Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer.
Mapping tumor metabolic remodeling and their spatial crosstalk with surrounding non-tumor cells can fundamentally improve our understanding of tumor biology, facilitates the designing of advanced therapeutic strategies. Here, we present an integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics to hierarchically visualize the intratumor metabolic heterogeneity and cell metabolic interactions in same gastric cancer sample. Tumor-associated metabolic reprogramming is imaged at metabolic-transcriptional levels, and maker metabolites, lipids, genes are connected in metabolic pathways and colocalized in the heterogeneous cancer tissues. Integrated data from spatial multi-omics approaches coherently identify cell types and distributions within the complex tumor microenvironment, and an immune cell-dominated "tumor-normal interface" region where tumor cells contact adjacent tissues are characterized with distinct transcriptional signatures and significant immunometabolic alterations. Our approach for mapping tissue molecular architecture provides highly integrated picture of intratumor heterogeneity, and transform the understanding of cancer metabolism at systemic level.


Machine learning-based prediction of delirium 24 h after pediatric intensive care unit admission in critically ill children: A prospective cohort study.
Accurately identifying patients at high risk of delirium is vital for timely preventive intervention measures. Approaches for identifying the risk of developing delirium among critically ill children are not well researched. To develop and validate machine learning-based models for predicting delirium among critically ill children 24 h after pediatric intensive care unit (PICU) admission. A prospective cohort study. A large academic medical center with a 57-bed PICU in southwestern China from November 2019 to February 2022. One thousand five hundred and seventy-six critically ill children requiring PICU stay over 24 h. Five machine learning algorithms were employed. Delirium was screened by bedside nurses twice a day using the Cornell Assessment of Pediatric Delirium. Twenty-four clinical features from medical and nursing records during hospitalization were used to inform the models. Model performance was assessed according to numerous learning metrics, including the area under the receiver operating characteristic curve (AUC). Of the 1576 enrolled patients, 929 (58.9 %) were boys, and the age ranged from 28 days to 15 years with a median age of 12 months (IQR 3 to 60 months). Among them, 1126 patients were assigned to the training cohort, and 450 were assigned to the validation cohort. The AUCs ranged from 0.763 to 0.805 for the five models, among which the eXtreme Gradient Boosting (XGB) model performed best, achieving an AUC of 0.805 (95 % CI, 0.759-0.851), with 0.798 (95 % CI, 0.758-0.834) accuracy, 0.902 sensitivity, 0.839 positive predictive value, 0.640 F1-score and a Brier score of 0.144. Almost all models showed lower predictive performance in children younger than 24 months than in older children. The logistic regression model also performed well, with an AUC of 0.789 (95 % CI, 0.739, 0.838), just under that of the XGB model, and was subsequently transformed into a nomogram. Machine learning-based models can be established and potentially help identify critically ill children who are at high risk of delirium 24 h after PICU admission. The nomogram may be a beneficial management tool for delirium for PICU practitioners at present.


Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment.
Calcitonin gene-related peptide (CGRP) is a potent vasodilator in brain vessels and it has been implicated in the pathogenesis of migraine headache. Blocking post-junctional CGRP receptors, mediators of trigeminal-induced vasodilation, has been suggested as a potential antimigraine strategy. In this study, we tested the ability of a new non-peptide CGRP receptor antagonist, BIBN4096BS, to inhibit the CGRP-induced dilation in human and/or bovine brain vessels and compared it to that of the antagonist alpha-CGRP(8-37). BIBN4096BS and alpha-CGRP(8-37) both blocked the alpha-CGRP-induced dilation in bovine middle artery segments with respective potency (pK(B) values) of 6.3 and 7.8. In human pial vessels, BIBN4096BS was particularly potent. When tested at 10(-14)-10(-9) M concentrations, it induced a rightward shift in the alpha-CGRP concentration-response curve and yielded a biphasic Schild plot suggesting interaction with more than one receptor population, as was also indicated by the significant best fit of the alpha-CGRP-induced dilation in human brain vessels with a two receptor site interaction. Schild plot analysis in the linear portion of the BIBN4096BS inhibition curve revealed interaction with one high affinity site (pA(2) value approximately 14). In bovine vessels, both alpha-CGRP(8-37) and BIBN4096BS concentration-dependently reversed a pre-established CGRP-induced dilation ( approximately 59 and 85%, respectively), BIBN4096BS being approximately tenfold more potent than alpha-CGRP(8-37) (respective pIC(50) values of 7.5 and 6.75). In human middle cerebral and middle meningeal arteries, BIBN4096BS reversed the alpha-CGRP-induced dilation (> or =70%) by interaction with two different receptor populations: it exhibited a high affinity for one population (pIC(50) value approximately 13) and a lower affinity for the other (pIC(50) value approximately 8). The present data demonstrate that BIBN4096BS is a very potent antagonist that could, depending on its bioavailability and in vivo affinity, be of potential benefit in the acute treatment of migraine headache by blocking and/or reversing the CGRP-mediated dilation of intracranial vessels induced by activation of trigeminovascular afferents.


BMPRIB and BMPRII mRNA expression levels in goat ovarian follicles and the in vitro effects of BMP-15 on preantral follicle development.
This study evaluated the levels of bone morphogenetic protein receptors BMPRIB and BMPRII mRNA in goat follicles and the effects of bone morphogenetic protein-15 (BMP-15) on the in vitro development of cultured preantral follicles. Real-time polymerase chain reaction (PCR) was used to analyze the levels of BMPRIB and BMPRII mRNA in caprine preantral follicles and in small and large antral follicles. Preantral follicles (≥150 μm) were also isolated from goat ovaries and cultured for 18 days in α-MEM(+) supplemented with or without BMP-15 (10, 50, or 100 ng/ml). At the end of culture, some follicles were fixed for ultrastructural evaluation. Real-time PCR showed a reduction in BMPRII mRNA levels from the primary to secondary follicles. Higher levels of BMPRIB mRNA were observed in granulosa/theca cells from large antral follicles compared with small antral follicles. Moreover, BMPRII mRNA was expressed to a greater extent in cumulus-oocyte complexes from large antral follicles than in their respective granulosa/theca cells. In culture, 50 ng/ml BMP-15 positively influenced antral cavity formation and follicle growth after 18 days and also maintained follicular integrity. Thus, BMPRIB and BMPRII mRNAs are present in all follicular categories. BMP-15 (50 ng/ml) stimulates growth, antrum formation and the ultrastructural integrity of isolated caprine preantral follicles after 18 days of culture.


Microscopy and the helminth parasite.
Microscopy has a long and distinguished history in the study of helminth parasites and has made a singularly outstanding contribution to understanding how these complex animals organise their lives and relate to their hosts. Increasingly, the microscope has been used as a powerful investigative tool in multidisciplinary approaches to parasitological problems, placing emphasis on functional correlates rather than anatomical detail. In doing so, microscopy has also uncovered a number of attributes of parasites that are of wider significance in the field of biology. Parasite surfaces have understandably demanded most of the attention of microscopists, largely as a result of the pioneering studies using transmission electron microscopy. Their findings focused the attention of physiologists and immunologists on the tegument and cuticle of helminths and in doing so helped unravel the complex molecular exchanges that are fundamental to understanding host-parasite interactions. Scanning electron microscopy succeeded in augmenting these data by revealing novel microtopographical features of the host-parasite relationship, as well as proving invaluable in helminth taxonomy and in assessing the efficacy of test substances in drug screens. Control of helminth parasites has never been more critical: problems of drug resistance demand urgent action to identify exploitable targets for new generation anthelmintics. In this regard, the neuropeptide signalling system of helminths is envisioned as central to nerve-muscle function, and thereby a crucial regulatory influence on their motility, alimentation and reproduction. The use of immunocytochemistry interfaced with confocal scanning laser microscopy has not only been instrumental in discovering the peptidergic system of helminths and its potential for chemotherapeutic exploitation, but through increasingly sophisticated bio-imaging technologies has continued to help dissect and analyse the molecular dynamics of this and other cellular systems within these important parasites.


Increased H. pylori stool shedding and EPIYA-D cagA alleles are associated with gastric cancer in an East Asian hospital.
Helicobacter pylori infection increases risk for gastric cancer. Geographic variation in gastric cancer risk has been attributed to variation in carriage and type of the H. pylori oncogene cagA. Colonization density may also influence disease and cagA has been associated with higher shedding in stool. However, the relationship between H. pylori load in the stool and in the stomach is not clear. To investigate possible differences in H. pylori load in the stomach and shedding in stool, H. pylori load and cagA genotype were assessed using droplet digital PCR assays on gastric mucosa and stool samples from 49 urea breath test-positive individuals, including 25 gastric cancer and 24 non-cancer subjects at Henan Cancer Hospital, Henan, China. Quantitation of H. pylori DNA indicated similar gastric loads among cancer and non-cancer cases, but the gastric cancer group had a median H. pylori load in the stool that was six times higher than that of the non-cancer subjects. While the cagA gene was uniformly present among study subjects, only 70% had the East Asian cagA allele, which was significantly associated with gastric cancer (Fisher's Exact Test, p = 0.03). H. pylori persists in a subset of gastric cancer cases and thus may contribute to cancer progression. In this East Asian population with a high prevalence of the cagA gene, the East Asian allele could still provide a marker for gastric cancer risk. This study contributes to our understanding of H. pylori dynamics in the context of pathological changes.


The anterolateral complex in anterior cruciate ligament deficient knees demonstrate sonographic abnormalities on high-resolution sonography.
The presence of anterolateral ligament of the knee is still controversial, and some physicians prefer to call this structure anterolateral complex (ALC) to infer plural nature of structures involved. The purpose of this study was to describe the scanning techniques and to classify various sonographic appearances of the tibial-side ALC of the knee in subjects with anterior cruciate ligament (ACL) injury. It was hypothesized that sonographic abnormity of the ALC would be associated with ACL injury history. Patients with a history of unilateral ACL injury were prospectively recruited, and the ALC was sonographically evaluated. During the evaluation, the lateral femoral epicondyle was visualized in anatomic transverse view first. At this location, the ALC was typically most conspicuous between the short head of the biceps femoris muscle and the posterior and deep aspect of the iliotibial band superficial to the origin of the lateral collateral ligament. The ALC was followed distally to the broad insertion centralizing to the area posterior to Gerdy's tubercle. The appearance of the distal insertion of the ALC was classified based both on echogenicity and on the presence of a Segond fracture as follows: Grade 0: isoechoic to the rest of the ALC, Grade 1: hypoechoic, Grade 2: anechoic, and Grade 3: Segond fracture. The uninjured side was similarly scanned for comparison. A total of 28 patients (13 men; mean age 22.1 ± 8.1 years old with range: 12-44; mean body mass index 25.0 with range: 18.9-39.2) were included in this study. The average time from injury to sonograhpic evaluation was 4 months (range: 2 days to 1 year). Of 28 ACL-deficient knees, 19 were (68%) graded as Grade 0 in the distal insertion of the ALC, 7 (25%) as Grade 1, 1 (3.5%) as Grade 2, and 1 (3.5%) as Grade 3. Contralateral knees showed 25 knees (89%) with Grade 0 and 3 knees (11%) with Grade 1. ACL injury history was associated with a higher incidence of sonographic abnormalities within the distal insertion of the anterolateral complex. III.


