Long-term forest resilience to climate change indicated by mortality, regeneration, and growth in semiarid southern Siberia.
Several studies have documented that regional climate warming and the resulting increase in drought stress have triggered increased tree mortality in semiarid forests with unavoidable impacts on regional and global carbon sequestration. Although climate warming is projected to continue into the future, studies examining long-term resilience of semiarid forests against climate change are limited. In this study, long-term forest resilience was defined as the capacity of forest recruitment to compensate for losses from mortality. We observed an obvious change in long-term forest resilience along a local aridity gradient by reconstructing tree growth trend and disturbance history and investigating postdisturbance regeneration in semiarid forests in southern Siberia. In our study, with increased severity of local aridity, forests became vulnerable to drought stress, and regeneration first accelerated and then ceased. Radial growth of trees during 1900-2012 was also relatively stable on the moderately arid site. Furthermore, we found that smaller forest patches always have relatively weaker resilience under the same climatic conditions. Our results imply a relatively higher resilience in arid timberline forest patches than in continuous forests; however, further climate warming and increased drought could possibly cause the disappearance of small forest patches around the arid tree line. This study sheds light on climate change adaptation and provides insight into managing vulnerable semiarid forests.


Prevalence, whole genome characterization and phylogenetic analysis of hepatitis B virus in captive orangutan and gibbon.
Hepatitis B virus (HBV) is a public health problem worldwide and apart from infecting humans, HBV has been found in non-human primates. We subjected 93 non-human primates comprising 12 species to ELISA screening for the serological markers HBsAg, antiHBs and antiHBc. Subsequently, we detected HBV DNA, sequenced the whole HBV genome and performed phylogenetic analysis. HBV infection was detected in gibbon (4/15) and orangutan (7/53). HBV DNA isolates from two gibbons and seven orangutans were chosen for complete genome amplification. We aligned the Pre-S/S, Pre-C/C and entire genomes with HBV sequences and performed phylogenetic analysis. The gibbon and orangutan viruses clustered within their respective groups. Both geographic location and host species influence which HBV variants are found in gibbons and orangutans. Hence, HBV transmission between humans and non-human primates might be a distinct possibility and additional studies will be required to further investigate this potential risk.


Total microvessel perimeter per tumor area is a predictor of radiosensitivity in early-stage glottic carcinoma.
To confirm that total number of microvessels per tumor area (TN/TA) and total microvessel perimeter per tumor area (TP/TA) are predictors for radiosensitivity in early-stage glottic carcinoma. One hundred twenty consecutive patients with T1-2N0M0 glottic cancer who were treated with radical radiotherapy in three different hospitals in Japan were included in this study. Biopsy specimens from patients were immunostained with anti-CD31 antibody. The TN/TA and TP/TA of each sample were analyzed using a computer-assisted image analysis system. Patients were stratified into high and low groups according to the cut-off values derived from receiver operating characteristic curve analysis. Progression-free survival rates of the different groups were compared. The relationship of microvessel perimeter to vessel maturation was also discussed. Survival analysis showed higher TP/TA to be associated significantly with longer progression-free survival, as compared with the lower-level group (p = 0.031). In multivariate analysis, both TP/TA (p = 0.037) and T stage (p < 0.001) proved to be independent predictive factors. Microvessel perimeter correlated closely with vessel maturity, which suggests that a tumor with high TP/TA contains more functional vessels and as a result contains more oxygenated and radiosensitive cells. Assessment of TP/TA in biopsy specimens, using a computer-assisted analysis system, can predict the radiosensitivity of early-stage glottic carcinoma. High TP/TA may be a better indication for radiotherapy than for partial laryngectomy or laser excision.


Application of geostatistical methods to arsenic data from soil samples of the Cova dos Mouros mine (Vila Verde-Portugal).
A total of 286 soil samples were collected in the Cova dos Mouros area. All samples were dry sieved into the <200 mesh size fraction and analysed for Fe, Cu, Zn, Pb, Co, Ni, Bi and Mn by atomic absorption spectrometry (AAS) and for As, Se, Sb and Te by atomic absorption spectrometry-hydrid generation (AAS-HG). Only the results of arsenic are discussed in this paper although the survey was extended to all analysed chemical elements. The purpose of this study was to make a risk probability mapping for arsenic that would allow better knowledge about the vulnerability of the soil to arsenic contamination. To achieve this purpose, the initial variable was transformed into an indicator variable using as thresholds the risk-based standards (intervention values) for soils, as proposed by [Swartjes 1999. Risk based assessment of soil and groundwater quality in the Netherlands: Standards and remediation. J. Geochem. Explor.73 1-10]. To account for spatial structure, sample variograms were computed for the main directions of the sampling grid and a spherical model was fitted to each sample variogram (arsenic variable and indicator variables). The parameters of the spherical model fitted to the arsenic variable were used to predict arsenic concentrations at unsampled locations. A risk probability mapping was also done to assess the vulnerability of the soil towards the mining works. The parameters of the spherical model fitted to each indicator variable were used to estimate probabilities of exceeding the corresponding threshold. The use of indicator kriging as an alternative to ordinary kriging for the soil data of Cova dos Mouros produced unbiased probability maps that allowed assessment of the quality of the soil.


Disulfiram accelerates diabetic foot ulcer healing by blocking NET formation via suppressing the NLRP3/Caspase-1/GSDMD pathway.
Diabetic foot ulcer (DFU) is among the most frequent complications of diabetes and is associated with significant morbidity and mortality. Excessive neutrophil extracellular traps (NETs) delay wound healing in diabetic patients. Therefore, interventions targeting NET release need to be developed to effectively prevent NET-based wound healing impairment. Gasdermin D (GSDMD), a pore-forming protein acts as a central executioner of inflammatory cell death and can activate inflammasomes in neutrophils to release NETs. A precise understanding of the mechanism underlying NET-mediated delay in diabetic wound healing may be valuable in identifying potential therapeutic targets to improve clinical outcomes. In this study, we reported that neutrophils were more susceptible to NETosis in diabetic wound environments of patients with DFU. By in vitro experiments and using in vivo mouse models of diabetic wound healing (wide-type, Nlrp3-/-, Casp-1-/-, and Gsdmd-/- mice), we demonstrated that NLRP3/caspase-1/GSDMD pathway on activation controls NET release by neutrophils in diabetic wound tissue. Furthermore, inhibition of GSDMD with disulfiram or genic deletion of Gsdmd abrogated NET formation, thereby accelerating diabetic wound healing. Disulfiram could inhibit NETs-mediated diabetic foot ulcer healing impairment by suppressing the NLRP3/Caspase-1/GSDMD pathway. In summary, our findings uncover a novel therapeutic role of disulfiram in inhibiting NET formation, which is of considerable value in accelerating wound healing in patients with DFU.


REM sleep deprivation increases preference for novelty in rats.
As a further test of the hypothesis that REM deprivation decreases fear, the behavior of 40 male rats was measured in a Y-maze adapted to test for preference for novelty. Prior to this test, the animals were exposed for 4 days to one of four treatments, i.e., either a dry environment control, a wet environment control, a 2-day REM deprivation period or a 4-day REM deprivation period. During the test both number of grid crossing in the novel and non-novel arms of the Y-maze and three indices of emotionality were recorded. The results were congruent with data we had reported earlier and offered convincing evidence in support of the hypothesis.


The questionable utility of mandatory screening for the human immunodeficiency virus.
Trauma patients have been identified as a high-risk group for human immunodeficiency virus (HIV) infection, particularly those patients with penetrating injuries from urban violence. We prospectively evaluated more than 2,000 trauma patients for HIV infection at our ACS-certified trauma center and report the results. Between September 1987 and December 1991, 2,004 patients were admitted to our trauma unit. All patients underwent HIV antibody assay by protocol. Three patients had positive test results, and all were confirmed as true positives. Two patients were known at the time of their trauma to be HIV positive, and the third had engaged in high-risk behavior. No health care worker reported inoculation with or mucosal exposure to HIV from any of these patients. In our trauma unit, the prevalence of HIV infection was only 0.15%. More than $74,000 was spent on screening without demonstrable benefit to the patients or increased protection for the trauma team. Routine testing of patients for HIV can be justified to establish epidemiologic parameters and in the case of high-risk groups, but it is not cost-effective in low-risk groups. Persistent testing of populations at low risk is a futile expenditure of precious health care dollars and is of questionable utility.


Slow binding kinetics of secreted protein, acidic, rich in cysteine-VEGF interaction limit VEGF activation of VEGF receptor 2 and attenuate angiogenesis.
VEGF-A (VEGF) drives angiogenesis through activation of downstream effectors to promote endothelial cell proliferation and migration. Although VEGF binds both VEGF receptor 1 (R1) and receptor 2 (R2), its proangiogenic effects are attributed to R2. Secreted protein, acidic, rich in cysteine (SPARC) is a matricellular glycoprotein thought to inhibit angiogenesis by preventing VEGF from activating R1, but not R2. Because R2 rather than R1 mediates proangiogenic activities of VEGF, the role of human SPARC in angiogenesis was reevaluated. We confirm that association of SPARC with VEGF inhibits VEGF-induced HUVEC adherence, motility, and proliferation in vitro and blocks VEGF-induced blood vessel formation ex vivo. SPARC decreases VEGF-induced phosphorylation of R2 and downstream effectors ERK, Akt, and p38 MAPK as shown by Western blot and/or phosphoflow analysis. Surface plasmon resonance indicates that SPARC binds slowly to VEGF (0.865 ± 0.02 × 10(4) M(-1) s(-1)) with a Kd of 150 nM, forming a stable complex that dissociates slowly (1.26 ± 0.003 × 10(-3) s(-1)). Only domain III of SPARC binds VEGF, exhibiting a 15-fold higher affinity than full-length SPARC. These findings support a model whereby SPARC regulates angiogenesis by sequestering VEGF, thus restricting the activation of R2 and the subsequent activation of downstream targets critical for endothelial cell functions.


