Besnoitia tarandi in Canadian woodland caribou - Isolation, characterization and suitability for serological tests.
In the present study, we report the first in vitro isolation of Besnoitia tarandi from North America and the second of B. tarandi at all. The parasite was isolated directly from the skin of a Canadian woodland caribou from the migratory ecotype. The animal belonged to the Leaf River Herd, in Northern Quebec, Canada. The isolate was designated Bt-CA-Quebec1. Sequencing of the 3'-end of the 18S rRNA gene, the complete sequence of the ITS1 and the 5'-end of the 5.8S rRNA gene of Bt-CA-Quebec1 revealed only minor differences to rDNA gene fragments of B. besnoiti. In contrast, the patterns for the microsatellite loci Bt-20 and Bt-21 varied substantially from those reported for B. besnoiti and B. bennetti. Surprisingly, the typing results in the loci Bt-6 and Bt-7 differed between Bt-CA-Quebec1 and results obtained for skin samples from caribou of the Canadian regions of Nunavut and the Northwest Territories reported by other investigators. This indicates that differences might exist among B. tarandi in caribou from different regions in Canada. Mice (γ-interferon knockout) intraperitoneally inoculated with 1.2 × 106 or 1.5 × 106 bradyzoites mechanically released from skin tissue cysts fell ill 8, 9 or 18 days post inoculation. GKO mice inoculated with 3.0 × 104 tachyzoites isolated from the peritoneal cavity of a bradyzoites-inoculated mouse became ill earlier, i.e. 5 days post inoculation. Lung was the predilection site in all mice. Bt-CA-Quebec1 tachyzoites rapidly grew in MARC-145 cells and were used for antigen production. Comparative Western blot analyses revealed only a few differences between B. tarandi Bt-CA-Quebec1 and B. besnoiti Evora antigen when probed with sera collected from chronically infected caribou. Due to its fast growth in vitro, the Bt-CA-Quebec1 isolate may represent an interesting antigen source to establish B. tarandi-specific serological tools and to study the biology of this parasite species further.


Assessment of Viral Targeted Sequence Capture Using Nanopore Sequencing Directly from Clinical Samples.
Shotgun metagenomic sequencing (SMg) enables the simultaneous detection and characterization of viruses in human, animal and environmental samples. However, lack of sensitivity still poses a challenge and may lead to poor detection and data acquisition for detailed analysis. To improve sensitivity, we assessed a broad scope targeted sequence capture (TSC) panel (ViroCap) in both human and animal samples. Moreover, we adjusted TSC for the Oxford Nanopore MinION and compared the performance to an SMg approach. TSC on the Illumina NextSeq served as the gold standard. Overall, TSC increased the viral read count significantly in challenging human samples, with the highest genome coverage achieved using the TSC on the MinION. TSC also improved the genome coverage and sequencing depth in clinically relevant viruses in the animal samples, such as influenza A virus. However, SMg was shown to be adequate for characterizing a highly diverse animal virome. TSC on the MinION was comparable to the NextSeq and can provide a valuable alternative, offering longer reads, portability and lower initial cost. Developing new viral enrichment approaches to detect and characterize significant human and animal viruses is essential for the One Health Initiative.


Carbon nanotubes in the liquid phase: addressing the issue of dispersion.
The inherent size and hollow geometry with extraordinary electronic and optical properties make carbon nanotubes (CNTs) promising building blocks for molecular or nanoscale devices. Unfortunately, their hydrophobic nature and their existence in the form of agglomerated and parallel bundles make this interesting material inadequately soluble or dispersible in most of the common solvents, which is crucial to their processing. Therefore, various ingenious techniques have been reported to disperse the CNTs in various solvents with different experimental conditions. However, by analyzing the published scientific research articles, it is evident that there is an important issue or misunderstanding between the term "dispersion" and "solubilization". As a result many researchers use the terms interchangeably, particularly when stating the interaction of CNTs with liquids, which causes confusion among the readers, students, and researchers. In this article, this fundamental issue is addressed in order to give basic insight to the researchers who are working with CNTs, as well as to the scientists who deal with nano-related research domains.


Recent advances in stimuli-responsive tailored nanogels for cancer therapy; from bench to personalized treatment.
To improve the quality of health in a personalized manner, better control over pharmacologically relevant cargo formulation, organ-specific targeted delivery, and on-demand release of therapeutic agents is crucial. Significant work has been put into designing and developing revolutionary nanotherapeutics approaches for the effective monitoring and personalized treatment of disease. Nanogel (NG) has attracted significant interest because of its tremendous potential in cancer therapy and its environmental stimuli responsiveness. NG is considered a next-generation delivery technology due to its benefits like as size tunability, high loading, stimuli responsiveness, prolonged drug release via in situ gelling mechanisms, stability, and its potential to provide personalized therapy from the investigation of human genes and the genes in various types of cancers and its association with a selective anticancer drug. Stimuli-responsive NGs can be used as smart nanomedicines to detect and treat cancer and can be tuned as personalized medicine as well. This comprehensive review article's major objectives include the challenges of NGs' clinical translation for cancer treatment as well as its early preclinical successes and prospects.


Post-operative radiograph assessment of children undergoing closed reduction and spica cast immobilization for developmental dysplasia of the hip: does experience matter?
Closed reduction and spica cast immobilization are routinely used for young patients with developmental dysplasia of the hip with reducible hips. Our primary objective was to assess the interpretation quality of immediate post-operative pelvis radiographs after treatment. A series of 28 randomly selected patients (30 hips) with pre- and post-operative pelvis radiographs and post-operative magnetic resonance imaging were included. Each was presented twice with an interval of two weeks, in alternating orders. Raters with different experience and specialties from different institutions rated the quality of reduction (hip in or out) after treatment. Thirteen surgeons and three radiologists evaluated 30 hips (28 patients). Agreement was not satisfactory (κ = 0.12). Experienced clinicians demonstrated similar agreement to inexperienced raters (κ = 0.04). Consistency at a two week interval was moderate (κ = 0.48, percent of agreement at 82%). The mean number of errors from the two ratings were 8.6 ± 2.5 and 8.9 ± 2.7, respectively (P = 0.72). There was no significant difference between surgeons with different levels of experience; radiologists did better than surgeons, but the difference was insignificant. Raters from different institutions had similar performance in poor judgment. Our results show poor concordance between observers and ratings. Post-operative radiographs are unreliable for assessing the quality of hip reduction. The level of experience, subspecialty, and geographical origin do not impact the radiographic assessment. Based on the present findings, we recommend performing post-operative magnetic resonance imaging rather than anteroposterior pelvis radiograph to assess the hip. Compared to standard radiographs, magnetic resonance imaging allows more reliable interpretation while decreasing radiation exposure.


Detection of transplacental melanoma metastasis using quantitative PCR.
To choose the most appropriate treatment for children affected by a transplacental metastasis, it is crucial to ascertain the maternal origin of the tumor. Up-to-date conclusive diagnosis is generally achieved through fluorescence in situ hybridization or karyotyping analysis. Herein, we report an alternative, reliable assay for rapidly defining vertical cancer transmission to the fetus by using quantitative polymerase chain reaction. Our assay indicates that quantification of the copy number of the sex chromosomes by specific short tandem repeats markers, in genomic DNA purified from the tumor biopsy cells, could be used to correctly evaluate transplacental metastasis events.


Modeling foreign exchange market activity around macroeconomic news: Hawkes-process approach.
We present a Hawkes-model approach to the foreign exchange market in which the high-frequency price dynamics is affected by a self-exciting mechanism and an exogenous component, generated by the pre-announced arrival of macroeconomic news. By focusing on time windows around the news announcement, we find that the model is able to capture the increase of trading activity after the news, both when the news has a sizable effect on volatility and when this effect is negligible, either because the news in not important or because the announcement is in line with the forecast by analysts. We extend the model by considering noncausal effects, due to the fact that the existence of the news (but not its content) is known by the market before the announcement.


Morphological study of the inferior transverse scapular ligament.
The suprascapular nerve can be compressed by the inferior transverse scapular ligament (ITSL), also known as the spinoglenoid ligament, and this entrapment results in dysfunction of the external rotation of the upper arm owing to isolated weakness of the infraspinatus muscle. The morphology of the ITSL has not been adequately characterized. The aim of this study was to clarify the morphological characteristics of the ITSL. In total, 110 shoulders from 72 cadavers were dissected in this study. The ITSL was present in 73 (66.4%) of the 110 specimens, and comprised membrane in 40 (36.4%), ligament in 25 (22.7%), and both membrane and ligament in eight (7.3%). This structure could be classified into three types on the basis of its shape: band-like (33.6%, type I), triangular (15.5%, type II), or irregular (17.3%, type III). In the spinoglenoid notch, the suprascapular nerve was always close to the lateral margin of the scapular spine. The length of the ligament between its origin and insertion sites ranged from 8.7 to 23.4 mm at its superior margin and from 8.9 to 17.5 mm at its inferior margin. The ligament width and thickness at its midportion ranged from 1.6 to 10.0 mm and from 0.1 to 1.2 mm, respectively. The results of this study improve understanding of the ITSL and will be helpful for successful diagnoses and treatments for selective suprascapular nerve entrapment.


Nitric oxide production by a murine macrophage cell line (RAW264.7) stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans.
The aim of this study was to determine whether Actinobacillus actinomycetemcomitans lipopolysaccharide (LPS-A. actinomycetemcomitans) could stimulate a murine macrophage cell line (RAW264.7 cells) to produce nitric oxide (NO). The cells were treated with LPS-A. actinomycetemcomitans or Escherichia coli LPS (LPS-Ec) for 24 h. The effects of N(G)-monomethyl-L-arginine (NMMA), polymyxin B and cytokines (IFN-gamma, TNF-alpha, IL-4 and IL-12) on the production of NO were also determined. The role of protein tyrosine kinase, protein kinase C and microtubulin organization on NO production were assessed by incubating RAW264.7 cells with genistein, bisindolylmaleide and colchicine prior to LPS-A. actinomycetemcomitans stimulation, respectively. NO levels from the culture supernatants were determined by the Griess reaction. The results showed that LPS-A. actinomycetemcomitans stimulated NO production by RAW264.7 cells in a dose-dependent manner, but was slightly less potent than LPS-Ec. NMMA and polymyxin B blocked the production of NO. IFN-gamma and IL-12 potentiated but IL-4 depressed NO production by LPS-A. actinomycetemcomitans-stimulated RAW264.7 cells. TNF-alpha had no effects on NO production. Genistein and bisindolylmalemaide, but not colchicine, reduced the production of NO in a dose-dependent mechanism. The results of the present study suggest that A. actinomycetemcomitans LPS, via the activation of protein tyrosine kinase and protein kinase C and the regulatory control of cytokines, stimulates NO production by murine macrophages.


