Paraoxonase 1 Activity and Survival in Sepsis Patients.
Sepsis is a state of augmented oxidative stress and diminished antioxidant capacity. High density lipoprotein (HDL) particles were shown to possess antioxidant and anti-inflammatory properties, as well as Paraoxonase 1 (PON1), which is an enzyme that is also protective against HDL oxidation. Previous studies suggested a possible role of decreased PON1 activity or HDL levels in sepsis patients. The present study was designed to test a hypothesis that higher PON1 activity and HDL-cholesterol levels could predict a better survival in sepsis patients. Observational study. Venous blood samples were collected from sepsis patients for HDL-cholesterol levels, PON1 activity and cytokine assays (TNF-α and IL-6) and Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores were calculated in order to weight patients' disease severity on the day of sepsis diagnosis. Patients were followed-up until the 28(th) day for any cause intra-hospital mortality. Data were statistically analyzed for effects of study parameters on patients' survival. In total, 85 patients with sepsis were included in the study. The mean age was 65.2±17.9 years and 48 were male; at the end of the 28-day follow-up period, 46 survived. TNF-α (86.9±10.5 vs 118.6±16.4) and IL-6 levels (906.7±82.7 vs 1323.1±54.3) were significantly higher in non-survivors, while PON1 activity (140.7±42.3 vs 66.7±46.6) and HDL-cholesterol levels (43.6±8.1 vs 34.5±8.9) were significantly higher in survivors (p<0.001 for all). TNF-α (r=-0.763) and IL-6 levels (r=-0.947) showed strong negative correlations, PON1 activity (r=0.644) and HDL-cholesterol levels (r=0.477) showed positive correlations with patient survival (p<0.001 for all). Survival estimates significantly favored TNF-α (Log Rank 59.5, p<0.001) and IL-6 levels (Log Rank 53.2, p<0.001) according to PON1 activity (Log Rank 5.4, p<0.03) and HDL-cholesterol levels (Log Rank 8.3, p<0.005). Regression analyses for relative contributions of parameters to survival showed that higher IL-6 levels (t: -16.489, p<0.001) were the most significant negative factor for survival, and TNF-α levels (t: -4.417, p<0.001), whereas PON1 activity had a positive effect (t:3.210, p<0.003). The present study showed that although low PON1 activity and HDL-cholesterol levels were related to mortality, higher levels were not found to be as predictive as cytokine levels for survival.


Impact of insurance and neighborhood socioeconomic status on clinical outcomes in therapeutic clinical trials for breast cancer.
The objective of this study was to evaluate the impact of insurance and neighborhood SES (nSES) on chemotherapy completion and overall mortality among participants in breast cancer clinical trials. The data sources for this study were two adjuvant breast cancer trials (ECOG E1199 and E5103) collectively including 9790 women. Insurance status at trial registration was categorized into private, government (Medicaid, Medicare, and other government type insurance), and self-pay. An Agency for Healthcare Research Quality (AHRQ) nSES index was calculated using residential zip codes linked to county level data on occupation, income, poverty, wealth, education, and crowding. Logistic regression and Cox Proportional Hazard models estimated odds ratios (OR) for chemotherapy treatment completion and hazard ratios (HR) for mortality, respectively, for insurance status and nSES. The models adjusted for: race, age, tumor size, nodal status, hormone receptor status, and primary surgery. The majority of patients had private insurance at trial registration: E1199: 85.6% (4154/4854) and E5103: 82.4% (3987/4836); median SES index was 53.8 (range: 41.8-66.8) and 54.1 (range: 44.5-66.1), respectively. Patients with government insurance were less likely to complete chemotherapy treatment (E1199 OR (95%CI): 0.73 (0.57-0.94); E5103 0.76 (0.64-0.91)) and had an increased risk of death (E1199 HR (95%CI): 1.44 (1.22-1.70); E5103 1.29 (1.06-1.58)) compared to the privately insured patients. There was no association between nSES and chemotherapy completion or overall mortality. Patients with government insurance at trial registration appeared to face barriers in chemotherapy completion and had a higher overall mortality compared to their privately insured counterparts.


Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis.
Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.


Disease parameters following ocular herpes simplex virus type 1 infection are similar in male and female BALB/C mice.
Sex related differences in the incidence or severity of infection have been described for multiple viruses. With herpes simplex viruses, the best example is HSV-2 genital infection where women have a higher incidence of infection and can have more severe infections than men. HSV-1 causes several types of infections including skin and mucosal ulcers, keratitis, and encephalitis in humans that do not appear to have a strong biological sex component. Given that mouse strains differ in their MHC loci it is important to determine if sex differences occur in multiple strains of mice. Our goal was to answer two questions: Are virus related sex differences present in BALB/C mice and does virulence of the viral strain have an effect? We generated a panel of recombinant HSV-1 viruses with differing virulence phenotypes and characterized multiple clinical correlates of ocular infection in BALB/c mice. We found no sex-specific differences in blepharitis, corneal clouding, neurovirulence, and viral titers in eye washes. Sex differences in neovascularization, weight loss and eyewash titers were observed for some recombinants, but these were not consistent across the phenotypes tested for any recombinant virus. Considering these findings, we conclude that there are no significant sex specific ocular pathologies in the parameters measured, regardless of the virulence phenotype following ocular infection in BALB/c mice, suggesting that the use of both sexes is not necessary for the bulk of ocular infection studies.


Effect of aqueous leaves extract of Ocimum gratissimum on hematological parameters in rats.
This study aims to elucidate the effect of Ocimum gratissimum on hematological parameters in rats. Thirty male albino Wistar rats were randomly assigned into three groups of ten rats each. Group 1 was control, while groups 2 (LD) and 3 (HD) received 500 mg/kg and 1000 mg/kg body weight, respectively, of the extract orally once daily. Rats in all three groups received normal rat chow and drinking water ad libitum for 28 days. Complete blood count was done using an automatic counter. The HD group had significantly (P<.05) higher red blood cell (RBC) counts, packed cell volume (PCV), hemoglobin (Hb), and platelet counts as compared with the control and LD groups. No significant changes were observed in the total white blood cell (WBC) count of the three groups, but significantly (P<.05) lower lymphocyte and higher neutrophil counts were observed in the HD group compared with the LD group. The mean platelet volume (MPV), platelet-large cell ratio (P-LCR), and platelet distribution width (PDW) were significantly (P<.05) reduced in the HD compared with the LD group. The mean corpuscular volume (MCV) and RBC distribution width-standard deviation were significantly (P<.05) lower in the HD group than in control. No significant changes were observed in levels of mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and RBC distribution width-coefficient of variation among the groups. We conclude that oral administration of O gratissimum increases RBC, PCV, Hb, platelet count, and neutrophils and also leads to a decrease in platelet indices (i.e., MPV, P-LCR, and PDW).


