Glomerular diseases in Iranian children: clinico-pathological correlations.
Glomerular disease constitutes an important part of renal disease. The purpose of this study was to describe and correlate the types of glomerular diseases reported in native kidney biopsy specimens and their clinical presentations in Iranian children. The medical records and pathological diagnoses of patients with glomerular disease whose native kidney biopsy specimens were received by our hospital during a 10-year period were reviewed. In each patient, pathological diagnosis, clinical presentation, age at onset of disease, gender, and presence of nephrotic proteinuria, hematuria, and hypertension, were determined. Minimal-change disease was the most frequent glomerular disease and nephrotic syndrome was the most frequent clinical presentation encountered. For each disease, correlations between the clinical presentation and pathological diagnosis were made. This study describes various glomerular diseases encountered in Iranian children, with their respective clinical presentations.


Long-term effect of previous swimtraining in girls. A 10-year follow-up of the "girl swimmers".
Thirty girls, studied in 1961 after 2.5 years of intensive swimtraining, were the subject of a follow-up for ten years. When last examined, seven and ten years after the original study, all the girls had given up swimtraining. The increased values for vital capacity observed in 1961 remained unchanged, but residual volume, functional residual capacity and total lung capacity showed small increases even after corrections for body growth. Such increases are, however, normal in these years. Heart volume which was high originally, was found to be lower ten years later, although mean values were still higher than normal. The decreases seen from 1961 to 1971 could mainly be ascirbed to a decrease in the subjects with the larges hearts originally. Both total hemoglobin and blood volume decreased to normal values in relation to body size. Maximal oxygen uptake, though, fell from 2.80 l/min (51. 4 ml/kg X min) to 2.18 l/min (36.4 ml/kg X min) ten years later. It is suggested that the functional capacity of the cardiovascular system declined more markedly than its dimensions.


Hybridization and introgression are prevalent in Southern European Erysimum (Brassicaceae) species.
Hybridization is a common and important force in plant evolution. One of its outcomes is introgression - the transfer of small genomic regions from one taxon to another by hybridization and repeated backcrossing. This process is believed to be common in glacial refugia, where range expansions and contractions can lead to cycles of sympatry and isolation, creating conditions for extensive hybridization and introgression. Polyploidization is another genome-wide process with a major influence on plant evolution. Both hybridization and polyploidization can have complex effects on plant evolution. However, these effects are often difficult to understand in recently evolved species complexes. We combined flow cytometry, analyses of transcriptomic sequences and pollen tube growth assays to investigate the consequences of polyploidization, hybridization and introgression on the recent evolution of several Erysimum (Brassicaceae) species from the South of the Iberian Peninsula, a well-known glacial refugium. This species complex differentiated in the last 2 million years, and its evolution has been hypothesized to be determined mainly by polyploidization, interspecific hybridization and introgression. Our results support a scenario of widespread hybridization involving both extant and 'ghost' taxa. Several taxa studied here, most notably those with purple corollas, are polyploids, probably of allopolyploid origin. Moreover, hybridization in this group might be an ongoing phenomenon, as pre-zygotic barriers appeared weak in many cases. The evolution of Erysimum spp. has been determined by hybridization to a large extent. Species with purple (polyploids) and yellow flowers (mostly diploid) exhibit a strong signature of introgression in their genomes, indicating that hybridization occurred regardless of colour and across ploidy levels. Although the adaptive value of such genomic exchanges remains unclear, our results demonstrate the significance of hybridization for plant diversification, which should be taken into account when studying plant evolution.


Stress Metabolites of the Potato and Other Solanaceous Plants.
The effect of stress on the chemical composition of the Solanaceae , primarily Solanum tuberosum (potato), may be profound and have significant health implications. Changes in glycoalkaloids, steroids, sesquiterpenes and other lipids that result from specific and non-specific stress are discussed. The biochemistry and toxicology of these compounds are reviewed.


[Subfoveal posterior ciliary arteries: Multimodal imaging and classification based on choroidal elevation].
To characterize the magnitude and consequences for interpretation of macular elevations associated with short posterior ciliary arteries (SPCA) extending to the fovea. Retrospective study of 96 eyes of 138 patients who underwent multimodal imaging (color photographs, SD-OCT with OCT-angiography analysis, fluorescein angiography [FA] and indocyanine green angiography [ICG]) over a two-year period. The authors selected patients with a focal choroidal elevation (FCE) associated with a SPCA extending to the fovea. FCEs were classified according to their magnitude as "Low" (<50μm), "Medium" (50μm to 100μm) and "High" (>100μm). Ten patients aged 80.10±11.82 years had a FCE associated with a macular SPCA. The patients were followed for advanced AMD with neovascularization (2 cases), advanced AMD with geographic atrophy (3 cases), intermediate AMD (1 case) ; one patient was followed for diabetes ; three patients had no identified retinal pathology. The FCE associated with the SPCAs was Low (3 cases), Medium (2 cases), High (3 cases). In 2 cases, the FCE was limited to an unmeasurable choroidal fold. The interpretation associated with these FCEs was not always related to the magnitude of the elevation. Our observations show the value of multimodal imaging in the identification of SPCA extending to the fovea, sometimes associated with a macular FCE. In some cases, the signs associated with FCE interfered with the monitoring of the condition for which the patient was being followed. Identifying these FCEs and grading their amplitude is relevant, as they should not be confused with pathological structures.


Use of a nylon-bag technique for pig feed digestibility studies.
1. The use of a nylon-bag technique for pig feed digestibility determination was studied. Bags, measuring 25 x 40 mm and containing feed samples, were introduced into the pig gastrointestinal tract through a duodenal cannula, and recovered in the faeces between 23 and 69 h later. The disappearance of organic matter and crude protein (nitrogen x 6.25) from the bags was compared with in vivo apparent digestibility, determined by conventional faecal-collection methods, and neutral-detergent-fibre content for eleven feeds. The residues left in the bags after passage through the intestine from whole-crop-pea (Pisum sativum) and barley-grain samples were analysed for starch, non-starch polysaccharide residues, Klason lignin, crude protein and ash. 2. Dry matter disappearance of barley or whole-crop peas was not influenced by increasing bag pore size from 10 to 36 microns or sample weight from 250 to 1000 mg. Pepsin (EC 188.8.131.52) pretreatment had no effect on the degradation in the bags of the feeds investigated. 3. Organic matter and crude protein disappearance from the bags exceeded in vivo apparent digestibility by up to 0.10 and 0.42 units respectively. In vivo apparent organic matter digestibility could be predicted (P less than 0.001) by the organic matter disappearance from the bags and the neutral-detergent-fibre content of the feed, while in vivo apparent crude protein digestibility was highly correlated (P less than 0.001) to all these indices but poorly to crude protein disappearance from the bags. 4. Klason lignin was the least degraded component measured in the whole-crop-pea and barley residues from the bags, while starch was completely digested.(ABSTRACT TRUNCATED AT 250 WORDS)


Diurnal variation and melatonin induction of hepatic molybdenum hydroxylase activity in the guinea-pig.
The activities of the xenobiotic metabolizing enzymes, aldehyde oxidase and xanthine oxidase, were determined in partially purified fractions of adult guinea-pig liver at given times in the day or night. A marked circadian variation in aldehyde oxidase activity was observed with several substrates (phthalazine, phenanthridine, N-phenylquinolinium and 3,4-dihydro-4-hydroxy-3-methyl-2-quinazolinone). The main peak occurred at 0300 hr with minimum activity from 1200 to 1800 hr, the differences between rhythmic extremes being statistically significant (P less than 0.005). Xanthine oxidase activity also exhibited a daily rhythm but with a lower amplitude. Guinea-pig serum melatonin showed a synchronous circadian fluctuation with peak values at 0300 hr falling throughout the day to a minimum at 1800 hr. Exogenously administered melatonin caused a significant increase in aldehyde oxidase activity at 0900 and 1200 hr and in xanthine oxidase activity at 0900 hr. It was concluded that melatonin concentrations may be related to the circadian variation in liver molybdenum hydroxylase activity.


Proximal Anchor Constructs and Its Influence on Surgical Outcome in Growth Rod Technique; A Comparison Between Rib Hooks and Pedicle Screws.
Retrospective. To compare outcomes and complications of all-pedicle screw against hybrid constructs as proximal anchors in traditional growth rod technique. Traditional distraction-based growth rods, although the preferred technique in treating progressive curves in early-onset scoliosis (EOS) is not free from complications. Surgical outcome and implant-related complications can be influenced by the choice of construct, but there is a paucity of evidence in literature comparing different constructs with these techniques. A retrospective review was performed of 28 consecutive patients with progressive EOS treated between 2009 and 2015 with growth rod technique. Patients were divided into two groups; Standard group (SG), where all pedicle screw construct was used; and Hybrid group (HG), where proximal rib hooks and distal pedicle screws were used. Pre- and postoperative clinical and radiologic parameters and complications were recorded and compared. There were 13 patients (8 females, 5 males) in SG and 15 patients (13 females, 2 males) in HG. There was statistically significant improvement in scoliosis correction and length gain after initial surgery in both groups, where patients in SG showed better correction than HG. However, neither the radiologic parameters nor the complication rates showed any statistically significant difference between the two groups. Data from our study indicate that the proximal anchors, whether spine-based or rib-based, do not differ much in their outcome and complication rates, and the success of growing-rod technique depends largely on the security of cephalad and caudal foundations. Level IV.


Organoid-based modeling of intestinal development, regeneration, and repair.
The intestinal epithelium harbors a remarkable adaptability to undergo injury-induced repair. A key part of the regenerative response is the transient reprogramming of epithelial cells into a fetal-like state, which drives uniform proliferation, tissue remodeling, and subsequent restoration of the homeostatic state. In this review, we discuss how Wnt and YAP signaling pathways control the intestinal repair response and the transitioning of cell states, in comparison with the process of intestinal development. Furthermore, we highlight how organoid-based applications have contributed to the characterization of the mechanistic principles and key players that guide these developmental and regenerative events.


