A systematic review and meta-analysis of prognostic indicators in patients with head and neck malignancy treated with immune checkpoint inhibitors.
Tumor immunotherapy has recently emerged as a crucial focal point in oncology treatment research. Among tumor immunotherapy approaches, tumor immune checkpoint inhibitors (ICIs) have attracted substantial attention in clinical research. However, this treatment modality has benefitted only a limited number of patients. We conducted a meta-analysis of various biomarkers to decipher their prognostic implications in patients with head and neck squamous cell carcinoma (HNSCC) who are treated with ICIs, and thus identify predictive markers with practical clinical relevance. A systematic search of electronic databases was conducted to identify clinical studies that examined the correlation between biomarkers and treatment outcomes in the HNSCC patients. The included articles were screened and analyzed to extract data regarding overall survival (OS) and progression-free survival (PFS). The relationship between the biomarkers included in the summary and prognosis was as follows: HPV positivity was associated with improved OS (HR = 0.76, 95% CI = 0.58-1.99), PFS (HR = 1.16, 95% CI = 0.81-1.67), and response (OR = 1.67, 95% CI = 1.37-2.99). PD-L1 positivity was associated with OS (HR = 0.71, 95% CI = 0.59-0.85), PFS (HR = 0.56 95% CI = 0.43-0.73), and response (OR = 2.16, 95% CI = 1.51-3.10). Neither HPV positivity nor PD-L1 positivity was associated with DCR. The following markers were collected for OS and PFS data and were associated with longer OS: lower Glasgow prognostic score (GPS/mGPS) grading, lower PS grading, high body mass index (BMI), low neutrophil-to-lymphocyte ratio (NLR), low platelet-to-lymphocyte ratio (PLR), high albumin (Alb), low lactate dehydrogenase (LDH). Factors associated with better PFS were lower GPS/mGPS grading, lower PS grading, high BMI, low NLR, high absolute lymphocyte count, and low LDH. Hyperprogressive disease was associated with worse OS and PFS. Fewer clinical studies have been completed on the tumor microenvironment and hypoxia, microsatellite instability/DNA mismatch repair, and microbiome and systematic analysis is difficult. In our meta-analysis, different immune checkpoint factors were associated with different prognoses in HNSCC patients receiving immunotherapy. HPV, PD-L1, BMI, Alb, HPD, PS, GPS/mGPS, LDH, NLR, and PLR predicted the ICI outcome in HNSCC patients.


Lost in translation: a genealogy of the "social capital" concept in public health.
To examine the genealogy of the social capital concept in public health, with attention to the epistemological concerns and academic practices that shaped the way in which this concept was translated into public health. A citation-network path analysis of the public health literature on social capital was used to generate a genealogy of the social capital concept in public health. The analysis identifies the intellectual sources, influential texts, and developments in the conceptualisation of social capital in public health. The population of 227 texts (articles, books, reports) was selected in two phases. Phase 1 texts were articles in the PubMed database with "social capital" in their title published before 2003 (n = 65). Phase 2 texts are those texts cited more than once by phase 1 articles (n = 165). The analysis shows how the scholarship of Robert Putnam has been absorbed into public health research, how three seminal texts appearing in 1996 and 1997 helped shape the communitarian form that the social capital concept has assumed in public health, and how both were influenced by the epistemological context of social epidemiology at the time. Originally viewed in public health research as an ecological level, psychosocial mechanism that might mediate the income inequality-health pathway, the dominance of the communitarian approach to social capital has given disproportionate attention to normative and associational properties of places. Network approaches to social capital were lost in this translation. Recovering them is key to a full translation and conceptualisation of social capital in public health.


Limited reproductive interference despite high rates of heterospecific pollen transfer among co-occurring bat-pollinated Burmeistera.
Many tropical plants are bat-pollinated, but these mammals often carry copious, multispecific pollen loads making bat-pollinated plants susceptible to heterospecific pollen deposition and reproductive interference. We investigated pollen transfer between sympatric bat-pollinated Burmeistera species and their response to heterospecific pollen deposition from each other. We quantified conspecific and heterospecific pollen deposition for two populations of B. ceratocarpa, a recipient species in heterospecific pollen transfer interactions, that co-occur with different donor relatives (B. borjensis and B. glabrata). We then used a cross-pollination scheme using pollen mixtures to assess the species' responses to heterospecific pollen deposition in terms of fruit abortion and seed production. Burmeistera ceratocarpa received significantly more heterospecific pollen from its relatives at both sites than its own pollen was deposited on its relatives. However, heterospecific pollen deposition only affected seed production by B. borjensis and B. glabrata, but not by B. ceratocarpa, suggesting that early acting post-pollination barriers buffer the latter against reproductive interference. Crosses between sympatric and allopatric populations suggest that the study species are fully isolated in sympatry, while isolation between allopatric populations is strong but incomplete. We did not observe evidence of reproductive interference among our study species, because either heterospecific pollen deposition did not affect their seed production (B. ceratocarpa) or they receive heterospecific pollen only rarely (B. borjensis and B. glabrata). Frequent heterospecific pollen deposition might favor the evolution of barriers against foreign pollen (as in B. ceratocarpa) that alleviate the competitive costs of sharing low fidelity pollinators with co-occurring species.


Targeted therapy against cancer stem cells.
Research into cancer stem cells (CSCs), which have the ability to self-renew and give rise to more mature (differentiated) cancer cells, and which may be the cells responsible for the overall organization of a tumor, has progressed rapidly and concomitantly with recent advances in studies of normal tissue stem cells. CSCs have been reported in a wide spectrum of human tumors. Like normal tissue stem cells, CSCs similarly exhibit significant phenotypic and functional heterogeneity. The ability of CSCs to self-renew results in the immortality of malignant cells at the population level, whereas the ability of CSCs to differentiate, either fully or partially, generates the cellular hierarchy and heterogeneity commonly observed in solid tumors. CSCs also appear to have maximized their pro-survival mechanisms leading to their relative resistance to anti-cancer therapies and subsequent relapse. Studies in animal models of human cancers have also provided insight into the heterogeneity and characteristics of CSCs, helping to establish a platform for the development of novel targeted therapies against specific CSCs. In the present study, we briefly review the most recent progress in dissecting CSC heterogeneity and targeting CSCs in various human tumor systems. We also highlight a few examples of CSC-targeted drug development and clinical trials, with the ultimate aim of developing more effective therapeutic regimens that are capable of preventing tumor recurrence and metastasis.


Gene amplification and functional diversification of melanocortin 4 receptor at an extremely polymorphic locus controlling sexual maturation in the platyfish.
In two swordtail species of the genus Xiphophorus, the onset of puberty has been shown to be modulated at the P locus by sequence polymorphism and gene copy-number variation affecting the type 4 melanocortin hormone receptor Mc4r. The system works through the interaction of two allelic types, one encoding wild type and the other dominant-negative receptors. We have analyzed the structure and evolution of the P locus in the platyfish Xiphophorus maculatus, where as many as nine alleles of P determining the onset of sexual maturity in males and females, fecundity in females, and adult size in males are located on both the X and Y chromosomes in a region linked to the master sex-determining locus. In this species, mc4r has been amplified to up to 10 copies on both the X and Y chromosomes through recent large serial duplications. Subsequently, mc4r paralogues have diverged considerably into many different subtypes. Certain copies have acquired new untranslated regions through genomic rearrangements, and transposable element insertions and other mutations have accumulated in promoter regions, possibly explaining observed deviations from the classical mc4r transcriptional pattern. In the mc4r-coding sequence, in-frame insertions and deletions as well as nonsense and missense mutations have generated a high diversity of Mc4r-predicted proteins. Most of these variants are expressed in embryos, adults, and/or tumors. Functional receptor characterization demonstrated major divergence in pharmacological behavior for Mc4r receptors encoded by different copies of platyfish mc4r, with differences in constitutive activity as well as binding and stimulation by hormones. The high degree of allelic and copy-number variation observed between individuals can explain the high level of polymorphism for sexual maturation, fecundity, and body size in the platyfish: multiple combinations of Mc4r variants with different biochemical properties might interact to modulate the melanocortin signaling that regulates the hypothalamus-pituitary-gonadal axis.


Outcome of overactive bladder in children.
One hundred forty-four children with a clinical diagnosis of overactive bladder were observed for a mean of 3.15 +/- 1.92 years. Initial management consisted of a behavioral modification program that included increased fluid intake, a timed voiding schedule and, if applicable, treatment of constipation. Those who failed to improve with the preceding intervention within 10 days to 2 weeks received an anticholinergic medication. Follow-up information was obtained by telephone. Caretakers and/or patients were asked a standard set of questions. The outcome with respect to urinary urgency, urinary frequency, daytime incontinence, posturing and urinary tract infections was recorded. After an average follow-up period of 3 years, 68 (47.2%) of the 144 children recovered from all symptoms of overactive bladder and 61 (42.4%) had decreased symptoms. Fifteen of the children, or 10.4%, still had all of the symptoms originally associated with overactive bladder. Children who had posturing as one of their symptoms had a significantly increased risk of urinary tract infection.


Hand function in subjects with spina bifida.
The aim of our study was to assess the influence of the Arnold-Chiari malformation, cervical cord dysraphism and hydrocephalus on hand function in subjects with meningomyelocele, but without many of the other confounding factors commonly found in this group e.g low IQ and cerebral palsy, which in themselves cause poor hand function. Three groups of subjects who attended main stream schools underwent a basic neurological examination of the upper limbs and a battery of hand function tests. Group 1 consisted of subjects with meningomyelocele and shunted hydrocephalus (n = 21), Group 2 subjects had isolated shunted hydrocephalus (n = 13) and Group 3 were normal controls (n = 18). The results show that subjects with meningomyelocele had weaker power in the small muscles of the hand as compared to the controls and those with isolated hydrocephalus (p = 0.01) and poorer fine motor control and co-ordination. The meningomyelocele group scored significantly poorer in all of the tests as compared to the control group using the dominant hand (overall, p = 0.0003), and all of the tests but one using the non-dominant hand (overall, p = 0.0005). Our study has demonstrated that children with meningomyelocele have poorer hand function than healthy controls, which is due to causes other than hydrocephalus, poor IQ or cerebral hemisphere pathology. Instead, cerebellar and cervical cord abnormalities appear to be exerting a significant deleterious influence on the function of the upper limbs.