A heat shock transcription factor in pea is differentially controlled by heat and virus replication.
Since some heat-inducible genes [heat shock (hs) genes] can be induced by virus infection in pea [e.g. Hsp70; Aranda et al. 1996, Proc. Natl Acad. Sci. USA 93, 15289-15293], we have investigated the effect that heat and virus replication may have on the expression of a heat-shock transcription factor gene (Hsf). We have characterized what appears to be the only member of the Hsf family in pea, PsHsfA. Similar to Hsp70, PsHsfA is heat-inducible in vegetative and embryonic tissues, which is concordant with the presence of heat shock elements (HSEs) and stress responsive elements (STREs) on its promoter sequence. The expression of PsHsfA during virus replication was studied in pea cotyledons and leaves, and compared to that of Hsp70. In situ hybridization experiments showed that whereas Hsp70 is induced, there is no detectable increased accumulation of PsHsfA RNA associated with the replication of pea seed-borne mosaic potyvirus (PSbMV). These experiments indicate that there is a selective control of virus-induced hs gene expression, and suggest that different regulatory pathways control hs gene expression during heat shock and virus replication.


Ovarian cancer relies on the PDGFRβ-fibronectin axis for tumorsphere formation and metastatic spread.
High-grade serous ovarian cancer (HGSOC) is the deadliest gynecological malignancy. The most common form of metastatic spread of HGSOC is transcoelomic dissemination. In this process, detached cells from the primary tumor aggregate as tumorspheres and promote the accumulation of peritoneal ascites. This represents an early event in HGSOC development and is indicative of poor prognosis. In this study, based on tumorspheres isolated from ascitic liquid samples from HGSOC patients, ovarian cancer spheroid 3D cultures, and in vivo models, we describe a key signal for tumorsphere formation in HGSOC. We report that platelet-derived growth factor receptor beta (PDGFRβ) is essential for fibronectin-mediated cell clustering of ovarian cancer cells into tumorspheres. This effect is mediated by the kinase NUAK family SNF1-like kinase 1 (NUAK1) and blocked by PDGFRβ pharmacological or genetic inhibition. In the absence of PDGFRβ, ovarian cancer cells can be provided with fibronectin by cancer-associated fibroblasts to generate chimeric spheroids. This work provides new insights that uncover potential targets to prevent peritoneal dissemination, the main cause of advanced disease in HGSOC patients.


Bioinformatics analysis of fibroblasts exposed to TGF‑β at the early proliferation phase of wound repair.
The aim of the current study was to identify gene signatures during the early proliferation stage of wound repair and the effect of TGF‑β on fibroblasts and reveal their potential mechanisms. The gene expression profiles of GSE79621 and GSE27165 were obtained from GEO database. Differentially expressed genes (DEGs) were identified using Morpheus and co‑expressed DEGs were selected using Venn Diagram. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. Protein‑protein interaction (PPI) networks of the DEGs were constructed using Cytoscape software. PPI interaction network was divided into subnetworks using the MCODE algorithm and the function of the top one module was analyzed using DAVID. The results revealed that upregulated DEGs were significantly enriched in biological process, including the Arp2/3 complex‑mediated actin nucleation, positive regulation of hyaluronan cable assembly, purine nucleobase biosynthetic process, de novo inosine monophosphate biosynthetic process, positive regulation of epithelial cell proliferation, whereas the downregulated DEGs were enriched in the regulation of blood pressure, negative regulation of cell proliferation, ossification, negative regulation of gene expression and type I interferon signaling pathway. KEGG pathway analysis showed that the upregulated DEGs were enriched in shigellosis, pathogenic Escherichia coli infection, the mitogen‑activated protein kinase signaling pathway, Ras signaling pathway and bacterial invasion of epithelial cells. The downregulated DEGs were enriched in systemic lupus erythematosus, lysosome, arachidonic acid metabolism, thyroid cancer and allograft rejection. The top 10 hub genes were identified from the PPI network. The top module analysis revealed that the included genes were involved in ion channel, neuroactive ligand‑receptor interaction pathway, purine metabolism and intestinal immune network for IgA production pathway. The functional analysis revealed that TGF‑β may promote fibroblast migration and proliferation and defend against microorganisms at the early proliferation stage of wound repair. Furthermore, these results may provide references for chronic wound repair.


Endocervical gastric-type adenocarcinoma, an unrelated HPV tumour: difficulties in screening and diagnosis.
Gastric-type adenocarcinoma of the cervix (GAS) is an uncommon and aggressive tumour unrelated to human papillomavirus (HPV) infection with distinctive histological and immunohistochemical characteristics. GAS may be associated with lobular endocervical glandular hyperplasia (LEGH), another unusual lesion. We report a case of a 59-year-old woman with screening cytology 'AGC-Neo' and cervical conisation exhibiting cervical intraepithelial neoplasia grade 1, extensive LEGH and canal sampling with abundant mucinous cells. Based on the possible association between LEGH and GAS, a total hysterectomy was performed. The histological diagnosis revealed a morphological gradient of lesions: LEGH, minimal deviation adenocarcinoma and GAS with lymphatic invasion. Immunohistochemistry revealed strong MUC6 expression and no p16 staining. After pelvic radiotherapy, the patient continues follow-up evaluation. The diagnostic difficulties of GAS and its relationship with LEGH are discussed. This rare tumour is important because it is poorly symptomatic and potentially aggressive. In addition, the methods for cancer control related to HPV do not affect this tumour.


Intonation and communicative intent in mothers' speech to infants: is the melody the message?
This study explores the power of intonation to convey meaningful information about the communicative intent of the speaker in speech addressed to preverbal infants and in speech addressed to adults. Natural samples of infant- and adult-directed speech were recorded from 5 mothers of 12-month-old infants, in 5 standardized interactional contexts: Attention-bid, Approval, Prohibition, Comfort, and Game/Telephone. 25 infant-directed and 25 adult-directed vocalizations were electronically filtered to eliminate linguistic content. The content-filtered speech stimuli were presented to 80 adult subjects: 40 experienced parents and 40 students inexperienced with infants. The subjects' task was to identify the communicative intent of the speaker using only prosodic information, given a 5-alternative forced choice. Listeners were able to use intonation to identify the speaker's intent with significantly higher accuracy in infant-directed speech than in adult-directed speech. These findings suggest that the prosodic patterns of speech to infants are more informative than those of adult-adult speech, and may provide the infant with reliable cues to the communicative intent of the speaker. The interpretation of these results proposed here is that the relation of prosodic form to communicative function is made uniquely salient in the melodies of mothers' speech, and that these characteristic prosodic patterns are potentially meaningful to the preverbal infant.