Determination of factors affecting the vaccination status of children aged 12-35 months in Lao People's Democratic Republic.
Vaccines are one of the most important achievements in public health, and a major contributor to this success is the Expanded Programme on Immunization. The utilisation of vaccination services and completion of the recommended schedule are determined by numerous factors. In Lao People's Democratic Republic (Lao PDR), the overall immunisation coverage has been improving. However, notwithstanding the improvement in immunisation coverage and the supplementary immunisation activities, there have been measles, diphtheria, and polio outbreaks in the country. The recent multicounty study of household health surveys revealed that the within-country economic-related inequality in the delivery of a vaccine was still high in Lao PDR. Our previous work evaluated the factors associated with vaccination status among the children aged 5-9 years old, which was older age group for this type of study. This study evaluated factors that affect vaccination status among children aged between 12 and 35 months. It is a nationwide population-based cross-sectional study that used data obtained through multistage cluster sampling. We found that the proportion of infants who were fully immunised was lower than the national target and that "maternal ethnicity" (odds ratio (OR) 0.34, 95% confidence interval [CI]: 0.20-0.60), "paternal education" (OR 1.87, 95% CI: 1.12-3.10), and "source of information about vaccination date by medical staff" (OR 1.65, 95% CI: 1.01-2.71) were significantly associated with the children's vaccination status. Numerous factors are associated with the completion of the recommended vaccine schedule, and some factors are location-specific. Identification of these factors should lead to actions for facilitating the optimal use of vaccination services by all the children in Lao PDR.


Functional implication of autophagy in steroid-secreting cells of the rat.
Autophagy, while frequently observed in embryonic cells undergoing differentiation and in pathologically altered cells, appears to occur less commonly in normal, fully differentiated cells. Our previous work revealed that the frequency of autophagic activity was rather high in the Leydig cells of rat testes, but the functional significance of autophagy in Leydig cells remains obscure. The purpose of the present study is to investigate the possible role of autophagy in steroid-secreting cells. The autophagic activity was investigated in two steroid-secreting cells, e.g., Leydig cells and adrenocortical fasciculata cells of rats. Cytidine monophosphatase (CMPase) cytochemistry was utilized to show the activity of lysosomal enzymes in autophagosomes. Electron microscopic morphometry was employed to analyze the frequencies of autophagy in the cells of the rats intact or treated with related hormones resulting in a hyper- or hypo-secretion of testosterone and corticosterone. Autophagy took place in normal steroid-secreting cells with higher frequencies than in many other cells including the tubular cells of kidney and hepatocytes. The large number of autophagosomes or autophagic vacuoles allowed to outline the autophagic process in these cells. The C-shaped double-membrane profiles tending to demarcate a portion of cytoplasm were referred to as pre-autophagosomes. So-called early autophagosomes were the vacuoles enclosed completely by double delimiting membranes, containing normal-looking cellular components. The majority of sequestered organelles appeared to be mitochondria and smooth endoplasmic reticulum. The autophagosomes starting digestion were considered as late autophagosomes or autophagic vacuoles, the indications of which were the destruction of their contents or the presence of lysosomal enzymes demonstrated by a positive CMPase reaction. Residual bodies were frequently observed to be exocytosed. The quantitative assay revealed an alteration of autophagic activity in close relation with steroid-secreting states. The number of autophagosomes was one-fold higher in hyposecreting Leydig cells after 2 days testosterone administration, and three-fold higher in hyposecreting adrenocortical fasciculata cells after one dosage of dexamethasone administration. In addition, the autophagosomes showed a four-fold decrease in hypersecreting Leydig cells stimulated by LRH for 2 days. Considering that most of the autophagocytosed organelles were steroid-producing apparatus, we may conclude that, by removing part of steroid-producing organelles, autophagy might play a role in adapting to or even regulating the secretory activity. This hypothesis was strongly supported by the fact that the intensity of autophagy varied in company with the fluctuation of steroid secretion.


Identity of the holotype and type locality of Rhabdophis leonardi (Wall, 1923) (Colubridae: Natricinae), with notes on the morphology and natural history of the species in southwestern China.
The original description of Natrix leonardi (currently Rhabdophis leonardi) by Frank Wall in 1923, based on a specimen from the "Upper Burma Hills," lacked important morphological details that have complicated the assignment of recently collected material. Furthermore, although the holotype was never lost, its location has been misreported in one important taxonomic reference, leading to further confusion. We report the correct repository of the holotype (Natural History Museum, London), together with its current catalog number. We also describe key features of that specimen that were omitted from the original description, and provide new details on the morphology of the species, including sexual dichromatism unusual for the genus, based upon specimens from southern Sichuan, China. Rhabdophis leonardi is distinguished from its congeners by the following characters: 15 or 17 DSR at midbody and 6 supralabials; distinct annulus around the neck, broad and red in males, and narrow and orange with a black border in females; dorsal ground color light green or olive; some lateral and dorsal scales possessing black edges, the frequency of black edges gradually increasing from anterior to posterior, forming irregular and ill-defined transverse black bands; eye with prominent green iris; black ventral spots with a red edge, most numerous at midbody but extending halfway down the length of the tail. In southwestern China, this species is frequently found at 1730-2230 m elevation. It has been documented to prey upon anuran amphibians, including toads. A recently published phylogenetic analysis showed this species to be deeply nested with the genus Rhabdophis, as a member of the R. nuchalis Group. That analysis also revealed the existence of two closely related but geographically distinct subclades in the molecular analysis, one of which may represent an unnamed taxon.


Underestimation of Cirrhosis-Related Mortality in the Medicare Eligible Population, 1999-2018.
The burden of cirrhosis may be increasing, especially among the elderly. A recent updated definition of cirrhosis has a >90% positive predictive value for identifying cirrhosis and cirrhosis-related complications.1 We hypothesized that cirrhosis-related mortality is underestimated, and that the elderly are disproportionally impacted. In this study, we aimed to examine trends in liver-related mortality using this updated definition among the elderly and to identify changes by relevant subsets of gender, race, and rurality.


Comparison of nephroscopy and cystoscopy used in the treatment of bladder stones: a systematic review and meta-analysis of randomized controlled trials.
A systematic review and meta-analysis was conducted to compare the safety and efficiency of nephroscopy and cystoscopy in transurethral cystolithotripsy (TUCL) for bladder stones (BS). The PubMed, Web of Science, Embase, EBSCO, and Cochrane Library databases were searched up to January 2021 for studies assessing the effect of different types of endoscopes among patients who underwent TUCL. The search strategy and study selection process were in accordance with the PRISMA statement. Five randomized controlled trials were included in the meta-analysis. The results showed no difference in stone-free rate (RR = 1.00, CI = 0.98-1.02, p = 1.00) between the two groups and nonsignificant heterogeneity (I2 = 0%, p = 1.00), and all patients were rendered stone free. Use of the nephroscope significantly shortened the operative time compared with the cystoscope group (RR= - 26.26, CI = - 35.84 to - 16.68, p < 0.00001), and there was significant heterogeneity (I2= 87%, p < 0.00001). There was no significant difference in mean urethral entries (RR = 0.66, CI = - 0.71 to - 2.04, p = 0.35), hospitalization (MD = 0.08, 95% CI = - 0.07 to 0.23, p = 0.31) or total complication rate (RR=1.37, 95% CI = 0.47-4.00, p = 0.56) between the two groups. In conclusion, this systematic review demonstrates that both nephroscopy and cystoscopy have high stone clearance efficiency, low rates of complications and short hospitalizations. The mean urethral entries depend on the treatment method for large stone fragments. However, the use of nephroscopy can significantly reduce the operative time.


Contrast-agent-enhanced ultrasound thermal ablation.
The small thermal lesions induced when using high-intensity focused ultrasound (HIFU) to ablate tumors results in long treatment duration. In this study, the effect of using ultrasound contrast agent (UCA, Definity) to enhance the ultrasound (US) thermal effects and, thus to enlarge the lesion size, was studied in transparent tissue phantoms insonified by 1.85-MHz US with acoustical powers of 28.9 and 40.4 W. The experimental results show that the lesion size depended strongly on the electrical power and the concentration of UCA. UCA also reduced the power required to form a lesion of a certain size by about 30%. However, UCA moved the greatest heating position from the transducer focus, by 2.16 cm for 0.015% UCA at 40.4 W, and with lesions forming at the surface for UCA concentrations higher than 0.1%. An optimal result was obtained when using 0.001% UCA and 28.9-W US, which produced a lesion 12 times larger and an acceptable shift (less than half of the lesion length). UCA can effectively increase the size of the HIFU lesions, but lesion shift should be carefully considered while performing HIFU ablations.


An azophenolic colorimetric reagent for use in enzyme-linked immunosorbent assays.
A colorimetric reagent, 4-(4'-nitro-2'-methylsulfonylphenylazo)phenyl phosphate (NMPP), has been shown to be an effective substrate of alkaline phosphatase. NMPP and p-nitrophenyl phosphate were applied in comparative studies using enzyme immunoassays for the detection of viral antigens and antiviral antibodies. The new substrate exhibited similar, or even higher, sensitivity than p-nitrophenyl phosphate depending on the substrate concentrations used. Positive and negative reactions were easier to define, even without cumbersome equipment. The enzyme reaction was terminated by the uncompetitive inhibitor, theophylline.


Influence of biochars, compost and iron grit, alone and in combination, on copper solubility and phytotoxicity in a Cu-contaminated soil from a wood preservation site.
Two biochars, a green waste compost and iron grit were used, alone and in combination, as amendment to improve soil properties and in situ stabilize Cu in a contaminated soil (964mgCukg(-1)) from a wood preservation site. The pot experiment consisted in 9 soil treatments (% w/w): untreated Cu-contaminated soil (Unt); Unt soil amended respectively with compost (5%, C), iron grit (1%, Z), pine bark-derived biochar (1%, PB), poultry-manure-derived biochar (1%, AB), PB or AB+C (5%, PBC and ABC), and PB or AB+Z (1%, PBZ and ABZ). After a 3-month reaction period, the soil pore water (SPW) was sampled in potted soils and dwarf beans were grown for a 2-week period. In the SPW, all amendments decreased the Cu(2+) concentration, but total Cu concentration increased in all AB-amended soils due to high dissolved organic matter (DOM) concentration. No treatment improved root and shoot DW yields, which even decreased in the ABC and ABZ treatments. The PBZ treatment decreased total Cu concentration in the SPW while reducing the gap with common values for root and shoot yields of dwarf bean plants. A field trial is underway before any recommendation for the PB-based treatments.


Biofunctionalization of natural extracts, trends in biological activity and kinetic release.
The health benefits provided by plant matrices is due to the presence of certain compounds that, in studies carried out in vitro and in vivo, have shown to have biological activity in certain conditions, not only as a natural treatment against various conditions, but also for the quality of preventing chronic diseases, these compounds, already identified and studied, they can increase their biological function by undergoing structural chemical modifications or by being incorporated into polymer matrices that allow, in the first instance, to protect said compound and increase its bioaccessibility, as well as to preserve or increase the biological effects. Although the stabilization of compounds is an important aspect, it is also the study of the kinetic parameters of the system that contains them, since, due to these studies, the potential application to these systems can be designated. In this review we will address some of the work focused on obtaining compounds with biological activity from plant sources, the functionalization of extracts through double emulsions and nanoemulsions, as well as their toxicity and finally the pharmacokinetic aspects of entrapment systems.