Identification of new mutations in primary hyperoxaluria type 1 (PH1).
Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). The AGXT gene, which codes for the 392 amino acid protein, has been mapped to chromosome 2q37.3. In order to identify new mutations in the AGXT gene we studied 79 PH1 patients using single strand conformation polymorphism analysis. In addition to a cluster of new mutations in exon 7 we report five novel mutations in exons 2, 4, 5, 9 and 10. These are T444C, G640A, G690A, 1008-1010delGCG and G1171A. These five new mutations contribute to our knowledge of the AGXT gene. Their possible consequences for PH1 phenotype and enzyme activity are discussed.


Structure-function relationships in the cysteine proteinases actinidin, papain and papaya proteinase omega. Three-dimensional structure of papaya proteinase omega deduced by knowledge-based modelling and active-centre characteristics determined by two-hydronic-state reactivity probe kinetics and kinetics of catalysis.
1. A model of the three-dimensional structure of papaya proteinase omega, the most basic cysteine proteinase component of the latex of papaya (Carica papaya), was built from its amino acid sequence and the two currently known high-resolution crystal structures of the homologous enzymes papain (EC 184.108.40.206) and actinidin (EC 184.108.40.206). The method used a knowledge-based approach incorporated in the COMPOSER suite of programs and refinement by using the interactive graphics program FRODO on an Evans and Sutherland PS 390 and by energy minimization using the GROMOS program library. 2. Functional similarities and differences between the three cysteine proteinases revealed by analysis of pH-dependent kinetics of the acylation process of the catalytic act and of the reactions of the enzyme catalytic sites with substrate-derived 2-pyridyl disulphides as two-hydronic-state reactivity probes are reported and discussed in terms of the knowledge-based model. 3. To facilitate analysis of complex pH-dependent kinetic data, a multitasking application program (SKETCHER) for parameter estimation by interactive manipulation of calculated curves and a simple method of writing down pH-dependent kinetic equations for reactions involving any number of reactive hydronic states by using information matrices were developed. 4. Papaya proteinase omega differs from the other two enzymes in the ionization characteristics of the common (Cys)-SH/(His)-Im+H catalytic-site system and of the other acid/base groups that modulate thiol reactivity towards substrate-derived inhibitors and the acylation process of the catalytic act. The most marked difference in the Cys/His system is that the pKa for the loss of the ion-pair state to form -S-/-Im is 8.1-8.3 for papaya proteinase omega, whereas it is 9.5 for both actinidin and papain. Papaya proteinase omega is similar to actinidin in that it lacks the second catalytically influential group with pKa approx. 4 present in papain and possesses a catalytically influential group with pKa 5.5-6.0. 5. Papaya proteinase omega occupies an intermediate position between actinidin and papain in the sensitivity with which hydrophobic interaction in the S2 subsite is transmitted to produce changes in transition-state geometry in the catalytic site, a fact that may be linked with differences in specificity in P2-S2 interaction exhibited by the three enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)


Combination of Rigid and Nonrigid Fixation Versus Nonrigid Fixation for Bilateral Mandibular Fractures: A Multicenter Randomized Controlled Trial.
We aimed to compare complication rates and functional outcomes in patients with bilateral mandibular fractures treated with different degrees of internal fixation rigidity. This international, multicenter randomized controlled trial included adults with bilateral mandibular fractures located at either the angle and body, angle and symphysis, or body and symphysis. Patients were treated with either a combination of rigid fixation for the anterior fracture and nonrigid fixation for the posterior fracture (mixed fixation) or nonrigid fixation for both fractures. The primary outcome was complications within 6 weeks after surgery. Secondary outcomes were complications within 3 months, Helkimo dysfunction index, and mandibular mobility at 6 weeks and 3 months after surgery. Of the 315 patients enrolled, 158 were randomized to the mixed fixation group and 157 to the nonrigid fixation group. The overall complication rate at 6 weeks in the intention-to-treat population was 9.6% (95% confidence interval [CI], 5.3% to 15.6%) in the mixed fixation group and 7.8% (95% CI, 4.0% to 13.5%) in the nonrigid fixation group. With an unadjusted odds ratio of 1.25 (95% CI, 0.51 to 3.17), there were no statistically significant differences in complication rates between the 2 groups (P = .591). A multivariable model for complication risk at 6 weeks found no significant differences between treatment groups, but patients with moderate or severe displacement had a higher complication rate than those with no or minimal displacement (adjusted odds ratio, 4.58; 95% CI, 1.16 to 18.06; P = .030). There were no significant between-group differences in complication rates at 3 months. Moreover, no significant differences in Helkimo dysfunction index and mandibular mobility index at 6 weeks and 3 months were found between groups according to treatment allocated and treatment received. A combination of rigid and nonrigid fixation in patients with bilateral mandibular fracture has similar complication rates and functional outcomes to nonrigid fixation for both fractures.


Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.
Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017. The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively. We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%). The estimate (95% CI) at 3 years for GF- and GVHD-II to IV-free survival as event-free survival (EFS) was 56% (46-69) for the entire cohort; 58% (46-72) and 56% (23-88) for LAD-I and LAD-III, respectively. Grade II to IV acute GVHD was a relevant risk factor for death (hazard ratio 3.6; 95% CI 1.4-9.1; P = .006). Patients' age at transplant ≥13 months, transplantation from a nonsibling donor, and any serological cytomegalovirus mismatch in donor-recipient pairs were significantly associated with severe acute GVHD and inferior EFS. The choice of busulfan- or treosulfan-based conditioning, type of GVHD prophylaxis, and serotherapy did not impact overall survival, EFS, or aGVHD. An intrinsic inflammatory component of LAD may contribute to inflammatory complications during allo-HSCT, thus providing the rationale for considering anti-inflammatory therapy pretreatment.


Prevalence of Renal and Cervical Vertebral Anomalies in Patients With Isolated Microtia and/or Aural Atresia.
The objective of this study was to determine whether patients with isolated microtia or aural atresia have an increased prevalence of renal or cervical vertebral anomalies. The study design was a retrospective medical record review. The setting was the following four distinct institutions: an urban tertiary care children's hospital, two urban academic medical centers, and a staff-model health maintenance organization. Patients diagnosed with microtia, aural atresia, or oculoauriculovertebral spectrum were identified. Patients with facial asymmetry, craniofacial microsomia, and other craniofacial abnormalities or syndromes were excluded. Main outcome measures were the number of patients with isolated microtia or aural atresia who underwent a renal ultrasound or cervical spine X-ray, the results of those studies, and further evaluation or treatment for any abnormalities found. A binomial analysis using a one-sided 95% confidence level was performed. A total of 514 patients with isolated microtia and/or aural atresia were identified. Of these patients, 145 (28%) had undergone a renal ultrasound and 81 (16%) had undergone cervical spine X-rays. A total of 3 patients (2%) had minimal renal pelviectasis, all of which had resolved on repeat ultrasound and required no treatment. There were no structural renal abnormalities identified, and there were no cervical spine abnormalities identified. The data suggest that there is no increased prevalence of structural renal or cervical vertebral anomalies in patients with isolated microtia and/or aural atresia. Therefore, these patients do not require routine screening renal ultrasound or cervical spine X-rays.


[Morphological types of the changes in the myofibrils of cardiac muscle cells].
Light microscopy and electron microscopy examinations showed the changes in myofibrils to be a criterion of early stages of cardiomyocyte involvement. Proceeding from this, the main types of acute cardiomyocyte damage are distinguished: contractures (segmentary and subsegmentary), primary clump degeneration, intracellular myocytolysis and cytolysis. The best way to detect the state of myofibrils by light microscopy is to use polarization microscopy which diagnoses in sections acute metabolic damages and early stages of myocardial infarction, repeated and relapsing infarctions, fibrillation of ventricles. The utilization of polarization microscopy in pathological practice permits one to diagnose definitely the early stages of acute damages of the heart in cases of sudden and unexpected death.


The Alpine LGM in the boreal ice-sheets game.
New chronologic and stratigraphic constraints from the Garda morainic amphitheater define the extension of the last glaciation in the Adige-Sarca system and improve the Alpine LGM dataset. Together with the available chronology of the Rhine and Tagliamento systems, our results indicate a synchronous maximum culmination of Alpine glaciers during the LGM, which anticipated by about 3.5 ka the maximum extension of the Eurasian Ice Sheet (EIS). This is ascribed to the sensitivity of Alpine glaciers to the availability of moisture from southerly circulation, as recently documented by speleothem δ18O curve from Sieben Hengste (7 H). According to global circulation models, the waxing of the North American Ice Sheet (NAIS) at 26-23 ka pushed the North Atlantic jet stream southwards. This enhanced precipitation rates in southern Europe by advection of moisture from the Mediterranean Sea, triggering expansion of the Alpine glaciers. NAIS waning after 23 ka led to the gradual re-establishment of westerly circulation and renewal of a moisture supply to northern Europe, feeding the EIS to its maximum volume. Reduced supply of moisture from the Mediterranean Sea sealed the fate of the Alpine glaciers, which entered a final recessional phase after 22 ka and faded out after 17.5 ka.


The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: I. Project BIOCORE (M212), a biological cosmic ray experiment: procedures, summary, and conclusions.
The primary objective of the experiment was to determine whether a specific portion of the high Z-high energy (HZE)* galactic cosmic ray particle spectrum, especially particles with Z greater than or equal to 6, can produce microscopically visible injury of brain and eye tissues. Pocket mice (Perognathus longimembris), obtained from the California desert, were selected as the biological target. Five of these mice were flown on Apollo XVII. Not only the brain and eyes but also many other tissues of these animals were studied for evidence of cosmic ray particle damage. The lack of prior experimental evidence as to the character of the potential injury induced by HZE particles required reliance on the physical characteristics of particle radiation in ascertaining the probable nature of the injruy. These characteristics and the key aspects of the experiment are summarized in this paper. Subsequent articles in this special supplement give details of the biological, engineering, and dosimetric aspects of BIOCORE together with the results.