Identification of a complex between alpha-actinin and the intermediate filament subunit skeletin in bovine heart Purkinje fibres.
A three-dimensional cytoskeleton, morphologically composed of intermediate filaments, desmosomes, and Z-disks, remains in bovine heart Purkinje fibres after extraction with Triton X-100 and low and high ionic strength solutions. Biochemically this cytoskeleton mainly consists of skeletin (Mr approximately 55 000) and of alpha-actinin (Mr approximately 95 000). Minor high molecular weight components are also present. By gel electrophoresis-derived enzyme-linked immunosorbent assay (GEDELISA) we show here that a 150 000-dalton component is a complex of alpha-actinin and skeletin. Furthermore, this 150 000-dalton component has now been purified and can be converted into 95 000- and 55 000-dalton subunits by reduction with a high concentration of beta-mercaptoethanol and heating. We also show that solubilized pure skeletin and pure alpha-ctinin from Purkinje fibres, after mixing, partly form a stable complex with a molecular weight of about 150 000 daltons.


Targeting Hemoglobin to Reduce Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.
Delayed cerebral ischemia (DCI) continues to be a sequela of aneurysmal subarachnoid hemorrhage (aSAH) that carries significant morbidity and mortality. Aside from nimodipine, no therapeutic agents are available to reduce the incidence of DCI. Pathophysiologic mechanisms contributing to DCI are poorly understood, but accumulating evidence over the years implicates several factors. Those have included microvessel vasoconstriction, microthrombosis, oxidative tissue damage, and cortical spreading depolarization as well as large vessel vasospasm. Common to these processes is red blood cell leakage into the cerebrospinal fluids (CSF) and subsequent lysis which releases hemoglobin, a central instigator in these events. This has led to the hypothesis that early blood removal may improve clinical outcome and reduce DCI. This paper will provide a narrative review of the evidence of hemoglobin as an instigator of DCI. It will also elaborate on available human data that discuss blood clearance and CSF drainage as a treatment of DCI. Finally, we will address a recent novel device that is currently being tested, the Neurapheresis CSF Management System™. This is an automated dual-lumen lumbar drainage system that has an option to filter CSF and return it to the patient.


Higher risk of 2-year cup revision of ceramic-on-ceramic versus ceramic-on-polyethylene bearing: analysis of 33,454 primary press-fit total hip arthroplasties registered in the Dutch Arthroplasty Register (LROI).
The influence of bearing on short-term revision in press-fit total hip arthroplasty (THA) remains under-reported. The aim of this study was to describe 2-year cup revision rates of ceramic-on-ceramic (CoC) and ceramic-on-polyethylene (CoPE). Primary press-fit THAs with one of the three most used cups available with both CoC or CoPE bearing recorded in the Dutch Arthroplasty Register (LROI) were included (2007-2019). Primary outcome was 2-year cup revision for all reasons. Secondary outcomes were: reasons for revision, incidence of different revision procedures and use of both bearings over time. 2-year Kaplan-Meier cup revision rate in 33,454 THAs (12,535 CoC; 20,919 CoPE) showed a higher rate in CoC (0.67% [95% CI, 0.54-0.81]) compared to CoPE (0.44% [95% CI, 0.34-0.54]) (p = 0.004). Correction for confounders (age, gender, cup type, head size) resulted in a hazard ratio (HR) of 0.64 [95%CI, 0.48-0.87] (p = 0.019). Reasons for cup revision differed only by more cup revision due to loosening in CoC (26.2% vs.1 3.2%) (p = 0.030). For aseptic loosening a revision rate of 0.153% [95% CI, 0.075-0.231] was seen in CoC and 0.058% [95%CI 0.019-0.097] in CoPE (p = 0.007). Correction for head size resulted in a HR of 0.475 [95% CI, 0.197-1.141] (p = 0.096). Incidence of different revision procedures did not differ between bearings. Over time the use of CoPE has increased and CoC decreased. A higher 2-year cup revision rate in press-fit THA was observed in CoC compared to CoPE. Cup loosening was the only significantly different reason for revision and seen more often in CoC and mostly aseptic. Future randomised controlled trials need to confirm causality, since the early cup revision data provided has the potential to be useful when choosing the bearing in press-fit THA, when combined with other factors like bone quality and patient and implant characteristics.


Impacts of revised dose coefficients for the inhalation of NORM-containing dusts encountered in the Western Australian Mining Industry.
The aim of this paper is to evaluate the impact of recent revisions to the dose coefficients published in ICRP-137 and ICRP-141 for members of the232Th,238U and235U decay series on radiation doses received by Western Australian mine workers via the inhalation of insoluble dusts containing long-lived alpha particle emitting radionuclides.Whilst some dose coefficients for individual members of the decay series have decreased, the nett effect is that the sum of all dose coefficients in all three decay series have increased as a result of the revisions. The increase is inversely related to Activity Median Aerodynamic Diameter.Assuming the radionuclides in the inhaled dusts are in secular equilibrium, the dose conversion factors (the mean committed effective dose per unit intake of alpha activity) will increase by a factor between 1.9 and 2.9 times.In 2019, 11 mining operations in Western Australia submitted an annual report of worker radiation exposures to the regulatory authority. The reports indicate that between 35% and 60% of the committed effective doses to workers arises from inhalation of insoluble radioactive dusts. Applying an AMAD of 5 μm and a232Th decay series to238+235U decay series ratio of 10:1, committed effective doses to the workforce are greater by a factor of between 0.74 and 1.26 times from those reported in 2018-19 as a result of the revised DCs published in ICRP-137 and ICRP-141.Guidance on how to calculate doses from the inhalation of radioactive dusts is provided in the regulatory authority's Guideline 'NORM-5: Dose Assessment', which will need revision to incorporate the revised dose coefficients. The Guideline has been widely distributed outside of Western Australia, and those jurisdictions which have adopted all, or sections of it, into their legal framework for radiation protection may need to consider the impact of the revision.


Clinical and immunological studies in patients with an increased serum IgD level.
Increased levels of serum IgD can be found in single patients with a variety of clinical syndromes and in the disease entity designated hyper-IgD syndrome which is associated with periodic fever and lymphadenopathy. We investigated 17 patients, both children and adults, with high serum IgD levels ranging from 220 to 5300 IU/ml. Eight patients had periodic fever and lymphadenopathy, four showed a humoral immunodeficiency, and the remainder had a variety of clinical abnormalities. Serum IgA levels were consistently high in all patients except in those with an immunodeficiency. Serum IgD complexes were detectable in each serum, which indicates that the occurrence is not pathognomic for the syndrome of periodic fever. Antibody formation against the primary antigen Helix pomatia hemocyanine and the secondary antigen tetanus toxoid showed no abnormalities in the patients without an immunodeficiency. Bone marrow origin of serum IgD was strongly suggested by enumeration of IgD-containing plasma cells. We conclude that no apparent relationship exists between the several clinical syndromes and increased serum IgD.


A systems biology approach for the study of cumulative oncogenes with applications to the MAPK signal transduction pathway.
The Extracellular signal Regulated Kinase (ERK) pathway is one of the most well-studied signaling pathways in cell cycle regulation. Disruption in the normal functioning of this pathway is linked to many forms of cancer. In a previous study [D.K. Pant, A. Ghosh, Automated oncogene detection in complex protein networks, with applications to the MAPK signal transduction pathway, Biophys. Chem. 113 (2005) 275-288.], we developed a novel approach to predict single point mutations that are likely to cause cellular transformation in signaling transduction networks. We have extended this method to study disparate pair mutation in enzyme/protein interactions and in expression levels in signal transduction pathway and have applied it to the MAPK signaling pathway to study how synergistic or cooperative mutation within signaling networks acts in unison to cause malignant transformation. The method provides a quantitative ranking of the modifier pair of ERK activation. It is seen that the highest ranking single point mutations comprise the highest ranking pair mutations. We validate some of our results with experimental literature on multiple mutations. A second order sensitivity analysis scheme is additionally used to determine the effect of correlations among mutations at different sites in the pathways.


Supporting Type 1 and 2 Diabetes Care in the Hemodialysis Unit: A Quality-improvement Initiative Throughout the COVID-19 Pandemic.
People living with diabetes (DM) and chronic kidney disease (CKD) can have difficulty attending multiple appointments to receive DM care. We developed and studied the utility of a DM outreach program to offer in the hemodialysis (HD) unit. We conducted a quality improvement project in a satellite HD unit in London, Ontario, Canada, between August 1, 2019 and July 31, 2022. We assessed for baseline gaps in DM care among those with DM, performed root-cause analysis with key stakeholders to identify critical drivers of gaps, and conceptualized a certified diabetes educator-led outreach program to offer in the HD unit. We aimed to improve DM self-monitoring, hypo- and hyperglycemia, and DM-related screening. We used run and control charts to track outcome measures over time and modified our outreach program iteratively. Fifty-eight persons with DM receiving HD participated in our program. Support spanned multiple waves of the COVID-19 pandemic. With 4 tests of change, we observed improvement in DM self-monitoring with a modest decline in self-reported hyperglycemia. There were no adverse consequences, and satisfaction with our program was high. Although we did not meet all measures of success during the pandemic, outreach DM support in the HD unit appeared to improve self-monitoring and self-reported hyperglycemia. Similar programs could be modified and implemented in other centres.


Assessing geriatric patients with head injury in the emergency department using the novel level III trauma protocol.
Intracranial injury in elderly patients presenting with minor head trauma is often overlooked in the emergency department (ED). Our suburban community-based level II trauma hospital developed and implemented the level III trauma protocol (L3TP) in January 2016 to better evaluate and diagnose intracranial injury in elderly patients presenting with minor head trauma after a fall. The L3TP requires that the ED physician immediately assess all patients meeting the following criteria 1) Age ≥ 65 years old. 2) Currently taking any anticoagulant or antiplatelet agents. 3) Presenting in the ED with a potential head injury after a fall. The ED physician determines if these high-risk patients require emergent imaging, obviating the need for trauma team activation unless an intracranial hemorrhage (ICH) is found. The purpose of this study was to assess the impact of the novel L3TP on resource utilization and patient outcome. Our retrospective cohort study included patients who met the L3TP inclusion criteria and had an ICH diagnosed by non-contrast computed tomography (CT). We compared patients triaged by the L3TP (January to December 2017) to patients triaged before the L3TP was implemented (January to August 2015) in order to assess the impact of the L3TP on resource utilization and patient outcome. The data was analyzed using two independent samples t-tests and Chi-square tests. Patients triaged by the L3TP had a significantly shorter average length of time from arrival in the ED to CT (level III trauma 0.64 h vs control 2.37 h, (d = 1.73; 95% CI = 1.42, 2.04), p ≤ 0.0001) and ED length of stay (level III trauma 2.55 h vs control 4.72 h, (d = 2.17; 95% CI = 1.21, 3.13), p ≤ 0.0001). There was insufficient evidence to conclude that there was any difference in health outcomes between the control and level III trauma groups. The L3TP is an effective and resource efficient protocol that quickly identifies ICH in elderly patients without activating the trauma team for every elderly patient presenting to the ED with a potential head injury after a fall.