Fluorescence examination and photodynamic therapy of facial squamous cell carcinoma--a case report.
To evaluate the usefulness and feasibility of fluorescence examination and photodynamic therapy (PDT) for facial squamous cell carcinoma. A 68-year-old male patient underwent 3 courses of PDT. The first treatment was carried out using topically applied 5-aminolevulinic acid (ALA) to the affected area (5.0 cm × 2.5 cm) 3h before light irradiation. ALA/PpIX-mediated fluorescence was used to visualize the lesion and its margin. The lesion was illuminated with a 630 nm laser at 120 J/cm². Thirty days later, the residual lesion received the second treatment at the same light dose after topical use of ALA. Despite the tumor was treated with two courses of PDT, The lesion was not cleared completely yet. At last we used topical ALA and intravenous injection of HiPorfin, with the same light dose, then the lesion was cured and the patient was tumor-free followed up for over 15 months. ALA/PpIX-mediated fluorescence visualized the lesion location. Complete cure was achieved after the third course of ALA/Hiporfin PDT. During the 15 months of followed up, no recurrence was noticed. ALA assisted fluorescence examination can be a useful tool to visualize the malignant lesion and determine its margin. ALA-PDT is effective for superficial lesions, but for thicker and deeper lesions, systemic administration of photosensitizer is indispensable.


Commentary on: "Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study." Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D. Bernard Escudier, Institut Gustave Roussy, Villejuif; Emmanuel Sevin, Centre François Baclesse, Caen; Sylvie Négrier, Leon Berard Cancer Center, Lyon, France; Camillo Porta, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico S. Matteo, Pavia; Cora N Sternberg, San Camillo Forlanini Hospital, Rome; Ugo De Giorgi, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; Petri Bono, Helsinki University Central Hospital, Helsinki, Finland; Thomas Powles, Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London; Tim Eisen, Cambridge University Health Partners, Cambridge; Omi Parikh, Royal Preston Hospital, Lancashire; Robert Hawkins, Christie Cancer Research UK, Manchester; Sadya Khan, Jose Diaz, and Faisal Mehmud, GlaxoSmithKline, Uxbridge, United Kingdom; Jürgen E Gschwend, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany; Suman Redhu, GlaxoSmithKline, Collegeville, PA; David Cella, Northwestern University Feinberg School of Medicine, Chicago, IL.: J Clin Oncol. 2014 May 10;32(14):1412-1418; doi: 10.1200/JCO.2013.50.8267. [Epub 2014 Mar 31].
Patient-reported outcomes may help inform treatment choice in advanced/metastatic renal cell carcinoma (RCC), particularly between approved targeted therapies with similar efficacy. This double-blind crossover study evaluated patient preference for pazopanib or sunitinib and the influence of health-related quality of life (HRQoL) and safety factors on their stated preference. Patients with metastatic renal cell carcinoma were randomly assigned to pazopanib 800mg per day for 10 weeks, a 2-week washout, and then sunitinib 50mg per day (4 weeks on, 2 weeks off, 4weeks on) for 10 weeks, or the reverse sequence. The primary end point, patient preference for a specific treatment, was assessed by questionnaire at the end of the two treatment periods. Other end points and analyses included reasons for preference, physician preference, safety, and HRQoL. Of 169 randomly assigned patients, 114 met the following prespecified modified intent-to-treat criteria for the primary analysis: exposure to both treatments, no disease progression before cross over, and completion of the preference questionnaire. Significantly more patients preferred pazopanib (70%) over sunitinib (22%); 8% expressed no preference (P<.001). All preplanned sensitivity analyses, including the intent-to-treat population, statistically favored pazopanib. Less fatigue and better overall quality of life were the main reasons for preferring pazopanib, with less diarrhea being the most cited reason for preferring sunitinib. Physicians also preferred pazopanib (61%) over sunitinib (22%); 17% expressed no preference. Adverse events were consistent with each drug׳s known profile. Pazopanib was superior to sunitinib in HRQoL measures evaluating fatigue, hand/foot soreness, and mouth/throat soreness. This innovative crossover trial demonstrated a significant patient preference for pazopanib over sunitinib, with HRQoL and safety as key influencing factors.


Rostral anterior cingulate volume predicts treatment response to cognitive-behavioural therapy for posttraumatic stress disorder.
To index the extent to which treatment response in posttraumatic stress disorder (PTSD) is predicted by rostral anterior cingulate cortex (rACC) volume. We used structural magnetic resonance imaging in a 1.5 T scanner to examine subjects with PTSD (n = 13), traumatized control subjects (n = 13) and nontraumatized control subjects (n = 13). Subjects with PTSD then participated in 8 sessions of cognitive-behavioural therapy, after which we reassessed them for PTSD. According to voxel-based morphometry, treatment responders had larger rACC volume than nonresponders. Further, symptom reduction was associated with larger rACC volume. Consistent with evidence for the neural bases of extinction learning, PTSD patients with larger rACC volume may be better able to regulate fear during cognitive-behavioural therapy and thus achieve greater treatment gains.


Polymorphisms of superoxide dismutase, glutathione peroxidase and catalase genes in patients with post-transplant diabetes mellitus.
Post-transplant diabetes mellitus (PTDM) is a metabolic disorder that develops in response to a relative insulin deficiency in patients after organ transplantation treated with immunosuppressive drugs. Several studies have suggested that oxidative stress may be associated with diabetes and its complications. The aim of this study was to examine the association of polymorphisms in superoxide dismutase, catalase and glutathione peroxidase genes with PTDM in patients after kidney transplantation. The study included 159 patients receiving kidney transplants. PTDM was diagnosed in 21 patients. Analyzing the C599T (Pro200Leu) polymorphism in the GPX1 gene PTDM was diagnosed in 8.45% of patients with CC genotype, 13.43% with CT and in 28.57% with TT. Allele T was significantly more frequent among patients with PTDM compared to patients without PTDM (OR = 2.14, 95% CI = 1.11-4.12, p = 0.024). There were no associations between SOD1, SOD2 and CAT polymorphisms and PTDM. The present results suggest that Pro200Leu polymorphism of the GPX1 gene may be associated with the risk of PTDM development in renal graft recipients.


Local excision of T1 colorectal cancer: good differentiation, absence of lymphovascular invasion, and limited tumor radial infiltration (≤4.25 mm) may allow avoiding radical surgery.
Early colorectal cancer (ECC) is defined as T1NXM0 colorectal cancer (CRC). Although a non-negligible number of T1-CRCs presents metastatic lymph-nodes, local excision is increasingly proposed as alternative to radical resection. Several criteria have been suggested to identify low-risk T1-CRC, but recommendations on this topic are still heterogeneous. This study aims to identify criteria associated with N+ T1-CRC, to select patients to undergo (or not) local excision. A retrospective analysis of demographic, clinical, and histology criteria of 122 consecutive T1-CRC patients undergoing radical resection at Parma University Hospital between 2000 and 2018 has been performed. Lymph-node metastasis (LNM) was observed in 15/122 patients (12.3%). No LNM was observed among well-differentiated (G1) tumors (0/37), while 10/65 (15.4%) G2 cases as well as 5/20 (25%) G3 patients presented LNM. G1 was associated with absence of LNM (p = 0.013). After excluding G1 patients, the rate of N + T1-CRC was 17.6% (15/85). LNM was observed in 4/8 (50%) patients with lymphovascular invasion (LVI) and in 11/77 (14.2%) without LVI. LVI resulted being associated with LNM (p < 0.042). LNM was reported in 28.3% of cases with a tumor infiltration >4.25 mm (13/46), compared to 5.1% in cases with an infiltration ≤4.25 mm (2/39) (p = 0.012). In Cox regression analysis, the higher hazard ratio (HR) was reported for the LVI + and infiltration >4.25 mm (HR 24.849). In patients with ECC (pT1NXM0), good differentiation (G1), absence of lymphovascular invasion (LVI-), and tumor radial infiltration ≤4.25 mm may allow performing local resection and avoiding radical surgery.


Light input pathways to the circadian clock of insects with an emphasis on the fruit fly Drosophila melanogaster.
Light is the most important Zeitgeber for entraining animal activity rhythms to the 24-h day. In all animals, the eyes are the main visual organs that are not only responsible for motion and colour (image) vision, but also transfer light information to the circadian clock in the brain. The way in which light entrains the circadian clock appears, however, variable in different species. As do vertebrates, insects possess extraretinal photoreceptors in addition to their eyes (and ocelli) that are sometimes located close to (underneath) the eyes, but sometimes even in the central brain. These extraretinal photoreceptors contribute to entrainment of their circadian clocks to different degrees. The fruit fly Drosophila melanogaster is special, because it expresses the blue light-sensitive cryptochrome (CRY) directly in its circadian clock neurons, and CRY is usually regarded as the fly's main circadian photoreceptor. Nevertheless, recent studies show that the retinal and extraretinal eyes transfer light information to almost every clock neuron and that the eyes are similarly important for entraining the fly's activity rhythm as in other insects, or more generally spoken in other animals. Here, I compare the light input pathways between selected insect species with a focus on Drosophila's special case.


Student perspectives on the diversity climate at a U.S. medical school: the need for a broader definition of diversity.
Medical schools frequently experience challenges related to diversity and inclusiveness. The authors conducted this study to assess, from a student body's perspective, the climate at one medical school with respect to diversity, inclusiveness and cross-cultural understanding. In 2008 students in the doctor of medicine (MD), physical therapy (PT) and physician assistant programs at a public medical school were asked to complete a diversity climate survey consisting of 24 Likert-scale, short-answer and open-ended questions. Questions were designed to measure student experiences and attitudes in three domains: the general diversity environment and culture; witnessed negative speech or behaviors; and diversity and the learning environment. Students were also asked to comment on the effectiveness of strategies aimed at promoting diversity, including diversity and sensitivity training, pipeline programs, student scholarships and other interventions. Survey responses were summarized using proportions and 95 percent confidence intervals (95% CI), as well as inductive content analysis. Of 852 eligible students, 261 (31%) participated in the survey. Most participants agreed that the school of medicine (SOM) campus is friendly (90%, 95% CI 86 to 93) and welcoming to minority groups (82%, 95% CI 77 to 86). Ninety percent (95% CI 86 to 93) found educational value in a diverse faculty and student body. However, only 37 percent (95% CI 30 to 42) believed the medical school is diverse. Many survey participants reported they have witnessed other students or residents make disparaging remarks or exhibit offensive behaviors toward minority groups, most often targeting persons with strong religious beliefs (43%, 95% CI 37 to 49), low socioeconomic status (35%, 95% CI 28 to 40), non-English speakers (34%, 95% CI 28 to 40), women (30%, 95% CI 25 to 36), racial or ethnic minorities (28%, 95% CI 23 to 34), or gay, lesbian, bisexual or transgendered (GLBT) individuals (25%, 95% CI 20 to 30). Students witnessed similar disparaging or offensive behavior by faculty members toward persons with strong religious beliefs (18%, 95% CI 14 to 24), persons of low socioeconomic status (12%, 95% CI 9 to 17), non-English speakers (10%, 95% CI 6 to 14), women (18%, 95% CI 14 to 24), racial or ethnic minorities (12%, 95% CI 8 to 16) and GLBT individuals (7%, 95% CI 4 to 11). Students' open-ended comments reinforced the finding that persons holding strong religious beliefs or conservative values were the most common targets of disparaging or offensive behavior. These data suggest that medical students believe that diversity and a climate of inclusiveness and respect are important to a medical school's educational and clinical care missions. However, according to these students, the institution must embrace a broader definition of diversity, such that all minority groups are valued, including individuals with conservative viewpoints or strong religious beliefs, the poor and uninsured, GLBT individuals, women and non-English speakers.


