A Review on Characterization Techniques for Carbon Quantum Dots and Their Applications in Agrochemical Residue Detection.
Carbon quantum dots (CQDs) have emerged as one of the most promising nanomaterials in the carbon nanostructures family in recent years due to their low toxicity, simple synthetic methods, unique fluorescence emission, good photostability, excellent water solubility, high specific surface areas and outstanding electronic properties. They have thus been employed in a wide range of applications, including fluorescent sensing, electrochemical sensing, bioimaging, drug delivery, antimicrobial studies, antioxidants, and photocatalysis. CQDs drawn great interest in sensing applications due to their unique photochemical, electrochemical and electrochemiluminescence properties. They exhibit excitation wavelength-dependent or -independent photoluminescence (PL) behaviour, high quantum yield, and promising binding ability with analytes, which make them an ideal candidate for use in PL based sensing platforms. Excessive use of agrochemicals in farm fields can pollute the environment and have potentially adverse health effects on aquatic and human life. Since there are very few monitoring techniques are available for sensing such harmful substances, there is an urgent need to develop a sensor for the facile, rapid and on-site detection and quantification of agrochemical residues in the environment. Several CQD-based fluorophores for detecting agrochemical residues employing static or dynamic quenching processes have recently been published. The key quenching mechanisms involved in the sensing process include FRET, PET and IFE. The first part of this review intends to provide a comprehensive overview of various techniques to characterize CQDs such as UV-vis., FT-IR, PL, XRD, NMR, TEM, TGA, XPS and Raman analysis. In addition application of CQDs as fluorescent sensors for agrochemical residue in different media are summarized in this reiew. The LOD values and rapid action of the sensor demonstrates significant advantages of these methods over conventional analytical procedures.


Persistent glomerular hematuria in living kidney donors confers a risk of progressive kidney disease in donors after heminephrectomy.
Although glomerular hematuria is likely a sign of chronic kidney disease that will develop into overt nephropathy after donation, it remains unclear whether prospective donors with hematuria should be excluded. We reviewed the medical records of 242 donors who donated at our institution from 2001 to 2007 and surveyed the prevalence of hematuria pre- and postdonation. We then investigated the association of hematuria with proteinuria postdonation and trends in glomerular filtration rate. Before donation, 8.3% of 242 donors presented with persistent hematuria, a finding that was significantly associated with dysmorphic hematuria before donation. Most cases of predonation persistent hematuria persisted after donation, and the overall prevalence increased to 15.3%. During a median follow-up period of 2.3 years after donation, 8.3% developed persistent proteinuria, with incidence being significantly higher in donors having persistent hematuria with dysmorphic red blood cells (d-RBC) both before and after donation. Postdonation persistent hematuria with d-RBC was also associated with a progressive decline in renal function. These results indicate that persistent glomerular hematuria is strongly associated with a higher incidence of postdonation progressive kidney disease. Potential donors with persistent glomerular hematuria should be excluded, while those with isolated hematuria need to be evaluated with heightened caution.


Locations of mouse DNA damage response and repair loci, and cancer risk modifiers.
An outline is presented of an electronically accessible database that compares the locations of mouse genes involved in DNA repair, apoptosis, cell cycle and signal transduction with those of known cancer risk modifier genes. The database has a primary but not exclusive focus on modifiers of ionizing radiation (IR) cancer risk and genes involved in IR-induced DNA damage responses. The database () provides a useful tool for assessing the role of DNA damage response genes in cancer predisposition.


Correlation of extracts obtained by high efficiency gel chromatography of lactic dehydrogenase virus infected mouse serum and cytosol from human tumors using leukocyte adherence inhibition assay.
Immunochemically active fractions were obtained using Separon Hema-300-glc(R) from serum of lactic dehydrogenase virus (LDV) infected mice and from homogenates of human tumors. The mixture of proteins of tumorous origin from the cytosol giving a positive reaction in the leukocyte adherence inhibition (LAI) test was found in the same fractions showing maximum of absorbance at 340 nm in the spectrophotometer and a corresponding peak in the refractometer. Analogous peaks were not proved in material obtained from healthy controls, but they were found in some human placentas and fetal organs. The LDV fraction obtained from mouse serum served as a "control" antigen in LAI test for human tumor testing, and results corresponded with those obtained using cytosol specific for the tumor under study.


Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion.
Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson's disease (aPD). The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.


PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine.
Full and partial synthetic agonists targeting the transcription factor PPARγ are contained in FDA-approved insulin-sensitizing drugs and used for the treatment of metabolic syndrome-related dysfunctions. Here, we discuss the association between PPARG genetic variants and drug efficacy, as well as the role of alternative splicing and post-translational modifications as contributors to the complexity of PPARγ signaling and to the effects of synthetic PPARγ ligands. PPARγ regulates the transcription of several target genes governing adipocyte differentiation and glucose and lipid metabolism, as well as insulin sensitivity and inflammatory pathways. These pleiotropic functions confer great relevance to PPARγ in physiological regulation of whole-body metabolism, as well as in the etiology of metabolic disorders. Accordingly, PPARG gene mutations, nucleotide variations, and post-translational modifications have been associated with adipose tissue disorders and the related risk of insulin resistance and type 2 diabetes (T2D). Moreover, PPARγ alternative splicing isoforms-generating dominant-negative isoforms mainly expressed in human adipose tissue-have been related to impaired PPARγ activity and adipose tissue dysfunctions. Thus, multiple regulatory levels that contribute to PPARγ signaling complexity may account for the beneficial as well as adverse effects of PPARγ agonists. Further targeted analyses, taking into account all these aspects, are needed for better deciphering the role of PPARγ in human pathophysiology, especially in insulin resistance and T2D. The therapeutic potential of full and partial PPARγ synthetic agonists underlines the clinical significance of this nuclear receptor. PPARG mutations, polymorphisms, alternative splicing isoforms, and post-translational modifications may contribute to the pathogenesis of metabolic disorders, also influencing the responsiveness of pharmacological therapy. Therefore, in the context of the current evidence-based trend to personalized diabetes management, we highlight the need to decipher the intricate regulation of PPARγ signaling to pave the way to tailored therapies in patients with insulin resistance and T2D.


Purification and characterization of peptides Ap2, Ap3 and Ap5 (ω-toxins) from the venom of the Brazilian tarantula Acanthoscurria paulensis.
Peptides isolated from spider venoms are of pharmacological interest due to their neurotoxic activity, acting on voltage-dependent ion channels present in different types of human body tissues. Three peptide toxins titled as Ap2, Ap3 and Ap5 were purified by RP-HPLC from Acanthoscurria paulensis venom. They were partially sequenced by MALDI In-source Decay method and their sequences were completed and confirmed by transcriptome analysis of the venom gland. The Ap2, Ap3 and Ap5 peptides have, respectively, 42, 41 and 46 amino acid residues, and experimental molecular masses of 4886.3, 4883.7 and 5454.7 Da, with the Ap2 peptide presenting an amidated C-terminus. Amongst the assayed channels - NaV1.1, NaV1.5, NaV1.7, CaV1.2, CaV2.1 and CaV2.2 - Ap2, Ap3 and Ap5 inhibited 20-30 % of CaV2.1 current at 1 μM concentration. Ap3 also inhibited sodium current in NaV1.1, Nav1.5 and Nav1.7 channels by 6.6 ± 1.91 % (p = 0.0276), 4.2 ± 1.09 % (p = 0.0185) and 16.05 ± 2.75 % (p = 0.0282), respectively. Considering that Ap2, Ap3 and Ap5 belong to the 'U'-unknown family of spider toxins, which has few descriptions of biological activity, the present work contributes to the knowledge of these peptides and demonstrates this potential as channel modulators.


Assessment and source analysis of heavy metal contamination in water and surface sediment in Dongping Lake, China.
Dongping Lake is the only natural lake in the lower Yellow River and an important hub of South-North Water Diversion Project, its water quality is of vital importance to the environmental protection and the security of water supply. To assess the heavy metal (HM) contamination in Dongping Lake, samples in water and surface sediment were taken from 59 sampling sites over the entire lake. The statistical characteristics, pollution conditions, and source identifications were analyzed using coupling methods of entropy water quality index (EWQI), modified pollution index (mCd), enrichment coefficient (EF), geo-accumulation index (Igeo), potential ecological risk index (PERI), and positive matrix factorization (PMF). In present study, the averaged concentrations of all studied HMs in water body of Dongping Lake were below the limit of drinking water quality standard recommended by WHO, and the EWQI and mCd of HM concentrations were identified to be in good and excellent conditions. The concentrations of almost all studied HMs in surface sediment of Dongping Lake exceeded the background values in the soil of Shandong Province, and Cd (cadmium) was the dominant pollutant. With EF > 2, Igeo > 1, and Er > 80, Cd in sediment was under moderate pollution. The outcomes of source analysis revealed that the HMs in surface sediment were mainly derived from the primary and secondary industries. Specifically, manufacturing industries contributed the most to the HM contaminations in sediment of Dongping Lake.


Quantitative PCR detection of Theileria equi using laboratory workflows to detect asymptomatic persistently infected horses.
Equine piroplasmosis is the most important tick-borne disease of horses. Regulations on movement of horses into disease-free countries are in place to preserve international trade. Introduction of infectious disease, such as equine piroplasmosis, into non-endemic countries remains a substantial risk owing to the wide-spread distribution of vectors. Identification and restriction of movement of Theileria equi persistently infected horses is an integral part of control strategies, because persistently infected horses with low parasitaemia are an important reservoir. We used real-time PCR for diagnosis of T. equi DNA in clinically healthy horses in an equine piroplasmosis endemic area. The sensitivity was assessed using a synthetic plasmid DNA and a laboratory workflow was developed to maximise detection of persistently infected horses. The detection limit was 10 rDNA copies of the plasmid DNA. Assuming that each red blood cell contains a single T. equi genome the detection limit corresponded to 2.5 T. equi/μl of total blood and parasitaemia as low as 2-3.8 × 10(-5)%. A laboratory workflow was developed and assessed on samples from Saudi Arabia. The laboratory workflow focused on samples returning no or single positive result in duplicate PCR. In total, we obtained 42% (59/141; 95% confidence interval: 33.85-50.15) T. equi positive samples, 26% (37/141) negative for T. equi samples. The remaining 45 samples were judged as suspect with no definitive diagnosis made. The Saudi Arabia's T. equi small subunit ribosomal DNA (SSU rDNA) sequencing (n=16) demonstrated A clade (n=15) as the dominant T. equi clade. Clade B was sequenced in a single case. We present an approach for diagnostic workflow to detect T. equi in clinically healthy but persistently infected horses. Results from Saudi Arabia confirm that T. equi is widespread in the Middle East region. High proportion of horses with low parasitaemia calls for caution with results based on a single blood sample. Understating of the fluctuation of the parasitaema in persistently infected horses in endemic areas is needed to establish the required sample numbers for reliable detection of T. equi.


