically distinct sectors of the striatum: the nucleus accumbens, the ventrolateral striatum and the anterodorsal striatum. Our findings demonstrate that site-specific behavioural responses are induced by microinjections of amphetamine, but not of quinpirole, into the striatum. Our results suggest that widespread areas of the striatum are implicated in the induction of a syndrome of sedation, yawning and motor inhibition, observed readily following microinjections of quinpirole into the striatum. This evidence supports both homogeneity and segregation of function in the striatum at the behavioural level. Further, the results suggest that the elicitation of site-specific action sequences at the level of the striatum seems to require cooperative interactions between D1-class and D2-class dopamine receptors.


Efficacy of manual acupuncture, electro-acupuncture, and warm acupuncture for knee osteoarthritis: study protocol for a randomized controlled trial.
Acupuncture is one of the most popular complementary and alternative treatments for knee osteoarthritis (KOA). There are many methods of acupuncture in the treatment of KOA, and the effects are different. According to our clinical observations and researches, it is found that manual acupuncture (MA), electro-acupuncture (EA), and warm acupuncture (WA) are used more frequently in the treatment of KOA, and the curative effects are satisfactory. However, there is currently a lack of efficacy comparison of efficacy between different acupuncture treatments, as well as a lack of standardized clinical research on the acupuncture treatment of KOA. Therefore, we will carry out a high-quality clinical randomized controlled trial to research the effect laws of MA, EA, and WA on KOA. A total of 200 eligible participants with KOA will be randomly assigned to group A, B, C, or D in a ratio of 1:1:1:1. Patients in group A will receive MA, while those in group B, group C, and group D will be treated with EA, WA, and sham acupuncture (SA), respectively. Patients will be treated with acupuncture once a day, 30 min per session, 5 sessions per week for 4 weeks. The primary outcome is the change of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at week 4. The secondary outcomes include WOMAC, visual analog scale (VAS), Arthritis Quality of Life Measurement Scale Simplified Scale (AIMS2-SF), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Credibility/Expectancy Questionnaire. The evaluation will be performed at baseline and weeks 4, 8, and 12 respectively after randomization. This is a randomized controlled trial. We will observe the clinical effect of MA, EA, and WA on KOA to research the effect laws of these three acupuncture treatments on KOA and set up standardized treatment programs for acupuncture for KOA. China Clinical Trials Registry ChiCTR2100049526. Registered on August 2, 2021.


Incorporating prior knowledge into regularized regression.
Associated with genomic features like gene expression, methylation and genotypes, used in statistical modeling of health outcomes, there is a rich set of meta-features like functional annotations, pathway information and knowledge from previous studies, that can be used post hoc to facilitate the interpretation of a model. However, using this meta-feature information a priori rather than post hoc can yield improved prediction performance as well as enhanced model interpretation. We propose a new penalized regression approach that allows a priori integration of external meta-features. The method extends LASSO regression by incorporating individualized penalty parameters for each regression coefficient. The penalty parameters are, in turn, modeled as a log-linear function of the meta-features and are estimated from the data using an approximate empirical Bayes approach. Optimization of the marginal likelihood on which the empirical Bayes estimation is performed using a fast and stable majorization-minimization procedure. Through simulations, we show that the proposed regression with individualized penalties can outperform the standard LASSO in terms of both parameters estimation and prediction performance when the external data is informative. We further demonstrate our approach with applications to gene expression studies of bone density and breast cancer. The methods have been implemented in the R package xtune freely available for download from https://cran.r-project.org/web/packages/xtune/index.html.


Local Regeneration of Cortisol by 11β-HSD1 Contributes to Insulin Resistance of the Granulosa Cells in PCOS.
Insulin resistance (IR) of the granulosa cells may account for the ovarian dysfunctions observed in polycystic ovarian syndrome (PCOS). The underlying mechanism remains largely unresolved. The objective of the study was to investigate the relationship of IR of the granulosa cells with cortisol in the follicular fluid and 11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD1 and -2) in the granulosa cells in PCOS. Follicular fluid and granulosa cells were collected from non-PCOS and PCOS patients with and without IR to measure cortisol concentration and the amounts of 11β-HSD1 and -2, which were then correlated with IR status. The effects of cortisol on the expression of genes pertinent to IR were studied in cultured human granulosa cells. Cortisol concentration in the follicular fluid, 11β-HSD1 but not 11β-HSD2 mRNA in the granulosa cells were significantly elevated in PCOS with IR. Increased reductase and decreased oxidase activities of 11β-HSD were observed in granulosa cells in PCOS with IR. In cultured granulosa cells, insulin-induced Akt phosphorylation was significantly attenuated by cortisol. Cortisol not only increased phosphatase and tensin homolog deleted on chromosome 10, an inhibitor of Akt phosphorylation, but also 11β-HSD1 in the cells. Increased 11β-HSD1 expression and its reductase activity in granulosa cells are the major causes of increased cortisol concentration in the follicular fluid of PCOS with IR. The consequent excessive cortisol might contribute to IR of the granulosa cells in PCOS patients by attenuating Akt phosphorylation via induction of phosphatase and tensin homolog deleted on chromosome 10 expression, which might be further exacerbated by the induction of 11β-HSD1.


Status, sources, and human health risk assessment of DDT pesticide residues in river sediments in a highly developed agricultural region in the upper Yangtze River in China.
The concentrations of DDT and its metabolites in 19 sediment samples from a highly developed agricultural region in the upper reaches of the Yangtze River were measured. Non-carcinogenic hazard quotient for different age groups was evaluated using reference doses provided by the USEPA, and the excess lifetime cancer risk due to eating fish was assessed based on the local eating habits. The results showed that this region had a high level of residual DDT (12.84 ± 8.97 ng/g), which mainly came from the historically used technical DDT in agriculture. The non-carcinogenic risk was just acceptable in the region, but 11 of the 19 sites showed an unacceptable carcinogenic risk. Although DDT has been banned for decades, there were still notable health risks, especially for children. Special attention should be given to the potential health risks in historically developed agricultural regions.


A case report of inhalation anthrax acquired naturally.
Anthrax is a zoonotic occupational disease caused by Bacillus anthracis, a rod-shaped immobile aerobic gram-positive bacteria with spore. Anthrax occurs in humans randomly and with low frequency. Most cases of anthrax are acquired through contact with infected animals or contaminated animal products. This old disease became particularly important since 2001 that the biological spores were exploited in America. Depending on the transmission method of the disease, clinical manifestations occur in three classes: Cutaneous, respiratory, and gastrointestinal anthrax. The respiratory form is considered as the most fatal and a rare form of anthrax intending to show complicated and unusual manifestations. In this case report a rare case of inhalation anthrax acquired naturally in southeast of Iran is presented. A blind 65-year-old man, living in a rural area, was admitted with respiratory infection, fever, dyspnea, loss of appetite, and myalgia. The patient was treated with outpatient antibiotics a week ago. After admission, the patient was again treated for pneumonia, but there was no improvement despite treatment and the patient was suffering from septicemia symptoms. Radiographic images showed wide mediastinum. Bacillus anthracis was isolated from blood and sputum culture and the results were confirmed by colony morphology, biochemical reactions and PCR. The treatment was changed to ciprofloxacin, clindamycin, and penicillin. On the second day of anthrax treatment, the patient was complicated with jaundice, elevation of liver enzymes, and a significant drop in hemoglobin, hematocrit, and platelet despite lack of obvious bleeding and was complicated with respiratory distress and sepsis and died a week after treatment. We could discover no specific exposure associated with anthrax infection for this patient. However, due to being located in an endemic and enzootic area, it is proposed that the exposure occurred through contact with infected airborne dust or an unknown contaminated item. Despite many advances in preventing anthrax, still some rare cases of respiratory and complicated anthrax are emerging. With regard to the threat of bioterrorism, medical staff's sensitivity to the clinical syndrome, methods of prophylaxis and treatment of anthrax must be raised. Fast diagnosis and successful treatment the lethal cases of this infection are of utmost important.


Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials.
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are related conditions with similar clinical features of variable severity. The objective of this systematic review is to evaluate the benefits and harms of available interventions for HUS and TTP. MEDLINE (1966 to June 2006), EMBASE (1980 to June 2006), the Cochrane Central Register, conference proceedings, and reference lists were searched to find randomized controlled trials (RCTs) of any intervention for HUS or TTP in patients of all ages selected for inclusion for this systematic review. Trials that compared an intervention with placebo, an intervention with supportive therapy, or one or more different interventions for HUS or TTP. For TTP trials, failure of remission at 2 weeks or less and at 1 month or longer, all-cause mortality rate, and relapse rate. For HUS trials, all-cause mortality, chronic reduced kidney function, and persistent proteinuria or hypertension at last follow-up. For TTP in adults, we found 6 RCTs of 331 patients. Two trials compared plasma infusion with plasma exchange using fresh frozen plasma and showed failure of remission at 2 weeks (2 trials, 140 patients; relative risk, 2.87; 95% confidence interval, 1.41 to 5.84), and all-cause mortality (relative risk, 1.91; 95% confidence interval, 1.09 to 3.33) occurred more frequently in the plasma infusion group. Three trials compared plasma exchange using cryosupernatant plasma with plasma exchange using fresh frozen plasma, and a meta-analysis of these trials showed no difference. Seven RCTs in 476 young children with postdiarrheal HUS have been conducted. None of the evaluated interventions (fresh frozen plasma transfusion, heparin with or without urokinase or dipyridamole, Shiga toxin-binding protein, and steroid) were superior to supportive therapy alone for any outcomes. Limitations of this review include the small number and suboptimal quality of reporting of included trials, possibility of publication bias, small number of participants with atypical HUS, and failure to report results for patients with atypical and typical HUS separately. No additional therapy has been shown to increase efficacy over plasma exchange for TTP. No intervention has been shown to be superior to supportive therapy in patients with postdiarrheal HUS.


Identification of direct targets and modified bases of RNA cytosine methyltransferases.
The extent and biological impact of RNA cytosine methylation are poorly understood, in part owing to limitations of current techniques for determining the targets of RNA methyltransferases. Here we describe 5-azacytidine-mediated RNA immunoprecipitation (Aza-IP), a technique that exploits the covalent bond formed between an RNA methyltransferase and the cytidine analog 5-azacytidine to recover RNA targets by immunoprecipitation. Targets are subsequently identified by high-throughput sequencing. When applied in a human cell line to the RNA methyltransferases DNMT2 and NSUN2, Aza-IP enabled >200-fold enrichment of tRNAs that are known targets of the enzymes. In addition, it revealed many tRNA and noncoding RNA targets not previously associated with NSUN2. Notably, we observed a high frequency of C→G transversions at the cytosine residues targeted by both enzymes, allowing identification of the specific methylated cytosine(s) in target RNAs. Given the mechanistic similarity of RNA cytosine methyltransferases, Aza-IP may be generally applicable for target identification.


Purification of IgM monoclonal antibody from murine ascitic fluid by a two-step column chromatography procedure.
Two IgM monoclonal antibodies (Mabs) were purified from murine ascitic fluid by a two-step procedure involving pseudoligand affinity chromatography on immobilized Cibacron Blue F3GA and gel filtration chromatography on ACA-22. The purified IgM from one ascites sample, H-1, was determined to be homogeneous by sodium dodecyl sulfate-polyacrylamide gel electrophoresis while ascites containing E3.1 IgM Mab, was purified to greater than 95% IgM. The retention of biological activity was confirmed by immunofluorescence staining of peripheral blood lymphocytes.


Sonography-based Automated Volume Count to estimate fetal urine production in twin-to-twin transfusion syndrome: comparison with Virtual Organ Computer-aided AnaLysis.
Sonography-based Automated Volume Count (SonoAVC) is an automated, operator-independent, 3-dimensional ultrasound technique. The study goal was to assess agreement between SonoAVC and Virtual Organ Computer-aided AnaLysis (VOCAL) for bladder volume measurements and fetal urine production (FUP). This was a prospective study of recipient bladder volumes in twin-to-twin transfusion syndrome acquired with SonoAVC and VOCAL every 2 minutes during 30 minutes before and 24 hours after laser coagulation. FUP formulas: (V(2) - V(1)) × 60/time interval in minutes; and slope of linear regression of ≥ 3 consecutively increasing bladder volumes × 60 minutes. Bland-Altman plots were used to compare techniques. In 38 pregnancies, 560 bladder measurements were acquired. Mean FUP was 7.29 mL/h (95% confidence interval, 5.66-8.92) using SonoAVC and 6.79 mL/h (95% confidence interval, 5.16-8.42) using VOCAL (P = .14). Limits of agreement were -0.20 to 0.22 cm(3). Fetal bladder volume and FUP measurements using SonoAVC were comparable to VOCAL. SonoAVC is operator independent, easy, and fast.


Ultrafast and Ultrahigh-Resolution Diffuse Optical Tomography for Brain Imaging with Sensitivity Equation based Noniterative Sparse Optical Reconstruction (SENSOR).
We introduce a novel image reconstruction method for time-resolved diffuse optical tomography (DOT) that yields submillimeter resolution in less than a second. This opens the door to high-resolution real-time DOT in imaging of the brain activity. We call this approach the sensitivity equation based noniterative sparse optical reconstruction (SENSOR) method. The high spatial resolution is achieved by implementing an asymptotic l 0-norm operator that guarantees to obtain sparsest representation of reconstructed targets. The high computational speed is achieved by employing the nontruncated sensitivity equation based noniterative inverse formulation combined with reduced sensing matrix and parallel computing. We tested the new method with numerical and experimental data. The results demonstrate that the SENSOR algorithm can achieve 1 mm3 spatial-resolution optical tomographic imaging at depth of ∼60 mean free paths (MFPs) in 20∼30 milliseconds on an Intel Core i9 processor.