Semi-permeable Diffusion Barriers Enhance Patterning Robustness in the C. elegans Germline.
Positional information derived from local morphogen concentration plays an important role in patterning. A key question is how morphogen diffusion and gene expression regulation shape positional information into an appropriate profile with suitably low noise. We address this question using a model system--the C. elegans germline--whose regulatory network has been well characterized genetically but whose spatiotemporal dynamics are poorly understood. We show that diffusion within the germline syncytium is a critical control of stem cell differentiation and that semi-permeable diffusion barriers present at key locations make it possible--in combination with a feedback loop in the germline regulatory network--for mitotic zone size to be robust against spatial noise in Notch signaling. Spatial averaging within compartments defined by diffusion barriers is an advantageous patterning strategy, which attenuates noise while still allowing for sharp transitions between compartments. This strategy could apply to other organs.


Temporomandibular joint arthroscopy technique using a single working cannula.
The traditional arthroscopy technique includes the creation of three ports in order to enable visualization, operation, and arthrocentesis. The aim of this study was to assess an advanced temporomandibular joint (TMJ) arthroscopy technique that requires only a single cannula, through which a one-piece instrument containing a visualization canal, irrigation canal, and a working canal is inserted, as an alternative to the traditional double-puncture technique. This retrospective study assessed eight patients (13 TMJs) with pain and/or limited range of movement that was refractory to conservative therapy, who were treated between June 2015 and December 2015. The temporomandibular joint disorder (TMD) was diagnosed by physical examination and mouth opening measurements. The duration of surgery was recorded and compared to that documented for traditional arthroscopies performed by the same surgeon. Operative single-cannula arthroscopy (OSCA) was performed using a holmium YAG (Ho:YAG) 230μm fibre laser for ablation. The OSCA technique proved effective in improving mouth opening in all patients (mean increase 9.12±1.96mm) and in reducing pain (mean visual analogue scale decrease of 3.25±1.28). The operation time was approximately half that of the traditional technique. The OSCA technique is as efficient as the traditional technique, is simple to learn, and is simpler to execute.


Serum hormone levels in pre-menopausal Chinese women in Shanghai and white women in Los Angeles: results from two breast cancer case-control studies.
To assess whether risk of breast cancer in young women is associated with differences in luteal-phase hormone production and to attempt to explain differences in risk of breast cancer of young Shanghai Chinese and Los Angeles white women, two concurrent case-control studies of serum hormone concentrations were conducted. Both studies were carefully controlled for the possible confounding effects of age, weight, height, pregnancy history, and day of the menstrual cycle, by individually matching cases and controls on these factors. Case eligibility was limited to women with localized breast cancer. Sixteen of 39 Shanghai breast-cancer cases were sampled prior to the histologic diagnosis of their disease. The remaining 23 Shanghai cases and all 42 Los Angeles cases were diagnosed, and treated by surgery only, at least six months prior to hormonal evaluation. All subjects were sampled on day 22 of the menstrual cycle. Overall, cases had 13.5% higher serum estradiol concentrations (p = 0.038) with a case-to-control excess of 16.6% in Shanghai subjects (p = 0.089) and 10.8% in Los Angeles subjects (p = 0.23). There were no appreciable differences in amounts of sex-hormone binding globulin between cases and controls. Cases had lower progesterone levels than controls, but the situation was reversed when the analysis was restricted to subjects with evidence of ovulation. Los Angeles controls had 20.6% greater estradiol concentrations than Shanghai controls (p = 0.036); adjustment for body weight accounted for only 25.7% of this difference.(ABSTRACT TRUNCATED AT 250 WORDS)


Early arthroscopic treatment of primary traumatic anterior shoulder dislocation. A follow-up study.
This study evaluates the results of early arthroscopic Bankart repair in patients with primary traumatic anterior dislocation of the shoulder. The patients' age range was 17-34 years. Arthroscopic Bankart repair was performed within 12 days after the dislocation. First follow-up was at 18 months. According to Rowe's score, 11 patients (73%) were excellent, 3 (20%) were good and 1 (7%) was poor. The median external rotation deficit was 4 degrees in the adducted position. At a second follow-up at 34 months, two patients had redislocated. Both of these patients had severe generalized joint laxity. Another patient reported frequent subluxations. We conclude that in young patients with primary anterior traumatic shoulder dislocation, early arthroscopic Bankart repair implies a low recurrence rate and restores shoulder function to normal. Generalized joint laxity could indicate an increased risk for recurrent dislocation.


Minimal cobalt metabolism in the marine cyanobacterium Prochlorococcus.
Despite very low concentrations of cobalt in marine waters, cyanobacteria in the genus Prochlorococcus retain the genetic machinery for the synthesis and use of cobalt-bearing cofactors (cobalamins) in their genomes. We explore cobalt metabolism in a Prochlorococcus isolate from the equatorial Pacific Ocean (strain MIT9215) through a series of growth experiments under iron- and cobalt-limiting conditions. Metal uptake rates, quantitative proteomic measurements of cobalamin-dependent enzymes, and theoretical calculations all indicate that Prochlorococcus MIT9215 can sustain growth with less than 50 cobalt atoms per cell, ∼100-fold lower than minimum iron requirements for these cells (∼5,100 atoms per cell). Quantitative descriptions of Prochlorococcus cobalt limitation are used to interpret the cobalt distribution in the equatorial Pacific Ocean, where surface concentrations are among the lowest measured globally but Prochlorococcus biomass is high. A low minimum cobalt quota ensures that other nutrients, notably iron, will be exhausted before cobalt can be fully depleted, helping to explain the persistence of cobalt-dependent metabolism in marine cyanobacteria.


Percentiles of waist-to-sitting-height ratio and its relationship with obesity and elevated blood pressure among children and adolescents in Shandong, China.
Waist circumference (WC) and related anthropometric indices have been recognized as useful measures of abdominal obesity. However, little is known about the association of waist-to-sitting-height ratio (WSHtR) with obesity and elevated blood pressure (BP). Data for this study were obtained from a large cross-sectional survey of school children. A total of 6889 students (3438 boys and 3451 girls) aged 7-17 years participated in this study. Height, sitting height, weight, WC, triceps and subscapular skinfold thickness, systolic blood pressure (SBP), and diastolic blood pressure (DBP) of all participants were measured. WSHtR was calculated as WC divided by sitting height. The BMI cutoff points recommended by the Working Group on Obesity in China (WGOC) were used to define overweight and obesity. Relatively high BP status was defined as SBP and/or DBP greater than or equal to the 95th percentile for age and sex. WSHtR was positively correlated with BMI, skinfold thickness, SBP, and DBP in both boys and girls in all age groups (7-17 years). Children and adolescents with high WSHtR (≥75th) had a higher prevalence of overweight and obesity and a relatively high BP compared with their peers with low WSHtR (<25th). The prevalence of overweight plus obesity was 0.57 versus 90.91% for boys and 0.81 versus 61.03% for girls, and the prevalence of relatively high BP was 6.78 versus 31.35% for boys and 6.04 versus 22.18% for girls. Large WSHtR is associated with obesity and elevated BP. Our results suggest that WSHtR may be a new useful index for screening obesity and related health risks.


Augmented FLAMSA-Bu versus FluBu2 reduced-intensity conditioning in patients with active relapsed/refractory acute myeloid leukemia: an EBMT analysis.
Comparative data of fludarabine, cytarabine and amsacrine (FLAMSA) chemotherapy followed by busulfan (Bu)-based reduced-intensity conditioning (RIC) (FLAMSA-Bu) versus RIC regimens are lacking in patients with active relapsed/refractory (R/R) acute myeloid leukemia (AML) at the time of allogeneic hematopoietic stem cell transplantation (alloSCT). Here, we retrospectively analyzed outcomes after FLAMSA-Bu versus fludarabine/busulfan (FluBu2) conditioning in this patient population. A total of 476 patients fulfilled the inclusion criteria, of whom 257 received FluBu2 and 219 FLAMSA-Bu. Median follow-up was 41 months. Two-year non-relapse mortality (21%), graft-versus-host disease-free, relapse-free survival (24%) and chronic graft-versus-host disease (GVHD) (29%) were not statistically different between cohorts. FLAMSA-Bu was associated with lower 2-year relapse incidence (RI) (38 vs 49% after FluBu2, p = 0.004), and increased leukemia-free survival (LFS) (42 vs 29%, p = 0.001), overall survival (47 vs 39%, p = 0.008) and grades II-IV acute GVHD (36 vs 20%, p = 0.001). In the multivariate analysis, FLAMSA-Bu remained associated with lower RI (HR 0.69, p = 0.042), increased LFS (HR 0.74, p = 0.048) and a higher risk of acute GVHD (HR 2.06, p = 0.005). Notwithstanding the limitations inherent in this analysis, our data indicate that FLAMSA-Bu constitutes a tolerable conditioning strategy, resulting in a long-term benefit in a subset of patients reaching alloSCT with active disease.


Comparison of Validated Assessment Scales and 3D digital fringe projection method to assess lifetime development of wrinkles in men.
The assessment of wrinkle severity is an important evaluation criterion to determine the efficacy of aesthetic treatments. Aim of the present study was to compare Validated Assessment Scales (VAS) and 3D fringe projection (PRIMOS(®) ) for the evaluation of facial wrinkles in men and to determine standard values for each level of the VAS. 150 male subjects (20 to 70 years) were selected following strict criteria. Wrinkle severity at periorbital, glabella and forehead lines was evaluated using the 3D fringe projection and 5-point photonumeric VAS. The results of both methods were matched by determining quantitative values for each level of the clinical rating scale. High average correlation with age was found for VAS, Wd, maxWd, lWd, Wv, aWa and pWa. With a Wd of 60 to 70μm crow's feet and forehead lines are pronounced first, whereas glabella lines develop in subject's mid-forties, by an Wd of 180μm. Wrinkle severity increases at all locations every 10 years of age by one level of the VAS. This increase corresponds to an increase of Wd about 100 μm at glabella and forehead lines, and about 50 μm at crow's feet. The presented reference values for the Validated Assessment Scale are an important step towards an optimized assessment of skin aging and aesthetic dermatological treatments. The data helps to combine the precession of a biophysical measurement with the practical relevance of a clinical rating.