Update on the pathogenesis and management of ocular rosacea: an interdisciplinary review.
Rosacea is one of the most common conditions affecting the ocular surface. The purpose of this review is to provide an update on the pathogenesis and treatment of rosacea based on the dermatology and ophthalmology literatures. Literature searches were conducted for rosacea and ocular rosacea. Preference was given to systematic reviews, meta-analysis, case-controlled studies, and documented case reports while excluding poorly documented case studies and commentaries. The data were examined and independently analyzed by more than two of the authors. Rosacea is a complex inflammatory condition involving the pilosebaceous unit. Its underlying mechanism involves an interplay of the microbiome, innate immunity, adaptive immunity, environmental triggers, and neurovascular sensitivity. The latest classification of rosacea includes three dermatologic subgroups and a fourth subgroup, ocular rosacea. Ocular rosacea clinically displays many features that are analogous to the cutaneous disease, such as lid margin telangiectasia and phlyctenulosis. The role of environmental triggers in the exacerbation of ocular rosacea appears to be understudied. While lid hygiene and systemic treatment with tetracycline drugs remain the mainstay of treatment for ocular rosacea, newer dermatologic targets and therapies may have potential application for the eye disease. Ocular rosacea appears to embody many of the manifestation of the dermatologic disease. Hence, the basic pathophysiologic mechanisms of the ocular and cutaneous disease are likely to be shared. Better understanding of the ocular surface microbiome and the immunologic mechanisms, may lead to novel approaches in the management of ocular rosacea.


Use of laparotomy in a staged approach for resolution of bilateral or complicated perineal hernia in 41 dogs.
To evaluate the value of laparotomy as the initial step in the treatment of bilateral or complicated perineal hernia (PH) in dogs. Retrospective study. Forty-one dogs with PH. Dogs with bilateral or complicated PH treated by a 2-step approach between November 1997 and December 2001 were studied. Inclusion criteria for complicated PH were: recurrence of PH, unilateral PH with a major rectal dilatation, PH with a concurrent surgical prostatic disease, and PH with retroflexed bladder. Colopexy, vas deferens pexy, cystopexy, and prostatic omentalization were performed during laparotomy as needed. Later, PH was performed by internal obturator muscle flap (IOMF) or if there was a perineal rent or weakness on the contralateral side, appositional herniorrhaphy was performed. Outcome was followed for >/=6 months. PH were bilateral (20 dogs) or unilateral (21). Twenty-one (51%) dogs had prostatic disease (clinical or ultrasonography diagnosis; 17 confirmed histologically) and 12 (29%) had urinary bladder retroflexion. Forty-one colopexies, 32 vas deferens pexies, 6 cystopexies, and 9 prostatic surgeries (omentalization or perineal cyst resection) were performed. PH was performed 2-20 days (median, 6 days) later: 61 IOMF transpositions, 13 appositional. Mean follow-up time was 26.6 months (range, 6-54 months, median, 27 months). PH was resolved in 37 (90%) dogs; 4 dogs had recurrence, and all occurred within 6 months. Thirty-eight (92%) dogs had an improved quality of life (good in 34 dogs, fair in 4 dogs). Wound complications occurred in 7 dogs (17%). Postoperative urine dribbling occurred in 15 dogs (37%) and was irreversible in 7 dogs (17%). Postoperative fecal straining persisted in 18 dogs (44%), and was permanent in 4 dogs (10%). Fecal incontinence did not occur. In bilateral or complicated PH, fixation of the urinary bladder and colon, and treatment of prostatic disease increase the chances of resolution. Emptying of the perineal space by organ pexy allows improved observation during herniorrhaphy. Despite a 90% clinical resolution, dogs with complicated PH treated by a 2-step protocol may have persistent urinary and fecal disorders. To improve the prognosis of bilateral or complicated PH, investigation and treatment of concomitant lesions (rectal, prostatic, bladder) should be part of a rational surgical strategy using a 2-step protocol.


Population ecology and the control of pests.
An understanding of the factors responsible for the numbers of animals observed is essential for effective integrated control of pests. An ecological study need not, however, be complete for it to be useful; many incomplete such studies have led to clues that have served as important guides in control programmes. However, it is important that the study of animal numbers be undertaken with a completely general model in mind. Some ecological models suggested are too restricted to be generally applicable. The generalized model proposed by the author is based on the proposition that the chance to survive and multiply depends on environment, which may be effectively studied as having five components: resources, climate, numbers of the same species, numbers of other species, and hazards. Any of these components may be important and different components may be important at different times in the history of an animal population.Populations are most often limited by inaccessibility of resources and by the shortage of time during which the environment is favourable to an increase in numbers. An understanding of these factors suggests ways in which numbers may be further restricted. The student of pest control must determine if such ways can be economically used in a programme of integrated control.


Efficacy and safety of tirofiban in patients with acute ischemic stroke treated with endovascular thrombectomy: A frequentist and Bayesian meta-analysis.
Tirofiban is an antiplatelet treatment approved for acute coronary syndrome, but it has not been rigorously evaluated for efficacy and safety in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT). Electronic databases were systematically searched for studies conducted from January 1, 2015, to July 31, 2021, that evaluated tirofiban administration for patients with AIS treated with EVT in comparison with control. Risk ratios (RRs) and confidence intervals (CIs) were estimated for favorable functional outcomes (FFOs), mortality, and symptomatic intracranial hemorrhage (SICH), each 90 days after AIS. Bayesian hierarchical modeling was performed to obtain posterior RR and its 95% highest posterior density (HPD) for validation. Compared with controls, tirofiban users exhibited increased FFOs (RR, 1.18; 95% CI, 1.08-1.30), decreased mortality (RR, 0.77; 95% CI, 0.64-0.92), and no difference in SICH (RR, 0.97; 95% CI, 0.77-1.23). Tirofiban users in the postbolus infusion subgroup exhibited increased FFOs (RR, 1.20; 95% CI, 1.07-1.35), decreased mortality (RR, 0.71; 95% CI, 0.58-0.88), and no increase in SICH (RR, 0.97; 95% CI, 0.72-1.29). The bolus-only subgroup showed no differences in FFO, mortality, or SICH between the tirofiban and control groups. Consistent results were obtained for posterior density of FFO (posterior RR, 1.20; 95% HPD, 1.06-1.34), mortality (posterior RR, 0.77; 95% HPD, 0.63-0.92), and SICH (posterior RR, 0.98; 95% HPD, 0.71-1.26). For patients with AIS treated with EVT, tirofiban improved FFOs, decreased mortality, and did not increase SICH compared with controls; postbolus infusion for administering tirofiban was more favored than the bolus-only regimen.


A data set of variants derived from 1455 clinical and research exomes is efficient in variant prioritization for early-onset monogenic disorders in Indians.
Given the genomic uniqueness, a local data set is most desired for Indians, who are underrepresented in existing public databases. We hypothesize patients with rare monogenic disorders and their family members can provide a reliable source of common variants in the population. Exome sequencing (ES) data from families with rare Mendelian disorders was aggregated from five centers in India. The dataset was refined by excluding related individuals and removing the disease-causing variants (refined cohort). The efficiency of these data sets was assessed in a new set of 50 exomes against gnomAD and GenomeAsia. Our original cohort comprised 1455 individuals from 1203 families. The refined cohort had 836 unrelated individuals that retained 1,251,064 variants with 181,125 population-specific and 489,618 common variants. The allele frequencies from our cohort helped to define 97,609 rare variants in gnomAD and 44,520 rare variants in GenomeAsia as common variants in our population. Our variant dataset provided an additional 1.7% and 0.1% efficiency for prioritizing heterozygous and homozygous variants respectively for rare monogenic disorders. We observed additional 19 genes/human knockouts. We list carrier frequency for 142 recessive disorders. This is a large and useful resource of exonic variants for Indians. Despite limitations, datasets from patients are efficient tools for variant prioritization in a resource-limited setting.


Autoantibodies within families of patients with systemic lupus erythematosus are not directed against the same nuclear antigens.
The presence of antinuclear autoantibodies in systemic lupus erythematosus (SLE) is influenced by genetic factors. The presence of autoantibodies in healthy family members of patients has been reported. Our hypothesis was that autoantibodies are directed against the same antigens in first-degree family members of patients with SLE as in their patient relative. Plasma was harvested from 50 patients with SLE, 154 unaffected first-degree family members, and 330 healthy controls. Presence of autoantibodies against 14 specific nuclear antigens was tested by the ELISA based line immunoassay INNO-LIA method. Seventy-four percent of patients, 32% of first-degree family members, and 1.5% of healthy controls had antibodies against any nuclear antigen. Most frequent autoantibodies in the patients were anti-histone and anti-SSA, whereas in the family members these were anti-RNP-C and anti-Topo-I/Scl. Presence and specificity of autoantibodies in family members were independent of the presence or absence of that autoantibody in their patient relative (chi-square p > 0.1 for all 14 antigens). Autoantibodies in family members and their patient relatives are not directed against the same nuclear antigens. Thus a familial aspecific dysfunction of the B lymphocyte is the most likely explanation for autoantibody production in SLE.


[Bone transplantation and bone replacement materials].
There is a growing need for immediately available material with appropriate qualities for reconstruction of large bone defects. Autologous spongy bone grafts are optimal as to biocompatibility, but are in short supply. Allogenic and xenogenic bone grafts evoke an immunological reaction after implantation and are not biocompatible. In the last thirty years ceramic implants and composites have been developed for bone substitution. New calcium phosphate bone substitutes undergo processes of resorption and precipitation of carbonate apatite that play a part in formation of new bone. These materials are easy to use because of their pastelike consistence. Resorption properties are influenced by particle size, crystallinity and composition. So far, no serious adverse reactions were reported. More clinical experience is necessary especially with composites and combinations with antibiotics, bone growth factors and collagen, to specify the place of these modern calcium phosphates in bone replacement and bone substitution.