Obacunone represses Salmonella pathogenicity islands 1 and 2 in an envZ-dependent fashion.
Obacunone belongs to a class of unique triterpenoids called limonoids, present in Citrus species. Previous studies from our laboratory suggested that obacunone possesses antivirulence activity and demonstrates inhibition of cell-cell signaling in Vibrio harveyi and Escherichia coli O157:H7. The present work sought to determine the effect of obacunone on the food-borne pathogen Salmonella enterica serovar Typhimurium LT2 by using a cDNA microarray. Transcriptomic studies indicated that obacunone represses Salmonella pathogenicity island 1 (SPI1), the maltose transporter, and the hydrogenase operon. Furthermore, phenotypic data for the Caco-2 infection assay and maltose utilization were in agreement with microarray data suggesting repression of SPI1 and maltose transport. Further studies demonstrated that repression of SPI1 was plausibly mediated through hilA. Additionally, obacunone seems to repress SPI2 under SPI2-inducing conditions as well as in Caco-2 infection models. Furthermore, obacunone seems to repress hilA in an EnvZ-dependent fashion. Altogether, the results of the study seems to suggest that obacunone exerts an antivirulence effect on S. Typhimurium and may serve as a lead compound for development of antivirulence strategies for S. Typhimurium.


CT coronary angiography-guided cardiovascular risk screening in asymptomatic patients: is it time?
Cardiovascular disease (CVD) is the leading cause of death in the UK, whilst millions live with various forms of the disease. Coronary artery disease constitutes a significant portion of this morbidity and mortality, and is the leading cause of premature death. Increasing focus is thus being placed on the optimisation of CVD prevention, where risk screening plays a key role. Indeed, the decline in age-adjusted cardiovascular mortality achieved up to now has been largely attributed to primary preventative therapies (e.g., statins) introduced earlier in the disease process. National initiatives exist to improve cardiovascular health at a population level, but in its current form, CVD screening at the individual level is predominantly undertaken using multivariate risk scores based on population-based data. These have multiple innate flaws, highlighted in this review. Non-invasive imaging plays a key role in the screening of other disease processes, helping to personalise the screening process. Although the coronary artery calcium score as a screening tool has a role in national and international guidance, whether a shift to screening with computed tomography coronary angiography (CTCA) is now appropriate is open for discussion. Image acquisition techniques continue to improve with reducing radiation exposure and an ever-expanding evidence-base for additional prognostic data offered by CTCA. This enables the potential identification of sub-clinical atherosclerosis, including with novel artificial intelligence techniques. This review aims to report current guidelines regarding cardiac CT imaging in the asymptomatic primary prevention setting, advances in various CT technologies and future opportunities for progress in this field.


Contamination of brake fluid by power steering fluid.
Analysis of a contaminated brake fluid revealed the contaminant to be power steering fluid. The sample received at the laboratory presented two immiscible phases, which were both organic. Both fluids were analyzed by GC-MS and compared with a library of known automotive fluids. The bottom layer (brake fluid) consisted of glycols while the top layer (power steering fluid) consisted of aliphatics ranging from C16 to C25+. An interesting phenomenon of diffusion of some of the glycols from the brake fluid phase into the power steering fluid phase was observed and needs to be taken into consideration in the interpretation of the results.


Posterior cranial fossa and cervical spine morphometric abnormalities in symptomatic Chiari type 0 and Chiari type 1 malformation patients with and without syringomyelia.
To better understand how anatomical features of Chiari malformation type 0 (CM0) result in the manifestation of Chiari malformation type 1 (CM1) signs and symptoms, we conducted a morphometric study of the posterior cranial fossa (PCF) and cervical canal in patients with CM1 and CM0. This retrospective study had a STROBE design and included 120 adult patients with MRI evidence of a small PCF (SPCF), typical clinical symptoms of CM1, and a diagnosis of CM1, CM0, or SPCF-TH0-only (SPCF with cerebellar ectopia less than 2 mm and without syringomyelia). Patients were divided by MRI findings into 4 groups: SPCF-TH0-only, SPCF-TH0-syr (CM0 with SPCF and syringomyelia), SPCF-CM1-only (SPCF with cerebellar ectopia 5 mm or more without syringomyelia), and SPCF-CM1-syr (CM1 with syringomyelia). Neurological examination data and MRI parameters were analyzed. All patient cohorts had morphometric evidence of a small, flattened, and overcrowded PCF. The PCF phenotype of the SPCF-TH0-only group differed from that of other CM cohorts in that the length of clivus and supraocciput and the height of the PF were longer, the upper CSF spaces of PCF were taller, and the area of the foramen magnum was smaller. The SPCF-TH0 groups had a more significant narrowing of the superior cervical canal and a smaller decrease in PCF height than the SPCF-CM1 groups. Patients with SPCF-TH0 with and without syringomyelia developed Chiari 1 symptoms and signs. Patients with SPCF-TH0-syr (Chiari 0) had more constriction of their CSF pathways in and around the foramen magnum than patients with SPCF-TH0-only.


Unexpected photophysical properties of symmetric indolylmaleimide derivatives.
Arcyriarubin A and arcyriaflavin A, two strongly emissive and intensely colored natural products containing both two indoles and a maleimide unit, are investigated (in the flavin the two indole moieties are coupled by a cyclization). The photophysical properties of these compounds were studied in several solvents using UV-vis absorption, steady-state and time-resolved emission, nano- and femtosecond transient absorption spectroscopy. Furthermore, the effect of complexation with zinc(II) 1,4,7,11-tetraazacyclododecane on the photophysical properties of these natural products has been investigated. The chemical structures of the compounds would suggest a charge transfer (CT) character in the ground and/or excited states, since indole is a well-known electron donor and maleimide is a good electron acceptor. Their solvatochromic behavior was investigated by using the Kamlet-Taft approach and indicates only a small CT character in the excited state. This is substantiated by the time-resolved spectroscopy and the complexation study. Molecular orbital calculations indicate that there are no electronic transitions in which a large electron density is transferred from one indole unit to the maleimide part. All calculated orbitals show a strong delocalization of the electron density over the whole molecule. These findings corroborate the experimental results. Whereas the two compounds do have a substantial (calculated) ground-state dipole moment (6 D) and show some solvatochromic behavior, they behave more like conjugated aromatic systems than like electron donor-acceptor systems.


Lawsuits After Primary and Revision Total Knee Arthroplasty: A Malpractice Claims Analysis.
As the number of total knee arthroplasties (TKAs) increases, the number of associated complications will also increase. Our goal with this study was to identify common causes of and financial trends relating to malpractice claims filed after TKA. We analyzed malpractice claims filed for alleged neglectful primary and revision TKA surgeries performed between 1982 and 2012 by orthopaedic surgeons insured by a large New York state malpractice carrier. We identified 69 primary and 8 revision TKAs in the malpractice carrier's database. All cases were performed between 1982 and 2012; all claims were closed between 1989-2015. The most frequent factor leading to lawsuits for primary TKA was chronic pain or dissatisfaction in 12 cases, followed by nerve palsy in 8, postoperative in-hospital falls in 5, and deep vein thrombosis or pulmonary embolism in 3. Medical complications included acute respiratory distress syndrome, cardiac arrest, and decubitus ulcers. Contracture was most common after revision TKA (three of eight cases). Mean indemnity was $325,369, and the largest single settlement was $2.42 million. The average expense relating to the defense of these cases was $66,365. Orthopaedic surgeons should continue to focus attention on prevention of complications and on preoperative patient education. Preoperative counseling regarding the risks of incomplete pain relief could reduce substantially the number of suits relating to primary TKAs.


Cardiac and vascular protection: the potential of ONTARGET.
Cardiovascular risk is determined by multiple risk factors. Blockade of the renin-angiotensin system is an important approach to the prevention of cardiovascular events. In the largest angiotensin receptor blocker cardiovascular outcome study to date, the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) program will compare the efficacy of therapy with telmisartan and ramipril, in reducing cardiovascular events in patients at high risk (history of coronary artery disease, stroke or transient ischemic attack, peripheral artery disease, or diabetes with evidence of end-organ damage). Recruited patients (n = 31,546) will be followed up for a period of 6 years, and more than 150,000 patient-years of data will be recorded. The primary endpoint is a composite of cardiovascular death, stroke, acute myocardial infarction, and hospitalization for congestive heart failure; secondary endpoints focus on reductions in newly diagnosed heart failure, new-onset type 2 diabetes, cognitive decline, atrial fibrillation, and nephropathy. In addition, an ambulatory blood pressure monitoring substudy will be conducted to assess the effect of treatment on endpoints after adjustment for 24-hour blood pressure values. Other substudies of the treatment effects on erectile dysfunction, blood markers, arterial stiffness, oral glucose tolerance, and the progression of target organ damage are also planned. The results of the ONTARGET program are due in 2008, and the findings are expected to have important clinical implications for the management of patients at high cardiovascular risk.


Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression.
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with increased production of terminally differentiated cells. The disease course is generally chronic, but some patients show disease progression (secondary myelofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify disease-associated somatic lesions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We identified 25 recurrent aberrations that were found in 3 or more samples. An increased number of chromosomal lesions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus kinase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with post-MPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 [FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZF1]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runt-related transcription factor 1 [RUNX1]). Our data provide insight into the genetic complexity of MPNs and implicate new genes involved in disease progression.


