Regulation of keratinocyte growth factor expression in human endometrium: implications for hormonal carcinogenesis.
Estrogen is thought to be an important etiologic agent in endometrial and breast cancers. However, the mechanism or mechanisms by which estrogen acts as a hormonal carcinogen are not well understood. We hypothesize that in response to chronic exposure to estrogens, human endometrial stromal fibroblasts (ESF) produce factors that facilitate neoplastic transformation in epithelial cells. To test this hypothesis, we assessed the regulation of keratinocyte growth factor (KGF) mRNA and protein in ESF by interleukin-1 (IL-1) and diethylstilbestrol (DES). Short-term treatments with IL-1 but not with DES increased the abundance of KGF mRNA in ESF. However, chronic treatment with DES significantly increased KGF mRNA levels and protein production. KGF protein in medium conditioned by ESF chronically treated with 1 nM DES reached concentrations of approximately 100 ng/mL. At this concentration, KGF increased endometrial epithelial cell numbers fourfold and enhanced anchorage independence tenfold. These results suggest that KGF may play a role in hormonal carcinogenesis by mediating estrogen-induced changes in the interactions between stromal and epithelial cells. To address the potential role of nuclear transcription factor kappa B (NF-kappaB) in regulating KGF expression, we determined the effect of increased expression of its inhibitor, IkappaBalpha, on KGF mRNA and protein levels. Transfection with IkappaBalpha blocked induction of KGF expression by IL-1 but had no effect on the increase in KGF mRNA caused by chronic treatment with DES. These results suggest that IL-1 exerts its effects on KGF by an NF-kappaB-mediated pathway but that chronic treatment with DES stimulates KGF expression by some other mechanism.


An investigation of solute-solvent interactions in binary liquid mixtures of 3'-methoxyacetophenone: using Raman spectroscopy and DFT calculations.
Raman spectral measurements have been carried out for neat 3'-methoxy acetophenone (3'-MAP) and binary liquid mixtures of 3'-MAP in three solvents of different polarity. Also Density Functional Theory (DFT) geometry optimization and vibrational wavenumber calculation have been performed on monomer and dimer structures of 3'-MAP to analyze the experimentally observed Raman spectrum. Mulliken charge analysis has also been made on optimized geometries of 3'-MAP with solvents. The changes associated with the observed peak position, intensity and linewidth in the carbonyl stretching mode of 3'-MAP are explained as a consequence of intermolecular interactions between solute-solute and solute-solvent molecules. This analysis reports that the solute-solvent interaction is dominant in the case of binary liquid mixtures of 3'-MAP with ethanol compared to DMF and benzene.


Global Maternal, Newborn, and Child Health: Successes, Challenges, and Opportunities.
Considerable progress has been made towards reducing under-5 childhood mortality in the Millennium Development Goals era. Reduction in newborn mortality has lagged behind maternal and child mortality. Effective implementation of innovative, evidence-based, and cost-effective interventions can reduce maternal and newborn mortality. Interventions aimed at the most vulnerable group results in maximal impact on mortality. Intervention coverage and scale-up remains low, inequitable and uneven in low-income countries due to numerous health-systems bottle-necks. Innovative service delivery strategies, increased integration and linkages across the maternal, newborn, child health continuum of care are vital to accelerate progress towards ending preventable maternal and newborn deaths.


Archaebacterial lipid membranes as models to study the interaction of 10-N-nonyl acridine orange with phospholipids.
The dye 10-N-nonyl acridine orange (NAO) is used to label cardiolipin domains in mitochondria and bacteria. The present work represents the first study on the binding of NAO with archaebacterial lipid membranes. By combining absorption and fluorescence spectroscopy with fluorescence microscopy studies, we investigated the interaction of the dye with (a) authentic standards of archaebacterial cardiolipins, phospholipids and sulfoglycolipids; (b) isolated membranes; (c) living cells of a square-shaped extremely halophilic archaeon. Absorption and fluorescence spectroscopy data indicate that the interaction of NAO with archaebacterial cardiolipin analogues is similar to that occurring with diacidic phospholipids and sulfoglycolipids, suggesting as molecular determinants for NAO binding to archaebacterial lipids the presence of two acidic residues or a combination of acidic and carbohydrate residues. In agreement with absorption spectroscopy data, fluorescence data indicate that NAO fluorescence in archaeal membranes cannot be exclusively attributed to bisphosphatidylglycerol and, therefore, different from mitochondria and bacteria, the dye cannot be used as a cardiolipin specific probe in archaeal microorganisms.


Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease.
Statistically, significant numbers of central bone specimens of suppurative osteomyelitis of the jaws (SOJ), bisphosphonate induced osteonecrosis of the jaws (BIONJ), and osteoradionecrosis of the jaws (ORNJ) were compared. All three evidenced the common finding of necrotic bone with empty osteocytic lacunae, Haversian and Volkmann canals, but each showed a distinctive histopathologic pattern indicating a different disease mechanism and treatment options. Suppurative osteomyelitis was characterized by intense marrow inflammation and marrow vessel thrombosis with retention of viable osteoclasts and periosteum. Bisphosphonate induced osteonecrosis was characterized by an empty marrow space with empty Howship's lacunae and an absence of osteoclasts but viable periosteum. Osteoradionecrosis was characterized by a collagenous hypocellular, hypovascular marrow space and nonviable periosteum. Histologic evidence in SOJ indicates a microorganism provoked intense inflammation and marrow vascular thrombosis creating an environment conducive to continual bacterial proliferation. BIONJ is seen as a non-inflammatory drug toxicity to bone by osteoclastic death leading to over suppression of bone renewal, and ORN as another non-inflammatory condition caused by a high linear energy transfer that impairs or kills numerous cell types in the field of radiation including periosteum, bone, and all soft tissue.


Enhancing healthcare quality and outcomes for peritoneal dialysis patients in Thailand: An evaluation of key performance indicators and PDOPPS cohort representativeness.
To assess whether the peritoneal dialysis (PD) centres included in the Peritoneal Dialysis Outcomes and Practise Patterns Study (PDOPPS) in Thailand are representative of other PD centres in the country, based on 8 key performance indicators (KPIs 1-8). A retrospective analysis was conducted comparing PD-related clinical outcomes between PD centres included in the PDOPPS (the PDOPPS group) and those not included (the non-PDOPPS group) from January 2018 to December 2019. Logistic regression analysis was used to identify predictors associated with achieving the target KPIs. Of 181 PD centres, 22 (12%) were included in the PDOPPS. PD centres in the PDOPPS group were larger and tended to serve more PD patients than those in the non-PDOPPS group. However, the process and outcome KPIs (KPIs 1-8) were comparable between the 2 groups. Large hospitals (≥120 beds), providing care to ≥100 PD cases and having experience for >10 years were independent predictors of achieving the peritonitis rate target of <0.5 episodes/year. Most PD centres in Thailand showed weaknesses in off-target haemoglobin levels and culture-negative peritonitis rate. The PD centres included in Thai PDOPPS were found to be representative of other PD centres in Thailand in terms of clinical outcomes. Thus, Thai PDOPPS findings may apply to the broader PD population in Thailand.


Correction to: Publication of Abstracts and Full Papers from the International Conference on the Origin of Life, San Diego, 2017.
Plans for the publication of Abstracts from the meeting have been cancelled. However, manuscripts for full papers will still be considered for publication in OLEB.


Surgical Collaboratives for Quality Improvement.
How best to improve the surgical quality remains unknown. Historically, most efforts were either top down national policy efforts or local hospital/practice level efforts. This article reviews the limitations of these methods and how collaborative quality improvement a mix of local, regional, and national efforts is the most effective means of achieving sustainable, meaningful improvement in surgical care.


Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity.
The selective inhibition of bacterial β-glucuronidases was recently shown to alleviate drug-induced gastrointestinal toxicity in mice, including the damage caused by the widely used anticancer drug irinotecan. Here, we report crystal structures of representative β-glucuronidases from the Firmicutes Streptococcus agalactiae and Clostridium perfringens and the Proteobacterium Escherichia coli, and the characterization of a β-glucuronidase from the Bacteroidetes Bacteroides fragilis. While largely similar in structure, these enzymes exhibit marked differences in catalytic properties and propensities for inhibition, indicating that the microbiome maintains functional diversity in orthologous enzymes. Small changes in the structure of designed inhibitors can induce significant conformational changes in the β-glucuronidase active site. Finally, we establish that β-glucuronidase inhibition does not alter the serum pharmacokinetics of irinotecan or its metabolites in mice. Together, the data presented advance our in vitro and in vivo understanding of the microbial β-glucuronidases, a promising new set of targets for controlling drug-induced gastrointestinal toxicity.


Opioids depress in vitro human monocyte chemotaxis.
Intravenous drug abusers (IDA) normally show functional defects in monocyte activity, in particular their chemotactic response. The aim of the present work was to study the action of several opioids on monocyte chemotaxis. To do so, monocytes from healthy individuals were incubated with heroin and morphine at three different concentrations (10(-5) M, 10(-6) M and 10(-7) M), with the finding of a significant depression in monocyte chemotaxis in all cases. This alteration could be due to a receptor effect or, conversely, to a non-specific effect. Accordingly, in the second phase of the study, monocytes from controls were incubated with a selective agonist of mu receptors (DAGO) and a selective agonist of delta receptors (DPDPE). In both cases a decrease in chemotactic function was observed similar to that following incubation with morphine or heroin. Preincubation of the monocytes with naloxone prevented the depression induced by both specific agonists. These findings suggest that opioids play an important role in the depression of monocyte chemotaxis observed in IDA. The results also suggest the presence of mu and delta opiate receptors in the cells of the phagocytic mononuclear system.


The Effect of PSD-93 Deficiency on the Expression of Early Inflammatory Cytokines Induced by Ischemic Brain Injury.
The aim of the study was to explore the effect of PSD-93 deficiency on the expression of early inflammatory cytokines induced by cerebral ischemia/reperfusion injury. Ten- to twelve-week-old male PSD-93 knockout (PSD-93 KO) mice (C57BL/6 genetic background) and wild-type (WT) littermates were randomly divided into sham and ischemia/reperfusion (I/R) group. The focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO) suture method. RT-PCR was used to detect the mRNA expression of IL-6, IL-10, Cox-2, iNOS, and TNF-α4h following reperfusion. Infarct volume at different time points after I/R was analyzed using 2,3,5-triphenyl tetrazolium staining, and neurological damage score (neurological severity scores, NSS) was used to evaluate the effect of PSD-93 gene knockout on the MCAO-induced neurological injury. In WT mice, early I/R injury led to the increase in the mRNA expression of proinflammatory cytokines IL-6, Cox-2, iNOS, and TNF-α that coincided with the decrease in the expression of anti-inflammatory cytokine IL-10, as compared to the sham group (P < 0.05). This effect was markedly attenuated by depleting PSD-93 levels by gene knockout. As compared to sham group, in PSD-93 KO mice I/R4h led to downregulation of Cox-2 and iNOS expression, and increase in the mRNA levels of IL-10 (P < 0.05). In addition, following MCAO, PSD-93 KO mice exhibited improved NSS and reduced infarct volumes, as compared with WT animals. PSD-93 knockout may play a neuroprotective role by mediating the early release of inflammatory cytokines induced by cerebral ischemia.