[Almitrine bismesylate in chronic obstructive lung disease and persistent hypoxemia. Controlled double-blind study with oral administration].
Almitrine bismesylate has been shown to be a respiratory stimulating substance which acts primarily via the peripheral chemoreceptors. The effect of the oral administration of Almitrine (200 mg/day for 9 days) was investigated in a controlled double-blind study with 18 patients suffering from chronic obstructive lung disease and hypoxemia (PaO2 less than 60 mm Hg). During the therapy with Almitrine an early and lasting improvement in the PaO2 and PaCO2 could be obtained. This improvement was significant compared with the placebo group. On the last day of treatment with Almitrine the PaO2 increased by 16.2 mm Hg (p less than 0.001) and the PaCO2 decreased by 7.3 mm Hg (p less than 0.01). Simultaneously, an increase in minute ventilation (5.24 liters on day 9) could be observed. This increase was not significant compared with the placebo group. There was a correlation of -0.61 between the changes in minute ventilation and in PaCO2. The lung functional parameters vital capacity (VC), forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF) increased on several days in both groups; a change in Rtot was observed in the treatment group only. A reduction of dyspnea also was observed in both groups. In addition to the ventilatory stimulant action on the peripheral chemoreceptors, the changes in blood gases induced by Almitrine also should be discussed as an improvement of the ventilation/perfusion ratio. In this therapeutical trial no side effects during the therapy with Almitrine have been observed.


Differences in tissue characterization of restenotic neointima between sirolimus-eluting stent and bare-metal stent: integrated backscatter intravascular ultrasound analysis for in-stent restenosis.
The pathogenesis of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation remains unclear. The purpose of this study is to analyse tissue characterizations of neointima in restenosis lesions after sirolimus-eluting stent (SES), comparing with those after bare metal stent (BMS) using integrated backscatter intravascular ultrasound (IB-IVUS). A total of 54 consecutive patients who had ISR lesions after SES (n = 20) or BMS (n = 34) implantation were enrolled. For tissue characterization of neointima, IB-IVUS was performed by cross-sectional (at the minimum lumen area) and volumetric (within the stented segment) analyses. In addition, angiographic patterns of restenosis were evaluated with division into focal and diffuse. The focal angiographic pattern of restenosis was predominantly observed in the SES group (SES vs. BMS; 80.0 vs. 26.5%; P = 0.0001), whereas the diffuse pattern was more common in the BMS group (SES vs. BMS; 20.0 vs. 73.5%; P = 0.0001). On both cross-sectional and volumetric IB-IVUS analyses, the neointimal tissue in restenosis lesions after SES implantation had a significantly larger percentage of lipid tissue (cross-sectional: 23.3 ± 12.7 vs. 15.7 ± 11.9%; P = 0.033; volumetric: 22.8 ± 10.4 vs. 16.3 ± 7.0%; P = 0.008) and a significantly smaller percentage of fibrous tissue compared with that after BMS implantation (cross-sectional: 73.6 ± 11.6 vs. 82.0 ± 11.2%; P = 0.011, volumetric: 73.8 ± 9.5 vs. 80.5 ± 6.7%; P = 0.004). This IB-IVUS study indicates that larger amounts of lipid tissue are present in neointima of SES when compared with BMS, suggesting that neoatherosclerosis may in part be responsible for ISR after SES implantation.


[Post-traumatic intrahepatic extraductal bile collection].
Intrahepatic extraductal biliary collections are a rare complication of abdominal trauma. To describe two patients with diagnosis of posttraumatic intrahepatic extraductal biliary collections. Two male patients suffered multiple severe injuries, one of them from blunt trauma and the other from penetrating trauma; their main clinical manifestations were fever and jaundice. CT scan was the best suited diagnostic tool for evidencing the intrahepatic collections. Both patients underwent surgical drainage, only one of them had a satisfactory evolution. Posttraumatic intrahepatic extraductal biliary collections are a rare complication of abdominal trauma, its presence should be suspected in patients with hepatic trauma showing jaundice, fever and/or right upper quadrant pain between the second and sixth week following abdominal trauma.


Solitary fibrous tumors of the soft tissues: imaging features with histopathologic correlations.
To describe the imaging features of soft tissue solitary fibrous tumors, with histopathological correlations and clinical outcome. Twenty-seven patients with histologically proven SFTs were retrospectively evaluated. Imaging studies included six radiographs, five U/S studies, eighteen CT scans, fourteen MRI exams, and one angiography. On CT scans, two lesions were isodense and five were mildly hypodense compared to muscle while 11 lesions appeared heterogeneous-mixed of iso and hypodense areas. Heterogeneous enhancement was depicted in 13 lesions and four lesions enhanced homogeneously. Six lesions were partially calcified. On T1W MR images, seven lesions were isointense and one was slightly hyperintense relative to adjacent muscles while five lesions appeared heterogeneous-mixed of iso and hypointense areas. T2W images showed high SI in two cases and heterogeneous-mixed in seven cases. Enhancement was heterogeneous in six and homogeneous in four lesions. Patchy unenhanced areas (on CT and T1W MR images) along with patchy areas of low to markedly high SI on T2W images were depicted in 19 lesions. The enhanced portions correlated to areas of increased vascularity and cellularity. The four clinically more aggressive lesions could not be predicted on imaging. Typical soft tissue SFTs are deep masses made of isodense and isointense areas relative to adjacent muscles mixed with hypodense and hypointense areas on unenhanced CT and MR T1W respectively. Variable enhancement patterns and mixed to high signal intensities on MRT2W are attributed to tumor's cellularity, vascularity, collagen distribution and/or degeneration. Heterogeneity of SFTs affects imaging features on MRI and CT modalities. The biological behavior of soft tissue SFTs can not be predicted based solely either on histopathologic or imaging evaluation.


A time-resolved immunofluorometric assay of autoantibodies to double-stranded DNA.
A time-resolved immunofluorometric assay (TRIFMA) of autoantibodies to double-stranded DNA (dsDNA) is described. Biotinylated DNA was bound to the polystyrene solid phase coated with streptavidin. F(ab1')2 fragments from antibodies raised in rabbits to human IgG were labelled with Eu3+, and used in the assay to label the bound autoantibodies to dsDNA. The measuring range covers three decades. The proposed assay has good analytical properties. For calibration the First International Standard for antibodies to double-stranded DNA Wo/80 was used. The 97.5th percentile in normal persons is 20 kIU/l. Comparison of the TRIFMA and the Farr-assay in the analysis of 56 sera from 20 patients with systemic lupus erythematosus or lupus-like disease, 13 with other autoimmune diseases, and 10 blood-bank donors indicates a high degree of concordance (Kendall's tau = 0.56, p < 0.001). Further evaluation in 102 patients with systemic lupus erythematosus, lupus-like disease and other autoimmune diseases shows that sensitivity for active classical systemic lupus erythematosus is adequate, and specificity is excellent.


Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T1 and T2 contrast agents.
The extracellular pH (pH(e) ) of solid tumors is acidic, and there is evidence that an acidic pH(e) is related to invasiveness. Herein, we describe an MRI single-infusion method to measure pH(e) in gliomas using a cocktail of contrast agents (CAs). The cocktail contained gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate (GdDOTA-4AmP) and dysprosium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetrakis(methylenephosphonic acid) (DyDOTP), whose effects on relaxation are sensitive and insensitive to pH, respectively. The Gd-CA dominated the spin-lattice relaxivity ΔR(1) , whereas the Dy-CA dominated the spin-spin relaxivity ΔR(2)*. The ΔR(2)* effects were used to determine the pixel-wise concentration of [Dy] which, in turn, was used to calculate a value for [Gd] concentration. This value was used to convert ΔR(1) values to the molar relaxivity Δr(1) and, hence, pH(e) maps. The development of the method involved in vivo calibration and measurements in a rat brain glioma model. The calibration phase consisted of determining a quantitative relationship between ΔR(1) and ΔR(2)* induced by the two pH-independent CAs, gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) and DyDOTP, using echo planar spectroscopic imaging (EPSI) and T(1) -weighted images. The intensities and linewidths of the water peaks in EPSI images were affected by CA and were used to follow the pharmacokinetics. These data showed a linear relationship between inner- and outer-sphere relaxation rate constants that were used for CA concentration determination. Nonlinearity in the slope of the relationship was observed and ascribed to variations in vascular permeability. In the pH(e) measurement phase, GdDOTA-4AmP was infused instead of GdDTPA, and relaxivities were obtained through the combination of interleaved T(1) -weighted images (R(1) ) and EPSI for ΔR(2)*. The resulting r(1) values yielded pH(e) maps with high spatial resolution.


Genomic islands 1 and 2 play key roles in the evolution of extensively drug-resistant ST235 isolates of Pseudomonas aeruginosa.
Pseudomonas aeruginosa are noscomially acquired, opportunistic pathogens that pose a major threat to the health of burns patients and the immunocompromised. We sequenced the genomes of P. aeruginosa isolates RNS_PA1, RNS_PA46 and RNS_PAE05, which displayed resistance to almost all frontline antibiotics, including gentamicin, piperacillin, timentin, meropenem, ceftazidime and colistin. We provide evidence that the isolates are representatives of P. aeruginosa sequence type (ST) 235 and carry Tn6162 and Tn6163 in genomic islands 1 (GI1) and 2 (GI2), respectively. GI1 disrupts the endA gene at precisely the same chromosomal location as in P. aeruginosa strain VR-143/97, of unknown ST, creating an identical CA direct repeat. The class 1 integron associated with Tn6163 in GI2 carries a blaGES-5-aacA4-gcuE15-aphA15 cassette array conferring resistance to carbapenems and aminoglycosides. GI2 is flanked by a 12 nt direct repeat motif, abuts a tRNA-gly gene, and encodes proteins with putative roles in integration, conjugative transfer as well as integrative conjugative element-specific proteins. This suggests that GI2 may have evolved from a novel integrative conjugative element. Our data provide further support to the hypothesis that genomic islands play an important role in de novo evolution of multiple antibiotic resistance phenotypes in P. aeruginosa.


