Clinically applicable bulk isolation of blood CD34+ cells for autografting in children.
CD34+ cells were purified in bulk from apheresis-collected cells of children with cancer using monoclonal antibody (MoAb) and magnetic beads (Baxter ISOLEX system). To improve the purity of the final product for possibly better tumor cell purging and to make the manufacturer's original procedure more cost-effective, we incubated the cells for 30 min with l-phenylalanine methylester hydrochloride (PME) to reduce the cell number by removing contaminating granulocytes and monocytes in the initial step before incubation with MoAb. Our modification prevented nonspecific interactions between MoAb and magnetic beads, and thereby saved expensive materials for purification. A total of 40 purifications were performed with samples containing a mean of 3.1 x 10(9) blood cells mobilized from 15 children by chemotherapy plus granulocyte colony-stimulating factor (G-CSF). The entire purification procedure, from the end of apheresis to storage, was completed within 5h. After incubation with PME and double-layered (40/60%) Percoll separation, the number of CD34+ cells was reduced to 48+/-29%, which suggests the possibility that half of the CD34+ cells in the inoculum were nonclonogenic in the hematopoietic progenitor assay. PME/Percoll-treated cells were then subjected to a final isolation procedure with MoAb according to the manufacturer's suggestions, and 52+/-42% and 32+/-22%, respectively, of the CFU-GM and CD34+ cells present in the initial bag inoculums were recovered. The recovery rates were, respectively, 54% and 67%, when the calculation was limited to the isolation procedure with MNoAb. The purity of isolated CD34+ cells and the plating efficiency in methylcellulose culture were, respectively, 77+/-24% and 33+/-13%. Fourteen children were subsequently autografted with purified CD34+ cells after marrow ablative chemotherapy. The median number of days to achieve an ANC of 0.5 x 10(9)/l was 12 and that to achieve a platelet count of 50 x 10(9)/l was 22.5, which were comparable to those in our historical group of 55 patients who underwent transplant with unmanipulated blood cells (13 and 16 days). These results suggest that our modified purification procedure with PME is useful for the initial reduction of cell numbers to save costly materials, and that cells isolated by this procedure can be directly used in clinical transplantation procedures.


FDA-approved drug screening in patient-derived organoids demonstrates potential of drug repurposing for rare cystic fibrosis genotypes.
Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF. We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators. In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy. This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies. We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.


[Effect of the peptide and amino acid composition of nutrient bases on the parameters of microorganism growth].
The parameters of the growth of three microbial strains cultivated in growth media prepared with the use of different nutrient bases, both locally produced and imported, have been studied. The characteristics of the processes of bacterial cultivation have been found to correlate with the peptide composition of hydrolysates used in the experiment. Nutrient bases containing a wide spectrum of peptides with different molecular weight have ensured the most favorable conditions for the growth of microorganisms belonging to the taxonomic groups under study.


Stable invariant models via Koopman spectra.
Weight-tied models have attracted attention in the modern development of neural networks. The deep equilibrium model (DEQ) represents infinitely deep neural networks with weight-tying, and recent studies have shown the potential of this type of approach. DEQs are needed to iteratively solve root-finding problems in training and are built on the assumption that the underlying dynamics determined by the models converge to a fixed point. In this paper, we present the stable invariant model (SIM), a new class of deep models that in principle approximates DEQs under stability and extends the dynamics to more general ones converging to an invariant set (not restricted in a fixed point). The key ingredient in deriving SIMs is a representation of the dynamics with the spectra of the Koopman and Perron-Frobenius operators. This perspective approximately reveals stable dynamics with DEQs and then derives two variants of SIMs. We also propose an implementation of SIMs that can be learned in the same way as feedforward models. We illustrate the empirical performance of SIMs with experiments and demonstrate that SIMs achieve comparative or superior performance against DEQs in several learning tasks.


Study of morphine-induced dependence in gonadectomized male and female mice.
In this study we evaluated the effects of sex difference and also sex hormones on the naloxone-precipitated morphine withdrawal in both orchidectomized (ORC) male and ovariectomized (OVX) female mice. Morphine (50, 50 and 75 mg/kg/day for 4 days, s.c.) was administered to animals and at 5th day naloxone (4 mg/kg, i.p.)-precipitated morphine withdrawal signs, jumpings and the percentage of weight loss, were measured. There was no significant alteration in withdrawal jumpings between male and female mice, though weight loss was significantly higher in male ones. Jumpings was significantly lower in both OVX and ORC mice and percentage of weight loss was significantly higher in OVX mice than corresponding non-operated or sham animals. In OVX mice, E(2)V (10 mg/kg, s.c.) increased number of jumpings and decreased percentage of weight loss. Progesterone (25 mg/kg, s.c.) had no effect on jumpings, whereas it decreased weight loss in OVX mice. Testosterone (2.5 mg/kg, s.c.) increased jumpings in ORC mice while it had no effect on percentage of weight loss. Our results demonstrated that sex hormones could play a role in the morphine withdrawal syndrome in both ORC male and OVX female mice.


Polydatin ameliorates dextran sulfate sodium-induced colitis by decreasing oxidative stress and apoptosis partially via Sonic hedgehog signaling pathway.
Inflammation, oxidative stress and epithelial barrier dysfunction have been implicated in inflammatory bowel disease (IBD) pathology. The targeted inhibition of these features may represent a promising therapeutic strategy for IBD. Polydatin is an effective natural antioxidant that possesses strong antioxidant and anti-apoptotic properties. Thus, we studied the protective effects of polydatin treatments on a mouse model of experimental colitis. Acute colitis was experimentally induced by adding 3% dextran sulfate sodium (DSS) to the drinking water provided to mice for 7 days and by administering different doses of polydatin (15, 30, or 45 mg/kg) during the same period. Mice were also treated with the Sonic hedgehog (Shh) pathway inhibitor cyclopamine to estimate the efficacy of polydatin and Shh inhibitors on colitis. The disease activity index (DAI), colon length, histology, levels of oxidative and apoptotic mediators and levels of Shh pathway components were evaluated. The polydatin treatment significantly attenuated the DAI, colon shortening and histological damage. In addition, polydatin administration effectively decreased malondialdehyde (MDA) levels and increased the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Polydatin also inhibited apoptosis in mice with colitis by downregulating the expression of the pro-apoptotic proteins Bax, caspase 3 and cleaved caspase 3 and increasing the expression of the anti-apoptotic protein Bcl-2. Furthermore, polydatin modulated Shh signaling pathway activation. After polydatin treatment, the main components of the Shh pathway, including Shh, Patched (Ptc), Smoothened (Smo), and glioblastoma-1 (Gli1), were upregulated at the mRNA and protein levels. Blockade of the Shh pathway using cyclopamine abolished the effects of polydatin on mice with colitis. Based on these observations, polydatin may suppress experimental colitis at least partially by regulating the Shh signaling pathway.


Lessons Learned After 101 Cases of Single-Site Magnetic-Assisted Cholecystectomy in Children.
The aim of this report is to present our experience with a magnetic-assisted single-site cholecystectomy technique ("magnachole") in pediatric patients. We performed a retrospective chart review of all patients who underwent magnachole between 2009 and 2019. We evaluated patients' demographics, diagnosis, operative time, complications, conversion rate and length of stay. Additionally, simple lineal regression analysis was conducted to determine if the surgeon's experience, the patient's age at surgery, the patient's gender or the patient's body weight affected operative time. A total of 101 patients were operated during the analyzed period. The mean age at surgery was 12.6 (range 4 to 19) years, and the mean body weight was 53.7 (range 13.5 to 123) kg. The most frequent indication (91%) was symptomatic cholelithiasis. Mean operative time was 85 (range 45 to 240) min. The mean operative time decreased by 22.7 min (p < 0.001, 95% [CI] 10.35 to 35.13) when we compared the first 51 cases to the last 50 cases. Simple lineal regression showed a reduction of 2.6 min in operative time per year. Age at surgery, gender, and weight did not influence operative time. There were no intraoperative complications. Only 1 case required an additional port to complete the operation. There were no conversions to open cholecystectomy. Median length of stay was 26 h (range 10 to 168). The magnachole technique is safe and effective, and has become our preferred surgical approach for children who need a cholecystectomy. As expected, the operative time decreased as surgeons gain experience with the technique. The technique is feasible regardless of the patient's body habitus. Treatment study. Level IV.


Unmet Needs of Asian American and Pacific Islander Cancer Survivors.
In the USA, cancer is the leading cause of death for Asian Americans and Pacific Islanders (AAPIs), but little is known about the unmet needs of AAPI cancer survivors, especially from a national perspective. Using a community-based participatory research approach, we partnered with the Asian and Pacific Islander National Cancer Survivors Network and the Asian American Cancer Support Network to design and conduct a cross-sectional survey to understand the unmet needs of a national sample of AAPI cancer survivors. We assessed unmet needs in 10 domains: day-to-day activities, financial expenses, emotional concerns, medical treatment, cancer information, home care, nutrition, physical concerns, family relationships, and spirituality. We also assessed self-reported measures related to quality of life. This national sample of AAPI cancer survivors included people from 14 states and two territories who had been diagnosed with a broad range of cancers, including cancer of the breast, ovary/uterus/cervix, prostate, blood, and other sites. Over 80 % reported at least one unmet need. Participants reported an average of 8.4 unmet needs, spanning an average of 3.9 domains. Most commonly reported were unmet needs pertaining to physical concerns (66 %), day-to-day activities (52 %), and emotional concerns (52 %). This is the first report of unmet needs in a national sample of AAPI cancer survivors with a range of different cancer types. It describes the areas of greatest need and points to the importance of devoting more resources to identifying and addressing unmet needs for the underserved population of AAPI cancer survivors.


Feeding the premature and compromised infant: gastrointestinal considerations.
We have presented the current concepts of gastrointestinal ontogeny--the various factors governing the ontogeny of the gastrointestinal tract and the interaction and intricate relationship between different determinants. It is only through a better understanding of the development of the gut and the various factors affecting it that pediatric gastroenterologists are able to design nutritional support strategies for managing very young and compromised neonates.