Rate-Limiting Steps in the Intramolecular C-H Activation of Ruthenium N-Heterocyclic Carbene Complexes.
Ruthenium (II) complexes with N-heterocyclic carbenes (NHC) are commonly used as efficient catalysts in hydrogenation of olefins with simultaneous intramolecular C-H activation. Using the DFT approach, we have investigated the entire hydrogenation reaction pathway for four new potential catalysts and ethylene, a model substrate. Our calculations imply that the dissociation of phosphine is the rate-limiting step of hydrogenation, contrary to recent computational results. We also found that catalysts bearing NHCs with aliphatic and aromatic side groups are energetically favorable over other aliphatic cyclohexyl-substituted NHC. To examine how electronic properties of various catalysts influence the energetic barrier in the crucial steps of the reaction, we applied the Noncovalent Interaction analysis, which allowed us to reveal crucial interactions which stabilize/destabilize important intermediates and transition states in the hydrogenation reaction.


Cheong-sang-bang-pung-san alleviated hepatic lipid accumulation by regulating lipid metabolism in vitro and in vivo.
Introduction: The occurrence of fatty liver disease, resulting from the accumulation of excessive fat within the liver, has been showing a significant and rapid increase. This study aimed to evaluate the therapeutic effects of Cheong-sang-bang-pung-san extract (CB) on fatty liver disease, and to elucidate the underlying mechanisms. Methods: We used a high-fat diet (HFD)-fed fatty liver mice and free fatty acid (FFA) induced HepG2 cell lipid accumulation model. The levels of serum, hepatic, and intracellular lipid content were assessed. Histopathological staining was used to evaluate the extent of hepatic lipid accumulation. Real-time polymerase chain reaction and Western blotting were conducted to examine the expression of factors associated with lipid metabolism. Results: We demonstrated that treatment with CB dramatically reduced body weight, liver weight, and fat mass, and improved the serum and hepatic lipid profiles in HFD-induced fatty liver mice. Additionally, CB alleviated lipid accumulation in HFD-fed mice by controlling lipid metabolism, including fatty acid uptake, triglyceride and cholesterol synthesis, and fatty acid oxidation, at the mRNA as well as protein levels. In free fatty acid-treated HepG2 cells, CB significantly reduced intracellular lipid accumulation by regulating lipid metabolism via the activation of AMP-activated protein kinase. Conclusion: These findings provide insights into the mechanisms underlying CB's effects on liver steatosis and position of CB as a potential therapeutic candidate for managing lipid metabolic disorders.


[Patients with solid organ transplantation and skin cancer: determination of risk factors with emphasis in photoexposure and immunosuppressive regimen. Experience in a third level hospital].
Non-melanoma skin cancer (NMSC) is the most common malignancy in transplant patients. The incidence of basal cell carcinoma (BCC) is 10 times greater than in the general population, while squamous cell carcinoma (SCC) is 100 times greater. The relationship between the BCC and SCC reverses and increases according to the degree of immunosuppression and sun exposure. One way to predict the risk of NMSC should be based on factors such as: total sun burden factor (TSB). To determine the influence of various risk factors in the development of NMSC and its relation to the type and duration of immunosuppressive treatment, type of transplant, and TSB. We worked with a fledgling historical cohort in which patients with kidney or liver transplant were identified and recorded if they developed some form of skin cancer. To study the factors associated with NMSC, we resorted to the strategy of a case-control study. Dermatological examination was performed and a questionnaire of risk factors made in both groups. Of the 140 patients enrolled, 51 were women and 89 men, 120 were renal transplant recipients and 20 liver transplants. Of patients who developed NMSC, 100% were renal transplant recipients. The median age was 48.5 years. Most cancer patients worked outdoors. A total of 78 lesions were found in 40 NMSC patients, 59 (76%) of them were SCC, and 19 (24%) BCC; 45% of all skin cancer patients had more than one injury. The worst affected areas were those photoexposed: 60% head and neck, trunk and upper extremities 18% 50%. In 30% of patients (12/40) 22 new tumors were identified (SCC 18 and BCC 4). No lesions were identified for melanoma. In multivariate logistic regression analysis, statistically significant features were: type-based immunosuppressive regimen of cyclosporine A, azathioprine and prednisone (OR: 59.7; 95% CI: 10.2-348), TSB > 10 (OR: 19; 95% CI: 3-120) and duration of use of immunosuppressive therapy (OR: 1.06; 95% CI: 0.9-1.1). The mean time from transplantation to first dermatological assessment was six years (+5.4). Of the patients, 93% had not regularly used sunscreen before and after transplantation. The dermatological assessment is convenient and easy to perform. Primary prevention, close monitoring, diagnosis, and treatment of skin lesions are essential components of a comprehensive program for the evaluation of transplant recipients, the purpose of which is to reduce the incidence and morbidity associated with cancer.


Tumor-derived microvesicles and the cancer microenvironment.
Tumor cells release microvesicles (MVs) that may remain in the extracellular space in proximity to the cell of origin, or that may migrate to distant sites by entering biological fluids. Increasing evidence indicates that MVs are mediators of cell-to-cell communication which are able to deliver specific signals, both within the tumor microenvironment and in the long-range. MVs are able to transfer bioactive lipids and proteins, including oncogene products and receptors, from the cell of origin to recipient cell. In addition, MVs may induce epigenetic changes in recipient cells by transferring genetic information in the form of mRNA, microRNA and oncogenes. Several changes in the phenotype and function that occur in stromal cells within the cancer microenvironment have been ascribed to tumor cell-derived MVs. In this review we discuss the various biological actions of tumor-derived MVs and their potential role in tumor biology.


Linking Peripartal Dynamics of Ruminal Microbiota to Dietary Changes and Production Parameters.
During the peripartal period, proper acclimatization of rumen microorganisms to variations in nutritional management can facilitate the transition into lactation. This study characterized the temporal shifts in the composition and functional properties of ruminal microbiota during the periparturient period in dairy cows subjected to a typical two-tiered feeding management approach. Ruminal digesta samples from eight multiparous fistulated Holstein cows were collected on days -14, -7, 10, 20, and 28 relative to parturition. High-throughput Illumina sequencing of the V4 region of the bacterial 16S rRNA gene revealed distinct clustering patterns between pre- and postpartal ruminal microbiota. During the prepartal period, when the voluntary dry matter intake was lower, we observed strikingly lower inter-animal variations in the composition of the ruminal microbiota. Genera Ruminococcus and Butyrivibrio, which are considered major fibrolytic rumen dwellers, were overrepresented in the prepartal rumen ecosystem. In contrast, increased postpartal voluntary DMI was associated with enrichment of bacterial genera mainly consisting of proteolytic, amylolytic, and lactate-producer species (including Prevotella, Streptococcus, and Lactobacillus). These, together with the postpartal enrichment of energy metabolism pathways, suggested a degree of acclimatization of the ruminal microbiota to harvest energy from the carbohydrate-dense lactation diet. In addition, correlations between ruminal microbiota and parameters such as milk yield and milk composition underscored the metabolic contribution of this microbial community to the cow's performance and production.


Inhibitory effect of high-density lipoproteins from plasma of schistosomiasis mansoni patients on the binding of normal low-density lipoproteins to cultured skin fibroblasts.
Total high-density lipoproteins (HDL) isolated from the plasma of patients suffering from hepatosplenic schistosomiasis mansoni have an abnormal apoprotein composition. The apoprotein E content is increased and one or two abnormal apoproteins with pI 6.0 and 6.5 are present in patient HDL. Whilst normal HDL have a negligible effect on the binding of 125I-labelled normal low density lipoproteins (LDL) by cultured human skin fibroblasts, patient HDL is inhibitory. It is concluded that the abnormal apoprotein composition of schistosomiasis HDL allows it to bind to the LDL receptor on the fibroblast membrane.


[Atypical urticaria disclosing acute basophilic leukemia. Apropos of a case associated with hyperhistaminemia].
Acute basophilic leukaemia (ABL) is a rare disease characterized by high fever, anaemia and haemorrhagic diathesis. Its prognosis is somber and its response to therapy mediocre. Death is mainly due to cerebral or digestive hemorrhage and coronary disease. In a very small number of cases ABL, like all diseases accompanied by an increase in basophils, may be associated with hyperhistaminemia responsible for cutaneous and gastric symptoms.


Application of leukocyte transcriptomes to assess systemic consequences of risk factors for cardiovascular disease.
Prevention of cardiovascular disease (CVD) remains a major health issue in the Western world. The diagnostic and therapeutic approach is currently based on risk factor assessment and treatment, which adequately predicts CVD at population level, but not at the level of a single individual. This may arise from the fact that the stage and activity of complex disease states are not likely to be captured by a single parameter or a small set of markers and thus may need a more complex representation. The aim of this review is to explore the possibility of pursuing the use of high-throughput gene expression profiling as a way to improve diagnosis, prognosis and monitoring of the disease. Novel chip-based techniques such as oligo- and cDNA microarrays can measure the abundance of thousands of mRNA transcripts in parallel and thus provide a comprehensive picture of the cell phenotype. Circulating white blood cells (WBCs), which are exposed to the systemic environment (including the risk factors) and are directly involved in the low-grade chronic inflammation related to CVD, have the potential to be used in this context to improve phenotyping of the patient. The paper reviews conceptual limitations in the use of risk factors and biomarkers, and shows the rationale beyond the possible use of circulating WBCs or subpopulations as representative cells to monitor systemic consequences of CVD. Methodological issues in performing microarray analysis of WBCs are also addressed, including controversies related to the choice of adequate cell populations and reference samples. Reproducibility and challenges occurring in the definition of a disease-specific gene panel are also discussed. The available proofs of principle from the literature presented in the last section of the review further support exploration of the application of circulating cell transcriptomics in CVD.