Online Health Information-Seeking Among Older Women With Chronic Illness: Analysis of the Women's Health Initiative.
Understanding how older patients with chronic illnesses use the internet to obtain health information is relevant for the design of digital interventions aimed at improving the health and well-being of adults aged 65 years and older; this cohort represents the sickest, most expensive, and fastest-growing segment of the US population. The objective of our study was to describe online health information-seeking behavior among older patients with chronic illnesses and to compare the characteristics of patients who report using the internet to obtain health information with those who do not. The study population included 72,806 women aged 65 years and older enrolled in the Women's Health Initiative (WHI), a national cohort study, who completed a 2014 supplemental questionnaire assessing everyday technology use and internet use for researching health conditions. Comparisons were made between participants with and without a history of chronic illness and between users and nonusers of online sources for health information. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% CIs. Of the total, 59% (42,887/72,806) of older women used the internet for health information. Compared with women who did not use the internet to obtain health information, those who used the internet were younger (median age: 76 vs 81 years), more likely to be non-Hispanic white (90% [38,481/42,887] vs 87% [26,017/29,919]), earned a higher income (over $US 50,000: 55% [23,410/42,887] vs 33% [9991/29,919]), achieved a higher educational level (more than high school: 87% [37,493/42,887] vs 75% [22,377/29,919]), and were more likely to live with a partner (52% [22,457/42,887] vs 36% [10,759/29,919]) (all P<.001). Women with Alzheimer disease were least likely to report online health information-seeking compared to those without the disease (OR 0.41, 95% CI 0.38-0.43). In contrast, women with a recent diagnosis of cancer, within the previous 2 years (OR 1.23, 95% CI 1.11-1.36) or 2-5 years ago (OR 1.09, 95% CI 1.00-1.19), were most likely to use the internet for health information. Nearly 6 in 10 older women participating in the WHI reported using the internet to obtain health information. Patients recently diagnosed with cancer are more likely to be looking for health information online, even after adjustment for age, suggesting that these patients may have a greater need for digital health resources.


Characterizing the species composition of European Culicoides vectors by means of the Köppen-Geiger climate classification.
Biting midges of the genus Culicoides spp. (Diptera: Ceratopogonidae) are vectors for the Bluetongue virus, the African horse sickness virus and the recently emerged Schmallenberg virus. Here, species of the C. obsoletus complex, the C. pulicaris complex and C. imicola were considered. The objective was to compile a map of these Culicoides species and their relation to the popular climate classification defined by Wladimir Köppen and Rudolf Geiger to provide a quick view on the species composition in Europe. Major parts of Central and Northern Europe are covered by a warm temperate fully humid climate, characterized by warm summers. For this so-called Cfb climate fractions of 89% C. obsoletus complex and 11% C. pulicaris complex were estimated. Further investigations comprise the continental climate Dfb (76% C. obsoletus, 24% C. pulicaris), the warm temperate climate with hot summers Cfa (35% C. obsoletus, 65% C. pulicaris), the warm temperate dry climate, characterized by warm summers Csb (38% C. obsoletus, 51% C. pulicaris, 11% C. imicola) and the warm temperate dry climate with hot summers Csa of the Mediterranean area (11% C. obsoletus, 12% C. pulicaris, 77% C. imicola). A highly significant association coefficient of RV = 0.64 (Cramer's V) confirms the correlation between Culicoides spp. and climate zones. Moreover, climate projections for the end of the century give an impression on expected changes in the European Culicoides spp. composition.


Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy.
Natural Killer T (NKT) cells are unique lymphocytes characterized by their expression of a single invariant antigen receptor encoded by Vα14Jα18 in mice and Vα24Jα18 in humans, which recognizes glycolipid antigens in association with the monomorphic CD1d molecule. NKT cells mediate adjuvant activity to activate both CD8T cells to kill MHC-positive tumor cells and NK cells to eliminate MHC-negative tumor at the same time in patients, resulting in the complete eradication of tumors without relapse. Therefore, the NKT cell-targeted therapy can be applied to any type of tumor and also to anyone individual, regardless of HLA type.Phase IIa clinical trials on advanced lung cancers and head and neck tumors have been completed and showed significantly prolonged median survival times with only the primary treatment. Another potential treatment option for the future is to use induced pluripotent stem cell (iPS)-derived NKT cells, which induced adjuvant effects on anti-tumor responses, inhibiting in vivo tumor growth in a mouse model.


Vascularized versus nonvascularized facial nerve grafts using a new rabbit model.
The use of vascularized nerve graft models has been limited because of the complexity of the operation. The authors sought to develop a simple and effective rabbit model for facial nerve repair and evaluated its advantages over conventional nerve grafts. Rabbits were divided into three groups consisting of six rabbits each. The central auricular nerve and its nutrient vessels were used as a vascularized graft. Rabbits were grafted with a vascularized facial nerve graft (vascularized nerve graft group), with a free nerve graft (free nerve graft group), or with a vascularized nerve graft and a free nerve graft on each side of the face (vascularized nerve graft/free nerve graft group). Four months after surgery, facial performance and electrophysiologic monitoring were evaluated. The rabbits were then killed to prepare the nerve specimens for histologic, immunohistochemical, and transmission electron microscope study. At 4 months after the facial nerve repair, the functional recovery of the facial nerve was observed and analyzed. The side grafted with vascularized nerve graft was superior to the side grafted with free nerve graft. Regenerated nerve fibers were observed in all groups, and rabbits grafted with vascularized nerve grafts had more regenerated axons than those that underwent free nerve grafting, although the regenerated nerves were not as good as the natural nerves. This study demonstrates that it is feasible to establish a vascularized nerve graft model in rabbits. The model offers the obvious advantages of operability and reliability. The vascularized nerve graft is demonstrated to have a superior value for facial nerve repair.


Evaluation of chitosan gel as antibiotic and photosensitizer delivery.
This work suggests the use of chitosan gel imbued with the photosensitizer Photogem and with the antibiotic Tetraclin as a possible drug delivery system. The results reveal a decrease in the photosensitizer level of toxicity. Besides, the interaction between Photogem and chitosan gel causes a red shift in the photosensitizer spectrum, increasing its absorption in the therapeutic window (600-700 nm). These characteristics indicate this compound as a promising natural polymer-based photosensitizer carrier for photodynamic therapy. In summary, our results show that pure and doped chitosan gel may have potential application for antimicrobial action, being an excellent alternative when local control of the drug administration, provided by the gel, is required.


Simultaneous Activation of Mu and Delta Opioid Receptors Reduces Allodynia and Astrocytic Connexin 43 in an Animal Model of Neuropathic Pain.
Neuropathic pain is a chronic condition triggered by lesions to the somatosensory nervous system in which pain stimuli occur spontaneously or as pathologically amplified responses. In this scenario, the exchange of signaling molecules throughout cell-to-cell and cell-to-extracellular environment communications plays a key role in the transition from acute to chronic pain. As such, connexin 43 (Cx43), the core glial gap junction and hemichannel-forming protein, is considered a triggering factor for disease chronicization in the central nervous system (CNS). Drugs targeting μ opioid receptors (MOR) are currently used for moderate to severe pain conditions, but their use in chronic pain is limited by the tolerability profile. δ opioid receptors (DOR) have become attractive targets for the treatment of persistent pain and have been associated with the inhibition of pain-sustaining factors. Moreover, it has been shown that simultaneous targeting of MOR and DOR leads to an improved pharmacological fingerprint. Herein, we aimed to study the effects of the benzomorphan ligand LP2, a multitarget MOR/DOR agonist, in an experimental model of neuropathic pain induced by the unilateral sciatic nerve chronic constriction injury (CCI) on male Sprague-Dawley rats. Results showed that LP2 significantly ameliorated mechanical allodynia from the early phase of treatment up to 21 days post-ligatures. We additionally showed that LP2 prevented CCI-induced Cx43 alterations and pro-apoptotic signaling in the CNS. These findings increase the knowledge of neuropathic pain development and the role of spinal astrocytic Cx43, suggesting new approaches for the treatment of neuropathic pain.


Fine mapping of quantitative trait loci using linkage disequilibria with closely linked marker loci.
A multimarker linkage disequilibrium mapping method was developed for the fine mapping of quantitative trait loci (QTL) using a dense marker map. The method compares the expected covariances between haplotype effects given a postulated QTL position to the covariances that are found in the data. The expected covariances between the haplotype effects are proportional to the probability that the QTL position is identical by descent (IBD) given the marker haplotype information, which is calculated using the genedropping method. Simulation results showed that a QTL was correctly positioned within a region of 3, 1.5, or 0.75 cM in 70, 62, and 68%, respectively, of the replicates using markers spaced at intervals of 1, 0.5, and 0.25 cM, respectively. These results were rather insensitive to the number of generations since the QTL occurred and to the effective population size, except that 10 generations yielded rather poor estimates of the QTL position. The position estimates of this multimarker disequilibrium mapping method were more accurate than those from a single marker transmission disequilibrium test. A general approach for identifying QTL is suggested, where several stages of disequilibrium mapping are used with increasingly dense marker spacing.


Combined type versus ADHD predominantly hyperactive-impulsive type: is there a difference in functional impairment?
The purpose of this study was to evaluate whether preschool children with attention-deficit/hyperactivity disorder predominantly hyperactive-impulsive type (ADHD-HI) and ADHD combined type (ADHD-C) have different levels of functional impairment in four domains: externalizing (oppositional and disruptive) behaviors, internalizing (anxious) behaviors, social skills, and preacademic functioning. The subjects were 102 children 3 to 5 years of age, meeting DSM-IV criteria for ADHD. Children with ADHD-C versus ADHD-HI were compared across at least two measures for each of the four functional domains. Oppositional and anxious behaviors were assessed on the Conners Parent and Teacher Rating Scales. In addition, off-task and disruptive behaviors were assessed by direct observation in the preschool setting. Social skills were assessed on the parent and teacher versions of the Social Skills Rating System and preacademic skills were assessed on the letter word identification, passage comprehension, and applied problems subtests of the Woodcock-Johnson III Tests of Achievement and the initial sound fluency subtest of the Dynamic Indicators of Basic Early Literacy Skills 5th Edition. There were no significant differences between the groups on rating scale T scores for parent-reported oppositional symptoms (ADHD-C vs ADHD-HI; 66.7 +/- 13.5 vs 65.7 +/- 11.7; p = .73); parent-reported anxious symptoms (53.5 +/- 11.1 vs 53.2 +/- 9.7; p = .90); teacher-reported oppositional symptoms (70.9 +/- 15.6 vs 75.5 +/- 14.7; p = .17); or teacher reported anxious symptoms (59.2 +/- 11.6 vs 58.5 +/- 12.2; p = .77). No statistically significant differences were found between the groups when examining off-task and/or disruptive behavior during structured and free play observations at school. No significant differences between the subtypes were found for social skills or preacademic functioning. Across the four areas of functioning assessed in this study, preschool children with ADHD-HI and those with ADHD-C demonstrated similar levels of functioning. This study, in combination with data from longitudinal studies demonstrating that most children with ADHD-HI are later diagnosed with ADHD-C, suggests that ADHD-HI may represent an earlier form of ADHD-C as opposed to a distinct subtype.