A finite element updating approach for identification of the anisotropic hyperelastic properties of normal and diseased aortic walls from 4D ultrasound strain imaging.
Computational analysis of the biomechanics of the vascular system aims at a better understanding of its physiology and pathophysiology and eventually at diagnostic clinical use. Because of great inter-individual variations, such computational models have to be patient-specific with regard to geometry, material properties and applied loads and boundary conditions. Full-field measurements of heterogeneous displacement or strain fields can be used to improve the reliability of parameter identification based on a reduced number of observed load cases as is usually given in an in vivo setting. Time resolved 3D ultrasound combined with speckle tracking (4D US) is an imaging technique that provides full field information of heterogeneous aortic wall strain distributions in vivo. In a numerical verification experiment, we have shown the feasibility of identifying nonlinear and orthotropic constitutive behaviour based on the observation of just two load cases, even though the load free geometry is unknown, if heterogeneous strain fields are available. Only clinically available 4D US measurements of wall motion and diastolic and systolic blood pressure are required as input for the inverse FE updating approach. Application of the developed inverse approach to 4D US data sets of three aortic wall segments from volunteers of different age and pathology resulted in the reproducible identification of three distinct and (patho-) physiologically reasonable constitutive behaviours. The use of patient-individual material properties in biomechanical modelling of AAAs is a step towards more personalized rupture risk assessment.


Perioperative visual loss: a rare complication of general surgery.
Perioperative visual loss (PVL) refers to the loss of vision following surgery performed at distance from the visual pathways. An ischemic optic neuropathy (ION) is the most frequent clinical presentation of PVL, and can be bilateral. A retrospective chart review of 11 consecutive patients with PVL examined between 2002 and 2007 was undertaken. An ION was found in all 11 cases: 8 were anterior (AION) and 3 were posterior (PION). Visual loss was bilateral in 9 patients. Mean visual acuity (VA) was 0.2 on the Snellen chart (0.74 LogMAR). Most frequently an arcuate/altitudinal visual field defect was present. PVL followed orthopedic (6), spinal (1), cardiac (2) and vascular (2) procedures. The average delay between surgery and visual loss was 32 hours (range: 0-96 hours). Average lowest perioperative hemoglobin level was 75 g/L. Average follow-up time was 14.7 months. VA improved by at least 2 Snellen lines in 5/20 eyes (25 %). PVL is a rare but dreadful complication of surgery, and is usually associated with severe anemia. Like other causes of ION, there is no specific therapy. Prompt correction of the anemia might decrease the rate of this complication.


Preoperative Frailty Status and Intensity of End-of-Life Care Among Older Adults After Emergency Surgery.
Emergency general surgery (EGS) is common and highly morbid for older adults, particularly for those who are frail. However, there are little data on the quality of end-of-life care (EOLC) for this population. We sought to examine the association of frailty with intensity of EOLC for older adults with and without frailty who undergo EGS but die within one year. This retrospective cohort study included 100% Medicare fee-for-service beneficiaries, ≥66 years, who underwent one of five EGS procedures with the highest mortality (partial colectomy, small bowel resection, peptic ulcer disease repair, adhesiolysis, or laparotomy) between 2008 and 2014 and died within one year. A validated claims-based frailty index (CFI) identified patients who were not frail (CFI < 0.15), prefrail (0.15 ≤ CFI < 0.25), mildly frail (0.25 ≤ CFI < 0.35), and moderately to severe frail (CFI ≥ 0.35). Multivariable adjusted logistic or Poisson regression compared post-discharge and EOL healthcare utilization. Among 138,916 older EGS adults who died within one year, 32.2% were not frail, 31.7% were prefrail, 29.8% had mild frailty and 6.3% had moderate-to-severe frailty. Decedents with any degree of frailty experienced high-intensity EOLC (P < 0.01), low rates of hospice use (P < 0.01), and fewer days at home. Of those who survived the index hospitalization but died within one year, moderate-to-severely frail decedents had the highest odds of visiting an emergency department (odds ratio [OR] = 1.19, CI = 1.13-1.27), rehospitalization (OR = 1.23, CI = 1.16-1.31), or an intensive care unit admission (OR = 1.22, CI = 1.13-1.30) in the last 30 days of life compared to nonfrail decedents. While all older patients undergoing EGS have poor end-of-life outcomes, frail EGS patients receive the highest intensity EOLC and represent a vulnerable population for whom targeted interventions could limit burdensome treatment.


Electronically interacted Co3O4/WS2 as superior oxygen electrode for rechargeable zinc-air batteries.
The electronically interacted Co3O4/WS2 with a maximum power density of 174 mW cm-2, 2.3 fold better than Pt/C-IrO2, shows its superiority as an oxygen electrode for rechargeable zinc-air batteries.


Brain patterns of pace - but not rhythm - are associated with vascular disease in older adults.
Distinct domains of gait such as pace and rhythm are linked to an increased risk for cognitive decline, falls, and dementia in aging. The brain substrates supporting these domains and underlying diseases, however, remain relatively unknown. The current study aimed to identify patterns of gray matter volume (GMV) associated with pace and rhythm, and whether these patterns vary as a function of vascular and non-vascular comorbidities. A cross-sectional sample of 297 older adults (M Age = 72.5 years ± 7.2 years, 43% women) without dementia was drawn from the Tasmanian Study of Cognition and Gait (TASCOG). Factor analyses were used to reduce eight quantitative gait variables into two domains. The "pace" domain was primarily composed of gait speed, stride length, and double support time. The "rhythm" domain was composed of swing time, stance time, and cadence. Multivariate covariance-based analyses adjusted for age, sex, education, total intracranial volume, and presence of mild cognitive impairment identified gray matter volume (GMV) patterns associated with pace and rhythm, as well as participant-specific expression (or factor) scores for each pattern. Pace was positively associated with GMV in the right superior temporal sulcus, bilateral supplementary motor areas (SMA), and bilateral cerebellar regions. Rhythm was positively associated with GMV in bilateral SMA, prefrontal, cingulate, and paracingulate cortices. The GMV pattern associated with pace was less expressed in participants with any vascular disease; this association was also found independently with hypertension, diabetes, and myocardial infarction. Both pace and rhythm domains of gait were associated with the volume of brain structures that have been linked to controlled and automatic aspects of gait control, as well as with structures involved in multisensory integration. Only the brain structures associated with pace, however, were associated with vascular disease.


Intra-amniotic pressure is not affected by amniocentesis between 13 and 18 weeks of gestation.
Changes in amniotic fluid pressure before and after amniocentesis fell within the range of +/- 5 mmHg, except when uterine contractions were present. Intra-amniotic pressure is not affected by amniocentesis between 13 and 18 weeks of gestation. Amniotic fluid pressure was recorded in 82 pregnancies of patients undergoing genetic amniocentesis to determine whether sampling of amniotic fluid between 13 and 18 weeks changed intra-amniotic pressure. Pressures were recorded through a needle and saline filled catheter with a zero-level at the needle tip. Amniotic fluid pressure was unrelated to gestational age (P = 0.962) during the weeks we performed our measurements. Fluid samples of 12.6% of the total volume in a group of early genetic amniocentesis (n = 65) and of 7.5% of the total volume in a group of late genetic amniocentesis (n = 17) did not change significantly amniotic fluid pressure values. An increase in pressure of more than 5 mmHg only occurred in cases where uterine contractions were present. Other than these cases, all pressure change values fell within the range of +/- 5 mmHg. No difference in pregnancy outcome were present within the two groups. An argument for a standard method for stationing pressure is presented.


Giant hydronephrosis of a duplex system associated with ureteral ectopia.
Giant hydronephrosis is an infrequent urological entity. To our knowledge, only 1 case has been reported previously that was associated with a duplicated collecting system and ureteral ectopia.


A review of 95 pit viper envenomations in Northcentral Florida (2018-2020).
The medical records of 95 pit viper envenomations in client-owned dogs presented to an academic emergency hospital in the Southeastern United States during the period spanning 2018 and 2020 were retrospectively examined. This study's primary objectives were to record the clinical abnormalities and treatment responses associated with envenomation and their relation to outcome. Approximately 80% of the bites involved the head region associated with varying degrees of hemorrhagic lymphedema. Some of the most common additional symptoms observed were; hypotension (10%), cardiac dysrhythmias (17%), and coagulopathy (21%). Treatment in most cases consisted of intravenous fluids, antivenom, and analgesic drugs. Blood products were used as indicated for anemia and persistent bleeding. The average dose of the F('ab')2 was 1-2 vials. Additional vials (3-22) were administered as needed to counteract persistent or recurrent coagulopathy and hemolysis. Only 3% of the dogs had mild clinical signs of Type 1 hypersensitivity during their treatment period. Antihistamine use at the tertiary hospital was restricted to the three dogs showing signs of a suspected allergic reaction in response to antivenom administration; these patients received diphenhydramine intramuscularly. A glucocorticoid drug was used in only one dog prior to referral but not subsequently. Ninety dogs had a good outcome, while five died. Historically, pit viper envenomation in dogs in the southeastern United States has been a potentially life-threatening problem. Most dogs will survive if treated promptly and appropriately with adequate amounts of intravenous fluids, and antivenom titrated on severity of clinical presentation.