Exploration of natural compounds against the human mpox virus DNA-dependent RNA polymerase in silico.
Last year, the human monkeypox virus (hMPXV) emerged as an alarming threat to the community, with a detectable outbreak outside the African continent for the first time. According to The American Centers for Disease Control and Prevention (CDC), the virus is reported globally, with 86,746 confirmed cases (until April 08, 2023). DNA-dependent RNA polymerase (DdRp) is an essential protein for viral replication; hence it is a promising drug target for developing antiviral drugs against DNA viruses. Therefore, this study was conducted to search for natural compounds that could provide scaffolds for RNA polymerase inhibitors. In this study, the DdRp structure of hMPXV was modeled and used to screen the natural compounds database (COCONUT). The virtual screening revealed 15 compounds able to tightly bind to the active site of the DdRp (binding energies less than -7.0 kcal/mol) compared to the physiological nucleotide, guanosine triphosphate (GTP). Molecular dynamics simulation was then performed on the top four hits and compared to GTP RESULTS: The results revealed the potential of four compounds (comp289, comp295, comp441, and comp449) in binding the hMPXV DdRp active site with a comparable binding affinity (-17.06 ± 2.96, -11.6 ± 5.34, -14.85 ± 2.66, and -10.79 ± 4.49 kcal/mol) with GTP (-21.03 ± 7.55 kcal/mol) CONCLUSION: These findings may also pave the way for developing new hMPXV inhibitors based on natural product scaffolds. These results need further experimental validation but promising as it was validated by unbiased all-atom MD simulations and binding free energy calculations.


Direct effects of wheat germ agglutinin on inositol phosphate formation and cytosolic-free calcium level in intestine 407 cells.
The interaction between dietary lectins, especially wheat germ agglutinin (WGA), and intestinal cells has been implicated in the pathogenesis of celiac disease. The present study was undertaken to investigate the immediate effects following such an interaction. Direct WGA-stimulation of Intestine 407 cells leads to an immediate rise in the cytosolic-free calcium concentration. The major part of this lectin-induced rise is due to an influx of calcium across the plasma membrane into the cytosol. However, WGA-exposure also results in an immediate mobilization of calcium from intracellular stores, most likely mediated via the simultaneous increase of inositol trisphosphate formation in these cells. The transduction mechanism described for WGA in these intestinal cells is not very sensitive towards pertussis toxin, indicating that if a G-protein is involved, it differs from those of most other systems. The suggested role for WGA in changing the functional and structural properties of intestinal cells might involve increases of inositol phosphate and cytosolic-free calcium levels.


Clinical factors associated with shock in bacteremic UTI.
Urinary tract infection (UTI) often causes bacteremia, resulting in shock. The purpose of this study is to investigate urological bacteremia and bacteremia shock cases and seek for the clinical factors associated with urological bacteremic shock. Seventy consecutive cases with bacteremia caused by UTI from the Department of Urology, Kobe University Hospital were studied. These cases were diagnosed from 2000 to 2010 and had full data available for analysis. We investigated the potential clinical factors associated with bacteremic shock (systolic blood pressure ≤ 90 mmHg with UTI), including: (1) the number of basal general diseases (such as diabetes, malignancy, immune diseases, heart diseases, liver diseases, and kidney diseases), (2) causative bacteria, (3) antibiotics and therapeutic intervention, (4) gram-negative bacteria, (5) resistance to imipenem (which is often used in this infection), and (6) serum white blood cell counts and C-reactive protein (CRP) at the time of diagnosis of bacteremic UTI. A total of 81 causative bacteria were isolated: 42 cases were gram-negative and 39 were gram-positive bacteria. In detail, Escherichia coli was the most common, followed by Methicillin-resistant Staphylococcus aureus. The comparison data revealed that urological bacteremic shock cases had significantly increased CRP (p < 0.001). Our univariate analyses showed indwelling urinary tract catheters (p = 0.02) as a significant clinical factor associated with urological bacteremic shock and multivariate analyses showed that the presence of indwelling urinary tract catheters before UTI was a significant clinical factor associated with urological bacteremic shock (p = 0.04). Indwelling urinary catheters before UTI and high CRP were clinical factors associated with urological bacteremic shock. This result should be considered during decision-making for UTI treatments in high risk cases or urological bacteremia cases.


Instability of glacial climate in a model of the ocean- atmosphere-cryosphere system.
In contrast to the relatively stable climate of the past 10,000 years, during glacial times the North Atlantic region experienced large-amplitude transitions between cold (stadial) and warm (interstadial) states. In this modeling study, we demonstrate that hydrological interactions between the Atlantic thermohaline circulation (THC) and adjacent continental ice sheets can trigger abrupt warming events and also limit the lifetime of the interstadial circulation mode. These interactions have the potential to destabilize the THC, which is already more sensitive for glacial conditions than for the present-day climate, thus providing an explanation for the increased variability of glacial climate.


Nanopharmaceuticals: Tiny challenges for the environmental risk assessment of pharmaceuticals.
Many new developments and innovations in health care are based on nanotechnology. The field of nanopharmaceuticals is diverse and not as new as one might think; indeed, nanopharmaceuticals have been marketed for many years, and the future is likely to bring more nanosized compounds to the market. Therefore, it is time to examine whether the environmental risk assessment for human pharmaceuticals is prepared to assess the exposure, fate, and effects of nanopharmaceuticals in an adequate way. Challenges include the different definitions for nanomaterials and nanopharmaceuticals, different regulatory frameworks, the diversity of nanopharmaceuticals, the scope of current regulatory guidelines, and the applicability of test protocols. Based on the current environmental risk assessment for human medicinal products in the European Union, necessary adaptations for the assessment procedures and underlying study protocols are discussed and emerging solutions identified.


Colloid-induced changes in bleeding following liver resection in the rat.
The effect of preoperative infusion of Ringer's solution, Ringer's acetate solution, dextran 70, dextran 40, degraded gelatin and hydroxyethyl starch on haemostasis after standardized liver resection was studied in the rat. Ringer's and Ringer's acetate solutions did not affect haemostasis more than expected from haemodilution. Dextrans, degraded gelatin and hydroxyethyl starch caused a significant increase in bleeding time and blood loss. APT time was significantly increased after infusion of hydroxyethyl starch. Dextran and hydroxyethyl starch impaired ADP- and collagen-induced aggregation. Platelet aggregation was not affected by the infusion of Ringer's solution or Ringer's acetate solution as compared to non-treated controls.


Resistance in cattle against Rhipicephalus appendiculatus with an assessment of cross-resistance to R. pulchellus (Acari: Ixodidae).
A comparison of the yield of engorged nymphs of Rhipicephalus appendiculatus and R. pulchellus was carried out between cattle highly resistant to R. appendiculatus but susceptible to R. pulchellus, and cattle and rabbits susceptible to both species. Resistant cattle yielded fewer and smaller R. appendiculatus nymphs than either susceptible cattle or rabbits. More nymphs of both tick species dropped from susceptible cattle but no differences were detected in the mean weight of engorged R. pulchellus nymphs fed on R. appendiculatus-resistant and susceptible cattle, although resistant animals yielded more nymphs of R. pulchellus than of R. appendiculatus. An acute inflammatory reaction, accompanied by intense pruritus and grooming, was observed in the ears of the resistant cattle infested with R. appendiculatus, but no reaction was detected in the opposite ears where R. pulchellus was feeding. The low cross-resistance between these two closely related tick species suggests that different antigens may be involved in the development of resistance in cattle to different tick species.


IgG subclass distribution in juvenile human tonsil: IgG3 and IgG4 results of specific antibody production using synthetic peptides.
A decapeptide with a sequence corresponding to a part of the hinge region of human IgG3 was used to prepare a mouse monoclonal antibody (Mab 330-2.2). The Mab recognized IgG3 in ELISA only when the IgG3 was denatured by mild heat. Mab specificity in immunohistochemistry was calibrated with a number of reference Mabs obtained through a WHO/IUIS collaborative study. Finally, Mab 330-2.2 was used in conjunction with a set of other isotype specific Mabs to study the (sub)class distribution of cytoplasmic Ig containing cells in palatine tonsil. IgG3 within the IgG class was strongly over-represented in our tonsil material if compared to the representation of IgG3 in serum.


Direct effects on proliferation, antigen expression and melanin synthesis of cultured normal human melanocytes in response to UVB and UVA light.
Ultraviolet (UV) radiation; induces a variety of responses in the skin, including tanning and inflammation, and may also act as a carcinogen. As epidermal melanocytes are seen as the major targets of UV light, the present study was conducted to evaluate the direct effects of UVA and UVB irradiation on melanocytes in vitro. Normal human epidermal melanocytes (NHM) were exposed on 3 consecutive days to UVA (0.072-7.2 J/cm2) and UVB (7.2-48 mJ/cm2), respectively, and changes of morphology, cell number, melanin synthesis and antigen expression (APAAP technique) were determined 5 days after the first exposure. UVA radiation caused only minimal effects on NHM by slightly inducing expression of the activation marker HMB-45 and decreasing expression of the proliferation marker Ki-67. No changes of morphology, cell number or melanin synthesis were detectable with any of the applied doses. On the other hand, UVB radiation significantly induced dendrite formation and decreased the number of NHM in a dose-dependent manner (74% of the controls at 7.2 mJ/cm2, 64% at 14.4 mJ/cm2 and 28% at 36 mJ/cm2). Significant induction of the activation marker HMB-45 was found in parallel to decreased expression of the differentiation marker K.1.2.58. UVB doses >or=9.6 mJ/cm2 also resulted in significant downregulation of the proliferation marker Ki-67, confirming the data of the cell counts, and melanin content was increased in NHM (20% over the controls, P<0.01) after applying 7.2 mJ/cm2 UVB. Our results may suggest that the effect of UVB radiation in skin is due to direct activation of melanocytes, whereas skin tanning caused by UVA is mediated rather in an indirect way.