A superfamily of voltage-gated sodium channels in bacteria.
NaChBac, a six-alpha-helical transmembrane-spanning protein cloned from Bacillus halodurans, is the first functionally characterized bacterial voltage-gated Na(+)-selective channel. As a highly expressing ion channel protein, NaChBac is an ideal candidate for high resolution structural determination and structure-function studies. The biological role of NaChBac, however, is still unknown. In this report, another 11 structurally related bacterial proteins are described. Two of these functionally expressed as voltage-dependent Na(+) channels (Na(V)PZ from Paracoccus zeaxanthinifaciens and Na(V)SP from Silicibacter pomeroyi). Na(V)PZ and Na(V)SP share approximately 40% amino acid sequence identity with NaChBac. When expressed in mammalian cell lines, both Na(V)PZ and Na(V)SP were Na(+)-selective and voltage-dependent. However, their kinetics and voltage dependence differ significantly. These single six-alpha-helical transmembrane-spanning subunits constitute a widely distributed superfamily (Na(V)Bac) of channels in bacteria, implying a fundamental prokaryotic function. The degree of sequence homology (22-54%) is optimal for future comparisons of Na(V)Bac structure and function of similarity and dissimilarity among Na(V)Bac proteins. Thus, the Na(V)Bac superfamily is fertile ground for crystallographic, electrophysiological, and microbiological studies.


Electrocardiographic manifestations of COVID-19.
Coronavirus disease of 2019 (COVID-19) is a lower respiratory tract infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease can impact the cardiovascular system and lead to abnormal electrocardiographic (ECG) findings. Emergency clinicians must be aware of the ECG manifestations of COVID-19. This narrative review outlines the pathophysiology and electrocardiographic findings associated with COVID-19. COVID-19 is a potentially critical illness associated with a variety of ECG abnormalities, with up to 90% of critically ill patients demonstrating at least one abnormality. The ECG abnormalities in COVID-19 may be due to cytokine storm, hypoxic injury, electrolyte abnormalities, plaque rupture, coronary spasm, microthrombi, or direct endothelial or myocardial injury. While sinus tachycardia is the most common abnormality, others include supraventricular tachycardias such as atrial fibrillation or flutter, ventricular arrhythmias such as ventricular tachycardia or fibrillation, various bradycardias, interval and axis changes, and ST segment and T wave changes. Several ECG presentations are associated with poor outcome, including atrial fibrillation, QT interval prolongation, ST segment and T wave changes, and ventricular tachycardia/fibrillation. This review summarizes the relevant ECG findings associated with COVID-19. Knowledge of these findings in COVID-19-related electrocardiographic presentations may assist emergency clinicians in the evaluation and management of potentially infected and infected patients.


Health anxiety and hypochondriasis in the light of DSM-5.
In the DSM-5, the diagnosis of hypochondriasis was replaced by two new diagnositic entities: somatic symptom disorder (SSD) and illness anxiety disorder (IAD). Both diagnoses share high health anxiety as a common criterion, but additonal somatic symptoms are only required for SSD but not IAD. Our aim was to provide empirical evidence for the validity of these new diagnoses using data from a case-control study of highly health-anxious (n = 96), depressed (n = 52), and healthy (n = 52) individuals. The individuals originally diagnosed as DSM-IV hypochondriasis predominantly met criteria for SSD (74%) and rarely for IAD (26%). Individuals with SSD were more impaired, had more often comorbid panic and generalized anxiety disorders, and had more medical consultations as those with IAD. Yet, no significant differences were found between SSD and IAD with regard to levels of health anxiety, other hypochondriacial characteristics, illness behavior, somatic symptom attributions, and physical concerns, whereas both groups differed significantly from clinical and healthy controls in all of these variables. These results do not support the proposed splitting of health anxiety/hypochondriasis into two diagnoses. Further validation studies with larger samples and additional control groups are warranted to prove the validity of the new diagnoses.


Evaluation of human monoclonal antibody 80R for immunoprophylaxis of severe acute respiratory syndrome by an animal study, epitope mapping, and analysis of spike variants.
In this report, the antiviral activity of 80R immunoglobulin G1 (IgG1), a human monoclonal antibody against severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) protein that acts as a viral entry inhibitor in vitro, was investigated in vivo in a mouse model. When 80R IgG1 was given prophylactically to mice at doses therapeutically achievable in humans, viral replication was reduced by more than 4 orders of magnitude to below assay limits. The essential core region of S protein required for 80R binding was identified as a conformationally sensitive fragment (residues 324 to 503) that overlaps the receptor ACE2-binding domain. Amino acids critical for 80R binding were identified. In addition, the effects of various 80R-binding domain amino acid substitutions which occur in SARS-like-CoV from civet cats, and which evolved during the 2002/2003 outbreak and in a 2003/2004 Guangdong index patient, were analyzed. The results demonstrated that the vast majority of SARS-CoVs are sensitive to 80R. We propose that by establishing the susceptibility and resistance profiles of newly emerging SARS-CoVs through early S1 genotyping of the core 180-amino-acid neutralizing epitope of 80R, an effective immunoprophylaxis strategy with 80R should be possible in an outbreak setting. Our study also cautions that for any prophylaxis strategy based on neutralizing antibody responses, whether by passive or active immunization, a genotyping monitor will be necessary for effective use.


Acylmorphinans. A novel class of potent analgesic agents.
A series of novel 2- and 3-acylmorphinans (8-14) was synthesized in our search for a potent analgesic agent with low addiction potential. The compounds were evaluated for antinociceptive potency and receptor binding affinity. Among these compounds, the levorotatory 3-acetyl-N-(cyclopropylmethyl)morphinan (12) was found to be an orally active analgesic, comparable in potency to morphine (1), yet only weakly able to substitute for morphine (1) in morphine-dependent rats.


A comparison of HLA genotype with inflammation in uveal melanoma.
Human leukocyte antigen (HLA) polymorphisms have been associated with the development of autoimmune diseases. In uveal melanoma, a high expression of HLA classes I and II, and infiltration with lymphocytes and macrophages are associated with a bad prognosis. Inflammation has an important role in this malignancy. The goal of our study was to determine whether specific HLA alleles are associated with increased inflammation. Records were analyzed of 45 patients who underwent enucleation for uveal melanoma. HLA typing, tumor HLA expression and tumor macrophage infiltration were determined in each case. Before correction for multiple testing, macrophage infiltration was less in HLA-A2 positive patients. Patients with HLA-DR6 had a higher tumor cell expression of HLA-DR. After correction for the number of analyses, no associations remained statistically significant. The results before correction suggest that the HLA genotype may influence inflammation as indicated by HLA expression and macrophage infiltration in uveal melanoma. However, after correction this association did not prove significant.