Sublingual indocyanine green films for non-invasive swallowing assessment and inflammation detection through NIR/SWIR optical imaging.
Indocyanine green (ICG) is the most commonly used FDA-approved agent for clinical optical imaging, administered through injections only, due to its poor membrane permeability. Although ICG has vast potential for non-invasive non-radioactive imaging in patients, the clinical applications are limited by the invasive administration and short half-life in blood circulation. To expand the clinical value of ICG, non-toxic chitosan-based ICG-loaded films were designed for sublingual administration for near-infrared (NIR) and short-wave infrared (SWIR) optical imaging. Two film formulations were developed with different ICG release rates. Mold-casted self-emulsifying films rapidly released ICG (80% in 4 h) in the form of nanosized droplets, which were mostly swallowed and produced significant contrast of upper digestive tract to enable in vivo swallowing evaluations using NIR/SWIR imaging. Regular films released ICG slowly (80% in 25 h), allowing for steady absorption of ICG to systemic circulation. Inflammation in mouse feet was detected within 30 min after sublingual administration with a 1.43-fold fluorescence increase within 1 h at the inflammation sites, comparable to a 1.76-fold increase through intravenous injection. Administering ICG using sublingual films displayed notable potential for non-invasive diagnosis and monitoring of inflammatory conditions and swallowing disorders, addressing a current need for alternatives to ICG parenteral administration.


Pre-culture in endothelial growth medium enhances the angiogenic properties of adipose-derived stem/stromal cells.
Considerable progress has been made on the development of adipose-derived stem/stromal cells (ASCs) as pro-angiogenic therapeutic tools. However, variable clinical results highlight the need for devising strategies to enhance their therapeutic efficacy. Since ASCs proliferate and stabilize newly formed vessels during the angiogenic phase of adipose tissue formation, we hypothesized that mimicking an angiogenic milieu during culture of ASCs would enhance their capacity to support endothelial cell survival and angiogenesis. To test this, we compared the effect of an endothelial growth medium (EGM-2) and conventional media (αMEM) on the progenitor and angiogenic properties of ASCs. ASCs cultured in EGM-2 (ASC-EGM) displayed the highest clonogenic efficiency, proliferative potential and multilineage potential. After co-culture under growth factor starvation, only ASC-EGM attenuated luciferase-expressing human umbilical vein endothelial cells (HUVECluc) apoptosis and supported the formation of endothelial cords in a dose-dependent manner. These effects were recapitulated by the conditioned medium of ASC-EGM, which displayed a 100-fold higher expression of hepatocyte growth factor in comparison with ASC-αMEM. Next, HUVECluc and ASCs were co-transplanted subcutaneously into immunodeficient mice, and the survival of HUVECluc was monitored by bioluminescent imaging. After 60 days, the survival of HUVECluc transplanted alone was equivalent to that of HUVECluc co-transplanted with ASC-αMEM (15.0 ± 0.7 vs. 13.0 ± 0.5%). Strikingly, co-transplantation with ASC-EGM increased HUVECluc survival to 105.0 ± 3.5%, and the resulting organoids displayed functional vasculature with the highest human-derived vascular area. These findings demonstrate that pre-conditioning of ASCs in endothelial growth medium augment their pro-angiogenic properties and could enhance their therapeutic efficacy against ischemic diseases.


Rational Design of High-Relaxivity EuII -Based Contrast Agents for Magnetic Resonance Imaging of Low-Oxygen Environments.
Metal-based contrast agents for magnetic resonance imaging present a promising avenue to image hypoxia. EuII -based contrast agents have a unique biologically relevant redox couple, EuII/III , that distinguishes this metal for use in hypoxia imaging. To that end, we investigated a strategy to enhance the contrast-enhancing capabilities of EuII -based cryptates in magnetic resonance imaging by controlling the rotational dynamics. Two dimetallic, EuII -containing cryptates were synthesized to test the efficacy of rigid versus flexible coupling strategies. A flexible strategy to dimerization led to a modest (114 %) increase in contrast enhancement per Eu ion (60 MHz, 298 K), but a rigid linking strategy led to an excellent (186 %) increase in contrast enhancement despite this compound's having the smaller molecular mass of the two dimetallic complexes. We envision the rigid linking strategy to be useful in the future design of potent EuII -based contrast agents for magnetic resonance imaging.


A case of extra pulmonary tuberculosis misdiagnosed as granulomatosis with polyangitis: Presenting with occipital condylar syndrome.
Sri Lanka is a tuberculosis (TB) prevalent country with an incidence of 8886 cases in 2016 of which 30% were extra pulmonary tuberculosis (EPTB). These figures may be an underestimation, considering the diagnostic challenge of EPTB due to its diverse presentations and difficulty in microbiological confirmation. Here we describe a case of EPTB which was first diagnosed as granulomatosis with polyangitis when he presented with fever, anorexia, wasting, large joint pains, cervical pain, erythema nodosum, high inflammatory markers with strongly positive Mantoux reaction and, necrotizing granulomatous lymphadenitis in the cervical region. Immunosuppression with methotrexate 15 mg weekly and prednisolone 30 mg daily, achieved resolution of symptoms and the inflammatory markers. After about 4 months on tailing off prednisolone, he developed fever, anorexia, wasting and worsening occipital pain which evolved in to occipital condylar syndrome causing hypoglossal nerve palsy. With the aid of serial radiological, histopathological and bacteriological investigations, he was eventually diagnosed to have EPTB involving the left base of the skull with upper mediastinal lymphadenitis. This case highlights the importance to have a high index of suspicion to diagnose EPTB, especially in a country with a high prevalence of TB and to revise the diagnosis with a close follow up to avoid disastrous consequences associated with misdiagnosis.


PCNT is critical for the association and conversion of centrioles to centrosomes during mitosis.
A centrosome consists of a pair of centrioles and pericentriolar material (PCM). We manipulated expression of PCNT, a key PCM protein, and investigated roles of PCM in centriole behavior during mitosis. Deletion of PCNT had little effect on interphase centrosomes. However, centrioles in PCNT-deleted mitotic cells prematurely separated and frequently amplified, revealing that centrioles are limited within the spindle poles by PCNT during mitosis. It is known that specific cleavage of PCNT is necessary for centriole separation during mitotic exit. We observed delayed centriole separation in the G0 phase when a non-cleavable mutant form of PCNT was removed or when PCNT was artificially cleaved by TEV protease. Furthermore, a daughter centriole converts to a mother centriole only after experiencing both mitotic exit and specific PCNT cleavage. Based on these results, we propose that a centriole pair disengages upon entering mitosis but remains associated with the surrounding PCM proteins throughout mitosis. During mitotic exit, specific cleavage of PCNT induces PCM disintegration. As a result, a daughter centriole separates from the mother centriole and converts to a young mother centriole.


[Advanced glycation and oxidation products in patients with atherosclerosis].
Oxidative stress can potentiate atherogenesis via modification of biological structures and formation of new compounds, e.g. advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP). The aim of the study was to determine AGEs and AOPP in patients with atherosclerosis, effect of statin therapy and relationship to parameters of lipid metabolism. AGEs (carboxymethyllysine - ELISA and fluorescent AGEs - spectrofluorimetry) and AOPP (spectrophotometry) were assessed in 42 patients with atherosclerosis and 21 healthy controls. AGEs are significantly elevated in patients with atherosclerosis in comparison with healthy subjects (carboxymethyllysine 9.02+/-1.66 microg/g prot. vs 7.52+/-1.18 microg/g prot., p<0.001, fluorescent AGEs 4.39 x 103+/-1.15 x 103 AU/g prot. vs 3.78 x 103+/-0.52 x 103 AU/g prot., p<0.001). Mean AOPP concentrations are also slightly higher, but this elevation is not quite significant (95.0+/-42.9 micromol/l vs 79.7+/-28.2 micromol/l, p=0.096). AGEs and AOPP correlate significantly with each other and with selected lipids. Patients with atherosclerosis treated with statins have slightly lower CML, AGEs and AOPP (it did not reach the statistical significance). Advanced glycoxidation products are elevated in patients with atherosclerosis and are related to parameters of lipid metabolism. Glycoxidation might be possibly therapeutically influenced by statins; however, further clinical studies are required to confirm this hypothesis.


Screening alcoholics for medical problems with the Cornell Medical Index.
Scores on the Cornell Medical Index were not useful in distinguishing alcoholic patients who required medical attention from those who did not.


Hair cortisol concentration, disease severity and quality of life in dogs with atopic dermatitis during lokivetmab therapy.
There are no studies which evaluate hair cortisol as a biological marker of stress and anxiety in pruritic dogs during atopic dermatitis therapy. A longitudinal evaluation of hair cortisol concentrations, the severity of disease and the QoL in dogs with cAD during therapy with lokivetmab. Ten client-owned dogs with cAD. Dogs were assessed at three time points: at the initial visit at day (D) 0 and at D28, when lokivetmab (2.2-3.2 mg/kg) was administered, and at D56 for one further evaluation. At all time points, pruritus and lesion severity was assessed using the pruritus Visual Analog Scale (PVAS) and Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04). Dog owners filled out a validated QoL questionnaire and hair cortisol concentrations were measured from samples collected from the same area on each dog. There was a significant reduction in PVAS (p < 0.001) and improvement in QoL of dogs (QoL1) and owners (QoL2) after lokivetmab administration, with a positive correlation of the PVAS with QoL1 and QoL2 (r = 0.71 and 0.52, respectively). There was no difference in CADESI-04 scores at the different time points (p = 0.515). A significant reduction in hair cortisol levels at D56 was measured compared with D28 (p < 0.001). Hair cortisol may be a useful marker of stress in dogs with cAD. These results highlight the negative impact of cAD on the QoL of dogs and their owners, and the positive benefit of lokivetmab therapy.


Long-term prognosis of cirrhotics with an upper gastrointestinal bleeding episode: does infection play a role?
We evaluated the effect of infection on the short- and long-term outcome of cirrhotic patients with upper gastrointestinal bleeding (UGIB), in a series of patients not submitted to antibiotic prophylaxis. The cirrhotic patients hospitalized for UGIB were prospectively followed up until the last visit, death, or transplantation. A standard screening protocol was used for bacterial infection at admission. In total, 205 patients were included in the study. Antibiotics were administered in 79 (38.5%) patients and an infection was documented in 64 (31.4%) patients. In total, 130 (63.4%) patients died after a mean (SD) follow up of 23.8 (30.9) months. Six-week mortality was higher in the infected patients (P < 0.0001). The mortality of patients who were alive 6 weeks after admission was not different between the infected and non-infected patients. Antibiotic use or bacterial infection, the Child-Pugh score, hepatocellular carcinoma, and creatinine were the independent predictors of 6-week mortality. Age and the Child-Pugh score were the only predictors of mortality of the patients who had survived for more than 6 weeks after acute bleeding. In total, 51 (24.9%) patients rebled, 37 (18.1%) within 5 days of admission. Rebleeding was more frequent (41.8% vs 14.3%, P < 0.0001) in infected patients, mostly due to differences in early rebleeding (31.6% vs 9.5%, P = 0.0001). Bacterial infection is associated with failure to control UGIB and early mortality in cirrhotic patients, but does not seem to affect the outcome of patients who overcome the bleeding episode.