Development of an LC-MS/MS-based method for quantification and pharmacokinetics study on SCID mice of a dehydroabietylamine-adamantylamine conjugate, a promising inhibitor of the DNA repair enzyme.
Earlier, it was found that the agent KS-389, a conjugate of dehydroabietylamine and 1-aminoadamantane, possess inhibiting activity with regard to Tdp1. It this study, LC-MS/MS-based methods of quantification of KS-389 in mice blood and several organs (brain, liver and kidney) were developed and validated. Validation of the methods was performed according to the guidelines of U.S. Food and Drug Administration and European Medicines Agency in terms of selectivity, linearity, accuracy, precision, recovery, matrix effect, stability and carry-over. Dried blood spots (DBS) method was used for blood sample preparation. HPLC separation was performed on a reversed-phase column; the total analysis time was 12 min. Mass spectral detection was performed on a 6500 QTRAP mass spectrometer in multiple reaction monitoring mode. Transitions 463.5→135.1/107.2 and 336.2→332.2/176.2 were scanned for KS-389 and 2,5-bis(4-diethylaminophenyl)-1,3,4-oxadiazole used as the internal standard, respectively. Pharmacokinetics of the compound as well as its distribution in the organs were studied on SCID mice after intraperitoneal administration of the substance at a dose of 5 mg/kg, and it was found that its maximum concentration in blood is reached in 1-1.5 h and was 80 ng/mL. The maximum concentration in all organs is reached after the same time and is approximately 1500 ng/g and 1100 ng/g in liver and kidney, respectively. This is the first report on the pharmacokinetics of Tdp1 inhibitor based on dehydroabietylamine and 1-aminoadamantane after a single administration to mice. Also, the substance was found to be able to penetrate the blood-brain barrier which is important for, and its maximum concentration was c.a. 25-30 ng/g. These results are important for glioma treatment and make it promising for this purpose.


Gamma-hydroxybutyric acid in the treatment of alcoholism: dosage fractioning utility in non-responder alcoholic patients.
Gamma-hydroxybutyric acid (GHB) has recently been introduced in clinical practice for alcoholism management, due to its utility in inducing abstinence from alcohol. In the present study we investigated the usefulness of greater dosage fractioning of GHB in non-responder alcoholics to the usual three administrations per day. A total of 154 alcoholics were admitted to the study and were treated with GHB (50 mg/Kg orally administered three times per day) for 8 weeks (phase 1); the patients who continued to drink alcohol in phase 1 were administered the same dose of GHB divided into six times per day for another 8 weeks (phase 2). Of the 154 patients, 115 completed phase 1; 78 (67.8%) of these began and maintained abstinence (group A) while 37 subjects (32.2%) continued to drink alcohol (group B) showing a craving significantly higher than group A at the end of phase 1 (P < 0.001); in these patients the major fractioning of the drug in phase 2 caused a significant reduction in craving (P < 0.005) and 26 (70.2%) began and maintained abstinence. Moreover no significant differences in final craving score between group A and B was observed. Within the limits of an open study, our data show that non-responder subjects to the conventional fractioning of GHB seem to benefit from the greater fractioning of the drug and seem to indicate the need for a slow-release form of GHB with a prolonged action.


Remibrutinib (LOU064) inhibits neuroinflammation driven by B cells and myeloid cells in preclinical models of multiple sclerosis.
Bruton's tyrosine kinase (BTK) is a key signaling node in B cell receptor (BCR) and Fc receptor (FcR) signaling. BTK inhibitors (BTKi) are an emerging oral treatment option for patients suffering from multiple sclerosis (MS). Remibrutinib (LOU064) is a potent, highly selective covalent BTKi with a promising preclinical and clinical profile for MS and other autoimmune or autoallergic indications. The efficacy and mechanism of action of remibrutinib was assessed in two different experimental autoimmune encephalomyelitis (EAE) mouse models for MS. The impact of remibrutinib on B cell-driven EAE pathology was determined after immunization with human myelin oligodendrocyte glycoprotein (HuMOG). The efficacy on myeloid cell and microglia driven neuroinflammation was determined in the RatMOG EAE. In addition, we assessed the relationship of efficacy to BTK occupancy in tissue, ex vivo T cell response, as well as single cell RNA-sequencing (scRNA-seq) in brain and spinal cord tissue. Remibrutinib inhibited B cell-dependent HuMOG EAE in dose-dependent manner and strongly reduced neurological symptoms. At the efficacious oral dose of 30 mg/kg, remibrutinib showed strong BTK occupancy in the peripheral immune organs and in the brain of EAE mice. Ex vivo MOG-specific T cell recall response was reduced, but not polyclonal T cell response, indicating absence of non-specific T cell inhibition. Remibrutinib also inhibited RatMOG EAE, suggesting that myeloid cell and microglia inhibition contribute to its efficacy in EAE. Remibrutinib did not reduce B cells, total Ig levels nor MOG-specific antibody response. In brain and spinal cord tissue a clear anti-inflammatory effect in microglia was detected by scRNA-seq. Finally, remibrutinib showed potent inhibition of in vitro immune complex-driven inflammatory response in human microglia. Remibrutinib inhibited EAE models by a two-pronged mechanism based on inhibition of pathogenic B cell autoreactivity, as well as direct anti-inflammatory effects in microglia. Remibrutinib showed efficacy in both models in absence of direct B cell depletion, broad T cell inhibition or reduction of total Ig levels. These findings support the view that remibrutinib may represent a novel treatment option for patients with MS.


Syntheses of novel antimycobacterial combinatorial libraries of structurally diverse substituted pyrimidines by three-component solid-phase reactions.
A new pyrimidine based scaffold has been developed by three-component solid-phase syntheses. The utility of scaffolds was demonstrated by synthesizing libraries of 80 substituted pyrimidines (a-p), (a-p), 14(a-p), 15(a-p), 16(a-p). Among 80 compounds screened, six compounds, 12i, 13c, 14d, 14e, 14o, and 15d showed in vitro activity against Mycobacterium tuberculosis (MABA) at a concentration of 50 and 25 microg/mL


Biotin supply affects rates of cell proliferation, biotinylation of carboxylases and histones, and expression of the gene encoding the sodium-dependent multivitamin transporter in JAr choriocarcinoma cells.
Placental transfer of nutrients and secretion of hormones is essential for normal fetal development. To determine whether biotin supply affects biotin homeostasis, proliferation rates, and progesterone secretion in placenta cells. JAr choriocarcinoma cells were cultured in media containing deficient (25 pmol/L), physiological (250 pmol/L), or pharmacological concentrations (10,000 pmol/L) of biotin for three weeks; markers for biotin homeostasis, proliferation, and hormone secretion were quantified. Biotin concentrations in culture media correlated negatively with expression of the biotin transporter SMVT, as judged by cellular transport rates of biotin, abundance of SMVT protein, and transcriptional activity of SMVT reporter-gene constructs. Notwithstanding this homeostatic mechanism, biotin concentrations in media correlated positively with activities of biotin-dependent propionyl-CoA carboxylase, abundance of biotinylated carboxylases, and with biotinylation of histones. Biotin deficiency was associated with decreased rates of thymidine uptake into JAr cells [pmol thymidine/( 10(6) cells x 24 h)]: 1.6 +/- 0.1 (25 pmol/L biotin) versus 2.3 +/- 0.2 (250 pmol/L biotin) versus 3.7 +/- 0.4 (10,000 pmol/L biotin), suggesting that cell proliferation depends on biotin. Secretion of progesterone was reduced in biotin-deficient cells; this effect was caused by reduced generation of new cells in deficient media rather than by an immediate effect of biotin on progesterone secretion at the singlecell-level. This study provides evidence that choriocarcinoma cells cannot maintain normal activities of biotin-dependent metabolic pathways if biotin concentrations in culture media are low. It is uncertain whether activities of biotin-dependent pathways in placenta affect fetal development in vivo.


Negative symptom improvement during cognitive rehabilitation: results from a 2-year trial of Cognitive Enhancement Therapy.
Cognitive rehabilitation has shown beneficial effects on cognition in patients with schizophrenia, which may also help to improve negative symptoms due to overlapping pathophysiology between these two domains. To better understand the possible relationship between these areas, we conducted an exploratory analysis of the effects of Cognitive Enhancement Therapy (CET) on negative symptoms. Early course schizophrenia outpatients (n=58) were randomized to 2 years of CET or an Enriched Supportive Therapy (EST) control condition. Results revealed significant and medium-sized (d=0.61) differential improvements favoring CET in overall negative symptoms, particularly social withdrawal, affective flattening, and motor retardation. Neurocognitive improvement was associated with reduced negative symptoms in CET, but not EST patients. No relationships were observed between improvements in emotion processing aspects of social cognition, as measured by the Mayer-Salovey-Caruso Emotional Intelligence Test, and negative symptoms. CET represents an effective cognitive rehabilitation intervention for schizophrenia that may also have benefits to negative symptoms. Future studies specifically designed to examine negative symptoms during the course of cognitive rehabilitation are needed.


Mutational scanning of spike RBD protein for enhanced ACE2 affinity emerging Southeast Asia in the late transmission phase.
The COVID-19 pandemic has changed the quality of life and economic systems all over the world, as the virus can be transmitted from human to human via air-droplets. Since the SARS-CoV-2 virus was first identified in 2019, the virus has naturally mutated over time. Southeast Asia is one of the areas in the world that has implemented various procedures and measures to slow down the disease outbreaks. The first cluster of COVID-19 was identified from the tourist-travel history, and then the diversity of coronavirus victims has posed a serious issue of human security on a massive scale. To evaluate whether or not naturally occurring mutations have strengthened the infectivity of SARS-CoV-2, we computed in silico the structural dynamics of the RBD-spike protein mutation enhancing ACE2-binding. When considering emerging variations in Southeast Asia, 14 dominant mutations were analyzed by applying the structural and energetic characterization using MD simulations. The ones in the RBD region displayed higher affinity to ACE2 due to the improved interfacial stability of the RBD β-strand surrounding the ACE2 across salt bridge hotspots. The binding hotspots and structurally conserved conformational-epitopes have been identified, which are deleterious for RBD mutation and ACE2 binding. We present an interactive visualization to facilitate the development of effective neutralizing agents for vaccination, prevention and treatment.