Mapping spoken language and cognitive deficits in post-stroke aphasia.
Aphasia is an acquired disorder caused by damage, most commonly due to stroke, to brain regions involved in speech and language. While language impairment is the defining symptom of aphasia, the co-occurrence of non-language cognitive deficits and their importance in predicting rehabilitation and recovery outcomes is well documented. However, people with aphasia (PWA) are rarely tested on higher-order cognitive functions, making it difficult for studies to associate these functions with a consistent lesion correlate. Broca's area is a particular brain region of interest that has long been implicated in speech and language production. Contrary to classic models of speech and language, cumulative evidence shows that Broca's area and surrounding regions in the left inferior frontal cortex (LIFC) are involved in, but not specific to, speech production. In this study we aimed to explore the brain-behaviour relationships between tests of cognitive skill and language abilities in thirty-six adults with long-term speech production deficits caused by post-stroke aphasia. Our findings suggest that non-linguistic cognitive functions, namely executive functions and verbal working memory, explain more of the behavioural variance in PWA than classical language models imply. Additionally, lesions to the LIFC, including Broca's area, were associated with non-linguistic executive (dys)function, suggesting that lesions to this area are associated with non-language-specific higher-order cognitive deficits in aphasia. Whether executive (dys)function - and its neural correlate in Broca's area - contributes directly to PWA's language production deficits or simply co-occurs with it, adding to communication difficulties, remains unclear. These findings support contemporary models of speech production that place language processing within the context of domain-general perception, action and conceptual knowledge. An understanding of the covariance between language and non-language deficits and their underlying neural correlates will inform better targeted aphasia treatment and outcomes.


Correction: Memory effects of climate and vegetation affecting net ecosystem CO2 fluxes in global forests.
[This corrects the article DOI: 10.1371/journal.pone.0211510.].


Ventilatory failure during resistive loaded breathing in the newborn primate.
Previous investigations have shown that ventilatory failure during severe inspiratory resistive loading (IRL) in the 21-day-old infant primate occurs secondary to a decrease in respiratory frequency, that is, central failure. To examine the response of the more immature newborn to IRL, minute ventilation (V'E), arterial blood gases and pH, minute diaphragmatic electromyogram (EMG) activity, peak inspiratory airway pressure, and the centroid frequency (Fc) of the diaphragmatic EMG power spectrum were measured in four unanesthetized tracheotomized 2-day-old monkeys during various levels of IRL, until either 1) ventilatory failure occurred (ventilatory failure run) or 2) normocapnia was sustained for 1 hr (successful trial). During successful trials, minute ventilation, breathing frequency, tidal volume, Fc, and PaCO2 were sustained at baseline levels and an increase in minute EMG activity and peak inspiratory airway pressure were observed. In contrast, during ventilatory failure runs, minute ventilation and tidal volume fell and PaCO2 rose compared to their respective baseline values. Respiratory frequency did not change. The decline in tidal volume occurred despite significant increases in minute diaphragmatic EMG activity and peak inspiratory airway pressure. No shifts in Fc were noted, suggesting that peripheral diaphragmatic fatigue did not occur. We conclude that ventilatory failure during IRL in the 2-day-old monkey is due to the animal's inability to defend tidal volume as opposed to central failure.


Comparison of the trapping effect and antioxidant enzymatic activities using three different light sources in cockchafers.
Light traps have been widely used for controlling underground pests. However, very little is known regarding the relationship between trapping effect and antioxidant enzymatic activities using light irradiation in underground pests. Thus, we determined the trapping effect of three light sources of the frequoscillation pest-killing lamp on two species of cockchafers, Serica orientalis Motschulsky (Coleoptera: Melolonthidae) and Anomala corpulenta Motschulsky (Coleoptera: Rutelidae), and evaluated the effect of the same three light sources on the activities of their antioxidant enzymes. The catches of S. orientalis were significantly higher compared to A. corpulenta using light source A in peanut fields in China. After irradiation by light source A, the malondialdehyde (MDA) contents and activities of superoxide dismutase (SOD) and glutathione S-transferases (GST) in S. orientalis were significantly and marginally significantly lower compared to A. corpulenta. Taken together, these results indicated a weaker antioxidant enzyme activity response to light stress and a larger quantity of trapping catches using light irradiation in cockchafers. Thus, we proposed a potential negative relationship between trapping effect and antioxidant enzymatic activities in response to light irradiation in cockchafers.


Acidic gases and nitrate and sulfate particles in the atmosphere in the city of Guadalajara, México.
Atmospheric concentrations of nitrous acid, nitric acid, nitrate and sulfate particles were obtained in this study from April to June 2008 in the center of the city of Guadalajara, while concentrations of ozone, sulfur dioxide, nitrogen dioxide and meteorological parameters (temperature and relative humidity), were acquired by the Secretaría del Medio Ambiente para el Desarrollo Sustentable del Estado de Jalisco (SEMADES). The results showed that nitric acid (2.7 μg m(-3)) was 2.7 times higher than nitrous acid (1.0 μg m(-3)). The sulfur dioxide (SO(2)) concentration indicated an opposite trend to sulfate (SO(4) (2-)), with the average concentration of SO(2) (6.9 μg m(-3)) higher in almost the entire period of study. The sulfur conversion ratio (Fs, 24.9%) and nitrogen conversion ratio (Fn, 6.2%), were revealed to be similar to that reported in other urban areas during warm seasons. It is also noted that ozone is not the main oxidizer of nitrogen dioxide and sulfur dioxide. This determination was made by taking into account the slightly positively correlation determined for Fn (r(2) = 0.084) and Fs (r(2) = 0.092) with ozone that perhaps suggests there are other oxidizing species such as the radical OH, which are playing an important role in the processes of atmospheric oxidation in this area.


Ischemia and reperfusion in skin flaps: effects of mannitol and vitamin C in reducing necrosis area in a rat experimental model.
The aim of the present study was to develop an experimental model of ischemia-reperfusion injury in rat skin flap and to verify the effect of mannitol and vitamin C on reducing necrosis area. A 6- x 3-cm groin skin flap was raised and submitted to 8 hours of ischemia by clamping the vascular pedicle and to 7 days of reperfusion. The animals were divided in four groups: S1 and S2 (10 animals each) and C and T (14 animals each). In groups S1 and S2 skin flaps were not submitted to ischemia and animals received lactated Ringer's solution (S1) and antioxidant solution (S2). In groups C and T, flaps were subjected to 8 hours of warm ischemia and animals received Lactated Ringer's solution (Group C) and antioxidant solution immediately before reperfusion, (Group T). Flap survival was evaluated on the seventh day using a paper template technique and computer-assistant imaging analysis of necrotic and normal areas. Statistical analysis showed no area differences between groups C and T. The experimental model provided consistent necrotic area in control groups and drugs used were not effective in improving skin flap survival.


Mineral oil (follicular) lipidosis: II. Histologic studies of spleen, liver, lymph nodes, and bone marrow.
Tissues obtained from 600 routine autopsies were studied. Mineral oil lipidosis was present in the spleen (76 per cent), liver (45 per cent), bone marrow (26 per cent), and lymph nodes; more than 50 per cent of the lymph nodes from the mesentery, porta hepatis, and mediastinum were affected. Mineral oil and its metabolic products produce a nonfibrogenic reaction in these tissues. The differential diagnosis of mineral oil lipidosis in lymph nodes with reaction to radiopaque oils and Whipple's disease is discussed. The presence of mineral oil in para-aortic (42 per cent) and internal iliac (15 per cent) lymph nodes could result in false-positive readings after lymphangiography.


Elevated phosphoglycerate kinase mRNA but not protein in monomorphic Trypanosoma brucei: implications for stage-regulation and post-transcriptional control.
Phosphoglycerate kinase (PGK) is present in high levels in the glycosomes of bloodstream stage Trypanosoma brucei, but is virtually absent in procyclic stage glycosomes. Glycosomes isolated from slender and stumpy stage bloodforms show similar levels of PGK, although levels are slightly lower in stumpy forms. Lower levels of glycosomal PGK transcripts are observed in stumpy form RNA, paralleling the decrease in glycosomal PGK activity. Monomorphic strains and pleiomorphic strains show similar glycosomal PGK activity, but monomorphic strains have much higher levels of the glycosomal PGK transcript. In three separate cases, predominantly monomorphic strains derived from highly pleiomorphic strains showed increased levels of glycosomal PGK (gPGK) mRNA. gPGK synthesis rates in monomorphic and pleiomorphic strains were similar, and no significant differences in turnover were observed. These data suggest the possibility of translational control of gPGK protein levels in trypanosome bloodforms. The data also indicate that the metabolism of gPGK mRNA in highly passaged laboratory strains is altered, and counsel caution when attributing differences in transcript levels to stage-specific regulation.


Radon measurements and dose estimate of workers in a manganese ore mine.
In the new European Basic Safety Standard (EU-BSS), a new reference level for indoor radon concentration in workplaces has recommended that the annual average activity concentration of indoor radon shall not be higher than 300Bqm-3. This paper describes the radon concentration level in an underground workplace (manganese ore mine) over long time intervals (4 years). Several common radon monitors devices - including NRPB and Raduet (as a passive method based on CR-39), AlphaGUARD PQ 2000Pro, SARAD EQF3220, TESLA and Pylon WLX (as active methods) - were used for continuous radon measurements. The output results were used, first, to comprised the result of each device, based on conditions present in underground mines; Second, to have comprehensive measurements about all factors that cause workers exposure to radiation (each monitoring device specified for a unique measurement). The results indicate that the mine's staff had successful efforts to reach the strict requirement of the new EU-BSS, and the average annual radon activity concentrations during the working hours were below 300Bqm-3 in the investigated period. The paper presents the effective dose calculations; applying different equilibrium factors suggested by the literature and calculated basing on our measurements at the site, concluding that the differences could be about threefold.