NCR1+ cells in dogs show phenotypic characteristics of natural killer cells.
No specific markers for natural killer (NK) cells in dogs have currently been described. NCR1 (NKp46, CD355) has been considered a pan species NK cell marker and is expressed on most or all NK cells in all species investigated except for the pig which has both a NCR1(+) and a NCR1(-) population. In this study peripheral blood mononuclear cells (PBMC) from 14 healthy dogs, 37 dogs with a clinical diagnosis, including a dog diagnosed with LGL leukemia, and tissue samples from 8 dogs were evaluated for NCR1(+) expression by a cross reacting anti bovine NCR1 antibody. CD3(-)NCR1(+) cells were found in the blood of 93 % of healthy dogs and comprised up to 2.5 % of lymphocytes in PBMC. In a selection of healthy dogs, sampling and immunophenotyping were repeated throughout a period of 1 year revealing a substantial variation in the percentage of CD3(-)NCR1(+) over time. Dogs allocated to 8 disease groups had comparable amounts of CD3(-)NCR1(+) cells in PBMC to the healthy individuals. All organs examined including liver, spleen and lymph nodes contained CD3(-)NCR1(+) cells. Circulating CD3(-)NCR1(+) cells were further characterized as CD56(-)GranzymeB(+)CD8(-). A CD3(+)NCR1(+) population was observed in PBMC in 79 % of the healthy dogs examined representing at the most 4.8 % of the lymphocyte population. In canine samples examined for CD56 expression, CD56(+) cells were all CD3(+) and NCR1(-). To our knowledge, this is the first examination of NCR1 expression in the dog. The study shows that this NK cell associated receptor is expressed both on populations of CD3(+) and CD3(-) blood lymphocytes in dogs and the receptor is found on a CD3(+) GranzymeB(+) CD8(+) leukemia. Our results support that CD56 is expressed only on CD3(+) cells in dogs and shows that NCR1 defines a different CD3(+) lymphocyte population than CD56(+)CD3(+) cells in this species. CD3(-)NCR1(+) cells may represent canine NK cells.


Significance of latent hyperthyroidism.
In euthyroidism the circadian rhythm and pulsatility of TSH is well known. With regard to hyperthyroidism only very preliminary data were described. In this study we investigated the secretion pattern of the pituitary-thyroid axis hormones during 24 h in latent and overt hyperthyroidism and in euthyroidism with regard to common and different properties. Blood was obtained for 24 h at 10-min intervals. In euthyroidism we found intraindividually three overlapping patterns of TSH, which are different in amplitude and frequency and can be found interindividually, too. These patterns are equal to the circadian rhythm, pulsatile secretion and lastly to the methodic rustle. The circadian rhythm in latent hyperthyroidism is distinctly suppressed and in overt hyperthyroidism totally. Whereas in latent hyperthyroidism pulsatile secretion is extant, in overt hyperthyroidism the TSH pulses are absent. To record the patients' TSH circadian rhythm with only three blood samples, we defined the TSH-Triplex. In young as well as in elderly healthy volunteers it demonstrated significantly higher TSH levels at midnight (at 24:00 h) than it did at 4 p.m. and 8 a.m. The present study shows a significantly different TSH pattern in latent hyperthyroidism compared to euthyroidism. It should be discussed whether latent hyperthyroidism could be defined as hyperthyroidism stage I. On the other hand, latent hyperthyroidism could be an illness with its own cause, different from hyperthyroidism. Our data suggest that the laboratory findings of latent hyperthyroidism in each age are non-physiological. However, the cause for this disorder is unclear until now; hence further investigations are necessary.


COVID-19-related health outcomes in people with primary immunodeficiency: A systematic review.
A better understanding of COVID-19 in people with primary immunodeficiency (PI), rare inherited defects in the immune system, is important for protecting this population, especially as population-wide approaches to mitigation change. COVID-19 outcomes in the PI population could have broader public health implications because some people with PI might be more likely to have extended illnesses, which could lead to increased transmission and emergence of variants. We performed a systematic review on COVID-19-associated morbidity and mortality in people with PI. Of the 1114 articles identified through the literature search, we included 68 articles in the review after removing 1046 articles because they were duplicates, did not involve COVID-19, did not involve PI, were not in English, were commentaries, were gene association or gene discovery studies, or could not be accessed. The 68 articles included outcomes for 459 people with PI and COVID-19. Using data from these 459 people, we calculated a case fatality rate of 9%, hospitalization rate of 49%, and oxygen supplementation rate of 29%. Studies have indicated that a number of people with PI showed at least some immune response to COVID-19 vaccination, with responses varying by type of PI and other factors, although vaccine effectiveness against hospitalization was lower in the PI population than in the general population. In addition to being up-to-date on vaccinations, current strategies for optimizing protection for people with PI can include pre-exposure prophylaxis for those eligible and use of therapeutics. Overall, people with PI, when infected, tested positive and showed symptoms for similar lengths of time as the general population. However, a number of people with X-linked agammaglobulinemia (XLA) or other B-cell pathway defects were reported to have prolonged infections, measured by time from first positive SARS-CoV-2 test to first negative test. As prolonged infections might increase the likelihood of genetic variants emerging, SARS-CoV2 isolates from people with PI and extended illness would be good candidates to prioritize for whole genome sequencing.


Further observations on associations between the ADA gene and past malaria morbidity in Sardinia.
Adenosine Deaminase (ADA) contributes to the regulation of adenosine concentration and in turn to T cell activation. Genetic variability of ADA activity may have, therefore, an important role in resistance to malaria. Indeed, previous studies in Sardinia have shown a lower frequency of ADA1 *2 allele (associated with low ADA activity) in areas, where malaria was heavily endemic compared to areas where malaria was not endemic. We have now studied the ADA2 locus, another polymorphic site with two alleles ADA2 *1 and ADA2 *2 within the ADA gene. In the area of Oristano (where malaria was endemic in the past) 51 consecutive newborns and in the area of Nuoro (where malaria was not as endemic) 48 consecutive newborns were examined. ADA1 and ADA2 genotypes were determined by DNA analysis. The low frequency of the ADA1 *2 allele in the area where malaria was endemic is confirmed. The frequency of the ADA2 *2 allele is higher in Oristano than in Nuoro resulting in a higher frequency of the ADA1 *1/ADA2 *2 haplotype in Oristano as compared to Nuoro. This suggests a selective advantage of this haplotype in a malarial environment. The ADA gene shows other polymorphic sites further studies on their role in human adaptation to malaria could be rewarding.


Differentiation of Schistosoma haematobium from related species using cloned ribosomal RNA gene probes.
The ribosomal RNA (rRNA) gene units of Schistosoma mansoni (lateral spined eggs) and six species of schistosomes with terminal spined eggs (S. haematobium, S. curassoni, S. bovis, S. intercalatum, S. margrebowiei and S. mattheei) have been studied. The schistosome rRNA gene unit consists of a regular interspersion of the two genes encoding the large and small rRNA units with two spacers. The large spacer is not transcribed while the small spacer is part of the transcription unit. Variation in the rRNA gene unit of the species studied is demonstrated and takes three forms: First, variation in DNA sequence leads to both reduced homology in the spacer regions between species and loss or gain of restriction sites. Second, variation in the length of the transcribed spacer is demonstrated and DNA insertions of 0.2 kilobases (kb) and 0.1 kb are observed in S. mattheei and S. margrebowiei, respectively. Third, the length of the non-transcribed spacer region varies between species. S. haematobium has a 0.5 kb deletion in this region, while that of S. margrebowiei contains varying numbers of a 0.4 kb DNA insert. These interspecific variations have been shown to be conserved within species. Analysis of the rRNA genes by DNA hybridisation techniques therefore serves as a means of species identification, whereby it is possible to differentiate S. haematobium from other schistosome species with terminal spined eggs. Similarly, S. margrebowiei and S. mattheei may be clearly distinguished, although no major variation has been detected between S. curassoni, S. bovis and S. intercalatum. All these species differ from S. mansoni by the absence of certain restriction sites in the non-transcribed spacer.


Antifactor Xa activity in critically ill patients receiving antithrombotic prophylaxis with standard dosages of certoparin: a prospective, clinical study.
Deep venous thrombosis with subsequent pulmonary embolism or post-thrombotic syndrome is a feared complication in the intensive care unit. Therefore, routine prophylactic anticoagulation is widely recommended. Aside from unfractionated heparin, low molecular weight heparins, such as certoparin, have become increasingly used for prophylactic anticoagulation in critically ill patients. In this prospective study, we evaluated the potency of 3,000 IU certoparin administered once daily to reach antithrombotic antifactor Xa (aFXa) levels of 0.1 to 0.3 IU/ml in 62 critically ill patients. AFXa levels were determined 4, 12 and 24 h after injection of certoparin. Prothrombin time, activated partial thromboplastin time, antithrombin, fibrinogen, hemoglobin, platelet count, serum urea and creatinine concentrations were documented before and 12 and 24 h after injection of certoparin. Four hours after certoparin injection (n = 32), 28% of patients were within the antithrombotic aFXa range. After 12 and 24 h, 6% achieved antithrombotic aFXa levels. Because of a severe pulmonary embolism in one study patient, an interim analysis was performed, and the dosage of certoparin was increased to 3,000 IU twice daily. This regime attained recommended antithrombotic aFXa levels in 47%, 27%, 40% and 30% of patients at 4, 12, 16 and 24 h, respectively, after twice daily certoparin injection (n = 30). Antithrombin and fibrinogen concentrations slightly increased during the observation period. Low antithrombin concentrations before certoparin were independently correlated with underdosing of certoparin. Patients with aFXa levels <0.1 IU/ml 4 h after certoparin injection required vasopressors more often and had lower serum concentrations of creatinine and urea than patients with antithrombotic aFXa levels. Standard dosages of certoparin of 3,000 IU given once or twice daily are ineffective for attaining the recommended aFXa levels of 0.1 to 0.3 IU/ml in critically ill patients. Low antithrombin levels before certoparin administration were independently associated with low aFXa levels. Renal function and vasopressor therapy may further influence the effectiveness of certoparin in ensuring adequate antithrombotic prophylaxis.