Characterization of Three Tetrabromobisphenol-S Derivatives in Mollusks from Chinese Bohai Sea: A Strategy for Novel Brominated Contaminants Identification.
Identification of novel brominated contaminants in the environment, especially the derivatives and byproducts of brominated flame retardants (BFRs), has become a wide concern because of their adverse effects on human health. Herein, we qualitatively and quantitatively identified three byproducts of tetrabromobisphenol-S bis(2,3-dibromopropyl ether) (TBBPS-BDBPE), including TBBPS mono(allyl ether) (TBBPS-MAE), TBBPS mono(2-bromoallyl ether) (TBBPS-MBAE) and TBBPS mono(2,3-dibromopropyl ether) (TBBPS-MDBPE) as novel brominated contaminants. Meanwhile, the mass spectra and analytical method for determination of TBBPS-BDBPE byproducts were presented for the first time. The detectable concentrations (dry weight) of TBBPS-MAE, TBBPS-MBAE and TBBPS-MDBPE were in the ranges 28-394 μg/g in technical TBBPS-BDBPE and 0.1-4.1 ng/g in mollusks collected from the Chinese Bohai Sea. The detection frequencies in mollusk samples were 5%, 39%, 95% for TBBPS-MAE, TBBPS-MBAE and TBBPS-MDBPE, respectively, indicating their prevailing in the environment. The results showed that they could be co-produced and leaked into the environment with production process, and might be more bioaccumulative and toxic than TBBPS-BDBPE. Therefore, the production and use of TBBPS derivatives lead to unexpected contamination to the surrounding environment. This study also provided an effective approach for identification of novel contaminants in the environment with synthesized standards and Orbitrap high resolution mass spectrometry.


Cellular functions of plasma membrane estrogen receptors.
Strong evidence now exists for the presence and importance of plasma membrane estrogen receptors (ER) in a variety of cells that are targets for steroid action. When estradiol (E2) binds cell surface proteins, the initiation of signal transduction triggers downstream signaling cascades that contribute to important functions. These functions include cell growth and survival, migration, and new blood vessel formation. In some instances these effects result from the initiation of gene transcription, upregulated through signaling from the membrane. The membrane ER probably originates from the same gene and transcript that produces the nuclear receptor. In the membrane, ER appear to localize mainly to discrete domains of the plasma membrane, known as caveolae, but the mechanisms by which this small pool of ER translocates to this site are currently unknown. At the caveolae, a cross talk with signaling molecules facilitates E2/ER cell biologic actions. This both includes direct stimulation of signaling via G protein activation, and a cross-activation of the epidermal growth factor receptor (EGFR). This review article highlights some of the important advances in understanding the cell biology of estrogen action that emanates from the membrane.


Hydride generation using a metallic atomizer after microwave-assisted extraction for inorganic arsenic speciation in biological samples.
The present speciation method reports the determination of inorganic arsenic forms, using metallic furnace hydride generation atomic absorption spectrometry. The inorganic As speciation is carried out using mild conditions for hydride formation, such as slightly acid pH media (4.50) and low tetrahydridoborate(1-) concentration (0.1% (w/v)). Limits of detection and quantification of 2.0 and 6.6 μg L(-1) of iAs(III) are obtained using optimized conditions. Additionally, microwave-assisted extraction using water as solvent is carried out to provide the appropriate environment for As species extraction as well as impeding inter-conversion between species. With these analytical strategies, As was accurately determined (at 99.9% confidence level) in water and plankton samples.


Extracellular space in the developing retina assessed by electron microscopy: laminar and topographic distribution.
The extent of extracellular space (ECS) in the developing retina of the cat has been measured by electron microscopy in material fixed using techniques developed by others to preserve ECS. ECS is generally greater in foetal than in adult material. It is particularly marked in the plexiform layers of retina at the time of synaptogenesis and in the axon layer at the time of axon growth. The changes in ECS occur first in the central retina, and spread to the periphery. These observations suggest that the high volumes of ECS found in the foetus are not artefactual, but accompany and may play a role in developmental processes.


Machine Learning Algorithms Predict Achievement of Clinically Significant Outcomes After Orthopaedic Surgery: A Systematic Review.
To determine what subspecialties have applied machine learning (ML) to predict clinically significant outcomes (CSOs) within orthopaedic surgery and to determine whether the performance of these models was acceptable through assessing discrimination and other ML metrics where reported. The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were queried for articles that used ML to predict achievement of the minimal clinically important difference (MCID), patient acceptable symptomatic state (PASS), or substantial clinical benefit (SCB) after orthopaedic surgical procedures. Data pertaining to demographic characteristics, subspecialty, specific ML algorithms, and algorithm performance were analyzed. Eighteen articles met the inclusion criteria. Seventeen studies developed novel algorithms, whereas one study externally validated an established algorithm. All studies used ML to predict MCID achievement, whereas 3 (16.7%) predicted SCB achievement and none predicted PASS achievement. Of the studies, 7 (38.9%) concerned outcomes after spine surgery; 6 (33.3%), after sports medicine surgery; 3 (16.7%), after total joint arthroplasty (TJA); and 2 (11.1%), after shoulder arthroplasty. No studies were found regarding trauma, hand, elbow, pediatric, or foot and ankle surgery. In spine surgery, concordance statistics (C-statistics) ranged from 0.65 to 0.92; in hip arthroscopy, 0.51 to 0.94; in TJA, 0.63 to 0.89; and in shoulder arthroplasty, 0.70 to 0.95. Most studies reported C-statistics at the upper end of these ranges, although populations were heterogeneous. Currently available ML algorithms can discriminate the propensity to achieve CSOs using the MCID after spine, TJA, sports medicine, and shoulder surgery with a fair to good performance as evidenced by C-statistics ranging from 0.6 to 0.95 in most analyses. Less evidence is available on the ability of ML to predict achievement of SCB, and no evidence is available for achievement of the PASS. Such algorithms may augment shared decision-making practices and allow clinicians to provide more appropriate patient expectations using individualized risk assessments. However, these studies remain limited by variable reporting of performance metrics, CSO quantification methods, and adherence to predictive modeling guidelines, as well as limited external validation. Level III, systematic review of Level III studies.


On the TRAIL of obesity and diabetes.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been extensively studied for its preferential ability to induce apoptosis of cancer cells. Beyond the cytotoxic capacity of TRAIL, new physiological and pathological roles for TRAIL have been identified, and there is now growing evidence supporting its involvement in the development of obesity and diabetes. This review summarizes the most recent findings associating TRAIL with obesity and diabetes in both humans and experimental settings. We also present and discuss some of the reported controversies behind TRAIL signaling and function. Understanding TRAIL mechanism(s) in vivo and its involvement in disease may lead to novel strategies to combat the growing pandemic of obesity and diabetes worldwide.


Neuropathology of dementia with Lewy bodies in advanced age: a comparison with Alzheimer disease.
Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by α-synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70-79, 80-89 and ≥ 90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80-89 and ≥ 90 year cases compared to 70-79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70-79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group.


Simplified methods for the evaluation of the risk of forming renal stones and the follow-up of stone-forming propensity during the preventive treatment of stone-formation.
Renal lithiasis is a complex multifactorial disease in which recurrence is common. Thus, simple and reliable procedures are needed to evaluate patients with previous kidney stones to determine the risk of recurrence. In this paper we review simple biochemical procedures that can be used to determine the risk for renal stone formation when the stone is available or unavailable for analysis. Our present knowledge of renal lithiasis indicates that renal stones form due to several well-defined factors. Analysis of the renal stone itself can provide important information about clinical factors that require further investigation. When the stone is unavailable, it is necessary to perform a general evaluation of main urinary risk factors associated to renal stone formation, but this study should be complemented considering information related to direct familial antecedents, recidivant degree, radiological images, medical history, and life style habits. Finally, tools for patient follow-up of stone-forming propensity during the preventive treatment are discussed .


Oral epithelial cells as the origin of pemphigus antigen in human saliva.
Absorption of pemphigus sera with normal human saliva or with scraped oral epithelial cells abolished the intercellular antibody titres, as revealed by indirect immunofluorescence. No pemphigus antigenic activity was detected on either human or macaque salivary glands, suggesting that the pemphigus antigen in saliva is a product of the epithelial lining of the oral mucosa. Indirect immunofluorescence on primary cultures of normal oral mucosa demonstrated that pemphigus antigen is synthesized by human oral epithelial cells. Salivary pemphigus antigen was isolated by affinity chromatography on Sepharose-linked IgG-fraction from pemphigus sera. Pemphigus antibody-binding material from the isolated fraction was detected in two bands with apparent molecular weights of 30,000 and 12,000 by immuno-blotting of reduced SDS-polyacrylamide gel electrophoretograms.


Spatial information with pictures and words in visual short-term memory.
In a delayed matching task, the influence of spatial congruence between study and test on visual short-term memory for geometric figures and words was investigated. Subjects processed series of pictures which showed three words or three geometric figures arranged as rows or as triangular configurations. At test, the elements were presented in the identical or in the alternative configuration as at study. In the non-matching case, one of the studied elements was exchanged. The delay was 5 s. Subjects judged whether the elements were the same as during study, independent of their configuration. In Exp. 1, pictures of figures and words were mixed within one list. For both modalities, the response times were longer if the configuration at test was incongruent to the one at study. This contradicts the results of Santa, who observed effects of spatial congruency for figures, but not for words. In Exp. 2 we therefore presented the same material as in Exp. 1, but now the lists were modality-pure, as in the experiment of Santa--i.e., words and figures were shown in different lists. This time, spatial incongruency impaired recognition of the figures, but not recognition of the words. These results show that in a non-verbal context, isolated visually presented words are spatially encoded as non-verbal stimuli (figures) are. However, the word stimuli are encoded differently if the task is a pure verbal one. In the latter case, spatial information is discarded.


First Molecular Detection and Characterization of Hemotropic Mycoplasma Species in Cattle and Goats from Uganda.
Hemoplasmas (hemotropic mycoplasmas) are small pleomorphic bacteria that parasitize the surface of red blood cells of several mammalian species including cattle, goats, and humans, causing infectious anemia. However, studies on hemoplasmas have been neglected and to date, there are no studies on bovine and caprine hemoplasmas in Uganda or the entire East African region. In this study, a polymerase chain reaction (PCR) assay targeting the 16S rRNA gene was used to investigate the presence of hemoplasma in 409 samples (cattle = 208; goats = 201) collected from Kasese district, western Uganda. Results showed that 32.2% (67/208) of cattle samples and 43.8% (88/201) of goat samples were positive for hemoplasmas. Sequencing analysis identified Candidatus Mycoplasma haemobos and Mycoplasma wenyonii in cattle, while Candidatus Mycoplasma erythrocervae and Mycoplasma ovis were identified in goats. Statistical analysis showed that goats were at a higher risk of infection with hemoplasmas compared with cattle. To the best of our knowledge, this is the first molecular evidence of hemoplasmas in bovine and caprine animals in Uganda and the entire east African region.