Heavy metal phyto-accretion, biochemical responses and non-carcinogenic human health risks of genetically diverse wheat genotypes cultivated with sewage of municipal origin.
Current study explored the effects of municipal sewage (MS) irrigation on heavy metal phyto-accretion, biochemical responses and human health risks of diverse wheat genotypes along with recycled municipal sewage (RMS). Mean concentrations of PO43-, NO3--N, chemical oxygen demand, biological oxygen demand, K, Co, Cu, Cd, Cr and Ni were found higher in MS than irrigation criteria. This led to significant increase in heavy metal contents in roots, stem and grains of MS irrigated wheat genotypes compared to RMS and control treatments. No adverse health risk effects for individual or multiple metals were recorded in RMS irrigated wheat genotypes on grounds of lowest heavy metal accumulation. Multivariate techniques i.e. principal component analyses (PCA) and hierarchical agglomerative cluster analyses (HACA) identified tolerant (inefficient metal accumulators) and sensitive (efficient metal accumulators) wheat genotypes in MS and RMS. Tolerant wheat genotypes showed lowest accumulation of heavy metals, efficient biochemical mechanisms to combat oxidative stress and lower health risks to adults/children. Cultivation of identified tolerant wheat genotypes is recommended in areas receiving municipal wastes to reduce human and environmental health risks. Moreover, genetic potential of identified tolerant wheat genotypes from MS and RMS can be utilized in breeding heavy metal tolerant wheat germplasm worldwide.


A proteomic road to acquire an accurate serological diagnosis for human tegumentary leishmaniasis.
Diagnostic tools are important for clinical management and epidemiological evaluation of Tegumentary (TL) and Visceral (VL) Leishmaniasis. Serology is not frequently used for the diagnosis of the TL form because low antibody titers and cross-reaction with VL. Therefore, it is crucial to identify specific and immunogenic antigens from species associated with the TL form. Here we employed a proteomic approach coupled to an in silico analysis and identified the most abundant and immunogenic proteins from Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum. Of 16 species specific proteins, nine were from the species causative of the TL form (L. amazonensis and L. braziliensis). In silico analysis revealed 18 B-cell epitopes with 0% similarity to Trypanosoma cruzi orthologs and, therefore, less likely to crossreact with sera of patients with Chagas disease. Two proteins reacted exclusively with serum from TL patients and presented several B-cell epitopes without similarity to T. cruzi orthologs: the hypothetical protein GI 134063939 and the metallo-peptidase Clan MA(E)-Family M3. The immunoassay revealed nine peptides with strong reactivity to sera from TL patients. These proteins and peptides may be good candidates to improve the specificity and sensibility of serological tests aiming to diagnose the TL of this neglected human disease. As no gold-standard test for tegumentary leishmaniasis (TL) exists, a combination of different diagnostic techniques is often necessary to obtain precise results. Thus, the identification of species-specific, highly immunogenic and abundant proteins that stimulate the humoral immune response in the host should help in the development of serological tests for human TL. Herein we searched for these potential antigens in Leishmania species related to American Leishmaniasis (L. amazonensis, L. braziliensis and L. infantum). To this end, we employed an immunoproteomic approach using proteins from these Leishmania species and sera from TL and Visceral Leishmaniasis (VL) patients. Our study unveils specific proteins and peptides that may represent antigens that will help the efforts to improve the accuracy of serological tests to diagnose the TL form.


1. Methods are described for continuous laboratory cultivation of the pelagic freshwater copepod Cyclops vicinus. 2. The embryonic development is temperature dependent in a manner typical of cyclopids. Isolated egg-sacs show a slight tendency to accelerated development. 3. Increasing day length, increasing light intensity and decreasing temperature delay the process of molting throughout the whole development, in both sexes. In the copepodid-phase development is faster in males than in females. 4. Molting activity shows a maximum in the middle of the light phase and a second maximum at the beginning of the dark phase.


Amino Acid Export in Developing Arabidopsis Seeds Depends on UmamiT Facilitators.
Essential amino acids cannot be synthesized by humans and animals. They often are limiting in plant-derived foods and determine the nutritional value of a given diet. Seeds and fruits often represent the harvestable portion of plants. In order to improve the amino acid composition of these tissues, it is indispensable to understand how these substrates are transported within the plant. Amino acids result from nitrogen assimilation, which often occurs in leaves, the source tissue. They are transported via the vasculature, the xylem, and the phloem into the seeds, the so-called sink tissue, where they are stored or consumed. In seeds, several tissues are symplasmically isolated, i.e., not connected by plasmodesmata, channels in the cell walls that enable a cytoplasmic continuum in plants. Consequently, amino acids must be exported from cells into the apoplast and re-imported many times to support seed development. Several amino acid importers are known, but exporters remained elusive. Here, we characterize four members of the plant-specific UmamiT transporter family from Arabidopsis, related to the amino acid facilitator SIAR1 and the vacuolar auxin transporter WAT1. We show that the proteins transport amino acids along their (electro)chemical potential across the plasma membrane. In seeds, they are found in tissues from which amino acids are exported. Loss-of-function mutants accumulate high levels of free amino acids in fruits and produce smaller seeds. Our results strongly suggest a crucial role for the UmamiTs in amino acid export and possibly a means to improve yield quality.


OmpA of Klebsiella pneumoniae ATCC 13883 induces pyroptosis in HEp-2 cells, leading to cell-cycle arrest and apoptosis.
Klebsiella pneumoniae is an opportunistic pathogenic bacterium that commonly causes pneumonia in elderly people. OmpA, a toxin that is highly expressed in the outer membrane of the bacterium, is one of the primary factors implicated in the pulmonary pathogenesis of K. pneumoniae. To evaluate the associated pyroptosis mechanism of infection, the ompA gene was cloned, and the protein was expressed, extracted, and used to treat human larynx epithelial cells. We observed that OmpA induces reactive oxygen species production and cell-cycle arrest in the G2/M phase in host cells, leading to subsequent apoptosis. Moreover, OmpA was found to induce IL-1β and IL-18 production in host cells, resulting in caspase-1 activation, which simultaneously stimulated pyroptosis, thus leading to the death of the host cells. We next sought to examine differential gene expression via RNA sequencing to better elucidate the mechanisms associated with these cellular changes, and found that genes associated with these pathways were more highly expressed in OmpA-treated cells than in K. pneumoniae-infected cells. Thus, cell-cycle arrest, apoptosis, and pyroptosis may serve as the primary defenses employed by host cells against OmpA. These results provide novel insights into the host defense against K. pneumoniae infection.