Fates of dietary sterols in the insect alimentary canal.
Sterols serve structural and physiological roles in insects. However, insects and other arthropods have lost many genes in the sterol biosynthesis pathway, so they must acquire sterols from their food. Sterols occur naturally as free (unconjugated) molecules, and as conjugated ones (mostly steryl esters). Once sterols are ingested and make their way into the gut, steryl esters can be converted into free sterols by Magro protein, a lipase excreted by enterocytes. Sterols in the free form enter midgut enterocytes through NPC1b and are then transported to the smooth endoplasmic reticulum membrane for possible metabolism. For most insect herbivores, phytosterol dealkylation converts plant sterols into cholesterol. Some ingested sterols may also be consumed by microbiota dwelling inside the insect gut lumen; bacteria use sterols as a source of carbon and energy. Further studies will reveal interesting and exciting discoveries regarding the pathways for the dietary sterols entering the insect alimentary canal.


Role of intracellular calcium in histamine release from rat mast cells.
Compound 48/80-induced histamine release may utilize both intracellular and extracellular calcium. The release is inhibited by La3+ and TMB-8 both in the presence and absence of calcium. The observations are consistent with a mobilization of calcium from the inner surface of the plasma membrane supporting the release. TMB-8 probably acts at more than one site. It has been shown to inhibit skeletal muscle contraction and this has been correlated to its inhibitory effect on the release of Ca2+ from the sarcoplasmic reticulum. TMB-8 also inhibits resting cellular influx and efflux of calcium in the ileum. Anaphylactic and dextran-induced histamine release is dependent on extracellular calcium; the inhibition of the release by TMB-8 seems to be primarily due to an interference with calcium transport across the plasma membrane. In the absence of extracellular calcium the inhibition of compound 48/80-induced histamine release by TMB-8 seems to be due to stabilization of Ca2+ binding to cellular stores.


Clonally rearranged T-cell receptor beta chain genes in HTLV-I carriers with abnormal, non-flower-like, lymphocytes.
The diagnosis of Adult T-cell leukemia/lymphoma ATLL subtypes in human T-lymphotropic virus type I (HTLV-I) carriers based in morphology and immunophenotype of lymphocytes can be challenger. We propose that polymerase chain reaction (PCR) amplification of the rearranged TCR gene in HTLV-I healthy carriers would be a convenient method for establishing the nature of the circulating T lymphocytes in asymptomatic HTLV-I carriers, presenting only mild and inconclusive signals of deviation from normality. Using PCR, we analyzed the genetic recombination pattern of the T-cell beta-chain receptor gene (TCR-beta) in order to identify clonal expansion of peripheral blood T lymphocytes in 17 HTLV-I-positive healthy carriers and in nine normal HTLV-I-negative blood donors. To evaluate the performance of PCR in detection of clonality, we also analyzed 18 patients with post-thymic/mature T-cell malignancies presenting circulating abnormal lymphocytes. Seven of the 17 HTLV-I positive individuals presented circulating abnormal lymphocytes; monoclonal or oligoclonal expansion of T-cells was detected in five of the 17 HTLV-I-positive individuals, all of them presenting abnormal lymphocytes. Clonal expansion was not detected in any of the negative controls or in any of the 12 remaining healthy carriers. All patients in the positive control group tested positive by PCR and Southern blots. Southern blots were negative for all 17 healthy carriers. PCR amplification of segments of rearranged TCR-beta is reliable for allowing early detection of small populations of clonal T cells in blood samples from asymptomatic HTLV-I carriers, providing an additional alert in the follow-up of carriers with abnormal circulating lymphocytes.


Extramedullary impedance monitoring and stimulation of the spinal cord surface in percutaneous cordotomy. Technical note.
A needle with an insulated inner stylet has been developed for monitoring of impedance when the subarachnoid space is punctured in percutaneous cordotomy. Electric stimulation of the surface of the spinal cord with a flat-tipped electrode has been used in order to locate the optimal site for the subsequent penetration of the cord with a sharp lesion-making electrode.


Long chain polyunsaturated fatty acid supplementation in infancy increases length- and weight-for-age but not BMI to 6 years when controlling for effects of maternal smoking.
Long chain polyunsaturated fatty acids (LCPUFA) are added to infant formula but their effect on long-term growth of children is under studied. We evaluated the effects of feeding LCPUFA-supplemented formula (n = 54) compared to control formula (n = 15) throughout infancy on growth from birth-6 years. Growth was described using separate models developed with the MIXED procedure of SAS(®) that included maternal smoking history and gender. Compared to children fed control formula, children who consumed LCPUFA supplemented formula had higher length-/stature-/and weight-for-age percentiles but not body mass index (BMI) percentile from birth to 6 years. Maternal smoking predicted lower stature (2-6 years), higher weight-for-length (birth-18 months) and BMI percentile (2-6 years) independent of LCPUFA effects. Gender interacted with the effect of LCPUFA on stature, and the relationship between smoking and BMI, with a larger effect for boys. Energy intake did not explain growth differences. A relatively small control sample is a limitation.


Transcription factor NRF2 as potential therapeutic target for preventing muscle wasting in aging chronic kidney disease patients.
Increased muscle protein catabolism leading to muscle wasting is a prominent feature of the syndrome of protein-energy wasting (PEW) in patients with chronic kidney disease (CKD). PEW and muscle wasting are induced by factors such as inflammation, oxidative stress and metabolic acidosis that activate the ubiquitin-proteasome system, the main regulatory mechanism of skeletal muscle degradation. Whether deficiency of nuclear factor erythroid 2-related factor 2 (NRF2), which regulates expression of antioxidant proteins protecting against oxidative damage triggered by inflammation, may exacerbate PEW has yet to be examined in aging patients with CKD. This review focuses on the hypothesis that NRF2 is involved in the maintenance of muscle mass and explores whether sustained activation of NRF2 by non-pharmacological interventions using nutraceutical activators to improve redox homeostasis could be a plausible strategy to prevent skeletal muscle disorders, including muscle wasting, sarcopenia and frailty associated with PEW in aging CKD patients.


[Study of reproductive health risks in Sicily. Congenital malformations and exposure to EDCs: a case-control study (study methodology)].
The incidence of Congenital Malformations may represent an early biological indicator for human toxicity to environmental and occupational contaminants. SCIENTIFIC OBJECTIVE: We are in the process of exploring the relation between various potential sources of parental periconceptional pregnancy exposures to Endocrine Disrupting Chemicals (EDCs) and selected Congenital Malformations in offspring. The low incidence of Congenital Malformations leads to an epidemiological "Case-Control" study. The areas of the study are the Ragusa Municipalities and the south-east Siracusa Municipalities. We are conducting personal interviews with parents of about 100 cases with orafacial clefts or male genital malformations and 200 nonmalformed controls. The infants for the study were selected from those born during 1998-2002 in these areas. The more important variables considered are: 1--parental occupation and workplace exposures. 2--relevant confounders and recall bias. The analysis of the data will use the classical approach of case-control study (matching procedure), comparing risk factor frequency between cases and controls. The results of the study will allow to clarify the relationship between parental exposure to EDCs compounds and human reproduction.


Interaction of indomethacin and naproxen with gastric surface-active phospholipids: a possible mechanism for the gastric toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs).
The possibility that the molecular mechanism underlying the topical gastric irritancy of nonsteroidal anti-inflammatory drugs (NSAIDs) may involve alterations in the surface-active properties of gastric phospholipids was investigated. Indomethacin and naproxen were intragastrically administered to rats and the hydrophobicity of the luminal surface of the stomach wall was assessed by contact angle analysis. Both NSAIDs have the ability to attenuate the phospholipid-related hydrophobic properties of the gastric mucosa by more than 80-85% in a dose-dependent fashion. Potential molecular interactions between both NSAIDs and surface-active phospholipids were analyzed using fluorescent probes. Indomethacin has the ability to displace, in a dose-dependent manner, ANS (1-anilino-8-naphthalene sulphonate), a fluorescent anionic probe previously bound to the head group of phosphatidylcholine molecules. Estimations of the resonance fluorescence transfer between naproxen and the surface probe ANS or the hydrophobic probe, pyrene, bound to dipalmitoylphosphatidylcholine (DPPC) vesicles revealed that naproxen diffuses within the phospholipid bilayers. The dynamic of the gastric lipid material extracted from the surface scraping material (SSM) of the mucosa was altered by the NSAID as shown by the increase in the steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) (at 25 degrees, rSSM = 0.106+/-0.006, rssM + indomethacin = 0.137+/-0.005, and rSSM + naproxen = 0.133+/-0.007, P < 0.001). The thermodynamic behavior of a model bilayer containing DPPC was also perturbed by the NSAIDs tested. These results provide evidence that NSAIDs may reduce the ability of gastric surface-active phospholipids to form a hydrophobic protective layer.


Biodegradation of PCBs in contaminated water using spent oyster mushroom substrate and a trickle-bed bioreactor.
Due to their persistence, polychlorinated biphenyls (PCBs) represent a group of important environmental pollutants, but conventional physicochemical decontamination techniques for their removal are usually expensive. The main aim of this work was to develop a cost-effective method for PCB bioremediation, focusing on contaminated water and utilizing the well-known degradation capability of Pleurotus ostreatus (the oyster mushroom). For this purpose, the conditions of several laboratory-scale reactors (working volume 1 L) were optimized. Spent oyster mushroom substrate obtained from a commercial farm was used as a fungal inoculum and growth substrate. The highest degradation efficiency (87%) was recorded with a continuous low-flow setup, which was subsequently scaled up (working volume 500 L) and used for the treatment of 4000 L of real contaminated groundwater containing 0.1-1 μg/L of PCBs. This trickle-bed pilot-scale bioreactor was able to remove 82, 80, 65, and 30-50% of di-, tri-, tetra- and pentachlorinated PCB congeners, respectively. No degradation was observed for hexa- or heptachlorinated congeners. Multiple mono- and dichlorobenzoic acids (CBAs) were identified as transformation products by mass spectrometry, confirming the role of biodegradation in PCB removal. A Vibrio fischeri bioluminescence inhibition test revealed slight ecotoxicity of the primary reactor effluent (sampling after 24 h), which was quickly suppressed once the effluent passed through the reactor for the second time. Moreover, no other effluent exhibited toxicity for the rest of the experiment (71 days in total). Microbial analyses (phospholipid fatty acid analysis and next-generation sequencing) showed that P. ostreatus was able to degrade PCBs in the presence of an abundance of other fungal species as well as aerobic and anaerobic bacteria. Overall, this study proved the suitability of the use of spent oyster mushroom substrate in a bioremediation practice, even for pollutants as recalcitrant as PCBs.