Prevalence and Risk Factors of Cerebral Small Vessel Disease from a Population-Based Cohort in China.
Cerebral small vessel disease (CSVD) is a significant burden of morbidity and mortality among elderly people around the world. Epidemiological data with complete CSVD evaluations and a large sample size in the general population are still limited. Community-dwelling residents in Lishui city in China from the cross-sectional survey of the PRECISE study (Polyvascular Evaluation for Cognitive Impairment and Vascular Events) were included in this study from 2017 to 2019. All participants underwent 3 Tesla brain magnetic resonance images to assess CSVD imaging markers. Demographic and risk factor data were collected. The general and age-specific prevalence of lacune, confluent white matter hyperintensity (WMH), moderate-severe enlarged perivascular spaces (EPVS), cerebral microbleed (CMB), and total CSVD score ( an ordinal scale from 0 to 4, counting the presence of four imaging markers of CSVD) was evaluated. Associations between vascular risk factors and these markers were analyzed by multivariable logistic regression. A total of 3063 participants were enrolled. The mean age was 61.2 years and 46.5% were men. The most prevalent CSVD marker was confluent WMH (16.7%), followed by CMB (10.2%), moderate-severe EPVS in the basal ganglia (BG-EPVS) (9.8%), and lacune (5.6%). 30.5% of the participants have at least one of the four markers (total CSVD score ≥ 1 points). The prevalence of CSVD markers increases as the age increases. Age and hypertension were independent risk factors for four CSVD markers and the total CSVD score. In this Chinese cohort with community-based adults aged 50 to 75 years, our findings showed a prevalence of 30.5% for CSVD. The most prevalent CSVD marker was confluent WMH, followed by CMB, moderate-severe BG-EPVS and lacune. The risk factors for CSVD must be strictly screened and controlled in adults living in the community.


Relationship between physician and hospital coronary angioplasty volume and outcome in elderly patients.
With the expectation that physicians who perform larger numbers of coronary angioplasty procedures will have better outcomes, the American College of Cardiology/ American Heart Association guidelines recommend minimum physician volumes of 75 procedures per year. However, there is little empirical data to support this recommendation. We examined in-hospital bypass surgery and death after angioplasty according to 1992 physician and hospital Medicare procedure volume. In 1992, 6115 physicians performed angioplasty on 97,478 Medicare patients at 984 hospitals. The median numbers of procedures performed per physician and per hospital were 13 (interquartile range, 5 to 25) and 98 (interquartile range, 40 to 181), respectively. With the assumption that Medicare patients composed one half to one third of all patients undergoing angioplasty, these median values are consistent with an overall physician volume of 26 to 39 cases per year and an overall hospital volume of 196 to 294 cases per year. After adjusting for age, sex, race, acute myocardial infarction, and comorbidity, low-volume physicians were associated with higher rates of bypass surgery (P < .001) and low-volume hospitals were associated with higher rates of bypass surgery and death (P < .001). Improving outcomes were seen up to threshold values of 75 Medicare cases per physician and 200 Medicare cases per hospital. More than 50% of physicians and 25% of hospitals performing coronary angioplasty in 1992 were unlikely to have met the minimum volume guidelines first published in 1988, and these patients had worse outcomes. While more recent data are required to determine whether the same relationships persist after the introduction of newer technologies, this study suggests that adherence to minimum volume standards by physicians and hospitals will lead to better outcomes for elderly patients undergoing coronary angioplasty.


Sigma-1 Receptor Agonist Fluvoxamine Ameliorates Fibrotic Response of Trabecular Meshwork Cells.
Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and outflow resistance. Previously, we demonstrated that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic properties in the kidney and lung. In this study, the localization of the S1R in TM cells was determined, and the anti-fibrotic efficacy of FLU was examined in both mouse and human TM cells. Treatment with FLU reduced the F-actin rearrangement, inhibited cell proliferation and migration induced by the platelet-derived growth factor and decreased the levels of fibrotic proteins. The protective role of the S1R in fibrosis was confirmed by a more pronounced increase in alpha smooth muscle actin and F-actin bundle and clump formation in primary mouse S1R knockout TM cells. Furthermore, FLU demonstrated its protective effects by increasing the production of nitric oxide and facilitating the degradation of the extracellular matrix through the elevation of cathepsin K. These findings suggest that the S1R could be a novel target for the development of anti-fibrotic drugs and offer a new therapeutic approach for glaucoma.


Nonshivering thermogenesis in king penguin chicks. II. Effect of fasting.
The effect of fasting on the energy metabolism of skeletal muscle and liver was investigated in cold-acclimatized short-term fasting (STF) (3 wk) and naturally long-term fasting (LTF) (4-5 mo) king penguin chicks, both groups exhibiting nonshivering thermogenesis (NST). A comparison was made with nourished cold-acclimatized controls. In these chicks, no brown adipose tissue deposits could be found on electron-microscopic observations of fat deposits. Protein content and cytochrome oxidase (CO) activity of tissue homogenates were measured in liver and pectoralis and gastrocnemius muscles, as were protein content, CO activity, and respiration rates of mitochondria isolated from these organs. Fasting-induced protein loss affected the pectoralis more than the gastrocnemius muscle, thus preserving locomotor function. In STF chicks, specific mitochondrial protein content and specific tissue CO activity were preserved but total organ CO capacity was reduced by half in pectoralis and liver following the fall in organ mass. In LTF chicks, both specific and total CO activity were drastically reduced in muscles, whereas specific CO activity was preserved in liver. In these LTF chicks, muscle mitochondria showed an energized configuration associated with an increased area of inner membrane in gastrocnemius. A reduction of respiratory control ratio (RCR) was observed in subsarcolemmal muscle mitochondria of STF chicks, whereas intermyofibrillar and liver mitochondria kept high RCR values.(ABSTRACT TRUNCATED AT 250 WORDS)


Complex vectorial optics through gradient index lens cascades.
Graded index (GRIN) lenses are commonly used for compact imaging systems. It is not widely appreciated that the ion-exchange process that creates the rotationally symmetric GRIN lens index profile also causes a symmetric birefringence variation. This property is usually considered a nuisance, such that manufacturing processes are optimized to keep it to a minimum. Here, rather than avoiding this birefringence, we understand and harness it by using GRIN lenses in cascade with other optical components to enable extra functionality in commonplace GRIN lens systems. We show how birefringence in the GRIN cascades can generate vector vortex beams and foci, and how it can be used advantageously to improve axial resolution. Through using the birefringence for analysis, we show that the GRIN cascades form the basis of a new single-shot Müller matrix polarimeter with potential for endoscopic label-free cancer diagnostics. The versatility of these cascades opens up new technological directions.


EBP-37, a new elastin-binding protein in human plasma: structural similarity to ficolins, transforming growth factor-beta 1-binding proteins.
In order to study the elastin-binding factors in blood, human plasma was applied to an alpha-elastin-Sepharose column. The column-binding fraction contained a 37-kDa protein, which was tentatively named EBP-37. Partial amino acid sequences of EBP-37 were determined. It had collagenous and non-collagenous domains. Homology searches of the sequences revealed that the protein is very similar but not identical to ficolins, transforming growth factor-beta 1 (TGF-beta 1)-binding proteins from porcine uterus membranes. Direct interaction of EBP-37 with elastin was confirmed by demonstrating the binding of the isolated EBP-37 to alpha-elastin on a nitrocellulose membrane using the EBP-37-specific antiserum. The existence of oligomers and multimers crosslinked by disulfide bonds was demonstrated by immunoblot analysis. Possible functions of EBP-37 are discussed.


Analysis of gene expression patterns by microarray hybridization in blood mononuclear cells of SLA-DRB1 defined Canadian Yorkshire pigs.
The Swine Leukocyte Antigen (SLA) system encodes molecules for self-nonself discrimination and is associated with immune responses and disease resistance. Three lines of pigs defined by their SLA-DRB1 alleles were developed at the University of Guelph for xenotransplantation and immune response studies. The aim of this project was to explore the potential association between defined SLA-DRB1 alleles and gene transcriptional patterns of other immune-related genes in blood mononuclear cells. Three SLA-DRB1 alleles were characterized using a RT-PCR-based sequencing method. The loci represented included a new allele, DRB1*04ns01. Next, microarray heterologous (bovine-porcine) hybridization together with qPCR were used to explore differential gene expression between SLA-DRB1-defined groups. Microarray analysis showed significant (p < 0.01) differential expression for 5 genes, mostly related to inflammation. Genes varied according to the comparison analyzed. Further testing with qPCR revealed the same trend of differential expression for 4 of the genes, although statistical significance was reached for only one. A new SLA-DRB1 allele was characterized. A potential association was found between SLA-DRB1 alleles and inflammation-related genes. However, the influence of other genes cannot be ruled out. These preliminary findings agree with other studies linking MHC haplotypes and inflammation processes, including autoimmune disease. The study provides an initial view of the biological interactions between the SLA complex and other immune-related genes. Future studies will focus on characterization of SLA-haplotypes associated with these particular alleles and the dynamics of the immune response to antigenic challenges.