Interspecific analysis of diurnal gene regulation in panicoid grasses identifies known and novel regulatory motifs.
The circadian clock drives endogenous 24-h rhythms that allow organisms to adapt and prepare for predictable and repeated changes in their environment throughout the day-night (diurnal) cycle. Many components of the circadian clock in Arabidopsis thaliana have been functionally characterized, but comparatively little is known about circadian clocks in grass species including major crops like maize and sorghum. Comparative research based on protein homology and diurnal gene expression patterns suggests the function of some predicted clock components in grasses is conserved with their Arabidopsis counterparts, while others have diverged in function. Our analysis of diurnal gene expression in three panicoid grasses sorghum, maize, and foxtail millet revealed conserved and divergent evolution of expression for core circadian clock genes and for the overall transcriptome. We find that several classes of core circadian clock genes in these grasses differ in copy number compared to Arabidopsis, but mostly exhibit conservation of both protein sequence and diurnal expression pattern with the notable exception of maize paralogous genes. We predict conserved cis-regulatory motifs shared between maize, sorghum, and foxtail millet through identification of diurnal co-expression clusters for a subset of 27,196 orthologous syntenic genes. In this analysis, a Cochran-Mantel-Haenszel based method to control for background variation identified significant enrichment for both expected and novel 6-8 nucleotide motifs in the promoter regions of genes with shared diurnal regulation predicted to function in common physiological activities. This study illustrates the divergence and conservation of circadian clocks and diurnal regulatory networks across syntenic orthologous genes in panacoid grass species. Further, conserved local regulatory sequences contribute to the architecture of these diurnal regulatory networks that produce conserved patterns of diurnal gene expression.


The fragility of statistically significant findings from randomized trials in spine surgery: a systematic survey.
Randomized controlled trials (RCTs) are the most trustworthy source for evaluating treatment effects, but RCTs of spine surgery interventions often produce discordant results. The Fragility Index is a novel metric to inform about the robustness of statistically significant results. The aim was to determine the robustness of statistically significant results from RCTs of spine surgery interventions. This was a systematic survey. The sample included RCTs of spine surgery interventions. The Fragility Index is the minimum number of patients in a trial whose status would have to change from a nonevent to an event to change a statistically significant result to a nonsignificant result. Events refer to the occurrence of any dichotomous outcome, such as successful fusion, incident fracture, adjacent segment degeneration, or achievement of a certain functional score. A small Fragility Index indicates that the statistical significance of a result hinges on only a few events, and a large Fragility Index increases one's confidence in the observed treatment effects. We systematically reviewed a database for evidence-based orthopedics and identified all the RCTs that reported at least one positive outcome (ie, p<.05). Two reviewers independently assessed eligibility and extracted data. We used the Fisher exact test to compute Fragility Index values and multivariable linear regression to evaluate potential associated factors. We identified 40 eligible RCTs with a median sample size of 132 patients (interquartile range [IQR] 79-208) and a median total number of outcome events for the chosen outcome of 31 (IQR 13-63). The median Fragility Index was two (IQR 1-3), which means that adding two events to one of the trial's treatment arms eliminated its statistical significance. The Fragility Index was less than or equal to three events in 75% of the trials, and was less than or equal to the number of patients lost to follow-up in 65% of the trials. Fragility Index values correlated positively with total sample size (r=0.35; p<.05). When adjusted for losses to follow-up and risk of bias, increasing Fragility Index values were associated only with increasingly significant reported p values (p<.01). Statistically significant results in spine surgery RCTs are frequently fragile. The addition of only a small number of outcome events can completely eliminate significance. Surgeons, researchers, and other evidence users should exercise caution when interpreting the findings from RCTs with low Fragility Index values and applying these results to patient care.


Smolign: a spatial motifs-based protein multiple structural alignment method.
Availability of an effective tool for protein multiple structural alignment (MSTA) is essential for discovery and analysis of biologically significant structural motifs that can help solve functional annotation and drug design problems. Existing MSTA methods collect residue correspondences mostly through pairwise comparison of consecutive fragments, which can lead to suboptimal alignments, especially when the similarity among the proteins is low. We introduce a novel strategy based on: building a contact-window based motif library from the protein structural data, discovery and extension of common alignment seeds from this library, and optimal superimposition of multiple structures according to these alignment seeds by an enhanced partial order curve comparison method. The ability of our strategy to detect multiple correspondences simultaneously, to catch alignments globally, and to support flexible alignments, endorse a sensitive and robust automated algorithm that can expose similarities among protein structures even under low similarity conditions. Our method yields better alignment results compared to other popular MSTA methods, on several protein structure data sets that span various structural folds and represent different protein similarity levels. A web-based alignment tool, a downloadable executable, and detailed alignment results for the data sets used here are available at http://sacan.biomed. drexel.edu/Smolign and http://bio.cse.ohio-state.edu/Smolign.


Mapping the transition state of the WW domain beta-sheet.
The folding kinetics of a three-stranded antiparallel beta-sheet (WW domain) have been measured by temperature jump relaxation. Folding and activation free energies were determined as a function of temperature for both the wild-type and the mutant domain, W39F, which modifies the beta(2)-beta(3) hydrophobic interface. The folding rate decreases at higher temperatures as a result of the increase in the activation free energy for folding. Phi-Values were obtained for thermal perturbations allowing the primary features of the folding free energy surface to be determined. The results of this analysis indicate a significant shift from an "early" (Phi(T)=0. 4) to a "late" (Phi(T)=0.8) transition state with increasing temperature. The temperature-dependent Phi-value analysis of the wild-type WW domain and of its more stable W39F hydrophobic cluster mutant reveals little participation of residue 39 in the transition state at lower temperature. As the temperature is raised, hydrophobic interactions at the beta(2)-beta(3) interface gain importance in the transition state and the barrier height of the wild-type, which contains the larger tryptophan residue, increases more slowly than the barrier height of the mutant.


[Prophylactic use of Neoton in cardiac failure in patients with myocardial infarction].
Echocardiography and integral body rheography were made in 174 patients with macrofocal myocardial infarction (MI) to study hemodynamics at six stages of hospital rehabilitation (MI day 1-28). 97 patients received neoton (4 different scheme) in the acute period of MI. Neoton administration was found to prevent progressive left ventricular dilation and emergence of cardiac insufficiency in subacute period of MI, to reduce the risk of cardiac aneurism, recurrence and postinfarction angina. The response to neoton rises with an increase of its dose on the first day of the disease and lessening of the time span from first symptoms of MI and first neoton injection. An optimal scheme of neoton use is proposed.