A soluble androgen receptor in the cytoplasm of the male Mastomys prostate.
A steroid receptor protein was isolated from the cytoplasmic fraction of Mastomys prostate. Following in vivo and in vitro labelling of the tissue with tritiated testosterone or dihydrotestosterone, samples were analysed by gel exclusion chromatography or sucrose density gradient centrifugation. A steroid receptor complex was isolated on Sephadex G-200. Analysis of the steroids associated with this complex showed that the major part of the bound radioactivity was 5 alpha-dihydrotestosterone. The binding was inhibited by unlabelled testosterone and could not be demonstrated in the liver cytosol. Using sucrose density gradient centrifugation, the dihydrotestosterone receptor complex sedimented at 5.6 s together with heavier aggregates. In the presence of 0.4 M KCl a single complex was sedimented at 4.6 s. The results demonstrate a receptor protein in the cytosol of the Mastomys prostate which binds to dihydrotestosterone and is comparable to that of rat prostate.


Steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT) presenting as major depression.
Hashimoto's encephalopathy is a neuropsychiatric disease with symptoms of cognitive impairment, stroke-like episodes, seizures, and psychotic or affective symptoms associated with autoimmune thyroiditis and excellent steroid responsiveness; therefore, it is also called "steroid responsive encephalopathy associated with autoimmune thyroiditis" (SREAT). We present the case of a 50-year-old woman who developed a first-onset depressive syndrome with predominant cognitive impairment and inability to work. Antidepressive treatment and cognitive behavioral therapy over two years were unsuccessful. Neurological examination was unremarkable. Serum analysis showed increased thyroid peroxidase and thyroglobulin antibodies. Cerebrospinal fluid protein and albumin quotient were increased. Magnetic resonance imaging depicted unspecific, supratentorial white matter lesions and frontal accentuated brain atrophy. Electroencephalography was normal. Neuropsychological testing for attentional performance was below average. High-dose intravenous treatment with methylprednisolone over 5 days and oral dose reduction over 3 weeks led to the sustained improvement of clinical symptoms. Following discharge from the hospital, the patient returned to work, and 6.5 months after the start of therapy, no neuropsychological deficit remained. This case report illustrates that SREAT might present with purely depressive symptoms, thus mimicking classical major depression. In such cases, corticosteroid therapy may be an effective treatment option.


Cholinergic activation enhances retinoic acid-induced differentiation in the human NB-4 acute promyelocytic leukemia cell line.
The non-neuronal cholinergic system (NNCS) has been shown to play a role in regulating hematopoietic differentiation. We determined the expression of cholinergic components in leukemic cell lines by Western blotting and in normal leukocyte subsets by flow cytometry and found a heterogeneous expression of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), choline transporter (CHT), M3 muscarinic acetylcholine receptor (M3-mAChR) and α7 nicotinic acetylcholine receptor (α7-nAChR). We then evaluated NNCS role in differentiation of human NB-4 acute promyelocytic leukemia cell line and discovered a dramatic induction of M3-mAChR after all-trans retinoic acid (ATRA) treatment (p<0.0001). Adding carbachol which is a cholinergic agonist to the ATRA treatment resulted in an increase of a granulocytic differentiation marker (CD11b) as compared with ATRA treatment alone (p<0.05), indicating that cholinergic activation enhanced ATRA in inducing NB-4 maturation. The combination of carbachol and ATRA treatment for 72h also resulted in decreased viability and increased cleaved caspase-3 expression when compared with ATRA treatment alone (p<0.05). However, this combination did not cause poly (ADP-ribose) polymerase (PARP) cleavage. Overall, we have shown that NB-4 cells expressed M3-mAChR in a differentiation-dependent manner and cholinergic stimulation induced maturation and death of ATRA-induced differentiated NB-4 cells.


Effects of polyamine hydrochlorides and salts on phosphoprotein phosphatase.
Polyamine hydrochlorides, NaCl and magnesium acetate stimulated the enzymatic dephosphorylation of phosphorylated H2B histone by two forms (large form, mol. wt. 250 000; small form, mol. wt. 30 000) of a pig heart phosphoprotein phosphatase (phosphoprotein phosphohydrolase, EC 22.214.171.124). These ionic compounds stimulated the large form of the enzyme 5--9-fold but stimulated the small form of theenzyme only 2-fold. With phosphorylated H2B histone as substrate, these effectors caused an increase in both Km and V values of the two forms of the enzyme. On the other hand, when a tryptic phosphodecapeptide derived from phosphorylated H2B histone was used as substrate, these effectors were always inhibitory apparently non-competitively with respect to the substrate. Using phosphorylated H1 histone as substrate, these effectors stimulated the large form of the enzyme 2-fold but inhibited the small form. With phosphorylase a as substrate, the reactions were also inhibited by these effectors irrespective of the enzyme employed. With respect to phosphorylase a, this inhibition was apparently of a competitive type for the large form and a non-competitive type for the small form of the enzyme.


m-AMSA: a new anticancer agent.
4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA; NSC-249992) is a new anticancer agent that has undergone extensive experimental investigation. Clinical trials have recently been initiated and current data suggest a wide spectrum of antitumor activity in human cancer.


MR imaging and MR cholangiopancreatography in the preoperative evaluation of hilar cholangiocarcinoma: correlation with surgical and pathologic findings.
The primary aim was to evaluate delayed contrast-enhanced MRI in depicting perineural spread of hilar cholangiocarcinoma (CCC) and consequently to determine the capability of MRI/MRCP for staging CCC. Fifteen patients that underwent MRI/MRCP and surgical treatment were retrospectively included. Two radiologists evaluated MR images to assess delayed periductal enhancement, extent of bile duct stenosis, liver parenchymal and vascular involvement and presence of liver atrophy. An agreement between delayed enhancement of the bile duct walls and perineural neoplastic spread showed a very good correlation factor (0.93). The overall accuracy in detecting biliary neoplastic invasion was higher for delayed T1-weighted images (93.3%) than for the MRCP images (80%), and T1-delayed image increased the MR accuracy in assessing the neoplastic resectability (p<0.05). MRI correctly predicted vascular involvement in 73% and liver involvement in 80% of the cases. The number of overall correctly assessed patients with regard to resectability was 11 true positive, 1 false positive and 3 true negative. The combination of MRI/MRCP is a reliable diagnostic method for staging hilar cholangiocarcinomas. Delayed periductal enhancement is accurate in the evaluation of neoplastic perineural spread, and it can improve diagnostic accuracy to identify resectable and unresectable tumours.


Clients' perceptions of how reorientation therapy and self-help can promote changes in sexual orientation.
Presented is a summary of 882 homosexual people's responses to 5 open-ended questions about sexual reorientation therapy. Of the 882 participants, 726 reported that they had received reorientation therapy from a professional therapist or a pastoral counselor. As a group, 779 (89.7%) of the participants viewed themselves as "more homosexual than heterosexual," "almost exclusively homosexual," or "exclusively homosexual" in their orientation before receiving reorientation therapy or making self-help efforts to change. The majority reported they believed sexual reorientation therapy and various forms of self-help were helpful to them, psychologically, spiritually, and sexually.


Neuromuscular patterns of stereotypic hindlimb behaviors in the first two postnatal months. II. Stepping in spinal kittens.
From birth to postnatal day 60, neuromuscular patterns for airstepping and treadmill stepping were assessed in kittens spinalized (T12) at birth (Day-1) or at the end of the second postnatal week (Day-14). Within 72 h after spinalization, all kittens displayed stepping motions, but exteroceptive facilitation (e.g. tail pinch) was required to initiate and sustain both behaviors. In Day-14 spinal kittens, the hindlimbs spontaneously and alternately airstepped, but in Day-1 spinal kittens exteroceptive stimulation was usually necessary to evoke airstepping, and the hindlimbs stepped synchronously. Kittens in both groups developed atypical neuromuscular patterns; flexor bursts were nearly twice as long in duration as extensor bursts. Development of bipedal treadmill stepping was similar for Day-1 and Day-14 spinal kittens, but differed from that for normal kittens. Tested at the same belt speeds, stepping was more easily elicited in spinal kittens, bouts of repetitive stepping were longer, and cycle periods were shorter than in normal kittens until postnatal week 6. Spinal kittens, however, seldom exhibited adequate weight support during hindlimbs stepping, and the neuromuscular patterns associated with bipedal stepping were atypical. For spinal kittens, the relationship between the extensor burst duration and the cycle period was reduced substantially, and flexor activity was initiated earlier in the step cycle and was longer in duration than that for normal kittens. These atypical intralimb synergies may have been the consequence of altered lumbosacral circuits produced by the spinal transection. It is also possible that these spinal circuits, lacking rostral input, were particularly susceptible to abnormal motion-dependent feedback resulting from reduced hindlimb weight support.


Triphasic waveforms are superior to biphasic waveforms for transthoracic defibrillation: experimental studies.
Our objective was to evaluate the efficacy of triphasic waveforms for transthoracic defibrillation in a swine model. Triphasic shocks have been found to cause less post-shock dysfunction than biphasic shocks in chick embryo studies. After 30 s of electrically induced ventricular fibrillation (VF), each pig in part I (n = 32) received truncated exponential biphasic (7.2/7.2 ms) and triphasic (4.8/4.8/4.8 ms) transthoracic shocks. Each pig in part II (n = 14) received biphasic (5/5 ms) and triphasic shocks (5/5/5 ms). Three selected energy levels (50, 100, and 150 J) were tested for parts I and II. Pigs in part III (n = 13) received biphasic (5/5 ms) and triphasic (5/5/5 ms) shocks at a higher energy (200 and 300 J). Although the individual pulse durations of these shocks were equal, the energy of each pulse varied. Nine pigs in part I also received shocks where each individual pulse contained equal energy but was of a different duration (biphasic 3.3/11.1 ms; triphasic 2.0/3.2/9.2 ms). Triphasic shocks of equal duration pulses achieved higher success than biphasic shocks at delivered low energies: <40 J: 38 +/- 5% triphasic vs. 19 +/- 4% biphasic (p < 0.01); 40 to <50 J: 66 +/- 7% vs. 42 +/- 7% (p < 0.01); and 50 to <65 J: 78 +/- 4% vs. 54 +/- 5% (p < 0.05). Shocks of equal energy but different duration pulses achieved relatively poor success for both triphasic and biphasic waveforms. Shock-induced ventricular tachycardia (VT) and asystole occurred less often after triphasic shocks. Triphasic transthoracic shocks composed of equal duration pulses were superior to biphasic shocks for VF termination at low energies and caused less VT and asystole.