MR imaging characteristics of uveal melanoma with histopathological validation.
To evaluate the magnetic resonance imaging (MRI) characteristics of uveal melanoma (UM), to compare them with fundoscopy and ultrasound (US), and to validate them with histopathology. MR images from 42 UM were compared with US and fundoscopy, and on 14 enucleated cases with histopathology. A significant relationship between the signal intensity on T1 and pigmentation on histopathology was found (p=0.024). T1 hyperintense UM were always moderately or strongly pigmented on histopathology, while T1-hypointense UM were either pigmented or non-pigmented. Mean apparent diffusion coefficient (ADC) of the UM was 1.16 ± 0.26 × 10-3 mm2/s. Two-thirds of the UM had a wash-out and the remaining a plateau perfusion time-intensity curve (TIC). MRI was limited in evaluating the basal diameter of flat tumors. US tends to show larger tumor prominence (0.5mm larger, p=0.008) and largest basal diameter (1.4mm larger, p<0.001). MRI was good in diagnosing ciliary body involvement, extrascleral extension, and optic nerve invasion, but limited on identifying scleral invasion. An increase of tumor prominence was associated with lower ADC values (p=0.030) and favored a wash-out TIC (p=0.028). An increase of tumor ADC correlated with a plateau TIC (p=0.011). The anatomical and functional MRI characteristics of UM were comprehensively assessed. Knowing the MRI characteristics of UM is important in order to confirm the diagnosis and to differentiate UM from other intra-ocular lesions and because it has implications for treatment planning. MRI is a good technique to evaluate UM, being only limited in case of flat tumors or on identifying scleral invasion.


Probing the interaction of cephalosporin antibiotic "cefoperazone" with lysozyme using spectroscopic and in silico methods: Effect of paracetamol on binding.
The interaction of lysozyme with cefoperazone was studied by means of spectroscopic and computational approaches. The change in the UV-visible spectrum of lysozyme in presence of cefoperazone was an indication of the complex formation between them. Fluorescence spectroscopy suggested that there was a fair interaction between the protein and drug which was taken place via dynamic quenching mechanism and the binding ratio was approximately 1:1. The binding was energetically feasible and principally supported by the hydrophobic forces. CD spectroscopic studies have shown that cefoperazone induced the secondary structure of lysozyme by increasing the α-helical contents of the latter. In silico studies revealed that the large nonpolar cavity was the preferred binding site of cefoperazone within lysozyme and the interaction was taken place mainly through hydrophobic forces with small involvement of hydrogen bonding and electrostatic interactions which is in good agreement with the experimental analyses. Effect of paracetamol was also seen on the binding and it was found that paracetamol had a negative influence on the binding between cefoperazone and lysozyme.


Blast effect on the lower extremities and its mitigation: a computational study.
A series of computational studies were performed to investigate the response of the lower extremities of mounted soldiers under landmine detonation. A numerical human body model newly developed at Wayne State University was used to simulate two types of experimental studies and the model predictions were validated against test data in terms of the tibia axial force as well as bone fracture pattern. Based on the validated model, the minimum axial force causing tibia facture was found. Then a series of parametric studies was conducted to determine the critical velocity (peak velocity of the floor plate) causing tibia fracture at different upper/lower leg angles. In addition, to limit the load transmission through the vehicular floor, two types of energy absorbing materials, namely IMPAXX(®) foam and aluminum alloy honeycomb, were selected for floor matting. Their performances in terms of blast effect mitigation were compared using the validated numerical model, and it has been found that honeycomb is a more efficient material for blast injury prevention under the loading conditions studied.


[Thorotrast carcinoma of the lung--contribution to the genesis of carcinoma after application of thorotrast and of old bullet wound (author's transl)].
A bronchogenic carcinoma was found in the sphere of the scar in a fifty-years-old man who suffered in 1945, 27 years before his death, from a pulmonary bullet wound caused by war influence. The histological examination furthermore disclosed considerable autoradiographic secured deposits of thorotrast in the carcinoma and scar sphere. One may suppose that in connection with the treatment of the results of this injury a bronchography or a preparation of the fistula followed. All available cases of a beginning of carcinoma after a pulmonary bullet wound as well as all cases of carcinoma of the lungs after thorotrast incorporation found in literature were collected, critically sorted out and represented in schedules. A summary of questions of the causes and pathogenesis is given.


Combined effects of disease management and food insecurity on physical and mental health in Korean adults.
The present study aimed to examine the combined effects of disease management and food insecurity on physical and mental health in a representative Korean population. A cross-sectional study. Data from the Korea National Health and Nutrition Examination Survey (KNHANES) 2012-2015. Adults aged ≥30 years (n 17 934) who participated in the KNHANES. Among health-care factors, unmet health-care needs and mental health counselling were different by food insecurity status, with a higher prevalence in adults with food insecurity. The prevalence of underweight was higher in men with food insecurity (5·9 %), whereas the prevalence of obesity was higher in women with food insecurity (37·4 %), than that in men and women with food security. Food insecurity was associated with a high risk of all mental health outcomes. For the combined effects of disease management and food insecurity, unmet health-care needs was related to increased risk of obesity for food-insecure men (Pinteraction = 0·029) and lack of participation in nutrition education or counselling was related to increased risk of obesity for food-insecure women (Pinteraction = 0·010). In addition, higher unmet health-care needs in adults with food insecurity was related to higher risk of mental health outcomes. Unmet health-care needs may exacerbate obesity for food-insecure men and mental health problems for both food-insecure men and women. In addition, lack of participation in nutrition education or counselling may exacerbate the obesity for food-insecure women.


[The usefulness of visual evoked potentials for the evaluation of visual pathways in children and adolescents with selected neuro-ophthalmological syndromes. (Summary of the doctor of medicine degree dissertation)].
Much study and care have been devoted to evaluated lesions of the visual pathway in children and adolescents with different neuroophthalmological disorders. The aim of the study was to determine the usefulness of visual evoked potentials (VEP) for evaluation of visual pathway in young patients with cerebral palsy, sclerosis multiplex and subacute sclerosing panencephalitis. During the research 63 healthy children and 78 pathological ones, between 5 and 18 years of age, were studied. First ophthalmological examination was performed and next VEPs were recorded. For poorly cooperative children, a flash on TV screen was used as a stimulus, and for normal mental children a pattern-reversal black and white checkboard was used. The comparison of VEP in normal healthy subjects and pathological ones was the last part of the investigation to evaluate visual system of patients. In all groups of patients, both with visual complains and without them, pathological results of VEP were found. The pathology of VEP were connected with shape, amplitudes and latencies of the peaks N75, P100, N145. The VEP is a good and objective method of diagnosis in neuroophthalmological patients, which supplies extra information about lesions of visual pathway. It allows to detect subclinical lesions. It is a noninvasive and painless diagnostical method and it can be repeated a few times in various periods of illness and even in poorly cooperative patients.


Gambling market and individual patterns of gambling in Germany.
In this paper individual patterns of gambling in Germany are estimated for the first time. The probit technique is used to test the influence of a set of individual characteristics on the probability of participating in each of the various legal games. A sample size of 1,586 adults collected for the pool of German lotteries provides a reliable set of data. All disaggregated estimations of participation are statistically significant at least at the 5 percent level. The basic findings suggest that gambling is a widespread normal (superior) consumption good because gambling participation tends to rise with income. Moreover, no demand anomaly can be found to justify assessing gambling as a social demerit. Only the participation in gaming machines is higher for younger, unemployed and less educated adults. While a moral evaluation of gambling is beyond the scope of this paper, the legislator's preference for a highly taxed state monopoly in gambling markets is to be rejected, at least for Germany. Additional statistical findings suggest distinct consumer perceptions of the characteristics of the various games and may be used for market segmentation. The paper starts with a descriptive introduction to the German gambling market.