Securing SIFT: Privacy-Preserving Outsourcing Computation of Feature Extractions Over Encrypted Image Data.
Advances in cloud computing have greatly motivated data owners to outsource their huge amount of personal multimedia data and/or computationally expensive tasks onto the cloud by leveraging its abundant resources for cost saving and flexibility. Despite the tremendous benefits, the outsourced multimedia data and its originated applications may reveal the data owner's private information, such as the personal identity, locations, or even financial profiles. This observation has recently aroused new research interest on privacy-preserving computations over outsourced multimedia data. In this paper, we propose an effective and practical privacy-preserving computation outsourcing protocol for the prevailing scale-invariant feature transform (SIFT) over massive encrypted image data. We first show that the previous solutions to this problem have either efficiency/security or practicality issues, and none can well preserve the important characteristics of the original SIFT in terms of distinctiveness and robustness. We then present a new scheme design that achieves efficiency and security requirements simultaneously with the preservation of its key characteristics, by randomly splitting the original image data, designing two novel efficient protocols for secure multiplication and comparison, and carefully distributing the feature extraction computations onto two independent cloud servers. We both carefully analyze and extensively evaluate the security and effectiveness of our design. The results show that our solution is practically secure, outperforms the state-of-the-art, and performs comparably with the original SIFT in terms of various characteristics, including rotation invariance, image scale invariance, robust matching across affine distortion, and addition of noise and change in 3D viewpoint and illumination.


Vav1 and Vav2 play different roles in macrophage migration and cytoskeletal organization.
Vav family proteins act as guanine nucleotide exchange factors for Rho family proteins, which are known to orchestrate cytoskeletal changes and cell migration in response to extracellular stimuli. Using mice deficient for Vav1, Vav2 and/or Vav3, overlapping and isoform-specific functions of the three Vav proteins have been described in various hematopoietic cell types, but their roles in regulating cell morphology and migration have not been studied in detail. To investigate whether Vav isoforms have redundant or unique functions in regulating adhesion and migration, we investigated the properties of Vav1-deficient and Vav2-deficient macrophages. Both Vav1-deficient and Vav2-deficient cells have a smaller adhesive area; yet, only Vav1-deficient cells have a reduced migration speed, which coincides with a lower level of microtubules. Vav2-deficient macrophages display a high level of constitutive membrane ruffling, but neither Vav1 nor Vav2 is required for colony stimulating factor-1-induced membrane ruffling and cell spreading. Our results suggest that the migration speed of macrophages is regulated independently of spread area or membrane ruffling and that Vav1 is selectively required to maintain a normal migration speed.


Where's the Noise? Key Features of Spontaneous Activity and Neural Variability Arise through Learning in a Deterministic Network.
Even in the absence of sensory stimulation the brain is spontaneously active. This background "noise" seems to be the dominant cause of the notoriously high trial-to-trial variability of neural recordings. Recent experimental observations have extended our knowledge of trial-to-trial variability and spontaneous activity in several directions: 1. Trial-to-trial variability systematically decreases following the onset of a sensory stimulus or the start of a motor act. 2. Spontaneous activity states in sensory cortex outline the region of evoked sensory responses. 3. Across development, spontaneous activity aligns itself with typical evoked activity patterns. 4. The spontaneous brain activity prior to the presentation of an ambiguous stimulus predicts how the stimulus will be interpreted. At present it is unclear how these observations relate to each other and how they arise in cortical circuits. Here we demonstrate that all of these phenomena can be accounted for by a deterministic self-organizing recurrent neural network model (SORN), which learns a predictive model of its sensory environment. The SORN comprises recurrently coupled populations of excitatory and inhibitory threshold units and learns via a combination of spike-timing dependent plasticity (STDP) and homeostatic plasticity mechanisms. Similar to balanced network architectures, units in the network show irregular activity and variable responses to inputs. Additionally, however, the SORN exhibits sequence learning abilities matching recent findings from visual cortex and the network's spontaneous activity reproduces the experimental findings mentioned above. Intriguingly, the network's behaviour is reminiscent of sampling-based probabilistic inference, suggesting that correlates of sampling-based inference can develop from the interaction of STDP and homeostasis in deterministic networks. We conclude that key observations on spontaneous brain activity and the variability of neural responses can be accounted for by a simple deterministic recurrent neural network which learns a predictive model of its sensory environment via a combination of generic neural plasticity mechanisms.


Spectrum of Radiological Manifestations in Lymphoproliferative Malignancies with Unusual Extra Nodal Soft Tissue Involvement.
Lymphoproliferative malignancies constitute a wide spectrum of haematological malignancies and their prevalence is widely increasing. Non-Hodgkin lymphomas and Hodgkin disease, frequently involve extranodal soft tissue structures in the head and neck, thorax and abdomen. These malignancies may involve virtually any type of soft tissues to any extent; hence many different imaging manifestations are possible which may mimic other disorders. The imaging characteristics of extranodal lymphomatous soft tissue involvement are described and classified here according to the site of involvement in 6 cases (primary diseases with orbital, muscle, extra testicular, scalp, sinonasal and pachymeningeal/dural involvement). In majority of these cases at presentation we found a predominantly homogeneous soft tissue mass with mildly high attenuation on CT and a T2 intermediate signal on MRI at these sites without any manifestation of disease elsewhere but on follow-up two out of these six cases developed systemic disease elsewhere. Few consistent patterns were noticed on CT and MRI which might help to include lymphomas as an important differential diagnosis of soft tissue masses. Though a definitive diagnosis requires a biopsy (bone marrow, lymph node, or mass), and other laboratory tests, imaging primarily aims at staging of the disease and identification of new or recurrent disease.


Immunization status of children admitted to a tertiary-care hospital of north India: reasons for partial immunization or non-immunization.
Reasons for the low coverage of immunization vary from logistic ones to those dependent on human behaviour. The study was planned to find out: (a) the immunization status of children admitted to a paediatric ward of tertiary-care hospital in Delhi, India and (b) reasons for partial immunization and non-immunization. Parents of 325 consecutively-admitted children aged 12-60 months were interviewed using a semi-structured questionnaire. A child who had missed any of the vaccines given under the national immunization programme till one year of age was classified as partially-immunized while those who had not received any vaccine up to 12 months of age or received only pulse polio vaccine were classified as non-immunized. Reasons for partial/non-immunization were recorded using open-ended questions. Of the 325 children (148 males, 177 females), 58 (17.84%) were completely immunized, 156 (48%) were partially immunized, and 111 (34.15%) were non-immunized. Mothers were the primary respondents in 84% of the cases. The immunization card was available with 31.3% of the patients. All 214 partially- or completely-immunized children received BCG, 207 received OPV/DPT1, 182 received OPV/DPT2, 180 received OPV/DPT3, and 115 received measles vaccines. Most (96%) received pulse polio immunization, including 98 of the 111 non-immunized children. The immunization status varied significantly (p<0.05) with sex, education of parents, urban/rural background, route and place of delivery. On logistic regression, place of delivery [odds ratio (OR): 2.3, 95% confidence interval (CI) 1.3-4.1], maternal education (OR=6.94, 95% CI 3.1-15.1), and religion (OR=1.75, 95% CI 1.2-3.1) were significant (p<0.05). The most common reasons for partial or non-immunization were: inadequate knowledge about immunization or subsequent dose (n=140, 52.4%); belief that vaccine has side-effects (n=77, 28.8%); lack of faith in immunization (n=58, 21.7%); or oral polio vaccine is the only vaccine required (n=56, 20.9%. Most (82.5%) children admitted to a tertiary-care hospital were partially immunized or non-immunized. The immunization status needs to be improved by education, increasing awareness, and counselling of parents and caregivers regarding immunizations and associated misconceptions as observed in the study.


Detection and identification of mycobacteria in formalin-fixed, paraffin-embedded tissues by nested PCR and restriction enzyme analysis.
A novel assay based on a nested PCR and restriction enzyme analysis of the PCR products was developed for the rapid detection and identification of Mycobacterium bovis and M. avium-M. intracellulare species in formalin-fixed, paraffin-embedded tissue (PET) specimens. On the basis of the nucleotide sequence data obtained in the present study, general nested primers were constructed to amplify a 424-bp segment of the gene encoding the 65-kDa surface antigen of mycobacteria. The nested PCR assay proved to be highly sensitive, since as little as 5 to 10 fg of extracted mycobacterial DNA was detected. The safety of the assay as a routine method for the diagnosis of M. bovis and M. avium-M. intracellulare in PET specimens was provided by taking various precautions. In order to prevent false positivity, specific tools and procedures were applied. To detect false-negative results and assess the efficiency of the PCR, an internal standard molecule of amplification was constructed. The digestion of the amplicons with the restriction endonuclease Sau96-I allowed the identification of M. bovis and M. avium-M. intracellulare in a large number of clinical specimens. The present results indicate that PCR combined with an internal control of amplification and restriction enzyme analysis of the amplicons provides a rapid, sensitive, and reliable method for routine diagnostic laboratories to detect and identify M. bovis and M. avium-M. intracellulare in PET specimens.


Difficulty and discrimination parameters of Boston naming test items in a consecutive clinical series.
The Boston Naming Test is one of the most widely used neuropsychological instruments; yet, there has been limited use of modern psychometric methods to investigate its properties at the item level. The current study used Item response theory to examine each item's difficulty and discrimination properties, as well as the test's measurement precision across the range of naming ability. Participants included 300 consecutive referrals to the outpatient neuropsychology service at Mayo Clinic in Florida. Results showed that successive items do not necessarily reflect a monotonic increase in psychometric difficulty, some items are inadequate to distinguish individuals at various levels of naming ability, multiple items provide redundant psychometric information, and measurement precision is greatest for persons within a low-average range of ability. These findings may be used to develop short forms, improve reliability in future test versions by replacing psychometrically poor items, and analyze profiles of intra-individual variability.