Management, administration, leadership: what's in a name?
In summary, I have argued that while research and publications in the field have tended to deal with management and administration--examining issues as if they were predominately structural, organizational and authority-oriented, the area that cries out for further attention is that of leadership. For, while managers can do, and administrators oversee--it is only leaders who can move us ahead. The field is in for a turbulent, difficult, but I suspect, exhilarating next new years. Our work is truly very different from that in most businesses--and while good "managers" may make money for business enterprises, for us, leadership is the critical ingredient. (I'm not even so sure that despite some experts disclaimer of the lack of importance of leadership in business, a closer look would not inevitably reveal a Kroc, Hewlett, DiLorenzo or Iacocca behind every successful corporate initiative anyway). With that in mind, we should increase both our study of the development of leaders and our attention to their development. To do less is to increase our difficulties, court further new disasters, and have even less control over our work and our future. We deserve and can achieve a better destiny.


Dietary intake and food sources of whole grains among US children and adolescents: data from the 1994-1996 Continuing Survey of Food Intakes by Individuals.
This study characterizes whole grain consumption among a nationally representative sample of US children and adolescents. Data used in this study were collected as part of the 1994-1996 US Department of Agriculture Continuing Survey of Food Intakes by Individuals (CSFII). CSFII was designed to obtain a nationally representative sample of noninstitutionalized persons of all ages residing in the United States. Analyses reported in this article are limited to participants aged 2 to 18 years with two days of dietary recall data (n=4,802). Foods reported in the survey were quantified in servings as defined by the Food Guide Pyramid using the US Department of Agriculture Pyramid Servings Database, which contains reference data for each food reported in CSFII in servings per 100 g for 30 Pyramid food groups, including whole grain and total grain. Means, frequencies, and logistic regression analyses were conducted as appropriate. Average whole grain intake ranged from 0.8 servings per day for preschool-aged children to 1.0 servings per day for adolescents. Ready-to-eat cereals, corn and other chips, and yeast breads were found to be the major food sources of whole grains accounting for 30.9%, 21.7%, and 18.1% of whole grain intake respectively among those aged two to 18 years. Given the apparent low level of whole grain intake among most children and adolescents in the United States, interventions are needed to increase intake of whole-grain foods.


New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: design, synthesis, crystal structures, and biological evaluation.
Mur ligases (MurC-MurF), a group of bacterial enzymes that catalyze four consecutive steps in the formation of cytoplasmic peptidoglycan precursor, are becoming increasingly adopted as targets in antibacterial drug design. Based on the crystal structure of MurD cocrystallized with thiazolidine-2,4-dione inhibitor I, we have designed, synthesized, and evaluated a series of improved glutamic acid containing 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD with IC(50) values up to 28 μM. Inhibitor 37, with an IC(50) of 34 μM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128 μg/mL. High-resolution crystal structures of MurD in complex with two new inhibitors (compounds 23 and 51) reveal details of their binding modes within the active site and provide valuable information for further structure-based optimization.


Nelarabine-induced peripheral and central neurotoxicity: can sequential MRI brain imaging help to define its natural history?
A 14-year-old boy with relapsed T cell acute lymphoblastic leukaemia received reinduction chemotherapy that included nelarabine, a purine nucleoside analogue known to cause dose-dependent neurotoxicity. Although he achieved aminimal residual disease negative remission after two cycles of chemotherapy he also developed severe, progressive peripheral and central neurotoxicities. Loss of grey-white differentiation was seen on a T2-weighted magnetic resonance imaging brain scan. This unusual clinical picture and previously unreported radiological findings are thought to be due to nelarabine toxicity. He was bridged with 6-mercaptopurine while transplant was deferred pending sustainable neurological improvement. This case posed clinical and ethical dilemmas while demonstrating previously unreported radiological features.


Evaluation of motor and sensory neuron populations in a mouse median nerve injury model.
Peripheral nerves can regenerate and restore function after injury but this process is hindered by many factors including chronic denervation, motor end-plate resorption and Schwann cell senescence. Forelimb injury models in rodents are becoming increasingly popular as they more accurately reflect the physiology and biomechanics of upper extremity nerve injuries. However several aspects of this surgical model remain poorly characterized. C57Bl/6 mice underwent enumeration of median nerve motor and sensory neuron pools using retrograde labeling with or without nerve transection. Distal histomorphometry of uninjured mouse median nerves was also examined. Baseline reference values of volitional forelimb grip strength measurements were determined and the rate of neural elongation was also estimated. We identified 1363 ± 165 sensory and 216 ± 16 motor neurons within the uninjured dorsal root ganglia (DRG) and ventral spinal cord, respectively. Eight days following injury, approximately 34% of motoneurons had elongated a distance of 5 mm beyond the repair site 8 days following injury. Volitional grip strength decreased 50% with unilateral median nerve transection and was negligible with contralateral flexor tendon tenotomy. Our spinal cord and DRG harvesting technique presented here was technically straightforward and reliable. Estimates of motor and sensory neuron numbers for the mouse median nerve compared favourably with studies using intramuscular injection of retrograde neurotracer. Histomorphometry data was consistent with and reinforced reference values in the literature. This study provides data that further develops an increasingly popular surgical model for studying peripheral nerve injury and repair.


Effect of continuous illumination on secretion of pregnane compounds by the rat ovary.
Differences in the secretion of pregnane compounds from rats with follicular polycystic ovaries under constant light and with normal preovulatory ovaries under light-dark conditions were compared. The injection of LH greatly increased the secretion of progesterone. 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one, in both types of ovaries, but the response of the two progesterone metabolites in the polycystic ovaries was low, suggesting low 5 alpha-reductase activity.


GSAMDA: a computational model for predicting potential microbe-drug associations based on graph attention network and sparse autoencoder.
Clinical studies show that microorganisms are closely related to human health, and the discovery of potential associations between microbes and drugs will facilitate drug research and development. However, at present, few computational methods for predicting microbe-drug associations have been proposed. In this work, we proposed a novel computational model named GSAMDA based on the graph attention network and sparse autoencoder to infer latent microbe-drug associations. In GSAMDA, we first built a heterogeneous network through integrating known microbe-drug associations, microbe similarities and drug similarities. And then, we adopted a GAT-based autoencoder and a sparse autoencoder module respectively to learn topological representations and attribute representations for nodes in the newly constructed heterogeneous network. Finally, based on these two kinds of node representations, we constructed two kinds of feature matrices for microbes and drugs separately, and then, utilized them to calculate possible association scores for microbe-drug pairs. A novel computational model is proposed for predicting potential microbe-drug associations based on graph attention network and sparse autoencoder. Compared with other five state-of-the-art competitive methods, the experimental results illustrated that our model can achieve better performance. Moreover, case studies on two categories of representative drugs and microbes further demonstrated the effectiveness of our model as well.


Topical cooling for myocardial protection: the results of a prospective randomized study of the "shallow technique".
Respiratory distress following cardiac surgery is a troublesome complication. In several cases it is associated to cool-related phrenic nerve injury (PNI) after adoption of iced slush or hypothermic cardiopulmonary bypass. We compare two different strategies for myocardial protection: the "shallow technique" (ST) (dripping and prompt removal of cold saline solution from the epicardial surface) plus normothermic cardiopulmonary bypass, versus mild hypothermic cardiopulmonary bypass plus iced slush. Two hundred forty-nine patients undergoing elective cardiac surgery were randomly assigned to receive either ST (Group A) or iced slush (Group B). Occurrence of postoperative PNI (abnormal diaphragmatic movement plus alteration of nerve conduction) was evaluated. Multivariate analysis was performed for identification of factors associated to PNI. Patients had a 6-month follow-up. PNI and failure of extubation occurred more frequently in Group B (p = 0.009 and p = 0.034, respectively), but there was no statistically significant difference in mean intensive care unit stay. Diabetes and the use of iced slush were independent predictors of phrenic dysfunction, while internal thoracic artery (ITA) harvest was a significant risk factor only among Group B patients. Abnormal diaphragmatic movement was persistent at 6 months only in 30% of Group B individuals who suffered this complication in the early postoperative. ST likely reduces the incidence of postoperative PNI and might be protective mainly in the event of ITA harvest. It should be considered as a valuable tool for myocardial protection protocols.


Surgical therapy for supraventricular tachycardia, a potentially curable disorder.
One hundred fifty-six patients underwent investigation and operation for supraventricular tachycardia: 145 had attempts at curative operations and 11 had His bundle section. Operative mortality was 0.68% and there were no late deaths among patients having curative operations. One patient died suddenly 1 year after His bundle section. All patients underwent electrophysiologic study before discharge and 6 months postoperatively. A satisfactory result, without supraventricular tachycardia and without medication, was achieved in 96.5% of all patients. Ninety-three percent have no supraventricular tachycardia and no demonstrable reentrant pathway at electrophysiologic study. All free wall accessory atrioventricular connections were divided and 97.7% of the patients were cured. Ninety percent of patients with posterior septal accessory atrioventricular connections had a satisfactory result, with cure demonstrated at late electrophysiologic study in 84%. Fifteen patients with atrioventricular junctional reentrant tachycardia were all cured, with preservation of normal atrioventricular conduction. Eight (88%) of nine patients with right atrial tachycardia were cured, and two patients with nodoventricular fibers and one patient with incessant atrioventricular junctional tachycardia had satisfactory results. Supraventricular tachycardia is now a potentially curable disorder when managed by low risk surgical procedures that offer a high cure rate.


Factors controlling the appearance of the immunofluorescent nuclear dots revealed with monoclonal antibody against microtubule-associated protein-1.
A monoclonal antibody raised against microtubule-associated protein-1 (MAP-1) binds to nuclei of normal human fibroblasts, its binding site being detected as intranuclear immunofluorescent dots. The percentage of cells showing these dots increased with insulin, hydrocortisone, epidermal growth factor (EGF), and transferrin in serum-free medium, their effects decreasing in this order. The appearance of dots induced by serum or insulin plus hydrocortisone was dependent on the Ca2+ concentration of the medium. The Ca2+ ionophore A23187 increased the rate of appearance of cells containing dots. Conversely, the calmodulin inhibitor W-7 blocked their appearance and decreased the number of cells containing dots. The dose-response curves of W-7 for inhibition of the appearance of dots and of DNA synthesis were essentially identical. These results suggest that the appearance of intranuclear MAP-1 antigen is controlled mainly by insulin, Ca2+ and calmodulin and is associated with DNA replication.