Transmission disequilibrium analysis of the GSN gene in a cohort of family trios with schizophrenia.
Apoptosis is thought to play a role in neuronal pathology in schizophrenia. Recently, the GSN gene was reported to have anti-apoptotic properties. In a genome-wide expression analysis on schizophrenia, GSN was also found to be significantly down-regulated in schizophrenia. All the hints suggest that GSN is a novel candidate gene in occurrence of schizophrenia. In this work, we genotyped 3 SNPs around the GSN locus in 493 sets of the Han Chinese trio sample using allele-specific PCR. A weak association or a marginally positive result was detected (0.05 for P-value of the overtransmitted haplotype and 0.02 for a global P-value).


Demethylase Kdm6a epigenetically promotes IL-6 and IFN-β production in macrophages.
Molecular regulation of innate signal-initiated proinflammatory cytokine production has been extensively investigated. However, the roles of epigenetic modifiers and their underlying mechanisms in regulating innate inflammatory response and development of autoimmune diseases need to be further understood. Demethylase Kdm6a promotes gene transcription in cell-lineage specification through demethylating histone H3 lysine di/tri-methylation (H3K27me2/3), and loss of Kdm6a results in developmental defects. However, the function of Kdm6a in innate immunity and inflammation remains largely unknown. Here we found that Kdm6a, significantly downregulated via JNK pathway upon innate stimuli, promotes cytokine IL-6 and IFN-β transcription in primary macrophages during innate response. Kdm6a promoted IL-6 expression through demethylating H3K27me3 at promoter in a demethylase enzymatic activity-dependent manner. Interestingly, Kdm6a promoted IFN-β expression independent of its demethylase enzymatic activity, but through increasing transcription of IFN-β-specific enhancer-derived RNA (eRNA) S-IRE1. For the underlying mechanism, Kdm6a interacted with MLL4 and promoted MLL4 recruitment and H3K4me2 level in S-IRE1 region of Ifnb1 gene for full activation of enhancer. Our results reveal a previously unknown role of kdm6a in promoting innate IFN-β gene transcription at enhancer, in addition to demethylation at promoter. The function of Kdm6a in promoting innate inflammatory response also adds insights to better understanding of epigenetic modifiers in inflammatory and autoimmune disease.


Oral clonidine premedication reduces postoperative pain in children.
Clonidine is an effective preanesthetic medication in children, providing a preoperative sedative effect. The analgesic properties of the drug have been well documented in adults. The current study was designed to investigate the effect of oral clonidine given preoperatively on postoperative pain in children undergoing minor surgery. In a prospective, randomized, controlled clinical trial, 90 children aged 5-12 yr undergoing elective ophthalmic, urologic, and otologic surgery received placebo (control), clonidine 2 micrograms/kg, or clonidine 4 micrograms/kg. These drugs were administered 105 min before the estimated time of induction of anesthesia and followed by treatment with oral atropine 0.03 mg/kg 60 min before anesthesia. Anesthesia was induced and maintained with halothane and nitrous oxide in oxygen. Postoperative pain was assessed by a blinded observer using an objective pain scale (OPS). Clonidine 4 micrograms/kg provided lower OPS (highest) scores during 12 h after surgery and reduced requirement for postoperative supplementary analgesic (diclofenac suppository) compared with the other two regimens. These data suggest that oral clonidine premedication (4 micrograms/kg) is a possible approach to facilitating postoperative analgesia in children undergoing minor surgery.


Exome sequencing implicates a novel heterozygous missense variant in DSTYK in autosomal dominant lower urinary tract dysfunction and mild hereditary spastic paraparesis.
DSTYK encodes dual serine/threonine and tyrosine protein kinase. DSTYK has been associated with autosomal-dominant congenital anomalies of the kidney and urinary tract and with autosomal-recessive hereditary spastic paraplegia type 23. Here, we report a father and his two dizygotic twin sons carrying a novel heterozygous missense variant in DSTYK, presenting with early onset lower urinary tract dysfunction due to dysfunctional voiding. Moreover, in the later course of the disease, both sons presented with bilateral spasticity in their lower limbs, brisk reflexes, and absence seizures. Exome sequencing in the affected father and his affected sons was performed. The sons presented clinically with urinary hesitancy, dysfunctional voiding, and night incontinence till adolescence, while the father reported difficulty in voiding. In the sons, cystoscopy excluded urethral valves and revealed hypertrophy of the bladder neck and trabeculated bladder. Additionally, both sons were diagnosed with absence epilepsy in early childhood. Filtering of exome data focused on rare (MAF < 0.01%), autosomal-dominant variants, predicted to be deleterious, residing in highly conserved regions of the exome. Exome analysis identified a novel, heterozygous missense variant (c.271C>A (p.Leu91Met)) in DSTYK segregating with the disease. In silico prediction analyses uniformly rated the variant to be deleterious suggesting the variant to be disease-causing in the family. To the best of our knowledge, this is the first report of early onset dysfunctional voiding, seizures, and bilateral spasticity of the lower limbs associated with a novel heterozygous dominant missense variant in DSTYK.


Inhibitory effect of topical antibiotics/antiseptics administration on bacterial growth in the open wound of the jawbone surgery: Randomized controlled, preliminary study.
TThe bone cavities after extirpation of cysts or tumor of the jawbone requires the insertion of gauze containing various antibiotics/antiseptics to minimize the risk of pain, bleeding, and surgical site infection (SSI). However, there have been few reports on the efficacy of topical administration of antibiotics/antiseptics to an open wound of the jawbone. To compare the inhibitory effects of topical povidone-iodine gel and tetracycline ointment on the jawbone wound bacterial growth after extirpation of cyst or tumor. This is a preliminary, randomized controlled, open-labeled trial. Eighteen patients were randomly assigned into two groups. In povidone-iodine (PI) group, gauze mixed with povidone-iodine gel was inserted into the bone cavity wound, and in tetracycline (TC) group gauze mixed with tetracycline ointment was inserted after extirpation of cyst or tumor of the jaw bone. In both groups, gauze was removed 48 h after surgery, and examined by bacterial culture and real-time polymerase chain reaction (PCR) using primers detecting total bacteria and MRSA. The topical application of tetracycline ointment was superior to that of povidone-iodine gel concerning inhibitory effects of total bacteria and methicillin-resistant Staphylococcus aureus (MRSA). This preliminary study suggests that the insertion of gauze mixed with tetracycline ointment is recommended for bone wounds after extirpation of cyst or tumor of the oral cavity.


Development and Validation of the Eating Disorders Screen for Athletes (EDSA): A Brief Screening Tool for Male and Female Athletes.
To develop and validate the Eating Disorders Screen for Athletes (EDSA), a brief eating disorders screening tool for use in both male and female athletes. Data from Division I athletes at a Midwestern university (N=434) were used to conduct exploratory factor analysis (EFA) by gender. Data from athletes competing at various levels at universities across the United States (N=862) were then used to conduct confirmatory factor analysis (CFA) and receiver operator characteristic (ROC) curve analysis by gender. Athletes from a range of lean and non-lean sports were included. Gender-specific empirically derived cut-offs on the Eating Disorder Examination-Questionnaire were used to classify high eating disorder risk for ROC curve analysis. Measurement invariance by gender, level of competition, and sport type was also examined. A six-item, one-factor structure for the EDSA was supported by EFA and CFA in both genders, and internal consistency was good for both male (α=. 80) and female athletes (α=.86). ROC curve analyses indicated that the EDSA was highly accurate in predicting eating disorder risk status and identified a score of 3.33 as the optimal cut-off for both male (sensitivity=.96, specificity=.80) and female athletes (sensitivity=.96, specificity=.64). Results also supported strong measurement invariance for the EDSA by gender, level of competition (Division I versus club), and sport type (lean versus non-lean). The EDSA shows promise as a brief screening tool to identify male and female athletes at risk for eating disorders.


Inguinal pain with limping: Iliopectineal bursitis as first sign of polymyalgia rheumatica.
An 83-year-old man presented with pain in his right groin, limping, and the ultrasound findings of an iliopectineal bursitis as the first sign of polymyalgia rheumatica. The systemic disease of polymyalgia rheumatica may begin with local signs caused by peripheral musculoskeletal inflammation. Ultrasound or magnetic resonance imaging (MRI) is appropriate in order to decide on early oral prednisolone.


Only SF3B1 mutation involving K700E independently predicts overall survival in myelodysplastic syndromes.
SF3B1 mutations (SF3B1mut ) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700E SF3B1mut is uncertain. The authors analyzed the clinicopathological features and outcomes of a single-institution series of 94 treatment-naive SF3B1mut MDS patients (18%) and 415 treatment-naive SF3B1wt MDS patients and explored the differences between K700E and non-K700E SF3B1mut MDS. Fifty-five patients (59%) carried K700E. Recurrent non-K700E mutations (39 [41%]) included R625, H662, and K666. Compared with SF3B1mut K700E patients, non-K700E patients had a lower median absolute neutrophil count (1.8 vs 2.4; P = .005) and were frequently "high" according to the Revised International Prognostic Scoring System (19% vs 4%; P = .031). Non-K700E MDS was associated frequently with RUNX1 (26% vs 7%; P = .012) and exclusively with BCOR, IDH2, and SRSF2 mutations. A splicing analysis showed the differential distribution of alternatively spliced events and gene expression profiles between K700 and non-K700E MDS patients. The majority (at least 80%) of SF3B1mut K700E, SF3B1mut non-K700E, and SF3B1wt patients were treated with hypomethylating agents. Over a median follow-up of 16 months, SF3B1mut had superior overall survival (OS) in comparison with SF3B1wt in all MDS patients (not reached vs 25.2 months; P = .0003), in patients with low-grade MDS, and in patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS). Compared with SF3B1wt , SF3B1mut K700E had superior outcomes in all MDS (median OS, 25 months vs not reached; P = .0001), in low-grade MDS (median OS, 41.3 months vs not reached; P = .0015), and in MDS-RS (median OS, 22.3 months vs not reached; P = .0001), but no significant difference was seen between non-K700E and SF3B1wt MDS. By multivariable analysis, the absence of SF3B1mut K700E mutations was independently associated with the prognosis. This study highlights the importance of the SF3B1 mutation subtype in MDS risk assessment. Myelodysplastic syndromes (MDS) with SF3B1 mutations are regarded as having a favorable prognosis by both the World Health Organization and the International Working Group for the Prognosis of Myelodysplastic Syndromes. However, this article shows that only MDS patients with SF3B1 K700E mutations have a favorable prognosis (and not MDS patients with SF3B1 mutations involving other codons). This has important implications for refining future MDS subclassification and risk assessment criteria.