Long-term results of cataract surgery combined with trabeculotomy.
There are different surgical approaches for cataract and concomitant primary open-angle glaucoma (POAG). In a retrospective study we examined the long-term results of cataract extraction combined with trabeculotomy. Between 1990 and 1997, 194 eyes with cataract and POAG were operated on in a combined manner. Eighty-eight eyes received a trabeculotomy (TT), in 82 eyes a trabeculectomy was added to the trabeculotomy (TT+TE) and in 24 eyes, in which probing of Schlemm's canal was impossible, standard trabeculectomy (TE) was performed. Pre- and postoperative intraocular pressure (IOP), glaucoma medication, and the intra- and postoperative complications of all patients were analyzed. Hyphema was the most common complication in the TT group (20.5%). Fibrin reaction occurred in 27.8% of all cases. There was no statistically significant difference in postoperative IOP between the TT group and the TT+TE group. A statistically significant decrease in IOP compared to preoperatively lasted 60 months in the TT group. In eyes with a preoperative IOP < or = 20 mmHg, none of the three procedures reduced IOP significantly (<20% of the preoperative IOP). In the first 2 years after operation 50% of the patients had no need for antiglaucomatous medication. Cataract surgery combined with TT resulted in few complications. In low-tension glaucoma the combination with TT is not sufficient to decrease the IOP. In patients with higher preoperative IOP, however, cataract surgery combined with TT could be--on the basis of a postoperative observation time of 72 months--a suitable method for lowering the IOP sufficiently. Furthermore, the use of antiglaucomatous substances was reduced by this combined procedure.


Surgical treatment of a patient with live intracranial sparganosis for 17 years.
The incidence of sparganosis, especially intracranial live sparganosis is very low in China. Due to the lack of typical clinical manifestations, it is difficult to make a clear preoperative diagnosis of the disease, which often leads to delays the disease and serious consequences. A 23-year-old man presented with a 17-year history of intermittent seizures and right extremity numbness and weakness. Magnetic resonance imaging (MRI) showed patchy, nodular and line-like enhancement. Enzyme-linked immunosorbent assay (ELISA) detected positive antibodies to Spirometra mansoni in peripheral blood and cerebrospinal fluid (CSF). In addition, during the operation, an ivory-colored live sparganosis was removed under the precise positioning of neuronavigation, and the patient was diagnosed with cerebral sparganosis. The patient began praziquantel and sodium valproate treatment after the operation, and was followed up for 3 months. There was no recurrence of epilepsy, and the weakness and numbness of the right limb improved. Nonspecific clinical manifestations often make the diagnosis of cerebral sparganosis difficult, and a comprehensive diagnosis should be made based on epidemiological history, clinical manifestations, ELISA results and imaging findings. Surgery is the preferred method for the treatment of cerebral sparganosis, and more satisfactory results can be achieved under the precise positioning of neuronavigation.


Transcriptomic profiling of human corneal epithelial cells exposed to airborne fine particulate matter (PM2.5).
To explore the molecular mechanisms of PM2.5-induced dysfunction in human corneal epithelial cells (HCECs) and the potential role of the plasminogen activator inhibitor type-2 (PAI-2) in PM2.5-induced autophagy in vitro and in vivo. RNA-Seq was performed to identify the differentially expressed genes (DEGs) in PM2.5-exposed HCECs compared to unexposed condition, followed by validation via real-time PCR (qRT-PCR). Corneal fluorescein staining and tear secretion were assessed in the PM2.5-exposed rat model. The expression of PAI-2 and autophagy-related markers were examined via immunoblotting, immunofluorescence staining and/or qRT-PCR in PM2.5-exposed or unexposed HCECs and rat corneas. PAI-2-knockdown HCECs were generated to study PAI-2's role in the PM2.5-induced autophagy in HCECs. A total of 434 DEGs-240 up-regulated and 194 down-regulated-were identified in PM2.5-exposed HCECs rather than unexposed HCECs. The expression of a few genes related to proliferation, inflammation, and aryl hydrocarbon stimulation were significantly altered by PM2.5 exposure. PAI-2 expression was up-regulated in PM2.5-exposed HCECs, sharing a similar fluctuation trend with autophagy-related markers LC3B II and BECN1 according to various exposure periods. Moreover, PAI-2 knockdown significantly suppressed the expression of LC3B and BECN1 in PM2.5-exposed HCECs. The corneal fluorescein staining was enhanced and tear secretion was significantly reduced in PM2.5-exposed rat eyes. PAI-2 expression was also increased in PM2.5-exposed rat corneas, together with the up-regulation of several autophagy-related markers. The present study identified the altered expression of hundreds of genes in PM2.5-exposed HCECs, which suggests the importance of PM2.5 for cornea health. The involvement of PAI-2 was discovered in the PM2.5-induced autophagy in HCECs as well as likely in rat corneas, which implied that PAI-2 may become a potential target of clinical treatment of PM2.5-associated ocular surface diseases.


Effect of cortisone on capsular contracture in double-lumen breast implants: ten years' experience.
Two groups of patients are compared with respect to capsular contracture after insertion of silicone breast prostheses. Six hundred seventy four women received single-lumen gel prostheses and 700 received double-lumen prostheses with cortisone. The addition of 12.5 mg of prednisolone to double-lumen prostheses diminished capsular contracture (Baker II to IV) dramatically; in patients with simple augmentation from 19% to 4.9%, in patients with subcutaneous mastectomy from 54% to 14.9%, and in patients with breast reconstruction from 64% to 24.4%. The use of double-lumen implants has three distinct advantages: (1) There is no bleeding and therefore no contact of the body with the silicone gel. (2) There is no danger of ruptured implants, even if the outer shell shows leakage. (3) If prednisolone is administered, capsular contracture is prevented to a significant degree.


Strategies for reducing radiation exposure from multidetector computed tomography in the acute care setting.
Many tools and strategies exist to enable reduction of radiation exposure from computed tomography (CT). The common CT metrics of x-ray output, the volume CT dose index and the dose-length product, are explained and serve as the basis for monitoring radiation exposure from CT. Many strategies to dose-optimize CT protocols are explored that, in combination with available hardware and software tools, allow robust diagnostic quality CT to be performed with a radiation exposure appropriate for the clinical scenario and the size of the patient. Specific emergency department example protocols are used to demonstrate these techniques.


Effect of Lawsonia inermis on tumor expression induced by Dalton's lymphoma ascites in Swiss albino mice.
The purpose of this study was investigating experimentally the possible antitumor effect of ethanol extract of root of Lawsonia inermis against Dalton's lymphoma ascites (DLA) bearing mice. Mice were administered with L. inermis at a dosage of 180 mg/kg of body weight for 15 days after 24 h of DLA inoculation. The ethanolic root extract of L. inermis reverted the increased number of the WBC count, platelets and lymphocytes and decreased the number of the RBC count, hemoglobin content and monocytes. The effect of root extract of L. inermis also increased the pathophysiological marker enzyme, lipid profile and decreased the enzymic and non enzymic antioxidants. A histopathological result shows the loss of liver hepatocytes and kidney architecture in DLA bearing mice. However, mice treatment with L. inermis extract improves the liver and kidney function and rearranges more or less normal architecture. The present work indicates that the ethanol extract of L. inermis exhibited significant antitumor activity.


Cardiac adverse reactions of COVID-19 vaccination: cardiac MRI findings.
The rapid development of COVID-19 vaccines in the wake of the COVID-19 pandemic has led to an equally expediently deployed vaccination campaign with more than 12 billion vaccinations administered worldwide. Reports of vaccine-associated adverse reactions (VAARs) have ranged from headaches and pain at the injection site to potentially life-threatening events such as cerebral venous sinus thrombosis. The heart has also not been spared of VAARs, as vaccine-associated myocardial infarction and more commonly, albeit still rare, myocarditis and perimyocarditis have been reported in predominantly young male recipients. Cardiac magnetic resonance imaging findings of vaccine-associated myocarditis such as prolonged T1 and T2 relaxation times, increased T2 signal intensity ratio, and subepicardial late gadolinium enhancement have been demonstrated to be similar to those in virus-induced myocarditis, enabling the use of the modified 2018 Lake Louise Criteria for diagnostic purposes to confirm vaccination-associated myocardial inflammation. Other reported cardiac findings such as cardiomyopathies and arrhythmias were confined to case reports. The incidence of myocardial infarction was not noted to be higher than in the overall population. The overall preliminary prognosis of vaccine- associated myocarditis seems to be good as suggested by initial reports, but long-term follow-up is needed to sufficiently assess possible sequelae and consequences.


Patent foramen ovale closure with the SeptRx device initial experience with the first "In-Tunnel" device.
The purpose of this study was to evaluate the safety and effectiveness of the SeptRx patent foramen ovale (PFO) closure device (SeptRx, Inc., Fremont, California). A PFO is a relatively common remnant of the fetal circulation that can be associated with cryptogenic stroke, transient ischemic attack, migraine, or decompression sickness. Percutaneous PFO closure with different devices has been performed for many years. However, most of the common devices leave a relatively large amount of material in the left and right atria. The SeptRx PFO device (SeptRx, Inc.) is the first PFO closure device designed to fit directly into the pocket of the PFO. From July 2006 to May 2007, 13 patients between 18 and 65 years of age with a history of cryptogenic stroke or transient ischemic attack were included into this first-in-man trial. All patients received 100 mg aspirin and 75 mg clopidogrel for 6 months. Follow-up was done at 1 and 6 months after procedure with transesophageal echocardiography and transcranial Doppler. In 11 of 13 patients, PFO closure with the SeptRx device was successfully performed. In 2 patients, PFO closure with this device was not possible due to the anatomy of the PFO; 1 device was retrieved before release, and the other was recaptured with a snare. After 30 days, 6 of the 11 PFOs were closed; after 6 months, all were closed. No adverse events occurred. The SeptRx PFO closure device appears to be safe and effective. The advantage of this occluder is that there is only minimal foreign material on the left and right sides of the interatrial septum. This is the first such "in-tunnel" PFO closure device.


Electron-light interaction in nonequilibrium: exact diagonalization for time-dependent Hubbard Hamiltonians.
We present a straightforward implementation scheme for solving the time-dependent Schrödinger equation for systems described by the Hubbard Hamiltonian with time-dependent hoppings. The computations can be performed for clusters of up to 14 sites with, in principle, general geometry. For the time evolution, we use the exponential midpoint rule, where the exponentials are computed via a Krylov subspace method, which only uses matrix-vector multiplication. The presented implementation uses standard libraries for constructing sparse matrices and for linear algebra. Therefore, the approach is easy to use on both desktop computers and computational clusters. We apply the method to calculate time evolution of double occupation and nonequilibrium spectral function of a photo-excited Mott-insulator. The results show that not only the double occupation increases due to creation of electron-hole pairs but also the Mott gap becomes partially filled.