Alcohol dehydrogenases, aldehyde dehydrogenases, and related enzymes.
Several new structures have recently been determined for dehydrogenases which are involved in alcohol metabolism. These structures give new insight into catalytic properties, structure-function relationships, and evolutionary connections. They also explain the structural basis for known metabolic deviations. Among alcohol dehydrogenases, the first primary structures for human enzyme forms have been reported (the beta 1, gamma 1, and "atypical" beta-chains). These structures explained functional properties and enzymatic differences, showed separate and parallel events of isozyme divergence, and suggested differential gene activations. Similarly, for aldehyde dehydrogenases, the first cytoplasmic isozyme structures have been reported in man and horse. The data showed positions of functionally important residues, and established clear differences between the mitochondrial and cytoplasmic isozymes of aldehyde dehydrogenase. For sorbitol dehydrogenase, the first complete structure which establishes a relationship with other "long" alcohol dehydrogenases in a scheme exhibiting both structural divergence and functional convergence has also been reported. Finally, glucose dehydrogenase has been structurally linked with sorbitol dehydrogenase, extending the scheme and adding further enzymes to the group of "short" alcohol dehydrogenases.


Exosome Biogenesis and Lysosome Function Determine Podocyte Exosome Release and Glomerular Inflammatory Response during Hyperhomocysteinemia.
Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation in podocytes is reportedly associated with enhanced release of exosomes containing NLRP3 inflammasome products from these cells during hyperhomocysteinemia (hHcy). This study examined the possible role of increased exosome secretion during podocyte NLRP3 inflammasome activation in the glomerular inflammatory response. Whether exosome biogenesis and lysosome function are involved in the regulation of exosome release from podocytes during hHcy in mice and upon stimulation of homocysteine (Hcy) in podocytes was tested. By nanoparticle tracking analysis, treatments of mice with amitriptyline (acid sphingomyelinase inhibitor), GW4869 (exosome biogenesis inhibitor), and rapamycin (lysosome function enhancer) were found to inhibit elevated urinary exosomes during hHcy. By examining NLRP3 inflammasome activation in glomeruli during hHcy, amitriptyline (but not GW4869 and rapamycin) was shown to have an inhibitory effect. However, all treatments attenuated glomerular inflammation and injury during hHcy. In cell studies, Hcy treatment stimulated exosome release from podocytes, which was prevented by amitriptyline, GW4869, and rapamycin. Structured illumination microscopy revealed that Hcy inhibited lysosome-multivesicular body interactions in podocytes, which was prevented by amitriptyline or rapamycin but not GW4869. Thus, the data from this study shows that activation of exosome biogenesis and dysregulated lysosome function are critically implicated in the enhancement of exosome release from podocytes leading to glomerular inflammation and injury during hHcy.


Regulation by histamine of cAMP-dependent protein kinase in guinea-pig stomach.
The present investigation describes experimental conditions under which histamine stimulates cAMP-dependent protein kinase in the guinea-pig stomach. A histamine-responsive cAMP-dependent protein kinase was shown to be present in the soluble fraction obtained after a low speed centrifugation of the stomach homogenate. There was a small, but detectable stimulation of protein kinase activity and cAMP formation when tissue was incubated with histamine. This response to histamine was highly pronounced in the presence of a phosphodiesterase inhibitor. Protein kinase activation was assessed by measuring protein kinase activity ratio (activity -cAMP/+cAMP). Results indicate that protein kinase activity ratios reflect cAMP tissue levels. Binding of free cAMP by charcoal lowered both cAMP levels and protein kinase activity ratio, but histamine activation was still evident. Results suggest that only a portion of intracellular cAMP, probably in a bound form, is actually responsible for protein kinase activation, and the large accumulation of cAMP in the presence of a phosphodiesterase inhibitor probably does not reflect physiological levels.


A high-density microelectrode-tissue-microelectrode sandwich platform for application of retinal circuit study.
Microelectrode array (MEA) devices are frequently used in neural circuit studies, especially in retinal prosthesis. For a high throughput stimulation and recording paradigm, it is desirable to obtain the responses of multiple surface RGCs initiated from the electrical signals delivered to multiple photoreceptor cells. This can be achieved by an high density MEA-tissue-MEA (MTM) sandwich configuration. However, the retina is one of the most metabolically active tissues, consumes oxygen as rapidly as the brain. The major concern of the MTM configuration is the supply of oxygen. We aimed to develop a high density MTM sandwich platform which consists of stacks of a stimulation MEA, retinal tissue and a recording MEA. Retina is a metabolically active tissue and the firing rate is very sensitive to oxygen level. We designed, simulated and microfabricated porous high density MEAs and an adjustable perfusion system that electrical signals can be delivered to and recorded from the clipped retinal tissue. The porous high-density MEAs linked with stimulation or recording devices within a perfusion system were manufactured and the MTM platform was assembled with a retina slice inside. The firing rate remained constant between 25 and 55 min before dramatically declined, indicating that within certain period of time (e.g. 30 min after habituation), the retina condition was kept by sufficient oxygen supply via the perfusion holes in the MEAs provided by the double perfusion system. MTM sandwich structure is an efficient platform to study the retinal neural circuit. The material and arrangement of high density microelectrodes with porous design make this MEA appropriate for sub-retina prosthesis. Finding ways to prolong the recording time and reduce the signal-to-noise ratio are important to improve our MTM prototype.


DNA sequences and proteic antigens of H. pylori in cholecystic bile and tissue of patients with gallstones.
Although Helicobacter pylori DNA sequences have been detected in cholecystic bile and tissue of patients with gallstones, controversial results are reported from different geographic areas. To detect H. pylori in cholecystic bile and tissue of patients with gallstones from a previously uninvestigated geographic area, southern Italy. Detection included both the bacterial DNA and the specific antigen (H. pylori stool antigen) identified in the stools of infected patients for diagnostic purposes. The study enclosed 33 consecutive patients undergoing laparoscopic cholecystectomy for gallstones. DNA sequences of H. pylori were detected by polymerase chain reaction in both cholecystic bile and tissue homogenate. Moreover, we assayed H.pylori stool antigen on gall-bladder cytosolic and biliary proteins after their extraction. Bacterial presence in the stomach was assessed by urea breath test in all patients and Deltadelta13CPDB value assumed as marker of intragastric load. Fisher's exact probability and Student's t-tests were used for statistical analysis. DNA sequences of H. pylori in bile were found in 51.5% and significantly correlated with its presence in cholecystic tissue homogenate (P<0.005), H. pylori stool antigen in gall-bladder (P=0.0013) and bile (P=0.04) proteins, gastric infection (P<0.01) and intragastric bacterial load (P<0.001). No correlation was found, however, with sex and age of the patients. Our prevalence value of bacterial DNA in bile and gall-bladder of patients with gallstones agreed with that of the only other Italian study. The simultaneous presence of both bacterial DNA and proteic antigen suggests that the same prototype of bacterium could be located at both intestinal and cholecystic level and, therefore, the intestine represents the source of biliary contagion.


Role of gap junctions and protein kinase A during the development of oocyte maturational competence in Ayu (Plecoglossus altivelis).
Meiotic resumption in teleost oocytes is induced by a maturation-inducing hormone (MIH). The sensitivity of oocytes to MIH, also known as oocyte maturational competence (OMC), is induced by LH via mechanisms that are not fully understood. A previous study of Ayu (Plecoglossus altivelis) showed the presence of functional heterologous gap junctions (GJs) between oocytes and their surrounding granulosa cells. The objectives of this study were to determine the role of ovarian GJs and of protein kinase A (PKA) during the acquisition of OMC. We examined the effects of the specific GJ inhibitor carbenoxolone (CBX) and 18alpha-glycyrrhetinic acid (alpha-GA) on the LH-(hCG)-dependent acquisition of OMC and on MIH-(17,20beta-dihydroxy-4-pregnen-3-one)-dependent meiotic resumption; measured the cAMP content of ovarian follicles during the hCG-dependent acquisition of OMC; and determined the effects of PK activators and inhibitors on hCG-dependent OMC. Production of follicular cAMP increased during the hCG-dependent acquisition of OMC. Both GJ inhibitors and the PKA inhibitor H8-dihydrochloride, but not the PKC inhibitor GF109203X, suppressed the hCG-dependent acquisition of OMC in a dose-dependent manner. The PKA activator forskolin induced OMC with a similar potency to hCG. Unlike previous observations with teleosts where disruption of heterologous GJ either blocks or stimulates meiotic resumption, treatment with GJ inhibitors did not affect MIH-dependent meiotic resumption in maturationally competent follicles of Ayu. These observations suggest that ovarian GJs are essential for LH-dependent acquisition of OMC but not for MIH-dependent meiotic resumption, and that the stimulation of OMC by LH is mediated by cAMP-dependent PKA. They are also consistent with the view that a precise balance between GJ-mediated signals (positive or negative) and oocyte maturational readiness is required for hormonally regulated meiotic resumption.


Effects of neuropeptide Y on left ventricular function in the conscious rabbit.
1. Changes in arterial pressure, heart rate and left ventricular contractility induced by intravenous injections of neuropeptide Y (NPY; 1-30 micrograms/kg) were studied in the conscious rabbit. 2. NPY has a brief pressor effect associated with a bradycardia, an increase in left ventricular end diastolic pressure, and a prolonged fall in peak left ventricular dP/dt (LVdP/dt). 3. The haemodynamic changes increase substantially with increasing doses up to 10 micrograms/kg. Beyond 10 micrograms/kg there are only slight effects on heart rate or peak LV dP/dt.