[Hepatitis B virus components and cytoplasmic virus-like corpuscles in chronic hepatitis (electron microscopic study)].
Author in the needle-biopsy specimen of the liver of a HBsAg positive patient previously treated with immunosupressive preparates (Corticosteroid + Imuran) in the nuclei of hepatocytes by the aid of electron microscope revealed ring-shaped particula of 20-25 nm in diameter (core), in the cytoplasma of ground-glass hepatocytes in the canals of the rough-surfaced endoplasmic reticulum filamentous formations in average of 23nm in diameter (surface antigen). In addition in a few number cytoplasmic core particula have also been revealed. Dane-particula were not seen. Further in the cytoplasma round or ring-shaped virus-like bodies of unknown origin of 80 nm in diameter were found. These particula could be easily distinguished from the Dane particula and from the B virus components (a second virus infection?). Author believe, that the immunsupressive therapy could play some role in the occurrence of the B virus components, since before the therapy with Imuran they could not be detected in the liver.


Manipulating denitrifying sulfide removal of Pseudomonas sp. C27 with nitrite as sole nitrogen source: Shotgun proteomics analysis.
Pseudomonas sp. C27 can effectively conduct denitrifying sulfide removal (DSR) reactions via autotrophic denitrification, heterotrophic denitrification and coupled-cycle pathway. This study is the first to cultivate strain C27 using nitrite as the sole nitrogen source, and to conduct shotgun proteomics analysis and investigate the characteristics of DSR growth of strain C27 with nitrate or nitrite as sole nitrogen source. Shotgun proteomics analysis identified a total of 42 specially expressed proteins of C27 in the nitrite medium, based on which, together with chemical analysis data, a supplementary pathway of sulfur metabolism for C27 from sulfate to thiosulfate via intermediate adenosine-5'-phosphosulfate and 3'-phosphoadenosine-5'-phosphosulfate was proposed. Based on the newly revised scheme, the use of nitrite as sole nitrogen source expands the assessible regime of DSR reactions by C27 and provides the potential to recover renewable chemicals such as pyruvate and succinate from the coupled-cycle pathway.


A Study Evaluating the Accuracy of Triage for Breast Referrals During the Covid-19 Pandemic in a Tertiary Hospital.
To evaluate the accuracy of breast referral triage during Covid-19. Retrospective case study. Primrose Breast Unit, Derriford Hospital, Plymouth. From March 17th to June 30th to encompass the height of the pandemic and the early enforced changes to practice. All referrals received, triaged, and seen (n = 870) in the unit, identified by referral records. The primary outcome measure of a positive disease state was of a histological diagnosis of cancer, with the absence of a cancer diagnosis representing a negative disease state. Accuracy has been determined by sensitivity and specificity calculations; thus defined by correctly triaging cancers to face-to-face clinics and benign cases to telephone or video clinics. Sixty-eight cancers (7.8% of referrals) were detected after initial triage and consultation, of which 51 (sensitivity = 75%) were triaged to one-stop-clinic; positive predictive value was 18.89%. Eight hundred two (specificity = 72.69%) of benign cases were triaged to phone or video clinic initially; negative predictive value was 97.15%. Comparing the study's incidence of cancer (7.8%) to the preceding year's (2019) of 6.8% with Yate's correction shows no significant difference (p < 0.05). Triage accuracy is sufficiently robust to diagnose cancer promptly, which should reassure clinicians and decision makers within the cancer networks.


Reinfection of Somali children with Trichuris trichiura after chemotherapy: relevance of immunostimulation.
The intestinal helminth status of an age-stratified sample (6 to 20 years old) from a Somalian community has been assessed and the typical pattern of highly aggregated parasite distribution found. A reinfection study on a sample of 40 children (treated and untreated with a pentapeptide identical to the active site of the thymic hormone thymopoietin) seemed to indicate that immunological factors play a significant role in modulating the population dynamics of infection in endemic communities.


Identification of key biomarkers for STAD using filter feature selection approaches.
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer death worldwide. Discovery of diagnostic biomarkers prompts the early detection of GC. In this study, we used limma method combined with joint mutual information (JMI), a machine learning algorithm, to identify a signature of 11 genes that performed well in distinguishing tumor and normal samples in a stomach adenocarcinoma cohort. Other two GC datasets were used to validate the classifying performances. Several of the candidate genes were correlated with GC tumor progression and survival. Overall, we highlight the application of feature selection approaches in the analysis of high-dimensional biological data, which will improve study accuracies and reduce workloads for the researchers when identifying potential tumor biomarkers.


A 20-Year-Old Woman With Thoracic Pain and Progressive Dyspnea on Exertion.
A 20-year-old woman presented with dry cough, right-sided thoracic pain, and gradually progressive dyspnea on exertion. She had no hemoptysis or fever. There was no relevant medical history. She was a never smoker and used no medication besides oral contraceptives. There were no other risk factors for a pulmonary embolism. There was a family history of ovarian and breast cancer. Physical examination showed a mildly ill-looking woman, with shallow breathing and normal blood oxygen saturation. Auscultation revealed normal breath sounds without crackles or wheezing. Laboratory testing showed a significantly increased D-dimer (4,560 μg/L [normal, < 500 μg/L]), elevated C-reactive protein (131 mg/L [normal, < 5 mg/L]), normal leucocytes, and elevated lactate dehydrogenase (825 units/L [normal, 50 to 250 units/L).


A novel fibrinolytic enzyme from marine Pseudomonas aeruginosa KU1 and its rapid in vivo thrombolysis with little haemolysis.
A direct acting, extracellular, fibrinolytic enzyme, ~50 KDa from marine Pseudomonas aeruginosa KU1 (PEKU1), was purified. It was found to be a metalloprotease. 60% of the total activity of the purified PEKU1 was retained at 70 °C and the enzyme was practically denatured at 80 °C, 2 h. Metal ions, such as Na+, K+ and Co2+, were found to enhance slightly the fibrinolytic activity, while Fe2+, Mn2+ and Zn2+ were found to be inhibiting. The enzyme showed only less than 5% haemolysis, suggesting its thrombolytic administration safe. Tryptic digestion revealed its similarity to serralysin like alkaline protease of P. aeruginosa. In silico studies showed its binding of protease substrates and fibrin D-dimer in its active site. High affinity binding of bradykinin to the active site of PEKU1, confirmed by in vitro cleaving, suggested its future use as an analgesic. The purified enzyme with Na+, K+ and Co2+, and without Fe2+, Mn2+ and Zn2+ showed thrombolysis in vivo in carrageenan induced murine tail thrombolytic model. The enzyme PEKU1, a novel protease from marine isolate Pseudomonas aeruginosa KU1 has great potential to be developed as a therapeutic agent to combat cardiovascular diseases, as well as analgesic and anti-inflammatory drug in appropriate sites.


Genetic susceptibility to diabetes in inbred strains of mice: measurements of proinsulin mRNA and response to dexamethasone.
The insulin resistance produced by the recessive db mutation has led to more severe diabetes in C57BL/KsJ mice relative to that in C57BL/6J mice, suggesting genetic differences between the two strains affecting insulin production or insulin action. To assess these parameters blood glucose, serum insulin, pancreatic insulin, and proinsulin mRNA were measured in both normal and diabetic (db/db) KsJ and 6J strains. The mice were compared at 5 weeks of age, prior to the development of insulin lack known to occur with age in KsJ db/db mice. As a further provocation to insulin production, another group of the normal and db/db mice were given dexamethasone for 4 days. In normal mice there were no strain differences in blood glucose, serum insulin, pancreatic insulin, or proinsulin mRNA. Dexamethasone, presumably by augmenting insulin resistance, induced increases in serum insulin and proinsulin mRNA to the same extent in KsJ and 6J mice. In db/db mice, while blood glucose, serum insulin, and proinsulin mRNA were considerably higher than in normal mice, there were no strain differences observed. After dexamethasone the db/db mice exhibited strain differences which included higher blood glucose and higher serum insulin levels in KsJ mice. These findings were compatible with greater insulin resistance in KsJ than in 6J db/db mice. While dexamethasone treatment increased serum insulin in KsJ db/db mice, there was no augmentation of proinsulin mRNA in either strain, suggesting a limit to the insulin synthesis. Analysis of serum insulin/glucose and proinsulin mRNA/glucose ratios demonstrated a dexamethasone-induced increase in serum insulin/glucose in normal and diabetic mice of both strains.(ABSTRACT TRUNCATED AT 250 WORDS)


Exchange interaction for the triplet superconductor UTe2.
UTe2 is one triplet superconductor that defies conventional relation between ferromagnetism and superconductivity. Our search for a theoretical explanation starts with one spin-triplet state of two electrons and construct a two-particle exchange interaction that favors the formation of Cooper pairs under the configuration. A modified application of the Bardeen-Cooper-Schrieffer (BCS) theory using parameters derived from ab-initio density functional calculations for electrons and phonons enables us to derive the critical temperature of 1.64 K and an average superconducting gap of 0.25 meV at 0 K. We extend the investigation further into the superconductivity under pressure, showing how Tc and the gap of UTe2 change under compression in ways that are consistent with the results of experiment.