False-Positive Tumor During Organ Retrieval: All Cats Are Gray in the Dark.
Efforts to expand the organ donor pool to meet growing transplant demands remains a top priority, as does maintaining the quality and safety standards of potential recipients. There is a short window of time from organ retrieval to decision making on organ acceptance, based on the available data. Furthermore, the limitations of intraoperative biopsy can often lead to donor or organ refusal due to a suspected tumor, which, if not confirmed in the final biopsy, results in the loss of a transplant opportunity. Donor characteristics and organs discarded on suspicion of neoplastic disease at the time of extraction were analyzed in Andalusia between January 2014 and July 2018. The variable analysis included sociodemographic data, type of donor, location of the potential malignancy, histopathologic examination, and discarded organs. A total of 43 cases were identified. The organs of 33 donors (76.7%) were discarded. Kidneys were the most frequent location for a suspected tumor (44%), followed by the liver (21%). In 18 of the 43 cases (42%), the suspected malignancy was not confirmed, and of these, only 3 livers and 1 kidney were implanted. Sixty potentially transplantable organs were discarded, including those that would have been extracted and/or implanted in the absence of a suspected tumor. These results highlight the need not only to improve the accuracy of intraoperative biopsies but to seek new decision-making strategies for the short interval after organ retrieval. This involves avoiding both extremes of donation contraindications, while maintaining quality and safety standards.


Vedolizumab Is Safe and Efficacious for the Treatment of Pediatric-Onset Inflammatory Bowel Disease Patients Who Fail a Primary Biologic Agent.
Vedolizumab (VDZ) is currently licensed for use in adults for the treatment of inflammatory bowel disease (IBD). We aimed to investigate the clinical course of pediatric-onset IBD following treatment with VDZ as more than a secondary biologic agent. We also evaluated factors associated with secondary loss of response (LOR) and durability of VDZ treatment. Pediatric-onset IBD patients diagnosed at an age younger than 18 years who had received VDZ as more than a secondary biologic agent were included in this retrospective observational study conducted at the Department of Pediatrics of two centers in Korea. Comparative analysis was conducted between groups divided according to the development of secondary LOR during VDZ treatment. A total of 24 patients comprising 10 patients with Crohn's disease and 14 with ulcerative colitis were included. Of these, 19 were male and 5 were female. The mean age at diagnosis was 14.6 ± 2.5 years. The mean age at initiation of VDZ was 20.5 ± 2.8 years. Nine patients (37.5%) had received two or more biologic agents before starting VDZ. During a median of 0.9 years follow-up from VDZ initiation, 9 patients (37.5%) experienced LOR requiring interval shortening and 4 patients (16.7%) were changed to a different biologic agent. According to multivariate Cox proportional hazard regression analysis, administration of two or more biologic agents before VDZ treatment was the only factor positively associated with LOR (hazard ratio [HR], 5.6; 95% confidence interval [CI], 1.026-30.56; P = 0.047), while LOR was the only factor negatively associated with VDZ durability (HR, 0.003; 95% CI, 0.00-0.08; P = 0.010). No adverse events were observed during treatment with VDZ. VDZ is safe and efficacious for the treatment of pediatric-onset IBD patients failing a primary biologic agent. The durability of VDZ may be enhanced by introducing VDZ earlier in the disease course. Further prospective studies in children are required in the future to validate these findings.


Chromatin and heritability: how epigenetic studies can complement genetic approaches.
Despite the success in using genome-wide association studies to identify many loci associated with human disease, there are several gaps in understanding of how common genetic diseases are manifested. Epigenetic studies, which focus on DNA and chromatin modifications, have the potential to complement genetic approaches and provide more insight into mechanism, environmental effects and modes of inheritance, including the potential for non-DNA-based heritability. However, there are considerable challenges in designing and interpreting epigenetic studies associated with disease. Here, I review recent studies focused on individual variation in chromatin, and outline how epigenome-based studies can be used to complement genetic studies. In particular, I see more benefit to epigenetic studies being performed in the context of genetic studies, rather than as separate investigations.


Thermodynamic limits for simultaneous energy harvesting from the hot sun and cold outer space.
The sun and outer space are two of the most important fundamental thermodynamic resources for renewable energy harvesting. A significant amount of work has focused on understanding the fundamental limit of energy harvesting from the sun. More recently, there have been several theoretical analyses of the fundamental limit of energy harvesting from outer space. However, far less is understood about the fundamental limits of simultaneous energy harvesting from both the sun and outer space. Here, we consider and introduce various schemes that are capable of simultaneous energy harvesting and elucidate the fundamental thermodynamic limits of these schemes. We show that the theoretical limits can far exceed the previously established limit associated with utilizing only one thermodynamic resource. Our results highlight the significant potential of simultaneous energy harvesting and indicate new fundamental opportunities for improving the efficiency of energy harvesting systems.


Ester hydrogenolysis via β-C-O bond cleavage catalysed by a phenanthroline-based PNNP-cobalt(I) complex.
A Co(I) catalyst bearing a phenanthroline-based PNNP ligand (2,9-bis((diphenylphosphanyl)methyl)-1,10-phenanthroline) exhibits long-range metal ligand cooperation behavior using a ligand backbone as a hydrogen reservoir and catalyses hydrogenolysis of benzyl benzoate derivatives via β-C-O cleavage with atmospheric pressure H2.


Can D3 Lymph Node Dissection for Patients With Colon Cancer With a Poor C-Reactive Protein/Albumin Ratio Improve Survival Outcomes?
D3 lymph node dissection (LND) for stage II and III colon cancer has been shown to improve prognosis, however, it generally increases surgical stress. Studies have reported that the C-reactive protein/albumin ratio (CAR) may be a useful inflammatory-nutritional biomarker to predict postoperative complications and poor prognosis for with various types of cancer. Our purposes were to assess the short- and long-term outcomes of D3 LND in patients with a high preoperative CAR (≥ 0.04). This was a retrospective cohort analysis reviewing a prospectively collected database of Yokohama City University and three affiliated hospitals. A total of 449 patients with stage II or III colon cancer with high CAR who underwent primary resection with D2 or D3 LND were identified between 2008 and 2020. The primary and secondary outcomes of interests were the 3-year recurrence-free survival and postoperative complication rates. After propensity matching, 230 patients were evaluated. There was no significant difference between the D3 and D2 groups in the rate of postoperative complications overall (14.8% versus 11.3%, p=0.558), however, the incidence of anastomotic leakage tended to be greater in the D3 group (9.6% versus 2.6%, p=0.050). The long-term findings showed that there was no significant difference between the two groups (3-year recurrence-free survival rate: 77.2% versus 77.2%, p=0.880). D3 LND did not improve survival outcomes for patients with colon cancer with a poor CAR in this study. D2 LND may be a treatment option for patients with stage II-III colon cancer with a high preoperative CAR.


A novel butyrylcholinesterase from serum of Leporinus macrocephalus, a Neotropical fish.
We show here that serum of piaussu, a Neotropical characin fish, has the highest butyrylcholinesterase activity so far described for humans and fish. To clarify whether this cholinesterase could protect piaussu against anticholinesterase pesticides by scavenging organophosphates, we purified it 1700-fold, with a yield of 80%. Augmenting concentrations (from 0.01 to 20 mM) of butyrylthiocholine activated it. The pure enzyme was highly inhibited by chlorpyriphos-oxon (ki=10,434x10(6) M-1 min-1) and by the specific butyrylcholinesterase inhibitor, isoOMPA (ki=45.7x10(6) M-1 min-1). Electrophoresis of total serum and 2-D electrophoresis of the purified cholinesterase showed that some enzyme molecules could circulate in piaussu serum as heterogeneously glycosylated dimers. The enzyme's N-terminal sequence was similar to sequences found for butyrylcholinesterase from sera of other vertebrates. Altogether, our data present a novel butyrylcholinesterase with the potential of protecting a fish from poisoning by organophosphates.


Clinical, light and electron microscopic features of recessive ichthyosis congenita type III.
The recessively inherited congenital ichthyoses have ultrastructural features which indicate abnormal epidermal lipid metabolism. The ultrastructural markers of the three recessive congenital ichthyosis groups are lipid droplets in horny layers (type I), cholesterol clefts (type II) and membrane structures (type III). We describe six patients from five families belonging to the last group. The variable clinical phenotype alone does not allow the delineation of this disease, but together with the ultrastructural characteristics the subtype is unequivocal. In addition to the membrane structures, half of the cases showed abnormal keratinosomes and vesicular complexes. Membrane-bound vacuoles and needle-like slits were exceptionally found. The onset of the ichthyosis was variable, in contrast to other patients described under the heading recessive congenital ichthyosis.


Does donor cardiopulmonary resuscitation time affect outcome in uncontrolled non-heart-beating donor renal transplants?
Uncontrolled non-heart-beating donors offer the opportunity to significantly expand the potential pool of kidney donors but are associated with a variable duration of cardiopulmonary resuscitation (CPR), where cardiac output is only 30% to 40% of normal. We were concerned that prolonged CPR would adversely affect the function of transplanted kidneys. In our series of 46 uncontrolled donors the mean duration of CPR was 60 minutes, which also represents a realistic cutoff point for CPR duration. Taking a cutoff point of 60 minutes, we found no differences in kidney discard rates following viability assessment, primary nonfunction rate, or duration of delayed graft function. We therefore conclude that if formal viability assessment is performed, kidneys may be retrieved from uncontrolled non-heart-beating donors irrespective of duration of CPR.


[Effects of prostaglandin E1 analogue and prostaglandin F2 alpha on uterine contraction, uterine blood flow and fetal circulation in pregnant and nonpregnant rabbits (author's transl)].
Effects of PGF2 alpha and PGE1 analogue (ONO-802) on uterine contraction, uterine blood flow and fetal circulation were studied in pregnant and mature nonpregnant rabbits. Uterine and fetal blood flows were measured by photoplethysmography. Ten ng of PGs were injected into aorta abdominalis. In pregnant rabbits, 10 ng of PGF2 alpha caused a great increase in uterine contraction (i.e., intrauterine pressure), slight decrease in uterine blood flow and a transient fetal bradycardia, while 10 ng of ONO-802 caused a slight increase in uterine contraction (i.e., frequency), moderate decrease in uterine blood flow and a transient fetal bradycardia. Responses in nonpregnant rabbits to these two PGs were almost the same as those in pregnant rabbits. These results indicate the different effects of these two PGs on the uterine blood flow.