Insulin stimulation of gamma-glutamylcysteine ligase catalytic subunit expression increases endothelial GSH during oxidative stress: influence of low glucose.
Previously, we demonstrated an important role for insulin in the protection of endothelial cells against hyperglycemic stress through maintaining cellular glutathione (GSH) redox balance. The current study focuses on the contribution of insulin to transcriptional control of endothelial cell GSH recovery during acute oxidative challenge and the influence of low glucose. The results show that insulin induced an approximate 2-fold increase in expression of gamma-glutamylcysteine ligase catalytic subunit (GCLc) mRNA and protein; interestingly, cellular GSH levels were not elevated accordingly. However, on tert-butylhydroperoxide challenge, insulin-treated cells demonstrated a robust GSH recovery that was attributed to a greater capacity for de novo synthesis via elevated GCLc levels. Notably, the effects of insulin were observed under low, but not normal, glucose conditions. Our results implicate a role for Nrf2 involvement in both constitutive and inducible endothelial GCLc expression and GSH synthesis, while PI3K/Akt/mTOR signaling appears to participate only in insulin-inducible GSH synthesis. Collectively, these results support the functional importance of insulin in Nrf2-dependent transcriptional upregulation of GCLc in GSH recovery during oxidative challenge and suggest a possible role for hypoglycemia in promoting insulin-mediated GCLc upregulation.


Disassociated molecular orientation distributions of a composite cellulose-lignin carbon fiber precursor: A study by rotor synchronized NMR spectroscopy and X-ray scattering.
Cellulose-lignin composite carbon fibers have shown to be a potential environmentally benign alternative to the traditional polyacrylonitrile precursor. With the associated cost reduction, cellulose-lignin carbon fibers are an attractive light-weight material for, e.g. wind power and automobile manufacturing. The carbon fiber tenacity, tensile modulus and creep resistance is in part determined by the carbon content and the molecular orientation distribution of the precursor. This work disassociates the molecular orientation of different components in cellulose-lignin composite fibers using rotor-synchronized solid-state nuclear magnetic resonance spectroscopy and X-ray scattering. Our results show that lignin is completely disordered, in a mechanically stretched cellulose-lignin composite fiber, while the cellulose is ordered. In contrast, the native spruce wood raw material displays both oriented lignin and cellulose. The current processes for fabricating a cellulose-lignin composite fiber cannot regain the oriented lignin as observed from the native wood.


An alternative method of wound pain control following hepatic resection: a preliminary study.
Epidural analgesia is considered one of the optimal methods for provision of postoperative pain relief in patients recovering from major upper abdominal operations. Concerns regarding the potential risk of neurological complications prompted an evaluation of an alternative strategy using a continuous intermuscular bupivacaine (CIB) infusion combined with patient-controlled analgesia (PCA). Two fine-bore catheters are inserted in the deep intermuscular intercostal neuronal plane during abdominal wound closure, and a continuous infusion of bupivacaine 0.25% is commenced for 72 h postoperatively. Simultaneously, patient-controlled analgesia provided intravenous morphine on demand. The study comprised 10 consecutive patients undergoing liver resection in whom CIB infusion and PCA were employed. The feasibility, safety and efficacy of the technique were investigated, analysing postoperative pain scores, morphine requirements, spirometry and oxygen saturation. There were no postoperative deaths. Postoperative morbidity included one urinary tract infection, one minor chest infection and acute confusional episodes in two patients. Median pain scores and morphine requirements at 12, 24, 48 and 72 h postoperatively were satisfactory. Spirometry and oxygen saturation values also remained within the normal range. Preliminary experience with CIB infusion/PCA in the aftermath of major liver resection has demonstrated its simplicity and safety as an alternative method of postoperative pain control. Further study is required to investigate the role of CIB infusion/PCA as a practical alternative to epidural analgesia or PCA alone.


Combinatorial Oxytocin Neuropharmacology in Social Cognition.
The efficacy and reliability of using intranasal oxytocin (OT) to clinically enhance social functions remains undependable. We discuss the potential benefit of concurrent administration of OT and naloxone (NAL) to robustly modulate social behavior. We further suggest that combinatorial neuropharmacology approaches should exploit the interactions between OT and serotonin to regulate social functions.


Rat hepatic sinusoidal endothelial cells in monolayer culture. Biochemical and ultrastructural characteristics.
Sinusoidal endothelial cells were isolated by collagenase-pronase digestion of rat livers followed by centrifugal elutriation. The main endothelial cell fraction consisted of more than 85% endothelial cells as shown by electron microscopy and enzyme histochemistry. Contamination by Kupffer cells was less than 5%. The endothelial cells formed a coherent stable monolayer on dishes coated with collagen type IV in the presence of an RPMI 1640 medium supplemented with 4% Ultroser. Fc receptors were undetectable immediately after elutriation but reappeared after 12 h in culture. Von Willebrand factor (formerly factor VIII-related antigen) could not be detected unequivocally by immunofluorescence. Unchallenged endothelial cells did not produce eicosanoids. In the presence of free arachidonate, however, prostaglandins D2 and E2 as well as thromboxane B2 and 6-keto-prostaglandin F1 alpha were detected by radioimmunoassay and by high-performance liquid chromatography analysis of [3H]arachidonate-exposed cells. Cells treated with the Ca2+ ionophore A23187 produced the same spectrum of immunologically measured prostanoids. In contrast to Kupffer cells in primary culture, eicosanoid formation by endothelial cells was neither triggered by phagocytotic stimuli nor suppressed by pretreatment with dexamethasone.


The influence of similar aggregation pheromones on the microhabitat choice of two parapatric species of reptile tick (Acari: Ixodidae).
Non-specificity of part of the sex pheromone system of three species of reptile tick has previously been suggested to result in reproductive interference between the species when they attach to the same host (Andrews et al. 1982). Two of the species, Aponomma hydrosauri and Amblyomma limbatum, have common aggregation pheromones which act when the ticks are detached from their hosts. As each species tends to occupy spatially separated microhabitats, the similarity of the aggregation pheromone could lead to interference between species when off their hosts by inducing one species to move away from its preferred microhabitat into that occupied by the other species. This study demonstrates that coaggregations of both species do occur, but that neither species shows a statistically significant shift in microhabitat preference attributable to interactions between species. We suggest that the behaviours leading to microhabitat choice in each species override the influence of the common aggregation pheromone.


Conduct disorder and initiation of substance use: a prospective longitudinal study.
To examine the influence of conduct disorder (CD) on substance use initiation. Community adolescents without CD (n = 1,165, mean baseline age = 14.6 years), with CD (n = 194, mean baseline age = 15.3 years), and youth with CD recruited from treatment (n = 268, mean baseline age = 15.7 years) were prospectively followed and re-interviewed during young adulthood (mean ages at follow-up respectively: 20, 20.8, and 24). Young adult retrospective reports of age of substance initiation for 10 substance classes were analyzed using Cox regression analyses. Hazard ratios of initiation for the CD cohorts (community without CD as the reference) at ages 15, 18, and 21 were calculated, adjusting for baseline age, gender, and race/ethnicity. Among community subjects, CD was associated with elevated adjusted hazards for initiation of all substances, with comparatively greater hazard ratios of initiating illicit substances at age 15 years. By age 18, the adjusted hazard ratios remained significant except for alcohol. At age 21, the adjusted hazard ratios were significant only for cocaine, amphetamines, inhalants, and club drugs. A substantial portion of community subjects without CD never initiated illicit substance use. Clinical youth with CD demonstrated similar patterns, with comparatively larger adjusted hazard ratios. CD confers increased risk for substance use initiation across all substance classes at age 15 years, with greater relative risk for illicit substances compared to licit substances. This effect continues until age 18 years, with the weakest effect for alcohol. It further diminishes for other substances by age 21, However, the likelihood of initiating cocaine, amphetamines, inhalants and club drug use among those who have not initiated yet continues to be highly elevated by age 21.


Bond strength and microleakage of current dentin adhesives.
The purpose of this in vitro study was to evaluate shear bond strengths and microleakage of seven current-generation dentin adhesive systems. Standard box-type Class V cavity preparations were made at the cemento-enamel junction on the buccal surfaces of eighty extracted human molars. These preparations were restored using a microfill composite following application of either All-Bond 2 (Bisco), Clearfil Liner Bond (Kuraray), Gluma 2000 (Miles), Imperva Bond (Shofu), OptiBond (Kerr), Prisma Universal Bond 3 (Caulk), Scotchbond Multi-Purpose (3M), or Scotchbond Dual-Cure (3M) (control). Lingual dentin of these same teeth was exposed and polished to 600-grit. Adhesives were applied and composite was bonded to the dentin using a gelatin capsule technique. Specimens were thermocycled 500 times. Shear bond strengths were determined using a universal testing machine, and microleakage was evaluated using a standard silver nitrate staining technique. Clearfill Liner Bond and OptiBond, adhesive systems that include low-viscosity, low-modulus intermediate resins, had the highest shear bond strengths (13.3 +/- 2.3 MPa and 12.9 +/- 1.5 MPa, respectively). Along with Prisma Universal Bond 3, they also had the least microleakage at dentin margins of Class V restorations. No statistically significant correlation between shear bond strength and microleakage was observed in this study. Adhesive systems that include a low-viscosity intermediate resin produced the high bond strengths and low microleakage. Similarly, two materials with bond strengths in the intermediate range had significantly increased microleakage, and one material with a bond strength in the low end of the spectrum exhibited microleakage that was statistically greater. Thus, despite the lack of statistical correlation, there were observable trends.


Open study with bromperidol (C-C 2489), a new neuroleptic, for the determination of the neuroleptic threshold and the neuroleptic-therapeutic range.
In an open study involving 30 schizophrenic patients the neuroleptic threshold dose (measured via Haase's graphopathological test), the maximum dose, and the maintenance dose were determined. The neuroleptic threshold dose was 5.6 mg/day (0.08 mg/kg body weight); the maximum dose was 11 mg/day (0.16 mg/kg body weight); and the maintenance dose was 6 mg/day (0.09 mg/kg body weight). With reference to the effectiveness, good to very good results were obtained in 19 cases. Regarding side effects 15 patients complained of extrapyramidal disturbances, this was to be expected in view of the study design aiming at the determination of the maximum dose level. When administered in one single dose in the evening, bromperidol influenced the night sleep positively, so that sleep-inducing drugs could be reduced, and, in some cases, even dispensed with.


Wood ash: an unusual cause of a chemical burn.
The case illustrates the dangers of wood ash even though it appears harmless. People believe that this folklore medicine remedy provides relief of pain, but it is obviously an inappropriate preparation and a risky procedure.