Vertical profile of aerosol number size distribution during a haze pollution episode in Hefei, China.
The vertical distribution of aerosols has important implications on haze formation as development, which is manifested to some extent by the planetary boundary layer (PBL)-aerosol interactions. Information on the number concentration and size of particles is essential to understand these processes, but studies on vertical profiles of particle number-size distribution are limited. Herein, an unmanned aerial vehicle (UAV) equipped with a custom-built optical particle counter (0.4-10 μm) was used to investigate the vertical profiles of particle number-size distribution in Hefei (China) during January 20-30, 2021. Combining ground-based scanning mobility particle sizer and meteorological data, the pollution accumulation and diffusion mechanisms were analyzed in depth. Results showed that as the pollution episode developed, the vertical distribution of the particle number concentration changed from a flat profile to a sharp vertical gradient. Under polluted conditions, a three-layer structure was clearly evident: uniform distribution in a mixed layer near the ground, a sharply reduced transition layer, and a low number concentration layer in the free atmosphere. Analysis revealed that fundamental to this conversion is that aerosols are highly affected by the PBL dynamics. Concurrent on-UAV and ground-based observations revealed that the ratio of particle numbers in the accumulation mode to that in the Aitken mode was 0.92 ± 0.05 in polluted days, which was almost three times that of clean days. This difference in the ratio of large to small particles suggests that hygroscopic growth of aerosol particles under high humidity conditions played an important role in haze development. Moreover, the sharp vertical gradient of the particle number concentration in the transition layer was identified as an important parameter for characterizing PBL height. The findings in this study highlight the importance of PBL dynamics on the under-studied vertical profiles of particle number-size distribution, especially during heavy pollution episodes.


High-rate conversion of lactic acid-rich streams to caproic acid in a fermentative granular system.
Lactic acid-driven chain elongation enables upgrading low-value organic streams into caproic acid. Recently, volumetric production rates over 0.5 g L-1 h-1have been reported for carbohydrate-rich streams in expanded granular sludge bed (EGSB) reactors. However, many target streams contain mixtures of carbohydrates and lactic acid, and little is known about their impact on product profile and microbial ecology, or the importance of carbohydrates as substrate to achieve high rates. This manuscript investigated varying glucose-to-lactate ratios and observed that decreasing glucose-content eliminated odd-chain by-products, while glucose omission required acetic acid addition to support lactic acid conversion. Decreasing the glucose-content fed resulted in decreasing amounts of granular biomass, with the disappearance of granules when no glucose was fed. Lowering the HRT to 0.3 days while feeding only lactic and acetic acid likely triggered re-granulation, enabling the highest lactic acid-driven caproic acid production rates reported thus far at 16.4 ± 1.7 g L-1 d-1.


Integral membrane polypeptides of rat liver peroxisomes: topology and response to different metabolic states.
Rats were treated with clofibrate, a hypolipidemic drug, and with thyroxine. Both drugs which are known to cause peroxisome proliferation, and a concomitant increase in peroxisomal fatty acid beta-oxidation activity in liver increased one of the major integral peroxisomal membrane polypeptides (PMPs), with apparent molecular mass of 69-kDa, six- and twofold, respectively. On the other hand hypothyroidism caused a decrease in peroxisomal fatty acid beta-oxidation activity and considerably lowered the concentration of PMP 69 in the peroxisomal membrane. Two other PMPs with apparent molecular masses of 36 and 22 kDa were not influenced by these treatments. The PMPs with apparent molecular masses of 42, 28, and 26 kDa were shown to be derived from the 69-kDa polypeptide by the activity of a yet uncharacterized endogenous protease during isolation of peroxisomes. Limited proteolysis of intact peroxisomes using proteinase K and subtilisin further substantiated that some portion of the 69-kDa polypeptide extends into the cytoplasm. The 36- and the 22-kDa polypeptides were accessible to proteolytic attack to a much lower extent and, therefore, are supposed to be rather deeply embedded within the peroxisomal membrane. It is demonstrated that peroxisomal acyl-CoA synthetase, an integral PMP extending partially into the cytoplasm, and PMP 69 are not identical polypeptides. Comparison of the peroxisomal membrane with that of mitochondria and microsomes revealed that the 69- and 22-kDa polypeptides as well as the bifunctional protein of the peroxisomal fatty acid beta-oxidation pathway were specifically located only in peroxisomes. Considerable amounts of a polypeptide cross-reacting with the antiserum against the 36-kDa polypeptide were found in mitochondria.


Detection of Pathologically Proven Silicone Lymphadenopathy: Ultrasonography Versus Magnetic Resonance Imaging.
To compare the abilities of ultrasonography (US) and magnetic resonance imaging (MRI) in diagnosing silicone lymphadenopathy. Consecutive patients with silicone breast implants who underwent axillary and intramammary lymph node core needle biopsies were retrospectively collected (December 2011-May 2017). Ultrasonographic examinations were analyzed for the presence of the US snowstorm sign, and MRI examinations were evaluated for the presence of the silicone signal. A pathologist reviewed all biopsied specimens. Ultrasonographic and MRI evaluations were compared to pathologic results. The sensitivity and specificity in diagnosing silicone lymphadenopathy were calculated for the snowstorm sign on US and the MRI silicone signal. Forty-one lymph node biopsies were included: 8 (19.5%) silicone-containing lymph nodes, 29 (70.7%) reactive nodes, and 4 (9.8%) malignant nodes. All nodes were evaluated by US, and 18 of 41 (43.9%) were evaluated by MRI. Seven of 8 (87.5%) silicone-containing nodes showed the snowstorm sign compared to none (0.0%) of the reactive or malignant nodes (P = .0001). One of 5 (20.0%) silicone-containing nodes evaluated by MRI showed the silicone signal compared to none (0.0%) of the reactive or malignant nodes (P = .278). The sensitivity and specificity of the snowstorm sign for diagnosing silicone lymphadenopathy were 87.5% and 100%, respectively, whereas those of the MRI silicone signal were 20.0% and 100%, respectively. The US snowstorm sign is much more sensitive for silicone lymphadenopathy than the MRI silicone signal. In cases of suspected silicone lymphadenopathy, the use of US in addition to MRI should be contemplated.


Inorganic carbon limitation and mixotrophic growth in Chlamydomonas from an acidic mining lake.
Plankton communities in acidic mining lakes (pH 2.5-3.3) are species-poor because they face extreme environmental conditions, e.g. 150mg l(-1) Fe2+ +Fe3+. We investigated the growth characteristics of the dominant pigmented species, the flagellate Chlamydomonas acidophila, in semi-continuous culture experiments under in situ conditions. The following hypotheses were tested: (1) Low inorganic carbon (IC) concentrations in the epilimnion (e.g. 0.3 mg l(-1)) arising from the low pH limit phototrophic growth (H-1); (2) the additional use of dissolved organic carbon (mixotrophy) leads to higher growth rates under IC-limitation (H-2), and (3) phagotrophy is not relevant (H-3). H-1 was supported as the culture experiments, in situ PAR and IC concentrations indicated that IC potentially limited phototrophic growth in the mixed surface layers. H-2 was also supported: mixotrophic growth always exceeded pure phototrophic growth even when photosynthesis was saturated. Dark growth in filtered lake water illuminated prior to inoculation provided evidence that Chlamydomonas was able to use the natural DOC. The alga did not grow on bacteria, thus confirming H-3. Chlamydomonas exhibited a remarkable resistance to starvation in the dark. The compensation light intensity (ca. 20 micromol photons m(-2) s(-1)) and the maximum phototrophic growth (1.50 d(-1)) fell within the range of algae from non-acidic waters. Overall, Chlamydomonas, a typical r-strategist in circum-neutral systems, showed characteristics of a K-strategist in the stable, acidic lake environment in achieving moderate growth rates and minimizing metabolic losses.


Central versus peripheral cannulation for acute type A aortic dissection.
This study sought to evaluate the impact of central aortic versus peripheral cannulation on outcomes after acute type A aortic dissection repair. This was an observational study using an institutional database of acute type A aortic dissection repairs from 2007 to 2021. Patients were stratified according to central, subclavian, or femoral cannulation. Kaplan-Meier survival estimation and multivariable Cox regression were performed. The study population consisted of 577 patients who underwent acute type A aortic dissection repair. Of these, central cannulation was used in 490 patients (84.9%), subclavian cannulation was used in 54 patients (9.4%), and femoral cannulation was used in 33 patients (5.7%). Rates of peripheral vascular disease, aortic insufficiency moderate or greater, and cerebral malperfusion differed significantly among the groups, but baseline characteristics were otherwise comparable (P > .05). Operative mortality was lowest in the central cannulation group (9.8%), but this did not differ significantly among the groups. Kaplan-Meier survival estimates were similar among the groups. On multivariable Cox regression, cannulation strategy was not significantly associated with long-term survival. Acute type A aortic dissection repair can be safely performed through central aortic cannulation, with outcomes comparable to those obtained with subclavian or femoral cannulation.


BNIP3-dependent mitophagy safeguards ESC genomic integrity via preventing oxidative stress-induced DNA damage and protecting homologous recombination.
Embryonic stem cells (ESCs) have a significantly lower mutation load compared to somatic cells, but the mechanisms that guard genomic integrity in ESCs remain largely unknown. Here we show that BNIP3-dependent mitophagy protects genomic integrity in mouse ESCs. Deletion of Bnip3 increases cellular reactive oxygen species (ROS) and decreases ATP generation. Increased ROS in Bnip3-/- ESCs compromised self-renewal and were partially rescued by either NAC treatment or p53 depletion. The decreased cellular ATP in Bnip3-/- ESCs induced AMPK activation and deteriorated homologous recombination, leading to elevated mutation load during long-term propagation. Whereas activation of AMPK in X-ray-treated Bnip3+/+ ESCs dramatically ascended mutation rates, inactivation of AMPK in Bnip3-/- ESCs under X-ray stress remarkably decreased the mutation load. In addition, enhancement of BNIP3-dependent mitophagy during reprogramming markedly decreased mutation accumulation in established iPSCs. In conclusion, we demonstrated a novel pathway in which BNIP3-dependent mitophagy safeguards ESC genomic stability, and that could potentially be targeted to improve pluripotent stem cell genomic integrity for regenerative medicine.


Open globe injuries in children: factors predictive of a poor final visual acuity.
Eye injuries are the leading cause of monocular blindness in children and are challenging to manage. However, limited follow-up studies currently exist. We describe the clinical characteristics and outcomes of open globe injuries presenting to a major UK centre and discuss factors affecting long-term prognosis. Identification of (1) demographic features, (2) causes, types and location of injuries, (3) initial clinical features and correlation with visual outcome, and (4) predictors of poor visual outcome. Retrospective study by reviewing and analysing records of 20 patients, aged 16 years and below, who had undergone repair of an open globe injuries at the Manchester Royal Eye Hospital, UK. Data recorded included demographic data, mechanisms and location of injury, visual acuity, clinical signs on presentation, surgical procedures, postoperative complications, and final visual acuity. The study group comprised of 85% male subjects, 15% female subjects. The average age was 9.8 years (range: 1-15). Average follow-up was 16.3 months (range: 3-48 months). Sharp objects (mainly glass or knife) accounted for the majority (65%) of injuries. Initial clinical signs associated with poor visual outcomes included poor initial visual acuity, cataract, RAPD, and no initial red reflex. Younger patients and blunt injuries (especially BB gun injuries) had worse visual outcomes. Factors suggesting unfavourable final visual acuity after open globe injuries in children are (1) young age at presentation, (2) poor initial visual acuity, (3) presence of a relative afferent papillary defect, (4) absence of red reflex, (5) cataract, and (6) types and number of surgeries performed.Awareness and education with regard to prevention of paediatric injuries need to be actively implemented.