Observations on bone formation and remodelling in advanced atherosclerotic lesions of human carotid arteries.
Immunolocalisation and histochemical techniques were used to examine mineralised bone deposits within late stage atherosclerotic plaques of human carotid arteries. These specimens showed characteristic features of osteogenesis. Large calcifications were often observed in close association with or integrated within mineralised bone. Smooth muscle cells (alpha-actin positive) were often located around osteoid-like matrix, together with focal accumulations of macrophages (CD68 and HAM56 positive). Local accumulations of mast cells (tryptase positive) were consistently observed in close association with the bone. Multinucleated giant cells in close apposition with mineralised bone demonstrated typical osteoclastic morphology, and were positively stained for acid phosphatase and the macrophage marker CD68. Thus, all the normal features of bone formation and resorption were observed in this microcosm of osteogenesis within atherosclerotic plaque; the term 'osteosome' seems appropriate for the structure. These osteosomes have numerous advantages for experimental studies of the various osteogenic factors responsible for bone metabolism, especially following short-term tissue culture. This ex vivo technique was used to demonstrate the distribution and the multiple cellular sources of bone morphogenetic protein 6.


[Anilides with analgesic and antipyretic activity].
Several trimethylcyclopentyl and trimethylcyclopentenyl acetanilides, mono- and di-substituted on the aromatic nucleus as well as the corresponding acyl derivatives from aniline it self and corresponding phenylacetanilides, were prepared and tested as analgesics and antipyretics. Several compounds exhibit considerable activity in some cases superior to that of acetanilide.


Compounds that induce autoimmunity in the brown Norway rat sensitize mast cells for mediator release and interleukin-4 expression.
Brown Norway (BN) rats given mercuric chloride (HgCl2), gold (Au) salts or D-penicillamine develop a T helper 2 (Th2) cell-mediated autoimmune syndrome. The recent observation of tissue injury within 24 h of HgCl2 treatment suggested the involvement of a non-T cell. We therefore examined the effect of these compounds on rat mast cells in vitro. Incubation of BN rat peritoneal mast cells with HgCl2 enhanced the release of serotonin in response to IgE cross-linking agents. Mast cells from Lewis rats, a strain not susceptible to the autoimmune syndrome in vivo, were affected to a lesser extent. The effect was observed with purified BN mast cells, suggesting a direct action. Similar effects were seen with D-penicillamine in the presence of copper ions, a combination that produces hydrogen peroxide, and Au. HgCl2 caused significant induction of interleukin (IL)-4 mRNA in mast cells from BN, but not Lewis rats. The data demonstrate a novel enhancing effect of a number of compounds on mast cell mediator release, and an inducing effect of HgCl2 on mast cell IL-4, expression. These findings are consistent with our hypotheses that mast cells may contribute to early tissue injury, and also, via production of IL-4, may initiate and/or augment, the Th2 response in the BN rat model of chemical-induced autoimmunity.


Diagnosis and management of out-of-hospital cardiac arrest secondary to coronary artery spasm.
The clinical features of coronary artery spasm as a cause of cardiac arrest were determined in a prospective study on out-of-hospital cardiac arrest (OHCA). Coronary angiography was performed at admission in 300 consecutive patients with no obvious non-cardiac cause of OHCA. In survivors with no or minimal coronary artery stenosis, a second angiography with provocation test and electrophysiological testing were performed at 1 month. Spasm was demonstrated in ten patients. Diagnosis was based upon (1) spontaneous spasm on the admission angiogram (3 patients), (2) transient significative ST-segment elevation at follow-up in patients with no or non-significant coronary artery lesions (4 patients) and (3) spasm during the 1 month provocation test (3 patients). Six patients survived at 1 month; spasm occurred during a new provocation test in five despite treatment with high dosage calcium channel blockers leading to coronary stenting in two, an internal cardiovertor defibrillator in one, and increased drug therapy with prolonged hospitalization in the remainder. At a mean follow-up of 55+/-27 months, no recurrent cardiac arrest occurred. Systematic coronary angiograms and provocation tests in survivors of OHCA allow prompt diagnosis of coronary artery spasm. Residual spasm despite treatment with calcium channel blockers is frequent. Therapy should therefore be guided by repetitive provocation tests, and seems to avoid recurrence of cardiac arrest.


Percutaneous left atrial appendage closure using the TrueFusion™ fusion-imaging technology.
To describe percutaneous left atrial appendage closure (LAAc) in a patient with recurrent gastric ulcer bleeding with the help of the TrueFusion™ fusion-imaging system. In a patient with paroxysmal atrial fibrillation, the need for an effective oral anticoagulation and recurrent gastrointestinal bleeding, left atrial appendage closure (LAAc) was performed under guidance of the TrueFusion™ fusion-imaging technology (Siemens Healthineers, Erlangen, Germany) to enhance procedural precision, save radiation time and contrast dye. Left atrial appendage closure was performed with the use of a 20 mm Amplatzer Amulet™ (Abbott Laboratories, Chicago, IL, USA) using the TrueFusion™ system under mild sedation with minimal use of contrast. Intraprocedural transesophageal echocardiography revealed complete LAA occlusion without residual flow. The patient was uneventfully discharged on the second postoperative day. LAAc using an integrated approach combining ultrasound and live fluoroscopy, as provided by the TrueFusion™, is safe and feasible. Target-oriented device navigation and synchronized image orientation as provided by fusion imaging may potentially be beneficial regarding radiation time, contrast dye and periprocedural risk of suboptimal device positioning.


Hemodynamic changes during a new procedure for regional chemotherapy involving occlusion of the thoracic aorta and inferior vena cava.
To describe the hemodynamic consequences of a regional chemotherapy procedure involving occlusion of the thoracic aorta and inferior vena cava (IVC) by intraluminal balloons. Prospective study. Operating rooms of an academic hospital. 10 patients with inoperable intraabdominal malignancy. After the induction of general anesthesia and the insertion of a pulmonary artery catheter the patients underwent the regional chemotherapy procedure. Occlusion of the thoracic aorta induced an increase in blood pressure (BP) and systemic vascular resistance (SVR) (41% +/- 8% and 80% +/- 15% from baseline, respectively), and a 30% +/- 7% decrease in cardiac output (CO). After aortic balloon deflation at the end of the procedure, we observed a decrease in BP to baseline values, decrease in SVR (to 62% +/- 12% below baseline), and increase in CO (to 80% +/- 15% above baseline). Those changes resemble those described during vascular surgery. Isolated occlusion of the IVC before aortic occlusion caused hemodynamic deterioration in only three of 10 patients, suggesting incomplete obstruction or collateral blood flow in others. Occluding the IVC while the aorta was occluded, caused minimal hemodynamic changes. Independent inflation of the IVC balloon should not be performed routinely because of possible unpredicted hemodynamic instability. Inferior vena cava occlusion should always be performed after complete aortic occlusion, because it is then that it produces negligible hemodynamic consequences. It is possible that a better assessment of IVC occlusion after balloon inflation needs to be done by contrast injection to prevent a possible leak of chemotherapeutic drugs.