Empagliflozin suppresses inflammation and protects against acute septic renal injury.
Sepsis-induced systemic inflammation response syndrome is the leading cause of morbidity and mortality among patients in intensive care units in North America. While sepsis is associated with multiple organ damage, acute renal injury represents a hallmark of sepsis. Since systemic and renal inflammation is known to play a vital role in morbidity and mortality associated with sepsis, identifying a potent anti-inflammatory agent may help minimize morbidity and mortality associated with acute septic kidney injury. Since recent work has suggested that empagliflozin, a renal sodium-glucose cotransporter 2 (SGLT2) inhibitor, may assist in the treatment of inflammatory diseases, our objective was to examine the effect of empagliflozin on acute sepsis-induced renal injury. Mice were treated with three daily doses of empagliflozin or vehicle, with lipopolysaccharide (LPS) administered on the third day, at the same time as the third dose of empagliflozin or vehicle. In another cohort, mice were injected with a single dose of LPS 3 h before a dose of empagliflozin. Our results show that empagliflozin improves survival in a mouse model of LPS-induced septic shock. We further demonstrate that the beneficial effects of empagliflozin are likely mediated via reducing LPS-induced acute renal injury. Moreover, our data indicate that empagliflozin significantly reduces systemic and renal inflammation to contribute to the improvements observed in an LPS-model of acute septic renal injury. Overall, the findings of this study suggest that empagliflozin could be repurposed to reduce morbidity and mortality in patients with acute septic renal injury. Not applicable.


Statistical processing: not so implausible after all.
Myczek and Simons (2008) have shown that findings attributed to a statistical mode of perceptual processing can, instead, be explained by focused attention to samples of just a few items. Some new findings raise questions about this claim. (1) Participants, given conditions that would require different focused attention strategies, did no worse when the conditions were randomly mixed than when they were blocked. (2) Participants were significantly worse at estimating the mean size when given small samples than when given the whole display. (3) One plausible suggested strategy--comparing the largest item in each display, rather than the mean size--was not, in fact, used. Distributed attention to sets of similar stimuli, enabling a statistical-processing mode, provides a coherent account of these and other phenomena.


CoV-Spectrum: analysis of globally shared SARS-CoV-2 data to identify and characterize new variants.
The CoV-Spectrum website supports the identification of new SARS-CoV-2 variants of concern and the tracking of known variants. Its flexible amino acid and nucleotide mutation search allows querying of variants before they are designated by a lineage nomenclature system. The platform brings together SARS-CoV-2 data from different sources and applies analyses. Results include the proportion of different variants over time, their demographic and geographic distributions, common mutations, hospitalization and mortality probabilities, estimates for transmission fitness advantage and insights obtained from wastewater samples. CoV-Spectrum is available at https://cov-spectrum.org. The code is released under the GPL-3.0 license at https://github.com/cevo-public/cov-spectrum-website.


The paradox of matrix metalloproteinases in infectious disease.
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that perform multiple roles in the normal immune response to infection. MMPs facilitate leucocyte recruitment, cytokine and chemokine processing, defensin activation and matrix remodelling. However, excess MMP activity following infection may lead to immunopathology that causes host morbidity or mortality and favours pathogen dissemination or persistence. Here, we review the normal functions of MMPs in immunity and then discuss viral and bacterial infections where excess MMP activity has been implicated in pathology, specifically examining HIV, HTLV-1, hepatitis B, endotoxin shock, Helicobacter pylori and Mycobacterium tuberculosis. Tissue destruction may be exacerbated further by bacterial-derived enzymes which activate the host pro-MMPs. Finally, the potential for therapeutic targeting of excess MMP activity in infection is considered.


Circulating ovarian hormones interact with protein interacting with C kinase (PICK1) within the medial prefrontal cortex to influence cocaine seeking in female mice.
Protein interacting with C kinase 1 (PICK1) is an AMPA receptor binding protein that works in conjunction with glutamate receptor interacting protein (GRIP) to balance the number of GluA2-containing AMPARs in the synapse. In male mice, disrupting PICK1 in the medial prefrontal cortex (mPFC) leads to a decrease in cue-induced cocaine seeking and disrupting GRIP in the mPFC has the opposing effect, consistent with other evidence that removal of GluA2-containing AMPARs potentiates reinstatement. However, PICK1 does not seem to play the same role in female mice, as knockdown of either PICK1 or GRIP in the mPFC leads to similar increases in cue-induced cocaine seeking. These previous findings indicate that the role of PICK1 in the prefrontal cortex is sex specific. The goal of the current study was to examine whether ovarian hormones contribute to the effect of prefrontal PICK1 knockdown on reinstatement of cocaine seeking. While we replicated the increased cue-induced cocaine seeking in prefrontal PICK1 knockdown sham mice, we did not see any difference between the GFP control mice and PICK1 knockdowns following ovariectomy. However, this effect was driven primarily by an increase in cocaine seeking in ovariectomized GFP control mice while there was no effect ovariectomy in PICK1 knockdown mice. Taken together, these findings suggest that circulating ovarian hormones interact with the effects of PICK1 on cue-induced reinstatement.


Subjective and objective sleep and circadian parameters as predictors of depression-related outcomes: A machine learning approach in UK Biobank.
Sleep and circadian disruption are associated with depression onset and severity, but it is unclear which features (e.g., sleep duration, chronotype) are important and whether they can identify individuals showing poorer outcomes. Within a subset of the UK Biobank with actigraphy and mental health data (n = 64,353), penalised regression identified the most useful of 51 sleep/rest-activity predictors of depression-related outcomes; including case-control (Major Depression (MD) vs. controls; postnatal depression vs. controls) and within-case comparisons (severe vs. moderate MD; early vs. later onset, atypical vs. typical symptoms; comorbid anxiety; suicidality). Best models (of lasso, ridge, and elastic net) were selected based on Area Under the Curve (AUC). For MD vs. controls (n(MD) = 24,229; n(control) = 40,124), lasso AUC was 0.68, 95 % confidence interval (CI) 0.67-0.69. Discrimination was reasonable for atypical vs. typical symptoms (n(atypical) = 958; n(typical) = 18,722; ridge: AUC 0.74, 95 % CI 0.71-0.77) but poor for remaining models (AUCs 0.59-0.67). Key predictors across most models included: difficulty getting up, insomnia symptoms, snoring, actigraphy-measured daytime inactivity and lower morning activity (~8 am). In a distinct subset (n = 310,718), the number of these factors shown was associated with all depression outcomes. Analyses were cross-sectional and in middle-/older aged adults: comparison with longitudinal investigations and younger cohorts is necessary. Sleep and circadian measures alone provided poor to moderate discrimination of depression outcomes, but several characteristics were identified that may be clinically useful. Future work should assess these features alongside broader sociodemographic, lifestyle and genetic features.


Dispersive solid-phase extraction of racemic drugs using chiral ionic liquid-metal-organic framework composite sorbent.
Nowadays, enantioseparation of racemic pharmaceuticals in preparations is a prime concern by drug authorities across the globe. In the present work, it was attempted to develop novel enantioselective extraction method for five clinically used drugs (atenolol, propranolol, metoprolol, racecadotril, and raceanisodamine in their tablets) as racemates. The enantioselective solid-liquid extraction of these racemic drugs was carried out successfully by the use of chiral ionic liquid (CIL) in combination with a metal organic framework (MOF) for the first time. The composite CIL@MOF was synthesized from tropine based chiral ionic liquids with L-proline anion ([CnTr][L-Pro], n=3-6) and HKUST-1 type MOF, which was comprehensively characterized before being used as sorbent for enantioselective dispersive solid-liquid extraction. Preliminary selection of appropriate CIL was carried out on thin layer chromatography (TLC); under the joint participation of copper ion in the developing reagent, [C3Tr][L-Pro] ionic liquid showed better resolution performance with ΔRf value of 0.35 between the enantiomers was obtained for racemic atenolol. Moreover, the effect of copper salt dosage, amount of CIL, soli-liquid ratio and extraction time were investigated. The optimal conditions were obtained after thorough investigations; i.e. sample solution: ethanol, elution solvent: methanol, solid-liquid ratio: 12.5 mg:50 mL, amount of copper salt: 8 mg L-1, amount of impregnated CIL: 30% and extraction time of 30 min. As a result, enantiomeric excess values are 90.4%, 95%, 92%, 81.6% and 83.2% for atenolol, propranolol, metoprolol, racecadotril and raceanisodamine, respectively. The developed enantioselective method was validated following ICH guidelines and it was proved to be simple, effective and enantioselective way for separation of racemic pharmaceuticals with similar behaviors.


Electrophysiological responses in Amazonian fish species Bryconops caudomaculatus (Osteichthyes: Characiformes) as biomarkers of xenobiotic toxicity.
Sublethal exposures to environmental pollutants may cause changes in physiological parameters. Thus, knowledge of basal physiological rates of the species and the development of methods to quantify these rates are extremely important. Considering the scarcity of cardiac and muscle physiological studies in native Amazonian fish species and that no evaluation of electrophysiological responses by exposure to a stressor has been reported in Bryconops caudomaculatus, the aim of this study was to develop techniques of electromyographic and electrocardiographic recordings of normal responses, during toxicity induction and short-term recovery. A total of 9 animals were used, divided into two groups: control group (n = 4) and treated group (n = 5), with records lasting 5 min. The results showed that the basal electromyographic records indicate that the studied species has a very intense swimming activity, whereas the basal cardiac parameters clearly showed the patterns in P wave tracing, QRS complex, T wave and Q-T and R-R intervals. During exposure to the stressor, muscle activity ceased presenting intense decrease and myorelaxant effect expected. Electrocardiographic responses confirmed cardiotoxicity with intense bradycardia, ventricular bigeminism, prolongation of QRS complex duration and cardiac arrhythmias, indicating cardiac dysfunction. It was concluded that the electrophysiological responses are excellent biomarkers and showed the susceptibility of the species to the tested substance. In addition, the electrocardiogram and the electromyogram are excellent techniques to reflect the degree of environmental stress when organisms are exposed to toxic substances in the environment.


The UDP-glycosyltransferase (UGT) superfamily expressed in humans, insects and plants: Animal-plant arms-race and co-evolution.
UDP-glycosyltransferases (UGTs) are major phase II enzymes of a detoxification system evolved in all kingdoms of life. Lipophilic endobiotics such as hormones and xenobiotics including phytoalexins and drugs are conjugated by vertebrates mainly with glucuronic acid, by invertebrates and plants mainly with glucose. Plant-herbivore arms-race has been the major driving force for evolution of large UGT and other enzyme superfamilies. The UGT superfamily is defined by a common protein structure and signature sequence of 44 amino acids responsible for binding the UDP moiety of the sugar donor. Plants developed toxic phytoalexins stored as glucosides. Upon herbivore attack these conjugates are converted to highly reactive compounds. In turn, animals developed large families of UGTs in their intestine and liver to detoxify these phytoalexins. Interestingly, phytoalexins, exemplified by quercetin glucuronides and glucosinolate-derived isocyanates, are known insect attractant pigments in plants, and antioxidants, anti-inflammatory and chemopreventive compounds of humans. It is to be anticipated that phytochemicals may provide a rich source in beneficial drugs.