Nonfixation of mesh in laparoscopic totally extraperitoneal inguinal hernia repair: A propensity score matched analysis.
Regarding the need for mesh fixation in total extraperitoneal inguinal hernia repair (TEP), several studies have found no significant differences in the recurrence rate between patients with and without fixation. Furthermore, there is no report on the outcome of this treatment from Japan. We aimed to analyze the outcomes of nonfixation TEP with those of fixation at our institute. In May 2016, the nonfixation TEP technique was launched. The fixation group (165 patients) was compared to the nonfixation group (195 patients). Because of the significant bias between the two groups, a propensity score matched analysis was performed (with 109 patients in each group). Moreover, only ordinary cases (with 58 patients in each group) were compared, excluding bilateral, large, and impaction cases. One patient in the nonfixation group experienced recurrence. It was a hernia case with a large orifice. In the fixation group, seroma was more prevalent; however, no differences were observed between the two groups in propensity score matching. In unilateral cases, the nonfixation group had a shorter operation time and stayed in the hospital for a shorter time postoperatively. The ordinary cases, excluding cases of bilateral hernias, large hernias on visual examination, impactions, and large hernial orifices, showed no recurrence or significance in surgical complications. The nonfixation TEP was considered acceptable at least for ordinary hernial cases.


Ramifications of a redox switch within a normal cell: its absence in a cancer cell.
A previously described model for cellular proliferation, based on the relationship of the cell cycle to redox parameters, is explored here to account for the origin of the cancerous cell and some of its key abnormal characteristics, such as the Warburg effect, apoptosis, aneuploidy, and uncontrolled proliferation. We describe how the redox switch that characterizes normal cells and its absence in cancer cells is responsible for the origin and characteristics of cancer cells. Metabolic and chromosomal changes resulting from the lack of such a redox switch in cancer cells are described. The effects of a well-known carcinogen, cigarette smoking, are also applied to the model. This report emphasizes the role of the threshold intracellular redox potential in regulating cells.


Efficient degradation of rhodamine B using modified graphite felt gas diffusion electrode by electro-Fenton process.
The electro-Fenton (EF) process treatment of 0.1-M (rhodamine B) RhB solution was studied with different graphite cathode materials, and graphite felt (GF) was selected as a promising material in further investigation. Then, the degradation performances of gas diffusion electrode (GDE) and graphite felt (GF) were compared, and GDE was confirmed to be more efficient in RhB removal. The operational parameters such as Fe(2+) dosage and current density were optimized, and comparison among different modified methods-polytetrafluoroethylene-carbon black (PTFE-CB), polytetrafluoroethylene-carbon nanotube (PTFE-CNT), electrodeposition-CB, and electrodeposition-CNT-showed 98.49 % RhB removal by PTFE-CB-modified cathode in 0.05 M Na2SO4 at a current density of 50 A/m(2) and an air flow rate of 1 L/min after 20 min. Meanwhile, after cathode modified by PTFE-CB, the mineralization efficiency and mineralization current efficiency performed absolutely better than the pristine one. Cyclic voltammograms, SEM images, contact angles, and BET surface area were carried out to demonstrate stronger current responses and higher hydrophilicity of GF after modified. The value of biochemical oxygen demand/chemical oxygen demand (BOD5/COD) increased from 0.049 to 0.331 after 90-min treatment, suggesting the solution was biodegradable, and the modified cathode was confirmed to be stable after ten circle runs. Finally, a proposed degradation pathway of RhB was put forward.


Sacral stress fractures: an unusual cause of low back pain in an athlete.
A case report of a sacral stress fracture causing low back pain in an athlete. To document the occurrence of sacral stress fractures in athletes and to recommend it in the differential diagnosis of low back pain, especially in runners and volleyball players. Low back pain is common both in the general population and in athletes. Athletes place high physical demands on their bodies, which often lead to stress fractures. Sacral stress fractures can cause back pain and are often not included in the differential diagnosis of back pain. The authors were involved in the care and treatment of this patient and reviewed all medical records, radiologic tests, and related literature. In a 16-year-old volleyball player with a 4-week history of low back pain, magnetic resonance imaging of her pelvis revealed a stress fracture of the left sacral ala. She was treated with nonsteroidal anti-inflammatory agents, rest, and conditioning exercises and had a good functional outcome. Sacral stress fractures should be included in the differential diagnosis of athletes with low back pain, particularly runners and volleyball players. To the authors' best knowledge, this is the first report of a volleyball player with a sacral stress fracture. A review of the literature yielded 29 cases of sacral stress fractures in athletes, mainly runners.


Issues and biases in matching medicaid pregnancy episodes to vital records data: the Arkansas experience.
This study examines the extent of selection biases identified in the process of linking Medicaid claims with evidence of pregnancy to vital records. Two years of Medicaid claims were scanned to identify pregnancy-related diagnoses and procedures. Information on 55,764 Medicaid recipients was provided to the Division of Health Statistics, which linked the information to vital records data on a range of identifying characteristics. Claims were then clustered by date and then into episodes of care surrounding the birth date of the infant. We identified 38,222 pregnancy episodes matched to vital records; 8,474 episodes unmatched to vital records that appeared to terminate before a delivery; and 5,278 episodes that appeared to include a delivery but did not match to vital records. The characteristics of matched episodes and unmatched episodes and the characteristics of matched episodes with and without delivery claims are compared. Unmatched episodes spanned fewer weeks than matched episodes, included more diagnostic indicators of elevated risk, and occurred more frequently in more impoverished populations. Among the matched records, 13% did not include claims for delivery services. These episodes occurred more frequently among Hispanic women, women delivering out of hospitals and women with preterm births and infant deaths. The results provide evidence, as other studies have demonstrated, that matching Medicaid claims and vital records data is feasible. However, the matched analytic data set does tend to under-represent the outcomes of high-risk pregnancies. An additional source of selection bias can be avoided by using evidence of pregnancy as the Medicaid index for matching against vital records, rather than using only index cases with evidence of delivery.


Accumbens-caudate-septal circuit as a system for hippocampal regulation: involvement of a GABAergic neurotransmission.
Hippocampal-based epileptiform activity may reach the basal ganglia via the nucleus accumbens. Previous data suggested that caudate nucleus is able to influence hippocampal epilepsy, probably sending a projection to the septum. In order to test the hypothesis of a retrograde activation of accumbens-caudate pathway in hippocampal regulation, we electrically stimulated both caudate nucleus and nucleus accumbens and studied modifications of hippocampal EEG in the feline focal epilepsy model. We also performed bilateral electrolytic lesion of nucleus accumbens and repeated caudate stimulation. Results showed that nucleus accumbens stimulation was ineffective in modifying hippocampal epilepsy; on the contrary, caudate stimulation caused a statistically significant decrease of hippocampal spike frequency and amplitude. On the other hand, in accumbens-lesioned animals caudate activation consistently reduced hippocampal epilepsy to a significant degree. As the caudate nucleus influences hippocampal activity and the septum may constitute a relay station of this functional relation, a possibility was tested concerning a GABAergic mediation. To this end, after a stable caudate-induced effect was reached, an intraseptal microinjection of picrotoxin (GABA receptor antagonist) was made and caudate stimulation repeated at the same parameters. Such a study showed that after intraseptal picrotoxin, caudate stimulation failed to elicit any type of modification of hippocampal activity. Experimental findings support the notion that the striatal modulation on hippocampus is mediated by an anterograde rather than a retrograde pathway, and underline the possibility of a GABAergic caudate-septal influence.


A sensitive and selective near-infrared fluorescent probe for mercuric ions and its biological imaging applications.
A new mercury(II) near-infrared region fluorescent probe 3,9-dithia-6-monoazaundecane-tricarbocyanine has been designed and synthesized. It consists of two functional moieties: the tricarbocyanine performs as the near-infrared region fluorophore, and the 3,9-dithia-6-monoazaundecane acts as the selected binding site for metal ions. The near-IR excitation and emission profiles of the probe can minimize cell and tissue damage and avoid native fluorescence from natural cellular species. It exhibits fluorescence increase upon the binding of the Hg(2+) based on the inhibition of the photoinduced electron transfer quenching mechanism. Excellent sensitivity and selectivity for mercuric ions are observed with this probe. The value of the system is demonstrated by its use in monitoring the real-time uptake of Hg(2+) within HepG2 cells and five day old zebrafish. The synthesis and remarkable properties of it help to extend the development of metal ions fluorescent probes for biological applications.


A co-payment for consultant services: primary care physicians' referral actualization.
Prospective evaluation of the effect of a new copayment for specialists consultations on actualization of referrals (2,432 patient), was examined. Actualization of the appointment, reasons for not actualizing, and sociodemographic characteristics were recorded. Actualization was 85.1% in community consultation clinics and 91.7% in hospital outpatient clinics. The main reasons for non actualization were: inability to reach the clinic (53.4%), the problem had resolved (15%), and co-payment (2%). In addition, 19.1% stated that they did not actualize a past consultant visit due to co-payment. Referring physicians noted that co-payment had some effect on their decision, especially with the elderly or lower income patients. A relatively small compulsory co-payment was not found to have a long term effect on utilization of specialists' services.