Changes in handgrip strength in children with cystic fibrosis compared to children without cystic fibrosis.
Cystic Fibrosis (CF) may impact nutritional status. Handgrip strength (HGS) may be used for nutrition assessment. The objective of the study was to evaluate changes in HGS over time in children with CF compared to children without CF. A secondary purpose was to analyze the relationship of clinical characteristics of CF with HGS. A prospective, longitudinal study was conducted. The non-CF group (n = 76) was recruited from a school and the CF group (n = 75) from an accredited CF center. Height, weight, mid-upper arm circumference, triceps skinfold, and HGS were measured at baseline and approximately three and six months in both groups. Data for pulmonary function, nutrition risk, enteral supplementation, CF transmembrane conductance regulator modulator, steroids, antibiotics, vitamin levels, CF related diabetes (CFRD), and recent hospitalization were collected for the CF group. A mixed model determined the difference in the change in HGS between the CF group and the non-CF group. For all analyses, p=<0.05 was significant. The rate of change in HGS z-score in the CF-group (0.18 ± 0.05) versus the non-CF group (0.06 ± 0.06) was not significant (p = 0.15). Initial mean dominant HGS z-score was significantly lower (p = 0.02) in those with vitamin D deficiency (-1.35 ± 0.09) versus those without (-1.02 ± 0.11). HGS z-score significantly (p = 0.02) decreased over time in children with CFRD (-0.19 ± 0.22) versus children without CFRD (0.32 ± 0.14), p = 0.02. Serial measurements of HGS may help detect changes in muscle function related to CFRD and vitamin D deficiency. Further investigation is warranted to elucidate HGS's role in nutrition assessment of children with CF.


NovaSure impedance controlled system for endometrial ablation: three-year follow-up on 107 patients.
This study was undertaken to assess the safety, efficacy, and data durability of the NovaSure ablation at 3 years after the procedure in women with menorrhagia secondary to dysfunctional uterine bleeding (DUB). A prospective, single-arm, observational pilot study (Canadian Task Force classification II-1) was carried out at a specialized center for gynecologic endoscopy with 107 premenopausal women with menorrhagia secondary to DUB. NovaSure ablation was performed in 107 patients. Pictorial Blood loss Assessment Chart diary sampling was used to assess menstrual blood loss. Ablation was performed without any type of endometrial pretreatment. No intraoperative or postoperative complications were observed. Treatment time averaged 94 seconds; 65% of the patients reported amenorrhea. Hysterectomy was avoided in 97.2% of patients at 3-year follow-up. Long-term clinical results demonstrate that the NovaSure system is a safe and effective method for treatment of women with menorrhagia secondary to DUB, yielding high amenorrhea and success rates, with low re-treatment rates.


Chromogranin A can act as a reversible processing enzyme inhibitor. Evidence from the inhibition of the IRCM-serine protease 1 cleavage of pro-enkephalin and ACTH at pairs of basic amino acids.
Bovine parathyroid chromogranin A inhibits the cleavage of Z-Ala-Lys-Arg-AMC by either trypsin or IRCM-serine protease 1 (IRCM-SP1), a putative novel processing enzyme originally isolated from porcine pituitary anterior and neurointermediate lobes. On larger substrates, chromogranin A is a reversible competitive inhibitor of the cleavage at pairs of basic amino acids by IRCM-SP1. The substrates tested included pituitary ACTH and adrenal medulla pro-enkephalin-derived peptides such as the 8.6 kDa synenkephalin-containing precursor and peptide B. Chromogranin A is itself selectively processed by IRCM-SP1, and ACTH was shown to compete for such cleavage. These data suggest that chromogranins as a class of acidic proteins could participate in the tissue-specific processing of pro-hormones.


Idiopathic orbital hemorrhage related to the inferior rectus muscle: a rare cause for acute-onset diplopia and unilateral proptosis.
To report 6 patients with spontaneous orbital hemorrhage in relation to the inferior rectus muscle. Retrospective observational case series. Six patients with acute onset orbital pain, diplopia, and proptosis referred to the orbital clinic at the Royal Victorian Eye and Ear Hospital, January 1995 through December 2004. Review of clinical history, imaging studies, and follow-up. Resolution of proptosis and diplopia and imaging studies of the orbit, including computed tomography (CT), magnetic resonance imaging (MRI), or both. Six patients (4 men, 2 women; mean age, 68 years) were referred with acute onset of unilateral proptosis and diplopia. None of the patients had a history of bleeding disorder. Visual acuity and intraocular pressure were normal; 3 patients showed marked limitation in upgaze on the affected side. Imaging studies of the orbit by CT, MRI, or both showed inferior orbital hemorrhage either within (4 patients) or adjacent to (2 patients) the inferior rectus muscle, possibly within the muscular sheath. Symptoms resolved completely in all but 1 patient, who had persistent diplopia in extreme upgaze. Follow-up CT, MRI, or both showed complete resolution in 3 patients and mild persistent inferior rectus muscle thickening in 2 patients. Acute onset proptosis and diplopia may be secondary to spontaneous orbital hemorrhage within the inferior rectus muscle or its sheath with no other orbital or systemic pathologic features. Symptoms resolved spontaneously over the course of days to weeks, and orbital imaging showed complete resolution or mild persistent enlargement of the muscle without significant symptoms.


Protein kinase C activity in platelets from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY).
Calcium-activated phospholipid dependent protein kinase (protein kinase C) activity in platelets was measured in 4, 12, and 20-week-old SHR and WKY. At age 4-weeks, there was no significant difference in protein kinase C activity and systolic blood pressure between SHR and WKY. In 12 and 20-week-old SHR, both protein kinase C activity and systolic blood pressure were significantly higher than in the age-matched WKY. These results suggest that protein kinase C may be involved in the control of blood pressure in SHR and WKY.


Osteoarthritis, genetic and molecular mechanisms.
Osteoarthritis (OA) is the most common musculoskeletal disorder world-wide and has enormous social and economic consequences. OA is a multifactorial disorder in which ageing, genetic, hormonal and mechanical factors are all major contributors to its onset and progression. The primary lesion in OA would appear to occur in the articular cartilage (AC) which covers the weight-bearing surfaces of diarthrodial joints. Studies on AC have shown a decline in the chondrocyte numbers and their viability with ageing; largely due to nitric oxide radical mediated apoptosis. Since chondrocytes are responsible for the synthesis of the extensive extracellular matrix of AC, their decline in numbers limits the AC's ability to maintain homeostasis and thus functionality. Moreover, the chondrocytes remaining in the AC show diminished capacity to respond to growth factors which also restricts repair and their metabolism is greatly affected by cytokines and nitric oxide free radical produced during synovial inflammation and the imposition of supranormal mechanical stresses. Proteoglycans (PGs) provide the resilience of AC and a reduction in their synthesis, molecular size and increased catabolism in OA joints, markedly impairs AC capacity to efficiently respond to mechanical stress, leading to fibrillation and erosion down to subchondral bone. Recent OA research has sought to identify modalities which retard, or even reverse these pathological events. While many claims of disease modifying drugs in OA (DMOAD) have been made, our research has indicated that calcium pentosan polysulfate (CaPPS) exhibits considerable potential in this regard. CaPPS corrects many of the phenotypic imbalances (described above) in chondrocyte metabolism and promotes the synthesis of large PGs. Furthermore, it inhibits the enzymes responsible for PG and collagen degradation and increases the translation of tissue inhibitor of metalloproteinase-3 (TIMP-3) by synoviocytes and chondrocytes, thereby, reducing proteolytic and angiogenic activity within the joint space.


Neuro-medical manifestations of fluorosis in populations living in the Main Ethiopian Rift Valley.
Prolonged exposure to higher concentrations of fluoride (> 1.5 mg/L) is associated with dental and skeletal fluorosis. The effects of fluoride on dental and skeletal system have been studied extensively; however, the neurological consequences of fluoride in population-based studies are limited. The study aims to assess the epidemiology of neurological and other manifestations of fluorosis among rural populations living in the Main Ethiopian Rift valley. In this cross-sectional study, we enrolled 316 individuals from 23 rural communities in the Main Ethiopian Rift valley. Fluoride concentration was measured in drinking water samples collected from 23 community wells. Association between fluoride concentrations and clinical features of fluorosis was assessed using student t test, chi square, multivariable regression using adjusted odds ratio (OR). The mean fluoride concentration in the drinking water was 6.8 ± 4.3 mg/L (range: 0.3-15.5 mg/L). At least one clinical sign of skeletal fluorosis was observed in 54.4% (n = 175) of the study participants. Headache and joint pain reported by 67.1% and 56.3% of the participants as the most common neurological manifestation, and skeletal fluorosis symptom, respectively. The mean fluoride level was higher for those individuals who reported paresthesia compared to those with no-paresthesia. Loss of appetite, constipation, and fatigue were reported by 48.0%, 45.6%, and 56.6% of the participants, respectively. Signs of crippling fluorosis were observed in small proportion (1.6%) of the participants. Individuals who reported headache are most likely exposed to higher fluoride concentrations in drinking water compared to those reported no-headache (p < 0.001). The study demonstrates high prevalence of neuro-medical manifestations of fluorosis in population living in the Main Ethiopian Rift valley. Fluoride concentration in drinking water and joint pain were independent predictors of fluorosis.


Splicing of an anti-sense Alu sequence generates a coding sequence variant for the alpha-3 subunit of a neuronal acetylcholine receptor.
In this report we demonstrate that an alpha-3 acetylcholine receptor subunit transcriptional variant originates through alternative splicing of a complementary sequence of the right arm of an Alu element. This element is located within the 5.1 Kb intron found between exons 5 and 6 of the alpha-3 acetylcholine receptor subunit gene. The transcriptional variant originates from the normal splicing process and carries an in-frame stop codon. If translated, it should encode for a peptide lacking the 4th transmembrane domain of the normal subunit.


Bereavement care for families part 1: a review of a paediatric follow-up programme.
The World Health Organization suggests that palliative care needs to offer a support system to the family during the patient's illness as well as during his/her bereavement. Bereavement follow-up services in paediatrics offer families an additional source of support in their grieving process. This article reviews the development of a bereavement follow-up programme delivered by the paediatric palliative care team and explores the lessons learnt and challenges faced in developing the programme.