Effect of thiocyanate on mammary gland growth in rats.
In growing rats from 3 weeks to 3 months old, 0.1% potassium thiocyanate (KSCN) decreased the plasma protein-bound iodine level by 47% and the total DNA in the mammary gland by 11%, but had no effect on the total RNA. Administration of thiocyanate in the form of 0.1, 0.3 and 0.5% KSCN during pregnancy and 14 d of lactation lowered the protein-bound iodine level by 48-66%, the total DNA by 11-47% and the total RNA by 14-63%, depending on the KSCN dosage. The 14-d-old litters of rats receiving thiocyanate weighed 4-41% less than those in the control group.


Elevated serum inhibin and tumor-associated trypsin inhibitor concentrations in a young woman with dysgerminoma of the ovary.
We describe a patient with dysgerminoma who had elevated serum inhibin, tumor-associated trypsin inhibitor (TATI), and CA 125 concentrations, which increased progressively during follow-up of the advancing disease. Inhibin levels correlated closely with disease behavior. In contrast to inhibin, serum TATI and CA 125 failed to reveal the presence of silent disease.


Study points out key barriers to compliance with CMS.
Documentation, physician involvement, inadequate resources top the list of barriers. Prioritization, accountability, and ownership cited as keys to improving compliance. Improving communication can help in addressing more than one of the key issues.


Evaluating the effect of the protector cap for castable implant abutments on reverse tightening values.
Screw loosening is the most common mechanical complication with implant prostheses. How the alteration of implant-to-abutment connection surfaces that occurs during laboratory procedures affects screw loosening is unclear. The purpose of this in vitro study was to compare the reverse tightening value (RTV) differences between custom castable abutments before casting, after casting in a conventional manner, and after casting with custom protector caps and pegs. Thirty implants with a standard-diameter conical connection (NobelReplace Conical Connection 4.3×13 mm; Nobel Biocare AG) and 30 premachined 4.3-mm GoldAdapt abutments (GoldAdapt; Nobel Biocare AG) were selected for this study. Specimens were divided into 3 groups (n=10): the uncast custom castable abutment group (UCCA) in which abutments were new and not cast; the unprotected custom castable abutment group (UPCCA) in which abutments were cast and devested with airborne-particle abrasion; and the protected custom castable abutment group (PCCA) in which abutments were cast by using protector caps and pegs made by milling zirconia and then devested with airborne-particle abrasion. All abutments in each group were tightened to 35 Ncm with a calibrated digital tightening device. After 10 minutes, all screws were retightened to 35 Ncm. At 3 hours, each screw was loosened, and the value at which the initial loosening occurred was documented as the RTV. The results were statistically analyzed with 1-way ANOVA to explore differences, and post hoc tests with Tukey adjustment were used for multiple comparisons. Among the tested groups, the mean RTV ranged from 19.89 Ncm to 27.19 Ncm: UCCA 27.19 Ncm, UPCCA 19.89 Ncm, and PCCA 24.24 Ncm. A significant difference was found among the tested groups (P<.05). Casting procedures, especially devestment with airborne-particle abrasion, affected implant-abutment connections and the seat site of the screw. Protecting the implant connection site and the seat site of the abutment screw with protector caps and pegs prevented a significant loss of the RTV.


Measurement of technical performance in surgery for congenital heart disease: the stage I Norwood procedure.
No method of measuring technical performance exists for the stage I Norwood procedure. Hospital mortality is usually used as a surrogate for technical performance, but evidence is lacking to support this concept. A technical score was designed by expert consensus. The technical score included the following steps: (1) Stage I was divided into subprocedures according to anatomic areas where an intervention is performed. (2) For each subprocedure, three score categories (optimal, adequate, and inadequate) were defined on the basis of echocardiography, catheterization, and/or clinical data. (3) Subprocedures were analyzed for the whole group and by surgeon. (4) Overall repair was also scored: optimal if all attempted subprocedures were optimal, inadequate if any was inadequate, and adequate for everything in between. (5) All patients undergoing the stage I procedure from January 2004 to December 2006 were retrospectively studied. One hundred ten patients were included (operated on by six surgeons), and 4 were excluded for lack of reliable postoperative data. Most subprocedures were scored as optimal. Subprocedures with the largest inadequate scores were distal arch reconstruction in 7 (6%) patients and aortopulmonary shunt in 3 (5%). No statistical differences were found among surgeons either by subprocedure or by overall outcome, although individual sample sizes were small. The overall score correlated with length of stay, extracorporeal membrane oxygenator support, and hospital mortality. Technical performance can be measured after the stage I procedure, and performance score correlates with early outcome. This score may also be useful as a self-assessment tool.


A "defined baseline" in PTH monitoring increases surgical success in patients with multiple gland disease.
Parathyroid hormone (PTH) monitoring with a quick intact PTH (QIPTH) assay is used in minimally invasive exploration for primary hyperparathyroidism (PHPT) in order not to miss multiple gland disease (MGD). Controversy exists on which criterion is most reliable to predict cure. QIPTH values of 310 consecutive patients (single gland disease [SGD]: n = 289; MGD: n = 21) with sporadic PHPT were analyzed using 3 different criteria: "Vienna Criterion": >/=50% decay from a defined "baseline" level (right after induction of anesthesia before skin incision) 10 min after excision. "Miami Criterion": >/=50% decay from highest (preincision or preexcision) value 10 min after excision; "Halle Criterion": decay of the PTH- level to less than or equal to 35 pg/mL within 15 min after excision. The "Vienna" and "Halle Criteria" correctly detected MGD in 19 (91%) and the "Miami Criterion" in 12 (57%) of 21 patients. Incorrect prediction of incomplete excision occurred in 22 patients (8%) with SGD, using the "Vienna Criterion" ("Miami Criterion": 2%, "Halle Criterion": 29%). All of these were recognized intraoperatively from unintended intraoperative manipulation (n = 18), technical failure (n = 2), or borderline increased PTH values (n = 2), and they did not lead to bilateral exploration. Analyzing patients with SGD and MGD, accuracy and specificity were 92% and 89% for the "Vienna Criterion," 93% and 54% applying the "Miami Criterion," and 72% and 89% using the "Halle Criterion." Strict definition of a PTH "baseline level" ("Vienna Criterion") improves intraoperative diagnosis of MGD, thus reducing reoperations and increasing long-term cure.


The relationship among IL-13, GSTP1, and CYP1A1 polymorphisms and environmental tobacco smoke in a population of children with asthma in Northern Mexico.
Exposure to environmental tobacco smoke (ETS) during early childhood increases the risk of developing asthma. The intention of this study was to genotype a population of children from Coahuila state in Northern Mexico and to determine whether polymorphisms of the CYP1A1, GSTP1, and IL13 genes are associated with exposure to ETS and subsequently a higher risk for asthma. IL13 plays an important role in the development of allergic response, particularly those related with airway inflammation. CYP1A1 and GSTP1 are xenobiotic-metabolizing enzymes induced by repeated exposure to toxicants. Polymorphisms of these genes have been related with ETS exposure and increased risk for asthma. To assess the effect of IL13 (-1112 C>T and Arg110Gln), GSTP1 (Ile105Val), and CYP1A1 (Ile462Val) on asthma risk and ETS exposure, we recruited 201 unrelated children and classified them into four groups: (1) control without ETS exposure; (2) control with ETS exposure; (3) with asthma and with ETS exposure and (4) with asthma and without ETS exposure. No association among ETS exposure, asthma, and the studied polymorphisms was denoted by multivariate analysis of this population.


Real-time differential tracking of human neutrophil and eosinophil migration in vivo.
Hitherto, in vivo studies of human granulocyte migration have been based on indiscriminate labeling of total granulocyte populations. We hypothesized that the kinetics of isolated human neutrophil and eosinophil migration through major organs in vivo are fundamentally different, with the corollary that studying unseparated populations distorts measurement of both. Blood neutrophils and eosinophils were isolated on 2 separate occasions from human volunteers by using Current Good Manufacturing Practice CD16 CliniMACS isolation, labeled with technetium 99m-hexamethylpropyleneamine oxime, and then reinfused intravenously. The kinetics of cellular efflux were imaged over 4 hours. Neutrophils and eosinophils were isolated to a mean purity of greater than 97% and greater than 95%, respectively. Activation of neutrophils measured as an increase in their CD11b mean fluorescence intensity in whole blood and after isolation and radiolabeling was 25.98 ± 7.59 and 51.82 ± 17.44, respectively, and was not significant (P = .052), but the mean fluorescence intensity of CD69 increased significantly on eosinophils. Analysis of the scintigraphic profile of lung efflux revealed exponential clearance of eosinophils, with a mean half-life of 4.16 ± 0.11 minutes. Neutrophil efflux was at a significantly slower half-life of 13.72 ± 4.14 minutes (P = .009). The migration of neutrophils and eosinophils was significantly different in the spleen at all time points (P = .014), in the liver at 15 minutes (P = .001), and in the bone marrow at 4 hours (P = .003). The kinetics of migration of neutrophils and eosinophils through the lung, spleen, and bone marrow of human volunteers are significantly different. Study of mixed populations might be misleading.


Acupuncture-related techniques for postoperative cognitive complications: a systemic review and meta-analysis.
Postoperative cognitive complications are major challenges for postoperative recovery. Acupuncture-related techniques have been used for treating neurocognitive dysfunctions. However, whether they help to prevent postoperative cognitive complicationss remains unclear. We intend to evaluate the effect of acupuncture-related techniques on the incidence of postoperative cognitive complications (PCC) in patients undergoing surgery under general anesthesia. Based on PRISMA guidelines, a search of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov was performed to identify eligible trials published from inception to June 6, 2021. The search was performed in June 2021. The inclusion criteria were prospective, randomized, controlled clinical trials that compared acupuncture-related techniques with other techniques or non-acupuncture treatment in patients undergoing surgery under general anesthesia. Pooled odds ratios (ORs), 95% CIs, and P values were estimated for end points using fixed and random effects statistical models. The analysis included 12 studies with 1058 patients. Compared with patients not receiving acupuncture, patients treated with acupuncture-related techniques had a lower incidence of PCCs (OR, 0.44; 95% CI, 0.33 to 0.59; P < 0.001; n = 968) and lower levels of biomarkers, including IL-6, TNF-α, and S100β. Acupuncture with needles and without needles showed similar effects on the prevention of PCCs. The effects of acupuncture-related techniques on PCCs were observed in both English and non-English articles. Subgroup analyses showed that both agitation and/or delirium (OR, 0.51; 95% CI, 0.34 to 0.76; P < 0.001; n = 490) and delayed cognitive recovery (OR, 0.33; 95% CI, 0.21 to 0.51; P < 0.001; n = 478) were reduced after treatment with acupuncture-related techniques. In adult studies evaluating MMSE scores, the scores were not different between groups (SMD, - 0.71; 95% CI, - 1.72 to 0.3; P = 0.17; n = 441). Acupuncture-related techniques, including needle techniques and electrical techniques, are associated with fewer postoperative cognitive complications, suggesting that acupuncture could be considered a potential option in the perioperative setting. Additional research is needed to develop higher-quality evidence and optimal regimens. PROSPERO (CRD42021258378).