Neurodevelopmental and psychiatric disorders in females with Turner syndrome: a population-based study.
Turner syndrome is the result of the partial or complete absence of an X chromosome in phenotypic girls. This can cause an array of medical and developmental difficulties. The intelligence quotient in females with Turner syndrome has previously been described as uneven, but considered within normal range. Although their social, intellectual, and psychiatric profile is described, it is unclear to what extent these females meet the clinical criteria for neurodevelopmental or psychiatric diagnoses. The aim of this study was to examine the prevalence of neurodevelopmental and psychiatric disorders in females with Turner syndrome. A retrospective cohort study was performed with a total of 1392 females with Turner syndrome identified through the Swedish National Patient Register and compared with 1:100 age- and sex-matched controls from the general population. The associations between Turner syndrome and diagnoses of neurodevelopmental and/or psychiatric disorders were calculated using conditional logistic regression and is presented as estimated risk (odds ratio, OR, 95% confidence interval, CI) in females with Turner syndrome compared with matched controls. Females with Turner syndrome had a higher risk of neurodevelopmental or psychiatric disorder (OR 1.37, 95% CI 1.20-1.57), an eightfold increased risk of intellectual disability (OR 8.59, 95% CI 6.58-11.20), and a fourfold increased risk of autism spectrum disorder (OR 4.26, 95% CI 2.94‑6.18) compared with the controls. In addition, females with Turner syndrome had twice the risk of a diagnosis of schizophrenia and related disorders (OR 1.98, 95% CI 1.36-2.88), eating disorders (OR 2.03, 95% CI 1.42-2.91), and behavioral and emotional disorders with onset in childhood (OR 2.01, 95% CI 1.35-2.99). Females with Turner syndrome have an increased risk of receiving a diagnosis of neurodevelopmental or psychiatric disorder. This warrants extensive assessment of intellectual and cognitive functions from early age, and increased psychiatric vigilance should be a part of lifelong healthcare for females with Turner syndrome.


Advances in biology of multiple myeloma: cell kinetics, molecular biology and immunology.
Bone marrow plasma cell proliferative activity has been evaluated in a large series of multiple myeloma (MM) patients. This kinetic parameter has been shown to be a useful tool for patient management, and contributes to a correct diagnosis and a selection of high-risk patients who can be offered high-dose chemotherapy. The role of ras oncogenes has been evaluated in the pathogenesis of MM. A point-mutated and activated H-ras oncogene, introduced in a human lymphoblastoid cell line, was able to induce neoplastic transformation and differentiation to plasma cell. Indeed, mutated alleles of ras genes have been detected in a high percentage of myeloma patients in relapse phase. Phenotypical and functional studies have been carried out in T-lymphocyte subsets and an impaired cellular immunity has been detected. Such an impairment was related to the disease status: marked alterations were detected in relapse phase, whereas a partial recovery was observed during remission phase.


Cytochrome P450 mRNA expression in peripheral blood lymphocytes as a predictor of enzyme induction.
Previous reports have supported the concept that messenger ribonucleic acid (mRNA) concentrations for cytochrome P450 (CYP) enzymes in peripheral blood mononuclear cells may be predictive of systemic enzyme activity. We investigated whether changes in mRNA expression for CYP1A2,CYP2C19, CYP2D6 and CYP3A4 in peripheral blood lymphocytes (PBLs) may serve as surrogate markers for changes in CYP enzyme activity following the administration of rifampin. On day 1 and day 9 of the study, 12 healthy volunteers were administered caffeine 100 mg, debrisoquine 10 mg and omeprazole 40 mg orally, along with midazolam 0.025 mg/kg intravenously. Blood samples and urine were collected for 8 h after drug administration. The subjects took rifampin 300 mg (n = 6) or 600 mg (n = 6) daily on days 2-8. Total RNA was isolated from PBLs on day 1 and day 9, and mRNA expression for the CYP enzymes and hGAPDH were determined by means of quantitative, real-time, reverse-transcriptase polymerase chain reaction. CYP1A2 activity was estimated by calculating the plasma paraxanthine to caffeine AUC ratio (caffeine metabolic ratio; CMR), CYP2C19 activity by the 2-h omeprazole hydroxylation index (HI), CYP2D6 activity by the urinary debrisoquine recovery ratio (DBRR) and CYP3A4 activity by midazolam clearance. Median midazolam clearance (0.362 to 0.740 l/kg/h), omeprazole HI (0.752 to 0.214), CMR (0.365 to 0.450) and DBRR (0.406 to 0.479) all changed significantly following rifampin, consistent with the expected enzyme induction. CYP1A2,CYP2D6 and CYP3A4 mRNA content were measurable in all samples. CYP2C19 mRNA was inconsistently detectable. There were no significant correlations between changes in enzyme activity and mRNA expression by Spearman's rank order correlation. The results do not support the use of mRNA expression assays for CYP1A2, CYP2C19, CYP2D6 and CYP3A4 enzymes in PBLs as surrogates for quantifying changes in systemic enzyme activity in the setting of enzyme induction.


The Utility of CTA in Pediatric Oropharyngeal Trauma: A Systematic Review and Meta-Analysis.
To analyze the utility of computed tomography angiography (CTA) in identifying internal carotid artery (ICA) injury and reducing cerebrovascular accident (CVA) incidence in children presenting with normal neurologic exams after oropharyngeal trauma (OT). PubMed, Scopus, CINAHL, and Cochrane. A systematic review and meta-analysis were performed following PRISMA guidelines. Of 1,185 studies screened, 95 studies of pediatric OT met inclusion criteria. Meta-analysis of proportions was performed. A total of 1224 children with OT were analyzed. Excluding case reports, the weighted proportion of a CVA after OT was 0.31% (95% CI 0.06-0.93). If a child presented without neurologic deficits, 0.30% (95% CI 0.05-0.95) returned with new neurologic deficits. An ICA injury was identified in 0.89% (95% CI 0.16-2.74) of screening CTAs. No difference in CVA incidence was seen in children with screening CTA (0.52% [95% CI 0.02-2.15]) compared to children without screening CTA (0.42% [95% CI 0.06-1.37]). Patients who developed CVA had a higher proportion of injuries >2 cm, injuries at the posterior pillar or tonsil, and injuries with a writing utensil or popsicle stick compared to patients without CVA. The proportion of children experiencing an ICA injury leading to CVA after sustaining OT is low. CTAs infrequently show ICA changes in children with normal neurological exams. Children who receive CTAs do not have a significantly lower incidence of CVAs than children who do not receive CTAs. Clinicians should weigh the risks and benefits of a CTA based on an individual child's presentation and discuss this with caregivers for shared decision-making. Laryngoscope, 133:25-37, 2023.


Successful use of "cryo-mapping" to avoid phrenic nerve damage during ostial superior vena caval ablation despite nerve proximity.
The SVC may require ablation to treat atrial fibrillation. Phrenic nerve proximity identified with pacing maneuvers may preclude ablation. We tested a new method using "cryo-mapping" to ablate despite nerve proximity. Of 833 patients undergoing ablation, 110 (12%) had arrhythmogenic substrate at the SVC/RA junction. Of these 110 patients, 66 (60%) had consistent diaphragmatic stimulation when pacing at 10 mA at the prospective site of ablation. Of these 66 patients, 7 had continued arrhythmogenicity despite attempts to modify this substrate. For these 7 patients, we paced 4 cm into the SVC where consistent phrenic nerve stimulation was obtained, and cryoablation at -30 degrees C was performed at sites requiring ablation. In 6 of 7 patients (86%), with continued diaphragmatic capture, cryoablation at -70/-80 degrees C was then performed. In 1 of 7 patients (14%), diaphragmatic stimulation ceased at -30 degrees C, and energy delivery stopped. In the 6 patients in whom cryoablation was completed, the arrhythmogenic substrate was successfully ablated without phrenic nerve injury. A novel "cryo-mapping" technique during phrenic nerve pacing can be used to successfully ablate arrhythmogenic substrate at the SVC/RA junction despite phrenic nerve proximity.


Recording sound from human skeletal muscle: technical and physiological aspects.
In order to examine technical factors that influence muscle sound recording, single twitches of muscle were utilized since their waveforms were likely to be reproducible. We observed that satisfactory recordings could be made with either Archer air interface, or Hewlett-Packard direct contact sensor, microphones. Firm contact and stability between the microphone and the skin surface were particularly important. Frequencies below 20 Hz, the lower limit of the human auditory range, must be recorded, since they account for at least 90% of the power of the muscle sound wave. The chief frequencies were below 4 Hz. The sound wave produced by a maximal twitch of human thenar muscle induced by median nerve stimulation at the wrist is maximal in amplitude over the center and recedes to near zero at the margins of the muscle. It is preceded by the muscle compound action potential and is followed by the force curve, recorded with a strain gauge attached to the thumb. The sound resembles force in total time course, and it increases with increasing strengths of nerve stimulation. However, it differs in its latency, phase relationships, and response to nerve stimulation at different frequencies. Some of the features of muscle sound suggest it relates to both the active contractile and the parallel elastic components of muscle during a twitch contraction, but not the series elastic component.


Effect of cyclic adenosine monophosphate, 5'-(N-ethylcarboxyamido)-adenosine and methylxanthines on the release of thromboxane and lysosomal enzymes from human alveolar macrophages and peripheral blood monocytes in vitro.
We have investigated the effect of the manipulation of intracellular cyclic adenosine monophosphate (cyclic AMP) and the stimulation of adenosine receptors on the function of human alveolar macrophages in vitro. Human alveolar macrophages harvested by bronchoalveolar lavage were stimulated by opsonised zymosan 1 mg/ml in the presence of N6,2'0-dibutyryladenosine 3':5' cyclic monophosphate (dibutyryl cyclic AMP) 5 x 10(-6) to 5 x 10(-3) M,8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo cyclic AMP) 5 x 10(-6) to 5 x 10(-3) M, 5'-(N-ethylcarboxamido)-adenosine (NECA) 10(-7) to 10(-4) M, adenosine 10(-7) to 10(-4) M, theophylline 5 x 10(-6) to 5 x 10(-3) M and enprofylline 5 x 10(-8) to 5 x 10(-4) M. The subsequent release of thromboxane B2 (TXB2) and N-acetyl-beta-D-glucosaminidase (NAG) activity was monitored. In addition, the release of TXB2 and NAG from zymosan stimulated human monocytes incubated in the presence of NECA 10(-7) to 10(-4) M was measured. The TXB2 release from alveolar macrophages were inhibited by dibutyryl cyclic AMP and 8-bromo cyclic AMP and to a lesser extent by NECA, theophylline and enprofylline. However, adenosine had no effect. None of the agents studied altered NAG release. In addition, monocytes showed greater sensitivity to the inhibitory effects of 5-N-ethylcarboxamido adenosine than alveolar macrophages. In conclusion, the alveolar macrophage was inhibited by stable analogues of cyclic AMP and xanthines at supratherapeutic concentrations but have no functional excitatory adenosine receptors and only a residual inhibitory adenosine receptor function compared to the precursor monocyte.