Histopathological alterations and induction of hsp70 in ramshorn snail (Marisa cornuarietis) and zebrafish (Danio rerio) embryos after exposure to PtCl(2).
The platinum group metals (PGMs) platinum (Pt), palladium (Pd), and rhodium (Rh) are used in automobile catalytic converters, from which they have been emitted into the environment to an increasing degree during the last 20 years. Despite the bioavailability of these metals to plants and animals, studies determining the effects of PGMs on organisms are extremely rare. In the present study, effects of various concentrations of PtCl(2) (0.1, 1, 10, 50 and 100 microg/L) were investigated with respect to the induction of hsp70 and histopathological alterations in the zebrafish, Danio rerio and the ramshorn snail, Marisa cornuarietis. Histopathological investigations revealed effects of Pt on both species, which varied between slight and strong cellular reactions, depending on the PtCl(2) concentration. The hsp70 level in M. cornuarietis did not show an increase following Pt exposure whereas it was significantly elevated at 100 micorg/L PtCl(2) in D. rerio.


Red marine alga Bryothamnion triquetrum lectin induces endothelium-dependent relaxation of the rat aorta via release of nitric oxide.
We have investigated the vascular relaxant effects of the lectin from a red marine alga Bryothamnion triquetrum (BTL), in particular, the endothelial-dependency and the participation of a specific glycoprotein-binding site. BTL (1-100 microg mL(-1)) was applied to rat isolated aortic rings, with or without endothelium, tonically precontracted with phenylephrine (0.1 microM). Endothelium-dependent relaxation was assessed in the presence of indometacin (10 microM), L-nitro arginine methyl ester (L-NAME, 100 microM) and tetraethylammonium (TEA, 500 microM). For the involvement of the glycoprotein-binding site, BTL was assayed in presence of mucin (300 microg mL(-1)) or N-acetyl D-glucosamine (GlcNAc; 300 microg mL(-1)), a specific and non-specific lectin-binding sugar, respectively. BTL fully and concentration dependently relaxed preparations that possessed an intact endothelium (IC50 (concn producing 50% contraction) = 12.1 +/- 1.6 microg mL(-1)), whereas no significant relaxation was observed in endothelial-denuded tissue. L-NAME, but not indometacin or TEA, completely inhibited the lectin relaxation, suggesting the involvement of nitric oxide (NO). The lectin in association with mucin, but not with GlcNAc, inhibited BTL-induced relaxation, implicating the involvement of the lectin binding site. Our data suggest that the relaxant effect of the red marine alga Bryothamnion triquetrumlectin on isolated aorta occurs via interaction with a specific lectin-binding site on the endothelium, resulting in a release of NO.


An unexpected directing effect in the asymmetric transfer hydrogenation of α,α-disubstituted ketones.
α,α-Disubstituted ketones containing an aromatic ring or alkene are reduced in high enantiomeric excess using an asymmetric transfer hydrogenation catalyst. The sense of reduction indicates that the unsaturated region of the ketone adopts a position adjacent to the Ru-bound η(6)-arene ring in the reduction transition state.


PDGF-D-induced immunoproteasome activation and cell-cell interactions.
Platelet-derived growth factor-D (PDGF-D) is abundantly expressed in ocular diseases. Yet, it remains unknown whether and how PDGF-D affects ocular cells or cell-cell interactions in the eye. In this study, using single-cell RNA sequencing (scRNA-seq) and a mouse model of PDGF-D overexpression in retinal pigment epithelial (RPE) cells, we found that PDGF-D overexpression markedly upregulated the key immunoproteasome genes, leading to increased antigen processing/presentation capacity of RPE cells. Also, more than 6.5-fold ligand-receptor pairs were found in the PDGF-D overexpressing RPE-choroid tissues, suggesting markedly increased cell-cell interactions. Moreover, in the PDGF-D-overexpressing tissues, a unique cell population with a transcriptomic profile of both stromal cells and antigen-presenting RPE cells was detected, suggesting PDGF-D-induced epithelial-mesenchymal transition of RPE cells. Importantly, administration of ONX-0914, an immunoproteasome inhibitor, suppressed choroidal neovascularization (CNV) in a mouse CNV model in vivo. Together, we show that overexpression of PDGF-D increased pro-angiogenic immunoproteasome activities, and inhibiting immunoproteasome pathway may have therapeutic value for the treatment of neovascular diseases.


[The role of the gonads in the maturation of corticotropic function in rats].
The rates of pituitary and adrenals growth, in male and female Rats, are reversed at puberty. It seems that the stress induced plasma corticosterone increase is inhibited by testis before puberty and stimulated by ovarian after puberty.


Molecular dynamics simulations of early steps in RNA-mediated conversion of prions.
The rate-limiting step in prion diseases is the initial transition of a prion protein from its native form into a mis-folded state in which the protein not only forms cell-toxic aggregates but also becomes infectious. Recent experiments implicate polyadenosine RNA as a possible agent for generating the initial seed. In order to understand the mechanism of RNA-mediated mis-folding and aggregation of prions, we dock polyadenosine RNA to mouse and human prion models. Changes in stability and secondary structure of the prions upon binding to polyadenosine RNA are evaluated by comparing molecular dynamics simulations of these complexes with that of the unbound prions.


Biosensors and Bioanalytical Devices based on Magnetic Particles: A Review.
Magnetic particles play an important role in current technology, and this field of technology extends to a broader progression. The term magnetic particles typically cover the paramagnetic particles and super-paramagnetic particles. Various materials like iron oxide are common, but other materials are available as well; a survey of such materials has been included in this work. They can serve for technological purposes like separation and isolation of chemical products or toxic waste, their use in the diagnosis of pathologies, drug delivery and other similar applications. In this review, biosensors, bioanalytical devices and bioassays, have been discussed. Materials for magnetic particles preparation, methods of assay, biosensors and bioassays working in stationary as well as flow-through arrangements are described here. A survey of actual literature has been provided as well.


The increasing indications of FDG-PET/CT in the staging and management of Invasive Bladder Cancer.
The management of locally advanced muscle invasive bladder cancer (MIBC) often necessitates neo-adjuvant chemotherapy (NAC) to eliminate any micro-metastatic disease prior to definitive radical cystectomy (RC) and pelvic lymph node dissection (PLND). The most common imaging techniques traditionally used during this process are computerised tomography (CT) and magnetic resonance imaging (MRI), both of which lack a high sensitivity for nodal staging. In this paper, we attempt to review the evolving indications of F-fluoro-2-deoxy-D-glucose positron emission tomography/computerised tomography (FDG-PET/CT) imaging, in the pre-clinical and post-treatment staging of bladder cancer, with a focus on its ability to evaluate response to NAC. We concluded that use of FDG-PET/CT allows for improved nodal staging and metastatic disease detection, compared to traditional imaging modalities. This enabled earlier detection of tumour response to NAC and/or residual disease, impacting factors such as duration of chemotherapy, with its associated adverse effects, and timing of surgical intervention. However, further studies are required to reliably assess its impact on both overall and disease-free survival.


Synthesis of Poly(ADP-ribose) Monomer Containing 2'-O-α-D-Ribofuranosyl Adenosine.
In this article, the earlier reported procedure for the synthesis of 2'-O-β-D-ribofuranosyl nucleosides was extended to the synthesis of 2'-O-α-D-ribofuranosyl adenosine, a monomeric unit of poly(ADP-ribose). It consists in condensation of a small excess of 1-O-acetyl-2,3,5-tri-O-benzoyl-α,β-D-arabinofuranose activated with tin tetrachloride with 3',5'-O-tetra-isopropyldisiloxane-1,3-diyl-ribonucleosides in 1,2-dichloroethane. The following debenzoylation and silylation of arabinofuranosyl residue and inversion of configuration at C-2'' atom of arabinofuranosyl residue and final removal of silyl protective groups gave 2'-O-α-D-ribofuranosyl adenosine in overall 13% to 21% yield. © 2019 by John Wiley & Sons, Inc.


A miniaturized liquid-liquid extraction method for further Na, K, Ca, and Mg determination in crude oil by FAAS.
In this study, a miniaturized liquid-liquid extraction (LLE) method for pre-concentration of Na, K, Ca, and Mg in crude oil was proposed. Analytes in crude oil were quantitatively extracted to the aqueous phase, followed by flame atomic absorption spectrometry (FAAS) determination. The following parameters were evaluated: type of extraction solution, sample mass, heating temperature and time, stirring time, centrifugation time, and the use of toluene and chemical demulsifier. Accuracy was evaluated by comparing the results obtained by the proposed method (LLE-FAAS) with those obtained after high-pressure microwave-assisted wet digestion and FAAS determination (reference values). No statistical difference was observed between the reference values and those using the optimized conditions for LLE-FAAS: 2.5 g of sample; 1000 μL of 2 mol L-1 HNO3, 50 mg L-1 of chemical demulsifier in 500 μL of toluene, 10 min of heating at 80 °C, 60 s of stirring, and 10 min of centrifugation. Relative standard deviations were lower than 6%. The limits of quantification (LOQ) were 1.2, 1.5, 5.0, and 0.50 μg g-1 for Na, K, Ca, and Mg, respectively. The proposed miniaturized LLE method presents several advantages, such as ease-of-use, high throughput (up 10 samples can be processed per 1 h), uses a high sample mass reaching low LOQs. In addition, the use of a diluted solution for extraction reduces the amount of reagents (around 40 times) and consequently laboratory residue generation, becoming an environmental friendly method. Suitable LOQs were achieved for analyte determination at low concentration even using a simple and low-cost sample preparation system (miniaturized LLE method) and a relatively low-cost determination technique (FAAS), avoiding the use of microwave ovens and more sensitivity techniques, which are required for routine analyses.


Autoimmunity in sarcoidosis: the tip of the Iceberg.
Sarcoidosis is a mysterious condition with an etiology that has to date eluded explanation. Innumerable clinical and serological organ- and non-organ-specific autoimmune associations have been reported. Many of the associated conditions are life-threatening but easily manageable if diagnosed early. Due to the long latency that precedes the clinical onset of autoimmune diseases, it is prudent to ensure a long follow-up and a broad viewing perspective while maintaining a high index of suspicion when viewing the autoimmunity iceberg in sarcoidosis.