Complete Calcified Ureteral Stent: A Combined 1-Session Approach.
To demonstrate a successful 1-session approach to a complete calcified ureteral stent, preserving the affected kidney without complications. A 33-year-old man presented at our service with an increased urinary frequency, afebrile urinary tract infection, and left lumbar pain. He underwent a ureterolithotripsy with ureteral stenting 3 years ago. After that intervention, he was lost to follow-up. A noncontrast computed tomography scan revealed a complete calcified ureteral stent (FECal V). After careful preoperative planning, the patient was submitted to a combined 1-step approach including left semirigid ureteroscopy, left percutaneous nephrolithotomy, and an open cystolithotomy in supine decubitus. This video demonstrates the surgical steps of the procedure for a FECal V (completely calcified) stent removal. Operative time was 240 minutes. The calcified stent was completely removed. A 6 Fr ureteral catheter and a 16 Fr nephrostomy tube were left at the end of the procedure. No double-J stent was used to avoid the same kind of complication. The patient had no peri- or postoperative complications. A computed tomography scan was performed in the first postoperative day (POD) and revealed 2 small residual fragments (7 mm and 6 mm). The ureteral catheter was removed on the first POD, and the nephrostomy tube on the second POD. The patient was discharged from hospital on the third POD. The patient is now scheduled to a flexible ureteroscopy to treat the small residual fragments. Forgotten ureteral stent is a surgical challenge, requiring multiple approaches and advanced urologic techniques. Our video illustrates that a less invasive and combined 1-step procedure to preserve the kidney is both safe and feasible, when performed by an experienced surgeon.


Radically novel prostaglandins in animals and plants: the isoprostanes.
Animal prostaglandins and plant jasmonates are well-known enzymatically formed cyclopentanoic lipids that have regulatory functions and serve as inducible mediators of host defense reactions. A novel group of prostaglandin-like compounds, the isoprostanes, generated in animals and plants by a nonenzymatic, free radical-catalyzed process, are now suspected to be mediators of oxidant injury in vivo.


A new perspective for Somatic Dysfunction in Osteopathy: the Variability Model.
Osteopathy uses manipulative techniques to support physiological function and adaptation. These conditions are modified by the presence of Somatic Dysfunction (SD), an altered function of the components of the body's framework system. Despite SD's widespread use in clinical practice and education, research has previously shown poor results in terms of reliability and validity. In this theoretical article, the authors' proposal is to argue for a new clinical perspective for SD, which suggests a different palpatory assessment of its clinical signs: the "Variability Model". A double simultaneous literature search was performed between January and March 2019 in Medline's electronic database. The first one critically analysed the clinical signs most used to detect SD. The second one informed authors' hypothesis related to movement variability assessment in the Neutral Zone (NZ). The Variability Model explains how the assessment of the range of motion in the NZ is essential to detect SD, its motion asymmetry and its relative restriction. The Variability Model explains SD semeiotics which could be related to "body adaptability", thus having implications with the concept of health. Finally, this paradigm aims to establish new developments in research, especially regarding SD reliability and clinical relevance. Movement variability allows to interpret SD clinical signs as an attempt by the body to maintain a healthy condition. This paradigm should be included in the future context of osteopathy which could better explain SD's pathophysiological mechanism, without ignoring the accuracy of its physical examination.


Bradykinin stimulates interleukin-8 production by human lung fibroblasts.
Bradykinin (BK) is a potent inflammatory mediator that is generated from kininogens by the actions of plasma and tissue kallikreins. Lung fibroblasts have the potential to participate in the inflammatory responses by releasing proinflammatory cytokines in response to a variety of stimuli. We postulated that human lung fibroblasts might produce interleukin-8 (IL-8) in response to BK stimulation. The present study showed that BK stimulated human lung fibroblasts to produce IL-8 in a dose- and time-dependent manner. Furthermore, Northern blot analysis showed that BK increased IL-8 mRNA expression. The stimulatory effect of BK on IL-8 production was detected at the concentration of 10 nm, and the maximal stimulation was achieved with 100 to 1000 nm. Phorbol 12-myristate 13-acetate pretreatment diminished the ability of BK to stimulate IL-8 production. In addition, GF109203X, a selective protein kinase C inhibitor, blocked BK-induced IL-8 production. These observations suggest that the stimulatory effect of BK on IL-8 production by lung fibroblasts is, at least partially, mediated through protein kinase C. These data suggest that BK may be involved in the inflammatory reaction leading to interstitial lung disorders through stimulating IL-8 production by lung fibroblasts.


The nitrogen reduction in eutrophic water column driven by Microcystis blooms.
During the bloom seasons, the dissolved inorganic nitrogen declines, which results in the occurrence of nitrogen limitation. It is unclear where the nitrogen goes. Our enclosure experiments and batch tests suggested that Microcystis blooms could significantly reduce the nitrogen in water bodies and the key mechanisms for the nitrogen reduction in different layers were different. The assimilation was the main pathway for nitrogen reduction in the surface layer, while denitrification played an important role both at the sediment-water interface and in the overlying water. Stable nitrogen isotope experiments showed that the nitrate reduction efficiency at sediment-water interface was enhanced by Microcystis, reaching to 76.5∼84.7 %. Dissimilation accounted for 63.8∼67.3 % of the nitrate reduction, and the denitrification rate was 7.4∼8.5 times of DNRA rate. In the water column, the Microcystis bloom facilitated the formation of dark/anoxic condition, which favored the denitrification. The Microcystis aggregates collected from the field showed a great potential in removing nitrogen, and the TN in the overly water was reduced by 3.76∼6.03 mg L-1 within two days. This study provided field evidences and deeper insights into the relationship between Microcystis blooms and nitrogen reduction in the whole water column and gave more details about the enhancing effects of Microcystis on nitrogen reduction.


Complex spinal reflexes during transcranial Doppler ultrasound examination for the confirmation of brain death.
Complex sets of movements of the extremities can be seen in patients with brain death (BD), and are typically observed during apnea testing or removal of ventilatory support (also called the Lazarus sign). We here describe brain-dead patients who had not shown previous movements, even during apnea testing, but presented complex spinal reflexes during transcranial Doppler (TCD) examination elicited by neck flexion. We performed a prospective TCD study of patients with the clinical diagnosis of BD. Four (2.5%) of 161 brain-dead patients presented complex spinal reflexes exclusively during TCD examination. TCD showed vertebro-basilar circulatory arrest in all four. Their systolic blood pressure was significantly lower than that of brain-dead patients not presenting movements during TCD examination. Hypotension and mechanical stimulation play a role in the pathophysiology of complex spinal reflexes present in BD, which are not exclusively seen in terminal hypoxia. Intensive care personnel and neurologists who perform TCD to confirm BD should be aware of these movements.


Can low frequency sound stimulation during posturography help diagnosing possible perilymphatic fistula in patients with sensorineural hearing loss and/or vertigo?
Perilymphatic fistula (PLF) is often difficult to diagnose because of the similar symptomatology, such as vertigo, tinnitus and hearing loss, which is found in several inner ear diseases. We attempted to correlate a positive result of low frequency sound (LFS) stimulation tests in posturography with the presence or absence of a PLF confirmed by transtympanic endoscopy in 209 patients with various inner ear diseases (Meniere's disease ( n=128), vestibulopathy ( n=41), cochleopathy ( n=28) and sudden deafness ( n=12). LFS provoked unsteadiness in posturography without PLF in 24 patients with Meniere's disease, in 5 patients with vestibulopathy, in 3 patients with cochleopathy and in 2 patients with sudden deafness. In one patient, tympanoscopy revealed fistula in the round window membrane that was covered with a fibrinous layer. In four cases there was abnormal light reflex in the round window but without PLF. In eight cases, Hennebert's sign was present with nystagmus, without PLF. We conclude that pathological responses to the LFS test in posturography can also be encountered in other inner ear diseases without PLF.


Spatial memory impairment in ventral subicular lesioned rats.
The present study examined the effects of ibotenic acid lesions of the ventral subiculum (SUB) on the ability of rats to memorize a rewarded alternation test in a T-maze. Results indicated that rats with ibotenic acid lesions (IL) of the ventral subiculum were impaired in postoperative acquisition of the spatial discrimination task, making more errors than the vehicle treated and normal control rats. In addition, all rats, including the IL group of rats, were able to memorize an acquired spatial behaviour. These findings suggest that the SUB play an important role in spatial information processing in rats.


Retinol-induced elevation of ornithine decarboxylase activity in cultured rat Sertoli cells is attenuated by free radical scavenger and by iron chelator.
We investigated retinol effects in ornithine decarboxylase activity in Sertoli cells. We also tested the hypothesis that free radical scavengers and iron chelators may attenuate the effect of retinol. Sertoli cells isolated from 15-day-old Wistar rats were previously cultured for 48 h and then treated with retinol by 24 h with or without mannitol (1 mM) or 1,10 phenanthroline (100 microM). We measured ornithine decarboxylase and catalase activities and malondialdehyde concentrations in response to retinol treatment. In response to 7 microM retinol treatment ornithine decarboxylase activity increased 30%. Retinol-induced ornithine decarboxylase activity was significantly decreased by addition of free radical scavenger (mannitol) or iron chelator (1,10 phenanthroline). In addition the same effect was observed in catalase increased activity and in malondialdehyde concentrations. These results suggest that retinol treatment induced ornithine decarboxylase and catalase activity and increased malondialdehyde concentration. These effects appear to be mediate by ROS.