The acute toxicity of cadmium to different larval stages of Chironomus riparius (Diptera: Chironomidae) and its ecological significance for pollution regulation.
Acute toxicity tests using a static-with-replacement testing procedure were carried out with the four larval instars of the freshwater detritivore Chironomus riparius (Meigen). Median lethal concentrations (10, 24, 48 and 96 h LC50's) indicated great differences in sensitivity to cadmium between instars. Larvae became more tolerant with increasing age, the most resistant stage (fourth instar) having a 24 h LC50 of 2,400 mg Cd l-1, approximately 950 times greater than the corresponding value of 2.1 mg Cd l-1 recorded for the most sensitive (first instar) stage. These observations are discussed in relation to the establishment of water quality standards.


Controlled Donation After Circulatory Death Program: Analysis and Results at a Tertiary Care Hospital.
The objective of the study was to evaluate the impact in organs obtained and transplanted from controlled donation after circulatory death (cDCD). Transplants from cDCD donors performed at the Hospital Universitario Marqués de Valdecilla from the beginning of the program (December 2013) to December 2020 were evaluated. All procedures were performed with normothermic regional perfusion. Donors after brain death (DBDs) during the same period were used as a control group. A total of 95 donors after cardiac death and 152 DBDs were included. Age was similar in both groups (60 years [IQR, 53-68 years vs 62 years {IQR, 51-79 years]; P = .390). The number of organs recovered per donor was higher in the DBD group (4 [IQR, 3-5] vs 3 [IQR, 2-4], P < .001], as well as the number of transplanted organs (4 [IQR, 2-4] vs 2 [IQR, 2-4]; P = .002]. However, the number of noneffective donors was similar. DBDs presented a higher rate of liver donation (30.5% vs 46.7%; P = .012), lung donation (25.3% vs 38.2%; P = .036), and cardiac donation (1.1% vs 21.7%; P < .001) with respect to the donors after cardiac death group, but kidney and pancreatic donation were similar. The cDCD with normothermic regional perfusion program is fully established in our center. The age of the cDCD donor has increased with experience and it is currently identical to the control group (DBD). After overcoming the learning curve, cDCD is a multiorgan donation that presents an excellent profitability in the number of organs extracted and transplanted.


The spin filtering effect and negative differential behavior of the graphene-pentalene-graphene molecular junction: a theoretical analysis.
Density functional theory (DFT) combined with nonequilibrium Green's function (NEGF) formalism are used to investigate the effects of substitutional doping by nitrogen and sulfur on transport properties of AGNR-pentalene-AGNR nanojunction. A considerable spin filtering capability in a wide bias range is observed for all systems, which may have potential application in spintronics devices. Moreover, all model devices exhibit a negative differential effect with considerable peak-to-valley ratio. Thus, our findings provide a way to produce multifunctional spintronic devices based on nitrogen and sulfur doped pentalene-AGNR nanojunctions. The underlying mechanism for this interesting behavior was exposed by analyzing the transmission spectrum as well as the electrostatic potential distribution. In addition, a system doped with an odd number of dopant shows a rectifying efficiency comparable to other systems. The above findings strongly imply that such a multifunctional molecular device would be a useful candidate for molecular electronics. Graphical abstract The graphene-pentalene-graphene molecular junction.


Acute labyrinthine disorders.
A patient seeking emergency treatment for a labyrinthine disorder is usually complaining of dizziness. The task at hand in the emergency room is, first, to rule out the truly life threatening emergent disorders, and then by means of a rapid but adequate history and physical examination to aid in the differentiation between central and peripheral etiologies. If the problem is central, and especially if there are signs of a true emergency, there should be no hesitation in sharing the responsibility for the care of this patient with a neurologist or neurosurgeon. If one is convinced that the problem is of a peripheral etiology, one most likely is dealing with Meniere's disease, vestibular neuronitis, benign paroxysmal positional vertigo, or true labyrinthitis. An acoustic tumor must always be considered. Appropriate laboratory and x-ray studies may be initiated and therapy begun. Although the emergency room evaluation can be inclusive and accurate, it is necessarily incomplete. There is no substitute for a more thorough history and physical examination under more relaxed conditions, complete audiometry, electronystagmography, polytomography, myelography, angiography, or whatever additional sophisticated studies are deemed necessary. If performed well, however, the emergency room encounter forms an invaluable foundation upon which further diagnostic and treatment decisions are based.


Diabetes Self-Management Education and Medical Nutrition Therapy: A Multisite Study Documenting the Efficacy of Registered Dietitian Nutritionist Interventions in the Management of Glycemic Control and Diabetic Dyslipidemia through Retrospective Chart Review.
Diabetes self-management education (DSME) and medical nutrition therapy (MNT) improve glycemic control and reduce risk of chronic comorbid disease. Document outcomes for patients with type 2 diabetes (T2D) completing DSME and MNT through American Diabetes Association-recognized programs. Descriptive, retrospective chart review. Four random samples of 100 records of patients with T2D completing DSME and MNT at each of four regional centers in Alabama, June 2013 to 2014, were chosen for review; after exclusions, 392 records were retained. Weight, body mass index (BMI), hemoglobin A1c (HbA1c), total cholesterol, low-density lipoprotein, high-density lipoproteins (HDL), triglycerides (TG), and TG-to-HDL ratio. Mixed-model analysis of variance was used to determine differences between continuous variables. McNemar test was used to assess frequency of patients reaching glycemic targets. Paired t tests were used to determine significance of lipid parameters. Significant reductions were observed at end of program and 1 year in weight (2.67±5.54 kg, P<0.001; 2.25±5.45 kg, P=0.001), BMI (0.93±1.91, P<0.001; 0.76±1.93, P=0.001), and HbA1c (1.82%±2.23%, P<0.001; 1.22%±2.15%, P<0.001). Patients managed by diet alone had a mean baseline HbA1c of 6.95% and exhibited a 0.8% reduction in HbA1c (P<0.001) at end of program. Those managed with diet plus drug therapy had a baseline HbA1c of 9% and exhibited a 2.09% reduction in HbA1c (P<0.001). Following DSME and MNT, 62% of patients reached glycemic targets (HcA1c≤7%), as compared with 32% at baseline (P<0.001). Significant reductions in TG were observed from baseline (162±74 mg/dL [4.19±1.91 mmol/L]) to follow-up (109±36 mg/dL [2.82±0.92 mmol/L]) (P<0.001). HDL increased from baseline (45±13 mg/dL [1.16±0.34 mmol/L]) to follow-up (48±11 mg/dL [1.24±0.28 mmol/L]) (P=0.05). The TG-to-HDL ratio improved from a baseline of 4.07±2.41 to 2.48±1.26 at follow-up (P<0.001). Reductions were observed in weight, BMI, HbA1c, TG, and TG-to-HDL ratio. Improved patient outcomes were achieved in the clinical setting and support universal coverage to increase patient access to DSME and MNT.


Genomic organization analysis of acidophilic chemolithotrophic bacteria using pulsed field gel electrophoretic techniques.
The genomic organization of acidophilic chemolithotrophic bacteria belonging to the genus Thiobacillus, Thiomonas and Leptospirillum was studied using pulsed field gel electrophoresis techniques (PFGE). The electrophoretic analysis of intact DNA prepared from different strains showed that all have a circular chromosome, with sizes ranging from 1.9 Mb for Leptospirillum ferrooxidans ATCC 49879, the smallest genome for an acidophilic strict chemolithoautotrophic microorganism, to 3.8 Mb for Thiomonas cuprina DSM 5495, the largest in this study. The number of extrachromosomal elements present varied from none, as observed in several isolates of Leptospirillum ferrooxidan, to five in Thiobacillus thiooxidans ATCC 8085. The mixotroph Thiomonas cuprina DSM 5495 was found to have a linear 50 kb megaplasmid which was inducible when the bacteria was grown in chemolithotrophic conditions. Low-frequency restriction fragment analysis (LFRFA) of different acidophilic chemolithotrophs and related species was carried out by PFGE to determine macrorestriction patterns for rare cutters (SpeI, XbaI, SwaI, PmeI), which were then used for taxonomic identification (karyotyping), genome size determination, and generation of physical and genetic maps.


Value of programmed ventricular stimulation in presumed carotid sinus syndrome.
This study determines the results of programmed stimulation in patients with syncope or near-syncope presumed to have the carotid sinus syndrome based on the finding of carotid sinus hypersensitivity and the absence of any other apparent cause for syncope or near-syncope after clinical evaluation. Fourteen patients had coronary artery disease, 1 had dilated cardiomyopathy and 18 patients did not have structural heart disease. Programmed simulation was performed at 2 basic drive cycle lengths and 2 right ventricular sites with 1 to 3 extrastimuli. Sustained unimorphic ventricular tachycardia (VT) was induced in 5 of 15 patients who had structural heart disease, and in none of the 18 patients who did not (p less than 0.05). Polymorphic VT or ventricular fibrillation (VF) was induced in 5 of 15 patients (33%) who had structural heart disease, and in 5 of 18 patients (27%) who did not (p greater than 0.05). Patients who had inducible unimorphic VT were treated with antiarrhythmic drugs that suppressed the induction of VT, and 4 of 5 patients also received a pacemaker; no patient had a recurrence of syncope during follow-up. Patients who had inducible polymorphic VT and VF (n = 10) or no inducible VT (n = 18) received treatment directed at only carotid sinus syndrome. Two patients with inducible VT or VF and 1 patient without inducible VT had recurrent syncope during follow-up, but none had cardiac arrest or died suddenly.(ABSTRACT TRUNCATED AT 250 WORDS)


Thromboxane synthetase inhibition reduces ventricular irritability after coronary occlusion and reperfusion.
Reperfusion of ischemic tissue is responsible for production of metabolites with deleterious local vascular effects. Thromboxane A2, a potent vasoconstrictor and platelet aggregator, has been implicated as a mediator of the "reperfusion injury." We studied the effect of an experimental thromboxane synthetase inhibitor, OKY-046, on coronary sinus thromboxane levels, ventricular irritability, myocardial contractility, infarct salvage, and histologic features of reperfusion. Sixteen sheep were randomized to OKY-046, 3 mg/kg, or saline vehicle before 3-hour occlusion and subsequent reperfusion of the left anterior descending artery. The OKY group demonstrated less ventricular irritability as measured by incidence of ventricular fibrillation and necessity for countershock to reverse tachyarrhythmias. Coronary sinus thromboxane levels were significantly lower in the OKY group compared with the control group. There is additional evidence to suggest that OKY increases infarct salvage and attenuates histologic features of microcirculatory damage.