Health outcomes from an innovative enhanced medication therapy management model.
To evaluate the impact of pharmacist-delivered medication safety reviews (MSRs) on total medical expenditures, hospitalizations, emergency department (ED) visits, and mortality in Medicare Part D beneficiaries, whose plan was a participant of the Enhanced Medication Therapy Management model. Retrospective, pre-post, cohort study. We evaluated the aforementioned outcomes for beneficiaries who were targeted, according to their MedWise Risk Scores (MRS), for MSR services in both 2018 and 2019. The "MSR" cohort included those who received their first-ever MSR in 2018 and received another MSR in 2019. The "failed to engage" (FTE) cohort included beneficiaries who were targeted in both 2018 and 2019 but did not engage in an MSR at any point through the end of 2019. For both cohorts, we calculated the change from 2018 to 2019 for each outcome and then determined whether unadjusted year-over-year changes differed significantly between cohorts. Additionally, these difference-in-differences (DiD) analyses were adjusted for baseline MRS and multimorbidity. A total of 11,436 beneficiaries were targeted for MSRs in both 2018 and 2019. Beneficiaries were, on average, aged 76.6 ± 10.0 years. The MSR cohort (N = 4384) outperformed the FTE cohort (N = 7052) in total medical costs (DiD = $958/y [7.5% savings]; P = .042), hospitalizations (DiD = 3.9 admissions/100 beneficiaries/y [10% reduction]; P = .032), ED visits (DiD = 6.2 visits/100 beneficiaries/y [10% reduction]; P = .014), and mortality (2.1% fewer died in 2019; P < .001). Each outcome remained significant after adjusting for baseline MRS and multimorbidity. MSRs were effective at improving annual health care costs, hospitalizations, ED visits, and mortality in Medicare beneficiaries targeted according to MRS.


The Graphical Query Language: a tool for analysis of gene expression time-courses.
The Graphical Query Language (GQL) is a set of tools for the analysis of gene expression time-courses. They allow a user to pre-process the data, to query it for interesting patterns, to perform model-based clustering or mixture estimation, to include subsequent refinements of clusters and, finally, to use other biological resources to evaluate the results. Analyses are carried out in a graphical and interactive environment, allowing expert intervention in all stages of the data analysis. The GQL package is freely available under the GNU general public license (GPL) at http://www.ghmm.org/gql


When zoo visitors "connect" with a zoo animal, what does that mean?
Connection with a zoo animal may increase conservation-mindedness in zoo visitors, potentially resulting in conservation-oriented behavior change. No research has attempted to establish what this "connection" actually means. Visitors (N = 85) to Melbourne Zoo were asked to name the animal with which they most connected, the extent to which they connected with it, and to qualitatively describe what it meant to connect with that animal. Many (but not all) participants connected with charismatic megafauna: primate, great ape, large carnivore, or large herbivore. Qualitative analysis revealed five common themes in the meaning of connection: Appreciation, Attribution, Inspires Emotions, Interaction, and Proximity. Overall connection level was significantly correlated with perceptions of conservation caring for the chosen species. Future research should aim to determine what factors affect a zoo visitor's connection level, which could impact attitudes and behaviors toward conservation.


[What is the optimal diet?]
Food intake is expected to cover our basal requirements in energy, proteins, minerals, vitamins, trace elements and water. As it has been already suggested by Hippocrates, food can play a role in preventing but also in caring some diseases. The type of diet has medical, mediatic, economic and cultural implications. Many diets are recommended but only a few of them have been validated. The fight against obesity has also created a lot of diet for losing weight. This article is a critical review of some diet in the domain of cancer, gluten sensitivity, irritable bowel syndrome and therapeutic fasting.


Non-invasive in situ dynamic monitoring of elastic properties of composite battery electrodes by EQCM-D.
Reversible Li-ion intercalation into composite Li-ion battery (LIB) electrodes is often accompanied by significant dimensional electrode changes (deformation) resulting in significant deterioration of the cycling performance. Viscoelastic properties of polymeric binders affected by intercalation-induced deformation of composite LIB electrodes have never been probed in situ on operating electrochemical cells. Here, we introduce a newly developed noninvasive method, namely electrochemical quartz-crystal microbalance with dissipation monitoring (EQCM-D), for in situ monitoring of elastic properties of polymeric binders during charging of LIB electrodes. As such, we find EQCM-D as a uniquely suitable tool to track the binder's structural rigidity/softness in composite Li insertion electrodes in real-time by the characteristic increase/decrease of the dissipation factor during the charging-discharging process. The binders partially swollen in aprotic solutions demonstrate intermediate viscoelastic charge-rate-dependent behavior, revealing rigid/soft behavior at high/low charging rates, respectively. The method can be adjusted for continuous monitoring of elastic properties of the polymeric binders over the entire LIB electrodes cycling life.


Influence of age on clinical characteristics, pharmacological management and exacerbations in children with asthma.
Asthma trials and guidelines often do not distinguish between adolescents and younger children. Using a large English data set, we evaluated the impact of age on asthma characteristics, management and exacerbations. Primary care medical records, 2004-2021, were linked to hospital records. Children were categorised by age at diagnosis and followed until the next age bracket. Ages (based on management guidelines) were 5-8 years, 9-11 years and adolescents (12-16 years). Characteristics evaluated included body mass index, allergies and events before and after diagnosis (symptoms, medication). Exacerbation incidence was calculated. Multivariable Cox proportional hazards determined associations with exacerbations. 119 611 children were eligible: 61 940 (51.8%) 5-8 years, 32 316 (27.7%) 9-11 years and 25 355 (21.2%) adolescents. Several characteristics differed by age; children aged 5-8 years had the highest proportion with eczema, food/drug allergy and cough, but adolescents had the highest proportion with overweight/obesity, aeroallergen sensitisation, dyspnoea and short-acting-beta-agonist only use. Exacerbation rates were highest in the youngest children (per 100 person-years (95% CI): 5-8 years =13.7 (13.4-13.9), 9-11 years =10.0 (9.8-10.4), adolescents =6.7 (6.5-7.0)). Exacerbation risk factors also differed by age; 5-8 years: male, eczema and food/drug allergy were strongly associated, but for children ≥9 years old, obesity and aeroallergen sensitisation were strongly associated. For all children, higher socioeconomic deprivation was significantly associated with having an exacerbation. Delayed diagnosis was most common in children aged 5-8 years and was associated with increased exacerbations across all ages. Children's baseline characteristics and exacerbation rates varied according to their age group. Clinical guidelines should consider age at time of diagnosis more discretely than the broad range, 5-16 years, as this appears to impact on asthma severity and management.


Severe SARS-CoV-2 Infection in a Cat with Hypertrophic Cardiomyopathy.
Coronavirus disease 19 (COVID-19), has claimed millions of human lives worldwide since the emergence of the zoonotic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China in December 2019. Notably, most severe and fatal SARS-CoV-2 infections in humans have been associated with underlying clinical conditions, including diabetes, hypertension and heart diseases. Here, we describe a case of severe SARS-CoV-2 infection in a domestic cat (Felis catus) that presented with hypertrophic cardiomyopathy (HCM), a chronic heart condition that has been described as a comorbidity of COVID-19 in humans and that is prevalent in domestic cats. The lung and heart of the affected cat presented clear evidence of SARS-CoV-2 replication, with histological lesions similar to those observed in humans with COVID-19 with high infectious viral loads being recovered from these organs. The study highlights the potential impact of comorbidities on the outcome of SARS-CoV-2 infection in animals and provides important information that may contribute to the development of a feline model with the potential to recapitulate the clinical outcomes of severe COVID-19 in humans.


[Methods in the assessment of combined effect of substances].
Russian and foreign approaches to estimating the combined effect of substances are considered depending on the problems to be solved Data are given on the relationship of the type of combined effect to the mechanism of the toxic action of components and acting doses (concentrations). Various mathematical models for calculating the combined efect of mixtures are discussed There is evidence that it is necessary to study the combined effects of the mixtures of constant composition, which are used in water supply upon chronic exposure of the substances that are constituents of the mixtures. Based on their studies and the data available in the literature, the authors inferred that the nature of the combined effect of such mixtures should be investigated under the conditions suiting those of application, as well as when used at low concentrations.


Japanese encephalitis: defining risk incidence for travelers to endemic countries and vaccine prescribing from the UK and Switzerland.
Large numbers of Western travelers visit countries endemic for Japanese encephalitis (JE). The risk of infection is unknown. This study attempts at estimating a risk incidence for visitors from two European countries with the available data. Using the total number of case reports between 1978 and 2008, the number of visits made by European tourists to endemic regions, and total doses of vaccines sold in the two study countries, the risk incidence of JE in travelers was estimated. The proportion of vaccinated visitors to endemic regions was retrieved from the data of two travel clinics (in London and Basel) and related to vaccine prescribing in UK and Swiss travelers. In 2004, an estimated 0.16% to 0.3% of UK and Swiss travelers were vaccinated against JE, with no surveillance reports of JE cases. Between 116,000 and 152,000 European travelers would receive vaccination. More than 99% travel to endemic countries without vaccination. Only 40 cases of JE infection have been reported in travelers for the past 30 years. The risk incidence is thus 1.3 per year in 7.1 million visits of the 17 million European travelers who are at a potential risk of JE infection. This study and the analysis of the existing literature support the recommendation that all travelers should be informed about the risk of JE infection but also suggest that there is no evidence for justifying a general recommendation for JE vaccination in travelers to endemic areas.


Intracellular signaling by 14-hydroxy-4,14-retro-retinol.
In mammals, retinol is the precursor for retinoids, which affect various aspects of morphogenesis and development. However, B lymphocytes, although retinol-dependent, do not use retinoic acid as mediator. Retinol is metabolized by B lymphocytes and other cell lines to optically active 14-hydroxy-4,14-retro-retinol; it is this compound that mediates the growth control. Thus another second messenger molecule, in addition to retinoic acid and retinal, is derived from retinol.