Selective changes in the phosphorylation of endogenous proteins in subcellular fractions from cyclic AMP-induced differentiated neuroblastoma cells.
The endogenous phosphorylation of specific proteins was studied in subcellular fractions from proliferating and cAMP-induced differentiated neuroblastoma cells. Fractions containing nuclear, membrane-bound, and cytosolic proteins were incubated with [gamma-32P]ATP, in the presence and absence of added cyclic nucleotides. Phosphate incorporation into specific proteins was determined by slab-gel electrophoresis of sodium dodecyl sulfate-solubilized reaction products. Cytosol fractions from differentiated cells demonstrated a twofold increase in cAMP-dependent phosphorylation of a specific protein with apparent mol wt of 59,000 daltons and a comparable decrease in cAMP-independent phosphorylation of another protein (97,000). The nuclear fraction of differentiated cells showed an increase in the cAMP-independent phosphorylation of two nonhistone proteins (110,000 and 102,000). Membrane fractions from differentiated cells exhibited a differential decrease in endogenous phosphorylation of specific proteins. Selective alterations in the phosphorylation of specific proteins in various subcellular components may be important biochemical events associated with the increased levels of differentiated functions in neuroblastoma cells in culture.


Copper deficiency with pancytopenia due to enteral nutrition through jejunostomy.
Copper deficiency is a rare complication of enteral nutrition. Haematologic abnormalities such as neutropenia and anaemia, but not pancytopenia, have been described associated to copper deficiency. We report the case of a patient requiring long term enteral nutrition through jejunostomy who developed copper deficiency and pancytopenia. In 1991, a 47-year-old woman was admitted with severe gastroesophageal mucositis after an attempted suicide with caustic intake. Enteral nutrition with a commercial, polymeric, fiber-containing formula was started. Twenty-eight months later, the patient developed anemia and neutropenia that did not respond to combined iron and parenteral vitamin B(12) supplementation. In 1996 the patient showed pancytopenia and low serum levels of copper and ceruloplasmin. Pancytopenia improved after copper supplementation. Possible mechanism causing copper deficiency and pancytopenia are discussed. We conclude that assessment of copper status is advisable in patients receiving long-term enteral nutrition by jejunostomy.


High-performance liquid chromatographic separation of ring-oxidized metabolites of nitro-polycyclic aromatic hydrocarbons.
Nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) are widespread genotoxic environmental pollutants, which require metabolic activation to exert their biological activities. Metabolism of nitro-PAHs generates ring-oxidized metabolites including epoxides, phenols, dihydrodiols and tetrahydrotetrols. Separation of the oxidized metabolites and related compounds of a series of isomeric nitro compounds derived from anthracene, benz[a]anthracene, benzo[a]pyrene and benzo[e]pyrene was studied by high-performance liquid chromatography (HPLC) of different types of columns (monomeric and polymeric; reversed-phase and normal-phase). In the reversed-phase HPLC system, the general elution order of these compounds is: parent nitro-PAHs greater than phenolic derivatives greater than epoxides greater than dihydrodiols greater than tetrahydrotetrols. Among the geometric isomers, trans-dihydrodiols with both hydroxyl groups at the quasiaxial positions were eluted earlier than those with the hydroxyl groups at the quasiequatorial positions. Orientation of the nitro substituent has also been found to be an important structural feature for determining the relative retention order. Among the geometric isomers of nitro-PAHs and trans-dihydrodiols, the isomers with their nitro groups perpendicular or nearly perpendicular to the aromatic rings were eluted faster than the analogues with their nitro groups parallel or nearly parallel to the aromatic rings. Normal-phase HPLC gave opposite retention order, but with different separability among some of the compounds. Therefore, combination of both reversed- and normal-phase HPLC provides efficient separation of the ring-oxidized derivatives of nitro-PAHs. Results are also presented to compare the separation efficiency among different types of columns used. The results suggest that the polarity of solutes is the principal factor for determining their HPLC retention time.


The microtubule-associated tau protein has intrinsic acetyltransferase activity.
Tau proteins are the building blocks of neurofibrillary tangles (NFTs) found in a range of neurodegenerative tauopathies, including Alzheimer's disease. Recently, we demonstrated that tau is extensively post-translationally modified by lysine acetylation, which impairs normal tau function and promotes pathological aggregation. Identifying the enzymes that mediate tau acetylation could provide targets for future therapies aimed at reducing the burden of acetylated tau. Here, we report that mammalian tau proteins possess intrinsic enzymatic activity capable of catalyzing self-acetylation. Functional mapping of tau acetyltransferase activity followed by biochemical analysis revealed that tau uses catalytic cysteine residues in the microtubule-binding domain to facilitate tau lysine acetylation, thus suggesting a mechanism similar to that employed by MYST-family acetyltransferases. The identification of tau as an acetyltransferase provides a framework to further understand tau pathogenesis and highlights tau enzymatic activity as a potential therapeutic target.


Inhibition of tumor growth by recombinant vaccinia virus expressing GA733/CO17-1A/EpCAM/KSA/KS1-4 antigen in mice.
The human colorectal carcinoma (CRC)-associated GA733 antigen (Ag), also named CO17-1A/EpCAM/KSA/KS1-4, has been a useful target in passive immunotherapy of CRC patients with monoclonal antibody (mAb) and in active immunotherapy with anti-idiotypic antibodies or with recombinant protein. These approaches have targeted single epitopes (monoclonal anti-GA733 antibodies and anti-idiotypic antibodies) or extracellular domain epitopes (recombinant protein), primarily by B cells. To determine whether a reagent that induces immunity to a larger number of both B- and T-cell epitopes might represent a superior vaccine, we analyzed the capacity of full-length GA733 Ag expressing multiple potentially immunogenic epitopes and encoded by recombinant vaccinia virus (VV GA733-2) to induce humoral, cellular, and/or protective immunity in mice. VV GA733-2 induced Ag-specific antibodies that reacted predominantly to unknown epitopes on the Ag and lysed Ag-positive CRC targets in conjunction with murine peritoneal macrophages as effector cells. Immunized mice developed Ag-specific, proliferative and delayed-type hypersensitive lymphocytes. VV GA733-2 inhibited growth of ras-transformed syngeneic tumor cells expressing the human GA733 Ag in mice. These results suggest the potential of VV GA733-2 as a candidate vaccine for patients with CRC, possibly in combination with recombinant GA733-2-expressing adenovirus, which has been shown to induce cytolytic antibodies and T cells as well as tumor protective effects in mice. The combined vaccine approach may be superior to the use of either vaccine alone in patients who are pre-immune to both viruses.


The functional development of input-output relationships in the rostral portion of the corpus callosum in the kitten.
Microstimulation of the rostral portion of the corpus callosum (CC) was carried out on 21 awake kittens ranging in age from 45 to 105 days to determine the age at which motor responses first appeared and that at which they assumed functional adult-like properties. Motor responses to microstimulation first appeared over an interval ranging from 78-86 days postnatally. As in adults, they consisted of discrete, well-localized contractions of shoulder, whisker, and eyelid muscles according to the stimulated sites. In the first days after their appearance, motor responses differed markedly from those in adults because: (a) they exhibited higher thresholds; (b) they did not faithfully follow pulse trains delivered at 10 s intervals; (c) they had variable and longer latencies. Thereafter, motor responses gradually became stable, faithfully followed suprathreshold stimulation delivered at 0.1/s frequency, and acquired lower thresholds and shorter latencies, until they exhibited adult-like properties at 93-100 days of age. Single-unit recordings were obtained from 138 fibres isolated in the same callosal region submitted to microstimulation in order to study the response properties of the callosal fibres to somatic stimuli in immature animals. On the basis of their reactivity to peripheral stimulation, fibres were classified into three main types: (1) unreactive units (58 fibres), which could not be driven by somatic stimuli. (2) Adult-like units (55 fibres), which were readily driven by somatic stimuli and were endowed with fixed and small receptive fields (RFs) indistinguishable from those of adults. (3) Immature units (25 fibres), which were unsteadily driven by somatic stimuli applied over large areas at the periphery. Neither the RFs nor the adequate stimuli could be reliably determined. This type of units was not found in the adult cat (Spidalieri et al. 1985). The proportion of unreactive units was the highest before the appearance of motor responses and gradually decreased, approaching the adult level after attaining adult-like motor responses. Conversely, the proportion of adult-like units was lowest before the appearance of motor responses and gradually increased, approaching the adult level after motor responses had acquired adult-like properties.


Nephron sparing surgery for renal cell carcinoma in a solitary kidney.
To determine functional and oncological outcomes of nephron sparing surgery (NSS) for renal cell carcinoma (RCC). We identified from our kidney database 103 consecutive patients undergoing NSS for solid renal tumors in a solitary kidney. After excluding 17 patients (16.5%) undergoing NSS with palliative intent in presence of preoperatively diagnosed metastatic disease (n = 15) or positive lymph nodes (n = 2) and 6 patients (5.8%) who turned out to have benign tumors, the remaining 80 patients with RCC were analyzed. Mean follow-up is 8.0 years (range: 0.1-25.8). Mean tumor size was 4.2 cm (range 1.2-11 cm). Chronic renal failure requiring hemodialysis developed after NSS in nine patients (11.2%). In the remainder, serum creatinine was 1.72 mg/dl (range: 0.45-4.6 mg/dl) at latest follow-up. The cancer specific survival rates at 1, 5 and 10 years were 97.2, 89.6 and 76%, respectively. The estimated local recurrence free survival rates at 1, 5 and 10 years were 97.8, 89.4 and 79.9%, respectively. Univariate analysis of correlation between clinical and pathologic features with death from RCC showed significant associations for grading and tumor size. The long-term data of our series support the concept of organ-sparing surgery for RCC in a solitary kidney since it provides excellent local tumor control and cancer specific survival and preserves renal function renal function so that 89% of patients remained free of dialysis in the long-run.


The quality of work life and turnover intentions among Malaysian nurses: the mediating role of organizational commitment.
Understanding the factors influencing nurses' turnover intention, particularly the work life quality and commitment to organization, is important to all countries suffering from nursing shortage. The study aims to determine the mediating role of commitment to organization on work life quality and its relationship with turnover intention among Malaysian nurses. A descriptive cross-sectional design, using a self-report survey was conducted on 430 nurses from a teaching hospital from February to April 2019. A structural equation model version 3 was used for testing study hypotheses. The mediating effect (indirect effect) of organizational commitment on the relationship between work life quality and turnover intention (QWL→OC→IT) was negative with path coefficient - 0.234, whereas the direct effect of work life quality on turnover intention (QWL→IT) was negative with smaller path coefficient - 0.228. This means that the relationship between work life quality and turnover intention was partially mediated by the organizational commitment (P < 0.001). Organizational commitment has a negative partial mediating effect between work life quality of nurses and intention of turnover in teaching hospitals where the organizational commitment significantly reduced the nurses' intention to leave. The study findings can guide nursing managers to be carefully attended to the levels of nurses' commitment to their organization.