DNA elements regulating alpha1-tubulin gene induction during regeneration of eukaryotic flagella.
Eukaryotic flagella are complex organelles composed of more than 200 polypeptides. Little is known about the regulatory mechanisms governing synthesis of the flagellar protein subunits and their assembly into this complex organelle. The unicellular green alga Chlamydomonas reinhardtii is the premier experimental model system for studying such cellular processes. When acid shocked, C. reinhardtii excises its flagella, rapidly and coordinately activates transcription of a set of flagellar genes, and ultimately regenerates a new flagellar pair. To define functionally the regulatory sequences that govern induction of the set of genes after acid shock, we analyzed the alpha1-tubulin gene promoter. To simplify transcriptional analysis in vivo, we inserted the selectable marker gene ARG7 on the same plasmid with a tagged alpha1-tubulin gene and stably introduced it into C. reinhardtii cells. By deletion of various sequences, two promoter regions (-176 to -122 and -85 to -16) were identified as important for induction of the tagged alpha1-tubulin gene. Deleting the region between -176 and -122 from the transcription start site resulted in an induction level which was only 45 to 70% of that of the resident gene. Deleting the region upstream of -56 resulted in a complete loss of inducibility without affecting basal expression. The alpha1-tubulin promoter region from -85 to -16 conferred partial acid shock inducibility to an arylsulfatase (ARS) reporter gene. These results show that induction of the alpha1-tubulin gene after acid shock is a complex response that requires diverse sequence elements.


In vivo and in vitro characterization of bone marrow-derived stem cells in the cochlea.
Stem cell replacement therapy has the potential to treat or cure an array of degenerative neurologic disorders, including sensorineural deafness. However, little is known about the potential for marrow-derived stem cells (MSCs) to take on properties of spiral ganglion neurons. The main purpose of this prospective animal study was to evaluate the survival of MSCs transplanted into the gerbil cochlea. Eight 3- to 4-month-old Mongolian gerbils were used as recipients. The animals received an intraperilymphatic transplantation of 100,000 green fluorescent protein (GFP)-positive MSCs with scala tympani injection and modiolar injection. Seven days after transplantation, MSC survival was evaluated by microscopic examination of frozen sections cut through the cochleae of the recipient animals. MSCs isolated from the TgN (ACTbEGFP) mouse line used in this study exhibited bright green florescence after five to seven passages in vitro. Seven days after postoperatively, most transplanted MSCs were found in the scala tympani and scala vestibule and only a small number located in the scala media in animals that received both forms of injection. There were no GFP-positive MSCs in the modiolus in animals with scala tympani injection. In contrast, the mean profile count in animals with modiolar injection was 28, which was the highest in all regions. Although MSCs have the potential to migrate, the anatomic barrier between the perilymphatic space and the modiolus might account for the absence of GFP-positive MSCs in this region. These findings may have important clinical implications as a means of delivering MSCs in the cochlea for cell replacement therapy.


Brevibacterium rongguiense sp. nov., isolated from freshwater sediment.
A Gram stain-positive, non-spore-forming, non-motile and rod-shaped actinomycete, strain 5221T, was isolated from the sediment of a river collected at Ronggui in the Pearl River Delta, PR China. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the strain formed a distinct lineage within the genus Brevibacterium and had the highest sequence similarity to Brevibacterium pityocampae Tp12T (96.7 %), followed by Brevibacterium daeguense 2C6-41T (96.5 %), Brevibacterium samyangense SST-8T (96.0 %) and Brevibacterium ravenspurgense 20T (95.9 %). The results of chemotaxonomic analyses, including detecting anteiso-C15 : 0, anteiso-C17 : 0, and C16 : 0 as the major cellular fatty acids, diphosphatidylglycerol, phosphatidylglycerol and three phosphoglycolipids as the polar lipids, MK-8(H2) as the major menaquinone, and a DNA G+C content of 72.4 mol%, supported that strain 5221T is a member of the genus Brevibacterium. Furthermore, low sequence similarities of 16S rRNA gene sequences, differences in fatty acid compositions and differential physiological characteristics such as enzyme activity and carbon sources utilization ability distinguished the isolate from its close relatives. Therefore, strain 5221T represents a novel species of the genus Brevibacterium, for which the name Brevibacterium rongguiense sp. nov. is proposed, with the type strain 5221T (=GDMCC 1.1766T=KACC 21700T).


Soybean-Derived Peptides Attenuate Hyperlipidemia by Regulating Trans-Intestinal Cholesterol Excretion and Bile Acid Synthesis.
Increased triglyceride, cholesterol, and low-density lipoprotein (LDL) levels cause hyperlipidemia. Despite the availability of statin-based drugs to reduce LDL levels, additional effective treatments for reducing blood lipid concentrations are required. Herein, soybean hydrolysate prepared via peptic and tryptic hydrolysis promoted trans-intestinal cholesterol excretion (TICE) by increasing ATP-binding cassette subfamily G member 5 (ABCG5) and ABCG8 expression. The peptide sequence capable of promoting TICE was determined via HPLC and LC-MS/MS. Based on this, pure artificial peptides were synthesized, and the efficacy of the selected peptides was verified using cellular and hyperlipidemic mouse models. Soybean hydrolysates, including two bioactive peptides (ALEPDHRVESEGGL and SLVNNDDRDSYRLQSGDAL), promoted TICE via the expression of ABCG5 and ABCG8 in enterocytes. They downregulated expression of hepatic cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1 via expression of fibroblast growth factor 19 (FGF19) in a liver X receptor α (LXRa)-dependent pathway. Administration of bioactive peptides to hyperlipidemic mouse models by oral gavage reduced cholesterol levels in serum via upregulation of ABCG5 and ABCG8 expression in the proximal intestine and through fecal cholesterol excretion, upregulated FGF 15/19 expression, and suppressed hepatic bile acid synthesis. Oral administration of soybean-derived bioactive peptides elicited hypolipidemic effects by increasing TICE and decreasing hepatic cholesterol synthesis.


A Risk Prediction Model for Evaluating the Disease Progression of COVID-19 Pneumonia.
Background and Objective: The epidemic of coronavirus disease 2019 (COVID-19) pneumonia caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has expanded from China throughout the world. This study aims to estimate the risk of disease progression of patients who have been confirmed with COVID-19. Methods: Meta-analysis was performed in existing literatures to identify risk factors associated with COVID-19 pneumonia progression. Patients with COVID-19 pneumonia were admitted to hospitals in Wuhan or Hangzhou were retrospectively enrolled. The risk prediction model and nomogram were developed from Wuhan cohort through logistic regression algorithm, and then validated in Hangzhou and Yinchuan cohorts. Results: A total of 270 patients admitted to hospital between Dec 30, 2019, and Mar 30, 2020, were retrospectively enrolled (Table 1). The development cohort (Wuhan cohort) included 87 (43%) men and 115 (57%) women, and the median age was 53 years old. Hangzhou validation cohort included 20 (48%) men and 22 (52%) women, and the median age was 59 years old. Yinchuan validation cohort included 12 (46%) men and 14 (54%) women, and the median age was 44 years old. The meta-analysis along with univariate logistic analysis in development cohort have shown that age, fever, diabetes, hypertension, CREA, BUN, CK, LDH, and neutrophil count were significantly associated with disease progression of COVID-19 pneumonia. The model and nomogram derived from development cohort show good performance in both development and validation cohorts. Conclusion: The severe COVID-19 pneumonia is associated with various types of risk factors including age, fever, comorbidities, and some laboratory examination indexes. The model integrated with these factors can help to evaluate the disease progression of COVID-19 pneumonia.