Three-dimensional ultrasound-guided placement of ventricular catheters.
Many studies demonstrate that the accuracy of freehand catheter placement for cerebrospinal fluid drainage is suboptimal. The aim of placement should be a single pass with a free-floating catheter tip in the intended position. The objective of this study was to achieve an accurate and user-friendly system for three-dimensional (3D) ultrasound-navigated catheter placement through a regular burr hole. A new phased-array ultrasound burr hole probe (4-10 MHz, 8 mm×9 mm footprint) was especially developed and optimized for navigated 3D ultrasound with the SonoWand Invite system. A catheter holder for optical tracking was also developed. Head immobilization was achieved with a vacuum cushion. With the described setup, 4 patients underwent surgery. Ultrasound image quality and visualization of the ventricles was good in all cases. Optimal placement of the catheter was achieved in a single pass in all patients. One of the trajectories was slightly more medial on postoperative computed tomography than anticipated from the neuronavigation system. None of the patients experienced any adverse event related to the procedure. 3D ultrasound with the described setup is a promising technique for accurate, fast, and user-friendly navigated placement of catheters for cerebrospinal fluid diversion.


Unilateral hydrothorax in small children on chronic continuous peritoneal dialysis.
Three small children whose weights were under 15 kg and who were on continuous ambulatory peritoneal dialysis or continuous cycling peritoneal dialysis developed massive unilateral hydrothorax. The occurrence of hydrothorax was late, 3-22 months after the initiation of dialysis. Two of the three fluid collections were left-sided. Each episode was preceded by retention of dialysate. After drainage of the hydrothorax a modified peritoneal dialysis regimen was successful in sustaining patients for a few weeks until further therapy for end-stage renal disease could be pursued.


Correction: Limited Clinical Utility of Remote Ischemic Conditioning in Renal Transplantation: A Meta-Analysis of Randomized Controlled Trials.
[This corrects the article DOI: 10.1371/journal.pone.0170729.].


B-type natriuretic peptide and survival in hypertrophic cardiomyopathy.
The aim of this study was to determine the relationship between B-type natriuretic peptide (BNP) and survival in patients with hypertrophic cardiomyopathy. Natriuretic peptides are released in response to neurohormonal activation, myocardial stretch, and wall tension and therefore reflect hemodynamic derangements. A total of 772 patients with hypertrophic cardiomyopathy had BNP obtained in conjunction with echocardiography and clinical evaluation, inclusive of cardiopulmonary exercise evaluation in 429 patients (56%). Survival free of all-cause mortality was lower across increasing levels of BNP (log-rank test, p = 0.002). Three-year survival by tertile was 99.2% (95% confidence interval: 94.3% to 99.9%; BNP level ≤98 pg/ml), 94.8% (95% confidence interval: 88.2% to 97.8%; BNP level, >98 to <298 pg/ml), and 89.9% (95% confidence interval: 82.0% to 94.5%; BNP level ≥298 pg/ml). Compared with patients in the first tertile, the hazard ratios for death in the second and third tertiles were 4.88 (p = 0.006) and 6.98 (p = 0.0003), respectively. This relationship persisted in patients without resting obstructive physiology (n = 497, p = 0.01). BNP levels were related to New York Heart Association functional status (p < 0.0001) and the subsequent need for septal reduction therapy in follow-up (p = 0.04). In this large cohort of patients with hypertrophic cardiomyopathy, BNP was an independent predictor of morbidity and mortality.


Biochemical and inhibition studies of glutamine synthetase from Leishmania donovani.
Leishmaniasis is a group of tropical diseases caused by protozoan parasites of the genus Leishmania. Leishmania donovani is a protozoan parasite that causes visceral leishmaniasis, a fatal disease if left untreated. Chemotherapy for leishmaniasis is problematic as the available drugs are toxic, costly and shows drug resistance, hence, there is a necessity to look out for the novel drug targets, chemical entities and vaccine. Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia. In the present study, we have identified and characterized GS from L. donovani. The nucleotide sequence encoding putative glutamine synthetase like sequence from L. donovani (LdGS, LDBPK_060370) was cloned. A 43.5 kDa protein with 6X-His tag at the C-terminal end was obtained by overexpression of LdGS in Escherichia coli BL21 (DE3) strain. Expression of native LdGS in promastigotes and recombinant L. donovani glutamine synthetase (rLdGS) was confirmed by western blot analysis. An increase in expression of GS was observed at different phases of growth of the parasite. Expression of LdGS in promastigote and amastigote was confirmed by western blot analysis. Immunofluorescence studies of both the promastigote and amastigote stages of the parasite revealed the presence of LdGS in cytoplasm. GS exists as a single copy gene in parasite genome. Kinetic analysis of GS enzyme revealed Km value of 26.3 ± 0.4 mM for l- glutamate and Vmax value of 2.15 ± 0.07 U mg-1. Present study confirms the presence of glutamine synthetase in L. donovani and provides comprehensive overview of LdGS for further validating it as a potential drug target.


Comprehensive analysis of cucumber C-repeat/dehydration-responsive element binding factor family genes and their potential roles in cold tolerance of cucumber.
Cold stress is one of the main abiotic stresses limiting cucumber (Cucumis sativus L.) growth and production. C-repeat binding factor/Dehydration responsive element-binding 1 protein (CBF/DREB1), containing conserved APETALA2 (AP2) DNA binding domains and two characteristic sequences, are key signaling genes that can be rapidly induced and play vital roles in plant response to low temperature. However, the CBF family has not been systematically elucidated in cucumber, and the expression pattern of this family genes under cold stress remains unclear. In this study, three CsCBF family genes were identified in cucumber genome and their protein conserved domain, protein physicochemical properties, gene structure and phylogenetic analysis were further comprehensively analyzed. Subcellular localization showed that all three CsCBFs were localized in the nucleus. Cis-element analysis of the promoters indicated that CsCBFs might be involved in plant hormone response and abiotic stress response. Expression analysis showed that the three CsCBFs could be significantly induced by cold stress, salt and ABA. The overexpression of CsCBFs in cucumber seedlings enhanced the tolerance to cold stress, and importantly, the transcript levels of CsCOR genes were significantly upregulated in 35S:CsCBFs transgenic plants after cold stress treatment. Biochemical analyses ascertained that CsCBFs directly activated CsCOR genes expression by binding to its promoter, thereby enhancing plant resistance to cold stress. This study provided a foundation for further research on the function of CsCBF genes in cold stress resistance and elucidating its mechanism.


Effect of ribavirin on Type 2 Herpesvirus hominis (HVH/2) in vitro and in vivo.
Ribavirin was found to inhibit five strains of HVH/2 tested in KB cells with the M1C range being 10-100 microgram/ml. In a mouse tail animal model, it effectively reduced HVH/2-induced lesions particularly at the peak lesion periods. Ribavirin was remarkably effective when intravaginal treatment was initiated late in the infection, which suggests that it may have potential for treatment of human cutaneous infections.


Naturally occurring erysipelas in rats.
Erysipelothrix rhusiopathiae was isolated from the main limb joints of two Sprague Dawley rats affected by spontaneous lesions of chronic fibrinopurulent polyarthritis, endocarditis and mycocarditis.


Safety and immunogenicity of Ad5-nCoV immunization after three-dose priming with inactivated SARS-CoV-2 vaccine in Chinese adults.
Data on the safety and immunity of a heterologous booster (fourth dose) after three-doses of inactivated SARS-CoV-2 vaccine in Chinese adults are limited. We evaluate the safety and immunogenicity of Ad5-nCoV in a randomized, double-blind, parallel-controlled phase 4 clinical trial in Zhejiang, China (NCT05373030). Participants aged 18-80 years (100 per group), administered three doses of inactivated SARS-CoV-2 vaccine ≥6 months earlier, are enrolled and randomized 1:1 into two groups, which are administered intramuscular Ad5-nCoV or inactivated SARS-CoV-2 vaccine (CoronaVac or Covilo). All observed adverse reactions are predictable and manageable. Ad5-nCoV elicits significantly higher RBD-specific IgG levels, with a geometric mean concentration of 2924.0 on day 14 post-booster, 7.8-fold that of the inactivated vaccine. Pseudovirus-neutralizing antibodies to Omicron BA.4/5 show a similar pattern, with geometric mean titers of 228.9 in Ad5-nCoV group and 65.5 in inactivated vaccine group. Ad5-nCoV booster maintains high antibody levels on day 90, with seroconversion of 71.4%, while that of inactivated vaccine is 5.2%, almost pre-booster levels. A fourth Ad5-nCoV vaccination following three-doses of inactivated SARS-CoV-2 vaccine is immunogenic, tolerable, and more efficient than inactivated SARS-CoV-2 vaccine. Ad5-nCoV elicits a stronger humoral response against Omicron BA.4/5 and maintains antibody levels for longer than homologous boosting.


Host-microbe interactions: shaping the evolution of the plant immune response.
The evolution of the plant immune response has culminated in a highly effective defense system that is able to resist potential attack by microbial pathogens. The primary immune response is referred to as PAMP-triggered immunity (PTI) and has evolved to recognize common features of microbial pathogens. In the coevolution of host-microbe interactions, pathogens acquired the ability to deliver effector proteins to the plant cell to suppress PTI, allowing pathogen growth and disease. In response to the delivery of pathogen effector proteins, plants acquired surveillance proteins (R proteins) to either directly or indirectly monitor the presence of the pathogen effector proteins. In this review, taking an evolutionary perspective, we highlight important discoveries over the last decade about the plant immune response.


Renal pseudotumor due to gas-filled hepatic flexure.
Renal pseudotumors--both intrinsic and extrinsic--are numerous. On a recent urogram, performed with abdominal pressure and tomography, a mass lesion was simulated by the gas-filled colon. The problem was resolved with a combination of ultrasonography, nephrotomography, and barium enema examinations.


PUMA: a puzzle piece in chloroquine's antimelanoma activity.
Chloroquine (CQ) can induce cell death in a subset of cancer cell lines, and some melanoma cell lines are quite susceptible. Although it is well known that CQ impairs lysosomal function and can serve as an autophagy inhibitor, the molecular target of CQ and the subsequent cascade of events that lead to cell death are not fully understood. Recent evidence indicates that in melanoma cell lines, CQ induces apoptosis by preventing degradation of the pro-apoptotic BH3-only protein p53-upregulated modulator of apoptosis. This finding adds to the unfolding story of CQ's mechanism of action as a cancer therapeutic agent.