Video-assisted thoracoscopic lobectomy after neoadjuvant chemotherapy for non-small cell lung cancer: a multicenter propensity-matched study.
The role of video-assisted thoracoscopic surgery for the treatment of non-small-cell lung cancer after neoadjuvant chemotherapy remains controversial. The aim of this study is to demonstrate the reliability of video-assisted lobectomy compared to the open approach by evaluating perioperative and long-term outcomes. In this retrospective, multicentric study from January 2010 to December 2018, we included all patients with non-small-cell lung cancer who underwent lobectomy through the video-assisted or open approach after neoadjuvant chemotherapy. The perioperative outcomes, including data concerning the feasibility of the surgical procedure, the occurrence of any medical and surgical complications and long-term oncological evidence, were collected and compared between the two groups. To minimize selection bias, propensity score matching was performed. A total of 286 patients were enrolled: 193 underwent thoracotomy lobectomy, and 93 underwent VATS lobectomy. The statistical analysis showed that surgical time (P < 0.001), drainage time (P < 0.001), days of hospitalization (P < 0.001) and VAS at discharge (P = 0.042) were lower in the VATS group. The overall survival and disease-free survival were equivalent for the two techniques on long-term follow-up. VATS lobectomy represents a valid therapeutic option in patients affected by non-small-cell lung cancer after neoadjuvant chemotherapy. The VATS approach in our experience seems to be superior in terms of the perioperative outcomes, while maintaining oncological efficacy.


Morphological effects of juvenile hormone mimics on embryonic development in the bug,Pyrrhocoris apterus.
Embryos ofPyrrhocoris apterus exposed to juvenile hormone mimics (JH) were examined throughout development to determine the progressive effects of treatment. Prior to blastokinesis whole experimental embryos did not differ morphologically from control embryos fixed at the same stage. Treated embryos failed to complete blastokinesis due to abnormal breakage of the extra-embryonic membranes.In the embryo-larva transition, JH exposure interfered with dorsal closure, with the consolidation of the nerve cord, and with the extension of appendages. Yet pigmentation and muscle differentiation occurred.These effects were interpreted and discussed with reference to the role of juvenile hormone in post-embryonic development.


An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity.
α1A-ARs play adaptive and protective roles in the heart. Dabuzalgron is an oral selective α1A-AR agonist that was well tolerated in multiple clinical trials of treatment for urinary incontinence, but has never been used to treat heart disease in humans or animal models. In this study, we administered dabuzalgron to mice treated with DOX, a widely used chemotherapeutic agent with dose-limiting cardiotoxicity that can lead to HF. Dabuzalgron protected against DOX-induced cardiotoxicity, likely by preserving mitochondrial function. These results suggest that activating cardiac α1A-ARs with dabuzalgron, a well-tolerated oral agent, might represent a novel approach to treating HF.


The DaBlaCa-13 Study: Short-term, Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in Non-muscle-invasive Bladder Cancer-A Randomised Controlled Trial.
Instillation therapy for non-muscle-invasive bladder cancer (NMIBC) reduces recurrences but is associated with side effects. Preoperative instillation of chemotherapy could potentially be associated with fewer side effects compared with adjuvant instillations and in some patients make tumour resection (transurethral resection of the bladder tumour [TURBT]) superfluous. To investigate tumour response and adverse events related to short-term, intensive chemoresection with mitomycin C compared with adjuvant instillations in patients with recurrent NMIBC. A randomised, controlled trial was conducted in two urological departments in Denmark from January 2018 to June 2019. In total, 120 participants with a history of Ta bladder tumours, low grade or high grade, were included upon recurrence. Intravesical mitomycin C (40 mg/40 ml) three times a week for 2 wk in the intervention group (59 patients) was compared with TURBT and six weekly adjuvant instillations in the control group (61 patients). Tumour response was evaluated in the intervention group by flexible cystoscopy after 4 wk. Side effects were prospectively registered in both groups using the National Cancer Institute's Common Terminology Criteria for Adverse Events. Groups were compared using χ2 or Fisher's exact test. Complete tumour response was seen in 33 participants (57%) in the intervention group. Fewer adverse events were reported in the intervention group than in the control group. Two patients in each group ceased instillation treatment due to adverse events. The main limitation is the current lack of long-term follow-up. Short-term, intensive chemoresection yields a tumour response of 57%. Hence, only half of those treated with chemoresection needed TURBT. The treatment was furthermore associated with fewer clinically significant side effects. Owing to small numbers, further investigations on Ta high-grade tumours are needed. We compared a nonsurgical treatment with standard treatment in patients with superficial bladder tumours. We found it to be safe and able to avoid surgery in more than half of the patients.


Improving Grain Yield via Promotion of Kernel Weight in High Yielding Winter Wheat Genotypes.
Improving plant net photosynthetic rates and accelerating water-soluble carbohydrate accumulation play an important role in increasing the carbon sources for yield formation of wheat (Triticum aestivum L.). Understanding and quantify the contribution of these traits to grain yield can provide a pathway towards increasing the yield potential of wheat. The objective of this study was to identify kernel weight gap for improving grain yield in 15 winter wheat genotypes grown in Shandong Province, China. A cluster analysis was conducted to classify the 15 wheat genotypes into high yielding (HY) and low yielding (LY) groups based on their performance in grain yield, harvest index, photosynthetic rate, kernels per square meter, and spikes per square meter from two years of field testing. While the grain yield was significantly higher in the HY group, its thousand kernel weight (TKW) was 8.8% lower than that of the LY group (p < 0.05). A structural equation model revealed that 83% of the total variation in grain yield for the HY group could be mainly explained by TKW, the flag leaf photosynthesis rate at the grain filling stage (Pn75), and flag leaf water-soluble carbohydrate content (WSC) at grain filling stage. Their effect values on yield were 0.579, 0.759, and 0.444, respectively. Our results suggest that increase of flag leaf photosynthesis and WSC could improve the TKW, and thus benefit for developing high yielding wheat cultivars.


[Structural and functional neuroimaging of the pathophysiology of apraxia].
A better understanding of the neural bases of apraxia is an important prerequisite to develop new therapeutic strategies for the disabling apraxic deficits after left-hemisphere stroke, like disturbed imitation of gestures, deficient pantomime, and object use deficits. Recently, functional and structural imaging methods allowed deeper insights into the pathophysiology of apraxia: While apraxic object use deficits result from the dysfunction of an extended fronto-parietal network within the left hemisphere, pantomime deficits are caused by impaired functioning of the left inferior frontal cortex. Further apraxia-related, motor cognitive processes (i.e., gesture imitation, integration of temporal and spatial movement information, and intentional movement planning) depend on the integrity of the left parietal cortex. Newly developed functional and structural imaging methods, like dynamic causal modelling (DCM) and diffusion tensor imaging (DTI), promise to further elucidate the pathophysiology of apraxia at the network level.


Expanding the calibration range of compound-specific chlorine isotope analysis by the preparation of a 37 Cl-enriched tetrachloroethylene.
The recent development of reliable GC/qMS methods for δ37 Cl compound-specific stable isotope analysis (CSIA) paves the way for dual carbon-chlorine isotope analysis of chlorinated ethenes and thus allows deeper insights into underlying transformation processes/mechanisms. A two-point calibration is indispensable for the precise and correct conversion of raw data to the international δ37 ClSMOC scale. The currently available calibration standards for tetrachloroethylene (PCE) span only a very narrow range from -2.52‰ (EIL2) to +0.29‰ (EIL1), which is considerably smaller than observed δ37 Cl isotope enrichment in (bio-)transformation studies (up to 12‰). We describe the preparation and evaluation of a new 37 Cl-enriched PCE standard to avoid bias in δ37 Cl CSIA arising from extrapolation beyond the calibration range. The preparation comprised: (i) partial PCE reduction by zero-valent zinc in a system of PCE, ethanol (initial volume ratio 3/5) and trace amounts of water followed by (ii) liquid-liquid extraction and (iii) a subsequent fractional distillation to purify the 37 Cl-enriched PCE. The obtained PCE (PCEenriched ) showed a purity of 98.8% (mole fraction) and a δ37 ClSMOC value of +10.8 ± 0.5‰. The evaluation of an experimental dataset with and without extrapolation showed no significant variation. The new PCE standard (PCEenriched ) expands the calibration range to 13.3‰ (previously 2.8‰) and thus prevents potential bias introduced by extrapolation beyond the calibration range.


Shot peening increases resistance to cyclic fatigue fracture of endodontic files.
The objective of this study was to assess the resistance to fatigue fracture of conventional nickel-titanium files after undergoing shot peening. Forty NITIFLEX endodontic files, number 30, were divided into two groups; one was submitted to shot peening treatment and the other was not. All instruments were tested for fatigue fracture in simulated canals with a TRI-AUTO ZX endodontic motor. One file of each group was subjected to a residual stress analysis by XRD. Finally, the fractured surface was observed and elemental analysis performed by means of SEM and EDX. Roughness analysis was made by focal variation microscope. The shot peening group showed greater resistance to fatigue fracture; there was no difference in the length of the fractured fragments. XRD results showed the presence of residual compression stresses in the file submitted to shot peening, a decrease in the interplanar spacing, and an increase in the full-width-at-half-maximum and the microstrains. SEM and EDX showed a ductile fracture with zones of fatigue and an equiatomic ratio between the nickel and titanium. Surface roughness increased after the file was subjected to the shot peening procedure. In conclusion, shot peening increases the resistance to fatigue fracture due to the presence of residual compression stresses in files manufactured from a conventional nickel-titanium alloy.