Hypothermia-induced reduction in the permeation of radiolabelled tracer substances across the blood-brain barrier.
The permeability of the rat blood-brain barrier during different levels of hypothermia was examined using a new and more sensitive quantitative radiotracer technique. In contrast to the findings of previous studies, tracer permeation as measured here by the calculated cerebrovascular permeability-area product (PA), did not increase during hypothermia. Rather, rats maintained at specific temperatures between 30-16 degrees C (1 h) by contact surface cooling, displayed lowered permeation (PA) of i.v. injected 14C-sucrose, 125I-bovine serum albumin and 3H-alpha-amino-isobutyric acid in all brain regions examined. This effect was temperature-dependent and reversible on rewarming to normothermic temperature. Elevated plasma tracer concentration vs. time was characteristic of hypothermic rats except those cooled to 30 degrees C. That no elevation in plasma tracer accompanied alterations in tracer permeation at 30 degrees C, indicates hypothermic induced reductions in PA are independent of altered plasma tracer levels. Furthermore, the nature of alpha-amino-isobutyric acid to rapidly distribute to intracellular vs. extracellular sites suggests the effects of hypothermia seen here are due primarily to the condition of cerebrovascular membranes.


Reducing Dose Uncertainty for Spot-Scanning Proton Beam Therapy of Moving Tumors by Optimizing the Spot Delivery Sequence.
To develop and validate a novel delivery strategy for reducing the respiratory motion-induced dose uncertainty of spot-scanning proton therapy. The spot delivery sequence was optimized to reduce dose uncertainty. The effectiveness of the delivery sequence optimization was evaluated using measurements and patient simulation. One hundred ninety-one 2-dimensional measurements using different delivery sequences of a single-layer uniform pattern were obtained with a detector array on a 1-dimensional moving platform. Intensity modulated proton therapy plans were generated for 10 lung cancer patients, and dose uncertainties for different delivery sequences were evaluated by simulation. Without delivery sequence optimization, the maximum absolute dose error can be up to 97.2% in a single measurement, whereas the optimized delivery sequence results in a maximum absolute dose error of ≤11.8%. In patient simulation, the optimized delivery sequence reduces the mean of fractional maximum absolute dose error compared with the regular delivery sequence by 3.3% to 10.6% (32.5-68.0% relative reduction) for different patients. Optimizing the delivery sequence can reduce dose uncertainty due to respiratory motion in spot-scanning proton therapy, assuming the 4-dimensional CT is a true representation of the patients' breathing patterns.


Presbycusis.
The inevitable deterioration in hearing ability that occurs with age--presbycusis--is a multifactorial process that can vary in severity from mild to substantial. Left untreated, presbycusis of a moderate or greater degree affects communication and can contribute to isolation, depression, and, possibly, dementia. These psychological effects are largely reversible with rehabilitative treatment. Comprehensive rehabilitation is widely available but underused because, in part, of social attitudes that undervalue hearing, in addition to the cost and stigma of hearing aids. Remediation of presbycusis is an important contributor to quality of life in geriatric medicine and can include education about communication effectiveness, hearing aids, assistive listening devices, and cochlear implants for severe hearing loss. Primary care physicians should screen and refer their elderly patients for assessment and remediation. Where hearing aids no longer provide benefit, cochlear implantation is the treatment of choice with excellent results even in octogenarians.


Pelvic inflammatory disease in virginal adolescent females without tubo-ovarian abscess.
Pelvic inflammatory disease (PID) is an infection of the upper genital tract that is often caused by an ascending sexually transmitted infection. The complications of PID include pyosalpinx and tubo-ovarian abscess, infertility or ectopic pregnancy, and chronic pelvic pain of varying degrees. These sequelae underscore the importance of prompt diagnosis. We present 2 cases of PID in young women who denied any history of sexual activity or sexual abuse. Both cases were brought to the operating room with suspected appendicitis; however, laparoscopic evaluation revealed purulent fluid surrounding the pelvic organs. The literature is scant with respect to PID in the virginal patient. It is important to keep pelvic infection in the differential diagnosis of virginal patients who present with clinical symptoms of an acute abdomen.


Student self-evaluations: how useful? How valid?
Skill in self-evaluation is necessary for life-long learning, for competent performances--in short, for professional practice in the health sciences. In addition, self-evaluation skills can be learned and can be taught, although they are not now purposefully taught in most programs. There is research evidence that self-evaluation is more useful for learners as a formative rather than a summative tool. The purposes of this paper are (a) to provide a critical review of the literature on the accuracy of student self-evaluation and (b) to describe our experience and preliminary research findings at McMaster University regarding the most profitable approach to incorporating self-evaluation in baccalaureate nursing education.


Mass spectrometric-based assessment of the serum kappa to lambda immunoglobulin light chain ratio (κ:λ) in dogs with immunoglobulin secretory diseases.
The ratio of κ light chains to λ light chains (κ:λ) in serum is used as a biomarker of immunoglobulin secreting neoplasia in humans but has not been evaluated in dogs. A mass-spectrometry based method for determining the canine serum κ:λ was developed and used to evaluate samples from control dogs, dogs with an infectious aetiology, dogs with secretory plasma cell tumours (sPCT) and dogs with non-secretory B cell neoplasia. A human-targeted immunoturbidometric κ:λ assay and immunofixation using antisera targeting human κ light chain or λ light chain was also performed on all samples. Using whole serum samples, the MS-based κ:λ method identified 5 sPCT as κ-predominant (mean κ:λ = 3.307) and 5 sPCT as λ-predominant (mean κ:λ = 0.023) and documented differences between these groups and all other groups (p < 0.05 for all). The infectious aetiology group had a lower mean κ:λ ratio (mean κ:λ = 0.069) than control samples (mean κ:λ = 0.103, p = 0.035). Similar results were obtained when samples were enriched for proteins between 10 and 50 kDa using size exclusion chromatography, except for the statistical difference between the control and infectious aetiology group. All λ-predominant cases had only anti-human λ light chain labelling by immunofixation. Three κ-predominant cases had only anti-human κ-light chain labelling and the remaining two cases did not label with either antisera by immunofixation. The immunoturbidometric method had high analytical CV% (λ light chain CV = 13%, κ light chain CV = 50%), was unable to measure light chains in 20.5% of samples and did not distinguish groups. The data suggests that the human-targeted immunoturbidometric method would not be diagnostically useful and that the MS-derived serum κ:λ may be a useful biomarker of canine immunoglobulin secretory neoplasia which may have the ability to distinguish neoplasia from infectious causes of immunoglobulin secretion.