Zero balance ultrafiltration for the correction of acute acidosis after a period of prolonged deep hypothermic circulatory arrest.
A 36-year-old woman with normal renal function underwent a total arch replacement requiring 110 minutes of deep hypothermic circulatory arrest. Prior to rewarming, a pH of 7.063 with a base deficit of 10.8 was obtained. Zero-balance ultrafiltration (Z-BUF) was initiated during rewarming 7 minutes after resumption of cardiopulmonary bypass. After one hour (10L) of Z-BUF, all electrolyte and acid-base disturbances were fully corrected. Our case illustrates that Z-BUF offers a valuable option for the correction of severe electrolyte and acid-base disturbances in adults undergoing cardiac surgery. Its use should be considered in addition to the more standard pharmacologic approaches to such derangements as it offers rapid and predictable electrolyte and acid-base correction and potential anti-inflammatory benefits.


Animal carcass- and wood-derived biochars improved nutrient bioavailability, enzyme activity, and plant growth in metal-phthalic acid ester co-contaminated soils: A trial for reclamation and improvement of degraded soils.
Reclamation of degraded soils such as those with low organic carbon content and soils co-contaminated with toxic elements and phthalic acid esters (PAEs) is of great concern. Little is known about the efficiency of plant- and animal-derived biochars for improving plant growth and physicochemical and biological properties of co-contaminated soils, particularly under low content of organic matter. Hence, a pot trial was carried out by growing pak choi (Brassica chinensis L.) to assess the influence of different doses (0, 0.5, 1, 2, and 4%) of animal (pig carcass) and wood (Platanus orientalis) derived biochars on soil properties, nutrient availabilities, plant growth, and soil enzyme activities in two soils containing low (LOC) and high (HOC) organic carbon contents and co-contaminated with di-(2-ethylhexyl) phthalic acid (DEHP) and cadmium (Cd). Biochar applications improved pH, salinity, carbon content, and cation exchange capacity of both soils. Addition of biochars significantly increased the bioavailability and uptake of phosphorus and potassium in the plants in both soils with greater effects from pig biochar than wood biochar. Biochar additions also significantly enhanced urease, sucrase, and catalase activities, but suppressed acid phosphatase activity in both soils. The impact of pig biochar was stronger on urease and acid phosphatase, while the wood biochar was more effective with sucrase and catalase activities. The biomass yield of pak choi was significantly increased after biochar addition to both soils, especially in 2% pig biochar treatment in the LOC soil. The positive response of soil enzymes activities and plant growth for biochar addition to the Cd and DEHP co-contaminated soils indicate that both biochars, particularly the pig biochar can mitigate the risk of these pollutants and prove to be eco-friendly and low-cost amendments for reclaiming these degraded soils.


Influence of alpha-lipoic acid on lipid peroxidation and antioxidant defence system in blood of insulin-resistant rats.
High fructose feeding induces insulin resistance and hyperinsulinaemia in rats. A role for oxidative stress in the occurrence of insulin resistance has been suggested by several workers. The aim of this study was to investigate the effect of alpha-lipoic acid (LA) on oxidant-antioxidant balance in rats fed on a high-fructose diet that showed characteristic features of insulin resistance. Male Wistar rats weighing 150-170 g were divided into seven groups. The control group received the control diet containing starch. The fructose group was given a high-fructose diet (>60% of total calories). The third and fourth groups were given fructose diet and were administered two different doses of LA at a low dose (35 mg/kg body weight) and high dose (70 mg/kg body weight) using olive oil as vehicle. The fifth group received fructose diet and olive oil. The sixth group received control diet and was administered LA (70 mg/kg body weight). And, the seventh group received the control diet and olive oil. Products of lipid peroxidation and activities of enzymic antioxidants, namely superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and glutathione reductase, in red blood cells were assayed. Levels of non-enzymic antioxidants alpha-tocopherol, ascorbic acid and reduced glutathione were determined in plasma. The levels of lipid peroxides, diene conjugates and thiobarbituric acid-reactive substances were significantly higher in fructose-fed rats. Inadequate antioxidant system was observed in high-fructose-fed rats. Treatment of fructose rats mitigated the imbalance between peroxidation and antioxidant defence system at both the doses tested. Increases in glucose, triglycerides, free fatty acids, insulin and insulin resistance were observed in fructose-fed rats. LA administration prevented these alterations and improved insulin sensitivity. Significant positive correlations were obtained between insulin resistance and lipid peroxidation indices. Increased lipid peroxidation and deficient antioxidant system are observed in high-fructose-fed rats. LA administration preserves the antioxidant system and lowers lipid peroxidation. The findings suggest an interrelationship between lipid peroxidation and insulin resistance.


Fast and stable photochromic oxazines for fluorescence switching.
The stringent limitations imposed by diffraction on the spatial resolution of fluorescence microscopes demand the identification of viable strategies to switch fluorescence under optical control. In this context, the photoinduced and reversible transformations of photochromic compounds are particularly valuable. In fact, these molecules can be engineered to regulate the emission intensities of complementary fluorophores in response to optical stimulations. On the basis of this general design logic, we assembled a functional molecular construct consisting of a borondipyrromethene fluorophore and a nitrospiropyran photochrome and demonstrated that the emission of the former can be modulated with the interconversion of the latter. This fluorophore-photochrome dyad, however, has a slow switching speed and poor fatigue resistance. To improve both parameters, we developed a new family of photochromic switches based on the photoinduced opening and thermal closing of an oxazine ring. These compounds switch back and forth between ring-closed and -open isomers on nanosecond-microsecond timescales and tolerate thousands of switching cycles with no sign of degradation. In addition, the attachment of appropriate chromophoric fragments to their switchable oxazine ring can be exploited to either deactivate or activate fluorescence reversibly in response to illumination with a pair of exciting beams. Specifically, we assembled three dyads, each based on either a borondipyrromethene or a coumarin fluorophore and an oxazine photochrome, and modulated their fluorescence in a few microseconds with outstanding fatigue resistance. The unique photochemical and photophysical properties of our fluorophore-photochrome dyads can facilitate the development of switchable fluorophores for superresolution imaging and, ultimately, provide valuable molecular probes for the visualization of biological samples on the nanometer level.


[Obstetric brachial plexus palsy--clinics, pathophysiology and surgical treatment].
Obstetric brachial plexus palsy is a rare but sometimes severe traction injury. Peripheral nerve microsurgery (neurolysis, interfascicular grafting) and secondary procedures including muscle and tendon transfers altogether with contracture releases have improved the prognosis over the last 20 years. This article includes a historical review, the ongoing discussion about the pathophysiology (frequent traction injury vs. rare intrauterine maladaptation) and the clinics. Based on a patient group of 500 children with 100 microsurgical plexus reconstructions, we describe the surgical technique and our experience with primary nerve reconstruction. A concept about secondary procedures according to the joint levels is shortly exposed together with various modalities of postoperative evaluation, including video-assisted movement analysis. We conclude that severe upper and complete plexus palsies without significant recovery should be explored and reconstructed by microsurgical techniques.


Alterations in Cortical Activation Among Individuals With Chronic Ankle Instability During Single-Limb Postural Control.
Chronic ankle instability (CAI) is characterized by repetitive ankle sprains and perceived instability. Whereas the underlying cause of CAI is disputed, alterations in cortical motor functioning may contribute to the perceived dysfunction. To assess differences in cortical activity during single-limb stance among control, coper, and CAI groups. Cross-sectional study. Biomechanics laboratory. A total of 31 individuals (10 men, 21 women; age = 22.3 ± 2.4 years, height = 169.6 ± 9.7 cm, mass = 70.6 ± 11.6 kg), who were classified into control (n = 13), coper (n = 7), and CAI (n = 11) groups participated in this study. Participants performed single-limb stance on a force platform for 60 seconds while wearing a 24-channel functional near-infrared spectroscopy system. Oxyhemoglobin (HbO2) changes in the supplementary motor area (SMA), precentral gyrus, postcentral gyrus, and superior parietal lobe were measured. Differences in averages and standard deviations of HbO2 were assessed across groups. In the CAI group, correlations were analyzed between measures of cortical activation and Cumberland Ankle Instability Tool (CAIT) scores. No differences in average HbO2 were present for any cortical areas. We observed differences in the standard deviation for the SMA across groups; specifically, the CAI group demonstrated greater variability than the control (r = 0.395, P = .02; 95% confidence interval = 0.34, 0.67) and coper (r = 0.38, P = .04; 95% confidence interval = -0.05, 0.69) groups. We demonstrated a strong correlation that was significant in the CAI group between the CAIT score and the average HbO2 of the precentral gyrus (ρ = 0.64, P = .02) and a strong correlation that was not significant between the CAIT score and the average HbO2 of the SMA (ρ = 0.52, P = .06). The CAI group displayed large differences in SMA cortical-activation variability. Greater variations in cortical activation may be necessary for similar static postural-control outcomes among individuals with CAI. Consequently, variations in cortical activation for these areas provide evidence for an altered neural mechanism of postural control among populations with CAI.