[Mexican older adults with a wide socioeconomic perspective: health and aging].
Describe the Estudio Nacional de Salud y Envejecimiento en México (ENASEM), also known by its name in English as the Mexican Health and Aging Study (MHAS). This article summarizes the study design, its fieldwork protocol, survey contents, scope and analytical potential. It also presents descriptive results on selected topics. This is a prospective panel study on persons aged 50 or older in the year 2000. In the baseline survey, completed in 2001 with a national and urban-rural representation, about 15 200 interviews were completed. In the follow-up survey of the same persons in 2003, 90% of the attempted contacts resulted in successful interviews, and 546 interviews were completed about individuals who had died between the 2001 and 2003 visits. Descriptive results are presented on demographic characteristics, health, life style, institutional support, pensions, employment, family help, and two-year changes in health. There is evidence of large heterogeneity among older adults in Mexico, which is illustrated in a brief and precise way in the results presented. This study and its data bases have great analytical potential for exploring multiple dimensions in the health of older adults.


A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.
Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention.


Valorization of Pomace Powder Obtained from Native Mexican Apple (Malus domestica var. rayada): Chemical, Techno-functional and Antioxidant Properties.
The aims of the work were to determine the chemical, techno-functional and antioxidant properties of native Mexican apple pomace powder (MAPP) obtained from cider industry. The proximate composition and the total, insoluble and soluble dietary fibre content were determined, as well as the water holding (WHC), oil holding (OHC), swelling (SWC) capacities and the polyphenolic profile. For antioxidant activity, three different test systems were used (DPPH, FIC and FRAP). The total, insoluble and soluble dietary fiber content of MAPP was 70.91, 48.43 and 22.48 g/100 g, respectively. MAPP had a WHC, OHC and SWC of 4.2 g water/g sample, 1.69 g oil/g sample and 3.2 mL/g sample, respectively. Polyphenolic profile showed 10 flavonoid compounds identified mainly quercetin glycosides. MAPP showed good antioxidant activity with high correlation between total phenolic compounds and antioxidant capacity. The results obtained showed that MAPP could be considered a good source of bioactive compounds with significant antioxidant activity.


Immunogenicity and Safety of SpikoGen, an Adjuvanted Recombinant SARS-CoV-2 Spike Protein, as a Heterologous Third Booster Dose in Kidney Transplant Patients: A Single-arm Clinical Trial.
Studies have found that immunocompromised patients have suboptimal responses to COVID-19 vaccines, leading to approval of a need for booster doses in this population. SpikoGen® is a subunit recombinant spike protein vaccine combined with Advax-CpG55.2™ adjuvant to protect against COVID-19. Previous clinical trials found this vaccine to be tolerable, immunogenic, and efficacious in reducing the risk of COVID-19, including severe disease. However, the effects of this vaccine have not been assessed in immunocompromised patients. This study sought to assess the immunogenicity and safety of the SpikoGen vaccine as a third booster dose in patients undergoing kidney transplant who were receiving immunosuppressive therapy and had received their primary vaccination based on an inactivated whole virus platform (Sinopharm). This single-arm trial was performed with 43 patients undergoing kidney transplant. The participants received a single booster dose of the SpikoGen vaccine 1 to 3 months after primary vaccination with 2 doses of the Sinopharm vaccine. Immunogenicity assessments were performed at baseline and 30 days after the booster dose. The primary outcomes were seroconversion rates of anti-S1 and surrogate virus neutralizing antibodies. Safety outcomes included the incidence of solicited and unsolicited adverse events in the 7 days and 1 month after the booster dose, respectively. The SpikoGen vaccine induced positive humoral and cellular responses 30 days after the booster dose in those patients who were seropositive or seronegative after 2 primary doses of the Sinopharm vaccine. Thirty days after the SpikoGen vaccine booster, seroconversion rates were 35.29% (95% CI, 19.75%-53.51%) to anti-S1 and 29.41% (95% CI, 13.27%-46.57%) to surrogate neutralizing antibodies. The most common local and systemic reported solicited adverse events were injection site pain and fatigue, which were largely mild and transient. No serious adverse events were reported. A single booster dose of SpikoGen vaccine given 1 to 3 months after primary vaccination with 2 doses of Sinopharm vaccine induced positive humoral and cellular immune responses in immunosuppressed patients undergoing renal transplant, thereby achieving spike antibody levels predictive of protection. This study was performed as a single-center study, and it will be important for future large multicenter studies to extend these results to other immunocompromised patient groups.


Hybrid corn beyond heterosis: reading George Shull's hybrid corn articles (1908-1909).
The theoretical conclusion of Shull's first article 'The composition of a field of maize'-the breeder's task is 'the development and maintenance of that hybrid combinationwhich possesses the greatest vigor'-has, for all practical matters, nothing to do with his breeding proposal to make 'as many self-fertilization as practicable... Then all possible crosses are to be made among these different pure strains', namely extending the small grain isolation method to maize. This conclusion should have been clear for an unprejudiced biologist as soon as Shull's second article (January 1909), and was inevitable after his third one (December 1909). This article highlights Shull's skillful rhetoric and semantic that shaped the prejudice blinding biologists for more than a century and their neglect of Shull's stated goals of crop uniformity and breeders' property rights.


A new paraplegin mutation in a patient with primary progressive multiple sclerosis.
Primary progressive multiple sclerosis (PPMS) presents with clinical signs of slowly progressive long tract dysfunction that can overlap with neurodegenerative disorders, such as hereditary spastic paraplegia (HSP). Herein, we present two siblings in whom we have identified a novel mutation in the paraplegin (SPG7) gene. The proband, a 49-year-old woman, presented with a five-year history of progressive spastic paraparesis and ataxia. Brain MRI showed mild cerebellar atrophy. The genetic study revealed a homozygous mutation in the SPG7 gene, that led to the diagnosis of HSP. Four years previously, the younger brother had complained of slowly progressive spastic-ataxic gait, that started one year before; MRI had disclosed multiple areas of white matter hyperintensity with contrast enhancement. A diagnosis of active PPMS was made, and the patient started Disease-Modifying Therapy with further clinical and radiological stability. Once a genetic diagnosis was achieved in his sister, the patient underwent SPG7 testing, which disclosed the same mutation. Whether MS is a mimicry of HSP or it represents "double trouble" condition in this patient, it remains undetermined.


The novel HLA-DRB1*14:07:03 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.
HLA-DRB1*14:07:03 differs from HLA-DRB1*14:07:01 by one nucleotide in exon 2.


Molecular treatment strategies and surgical reconstruction for metastatic bone diseases.
Molecular mechanism of bone metastasis development is extremely complex. It is determined by intrinsic properties of cancer cells or cancer stem cells (CSCs) and intricate bone microenvironment. Therefore, molecular treatment strategies have been suggested to directly induce cancer cells apoptosis and to target vascular and bone microenvironment as well, thus inhibiting vicious cycles established between osteoblasts/osteoclasts and metastatic cancer cells. Chemokine/chemokine receptor pathway, adhesion molecules, and proteinases are crucial for bone metastatic process, including migration, adhesion and invasion into bone, angiogenesis and cell proliferation, which could provide potential targets for prevention and treatment of bone metastasis. Restoration of metastasis suppressor genes and microRNAs inhibits bone metastasis. Furthermore, targeting the bone marrow endothelium around cancer cells by use of both antiangiogenic inhibitors and vascular disrupting agents is another promising and valid therapeutic approach. On the other hand, many antitumor drugs/small molecules are limited in reaching tumor site due to a very complex vasculature. Nanotechnology aids in the targeted delivery of antitumor drugs/small molecules. For severe bone lesion, multifunctional implants integrating with antitumor drugs/small molecules and bone forming factors could be effective to reconstruct bone defects and to improve the quality of life in patients with bone metastasis.


Elastase 1 and chymotrypsin B in pancreatic juice and feces.
A chymotrypsin-like protease was detected along with elastase 1 in pancreatic secretion and stool. This enzyme was isolated from necrobiotic human pancreas, purified, partially characterized and designated as chymotrypsin B. Quantitative studies by rocket immunoelectrophoresis indicated that neither elastase 1 nor chymotrypsin B was degraded during intestinal passage. On the basis of a clinical study, both enzymes were found to reflect pancreatic function.


Prediction of biological age by morphological staging of sarcopenia in Caenorhabditis elegans.
Sarcopenia encompasses a progressive decline in muscle quantity and quality. Given its close association with ageing, it may represent a valuable healthspan marker. The commonalities with human muscle structure and facile visualization possibilities make Caenorhabditis elegans an attractive model for studying the relationship between sarcopenia and healthspan. However, classical visual assessment of muscle architecture is subjective and has low throughput. To resolve this, we have developed an image analysis pipeline for the quantification of muscle integrity in confocal microscopy images from a cohort of ageing myosin::GFP reporter worms. We extracted a variety of morphological descriptors and found a subset to scale linearly with age. This allowed establishing a linear model that predicts biological age from a morphological muscle signature. To validate the model, we evaluated muscle architecture in long-lived worms that are known to experience delayed sarcopenia by targeted knockdown of the daf-2 gene. We conclude that quantitative microscopy allows for staging sarcopenia in C. elegans and may foster the development of image-based screens in this model organism to identify modulators that mitigate age-related muscle frailty and thus improve healthspan.


Transcutaneous electrical nerve stimulation improves fatigue performance of the treated and contralateral knee extensors.
Transcutaneous electrical nerve stimulation (TENS) can reduce acute and chronic pain. Unilateral fatigue can produce discomfort in the affected limb and force and activation deficits in contralateral non-exercised muscles. TENS-induced local pain analgesia effects on non-local fatigue performance are unknown. Hence, the aim of the study was to determine if TENS-induced pain suppression would augment force output during a fatiguing protocol in the treated and contralateral muscles. Three experiments were integrated for this article. Following pre-tests, each experiment involved 20 min of TENS, sham, or a control condition on the dominant quadriceps. Then either the TENS-treated quadriceps (TENS_Treated) or the contralateral quadriceps (TENS_Contra) was tested. In a third experiment, the TENS and sham conditions involved two\; 100-s isometric maximal voluntary contractions (MVC) (30-s recovery) followed by testing of the contralateral quadriceps (TENS_Contra-Fatigue). Testing involved single knee extensors (KE) MVCs (pre- and post-test) and a post-test 30% MVC to task failure. The TENS-treated study induced greater (p = 0.03; 11.0%) time to KE (treated leg) failure versus control. The TENS_Contra-Fatigue induced significant (p = 0.04; 11.7%) and near-significant (p = 0.1; 7.1%) greater time to contralateral KE failure versus sham and control, respectively. There was a 14.5% (p = 0.02) higher fatigue index with the TENS (36.2 ± 10.1%) versus sham (31.6 ± 10.6%) conditions in the second fatigue intervention set (treated leg). There was no significant post-fatigue KE fatigue interaction with the TENS_Contra. Unilateral TENS application to the dominant KE prolonged time to failure in the treated and contralateral KE suggesting a global pain modulatory response.