Chronic kidney disease in postmenopausal women.
Menopause is derived from the Greek words men (month) and pauses (cessation) and means permanent cessation of menstruation after the loss of ovarian activity. Chronic kidney disease (CKD) has recently been associated with cardiovascular events in several studies. CKD patients have a heavy burden of traditional cardiovascular risk factors in addition to a range of nontraditional risk factors such as inflammation and abnormal metabolism of calcium and phosphate. In this review, the association of CKD and cardiovascular disease (CVD), as well as of osteoporosis in postmenopausal women is discussed. CKD mineral and bone disorder, characterized by disturbances of calcium/phosphate/parathyroid hormone, bone abnormalities and vascular and soft tissue calcification, is highly prevalent in CKD and is a strong, independent predictor of bone fracture, CVD and death. Estrogen has been shown to: (a) decrease the expression of angiotensin type 1 receptors in vasculature and kidneys; (b) reduce the expression and activity of angiotensin-converting enzyme, and (c) cause the release of angiotensinogen substrate from the liver. However, the degree of activation or suppression of the renin-angiotensin-aldosterone system by estrogen has not been clearly established. Clinical data on the effects of estrogen therapy on bone mineral densities are extremely limited in the ESRD population. CVD is the most common cause of death in postmenopausal women with CKD and many contributing factors have been explored. Future research for prevention of CVD in postmenopausal women with CKD would focus on the biology of vascular calcification as well as bone loss.


Applicability of LC-MS/MS to optimize derivatization of topiramate with FMOC-Cl using reacted/intact drug ratio.
Topiramate is an antiepileptic agent, which is structurally different from the other anticonvulsants. The drug has no UV-Vis absorption or emits fluorescence. Thus for its analysis using high performance liquid chromatography (HPLC) with conventional UV or fluorescence detectors, the drug should be derivatized with a suitable reagent. In previous study using fluorenylmethyl chloroformate (FMOC-Cl) and HPLC coupled with fluorescence detector, we reported an analytical method for derivatization and analysis of the drug in human serum. In this method, several factors including time and temperature of the reaction, pH and concentration of the used buffer, ratio of organic phase in the medium and removal of the reagent excess by glycine should be optimized to obtain maximum yield of the product. In HPLC coupled with fluorescence detector, there is not any signal from intact topiramate and only the final product (FMOC-topiramate) is appeared. Thus to optimize the reaction conditions for obtaining the highest derived yield, intensity of the final product peak is considered as a criteria for progression of the reaction. In LC-MS/MS system however, both free and reacted topiramate are visible in observed spectra. In the present study reaction of the drug with FMOC-Cl was re-optimized using LC-MS/MS technique on the basis of reacted/free topiramate ratio as the new and more accurate index. The results showed that, ratio of organic/aqueous phase has a dominant effect on the reaction, the most efficient temperature is 70°C and the reaction is reversed following addition of the glycine.


[Labile blood products from donors immunized against the HLA system. Apropos of a case of transfusional pulmonary edema].
A case of transfusion-related acute lung injury (TRALI) due to HLA antibodies present in one unit of packed red blood cells led us to discuss the screening of HLA antibodies for female donors having been pregnant, and the use of labile blood products.


Fluorescence enhancement of surface plasmon coupled emission by Au nanobipyramids and its modulation effect on multi-wavelength radiation.
Surface plasmon coupled emission (SPCE), a novel surface-enhanced fluorescence technique, can generate directional and amplified radiation by the intense interaction between fluorophores and surface plasmons (SPs) of metallic nanofilms. For plasmon-based optical systems, the strong interaction between localized and propagating SPs and "hot spot" structures show great potential to significantly improve the electromagnetic (EM) field and modulate optical properties. Au nanobipyramids (NBPs) with two sharp apexes to enhance and restrict the EM field were introduced through electrostatic adsorption to achieve a mediated fluorescence system, and the emission signal enhancement was realized by factors over 60 compared with the normal SPCE. It has been demonstrated that the intense EM field produced by the NBPs assembly is what triggered the unique enhancement of SPCE by Au NBPs, which effectively overcomes the inherent signal quenching of SPCE for ultrathin sample detection. This remarkable enhanced strategy offers the chance to improve the detection sensitivity for plasmon-based biosensing and detection systems, and expand the range of applications for SPCE in bioimaging with more comprehensive and detailed information acquisition. The enhancement efficiency for various emission wavelengths was investigated in light of the wavelength resolution of SPCE, and it was discovered that enhanced emission for multi-wavelength could be successfully detected through the different emission angles due to the angular displacement caused by wavelength change. Benefit from this, the Au NBP modulated SPCE system was employed for multi-wavelength simultaneous enhancement detection under a single collection angle, which could broaden the application of SPCE in simultaneous sensing and imaging for multi-analytes, and expected to be used for high throughput detection of multi-component analysis.


Dentine hypersensitivity - an enigma? A review of terminology, mechanisms, aetiology and management.
Dentine hypersensitivity is a relatively common problem experienced in clinical dental practice. This condition may disturb the patient during eating, drinking, brushing and sometimes even breathing. Therapeutic intervention by desensitising agents may provide only partial pain relief and recurrence is common. Much remains unknown about dentine hypersensitivity, even the terminology can be questioned. Most of the literature over decades has been concerned with reporting clinical trials proving the efficacy of numerous treatments for dentine hypersensitivity. Indeed, besides haemorrhoids, there can be few other diseases or conditions known to man that can apparently be successfully treated by so many and extremely varied agents and formulations applied topically. This paper will discuss the epidemiology, mechanisms of pain production and aetiological factors for the condition in the hope of developing ideas for more realistic prevention and management strategies.


Identification of hub genes in AR-induced tamoxifen resistance in breast cancer based on weighted gene co-expression network analysis.
Approximately 30% of patients with oestrogen receptor (ER)-positive breast cancer (BC) exhibit intrinsic or recurrent resistance to tamoxifen (TAM) adjuvant endocrine therapy. The androgen receptor (AR) is expressed in about 90% of ER-positive patients. Our previous studies found that BC patients with an AR:ER expression ratio ≥ 2.0 are more susceptible to TAM resistance. However, the specific mechanism by which a high AR:ER ratio promotes TAM resistance remains unknown. RNA sequencing was performed on 10 cases of BC tissues with AR:ER ratios ≥ 2.0 and 3 cases with AR:ER ratios < 2.0. We then compared our data with the screened TAM-resistant and TAM-sensitive cases from the TCGA BC database. Bioinformatics methods were used to screen differentially expressed genes (DEGs) and to perform gene enrichment analysis. Weighted correlation network analysis (WGCNA) was used to screen hub genes in the AR-induced TAM resistance process. PAM50 analysis showed that the molecular phenotype of BC patients with AR:ER ratios ≥ 2.0 was similar to that of triple-negative breast cancer (TNBC), whereas the BC samples with AR:ER ratios < 2.0 were classified as the luminal subtype. Among the AR:ER ratio ≥ 2.0 and AR:ER < 2.0 BC tumours, 1855 DEGs were identified. Gene enrichment analysis showed that DEGs were enriched mainly in proliferation-related molecular pathways, such as the cell cycle, necroptosis, metabolic pathways and DNA replication. WGCNA analysis showed that SEC14L2, RIIAD1, STC2 and MAGEA6 served as hub genes in AR-induced TAM resistance and were associated with BC survival prognosis in the TCGA cohort. A high AR:ER expression ratio is a biomarker for patients who might develop TAM resistance, and AR expression seems to be a possible mechanism of resistance to endocrine therapy.


DNA binding to proteolytically activated TLR9 is sequence-independent and enhanced by DNA curvature.
Toll-like receptor 9 (TLR9) recognizes microbial DNA in endolysosomal compartments. The ectodomain of TLR9 must be proteolytically cleaved by endosomal proteases to produce the active receptor capable of inducing an innate immune signal. We show that the cleaved TLR9 ectodomain is a monomer in solution and that DNA ligands with phosphodiester backbones induce TLR9 dimerization in a sequence-independent manner. Ligands with phosphorothioate (PS) backbones induce the formation of large TLR9-DNA aggregates, possibly due to the propensity of PS ligands to self-associate. DNA curvature-inducing proteins including high-mobility group box 1 and histones H2A and H2B significantly enhance TLR9 binding, suggesting that TLR9 preferentially recognizes curved DNA backbones. Our work sheds light on the molecular mechanism of TLR9 activation by endogenous protein-nucleic acid complexes, which are associated with autoimmune diseases including systemic lupus erythematosus.


pH gradient across the lysosomal membrane generated by selective cation permeability and Donnan equilibrium.
The pH within isolated Triton WR 1339-filled rat liver lysosomes was determined by measuring the distribution of [14C]methylamine between the intra- and extralysosomal space. The intralysosomal pH was found to be approximately one pH unit lower than that of the surrounding medium. Increasing the extralysosomal cation concentration lowered the pH gradient by a cation exchange indicating the presence of a Donnan equilibrium. The lysosomal membrane was found to be significantly more permeable to protons than to other cations. The relative mobility of cations through the lysosomal membrane is H+ greater than Cs+ greater than Rb+ greater than K greater than Na+ greater than Li+ greater than Mg2+, Ca2+. The presented data suggest that the acidity within isolated Triton WR 1339-filled lysosomes is maintained by: (1) a Donnan equilibrium resulting from the intralysosomal accumulation of nondiffusible anions and (2) a selective permeability of the lysosomal membrane to cations.