Prebiotic galacto-oligosaccharides mitigate the adverse effects of iron fortification on the gut microbiome: a randomised controlled study in Kenyan infants.
Iron-containing micronutrient powders (MNPs) reduce anaemia in African infants, but the current high iron dose (12.5 mg/day) may decrease gut Bifidobacteriaceae and Lactobacillaceae, and increase enteropathogens, diarrhoea and respiratory tract infections (RTIs). We evaluated the efficacy and safety of a new MNP formula with prebiotic galacto-oligosaccharides (GOS) combined with a low dose (5 mg/day) of highly bioavailable iron. In a 4-month, controlled, double-blind trial, we randomised Kenyan infants aged 6.5-9.5 months (n=155) to receive daily (1) a MNP without iron (control); (2) the identical MNP but with 5 mg iron (2.5 mg as sodium iron ethylenediaminetetraacetate and 2.5 mg as ferrous fumarate) (Fe group); or (3) the identical MNP as the Fe group but with 7.5 g GOS (FeGOS group). Anaemia decreased by ≈50% in the Fe and FeGOS groups (p<0.001). Compared with the control or FeGOS group, in the Fe group there were (1) lower abundances of Bifidobacterium and Lactobacillus and higher abundances of Clostridiales (p<0.01); (2) higher abundances of virulence and toxin genes (VTGs) of pathogens (p<0.01); (3) higher plasma intestinal fatty acid-binding protein (a biomarker of enterocyte damage) (p<0.05); and (4) a higher incidence of treated RTIs (p<0.05). In contrast, there were no significant differences in these variables comparing the control and FeGOS groups, with the exception that the abundance of VTGs of all pathogens was significantly lower in the FeGOS group compared with the control and Fe groups (p<0.01). A MNP containing a low dose of highly bioavailable iron reduces anaemia, and the addition of GOS mitigates most of the adverse effects of iron on the gut microbiome and morbidity in African infants. NCT02118402.


Human 8-oxoguanine DNA glycosylase increases resistance to hyperoxic cytotoxicity in lung epithelial cells and involvement with altered MAPK activity.
It is unknown whether base excision DNA repair (BER) proteins interact with mitogen-activated protein kinases (MAPK) under oxidation. Here, we explored roles of BER proteins in signaling transduction involving MAPK during hyperoxia. We demonstrated that ERK1/2 phosphorylation in A549 cells was increased in 95% O(2). p38 activity in A549 cells was also increased by exposure to 95% O(2). To evaluate regulatory roles of MAPK, we have transduced A549 cells and primary alveolar epithelial type II cells (AECII) to overexpress 8-oxoguanine DNA glycosylase (hOgg1). Overexpression of hOgg1 reduced hyperoxic toxicity in A549 and AECII cells. Furthermore, protection by BER against hyperoxia appeared to involve an upregulation of ERK1/2 and downregulation of p38. These observations demonstrate, for the first time, that reduction of hyperoxic toxicity by BER proteins may be involved with MAPK activity, thereby impacting cell survival. Furthermore, our studies suggest that modulation of MAPK may be used in combination with BER proteins to counteract hyperoxic toxicity.


Phasic firing enhances vasopressin release from the rat neurohypophysis.
1. Isolated rat neural lobes were incubated in vitro and electrically stimulated to release vasopressin. The released vasopressin was assayed using a radioimmunoassay and there was a reasonably good correlation (r = 0.81) between results obtained with this assay and those obtained by bioassay with the rat blood pressure method.2. Regular stimulation at frequencies of 5, 10 and 20 Hz released progressively more vasopressin and the release could be blocked by addition of tetrodotoxin to the incubation medium.3. Stimulation with pulse patterns derived from tape recordings of phasically firing units in the supraoptic nucleus of dehydrated rats released more vasopressin than the same number of pulses regularly spaced in time. In the range 2-8 pulses/sec vasopressin release was related to the pulse frequency within the bursts (r = 0.90) and the number of short (< 100 msec) interpulse intervals (r = 0.92). Vasopressin released per pulse increased over the frequency range 3-6 pulses/sec, but above 6 pulses/sec vasopressin release per pulse tended to diminish.4. We conclude that phasic firing of vasopressin neurosecretory cells may enhance vasopressin release in vivo and that an important factor in determining release is the number of short interspike intervals.


Aberrant carotid artery: radiologic diagnosis with emphasis on high-resolution computed tomography.
The authors here enumerate the high resolution CT findings they believe distinguish this lesion from other retrotympanic pulsatile masses.


Toxic effects of patulin on mouse oocytes and its possible mechanisms.
Patulin is a secondary metabolite mainly secreted by fungi and is the most common mycotoxin found in apples and apple-based products. For the past few years, numerous studies suggested the wide distribution and toxicity of patulin. In this study, we investigated the toxic effect of patulin on mouse oocytes and its possible mechanisms. The results showed that patulin treatment did not affect meiotic resumption, but inhibited oocyte maturation as indicated by failure of first polar body extrusion. Further mechanistic study showed that patulin treatment disturbed normal spindle assembly, chromosome alignment and morphology. We also found increased oxidative stress by testing the level of ROS and decreased mitochondrial membrane potential, indicating mitochondria dysfunction. In summary, our results suggest that patulin treatment causes oocyte meiotic arrest by disturbing normal spindle assembly and chromosome alignment, which may be caused by dysfunctions of mitochondria.


Imaging and Characterization of Macrophage Distribution in Mouse Models of Human Prostate Cancer.
Prostate carcinoma consists of tumor epithelium and malignant stroma. Until recently, diagnostic and therapeutic efforts have focused exclusively on targeting characteristics of the tumor epithelium, ignoring opportunities to target inflammatory infiltrate and extracellular matrix components. Prostate tumors are rich in tumor-associated macrophages (TAMs), which can be either of the cytotoxic M1 or protumorigenic M2 phenotype. We have quantified the proportion of each in seven common human prostate tumor lines grown subcutaneously in athymic nude mice and have imaged macrophage densities in vivo in xenografts derived from these lines. A panel of seven human prostate cancer xenografts was generated in intact male athymic nude mice reflecting variable expression of the androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Mice were imaged ex vivo using near-infrared fluorescence (NIRF) imaging for PSMA expression and total macrophage densities to enable direct comparison between the two. Tumors were harvested for sectioning and additional staining to delineate M1 and M2 phenotype along with vascular density. Macrophage polarization analysis of sections revealed that all xenografts were > 94% M2 phenotype, and the few M1-polarized macrophages present were confined to the periphery. Xenografts displaying the fastest growth were associated with the highest densities of macrophages while the slowest growing tumors were characterized by focal, tumor-infiltrating macrophage densities. Xenograft sections displayed a strong positive spatial relationship between macrophages, vasculature, and PSMA expression. Prostate TAM disposition can be imaged ex vivo and is associated with growth characteristics of a variety of tumor subtypes regardless of PSMA or AR expression.