The dynamic triple peak impact factor in traumatic brain injury influences native protein structures in gray and white matter as measured with computational simulation.
Traumatic brain injuries (TBIs) cause a substantial burden to the patient, relatives, and the society as a whole. Much experience and knowledge during the last two decades have improved the neurosurgical treatment as well as the outcome. However, there is still much debate on what actually happens when external kinetic energy is transferred to the head immediately after a TBI. Better knowledge about the cascades of mechanical events at the time of accident is a prerequisite to further reduce the burden in all categories and improve the neurosurgical care of TBI patients. In the present study, we use the finite element modeling of the human brain to numerically simulate impact velocities of 10, 6, and 2 m/s to clarify some of the immediate consequences of the external kinetic energy transfer focusing on the gray (GM) and white matters (WM). The numerical simulation was focused on the external kinetic energy transfer with a level of 227·3 J reaching the head, intracranial pressure (ICP), strain energy density, 1st principal strain level, and their respective impacts on the brain tissue. The results show that, for a 10 m/s impact, a total internal potential energy of 208·6 J was absorbed, of which 14·3% (29·81 J) was absorbed by the scalp, 22·05% (46·0 J) by the outer compact bone, 17·12% (35·72 J) by the porous bone, 27·44% (57·23 J) by the inner compact bone, and 7·31% (15·24 J) by the facial bone. The rest of the internal potential energy was defined to reach the GM (3·6%, 7·51 J) and the WM 1·59% (3·31 J). Also, the ICP, strain energy density, and 1st principal strain levels, defined as the dynamic triple peak impact factor, influenced the GM and WM with their own impact peaks during the first 10 ms after the accident and were the highest for the 10 and 6 m/s impacts, while the 2 m/s impact had only a slight influence on the GM and WM structures. The present study shows for the first time that following an impact of 10 m/s, 88·31% of the calculated external kinetic energy was absorbed by the external parts of the head before the remaining energy of 5·19% reached the GM and WM. GM absorbed about twice as much of the energy compared to the WM. It is suggested that the dynamic triple peak impact factor may have a profound effect on native protein structures in the cerebral metabolism after a TBI.


[Adherence of people with type 2 diabetes mellitus to drug treatment].
This cross-sectional and quantitative study aimed to evaluate the adherence to drug treatment of the people with diabetes mellitus and its relation to clinical, treatment and metabolic control variables. Sample consisted of 162 people with type 2 diabetes mellitus on follow-up outpatient care. The Measure of Treatment Adherence and consultation to the participants' medical records were used for data collection. A high adherence to drug treatment was obtained. For a p<0.05, it was obtained an inverse correlation with diastolic blood pressure and a direct correlation with the frequency of daily administration of insulin and oral antidiabetic agents. There were no statistically significant correlations between adherence and metabolic control variables. Results diverge from the literature regarding the adherence to drug treatment in chronic diseases, as well as in the correlation between adherence and complexity of drug regimen, which points to the need for more studies on this theme.


Effects of research disturbance on nest survival in a mixed colony of waterbirds.
Long-term research is crucial for the conservation and development of knowledge in ecology; however, it is essential to quantify and minimize any negative effects associated with research to gather reliable and representative long-term monitoring data. In colonial bird species, chicks are often marked with coded bands in order to assess demographic parameters of the population. Banding chicks in multi-species colonies is challenging because it involves disturbances to species that are at different stages of progress in their reproduction. We took advantage of a long term banding program launched on Glossy Ibis (Plegadis falcinellus) breeding in a major mixed colony of herons in Camargue, southern France, to assess the effect of banding operation disturbance on the reproductive success of the three most numerous waterbirds species in the colony. Over two breeding seasons (2015 and 2016), 336 nests of Glossy Ibis, Little Egrets (Egretta garzetta) and Cattle Egrets (Bubulcus ibis) were monitored from a floating blind in two zones of the colony: one zone disturbed twice a year by the banding activities and another not disturbed (control zone). We applied a logistic-exposure analysis method to estimate the daily survival rate (DSR) of nests and chicks aged up to three weeks. Daily survival rate of Glossy Ibis was reduced in the disturbed zone while DSR increased for Little and Cattle Egrets in the disturbed zone. Nevertheless, DSR was not reduced on the week following the banding, thus discarding a direct effect of handling on breeding success of Glossy Ibis. The protocol and statistical analysis presented here are robust and can be applied to any bird species to test for the effect of a research disturbance or other short and repeated temporal events that may affect reproductive success over one or more breeding seasons.


Linking fluorescence induction curve and biomass in herbicide screening.
A suite of dose-response bioassays with white mustard (Sinapis alba L) and sugar beet (Beta vulgaris L) in the greenhouse and with three herbicides was used to analyse how the fluorescence induction curves (Kautsky curves) were affected by the herbicides. Bentazone, a photosystem II (PSII) inhibitor, completely blocked the normal fluorescence decay after the P-step. In contrast, fluorescence decay was still obvious for flurochloridone, a PDS inhibitor, and glyphosate, an EPSP inhibitor, which indicated that PSII inhibition was incomplete. From the numerous parameters that can be derived from OJIP-steps of the Kautsky curve the relative changes at the J-step [Fvj = (Fm - Fj)/Fm] was selected to be a common response parameter for the herbicides and yielded consistent dose-response relationships. Four hours after treatment, the response Fvj on the doses of bentazone and flurochloridone could be measured. For glyphosate, the changes of the Kautsky curve could similarly be detected 4 h after treatment in sugar beet, but only after 24 hs in S alba. The best prediction of biomass in relation to Fvj was found for bentazone. The experiments were conducted between May and August 2002 and showed that the ambient temperature and solar radiation in the greenhouse could affect dose-response relationships. If the Kautsky curve parameters should be used to predict the outcome of herbicide screening experiments in the greenhouse, where ambient radiation and temperature can only partly be controlled, it is imperative that the chosen fluorescence parameters can be used to predict accurately the resulting biomass used in classical bioassays.


Synthesis and biological evaluation of some novel fused pyrazolopyrimidines as potential anticancer and antimicrobial agents.
Synthesis and evaluation of anticancer and antimicrobial activity of some novel pyrazolopyrimidines and fused pyrazolopyrimidines are reported. Twelve analogs were selected to be evaluated for their in vitro anticancer potential against a panel of three human tumor cell lines: hepatocellular carcinoma HepG2, cervical carcinoma HelaS3 and colon carcinoma CaCo. The obtained data revealed that eight compounds namely; 6b, 6d, 7c, 8c, 10b, 12b, 13a and 13b were able to exhibit variable degrees of anticancer activities against the three used cell lines, of which compound 6d proved to be the most active. On the other hand, all the newly synthesized compounds were subjected to in vitro antibacterial and antifungal screening. Almost all the tested compounds were found to possess variable degrees of antimicrobial activities. Collectively, compounds 7c, 8c, 12b, 13a and 13b could be considered as possible agents with dual anticancer and antimicrobial activities.


Cytolethal distending toxin family members are differentially affected by alterations in host glycans and membrane cholesterol.
Cytolethal distending toxins (CDTs) are tripartite protein exotoxins produced by a diverse group of pathogenic Gram-negative bacteria. Based on their ability to induce DNA damage, cell cycle arrest, and apoptosis of cultured cells, CDTs are proposed to enhance virulence by blocking cellular division and/or directly killing epithelial and immune cells. Despite the widespread distribution of CDTs among several important human pathogens, our understanding of how these toxins interact with host cells is limited. Here we demonstrate that CDTs from Haemophilus ducreyi, Aggregatibacter actinomycetemcomitans, Escherichia coli, and Campylobacter jejuni differ in their abilities to intoxicate host cells with defined defects in host factors previously implicated in CDT binding, including glycoproteins, and glycosphingolipids. The absence of cell surface sialic acid sensitized cells to intoxication by three of the four CDTs tested. Surprisingly, fucosylated N-linked glycans and glycolipids, previously implicated in CDT-host interactions, were not required for intoxication by any of the CDTs tested. Finally, altering host-cellular cholesterol, also previously implicated in CDT binding, affected intoxication by only a subset of CDTs tested. The findings presented here provide insight into the molecular and cellular basis of CDT-host interactions.


Membraneless glucose/oxygen enzymatic fuel cells using redox hydrogel films containing carbon nanotubes.
Co-immobilisation of three separate multiple blue copper oxygenases, a Myceliophthora thermophila laccase, a Streptomyces coelicolor laccase and a Myrothecium verrucaria bilirubin oxidase, with an [Os(2,2'-bipyridine)2 (polyvinylimidazole)10Cl](+/2+) redox polymer in the presence of multi-walled carbon nanotubes (MWCNTs) on graphite electrodes results in enzyme electrodes that produce current densities above 0.5 mA cm(-2) for oxygen reduction at an applied potential of 0 V versus Ag/AgCl. Fully enzymatic membraneless fuel cells are assembled with the oxygen-reducing enzyme electrodes connected to glucose-oxidising anodes based on co-immobilisation of glucose oxidase or a flavin adenine dinucleotide-dependent glucose dehydrogenase with an [Os(4,4'-dimethyl-2,2'-bipyridine)2(polyvinylimidazole)10Cl](+/2+) redox polymer in the presence of MWCNTs on graphite electrodes. These fuel cells can produce power densities of up to 145 μW cm(-2) on operation in pH 7.4 phosphate buffer solution at 37 °C containing 150 mM NaCl, 5 mM glucose and 0.12 mM O2. The fuel cells based on Myceliophthora thermophila laccase enzyme electrodes produce the highest power density if combined with glucose oxidase-based anodes. Although the maximum power density of a fuel cell of glucose dehydrogenase and Myceliophthora thermophila laccase enzyme electrodes decreases from 110 μW cm(-2) in buffer to 60 μW cm(-2) on testing in artificial plasma, it provides the highest power output reported to date for a fully enzymatic glucose-oxidising, oxygen-reducing fuel cell in artificial plasma.


IL-10-producing B cells are enriched in murine pericardial adipose tissues and ameliorate the outcome of acute myocardial infarction.
Acute myocardial infarction (MI) provokes an inflammatory response in the heart that removes damaged tissues to facilitate tissue repair/regeneration. However, overactive and prolonged inflammation compromises healing, which may be counteracted by antiinflammatory mechanisms. A key regulatory factor in an inflammatory response is the antiinflammatory cytokine IL-10, which can be produced by a number of immune cells, including subsets of B lymphocytes. Here, we investigated IL-10-producing B cells in pericardial adipose tissues (PATs) and their role in the healing process following acute MI in mice. We found that IL-10-producing B cells were enriched in PATs compared to other adipose depots throughout the body, with the majority of them bearing a surface phenotype consistent with CD5+ B-1a cells (CD5+ B cells). These cells were detected early in life, maintained a steady presence during adulthood, and resided in fat-associated lymphoid clusters. The cytokine IL-33 and the chemokine CXCL13 were preferentially expressed in PATs and contributed to the enrichment of IL-10-producing CD5+ B cells. Following acute MI, the pool of CD5+ B cells was expanded in PATs. These cells accumulated in the infarcted heart during the resolution of MI-induced inflammation. B cell-specific deletion of IL-10 worsened cardiac function, exacerbated myocardial injury, and delayed resolution of inflammation following acute MI. These results revealed enrichment of IL-10-producing B cells in PATs and a significant contribution of these cells to the antiinflammatory processes that terminate MI-induced inflammation. Together, these findings have identified IL-10-producing B cells as therapeutic targets to improve the outcome of MI.