Intestinal absorption mechanisms of prenylated flavonoids present in the heat-processed Epimedium koreanum Nakai (Yin Yanghuo).
The purpose is to determine absorption mechanism of five bioactive prenylated flavonoids (baohuoside I, icariin, epimedine A, B, and C) present in heat-processed Epimedium koreanum Nakai (Yin Yanghuo). Transport of five prenylated flavonoids present in heat-processed herbs were studied in the human intestinal Caco-2 model and the perfused rat intestinal model. In the perfused rat intestinal model, prenylated flavonoids with a monoglucosidic bond (e.g., icariin) was rapidly hydrolyzed into corresponding metabolites (e.g., baohuoside I). In the Caco-2 model, apical to basolateral permeability of a monoglycoside baohuoside I (1.46 x 10(-6) cm/sec) was more than 2 folds greater than four prenylated flavonoids with 2 or more sugar moieties (<0.6 x 10(-6) cm/sec). The slow apical to basolateral transport of baohuoside I was the result of efflux. This efflux was carrier-mediated and active since its transport was vectorial, concentration- and temperature-dependent with activation energies greater than 15 kcal/mol. Efflux of baohuoside I was significantly suppressed by inhibitors of BCRP and MRP2, whereas efflux of icariin was significantly inhibited only by p-glycoprotein inhibitor verapamil. Because YHH is often heat-processed for better efficacy, we determined and found the optimal condition for increasing contents of more bioavailable flavonoids (i.e., baohuoside I) to be 160-170 degrees C for 5-7 min. Poor bioavailability of prenylated flavonoids results from their poor intrinsic permeation and transporter-mediated efflux. Heat processing parameters may be optimized to preserve the herb's bioavailable flavonoids, which help retain and improve its efficacy during processing.


HPLC-fluorescence determination of bile acids in pharmaceuticals and bile after derivatization with 2-bromoacetyl-6-methoxynaphthalene.
2-Bromoacetyl-6-methoxynaphthalene was used as a pre-chromatographic fluorescent labelling reagent for the high-performance liquid chromatographic (HPLC) analysis of bile acids. The derivatization reaction was performed in an aqueous medium in the presence of tetrahexylammonium bromide by ultrasonication at 40 degrees C to give fluorescent esters which were separated by reversed-phase HPLC and detected fluorimetrically (lambda ex = 300 nm, lambda em = 460 nm). Applications to the determination of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) in their pharmaceutical formulations are described. The method was also applied to the determination of free and conjugated bile acids in human bile samples.


Nuclear omnipotent suppressors of premature termination codons in mitochondrial genes affect the 37S mitoribosomal subunit.
nam3 and R705, yeast nuclear omnipotent suppressors of mitochondrial mit- mutations, reverse the superimposed spectrum of trans-recessive splicing defects by affecting the protein composition of the small mitoribosomal subunit. Analysis of the suppressor's interaction suggests that suppression results from mutations in the mitoribosomal polypeptides. These data indicate an obligatory connection between mitoribosome function and splicing of introns bI2, bI4 and aI1 in yeast mitochondria.


Persistence of SARS-CoV-2 RNA in post-mortem swab 35 days after death: A case report.
Post-mortem swabs for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA detection have been recommended by several Scientific Committees and Institutions as a standard procedure for post-mortem assessment of potential Coronavirus Disease-19 (COVID-19) related deaths. To date there is no data about the SARS-CoV-2 RNA detectability period in human bodies after death. The present case documents the persistence of SARS-CoV-2 RNA in the upper respiratory tract 35-days after death. Post-mortem swabs could be used as a valuable tool in preventive evaluation of the risks-benefits ratio associated with autopsy execution. SARS-CoV-2 RNA post-mortem detection could have a key diagnostic role in deaths lacking medical assistance, unattended deaths, and patients with multiple comorbidities. Based on the present report, staged post-mortem swabs should be performed even after a long post-mortem interval.


The effects of nerve growth factor and dibutyryl cyclic AMP on cytoskeletal densities in cultured sensory ganglia.
The effects of nerve growth factor (NGF) and dibutyryl cyclic AMP (DBC) on the density of cytoskeletal structures in cultured dorsal root ganglia were examined using morphometric techniques. After 24 hr in culture, NGF-treated neurites were longer than either DBC-treated or control neurites. At 48 hr, neurites produced in response to NGF and DBC were of equivalent length, while controls were considerably shorter. Comparison of electron micrographs of neuritic profiles revealed some differences of area and cytoskeletal density between treatment groups. Morphometric analysis was used to determine these differences under several growth conditions, at various rates of elongation and at different neurite lengths. As shown by analysis of variance, both NGF-treated and control neurites tapered in diameter at 48 hr in vitro, while DBC-induced neurites increased in area. An increase in cytoskeletal density for all treatment groups indicated that density was not always correlated with changes in area. An increased density of microtubules as compared to neurofilaments was seen at 24 hr, with equal densities of both cytoskeletal elements present after 48 hr in vitro. Comparisons between individual groups of data indicated that NGF-treated neurites relied primarily on microtubular density at 24 hr in vitro, when NGF induced longer, faster growing neurites. At 48 hr, there was an increase in neurofilaments proximal to the explant in the presence of DBC, implying that DBC may cause increased synthesis and/or transport of these structures. A comparison of microtubule to neurofilament ratios indicated that at 24 hr, there was always a greater density of microtubules. However, after 48 hr, neurofilament density increased such that there were equivalent densities of both cytoskeletal elements, possibly due to the overall increase in length observed in each treatment group. These data imply that 1) neurites with different rates of elongation may exhibit differences in cytoskeletal density; 2) neurites of equivalent lengths may be of differing stabilities; 3) NGF and DBC produce neurites with different cytoskeletal densities, implying divergent mechanisms of neurite induction; 4) the presence or absence of NGF may be partially responsible for variations in cytoskeletal densities observed between peripheral and central processes of DRG during development.


Burnout in Surgical Residents of Underrepresented in Medicine Backgrounds: Key Influencing Factors and Possible Solutions.
Alarming rates of burnout in surgical training pose a concern due to its deleterious effects on both patients and providers. Datum remains lacking on rates of burnout in surgical residents based on race and ethnicity. This study aims to document the frequency of burnout in surgical residents of racially underrepresented backgrounds and elucidate contributing factors. A 35-question anonymized survey was distributed to general surgery residents from 23 programs between August 2018 and May 2019. This survey was designed from the validated Maslach Burnout Inventory, and included additional questions assessing participant demographics, educational, and social backgrounds. Responses were analyzed utilizing chi-square tests and Wilcoxon rank sum tests. There was also a free response portion of the survey which was evaluated using thematic analysis. We received 243 responses from 23 general surgery programs yielding a 9% (23/246) program response rate and 26% (243/935) response rate by surgical residents. One hundred and eighty-five participants (76%) identified as nonunderrepresented in medicine and 58 (24%) of participants identified as underrepresented in medicine. Fifty-three percent were male and 47% female. Overall, sixty-six percent of all surgical residents (n = 161) endorsed burnout with racially underrepresented residents reporting higher rates of burnout at 76% compared to 63% in their nonunderrepresented counterparts (P = 0.07). Although the generalizability of these results is limited, higher rates of reported burnout in racially underrepresented trainees noted in our study illuminates the need for continual dialogue on potential influencing factors and mitigation strategies.


Trends in the consumption of attention deficit hyperactivity disorder medications in Castilla y León (Spain): changes in the consumption pattern following the introduction of extended release methylphenidate.
Attention deficit hyperactivity disorder (ADHD) is the most diagnosed behavioural disorder in children and adolescents; prevalence has been estimated around 5%. Studies have shown an increase in the use of ADHD medications during the last years. The aim of the present study was to learn the pattern and the evolution of ADHD medication consumption in Castilla y León (Spain). Consumption data for the period 1992-2009 were obtained from databases containing information upon consumption and cost of medications dispensed by pharmacies at the expense of the Spanish National Health System. The data were expressed in defined daily doses (DDDs) per 1000 inhabitants per day (DDD/1000 inhabitants/day). A model to forecast consumption was built. Attention deficit hyperactivity disorder medication consumption increased in Castilla y León from 0.1 DDD/1000 inhabitants/day in 1992 to 1.5 DDD/1000 inhabitants/day in 2009; expected consumption will reach 2.5 DDD/1000 inhabitants/day by 2013. The drugs accounting for this increase were mainly made up of methylphenidate preparations (1.4 DDD/1000 inhabitants/day in 2009). From 1992 to 1999, there was a slight reduction in methylphenidate use; following amphetamine withdrawal, the consumption of stimulants began to increase, and figures showed a sharp rise after marketing of extended-release formulations in 2003. There has been an enormous increase in ADHD medication consumption in Castilla y León in the last few years; increase rocketed when extended-release methylphenidate was marketed. A rapid increase in the consumption is a warning on possible overdiagnosis and inappropriate prescription.


Flexible three-dimensional artificial synapse networks with correlated learning and trainable memory capability.
If a three-dimensional physical electronic system emulating synapse networks could be built, that would be a significant step toward neuromorphic computing. However, the fabrication complexity of complementary metal-oxide-semiconductor architectures impedes the achievement of three-dimensional interconnectivity, high-device density, or flexibility. Here we report flexible three-dimensional artificial chemical synapse networks, in which two-terminal memristive devices, namely, electronic synapses (e-synapses), are connected by vertically stacking crossbar electrodes. The e-synapses resemble the key features of biological synapses: unilateral connection, long-term potentiation/depression, a spike-timing-dependent plasticity learning rule, paired-pulse facilitation, and ultralow-power consumption. The three-dimensional artificial synapse networks enable a direct emulation of correlated learning and trainable memory capability with strong tolerances to input faults and variations, which shows the feasibility of using them in futuristic electronic devices and can provide a physical platform for the realization of smart memories and machine learning and for operation of the complex algorithms involving hierarchical neural networks.High-density information storage calls for the development of modern electronics with multiple stacking architectures that increase the complexity of three-dimensional interconnectivity. Here, Wu et al. build a stacked yet flexible artificial synapse network using layer-by-layer solution processing.