Minimizing liver uptake of cationic Tc radiotracers with ether and crown ether functional groups.
Ischemia-related diseases, particularly coronary artery disease (CAD), account for the majority of deaths worldwide. Myocardial ischemia is a serious condition and the delay in reperfusion of ischemic tissues can be life-threatening. This is particular true in the aged population. Rapid and accurate early detection of myocardial ischemia is highly desirable so that various therapeutic regiments can be given before irreversible myocardial damage occurs. Myocardial perfusion imaging with radiotracers is an integral component in evaluations of patients with known or suspected CAD. (99m)Tc-Sestamibi and (99m)Tc-Tetrofosmin are commercial radiopharmaceuticals currently available for myocardial perfusion imaging. Despite their widespread clinical applications, both (99m)Tc-Sestamibi and (99m)Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent, largely due to their high liver uptake. The intense liver uptake makes it difficult to interpret the heart activity in the inferior and left ventricular wall. Photon scattering from the high liver radioactivity accumulation remains a significant challenge for diagnosis of heart diseases. This review will summarize the most recent research efforts to minimize the liver uptake of cationic (99m)Tc radiotracers by using ether and crown ether-containing chelators. Fast liver clearance will shorten the duration of imaging protocols (< 30 min post-injection), and allow for early acquisition of heart images with high quality. Improvement of heart/liver ratio may permit better detection of the presence and extent of coronary artery disease. Identification of such a new radiotracer that allows for the improved noninvasive assessment of myocardial perfusion would be of considerable benefit in treatment of patients with suspected CAD.


Striatal blood flow, glucose metabolism and 18F-dopa uptake: difference in Parkinson's disease and atypical parkinsonism.
Striatal blood flow, glucose metabolism and 18F-Dopa uptake were studied with positron emission tomography (PET) in eight non-demented patients with idiopathic Parkinson's disease and eight with atypical Parkinsonism. Patients with atypical Parkinsonism had no specific cause for the Parkinsonian symptoms and were clinically different from Parkinson's disease with lack of resting tremor and a poor response to dopaminergic drugs. Decreased 18F-Dopa uptake in the putamen was observed in patients with Parkinson's disease and atypical Parkinsonism compared with normal controls. 18F-Dopa uptake in the head of the caudate was also significantly reduced in both conditions but relatively less in Parkinson's disease. Decreased blood flow and glucose metabolism in the striatum associated with a global cerebral decrease were also observed in patients with atypical Parkinsonism compared with controls, while they were preserved in patients with Parkinson's disease, indicating affected neurons not only in the striatum but also in the cerebrum in patients with atypical Parkinsonism compared with patients with Parkinson's disease. The differences in the caudate 18F-Dopa uptake, and blood flow and glucose metabolism in the cerebrum including the striatum between Parkinson's disease and atypical Parkinsonism assessed by PET may be due to the differences in the pathophysiological mechanism between Parkinson's disease and atypical Parkinsonism.


The pulpal anesthetic efficacy of articaine versus lidocaine in dentistry: a meta-analysis.
The authors evaluated published evidence from controlled clinical trials regarding the efficacy of two local anesthetic solutions in providing successful pulpal anesthesia. The authors searched MEDLINE and Embase databases to identify peer-reviewed randomized controlled trials in which researchers directly compared articaine and lidocaine local anesthetic solutions in adult participants. They extracted study characteristics and outcomes data as a basis for meta-analysis. They completed subgroup analyses for both infiltration and mandibular inferior alveolar block anesthetic techniques. Articaine solutions had a probability of achieving anesthetic success superior to that of lidocaine, with an odds ratio of 2.44 (95 percent confidence interval [CI], 1.59-3.76; P < .0001). The greater odds ratio for articaine increased to 3.81 (95 percent CI, 2.71-5.36; P < .00001) when the authors analyzed only infiltration data. There was weaker, but still significant, evidence of articaine's being superior to lidocaine for mandibular block anesthesia, with an odds ratio of 1.57 (95 percent CI, 1.12-2.21; P = .009), and no difference when the authors considered only symptomatic teeth. Research evidence supports using articaine versus lidocaine for achieving pulpal anesthesia when the infiltration mode of administration is used. It is premature to recommend articaine for mandibular block anesthesia in cases involving irreversible pulpitis.


Walking a high beam: the balance between employment stability, workplace flexibility, and nonresident father involvement.
Compared with resident fathers, nonresident fathers are more likely to be unemployed or underemployed and less likely, when they are employed, to have access to flexible work arrangements. Although lack of employment stability is associated with lower levels of father involvement, some research shows that increased stability at work without increased flexibility is negatively related to involvement. Using data from the Fragile Families and Child Wellbeing Study (N = 895), the authors examined the relationship between nonresident fathers' employment stability, workplace flexibility, and father involvement. Results indicate that workplace flexibility, but not employment stability, is associated with higher levels of involvement. Policy and practice implications are discussed.


A novel process for updating recommendations for managing hypertension: rationale and methods.
There are numerous hypertension consensus recommendations intended for practising physicians. However, recommendations in their current format have limited impact on improving hypertension control. A group of national societies, headed by the Canadian Hypertension Society, the Heart and Stroke Foundation of Canada, the Canadian Coalition for High Blood Pressure Prevention and Control, and Health Canada has developed strategies to maintain annually updated recommendations for hypertension management and to provide greater opportunities for their implementation into clinical practice. The process is overseen by a steering committee. Subcommittees have been formed for each of a list of topics seen as important to the control of hypertension. The subcommittees, with the aid of a central librarian, conduct annual literature reviews in accordance with Cochrane Collaboration strategies. Modified existing and new recommendations are forwarded to a group with expertise in clinical epidemiology. Grades of evidence are assigned to each recommendation. Revised recommendations based on the above process will be presented annually at the conjoint Canadian Hypertension Society/Canadian Cardiovascular Congress meeting. Under the leadership of the Cardiovascular Disease Division of the Laboratory Centre for Disease Control, Health Canada, a committee has been charged with the implementation process. The improvements of the current process over previous national hypertension recommendations are four-fold. First, the recommendations will be updated annually. Second, the methodology has been improved. Third, the grading system can be used in the evaluation of complex study designs. Finally, the implementation process is extended. The authors are optimistic that these changes will contribute to the improvement of hypertension control in the Canadian population.