Digalloylresveratrol, a new phenolic acid derivative induces apoptosis and cell cycle arrest in human HT-29 colon cancer cells.
Digalloylresveratrol (DIG) is a new synthetic ester of the naturally occurring polyhydroxyphenolic substances gallic acid and resveratrol which both exert anti-cancer activity in a number of tumor cell lines. The aim of the study was to identify the biochemical effects of DIG in HT-29 human colon cancer cells. DIG induced dose-dependently apoptosis after treatment for 72 h (40 microM DIG caused apoptosis in 45% of cells). DIG led to a substantial imbalance of deoxyribonucleoside triphosphates (dNTPs), the products of the enzyme ribonucleotide reductase (RR) and directly inhibited RR as it significantly reduced the incorporation of (14)C-labeled cytidine into the DNA of tumor cells. Furthermore, DIG affected the cell division and inhibited the transition from S to G2/M phase of the cell cycle. In contrast to resveratrol or gallic acid, DIG did not inhibit cyclooxygenases I and II. When HT-29 cells were simultaneously treated with DIG and 5-FU, the standard chemotherapeutic substance for colon cancer, additive growth inhibitory effects could be observed. With respect to the various biochemical and anti-proliferative effects of DIG in HT-29 cells, we regard DIG as a potential candidate for future treatment options of colon cancer and conclude that further preclinical and in vivo studies are warranted.


What Is the Rate of Displacement of Occult Posterior Malleolus Fractures in Nailed Tibial Shaft Fractures?
To describe the radiographic consequences of posterior malleolus fractures (PMF) present with tibial shaft fractures fixed with intramedullary nails. Retrospective cohort study. Level 1 trauma center. Seven hundred thirty-three patients with tibial shaft fractures. Intramedullary nail fixation and prophylactic articular fixation. Displacement of PMF with intramedullary nail insertion. Seven hundred thirty-three patients were identified with tibial shaft fractures treated with intramedullary nail fixation at a Level 1 trauma center without a uniform preoperative computed tomography protocol. One hundred thirty-three patients had an identifiable PMF appreciated on preoperative imaging. Of the 600 remaining patients without a known PMF, 29 had PMF identified after nail insertion: 24 patients with nondisplaced fractures that all healed radiographically at final follow-up, 3 patients had fractures <30% of the articular surface displaced 1-2 mm, and 2 patients had fractures >30% of the joint surface that displaced 1-2 mm. The incidence of radiographically observable PMF associated with tibial shaft fractures is high, even without a preoperative computed tomography screening protocol in place. In patients without an appreciable PMF on injury films, less than 1% (2/600) had displacement of a large, clinically significant PMF with nail placement. Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


High consumption rate by Neodiprion sertifer?-A comment on a paper by Larsson and Tenow.
In a recently published food utilization study of larvae of the European pine sawfly, Neodiprion sertifer (Larsson and Tenow, Oecologia (Berl) 43 (1979) 157-172), it was concluded that a high consumption rate was part of a suite of presumed adaptations exhibited by these larvae for feeding on a food with a low nitrogen content. In this note it is shown that larvae of N. sertifer exhibit a relative consumption rate which is comparable to that of other sawflies and intermediate in comparison to other herbivorous insects.


Lysosomal membrane stability and metallothioneins in digestive gland of Mussels (Mytilus galloprovincialis Lam.) as biomarkers in a field study.
The lysosomal membrane destabilization and the metallothionein content in the digestive gland cells of mussels (Mytilus galloprovincialis Lam.), collected along the east coast of the North Adriatic (Istrian and Kvarnerine coast, Croatia), were examined over a period of four years (1996-1999). The lysosomal membrane stability, as a biomarker of general stress, showed that the membrane labilization period in mussels from polluted, urban- and industrial-related areas was significantly decreased (p < 0.05) when compared to mussels from control, clean seawater sites. In the harbour of Rijeka, the most contaminated site, the lysosomal membrane stability was reduced by more than 70% compared to the control. This method also proved to be a useful biomarker for detection of additional stress caused by short-term hypoxia that occurred once during this study inside the polluted and periodically quite eutrophic Pula Harbour. The concentration of metallothioneins in the mussel digestive gland, as a specific biomarker of exposure to heavy metals, did not reveal significant differences (p < 0.05) between sites covered by this study.


Dosage Optimization of Digoxin in Older Patients with Heart Failure and Chronic Kidney Disease: A Population Pharmacokinetic Analysis.
Renal function is an important index for digoxin dose adjustment, especially in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is common in older patients with cardiovascular disease. The aim of this study was to establish a digoxin population pharmacokinetic model in older patients with heart failure and CKD and to optimize the digoxin dose strategy. Older patients with heart failure and CKD aged > 60 years from January 2020 to January 2021 and who had an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 or urine protein production were enrolled in this retrospective study. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using NONMEN software. The precision and stability of the final model were analyzed by graphical and statistical methods. Overall, 269 older patients with heart failure were enrolled. A total of 306 digoxin concentrations were collected, with a median value of 0.98 ng/mL (interquartile range [IQR] 0.62-1.61, range 0.04-4.24). The median age was 68 years (IQR 64-71, range 60-94) and eGFR was 53.6 mL/min/1.73 m2 (IQR 38.1-65.2, range 11.4-89.8). A one-compartment model with first-order elimination was developed to describe the digoxin pharmacokinetics. Typical values for clearance and volume of distribution were 2.67 L/h and 36.9 L, respectively. Dosage simulations were stratified by eGFR and metoprolol. Doses of 62.5 and 125 μg were recommended for older patients with eGFR < 60 mL/min/1.73 m2. A population pharmacokinetic model of digoxin in older patients with heart failure and CKD was established in this study. A novel digoxin dosage strategy was recommended in this vulnerable population.


Bipolar affective symptoms associated with use of captopril and abrupt withdrawal of pargyline and propranolol.
A woman with a family history but no personal history of depression developed bipolar symptoms associated with manipulations of her antihypertensive regimen. The author discusses hypotheses regarding the effects of these manipulations and the implications for treatment.


Complement activation in IgA nephropathy.
Activation of alternative complement pathway is presumed to be important pathogenically in IgA nephropathy since renal biopsies usually exhibit glomerular deposition of C3 and P (properdin). Surprisingly, little is known about plasma complement activation in this disease, and the plasma C3 and C4 concentrations are usually normal or increased. We quantitated C3 activation in 202 plasmas from 81 patients with IgA nephropathy using a sensitive new assay that detects a neoantigen [iC3b-C3d neoantigen) which appears when C3b is inactivated to iC3b, C3dg, or C3d. This assay accurately quantitates small amounts of in vivo C3 activation. The concentration of iC3b-C3d neoantigen in plasma was significantly increased, indicating C3 activation in 37% of the pediatric and 57% of the adult plasmas assayed. When data from serial determinations in the patients were analyzed, 75% of the adult and 57% of the pediatric patients had C3 activation on at least one occasion. Classical pathway activation, quantitated by C4 activation was found in 20% of the adult and 5% of the pediatric plasmas. No association was found between elevated iC3b-C3d neoantigen concentration and history of macroscopic hematuria, chronic renal insufficiency or degree of proteinuria. These studies show that complement activation can frequently be detected in the plasma of IgA nephropathy patients. However, the pathophysiologic significance of this complement activation remains to be determined.