Therapeutic potential of low-intensity ultrasound (part 1): thermal and sonomechanical effects.
In this first part of the review, we will focus on and discuss various aspects of low-intensity ultrasound (US), with emphasis on mild thermal effects, apoptosis induction, and sonomechanical effects. Mild thermal effects of US have been commonly applied to physical therapy. Though US has clear beneficial effects, the advantage of using US over other heating modalities remains unclear. US has also been used in vivo and clinically in the treatment of wounds and fractures, with promising results. On the biomolecular level, studies have shown that US can induce apoptosis and that certain conditions can provide optimal apoptosis induction. As to potential therapeutic applications, in addition to the thermal and other physical effects, apoptosis induction by US may offer direct and rapid treatment of tumors or cancer tissues. Technological advances and rapidly accelerating research in this field are providing an ever-increasing array of therapeutic options for lowintensity US.


[1-14C]Ethanol breath test in alcoholic liver disease.
The activity of ethanol metabolising enzymes was assessed in 51 patients with alcoholic and non-alcoholic liver disease using tracer doses of [1-14C]ethanol and measuring 14CO2 excretion in the breath. Alcoholic patients with only fatty infiltration of the liver showed significantly increased activity compared with controls. Comparing alcoholic patients with cirrhosis and a serum albumin greater than 28 g/l, activity in those with a recent history of continued heavy drinking was significantly greater than in patients who had abstained from alcohol. In addition, both groups of alcoholic cirrhosis showed significantly more activity than patients with non-alcoholic cirrhosis. The activities of patients with acute alcoholic or viral hepatitis were normal when their prothrombin times were less than 7 sec prolonged, but were reduced when prolongation exceeded 7 sec. These results demonstrate that in chronic alcoholic liver disease, even with cirrhosis, alcohol can still increase the activity of ethanol oxidising enzymes provided hepatic function remains adequate. However, this response is lost in acute liver damage and in chronic alcoholic disease with severe hepatic dysfunction.


Molecular cloning of polyoma virus DNA in Escherichia coli: plasmid vector system.
A series of recombinant plasmids containing polyoma virus (PY) DNA were constructed, and their biological activity was evaluated in mice and in cultured mouse cells. While all of the recombinants studied contain the complete, potentially infectious viral DNA, in no case was the intact recombinant PY-plasmid DNA, or live Escherichia coli containing the recombinant plasmids, capable of inducing PY infection of mice, either by feeding or by parenteral injection.


Inguinal hernia in very low-birthweight infants: Follow up to adolescence.
This study reviewed the medical records of very low-birthweight infants (VLBWI) followed up to adolescence, with emphasis on inguinal hernia (IH), to discuss the ideal time for IH repair in VLBWI. Medical records from 274 VLBWI treated in the neonatal intensive care unit (NICU) between 1994 and 1999 were collected retrospectively. Outpatient data after NICU discharge were included. Additionally, a follow-up study was undertaken via questionnaire sent to the families of VLBWI in 2011. During NICU hospitalization, IH was diagnosed in 39 of 274 VLBWI, and two developed incarceration. Thirty-eight VLBWI were discharged with known hernia, and elective repair was performed in 19. Three developed incarceration before elective repair at the mean age of 316 days. In the remaining 18 cases of IH, spontaneous regression occurred at a mean age of 180 days and repair was not performed. New IH appeared in 25 VLBWI after NICU discharge. The high incidence of IH in VLBWI was confirmed during follow up to adolescence. The rate of incarceration was low and the incidence of spontaneous regression was high. Observation up to 6 months without surgery, with the expectation of spontaneous regression, is one option to avoid unnecessary surgery, but repair should be performed before 10 months to reduce the risk of incarceration. Further large, prospective, and randomized controlled studies with a long follow up are necessary to validate the present results and to define the ideal time for IH repair in VLBWI.


Comparing the role of Ginkgolide B and Ginkgolide K on cultured astrocytes exposed to oxygen‑glucose deprivation.
Ginkgolide B (GB) and ginkgolide K (GK) are two main active monomers of ginkgolides that present a unique group of diterpenes found naturally in the leaves of the Ginkgo biloba tree. Astrocytes are the most abundant cell type within the central nervous system (CNS) and serve essential roles in maintaining healthy brain function. The present study compared the biological effects of GB and GK on astrocytes exposed to oxygen‑glucose deprivation (OGD). The results demonstrated that GB and GK exhibit many different actions. The level of the platelet‑activating factor (PAF) was elevated on astrocytes exposed to OGD, and inhibited by GB and GK treatment. Although GB and GK inhibited the expression of p‑NF‑κB/p65, GK exerted stronger anti‑inflammatory and antioxidant effects on astrocytes exposed to OGD than GB by inhibiting interleukin (IL)‑6 and tumor necrosis factor‑α, and inducing IL‑10 and the nuclear factor‑erythroid 2‑related factor 2/HO‑1 signaling pathway. When compared with GB treatment, GK treatment maintained high levels of phosphoinositide 3‑kinase/phosphorylated‑protein kinase B expression, and induced a marked upregulation of Wnt family member 1 and brain derived neurotrophic factor, indicating that GK, as a natural plant compound, may have more attractive prospects for clinical application in the treatment of neurological disorders than GB.


2,4-Diamino-N10-methylpteroic acid (DAMPA) crystalluria in a patient with osteosarcoma treated with carboxypeptidase-G2 rescue after high-dose methotrexate-induced nephrotoxicity.
High-dose methotrexate (HDMTX) therapy is a key component of many chemotherapy protocols. However, some patients develop HDMTX-induced nephrotoxicity. Carboxypeptidase-G2 (CPDG2) hydrolyses MTX into 2,4-diamino-N10-methylpteroic acid (DAMPA) and glutamic acid, and is used as a rescue agent in patients with nephrotoxicity and delayed elimination. Despite the frequency of HDMTX-induced renal injury, crystalluria is uncommon. Furthermore, crystals are rarely identified by conventional chemical methods. To determine the composition of crystalluria in a patient with osteosarcoma who was treated with CPDG2. Crystalluria was evaluated by optical microscopy, and chemical identification was performed by Fourier-transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM) and Orbitrap™ high-resolution mass spectrometry (HRMS). The HRMS spectra of the patient's urine sediment showed a main peak at m/z 326.13, corresponding to the molecular mass of DAMPA [(C15H15O2N7) + H+]. The FT-IR spectral patterns of the sediment and DAMPA were not identical. SEM was unable to identify the crystal. DAMPA crystalluria was identified by Orbitrap™ HRMS in a patient treated with CPDG2 after HDMTX nephrotoxicity. This case reinforces the need to implement adequate measures to prevent nephrotoxicity. In cases of HDMTX-induced nephrotoxicity, urine sediment analysis should be requested.


Safety of percutaneous transfemoral coronary and peripheral procedures via aortofemoral synthetic vascular grafts.
Our objective was to evaluate the safety of percutaneous transfemoral catheterization performed by way of synthetic aortofemoral vascular grafts. Between 1994 and 2003, 123 catheterization procedures were performed using a synthetic aortofemoral graft (median graft age 2.5 years, range 4 days to 10.3 years), including 63 (51%) interventional and 60 (49%) diagnostic procedures. Adverse events related to vascular access occurred in 7 of 123 procedures (5.7%), including blood transfusion (4.1%), thrombotic occlusion (1.6%), transient limb ischemia (0.8%), and retroperitoneal hemorrhage (0.8%). No deaths, graft infections, or pseudoaneurysms occurred.


Publisher Correction: Evoking and tracking zebrafish eye movement in multiple larvae with ZebEyeTrack.
The version of this paper originally published contained the following text errors: (1) In the abstract, "(ii) visual stimulation with moving bars; (ii) eye detection and tracking, as well as general motion detection" should have been "(ii) visual stimulation with moving bars; (iii) eye detection and tracking, as well as general motion detection." (2) In the legend for Table 1, "vertical pixel coordinate; LE, left eye; RE, right eye; x, horizontal pixel coordinate; y" should have read "LE, left eye; RE, right eye; x, horizontal pixel coordinate; y, vertical pixel coordinate." These errors have been corrected in the HTML and PDF versions of the paper.


Complex association of apolipoprotein E-containing HDL with coronary artery disease burden in cardiovascular disease.
BackgroundAlthough traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed.MethodsIn a prospective, observational study, 795 individuals had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E-containing HDL-cholesterol (ApoE-HDL-C). Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiography (CCTA) characterization of total burden, noncalcified burden (NCB), and fibrous plaque burden (FB) was performed in a subcohort (n = 300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured.ResultsMost patients had a clinical diagnosis of coronary artery disease (CAD) (n = 80.4% of 795), with mean age of 59 years, a majority being male (57%), and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P < 0.001), with higher CAC as compared with high ApoE-HDL-C. On quantitative CCTA, the high ApoE-HDL-C group had lower NCB (β = -0.24, P = 0.0001), which tended to be significant in a fully adjusted model (β = -0.32, P = 0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (β = 0.31; P = 0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P = 0.0001) in a fully adjusted model.ConclusionApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity.Trial RegistrationClinicalTrials.gov: NCT01621594.FundingThis work was supported by the NHLBI at the NIH Intramural Research Program.


Clonality testing of lymphoproliferative disorders in a large cohort of primary and consultant biopsies.
Lymphoproliferative disease often presents the clinician and pathologist with a diagnostic dilemma, particularly in the early course of the disease. We used modified BIOMED-2 protocols to detect monoclonal expansions of immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) genes in 957 formalin-fixed paraffin-embedded samples from 717 patients. To eliminate false-positive results, heteroduplex analysis was used after PCR reactions. The impact of different fixatives on DNA quality and performance of PCR was assessed. In the class of B lymphomas we detected clonal IgH rearrangement in nearly 80% of cases and in the class of T lymphomas in 64% of cases. Performance of the assays was 94.7% and 92.5% for IgH and TCR clonality, respectively. Clonality rates in various B and T lymphomas were in concordance with previous studies. We also present 10 difficult cases where PCR analysis of IgH and TCR gene rearrangements significantly contributed to a decision on the correct diagnosis. These results confirm that the PCR-based analysis is suitable as a routine method and is helpful in establishing a diagnosis in morphologically unclear cases.