Adjuvant chemotherapy for stage II and III breast carcinoma.
Stage II or III breast carcinoma patients were assigned to one of three adjuvant chemotherapy groups after mastectomy. The efficacy of melphalan, vs cyclophosphamide, fluorouracil, and prednisone (CFP), vs CFP plus BCG vaccine was compared in 173 patients treated for five days every six weeks for the first postoperative year. Tumor size, unfavorable local signs, extent of axillary nodal involvement, menopausal status, and participating hospital were considered in assigning patients to treatment groups. The median follow-up time was 26 months; 24.2% of the patients were studied for more than three years. Recurrent disease occurred in 31.6% of the patients in the melphalan group and in 13.4% and 13.2% in the other two groups. Six patients died of metastatic tumor; three others died of other causes. A favorable significant difference exists for polychemotherapy in prolonging disease-free interval in our series.


Aqueous Flow Reactor and Vapour-Assisted Synthesis of Aluminium Dicarboxylate Metal-Organic Frameworks with Tuneable Water Sorption Properties.
Energy-efficient indoors temperature and humidity control can be realised by using the reversible adsorption and desorption of water in porous materials. Stable microporous aluminium-based metal-organic frameworks (MOFs) present promising water sorption properties for this goal. The development of synthesis routes that make use of available and affordable building blocks and avoid the use of organic solvents is crucial to advance this field. In this work, two scalable synthesis routes under mild reaction conditions were developed for aluminium-based MOFs: (1) in aqueous solutions using a continuous-flow reactor and (2) through the vapour-assisted conversion of solid precursors. Fumaric acid, its methylated analogue mesaconic acid, as well as mixtures of the two were used as linkers to obtain polymorph materials with tuneable water sorption properties. The synthesis conditions determine the crystal structure and either the MIL-53 or MIL-68 type structure with square-grid or kagome-grid topology, respectively, is formed. Fine-tuning resulted in new MOF materials thus far inaccessible through conventional synthesis routes. Furthermore, by varying the linker ratio, the water sorption properties can be continuously adjusted while retaining the sigmoidal isotherm shape advantageous for heat transformation and room climatisation applications.


Pharmacological inhibition of forskolin-stimulated adenylate cyclase activity in rat brain by melatonin, its analogs, and diazepam.
Preincubation of rat forebrain membranes for 30-60 min with micromolar concentrations of the pineal hormone, melatonin, significantly inhibited forskolin-stimulated adenylate cyclase (AC) activity. Melatonin had an EC25 (concentration which inhibited AC activity by 25%) of 600 microM and caused a maximal inhibitory effect of approximately 30% at a concentration of 1000 microM. A comparison of the effects of melatonin and its analogs, 6-chloromelatonin and 2-iodomelatonin, in the striatum revealed that these halogenated drugs were 2-3 times more potent than melatonin in inhibiting AC activity. The EC25 values were 611, 226 and 189 microM for melatonin, 6-chloromelatonin and 2-iodomelatonin respectively. The receptor antagonists phentolamine (alpha-adrenergic), propranolol (beta-adrenergic), and metergoline (serotonergic) did not block the effect of melatonin in forebrain membranes. The central-type benzodiazepine (BZ) antagonist, Ro 15-1788 (flumazenil), also failed to block the inhibitory effects of melatonin, and the benzodiazepines, diazepam and Ro 5-4864, on AC activity. Evidence that inhibition of adenylate cyclase activity may be involved in the prevention of seizures suggests that the reported anticonvulsant effect of large doses of melatonin may be due to this mechanism. The greater potency of the halogenated melatonin analogs in inhibiting AC suggests that further study of their potential usefulness as anticonvulsants would be worthwhile.


Difficult Airway Management in Adult Coronavirus Disease 2019 Patients: Statement by the Society of Airway Management.
The coronavirus disease 2019 (COVID-19) disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), often results in severe hypoxemia requiring airway management. Because SARS-CoV-2 virus is spread via respiratory droplets, bag-mask ventilation, intubation, and extubation may place health care workers (HCW) at risk. While existing recommendations address airway management in patients with COVID-19, no guidance exists specifically for difficult airway management. Some strategies normally recommended for difficult airway management may not be ideal in the setting of COVID-19 infection. To address this issue, the Society for Airway Management (SAM) created a task force to review existing literature and current practice guidelines for difficult airway management by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. The SAM task force created recommendations for the management of known or suspected difficult airway in the setting of known or suspected COVID-19 infection. The goal of the task force was to optimize successful airway management while minimizing exposure risk. Each member conducted a literature review on specific clinical practice section utilizing standard search engines (PubMed, Ovid, Google Scholar). Existing recommendations and evidence for difficult airway management in the COVID-19 context were developed. Each specific recommendation was discussed among task force members and modified until unanimously approved by all task force members. Elements of Appraisal of Guidelines Research and Evaluation (AGREE) Reporting Checklist for dissemination of clinical practice guidelines were utilized to develop this statement. Airway management in the COVID-19 patient increases HCW exposure risk. Difficult airway management often takes longer and may involve multiple procedures with aerosolization potential, and strict adherence to personal protective equipment (PPE) protocols is mandatory to reduce risk to providers. When a patient's airway risk assessment suggests that awake tracheal intubation is an appropriate choice of technique, and procedures that may cause increased aerosolization of secretions should be avoided. Optimal preoxygenation before induction with a tight seal facemask may be performed to reduce the risk of hypoxemia. Unless the patient is experiencing oxygen desaturation, positive pressure bag-mask ventilation after induction may be avoided to reduce aerosolization. For optimal intubating conditions, patients should be anesthetized with full muscle relaxation. Videolaryngoscopy is recommended as a first-line strategy for airway management. If emergent invasive airway access is indicated, then we recommend a surgical technique such as scalpel-bougie-tube, rather than an aerosolizing generating procedure, such as transtracheal jet ventilation. This statement represents recommendations by the SAM task force for the difficult airway management of adults with COVID-19 with the goal to optimize successful airway management while minimizing the risk of clinician exposure.


Biomechanical considerations in the pathogenesis of osteoarthritis of the knee.
Osteoarthritis is the most common joint disease and a major cause of disability. The knee is the large joint most affected. While chronological age is the single most important risk factor of osteoarthritis, the pathogenesis of knee osteoarthritis in the young patient is predominantly related to an unfavorable biomechanical environment at the joint. This results in mechanical demand that exceeds the ability of a joint to repair and maintain itself, predisposing the articular cartilage to premature degeneration. This review examines the available basic science, preclinical and clinical evidence regarding several such unfavorable biomechanical conditions about the knee: malalignment, loss of meniscal tissue, cartilage defects and joint instability or laxity. Level of evidence IV.


Coordination polymers of osmium: the nature of osmium black.
The design of cytochemical reagents that yield osmiophilic products from which an osmium black may be derived on exposure to osmium tetroxide has resulted in new methods described previously for the ultrastructural demonstration of enzyme activity and functional groups of macromolecules with the electron microscope. Attempts to determine the nature of the osmium black end products have been frustrated by their insolubility. The preparation of watersoluble analogs and their characterization as polymers suggest that the insoluble osmium blacks are coordination polymers. This is consonant with the unusually favorable properties of osmium black in electron microscopy. Although polymers of osmium have frequently been postulated as the end products of reaction of osmium tetroxide with tissue conistituents or with other organic compounds, this is the first example of their characterization.


Acinar cell carcinoma: a rare pancreatic malignancy.
Acinar cell carcinoma of the pancreas is a rare pancreatic malignancy, constituting only 1-2% of all the pancreatic tumors. A young adult male presented with chronic diarrhea and upper abdominal pain, on investigations was found to have a large pancreatic tumor of size 12×7.5 cm involving the body of the pancreas. Pancreatic body and tail resection with splenectomy was done and final histopathological examination showed acinar cell carcinoma of the pancreas. Prognosis of acinar cell carcinoma is better than adenocarcinoma of the pancreas.


Combined exposure to deoxynivalenol facilitates lipid metabolism disorder in high-fat-diet-induced obesity mice.
Deoxynivalenol (DON) is a trichothecene toxin that mainly produced by strains of Fusarium spp. DON contamination is widely distributed and is a global food safety threat. Existing studies have expounded its harmful effects on growth inhibition, endocrine disruption, immune function impairment, and reproductive toxicity. In energy metabolism, DON suppresses appetite, reduces body weight, triggers lipid oxidation, and negatively affects cholesterol and fatty acid homeostasis. In this study, high-fat diet (HFD) induced obese C57BL/6J mice were orally treated with 0.1 mg/kg bw/d and 1.0 mg/kg bw/d DON for 4 weeks. The lipid metabolism of mice and the molecular mechanisms were explored. The data showed that although DON reduced body weight and fat mass in HFD mice, it significantly increased their serum triglyceride concentrations, disturbance of serum lipid metabolites, impaired glucose, and resulted in insulin intolerance in mice. In addition, the transcriptional and expression changes of lipid metabolism genes in the liver and epididymis (EP) adipose indicate that the DON-mediated increase in serum triglycerides is caused by lipoprotein lipase (LPL) inhibition in EP adipose. Furthermore, DON down-regulates the expression of LPL through the PPARγ signaling pathway in EP adipose. These results are further confirmed by the serum lipidomics analysis. In conclusion, DON acts on the PPARγ pathway of white adipose to inhibit the expression of LPL, mediate the increase of serum triglyceride in obese mice, disturb the homeostasis of lipid metabolism, and increase the risk of cardiovascular disease. This study reveals the interference mechanism of DON on lipid metabolism in obese mice and provides a theoretical basis for its toxic effect in obese individuals.