Haemodynamic validation of the three-step HFA-PEFF algorithm to diagnose heart failure with preserved ejection fraction.
The HFA-PEFF algorithm (Heart Failure Association-Pre-test assessment, Echocardiography and natriuretic peptide score, Functional testing in cases of uncertainty, Final aetiology) is a three-step algorithm to diagnose heart failure with preserved ejection fraction (HFpEF). It provides a three-level likelihood of HFpEF: low (score < 2), intermediate (score 2-4), or high (score > 4). HFpEF may be confirmed in individuals with a score > 4 (rule-in approach). The second step of the algorithm is based on echocardiographic features and natriuretic peptide levels. The third step implements diastolic stress echocardiography (DSE) for controversial diagnostic cases. We sought to validate the three-step HFA-PEFF algorithm against a haemodynamic diagnosis of HFpEF based on rest and exercise right heart catheterization (RHC). Seventy-three individuals with exertional dyspnoea underwent a full diagnostic work-up following the HFA-PEFF algorithm, including DSE and rest/exercise RHC. The association between the HFA-PEFF score and a haemodynamic diagnosis of HFpEF, as well as the diagnostic performance of the HFA-PEFF algorithm vs. RHC, was assessed. The diagnostic performance of left atrial (LA) strain < 24.5% and LA strain/E/E' < 3% was also assessed. The probability of HFpEF was low/intermediate/high in 8%/52%/40% of individuals at the second step of the HFA-PEFF algorithm and 8%/49%/43% at the third step. After RHC, 89% of patients were diagnosed as HFpEF and 11% as non-cardiac dyspnoea. The HFA-PEFF score resulted associated with the invasive haemodynamic diagnosis of HFpEF (P < 0.001). Sensitivity and specificity of the HFA-PEFF score for the invasive haemodynamic diagnosis of HFpEF were 45% and 100% for the second step of the algorithm and 46% and 88% for the third step of the algorithm. Neither age, sex, body mass index, obesity, chronic obstructive pulmonary disease, or paroxysmal atrial fibrillation influenced the performance of the HFA-PEFF algorithm, as these characteristics were similarly distributed over the true positive, true negative, false positive, and false negative cases. Sensitivity of the second step of the HFA-PEFF score was non-significantly improved to 60% (P = 0.08) by lowering the rule-in threshold to >3. LA strain alone had a sensitivity and specificity of 39% and 14% for haemodynamic HFpEF, increasing to 55% and 22% when corrected for E/E'. As compared with rest/exercise RHC, the HFA-PEFF score lacks sensitivity: Half of the patients were wrongly classified as non-cardiac dyspnoea after non-invasive tests, with a minimal impact of DSE in modifying HFpEF likelihood.


Signal averaging of the surface QRS complex predicts inducibility of ventricular tachycardia in patients with syncope of unknown origin: a prospective study.
Forty patients with syncope of unknown origin underwent quantitative signal averaging of the surface QRS complex before invasive electrophysiologic testing with programmed ventricular stimulation. Of 34 patients without bundle branch block, 12 had inducible ventricular tachycardia (Group I) and 22 did not (Group II). The duration of low amplitude signals, the root mean square voltage of the terminal 40 ms and the signal-averaged QRS vector duration were measured in each case. One or more abnormal signal averaging variables were present in 92% of patients in Group I, but in only 27% of patients in Group II (p less than 0.005). An abnormal root mean square voltage of the terminal 40 ms was the most significant distinguishing variable, being present in 83% of Group I patients and in only 14% of Group II patients (p less than 0.005). The QRS vector duration was prolonged in 58% of Group I patients, but in only 9% of Group II patients (p less than 0.05). Likewise, the duration of low amplitude signals was prolonged in 58% of Group I patients, but in only 19% of Group II patients (p less than 0.05). When compared with 24 hour ambulatory electrocardiographic monitoring, the presence of abnormal signal averaging variables was more predictive of inducible ventricular tachycardia. Seven (32%) Group II patients had greater than or equal to 10 ventricular premature beats/h, couplets or episodes of nonsustained ventricular tachycardia; however, none had abnormal late potentials recorded. In contrast, three patients (25%) in Group I had less than 10 ventricular premature beats/h, although all in that group had one or more abnormal signal-averaged variables.(ABSTRACT TRUNCATED AT 250 WORDS)


Consumption of Chinese herbal medicines during pregnancy and postpartum: A prospective cohort study in China.
to investigate usage patterns and factors associated with maternal consumption of Chinese herbal medicines in China. prospective cohort study. Information on the use of Chinese herbal medicines was collected from mothers by personal interview at hospital discharge and followed up by telephone at one, three and six months postpartum. seven hospitals in Jiangyou, Sichuan Province of China. 695 mothers who gave birth to a singleton infant. prevalence, type, frequency and duration of herbal medicine usage. Logistic mixed regression analyses were performed to determine factors affecting the use. a total of 43.5% and 45.0% of mothers consumed Chinese herbal medicines during pregnancy and postpartum, respectively. Angelica sinsensis was the most popular herbal medicine among the participants (pregnancy 28.8%, postpartum 26.8%). Although herbal medicines were taken more regularly by postpartum users, the median usage duration varied from two to three months during pregnancy but 1-1.6 months postpartum. The majority of users (pregnancy 42.9%, postpartum 55.1%) were advised by their mother or mother-in-law to take Chinese herbal medicines. Antenatal alcohol drinking (adjusted odds ratio 2.75, 95% confidence interval 1.01-7.53) was associated with a marginally higher prevalence of herbal consumption during pregnancy, whereas mothers with a lower family income (adjusted odds ratio 1.52, 95% confidence interval 1.12-2.04) were more likely to consume Chinese herbal medicines in the postpartum period. consumption of Chinese herbal medicines appears to be prevalent among Chinese mothers, especially those drinking alcohol whilst pregnant and women from a lower income household. Maternity health professionals need to be aware of the lack of evidence to support the use of Chinese herbal medicines during pregnancy and postpartum, and to provide their clients with scientifically based advice regarding herbal medicine use.


Measuring health-status improvement after surgery: experience with the SF-36.
The outcomes of care delivery are increasingly being measured and managed by health care providers and clinicians. The authors describe an outcomes monitoring program implemented in one tertiary care center that uses both generic and condition-specific instruments to monitor patient recovery after routine surgery. The SF-36 Health Survey was shown to be a useful tool for measuring changes in functional status and well-being after inguinal hernia repair, cholecystectomy, and parathyroidectomy. Recommendations for its successful adoption in a clinical setting are presented.


Novel Bis-pyrazoline Fluorescent Probe for Cu2+ and Fe3+ Detection and Application in Cell Imaging.
A fluorescent probe Y((1,1'-([1,1'-biphenyl]-4,4'-diylbis(3-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazole-5,1-diyl)) bis(ethan-1-one))) was designed and synthesized, which could be used to Cu2+ and Fe3+ sensors. Through the study of optical properties, the probe Y shows good selectivity and sensitivity to Cu2+ and Fe3+ in aqueous tetrahydrofuran solution [10.0 mM HEPES, pH 7.4, THF-H2O = 9:1(v/v)] with has excellent anti-interference performance, and its detection limits were 0.931 uΜ for Cu2+ and 0.401uΜ for Fe3+. The coordination mechanism of probe Y with Cu2+ and Fe3+ was speculated and verified at DFT level and HRNM. By Hela cytotoxicity and imaging tests, probe Y not only has good biocompatibility, but also can be used for sensing Cu2+ in cells.


RhoA activity and post-ischemic inflammation in an experimental model of adult rodent anterior ischemic optic neuropathy.
Activation of inflammatory cells and the RhoA signaling pathway may contribute to optic nerve damage following non-arteritic anterior ischemic optic neuropathy (NAION). We induced an optic nerve infarct with a photothrombotic mechanism in a rat model of AION (rAION). Immunohistochemistry and Western blot were performed to detect activation of RhoA signaling and inflammation. The extent of Rho activity, inflammation, retinal ganglion cell (RGC) loss and extent of axon regeneration were determined at 8 and 14 days after infarct. Eight days after stroke, we observed significant inflammation and RhoA activity at the site of infarction as well as loss of cells in the RGC layer. RhoA activity had decreased and inflammation had decreased at day 14 compared with day 8; however, loss of RGCs was greater at 14 days than at 8 days. Stroked eyes showed minor axon regeneration around the optic nerve lesion site at both 8 and 14 days. These results demonstrate that inflammation and RhoA activation occur in rAION at the site of infarction.


PinQ: a valid, reliable and reproducible quality-of-life measure in children with bladder dysfunction.
Recently, a cross-cultural continence-specific paediatric quality-of-life measurement tool (PinQ) has been developed and tested psychometrically. The aim of this study was to evaluate the test re-test reliability of this new tool in a cohort of children with bladder dysfunction in order to evaluate the reproducibility of scores. A secondary aim was to compare the parent-completed proxy version with child-reported scores. PinQ was translated and back-translated from English into Chinese and Dutch and scrutinized for cultural and linguistic appropriateness or ambiguity. Forty children aged 6-15 years from both countries were asked to self-complete the measure at first consultation and then again 14 days later. No new treatment was implemented between data collection points. On the initial visit, parents also completed a proxy version of PinQ. Intraclass correlations (one-way random effects model) were used to analyze the data. The intraclass correlation coefficient (ICC) for comparison between items and factors showed little variability in scoring. One item was not reproducible and was removed from the tool. Overall proxy scores varied little from the child-reported scores. However, the impact on the child of his/her parent's concern about the bladder problem was poorly perceived (ICC=0.18) as was the impact on the child's sense of self-worth (0.17). PinQ has been shown to be reliable under test re-test conditions when completed by children from the age of 6 years. Proxy PinQ suggests that parents accurately evaluate the effect of bladder dysfunction on wellbeing in their children. A 20-item measurement tool will now be introduced clinically and subjected to sensitivity testing for treatment outcome and diagnostic grouping.