Frameshifting by eukaryotic ribosomes during expression of Escherichia coli release factor 2.
Normal translation of the gene for E. coli release factor 2 (RF-2) is characterized by a +1 frameshift event that occurs with 30-50% efficiency. Frameshifting on synthetic RF-2 mRNA by eukaryotic ribosomes has also been observed, even though they lack the capability to interact with the frameshift signal in the same manner as prokaryotic ribosomes. We have mutagenized the sequence of the RF-2 gene to eliminate the need for a frameshift, thereby allowing frameshifting efficiency to be measured by direct comparison of RF-2 production from the mutant with production from the wild-type. Measurements using this approach confirm that frameshifting by rabbit reticulocyte lysate ribosomes occurs at the frameshift region, but with a limited efficiency of approximately 0.4%.


Application of Model Informed Precision Dosing to Address the Impact of Pregnancy Stage and CYP2D6 Phenotype on Foetal Morphine Exposure.
Guidance regarding the effect of codeine and its metabolites on foetal development is limited by small studies and inconsistent findings. The primary objective was to use physiologically based pharmacokinetic modelling to investigate the impact of gestational stage and maternal CYP2D6 phenotype on foetal morphine exposure following codeine administration. Full body physiologically based pharmacokinetic models were developed and verified for codeine and morphine using Simcyp (version 19.1). The impact of gestational age and maternal CYP2D6 phenotype on foetal and maternal morphine and codeine exposure following oral codeine administration was modelled in a cohort of 250 pregnant females and foetuses at gestational weeks 0 (mothers only), 6, 12, 24 and 36. Consistent with the known effect on codeine metabolism, a clinically meaningful (> 1.65-fold) increase in foetal morphine AUC was observed in the CYP2D6 UM phenotype cohort compared to the CYP2D6 EM and PM phenotype cohorts. The mean (95% CI) foetal morphine AUC in the CYP2D6 UM cohort of 0.988 (0.902 to 1.073) ng/mL.h was 1.8-fold higher than the CYP2D6 EM cohort of 0.546 (0.492 to 0.600) ng/mL.h (p < 0.001). Despite a 2.8-fold increase in maternal CYP2D6 protein abundance between gestational weeks 6 and 36, the mean foetal morphine AUC in the CYP2D6 EM and UM phenotype cohorts reduced by 1.55- and 1.75-fold, respectively, over this period. Maternal CYP2D6 phenotype is a significant determinant of foetal morphine AUC. Simulations suggest that the greatest risk with respect to foetal morphine exposure is during the first trimester of pregnancy, particularly in CYP2D6 UM phenotype mothers.


Healthy Lifestyle: a community-based cancer awareness and prevention intervention program.
Healthy Lifestyle engages the community in the development of a health behavior modification program to reduce cancer risk among African Americans. The objectives are 1) to assess knowledge, attitudes, and behaviors that affect cancer risk through focus group discussions; and 2) to identify community members to implement programs and practices that facilitate healthy behavior routines. Thirty-four African American focus group participants completed surveys regarding health knowledge and behavioral practices. Results from the focus groups identified three themes: 1) Health and Nutrition; 2) Environment; and 3) Family. The majority of focus group participants (94%) indicated that annual physical exams were important. However, of that group, 47% had not had a physical within the last 12 months and only 44% had scheduled appointments. Of the 79% who indicated they could commit to a two-year study, only 64% felt they could be leaders.


Comparative dose-response tumorigenicity studies of dibenzo[alpha,l]pyrene versus 7,12-dimethylbenz[alpha]anthracene, benzo[alpha]pyrene and two dibenzo[alpha,l]pyrene dihydrodiols in mouse skin and rat mammary gland.
Comparative studies were conducted of the tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a,l]pyrene (DB[a,l]P) versus 7,12-dimethyl-benz[a]anthracene (DMBA), the most potent recognized carcinogenic polycyclic aromatic hydrocarbon (PAH); benzo[a]pyrene (B[a]P), the most potent recognized carcinogenic environmental PAH; DB[a,l]P 8,9-dihydrodiol, the K-region dihydrodiol; and DB[a,l]P 11,12-dihydrodiol, precursor to the bay-region diolepoxide. The tumor-initiating activity of DB[a,l]P and B[a]P was compared in the skin of female SENCAR mice at doses of 300, 100 and 33.3 nmol. The mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) twice-weekly for 13 weeks. DB[a,l]P at all doses induced significantly more tumors than B[a]P at the corresponding dose, with a significantly shorter latency. Subsequently, the tumor-initiating activity of DB[a,l]P was compared in the skin of female SENCAR mice to that of DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol and DB[a,l]P 11,12-dihydrodiol at doses of 100, 20 and 4 nmol. The mice were promoted with TPA twice-weekly for 24 weeks. In addition, groups of mice were initiated with 100 nmol of DB[a,l]P, DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol or DB[a,l]P 11,12-dihydrodiol and kept without promotion. This experiment showed that in the mouse skin, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol displayed similar tumor-initiating activity with a response inversely proportional to the dose, presumably due to the toxicity of the compounds. At the high dose they elicited tumors earlier than DMBA, though DMBA produced a much higher tumor multiplicity. At the low dose, DMBA, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol exhibited similar tumorigenicities. DB[a,l]P 8,9-dihydrodiol was a marginal tumor initiator. Once again, DB[a,l]P was by far a much stronger tumor initiator than B[a]P. Female Sprague-Dawley rats were treated with 1.0 or 0.25 mumol of DB[a,l]P, DMBA or B[a]P by intramammillary injection at eight teats. DB[a,l]P at both doses was a more potent carcinogen than DMBA at the corresponding dose in the rat mammary gland. B[a]P was a marginal mammary carcinogen, eliciting only a few fibrosarcomas. Thus, these data suggest that DB[a,l]P is the strongest PAH carcinogen ever tested.


PI-PfuI and PI-PfuII, intein-coded homing endonucleases from Pyrococcus furiosus. I. Purification and identification of the homing-type endonuclease activities.
We screened for proteins with specific binding activity to Holliday junction DNA from the hyperthermophilic archaeon Pyrococcus furiosus and found a protein that has specific affinity for DNA with a branched structure, like a three-way or four-way junction. The protein was identified as one of the two inteins encoded in the gene for ribonucleotide reductase (RNR) by gene cloning. These two inteins were spliced out from the precursor protein as polypeptides with molecular weights of 53.078 and 43.976 kDa, respectively. The amino acid sequences of these inteins have two copies of the LAGLIDADG motif, which is found in the site-specific DNA endonucleases. The purified proteins actually cleaved double-stranded DNA with the sequence of the intein(-)allele, and, therefore, they were designated PI- Pfu I and PI- Pfu II. They generate a 4 bp 3'-OH overhang with a 5'-phosphate, like other known homing endonucleases originating from inteins. The optimal conditions of the DNA cleavage reaction, including temperature, pH, and concentrations of KCl and MgCl(2), have been determined. The high affinity for junction DNA of PI- Pfu I was confirmed using the purified protein.