Age-related changes in the midpalatal suture: Comparison between CBCT staging and bone micromorphology.
The age-related maturation of the human midpalatal suture is challenging to predict, but critical for successful non-surgical rapid maxillary expansion (RME). While cone-beam computed tomography (CBCT) can be used to categorize the suture into stages, it remains unclear how well the stages predict the actual micromorphology of the palate. To address this clinically relevant question, we used CBCT together with three-dimensional micro-computed tomography (μCT) analysis on 24 human palate specimens from individuals aged 14-34 years. We first classified the specimens into stages (A-E) using CBCT images and then correlated the results with our comprehensive μCT analysis. Our analysis focused on several factors, including bone volume fraction (BV/TV), sutural width, volume, interdigitation, ossification, and their associations with age, CBCT stage, and sex. Our μCT analysis revealed a decrease in sutural width and volume after the age of 20 years, accompanied by sutural closure beginning in the palatal segment. The overall rate of ossification remained low but increased after the age of 20 years. No significant differences were found between males and females. Importantly, we also found no correlation between individual age and CBCT stages. Furthermore, there was no association between CBCT stages and patalal suture volume, ossification and interdigitation. Taken together, our findings cast doubt on the reliability of CBCT stage as a means of predicting skeletal maturity of the palatal suture, as it appears to lack the precision required to accurately assess the true micromorphology of the palatal suture. Future investigations should explore whether alternative CBCT parameters may be more useful in addressing the challenging question of whether RME requires surgical bone weakening.


Fatigue, depression, and physical impairment in multiple sclerosis.
Fatigue, depression, and physical impairment are common among multiple sclerosis (MS) patients. The aim of this study was to determine the relationship between depression, physical impairment, and fatigue in an Iranian MS cohort. Fifty consecutive relapsing-remitting MS patients and 50 age- and sex-matched healthy controls (HCs) were recruited from Sina Rehabilitation Clinic, Tehran, Iran. The depression substance of Hospital Anxiety and Depression Scale (HADS), Expended Disability Status Scale, and Fatigue Severity Scale questionnaires were used to assess depression, physical impairment, and fatigue, respectively. This study included 38 (76%) females and 12 (24%) males in both patients and HC groups. The depression substance of the HADS in MS and HCs showed a mean value of 1.92 ± 0.80 and 1.17 ± 0.38, respectively (P < 0.001). Pearson's correlation analyses showed that in the MS group depression was associated with fatigue (r = 0.54, P = 0.01), but not with physical impairment (r = 0.16, p = 0.01), while fatigue was associated with both depression (r = 0.54, P = 0.01) and physical impairment (r = 0.36, P = 0.01). Depression in HCs group was also associated with fatigue (r -0.64, P = 0.01). Fatigue is associated with both depression and physical impairment, and an intervention in one of these conditions might improve others.


Spontaneous angiographic regression of cerebral arteriovenous malformations: angiographic disappearance is not the real cure.
Angiographically occult arteriovenous malformations (AOAVMs) are poorly understood. AOAVMs include spontaneous regression of cerebral AVMs. Here we discuss spontaneous angiographical regression of cerebral arteriovenous malformations (SRAVM). We present the case of a 34-year-old male patient with SRAVM in whom an arteriovenous (AV) shunt remnant was revealed by intraoperative indocyanine green videoangiography (ICG-VAG). Preoperative angiography indicated spontaneous regression of AVM. We reviewed the literature for articles having specific citations or case histories of SRAVMs. On the basis of our ICG-VAG findings, we confirmed the possibility of an AV shunt remnant being present in patients with SRAVMs. In addition to our own case, we reviewed previously reported cases and analyzed the data from 132 patients with SRAVMs. Ninety-five (72%) such patients received conservative therapy without surgical removal, and 37 (28%) were treated surgically. Only three patients in whom an SRAVM recanalized after 39, 31, and 16 months have been reported. The rate of recanalization in SRAVM including 3 previously reported cases and the present case, is 3.0% (4/132). Intraoperative ICG-VAG can reveal more SRAVMs that recanalize within a short period even if AV shunts are not depicted by angiography. Therefore, surgical removal of the AOAVM should be considered in cases with low surgical risk.


No differences in growth or body composition from age 12 to 24 months between toddlers consuming 2% milk and toddlers consuming whole milk.
To determine whether consumption of 2% milk during the second year of life leads to reduced growth or lower percentage body fat compared with consumption of whole milk. Subjects were healthy toddlers who participated in a larger trial examining the effects of the timing of introduction of solid foods on growth. Three-day diet diaries, anthropometric measurements, and body composition determined by dual-energy x-ray absorptiometry were assessed at 12, 18, and 24 months of age. At age 12 months, the toddlers were similar in length, weight, percentage body fat, and total energy intake. From 12 to 24 months of age, milk consumption consisted of whole milk exclusively in one group (n = 23) and 2% milk exclusively in another group (n = 28). Differences between the 2 groups in anthropometric measurements, changes in anthropometric measurements, and dietary intakes were determined by Student t tests. Mean differences were considered significant at the P = .05 level. Data are presented as mean +/- standard deviation. Despite lower intakes of total fat and saturated fat in the 2% milk group, there were no differences in height, weight, and percentage body fat. Total energy intake was not reduced in the 2% milk group. Reductions in total fat and saturated fat intake in toddlers can be achieved through the use of 2% milk without compromising growth.


Immunosuppression in patients who die of sepsis and multiple organ failure.
Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009-2011). Control spleens (n = 29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n = 20) were obtained from transplant donors or from lung cancer resections. Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28-stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, -5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, -269 to 1534) vs 58 (95% CI, -39 to 156) pg/mL; (P < .001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells. Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immunosuppression. Targeted immune-enhancing therapy may be a valid approach in selected patients with sepsis.


Assessment of the Placenta in Intrauterine Growth Restriction by Diffusion-Weighted Imaging and Proton Magnetic Resonance Spectroscopy.
Placental insufficiency is a major cause of intrauterine growth restriction (IUGR) and seriously affects fetal development. When placental insufficiency happened, the diffusion of water molecule was restricted and the metabolic balance was destroyed in the placenta. In this prospective study, we aimed to evaluate the diagnostic value of diffusion-weighted imaging (DWI) in combination with proton magnetic resonance spectroscopy (1H MRS) for placental insufficiency in IUGR. The apparent diffusion coefficient (ADC) values were calculated using DWI, and the metabolism of N-acetylaspartate (NAA), choline, and lipid and their ratios in the placenta were calculated using 1H MRS. Data were statistically analyzed by receiver operating characteristic (ROC) curves and logistic regression analysis. The NAA and choline peaks were decreased in IUGR placentas compared with normal placentas, while lipid peaks showed an opposite trend. The average ADC value and the NAA/lipid and choline/lipid ratios were lower in the IUGR group than in the normal group ( P < .01). Logistic regression with multiple parameters showed that combination of the ADC value and choline/lipid ratio was more favorable than either parameter alone in analyzing placental insufficiency of IUGR ( P < .05). The area under the ROC curve for the combination was 0.939, indicating reasonably good discrimination. We concluded that reduced ADC and NAA/lipid and choline/lipid ratios could serve as potential markers for placental insufficiency of IUGR. Furthermore, the combination of ADC value and choline/lipid ratio greatly improved the diagnostic value.


Identification of a deuterated alkanethiol inserted in a hydrogenated alkanethiol self-assembled monolayer by mapping of an inelastic tunneling signal.
We show an experimental technique for visualizing distributions of vibrational modes of molecules through mapping of an inelastic tunneling signal with a scanning tunneling microscope. A topographic information and d(2)I/dV(2) signal processed by a lock-in amplifier were simultaneously imaged, where the feedback loop for the tunneling gap was engaged and a modulation voltage was superimposed to the gap voltage. The current signal used for the tunneling gap control was tuned by the filtering in order to minimize the response of the feedback loop caused by the modulation voltage. The effectiveness of this technique was demonstrated for a self-assembled monolayer composed of a mixture of normal and deuterated hexanethiol molecules, where both molecules have the same molecular length and the former was embedded in the matrix of the latter. Two types of molecules were successfully discriminated by chemical properties.


Physiology and pathology of gastrin.
Gastrin release does play a part in the cephalic phase of acid secretion in man and is the major mechanism for the gastric phase of acid secretion. The vagal control of gastrin release is most likely mediated by cholinergic and possibly non-cholinergic excitatory fibres, as well as by cholinergic inhibitory fibres. Gastric luminal control of gastrin release is by local food and possibly distension stimulation, as well as by acid inhibition. Of the various causes of hypergastrinaemia, those associated with gastrinoma, G-cell hyperfunction and retained antrum have definite pathogenetic roles. Duodenal ulcer disease is a heterogeneous goup of disorders having different pathogenetic mechanisms. Parietal cell hyperplasia and G-cell dysfunctions, consisting of modest to florid G-cell hyperfunction and hyperplasia with secondary parietal cell hyperplasia, are but some facets of abnormalities that we have been able to identify.


Glycolic acid peels compared to microdermabrasion: a right-left controlled trial of efficacy and patient satisfaction.
Glycolic acid peels and microdermabrasion are widely recommended by dermatologists and others for facial skin rejuvenation, but few studies have assessed their clinical efficacy. To compare the relative efficacy of glycolic acid peels and microdermabrasion for facial skin rejuvenation. An unblinded, randomized controlled trial was used. Each of 10 patients received paired treatments with glycolic acid peels (20%) and microdermabrasion (mild setting) for 6 consecutive weeks. The right and left sides of the face were treated with different modalities. Once a patient was assigned to receive a particular modality to a particular side of the face, all subsequent treatments were delivered in the same manner. Patient ratings, investigator ratings, and photographs were obtained before the first treatment and 1 week after the last treatment. In terms of overall preference for a given type of treatment, seven patients chose glycolic acid peels, one selected microdermabrasion, and two had no favorite treatment. The relative preference for glycolic acid peels approached significance (P =.0578). Investigator ratings and photographic comparisons did not reveal treatment-specific differences or significant improvement from baseline. No serious side effects were seen with either treatment, and even mild effects were seldom reported. In this study, patients appeared to prefer low-strength glycolic acid peels to low-intensity microdermabrasion for facial rejuvenation. Differences in patient satisfaction were subtle and may be technique dependent.