The role of district hospitals and the action in international medicine network.
As the first-referral hospitals for the primary health care (PHC) services, district hospitals providing secondary health care (SHC) have a peculiar importance in the developing world. The World Health Organization has led the way in defining their functions and adopting the concept of the district health system linking PHC and SHC in a vital relationship. The author's personal experience in this area over many years in Nigeria is presented in this article. The need for postgraduate training programs to encourage physicians to pursue a career at the district level is becoming widely recognized as an extension of the discipline of general practice/family medicine.


Biofeedback assisted diaphragmatic breathing and systematic relaxation versus propranolol in long term prophylaxis of migraine.
To evaluate utility of biofeedback assisted diaphragmatic breathing and systematic relaxation in migraine and to compare their efficacy with propranolol in long term prophylaxis of migraine. 192 migraine patients were randomly distributed into two groups. Propranolol group received propranolol 80 mg/day while biofeedback group received electromyogram (EMG) and temperature biofeedback assisted diaphragmatic breathing and systematic relaxation training accompanied by home practice for 6 months. Significant clinical response was seen with biofeedback in 66.66% and with propranolol in 64.58% of patients. Frequency, severity, duration of attacks and number of vomiting episodes were significantly reduced in both the groups at 6 months but inter-group differences were statistically insignificant. During 1 year post-treatment period, significantly lesser resurgence of migraine was seen in biofeedback group as whole (9.37%) and in biofeedback responders in biofeedback group (9.37%) in comparison to resurgence of migraine in propranolol group as whole (38.54%) and in propranolol responders in propranolol group (53.22%) respectively. Biofeedback assisted diaphragmatic breathing and systematic relaxation were very useful in migraine and had significantly better long-term prophylactic effect than propranolol in migraine.


Nucleolar p14(ARF) overexpression in Reed-Sternberg cells in Hodgkin's lymphoma: absence of p14(ARF)/Hdm2 complexes is associated with expression of alternatively spliced Hdm2 transcripts.
The development of human cancers is frequently associated with the silencing of the two major tumor suppressor pathways represented by retinoblastoma protein and p53. As the incidence of p53 mutations is significantly lower in Hodgkin's lymphoma than in other neoplasias, we investigated whether the malfunction of other proteins in this pathway could be responsible for its inactivation. Because the existence of nucleolar complexes between p14(ARF) and Hdm2 has been described as having a critical effect on p53 function by inhibiting its degradation, we analyzed the expression and subcellular localization of these proteins in 52 cases and in Hodgkin's cell lines. Two of four cell lines revealed loss of p14(ARF) expression secondary to gene promoter methylation, this being mutually exclusive with p53 mutations (1 of 4), illustrating the existence of selective pressure to inactivate the p53 pathway. The majority of Hodgkin's samples showed a strong nucleolar expression of p14(ARF) that was not associated with Hdm2. They also showed the existence of Hdm2/p53 complexes, and the absence of complexes containing either p14(ARF)/Hdm2 or p14(ARF)/p53. The different localization of Hdm2 (nucleoplasm) and p14(ARF) (nucleoli) observed in Hodgkin's tumors and cell lines is associated with the presence of short alternatively spliced transcripts of Hdm2 lacking the ARF-binding region and the nuclear export signal. The absence of these p14(ARF)/Hdm2 nucleolar complexes could be sufficient to inactivate the pathway and may explain the low frequency of p53 mutations in this tumor.


Ocular inflammation and infection.
Ocular inflammation and infection may involve any part of the eye and surrounding tissue. A complete examination, including visual acuity, extraocular movements, pupillary response, slit lamp examination, and fluorescein staining, is often required to establish the diagnosis. Pain relief may be achieved with oral analgesics and cycloplegics. In most cases, prompt follow-up is required.


Developmental restrictions on transcription: determinants of the developmental program and their role in aging.
A developing plant system, the soybean hypocotyl has been used to investigate early transcription events which restrict auxin induced cellular proliferation to the appropriate developmental stage. Auxin treatment of 4-day old seedlings resulted in an early (6 hour) activation of chromatin-bound RNA polymerase activity wihich approached 200% of control values by 18 hours. This occurred without a detectable alteration in chromatin template capacity (assayed with exogenous RNA polymerase) and resulted in the synthesis of "induced RNA transcripts" as determined in vitro by nearest neighbor analysis. In contrast, auxin treatment of unresponsive 8-day old seedlings did not alter the chromatin-bound RNA polymerase activity. Hormonal activation did, however, result in the exposure of "induced template" regions in chromatin which could only be transcribed in vitro if exogenous RNA polymerase was included in the transcription reaction. Isoelectric focusing of the endogenous chromatin-bound and soluble RNA polymerase enzymes from successive developmental stages revealed that the chromatin-bound enzymes at the 2-day stage were first released from the chromatin complex and could be recovered in the soluble pool (4-day stage). This was followed by a gradual disappearance of these subspecies (6-day stage) until only a limited ensemble of RNA polymerase subspecies remained bound to chromatin and free in the soluble pool (8-day stage). Similar analyses of both the bound and free enzymes at the 4 and 8-day stages following auxin treatment revealed that the 4-day soluble enzymes could be induced to rebind to the chromatin complex in a defined sequence after hormone treatment while those of the 8-day hypocotyl were unable to do so. These developmental events indicate that the select loss of certain RNA polymerase subspecies serves to restrict the hormone responsivness of this tissue to the early developmental stages. Such restrictions could thus commit the constituent hypocotyl cells to their terminal post-mitotic phase of development.


Arginine deprivation, growth inhibition and tumour cell death: 3. Deficient utilisation of citrulline by malignant cells.
Arginine deprivation causes death of up to 80% of cancer cell lines in vitro, but in the body, citrulline would be available as a convertible source of this amino acid in vivo. Some tumour cell lines, notably the vast majority of melanomas and hepatocellular carcinomas, tend to be deficient in argininosuccinate synthetase (EC 220.127.116.11.), and therefore cannot recycle citrulline to arginine. Argininosuccinate synthetase is present at levels that convert enough citrulline to arginine to allow limited growth in about half of a modest range of malignant cell types analysed in this study. Attempts to rescue cells that are unable to utilise citrulline with the immediate downstream product, argininosuccinate, had very limited success in a few tumour cell lines. Particularly noteworthy is the demonstration that argininosuccinate was totally incapable of rescuing cells that utilise citrulline efficiently, consistent with tight channelling (coupling) of argininosuccinate synthetase and argininosuccinate lyase in the urea cycle. The findings suggest that an excellent opportunity exists for further exploitation of arginine deprivation in the selective killing of tumour cells.


Microstructural damage sensitivity prediction using spatial statistics.
The vast compositional space of metallic materials provides ample opportunity to design stronger, more ductile and cheaper alloys. However, the substantial complexity of deformation micro-mechanisms makes simulation-based prediction of microstructural performance exceedingly difficult. In absence of predictive tools, tedious experiments have to be conducted to screen properties. Here, we develop a purely empirical model to forecast microstructural performance in advance, bypassing these challenges. This is achieved by combining in situ deformation experiments with a novel methodology that utilizes n-point statistics and principle component analysis to extract key microstructural features. We demonstrate this approach by predicting crack nucleation in a complex dual-phase steel, achieving substantial predictive ability (84.8% of microstructures predicted to crack, actually crack), a substantial improvement upon the alternate simulation-based approaches. This significant accuracy illustrates the utility of this alternate approach and opens the door to a wide range of alloy design tools.


Neck Loads During Head-First Entries into Trampoline Dismount Foam Pits: Considerations for Trampoline Park Safety.
Serious cervical spine injuries have been documented from falls into foam pits at trampoline parks. To address the lack of evidence on how foam pits should be designed for mitigating neck injury risk, this study aimed to quantify neck loads during head-first entry into varying foam pit designs. An instrumented Hybrid III anthropomorphic test device was dropped head-first from a height of up to 1.5 m into three differently constructed foam pits, each using a different mechanism to prevent direct contact between the falling person and the floor (foam slab, trampoline or net bed). Measured neck loads were compared to published injury reference values. In the simplest, foam-only pit design, increasing foam depth tended to reduce peak compressive force. At least one injury assessment reference metric was exceeded in all pit conditions tested for 1.5 m falls, most commonly the time-dependent neck compression criterion. The results highlight the importance of adequate foam depth in combination with appropriate pit design in minimizing injury risk. The risk of cervical spine injury may not be reduced sufficiently with current foam pit designs.


Regional variations in human newborn cerebral blood flow.
Regional differences in the local cerebral metabolic rate of glucose have been reported in newborn infants. This study was performed to determine if comparable differences exist in neonatal regional cerebral blood flow (rCBF). In 21 infants, rCBF was measured with a modified xenon 133 (133Xe) clearance technique by means of eight extracranial detectors positioned over four homologous regions (frontal, parietal, temporal, and occipital). The rCBF was lowest in the frontal region, higher in the parietal region, and highest in the temporal and occipital regions. Regional differences in rCBF may be caused by regional differences in brain development and function.


Phosphoglucoisomerase-catalyzed interconversion of hexose phosphates: a model for the interconversion of D-[2-3H]glucose 6-phosphate and D-[1-3H]fructose 6-phosphate.
Based on experimental data, a model is proposed for the interconversion of either unlabelled hexose phosphates or D-[2-3H]glucose 6-phosphate and D-[1-3H]fructose 6-phosphate in the reaction catalyzed by phosphoglucoisomerase. This model takes into account the known differences in maximal velocity and affinity for each substrate, the intramolecular transfer of tritium between C1 and C2, and the isotopic discrimination between unlabelled and tritiated esters. This model reveals that, in a close system characterized by the progressive detritiation of hexose phosphates, the concentration ratio of D-glucose 6-phosphate to D-fructose 6-phosphate is much higher with the tritiated than unlabelled esters, a paradoxical increase in the specific radioactivity of D-glucose 6-phosphate above its initial value being even observed during the initial period of exposure of D-[2-3H]glucose 6-phosphate to phosphoglucoisomerase. The extension of this model to an open system may be essential for the correct interpretation of radioactive data collected in intact cells exposed to D-[2-3H]glucose.