[Specific immunization for the prevention of recurrent nephrolithiasis after percutaneous nephrolithotomy].
To study the effect of prophylactic immunization with combined Staphylococcus-Proteus-Pseudomonas vaccine in combination with the probiotic Bacillus subtilis on the development of recurrent nephrolithiasis in patients after percutaneous nephrolithotomy (PCNL). A total of 76 patients with a high infectious risk of stone formation in the early postoperative period after PCNL were included in the study. All patients received antibiotic therapy in accordance with the current guidelines as indicated. The patients were divided into 3 groups. In the comparison group (n=30), patients continued to receive antibiotics on the outpatient basis. In the group A (n=20), in addition to antibiotics, two-stage immunization with Staphylococcus-Proteus-Pseudomonas vaccine was performed. In the group B (n=26), additionally, patients received probiotic preparation "Bactisporin dry", which is a lyophilized spore-forming bacteria Bacillus subtilis strain 3N. All participants had urine culture and stone analysis using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A study of specific antibodies level and factors of cellular and humoral immunity was carried out at specific time points. The duration of follow-up was 36 months. The study revealed a difference in the pathogens isolated from urine and infection stones in the same patient. This convincingly suggests that pathogens form biofilms in the stones and are not detected during routine urine culture. The main pathogens isolated from the stones were Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus epidermidis and Klebsiella pneumonia. Microbial associations were found in 25.7% of cases. The Staphylococcus-Proteus-Pseudomonas vaccine demonstrated good immunogenicity, its antigenic components provided protective properties against autologous and opportunistic bacteria. In addition to the ability to induce a specific response to antigens, the vaccine stimulated the phagocytic activity of neutrophils. Immunization with the combined Staphylococcus-Proteus-Pseudomonas vaccine in combination with probiotic results in uncomplicated postoperative course in 84% of patients. Hospital-acquired infectious and inflammatory complications were seen in 16.2% of cases. The recurrence of stone formation in this group of patients within 36 months was 8.2%. In patients receiving only combined Staphylococcus-Proteus-Pseudomonas vaccine after PCNL, the postoperative period was uneventful in 65% of cases. The rate of upper urinary tract infection was 35%, while the inflammatory process was accompanied by mild clinical manifestations and quickly resolved. Recurrence of stone formation during the follow-up was seen in 18% of patients. In the control group, the proportion of uncomplicated cases in patients with nephrostomy tube was 40%, the development of pyelonephritis was noted in 60% of cases, and recurrent stones within 36 months were diagnosed in 46.7% of cases. Our results emphasize that the role of an infectious factor in the development of recurrent nephrolithiasis after PCNL is often underestimated. The use of a specific vaccination and the Bacillus subtilis preparation in patients with a high infectious risk of recurrent stone formation allows to achieve a significant reduction in the recurrence rate (more than 5 times) compared to the control group during 36 months of postoperative follow-up.


Probabilities for a probabilistic network: a case study in oesophageal cancer.
With the help of two experts in gastrointestinal oncology from The Netherlands Cancer Institute, Antoni van Leeuwenhoekhuis, a decision-support system is being developed for patient-specific therapy selection for oesophageal cancer. The kernel of the system is a probabilistic network that describes the presentation characteristics of cancer of the oesophagus and the pathophysiological processes of invasion and metastasis. While the construction of the graphical structure of the network was relatively straightforward, probability elicitation with existing methods proved to be a major obstacle. To overcome this obstacle, we designed a new method for eliciting probabilities from experts that combines the ideas of transcribing probabilities as fragments of text and of using a scale with both numerical and verbal anchors for marking assessments. In this paper, we report experiences with our method in eliciting the probabilities required for the oesophagus network. The method allowed us to elicit many probabilities in reasonable time. To gain some insight in the quality of the probabilities obtained, we conducted a preliminary evaluation study of our network, using data from real patients. We found that for 85% of the patients, the network predicted the correct cancer stage.


The safety of blood donation by elderly blood donors.
BACKGROUND Due to the ageing population, blood donation by the elderly is necessary to maintain blood supply. We initiated a prospective study, to assess whether there is an increased risk of donor reactions in elderly donors. STUDY DESIGN AND METHODS In this prospective study, regular donors aged from 66 to 68 and 69 to 71 years were invited to continue blood donation on mobile collection sites of the German Red Cross Blood Service West. A control group (50-52 years) was established. Admission of donors in all groups followed the German national guidelines for blood donation. Donor deferrals and all kinds of donor reactions during donation (on-site) and in the 48 h following donation (off-site) were monitored. RESULTS A total of 64 260 valid cases were entered in the study. Donor deferrals increased with age from 1·12% in the control group up to 8·74 in female donors aged 69-71 years. Adverse reactions to blood donation were rare with an overall reaction rate of 0·63% (0·05% on-site; 0·58% off-site). Off-site reactions significantly decreased with increasing age. The relative risk (RR) for adverse reactions in elderly donors compared to the control group (50-52 years) was slightly increased for on-site reactions in the 69- to 71-year-old donors (RR 1·0309; 95% CI 1·0292-1·0325). In all other comparisons, the RR for adverse reactions was distinctively lower in elderly donors (RR 0·3785 - 0·7778). CONCLUSIONS Our data confirm that elderly regular blood donors may safely continue blood donation at least to the age of 71. Based on these data, we increased the upper age limit.


Solving the leading-order evolution equation for generalized parton distributions.
An analytic method for the solution of the evolution equation for generalized parton distributions (GPDs) is presented. The small x, xi asymptotics of GPDs are calculated.


Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism.
Venous thromboembolism (VTE) is highly heritable (estimated heritability [h(2)]=0.62) and likely to be a result of multigenic action. To systematically test variation within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways for an independent association with VTE. Non-Hispanic adults of European ancestry with objectively-diagnosed VTE, and age- and sex- matched controls, were genotyped for 13 031 single nucleotide polymorphisms (SNPs) within 764 genes. Analyses (n=12296 SNPs) were performed with plink using an additive genetic model and adjusted for age, sex, state of residence, and myocardial infarction or stroke. Among 2927 individuals, one or more SNPs within ABO, F2, F5, F11, KLKB1, SELP and SCUBE1 were significantly associated with VTE, including factor (F) V Leiden, prothrombin G20210A, ABO non-O blood type, and a novel association with ABO rs2519093 (OR=1.68, P-value=8.08×10(-16) ) that was independent of blood type. In stratified analyses, SNPs in the following genes were significantly associated with VTE: F5 and ABO among both genders and LY86 among women; F2, ABO and KLKB1 among FV Leiden non-carriers; F5, F11, KLKB1 and GFRA1 in those with ABO non-O blood type; and ABO, F5, F11, KLKB1, SCUBE1 and SELP among prothrombin G20210A non-carriers. The ABO rs2519093 population-attributable risk (PAR) exceeded that of FV Leiden and prothrombin G20210A, and the joint PAR of FV Leiden, prothrombin G20210A, ABO non-O and ABO rs2519093 was 0.40. Anticoagulant, procoagulant, fibrinolytic and innate immunity pathway genetic variation accounts for a large proportion of VTE among non-Hispanic adults of European ancestry.


An update on epidemiology and clinical aspects of besnoitiosis in livestock and wildlife in sub-Saharan Africa: A systematic review.
Besnoitiosis is a parasitic disease of economic importance caused by cyst-forming protozoa from the genus Besnoitia. The disease affects the skin, subcutis, blood vessels, and mucous membranes of the animals. It is traditionally endemic in the tropical and sub-tropical regions of the world, and causes enormous economic loss associated with impaired productivity and reproduction, as well as skin lesions. Therefore, knowledge of the epidemiology of the disease, including the current Besnoitia species occurring in sub-Saharan Africa, the wide range of mammalian species hosts they use as intermediate hosts, and the clinical signs manifested by infected animals is crucial in developing effective prevention and control measures. This review collected information from peer-reviewed publications involving the epidemiology and clinical signs of besnoitiosis in sub-Saharan Africa using four electronic databases. Results showed that B. besnoiti, B. bennetti, B. caprae, B. darlingi-like and unidentified Besnoitia spp. were found naturally infecting livestock and wildlife across nine reviewed sub-Saharan African countries. Besnoitia besnoiti was the most common species, occurring in all nine reviewed countries, and utilised a wide range of mammalian species as intermediate hosts. Prevalence of B. besnoiti ranged from 2.0 to 80.3%, and B. caprae 5.45-46.53%. Infection rate was high with serology compared to other techniques. Some of the typical signs of besnoitiosis included sand-like cysts on the sclera conjunctiva, nodules in the skin, thickening and wrinkling of the skin and alopecia. Inflammation, thickening and wrinkling of the scrotum were observed in bulls, and lesions on the scrotum deteriorated progressively and became generalized in some cases in spite of treatment. There is still a need for surveys focusing on detecting and identifying Besnoitia spp. using molecular techniques in combination with serological, histology and visual observation, and scoping their natural intermediate and definitive hosts, as well as assessing the burden of the disease animals reared on different husbandry systems in sub-Saharan Africa.


Expression of mdr1 gene in human breast primary tumors and metastases.
Expression of mdr1 gene has been evaluated in 34 tumor samples obtained from breast cancer patients who were classified according to their treatment, and clinical follow-up. No gene amplification was found. mdr1-RNA was never detected in 29 primary breast tumors including 5 samples from patients previously treated by 6 courses of 5-fluorouracil, epirubicin, cyclophosphamide (FEC). On the other hand, mdr1-RNA expression was detected in 1 local recurrence and 2 out of 3 metastases, all of them being treated and exhibiting a poor evolution. A second, untreated local recurrence remained negative. Clinical follow-up for 7 to 48 months in patients receiving chemotherapy showed that absence of mdr1-RNA could not be an accurate factor of satisfactory response to chemotherapy. But, all the patients with detectable mdr1-RNA exhibited a poor evolution and response to treatment. In conclusion, evaluation of mdr1-RNA seemed to be of little interest in primary breast tumors. However, the concomitant presence of an mdr1-RNA and a metastatic phenotype could give a new insight into the relationship between invasive and resistance properties of cancer cells. Such situations would need to be analyzed very carefully for a better utilization of chemotherapy.


Acute metabolic actions of des-(B27-B30)-insulin and related analogues in adult rats.
Metabolic potencies of the destetrapeptide insulin analogues des-(B27-B30)-insulin, des-(B27-B30)-insulin-B26-amide, [ThrB26] des-(B27-B30)-insulin-B26-amide and [GluB26] des-(B27-B30)-insulin-B26-amide were studied in anaesthetized adult rats and in primary cultures of rat hepatocytes and compared with that of the native hormone. Hypoglycaemic effects following intravenous bolus injection of insulin or analogues were similar, as were the stimulatory actions on total body glucose disposal during euglycaemic clamping. In these latter studies a maximal stimulation in the range 16-20 mg glucose/kg per hour was observed and identical half-maximally effective serum concentrations for all peptides of about 1 pmol/ml were obtained. Analogue actions on individual peripheral tissues estimated by the uptake of 2-deoxyglucose were not different from those of insulin. In hepatocyte cultures the stimulatory action of destetrapeptide analogues on glycogenesis and on aminoisobutyric acid transport was indistinguishable from that of native insulin, with identical half-maximally effective concentrations. These data demonstrate that des-(B27-B30)-insulin and related destetrapeptide analogues have high biological activity. Since the truncated non-amidated analogue appeared to be monomeric in solution, this peptide could be a candidate for an insulin preparation potentially showing rapid absorption from subcutaneous tissue.