Reactive Persulfides from Salmonella Typhimurium Downregulate Autophagy-Mediated Innate Immunity in Macrophages by Inhibiting Electrophilic Signaling.
Reactive persulfides such as cysteine persulfide and glutathione persulfide are produced by bacteria including Salmonella during sulfur metabolism. The biological significance of bacterial reactive persulfides in host-pathogen interactions still warrants investigation. We found that reactive persulfides produced by Salmonella Typhimurium LT2 regulate macrophage autophagy via metabolizing 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), an electrophilic product of reactive oxygen species and nitric oxide signaling. 8-Nitro-cGMP signaling was required for efficient autophagy-mediated clearance of Salmonella from infected macrophages. In the infected cells, 8-nitro-cGMP caused cGMP adduct formation (S-guanylation) of bacterial surface proteins, which triggered recruitment of autophagy-related proteins p62 and LC3-II to the intracellular bacteria. We also found that Salmonella-produced reactive persulfides downregulated this autophagy by decreasing cellular 8-nitro-cGMP content, thereby inhibiting electrophilic signaling. These data reveal a pathogenic role of bacteria-derived reactive persulfides via suppression of anti-bacterial autophagy.


Pharmacist-driven antimicrobial stewardship interventions in patients with COVID-19: a scoping review.
Coronavirus Disease 2019 (COVID-19) is a highly infectious disease that can be treated with antivirals in addition to other antimicrobials in cases of secondary or concomitant infections. This creates potential for antimicrobials misuse, which increases antimicrobial resistance (AMR). Pharmacists are known to undertake prominent roles in combatting AMR. The aim of this review was to characterize pharmacist-driven interventions that have been performed in patients with COVID-19 globally and describe their impact on antimicrobial use. We followed the Joanna Briggs Institutes manual framework for scoping reviews in our study. Studies that reported antimicrobial stewardship (AMS) interventions performed by pharmacists in COVID-19 patients were included. Articles that did not report outcomes or did not mention pharmacists in the intervention were excluded. Restrictions included English-only articles from inception date until June 2022. Articles were searched from four databases. Eleven publications were included in the review. The most common AMS intervention was pharmacist-driven interventions reported in 63.2% of all studies, followed by guideline development and application (26.3%), and medication supply coordination (10.5%), respectively. The outcomes of the interventions were difficult to compare but showed a reduction in antimicrobial use and prevention of adverse drug reactions with a relatively high acceptance rate from physicians. Pharmacists played an important role in performing AMS-related interventions in COVID-19 patients and helped in the fight against the worsening of AMR during the pandemic. The impact of pharmacist-driven AMS interventions in patients with COVID-19 seemed to be positive and improved outcomes related to antimicrobial use.


Low-cost compact optical spectroscopy and novel spectroscopic algorithm for point-of-care real-time monitoring of nanoparticle delivery in biological tissue models.
Real-time monitoring of nanoparticle delivery in biological models is essential to optimize nanoparticle-mediated therapies. However, few techniques are available for convenient real-time monitoring of nanoparticle concentrations in tissue samples. This work reported novel optical spectroscopic approaches for low-cost point-of-care real-time quantification of nanoparticle concentrations in biological tissue samples. Fiber probe measured diffuse reflectance can be described with a simple analytical model by introducing an explicit dependence on the reduced scattering coefficient. Relying on this, the changes on the inverse of diffuse reflectance are proportional to absorption change when the scattering perturbation is negligible. We developed this model with proper wavelength pairs and implemented it with both a standard optical spectroscopy platform and a low-cost compact spectroscopy device for near real-time quantification of nanoparticle concentrations in biological tissue models. Both tissue-mimicking phantom and ex vivo tissue sample studies showed that our optical spectroscopic techniques could quantify nanoparticle concentrations in near real-time with high accuracies (less than 5% error) using only a pair of narrow wavelengths (530 nm and 630 nm). Novel low-cost point-of-care optical spectroscopic techniques were demonstrated for rapid accurate quantification of nanoparticle concentrations in tissue-mimicking medium and ex vivo tissue samples using optical signals measured at a pair of narrow wavelengths. Our methods will potentially facilitate real-time monitoring of nanoparticle delivery in biological models using low-cost point-of-care optical spectroscopy platforms, which will significantly advance nanomedicine in cancer research.


Sustaining Health Care Interventions to Achieve Quality Care: What We Can Learn From Rapid Response Teams.
Rapid response team (RRT) adoption and implementation are associated with improved quality of care of patients who experience an unanticipated medical emergency. The sustainability of RRTs is vital to achieve long-term benefits of these teams for patients, staff, and hospitals. Factors required to achieve RRT sustainability remain unclear. This study examined the relationship between sustainability elements and RRT sustainability in hospitals that have previously implemented RRTs.


Surgical Dissection of the Anterolateral Ligament.
Recent investigations into the structure and function of the anterolateral ligament (ALL) have resulted in renewed interest in the role of the lateral extra-articular structures in rotational control of the knee. With increased focus on the ALL, debate about the anatomic characteristics, the functional role in knee stability, and even the existence of this lateral structure has ensued. This article describes our dissection method for the ALL. Through careful dissection and precise elevation of the iliotibial band, the ALL can be clearly identified as a distinct structure with an attachment near the lateral epicondyle on the femur and an insertion in a fan-like fashion onto the tibia, between the Gerdy tubercle and the fibular head. This investigation provides the surgeon with anatomic landmarks to use during surgical reconstruction of the ALL.


Dibenzo[a,l]pyrene induced DNA adduct formation in lung tissue in vivo.
Polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens present in the atmosphere from combustion sources such as cigarette smoke, diesel exhaust, residential heating processes, and industrial coke production. To date, dibenzo[a,l]pyrene (DBP) has been found to be the strongest tumor-initiating PAH ever tested in rodent skin and mammary tumor models. Here we show for the first time that systemic exposure to DBP causes DNA damage in mouse lung tissue. C57BL/6 mice were gavaged with 1, 5 or 20 mg DBP/kg body weight, daily for 10 days. Toxicity of DBP was revealed by a decrease in body and organ weight of mice while no apparent cell death was observed on P815 mastocytoma cells (allograft model) in vitro. However, treatment of P815 cells in vitro with the ultimate carcinogenic metabolite of DBP, the fjord region (-)-anti-11,12-diol 13,14-epoxide [(-)-anti-DBPDE], resulted in the total loss of cell viability. Lungs from the animals were removed and subjected to DBP-DNA adduct analysis. A dose dependent adduct formation was revealed by 33P-postlabeling analysis of DNA from lung tissue. The majority of DNA adducts formed in lungs of mice after systemic exposure to DBP were contributed by (-)-anti-DBPDE. The data from this in vivo model are consistent with previous metabolic activation results obtained with DBP in human cells in culture.


Somatic Cell Nuclear Transfer in Mice: Basic Protocol and Its Modification for Correcting X Chromosome Inactivation Status.
Somatic cell nuclear transfer (SCNT) enables the production of animals from single cell nuclei. Unlike normally fertilized embryos, SCNT-derived embryos ectopically express the Xist gene from the maternal allele, because of the lack of Xist-repressing imprints in the somatic donor genome. This has severely compromised the development of SCNT-derived embryos, at least in mice. Here, we describe the basic protocol of mouse SCNT as well as a Xist knockdown SCNT procedure, which remarkably increases the efficiency of cloning mice.


Is primary care access to CT brain examinations effective?
Primary care access to CT head examinations could enable common neurological conditions to be managed within primary care. Outcome data from the first 8 years of a local service were used to identify effective referral criteria. Primary care head CT results from 1 March 1995 to 31 October 2003 were categorized as normal, incidental or significant findings. Normal reports were cross-referenced for referral to secondary care. Case notes with incidental or significant CT findings were reviewed for secondary care attendance and outcome. Records of 1403/1645 CT head examinations (85%) were available for review. Of these 1403, 951 (67.8%) returned normal findings, 317 (22.6%) incidental findings and 135 (9.6%) significant findings. The commonest indication for referral was investigation of headaches (46.6%). Of the total 533 patients under 50 years of age, 13 (2.4%) yielded significant findings and all 13 showed other features in addition to headache. Of 314 cases presenting with focal neurology, 83 (26.4%) showed significant findings. 314 patients were referred from primary to secondary care. 189 had normal scans and 74 had findings described as incidental. 60% of secondary care referrals were for normal CT scans. In patients with focal neurology, 90 of 314 were referred, allowing 71% to be managed in primary care. Yield was also 0% for headaches, dizziness, visual disturbance or nausea and vomiting. Primary care access to CT brain examinations is effective for patients with focal neurology, neurological symptoms or a known malignancy, but not for patients aged less than 50 years, or with uncomplicated headaches, dizziness or diplopia.


Anti-fas activating antibody enhances trophoblast outgrowth on endometrial epithelial cells by induction of P38 MAPK/JNK-mediated apoptosis.
In species with hemochorial placentation, such as the mouse and human, trophoblast cells of the implanting blastocyst induce apoptosis and displace endometrial epithelial cells (EEC) to cross the luminal epithelium of the endometrium. Since Fas and Fas ligand (FasL) are expressed in EEC and trophoblast cells respectively and mitogen-activated protein kinases (MAPKs) mediate Fas-induced apoptosis, the roles of Fas/FasL and MAPK signaling in trophoblast-EEC interactions were studied. By co-culturing BeWo trophoblast spheroids with RL95-2 EEC monolayers to mimic blastocyst-endometrial interactions, we found that trophoblast spheroid outgrowth on EEC was significantly enhanced by anti-Fas activating antibody. Since anti-Fas activating antibody had no effect on spheroid expansion on EEC-free culture surfaces, its enhancing effect on spheroid outgrowth on EEC may be mediated by acting on EEC to facilitate trophoblast-induced EEC apoptosis and displacement. Valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (VAD-FMK) staining showed that the percentage of apoptotic EEC at the spheroid-EEC interface was markedly increased by anti-Fas activating antibody. Moreover, the pancaspase inhibitor benzyloxycarbonyl-VAD-FMK was able to suppress the enhancing effect of anti-Fas activating antibody on spheroid expansion on EEC. Upon anti-Fas activating antibody stimulation, both p38 MAPK and c-Jun NH(2)-terminal kinase (JNK) were activated. Furthermore, the anti-Fas activating antibody-enhanced EEC apoptosis and spheroid expansion on EEC were significantly inhibited by the p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125. Our results establish that anti-Fas activating antibody could activate p38 MAPK and JNK to induce EEC apoptosis, thereby promoting trophoblast outgrowth on EEC.