Traumatic brain injury and Alzheimer's Disease biomarkers: A systematic review of findings from amyloid and tau positron emission tomography (PET).
Traumatic brain injury (TBI) has been discussed as a risk factor for Alzheimer's disease (AD) due to its association with dementia risk and earlier cognitive symptom onset. However, the mechanisms behind this relationship are unclear. Some studies have suggested TBI may increase pathological protein deposition in an AD-like pattern; others have failed to find such associations. This review covers literature that uses positron emission tomography (PET) of amyloid-β and/or tau to examine subjects with history of TBI who are at risk for AD due to advanced age. A comprehensive literature search was conducted on January 9, 2023, and 24 resulting citations met inclusion criteria. Common methodological concerns included small samples, limited clinical detail about subjects' TBI, recall bias due to reliance on self-reported TBI, and an inability to establish causation. For both amyloid and tau, results were widespread but inconsistent. The regions which showed the most compelling evidence for increased amyloid deposition were the cingulate gyrus, cuneus/precuneus, and parietal lobe. Evidence for increased tau was strongest in the medial temporal lobe, entorhinal cortex, precuneus, and frontal, temporal, parietal, and occipital lobes. However, conflicting findings across most regions of interest in both amyloid- and tau-PET studies indicate the critical need for future work in expanded samples and with greater clinical detail to offer a clearer picture of the relationship between TBI and protein deposition in older subjects at risk for AD.


Phosphorylation of serine 10 in histone H3, what for?
Eukaryotic cells must possess mechanisms for condensing and decondensing chromatin. Chromatin condensation is particularly evident during mitosis and cell death induced by apoptosis, whereas chromatin decondensation is necessary for replication, repair, recombination and transcription. Histones are among the numerous DNA-binding proteins that control the level of DNA condensation, and post-translational modification of histone tails plays a critical role in the dynamic condensation/decondensation that occurs during the cell cycle. Phosphorylation of Ser10 in the tails of histone H3 has been extensively studied in many organisms. Interestingly, this modification is involved in both transcription and cell division, two events requiring opposite alterations in the degree of chromatin compaction. How does one and the same modification of histone H3 fulfil such roles? For instance, in interphase, phosphorylation of H3 correlates with chromatin relaxation and gene expression, whereas in mitosis it correlates with chromosome condensation. What is the kinase and under what circumstances does Ser10 becomes phosphorylated? Most importantly, what are the consequences of phosphorylation of this residue?


Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation.
Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL-22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL-22BP deficiency (Il22ra2-/-) displayed exacerbated disease that associated with enhanced expression of IL-22-inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti-IL-22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22-inducible molecules (IL-20, IL-24, IL-36γ, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis.


Measurement of the shear modulus in thin-layered tissues using numerical simulations and shear wave elastography.
Measurement of mechanical properties of thin-layered tissues has broad applications in the diagnosis of several pathologies. Ultrasound shear wave elastography (SWE) measures the shear wave speed as a means of estimating the mechanical properties of tissues. However, the wave speed in thin-layered tissues is affected by their thickness and the properties of surrounding tissues. The objective of this study is to introduce a method that combines numerical simulations and SWE measurements to provide a more accurate calculation of shear modulus in layered tissues. In the proposed method, the spatial distribution of the acoustic radiation force (ARF) emitted by the transducer was first computed. The ARF was then used as input for simulating the guided wave propagation in the thin layer with its surroundings. The simulations were repeated for several values of the shear modulus of the layer to obtain the corresponding simulated wave speed. By comparing the measured and simulated wave speeds, a more accurate (corrected) shear modulus can be obtained. The proposed method was validated using experiments in agarose gels. In-vivo SWE measurements were also performed for the fascia of the tibialis anterior (TA) muscle and the aponeurosis of musculotendinous junction (MTJ) in medial gastrocnemius (MG) head in a group of healthy individuals. The simulated and measured wave speed in gel constructs were in good agreement with a maximum error of 7.22%. The average of measured wave speed of fascia and aponeurosis was 3.90 ± 0.16 m/s and 2.33 ± 0.60 m/s, while the corresponding corrected shear modulus was 95.63 ± 17.89 kPa and 6.36 ± 8.98 kPa, respectively. Thickness had a substantial effect on the wave speed in thin-layered tissues with decreasing speed for thinner tissues. The SWE-based simulation method presented in this study has the potential of enhancing clinical assessment for several musculoskeletal conditions involving thin-layered tissues.


Rosette inhibition test in severely burned patients.
The rosette inhibition test has been advocated as a test of immune reactivity in patients given transplants. We have done the test in lymphocytes from patients with severe burns, non-burnt control patients, and normal subjects. There was no correlation with the period of immunosuppression which follows a severe burn, though both groups of patients showed a wider range of minimal inhibitory concentrations (M.I.C.) than the normal group. Wide day-to-day variation of M.I.C. in burn and control patients was noted; this seemed to correlate with the ratio of sodium to potassium excreted in the urine. In-vitro experiments suggest that the M.I.C. is correlated with a plasma constituent which may be similar in action to hydrocortisone and that the rosette inhibition test is not a direct measure of immune reactivity.


Evaluation of activity of selected antioxidants on proteins in solution and in emulsions.
Protection against protein oxidation by lipophilic and hydrophilic antioxidants in model systems using bovine serum albumin (BSA) in solution alone, or in an emulsion with linolenic acid methyl ester (LnMe) was found to be strongly dependent on the oxidation initiator. Tocopherol, Trolox, or the carotenoids astaxanthin and canthaxanthin were incubated with BSA or BSA/LnMe and oxidation was initiated either with the water-soluble azo-initiator 2,2' azo-bis-(2-amidinopropane) hydrochloride (AAPH), or FeCl3 and ascorbate, or the Fenton system using FeCl2/EDTA/H2O2, or with the singlet oxygen generating species anthracene-9,10-dipropionic acid disodium 1,4 endoperoxide (NDPO2). The results show that all the antioxidants tested were inefficient in the system with FeCl3/ascorbate. However, with the other initiating agents, the hydrophilic antioxidant, Trolox, was the most effective in preventing both protein and lipid oxidation. In contrast the lipophilic antioxidants were ineffective in preventing oxidation of BSA in aqueous solution, but did show some moderate antioxidative activity on protein and lipid in the BSA/LnMe system. Using the singlet oxygen generating system it was also demonstrated that Trolox always provided better protection of the protein than tocopherol and the carotenoids in both the BSA and the BSA/LnMe systems. In conclusion, prevention of protein oxidation using a water-soluble antioxidant has a protective effect on the lipid fraction and this approach deserves further attention in complex biological systems.


Instrumental variability of respiratory blood gases among different blood gas analysers in different laboratories.
The aim of this study was to test the hypothesis that differences in oxygen tension (PO2) and carbon dioxide tension (PCO2) values from measurements performed on different blood gas analysers in different laboratories are clinically insignificant. Samples of fresh whole human tonometered blood (PO2 8.1 kPa (60.8 mmHg); PCO2 5.3 kPa (39.9 mmHg)) were placed in airtight glass syringes and transported in ice-water slush. Blood gas analysis was performed within 3.5 h by 17 analysers (10 different models) in 10 hospitals on one day. The mean of the differences between the measured and target values was -0.01+/-0.19 and 0.21+/-0.13 kPa (-0.06+/-1.45 and 1.55+/-1.01 mmHg) for PO2 and PCO2, respectively. The mean of the differences between two samples on one analyser was 0.06+/-0.06 and 0.04+/-0.03 kPa (0.47+/-0.48 and 0.29+/-0.24 mmHg), respectively. For PO2 and PCO2 the interinstrument standard deviations (s(b)) were 0.18 and 0.13 kPa (1.38 and 0.99 mmHg), respectively, whereas the intra-instrument standard deviations (s) were 0.06 and 0.03 kPa (0.47 and 0.26 mmHg), respectively. Both for PO2 and PCO2 the ratios of s(b)2 and s2 were statistically significant (analysis of variance (ANOVA) p<0.001). The standard deviations of a random measurement on a random analyser were 0.19 and 0.14 kPa (1.46 and 1.02 mmHg) for PO2 and PCO2, respectively. We conclude that the variability in measurement of blood gas values among different blood gas analysers, although negligible, depends much more on inter- than intra-instrument variation, both for oxygen tension and carbon dioxide tension. Technical improvements and adequate quality control programmes, including tonometry, may explain why the variability in blood gas values depends mainly on errors in the pre-analytical phase.


Neutrophil Extracellular Traps Contain Selected Antigens of Anti-Neutrophil Cytoplasmic Antibodies.
Neutrophil extracellular traps (NETs) are chromatin filaments decorated with enzymes from neutrophil cytoplasmic granules. Anti-neutrophil cytoplasmic antibodies (ANCAs) bind to enzymes from neutrophil cytoplasmic granules and are biomarkers for the diagnosis of systemic vasculitides. ANCA diagnostics are based on indirect immunofluorescence (IIF) of ethanol-fixed neutrophils. IIF shows a cytoplasmic staining pattern (C-ANCA) due to autoantibodies against proteinase 3 (PR3) or a perinuclear staining pattern (P-ANCA) due to autoantibodies against myeloperoxidase (MPO). The distinct ANCA-staining patterns are an artifact of ethanol fixation. Here, we tested NETs as a substrate for the detection of ANCAs in human sera. We observed that P-ANCAs specifically stained NETs, while C-ANCAs targeted the cell bodies of netting neutrophils. The distinct ANCA-staining patterns were caused by the presence of MPO, but not PR3, in NETs. Using NETs as a substrate for IIF, we characterized ANCAs in sera of patients with ANCA-associated vasculitis (AAV). Furthermore, we inhibited serine proteases by diisopropylfluorophosphate to prevent chromatin unfolding and the release of NETs and thus generated neutrophils with MPO-positive nuclei and PR3-positive cytoplasm, which resembled the appearance of ethanol-fixed neutrophils. In conclusion, our data suggest that NETs are selectively loaded with antigens recognized by P-ANCAs, and netting neutrophils provide a physiological substrate for ANCA detection in patients with AAV.