Mapping of antigenic determinants of human apolipoprotein B using monoclonal antibodies against low density lipoproteins.
The reactivity of a series of monoclonal antibodies directed against human low density lipoproteins (LDL) has been tested with hepatic and intestinal apolipoprotein B (apo-B) termed B-100 and B-48, respectively (Kane, J. P., Hardman, D. A., and Paulus, H. E. (1980) Proc. Natl. Acad. Sci. U. S. A. 77, 2465-2469). Whereas those antibodies that have been previously shown to recognize determinants close to the LDL receptor recognition site reacted only with B-100, two antibodies specific for other regions of apo-B reacted with both B-100 and B-48. Therefore, it is probable that sequence homologies exist between the two proteins and it must be considered that all or parts of the B-48 sequence may be contained within that of B-100. The specificity of the reaction of these antibodies with proteins designated B-74 and B-26 supports the concept that they represent complementary fragments of B-100. The present results have been incorporated in a theoretical map of the antigenic determinants recognized by these antibodies on the LDL apo-B.


Cerebellar mutism syndrome of non-tumour surgical aetiology-a case report and literature review.
Cerebellar mutism syndrome (CMS) is a well-known complication of posterior fossa (PF) tumour surgery. CMS has previously been reported in cases of non-tumour surgical aetiology in a limited number of publications. We report a case of a 10-year-old girl who suffered a cerebellar haemorrhage and subsequent CMS following surgical treatment of a ruptured arteriovenous malformation (AVM) in the cerebellar vermis. The AVM was removed acutely through a transvermian access, and hydrocephalus was treated with temporary external drainage. In the postoperative period, she suffered diffuse vasospasms of the anterior cerebral circulation and had a permanent shunt placed for hydrocephalus. Her mutism resolved after 45 days but severe ataxia persisted. To our knowledge, this is the first reported case of CMS related to a vermian haemorrhagic stroke with postoperative diffuse vasospasms. Based on this case, we present a literature review on CMS of non-tumour surgical origin in children.


Clostridium innocuum bacteremia secondary to infected hematoma with gas formation in a kidney transplant recipient.
Clostridium innocuum is a relatively antimicrobial resistant, frequently misidentified anaerobe that has only rarely been associated with bacteremia. A 38-year-old female with chronic hepatitis C underwent a second kidney transplant operation. Two weeks after surgery a computed tomography scan of the abdomen showed a heterogeneous hematoma with pockets of gas adjacent to the allograft, which extended into the pelvis and left abdominal wall, associated with low-grade fever. An anaerobic blood culture grew a Clostridium initially identified as C. subterminale and later re-identified as C. innocuum. At abdominal exploration liquefied blood was evacuated, and the patient completed a course of antibiotics and recovered. C. innocuum should be considered as a cause of gas-producing anaerobic infection in transplant patients. Because C. innocuum is frequently misidentified by the use of commercial anaerobic identification kits, its true incidence in serious infections is likely underestimated.


An observational study of clozapine induced sedation and its pharmacological management.
Clozapine induced sedation is common but its management is unclear. We analyzed the factors associated with clozapine-induced sedation and the efficacy of common pharmacological strategies. We conducted a naturalistic observational study using two years electronic records of a cohort patients and three analyses: a cross sectional analysis of factors associated with total number of hours slept (as an objective proxy of sedation), and two prospective analyses of which factors were associated with changes in hours slept and the efficacy of two pharmacological strategies. 133 patients were included, of which 64.7% slept at least 9h daily. Among monotherapy patients (n=30), only norclozapine levels (r=.367, p=.03) correlated with hours slept. Using the prospective cohort (n=107), 42 patients decreased the number of hours slept, due to decreasing clozapine (40%) or augmenting with aripiprazole (36%). These two strategies were recommended to 22 (20.6%) and 23 (21.5%) subjects respectively but the majority (81.8% and 73.9%) did not reduce number of hours slept. Thus, pharmacological and non-pharmacological factors are involved in sedation. Norclozapine plasma levels correlated with total sleeping hours. Reducing clozapine and aripiprazole augmentation were associated to amelioration of sedation, although both strategies were effective only in a limited numbers of subjects.


Multiple pulmonary aneurysms secondary to Hughes-Stovin syndrome: demonstration by MR angiography.
We report a case of a 41-year-old patient with multiple pulmonary aneurysms secondary to Hughes-Stovin syndrome. Conventional pulmonary angiography could not be performed, because thrombus in both the inferior and superior vena cavae prevented catheter passage. Contrast-enhanced three-dimensional (3D) MR angiography (MRA) showed two segmental pulmonary aneurysms in the right lung. The affected segments of the lung were resected successfully, predicated on the MRA findings.


Synthetic biology and its alternatives. Descartes, Kant and the idea of engineering biological machines.
The engineering-based approach of synthetic biology is characterized by an assumption that 'engineering by design' enables the construction of 'living machines'. These 'machines', as biological machines, are expected to display certain properties of life, such as adapting to changing environments and acting in a situated way. This paper proposes that a tension exists between the expectations placed on biological artefacts and the notion of producing such systems by means of engineering; this tension makes it seem implausible that biological systems, especially those with properties characteristic of living beings, can in fact be produced using the specific methods of engineering. We do not claim that engineering techniques have nothing to contribute to the biotechnological construction of biological artefacts. However, drawing on Descartes's and Kant's thinking on the relationship between the organism and the machine, we show that it is considerably more plausible to assume that distinctively biological artefacts emerge within a paradigm different from the paradigm of the Cartesian machine that underlies the engineering approach. We close by calling for increased attention to be paid to approaches within molecular biology and chemistry that rest on conceptions different from those of synthetic biology's engineering paradigm.


Cyanobacterial photosystem II at 3.2 A resolution - the plastoquinone binding pockets.
Photosystem II from thylakoid membranes of the thermophilic cyanobacterium Thermosynechococcus elongatus was solubilized with n-beta-dodecylmaltoside and purified using anion exchange chromatography. Molecular weight, pigment stoichiometry and subunit composition were assayed using various techniques. The holocomplex is dimeric with a molecular mass of 756 +/- 18 kDa and functionally fully active. Crystals obtained from these samples showed significantly improved quality leading to a 3D structure at 3.2 A resolution. Several loop regions of the principal protein subunits are now defined that were not interpretable at lower (3.8 A) resolution, thus resulting in a more complete model. The head groups of the cofactors of the electron transfer chain and of the antennae have been modeled, coordinating and hydrogen bonding amino acids identified and the nature of the binding pockets derived. The orientations of these cofactors resemble those of the reaction centre from anoxygenic purple bacteria. For the two plastoquinones, electron density was only found for the head group of QA and none for QB indicating low or even no occupancy of this site in the crystal structure. Both binding pockets and problems related to the QB site are discussed here and compared to the situation in the purple bacterial reaction centre.


Argon Plasma Treated Phosphatic Clays for Efficient Heavy Metal Pb(II) Immobilization.
Phosphatic clays, one type of phosphorite industry wastes, could induce environmental issues and geological disasters when they are piled in the open air. Previous research demonstrated that phosphatic clays usually exhibit poor performance in heavy metal immobilization mostly due to low phosphate content. Thus, phosphatic clays could not be applied in practical heavy metal remediation without pretreatment. If the adsorption performance of phosphatic clays could be improved, employing phosphatic clays for heavy metal immobilization may act as an eco-friendly, economic way to not only reutilize phosphorite industry wastes but also remedy environmental heavy metal pollution at the same time. In this study, we propose an argon plasma treatment approach to remarkably improve the effectiveness of phosphatic clay performances in heavy metal immobilization. The optimal Pb(II) sorption capacity of 66.7 mg g-1 can be obtained at pH 6 and 25°C by using 15-min argon plasma treated phosphatic clays, which is two times as large as those of the untreated phosphatic clays and almost reaches those of raw apatite minerals. Moreover, the Pb(II) desorption ratios of Pb(II)-adsorbed phosphatic clays are also reduced by 30%-60% at different pH conditions. Therefore, applying argon-plasma technique to transform waste phosphatic clays into efficient heavy-metal sorbents is a promising road to phosphorite waste reclamation and environmental remediation.


Congenital retinal folds in Sheffield-Wistar rats.
Retinal folds are described in male rats of a Wistar-derived strain, which occasionally shows microphthalmia and cataract. The less severe lesions mainly affect the outer retinal layers and contain microretinal detachment, cell rosettes, phagocytic cells and lipid debris. More severe folds involve all the retinal layers, exhibit subretinal haemorrhage, and photoreceptor outer segment debris throughout the lesion and on the vitreal surface. The lesions are discussed in relation to previous observations of retinal folds.


Infection and morbidity in patients with tuberculosis in Nairobi, Kenya.
To examine the role of acute infection as a cause of morbidity in patients with tuberculosis. Cross-sectional documentation of predefined acute morbid events. Infectious Diseases Hospital, Nairobi, Kenya. Adults (> or = 15 years), inpatients and outpatients with a diagnosis of tuberculosis presenting with one or more of a series of clinical features. A new event was defined as one occurring at least 1 week after the initial event. Patients' treatment was modified depending on the results of laboratory investigations. There were 642 events from 398 patients, 235 HIV-positive patients had 438 events and 163 HIV-negative patients had 204 events (P < 0.0001). Forty-two out of the 235 (18%) HIV-positive patients were bacteraemic compared with nine out of the 163 (6%) HIV-negative patients (P = 0.0003). The most common isolates from blood were Salmonella typhimurium and Streptococcus pneumoniae. Faecal specimens were obtained more commonly from HIV-positive patients (P < 0.001), and often contained bacterial pathogens. Many of the causes of morbidity in patients with tuberculosis and HIV are not due to tuberculosis or antituberculous therapy, and will not be identified without microbiological investigation.


Duration of Dual Antiplatelet Therapy in Coronary Artery Disease: a Review Article.
Dual antiplatelet therapy (DAPT) following an acute coronary syndrome or after placement of a coronary artery stent is superior to aspirin alone for prevention of atherothrombotic events but carries an increased bleeding risk. DAPT should be continued for at least 12 months based on current guidelines. Recent randomized trials demonstrate reduced ischemic events including myocardial infarction (MI), stroke, and death with continued DAPT for up to 30 months or longer, particularly in the post-MI population. However, this clinical benefit is accompanied by an increased risk of bleeding. Additional trials show mixed safety and efficacy with duration of DAPT of less than 12 months. The current data emphasizes the need to individualize DAPT duration at the patient level to balance the clinical benefits of a reduced risk of cardiovascular ischemic events with the greater risk of clinically significant bleeding. Patients at an increased risk of ischemic events and a lower risk of bleeding should be strongly considered for prolonged DAPT beyond the 1 year currently recommended in the practice guidelines.