Continuous renal replacement therapy in children with severe sepsis and multiorgan dysfunction - A pilot study on timing of initiation.
Scanty literature is available regarding continuous renal replacement therapy (CRRT) utility in severe sepsis with multiorgan dysfunction syndrome (MODS) from developing countries. Author unit's experience in pediatric CRRT is described and outcome of early initiation of CRRT with sepsis and MODS is assessed. Children aged <16 years with sepsis and MODS who required CRRT from September 2010 to February 2015 were analyzed on demographic factors, timing of initiation of CRRT, mode of CRRT, effect of CRRT onhemodynamics, oxygenation parameters, and outcome. Twenty-seven children required CRRT (male - 16). The median age was 11 years (range 1.1-16). Twenty-one had severe sepsis with MODS. Eighteen patients were given CRRT within 48 h of admission to Intensive Care Unit (ICU). Statistically significant improvement in the P/F ratio, decrement in plateau pressure and vasoactive-inotropic score were noted in survivor group compared to nonsurvivor group (P = 0.022, 0.00, and 0.03, respectively). There was no statistically significant difference in duration of ICU stay, fluid overload, CRRT duration, PRISM score at 12 and 24 h, percentage of decrease in inotrope score, plateau pressure, and percentage of increase in P/F ratio in relation to timing of CRRT initiation. However, the survival rate was 61.1% (11/18) who received CRRT within 48 h of ICU admission compared to 33.3% (3/9) who received after 48 h (P = 0.0001). Our study emphasizes the CRRT role in improving the oxygenation status and hemodynamics. Survival benefit may be expected in those children who receive CRRT early in the course of sepsis. However, multicenter RCTs are required to prove mortality benefit.


Conventional microsurgical treatment of paraclinoid aneurysms: state of the art with the use of the selective extradural anterior clinoidectomy SEAC.
Surgical treatment of paraclinoid aneurysms is considered to be difficult due to their complicated anatomical location in the vicinity of important neural, vascular and bony structures. We present our clinical experience of the past 10 years of conventional microsurgical treatment of 81 paraclinoid aneurysms in 75 patients with the use of selective extradural anterior clinoidectomy SEAC and discuss the method of therapy option by reviewing recent reports on results of endovascular coiling method and the combination of these with conventional microsurgical therapy. The favorable surgical results with the use of SEAC and no recurrence of the treated aneurysm after clipping procedure in our series indicate that direct surgery can still be a standard technique for paraclinoid aneurysms in view of the fact that the endovascular aneurysm coiling methods are still associated with a considerable percentage of incomplete occlusion and present the problem of coil packing.


Crystal structure of the carbohydrate recognition domain of p58/ERGIC-53, a protein involved in glycoprotein export from the endoplasmic reticulum.
p58/ERGIC-53 is an animal calcium-dependent lectin that cycles between the endoplasmic reticulum (ER) and the Golgi complex and appears to act as a cargo receptor for a subset of soluble glycoproteins exported from the ER. We have determined the crystal structure of the carbohydrate recognition domain (CRD) of p58, the rat homologue of human ERGIC-53, to 1.46 A resolution. The fold and ligand binding site are most similar to those of leguminous lectins. The structure also resembles that of the CRD of the ER folding chaperone calnexin and the neurexins, a family of non-lectin proteins expressed on neurons. The CRD comprises one concave and one convex beta-sheet packed into a beta-sandwich. The ligand binding site resides in a negatively charged cleft formed by conserved residues. A large surface patch of conserved residues with a putative role in protein-protein interactions and oligomerization lies on the opposite side of the ligand binding site. Together with previous functional data, the structure defines a new and expanding class of calcium-dependent animal lectins and provides a starting point for the understanding of glycoprotein sorting between the ER and the Golgi.


Epigenesis and the evolution of the human brain.
This article proposes an hypothesis for the evolution of the human brain. It is based on the concepts of (i) regulation of nerve cell proliferation, and (ii) selective stabilisation of synapses during development. The former process is supposed to be rigidly regulated by the genome, while the latter (selective stabilisation) is proposed as developing in a more plastic manner. It is suggested here that genetic alterations of the regulation of neuroblast proliferation led to epigenetic rearrangements in selective synapse stabilisation, thus producing significant changes in cerebral connectivity. This view is in agreement with the punctuationalist theory of human evolution, and differs from other approaches to human nature, such as structuralist grammar and sociobiology.


Behavioral effects and drug vulnerability in rats exposed to Pfiesteria toxin.
Pfiesteria piscicida is a dinoflagellate which has a lethal effect on fish and also causes a syndrome of toxic effects in humans. Cognitive impairment is a prominent aspect of Pfiesteria's toxicity, and this neurocognitive effect resulting from toxin exposure has been demonstrated previously in a rat model. Four experiments are presented here, which replicate, confirm and extend some of the initial research and also show that similar cognitive deficits result from exposure to the toxin of another species, Pfiesteria shumwayae. Rats were given intraperitoneal injections of filtered water taken from toxic Pfiesteria cultures and tested in the radial arm maze (RAM). In two experiments, exposure to toxin from either species (piscicida or shumwayae) retarded acquisition of RAM performance in a non-interrupted win-shift RAM paradigm. A scopolamine challenge showed increased vulnerability to anticholinergic effects in exposed rats, even after nondrugged RAM performance was not different from controls. A third experiment featured a more difficult RAM test which included a 150-min interruption-delay. Toxin exposure also degraded performance in this version of the RAM, and the impairment was potentiated by the scopolamine challenge. The fourth experiment demonstrated retarded learning of the reversal of a RAM procedure which tested reference memory. In agreement with earlier research, these results indicate that Pfiesteria toxin interferes with the learning required to adapt to changing behavioral requirements. They also demonstrate that a latent toxin-produced CNS dysfunction persists after behavior appears normal, as revealed by potentiation of scopolamine's impairment of efficient RAM performance.


The psychophysics of glaucoma: improving the structure/function relationship.
Perimetry of some kind remains an important tool in the detection, diagnosis and monitoring of glaucomatous damage to the visual pathway. However, recent studies have served to reinforce the suspicion that conventional perimetry does not possess the sensitivity to detect the earliest signs of functional loss resulting from glaucoma. The relationship between differential light threshold and ganglion cell loss is extremely weak and, in the early stages of glaucoma, non-existent. Alternative, more novel perimetric techniques seem to offer promise of better detectability for early loss by claiming to tap in to one or other of the separate parallel pathways of the visual system. While some of these tests show potential for better detection and monitoring of glaucoma, the reasons why this might be so are not always clearly formulated or represented. This leads to misunderstanding of what the test actually measures and of the glaucomatous disease process itself. This paper seeks to revisit and review the theory underlying psychophysical testing of visual function related to glaucoma and stresses the importance of developing tests that are based on a firm theoretical understanding of visual function and processing in order to both detect glaucoma at an earlier stage and better understand the mechanisms of loss from the disease process.


Impacts of human pressure and climate on biodiversity-multifunctionality relationships on the Qinghai-Tibetan Plateau.
Many studies have investigated the effects of environmental context on biodiversity or multifunctionality in alpine regions, but it is uncertain how human pressure and climate may affect their relationships. Here, we combined the comparative map profile method with multivariate datasets to assess the spatial pattern of ecosystem multifunctionality and further identify the effects of human pressure and climate on the spatial distribution of biodiversity-multifunctionality relationships in alpine ecosystems of the Qinghai-Tibetan Plateau (QTP). Our results indicate that at least 93% of the areas in the study region show a positive correlation between biodiversity and ecosystem multifunctionality across the QTP. Biodiversity-multifunctionality relationships with increasing human pressure show a decreasing trend in the forest, alpine meadow, and alpine steppe ecosystems, while an opposite pattern was found in the alpine desert steppe ecosystem. More importantly, aridity significantly strengthened the synergistic relationship between biodiversity and ecosystem multifunctionality in forest and alpine meadow ecosystems. Taken together, our results provide insights into the importance of protecting and maintaining biodiversity and ecosystem multifunctionality in response to climate change and human pressure in the alpine region.


Quantitative monitoring of nucleotide sequence data from genetic resources in context of their citation in the scientific literature.
Linking nucleotide sequence data (NSD) to scientific publication citations can enhance understanding of NSD provenance, scientific use, and reuse in the community. By connecting publications with NSD records, NSD geographical provenance information, and author geographical information, it becomes possible to assess the contribution of NSD to infer trends in scientific knowledge gain at the global level. We extracted and linked records from the European Nucleotide Archive to citations in open-access publications aggregated at Europe PubMed Central. A total of 8,464,292 ENA accessions with geographical provenance information were associated with publications. We conducted a data quality review to uncover potential issues in publication citation information extraction and author affiliation tagging and developed and implemented best-practice recommendations for citation extraction. We constructed flat data tables and a data warehouse with an interactive web application to enable ad hoc exploration of NSD use and summary statistics. The extraction and linking of NSD with associated publication citations enables transparency. The quality review contributes to enhanced text mining methods for identifier extraction and use. Furthermore, the global provision and use of NSD enable scientists worldwide to join literature and sequence databases in a multidimensional fashion. As a concrete use case, we visualized statistics of country clusters concerning NSD access in the context of discussions around digital sequence information under the United Nations Convention on Biological Diversity.


FDG--a marker of tumour hypoxia? A comparison with [18F]fluoromisonidazole and pO2-polarography in metastatic head and neck cancer.
Experimental data suggest that the accumulation of [(18)F]fluorodeoxyglucose (FDG) in malignant tumours is related to regional hypoxia. The aim of this study was to evaluate the clinical potential of FDG positron emission tomography (PET) to assess tumour hypoxia in comparison with [(18)F]fluoromisonidazole (FMISO) PET and pO(2)-polarography. Twenty-four patients with head and neck malignancies underwent FDG PET, FMISO PET, and pO(2)-polarography within 1 week. Parameters of pO(2)-polarography were the relative frequency of pO(2) readings <or=2.5 mmHg, <or=5 mmHg and <or=10 mmHg, respectively, as well as the mean and median pO(2). We observed a moderate correlation of the maximum standardised uptake value (SUV) of FDG with the tumour to blood ratio of FMISO at 2 h (R=0.53, p<0.05). However, SUV of FDG was similar in hypoxic and normoxic tumours as defined by pO(2)-polarography (6.9+/-3.2 vs 6.2+/-3.0, NS), and the FDG uptake was not correlated with the results of pO(2)-polarography. The retention of FMISO was significantly higher in hypoxic tumours than in normoxic tumours (tumour to muscle ratio at 2 h: 1.8+/-0.4 vs 1.4+/-0.1, p<0.05), and the FMISO tumour to muscle ratio showed a strong correlation with the frequency of pO(2) readings <or=5 mmHg (R=0.80, p<0.001). These results support the hypothesis that tumour hypoxia has an effect on glucose metabolism. However, other factors affecting FDG uptake may be more predominant in chronic hypoxia, and thus FDG PET cannot reliably differentiate hypoxic from normoxic tumours.