Adolescent and adult cleft lip and palate, in Ile-Ife, Nigeria.
Congenital cleft lip and palate (CLP) defects usually present in childhood, especially in places with available and affordable care. In Nigeria, their incidence is low but late presentation in Adult life have been reported. This article aims at reviewing adolescent and adult CLP patients in our center, with the advent of free and available care, and to document the patterns and management outcomes of these patients as an addition to existing literature on the subject of adult CLP. A retrospective review of adolescent and adult CLP patients managed from May 2006 to April 2010. Demographic data as well as clinical information were retrieved from the hospital records and include the type of cleft deformity, surgical intervention prior to presentation, the type of surgery performed and postoperative outcomes. Some pertinent clinical photos were also reviewed. Adolescent and adults constituted 24% of the 137 patients, their age ranged from 13 to 76 years, with a mean, median and modal age of 28, 22 and 20 years respectively. Unilateral cleft of primary palate was commonest with female preponderance. Most never had surgery, others desired revision surgery or secondary procedures. The outcomes were satisfactory in the 37 procedures performed on 33 patients. A relatively high ratio of adolescent and adult clefts is observed. Most of them have never had surgical intervention. Some had failed surgical intervention prior to presentation. Satisfactory outcomes were achieved despite late intervention but failed initial intervention was associated with poorer outcomes.


Feature-Based Machine Learning Model for Real-Time Hypoglycemia Prediction.
Hypoglycemia is a serious health concern in youth with type 1 diabetes (T1D). Real-time data from continuous glucose monitoring (CGM) can be used to predict hypoglycemic risk, allowing patients to take timely intervention measures. A machine learning model is developed for probabilistic prediction of hypoglycemia (<70 mg/dL) in 30- and 60-minute time horizons based on CGM datasets obtained from 112 patients over a range of 90 days consisting of over 1.6 million CGM values under normal living conditions. A comprehensive set of features relevant for hypoglycemia are developed and a parsimonious subset with most influence on predicting hypoglycemic risk is identified. Model performance is evaluated both with and without contextual information on insulin and carbohydrate intake. The model predicted hypoglycemia with >91% sensitivity for 30- and 60-minute prediction horizons while maintaining specificity >90%. Inclusion of insulin and carbohydrate data yielded performance improvement for 60-minute but not for 30-minute predictions. Model performance was highest for nocturnal hypoglycemia (~95% sensitivity). Shortterm (less than one hour) and medium-term (one to four hours) features for good prediction performance are identified. Innovative feature identification facilitated high performance for hypoglycemia risk prediction in pediatric youth with T1D. Timely alerts of impending hypoglycemia may enable proactive measures to avoid severe hypoglycemia and achieve optimal glycemic control. The model will be deployed on a patient-facing smartphone application in an upcoming pilot study.


Structural and Functional Characterization of the Histidine Phosphatase Domains of Human Sts-1 and Sts-2.
The suppressor of T cell signaling (Sts) proteins, Sts-1 and Sts-2, are homologous phosphatases that negatively regulate signaling pathways downstream of the T cell receptor. Functional inactivation of Sts-1 and Sts-2 in a murine model leads to resistance to systemic infection by the opportunistic pathogen, Candida albicans. This suggests that modulation of the host immune response by inhibiting Sts function may be a viable strategy for treating these deadly fungal pathogen infections. To better understand the molecular determinants of function and structure, we characterized the structure and steady-state kinetics of the histidine phosphatase domains of human Sts-1 (Sts-1HP) and Sts-2 (Sts-2HP). We determined the X-ray crystal structures of unliganded Sts-1HP and Sts-1HP in complex with sulfate to 2.5 and 1.9 Å, respectively, and the structure of Sts-2HP with sulfate to 2.4 Å. The steady-state kinetic analysis shows, as expected, that Sts-1HP has a phosphatase activity significantly higher than that of Sts-2HP and that the human and mouse proteins behave similarly. In addition, comparison of the phosphatase activity of full-length Sts-1 protein to Sts-1HP reveals similar kinetics, indicating that Sts-1HP is a functional surrogate for the native protein. We also tested known phosphatase inhibitors and determined that the SHP-1 inhibitor, PHPS1, is a potent inhibitor of Sts-1 (Ki = 1.05 ± 0.15 μM). Finally, we demonstrated that human Sts-1 has robust phosphatase activity against the substrate, Zap-70, in a cell-based assay. Collectively, these data suggest that the human Sts proteins are druggable targets and provide a structural basis for future drug development efforts.


Internet addiction and problematic Internet use: A systematic review of clinical research.
To provide a comprehensive overview of clinical studies on the clinical picture of Internet-use related addictions from a holistic perspective. A literature search was conducted using the database Web of Science. Over the last 15 years, the number of Internet users has increased by 1000%, and at the same time, research on addictive Internet use has proliferated. Internet addiction has not yet been understood very well, and research on its etiology and natural history is still in its infancy. In 2013, the American Psychiatric Association included Internet Gaming Disorder in the appendix of the updated version of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) as condition that requires further research prior to official inclusion in the main manual, with important repercussions for research and treatment. To date, reviews have focused on clinical and treatment studies of Internet addiction and Internet Gaming Disorder. This arguably limits the analysis to a specific diagnosis of a potential disorder that has not yet been officially recognised in the Western world, rather than a comprehensive and inclusive investigation of Internet-use related addictions (including problematic Internet use) more generally. The systematic literature review identified a total of 46 relevant studies. The included studies used clinical samples, and focused on characteristics of treatment seekers and online addiction treatment. Four main types of clinical research studies were identified, namely research involving (1) treatment seeker characteristics; (2) psychopharmacotherapy; (3) psychological therapy; and (4) combined treatment. A consensus regarding diagnostic criteria and measures is needed to improve reliability across studies and to develop effective and efficient treatment approaches for treatment seekers.


Comparison of adrenal vein sampling and computed tomography in the differentiation of primary aldosteronism.
Determination of the etiology of primary aldosteronism remains a diagnostic challenge. The most common types of primary aldosteronism are bilateral adrenal hyperplasia (BAH), aldosterone-producing adenomas (APA), and primary adrenal hyperplasia. Computed tomography (CT) and adrenal vein sampling (AVS) are the primary modalities used to differentiate these subtypes. The purpose of this study was to compare AVS and CT imaging of the adrenal glands in patients with hyperaldosteronism in whom CT imaging was normal or in whom focal unilateral or bilateral adrenal abnormalities were detected. The diagnosis of primary aldosteronism was made in 62 patients based on an elevated plasma aldosterone to PRA ratio and an elevated urinary aldosterone excretion rate. Thirty-eight patients had CT imaging and successful bilateral adrenal vein sampling and were included in the final analysis. AVS was considered the gold standard in determining the specific subtype of primary aldosteronism. There were 15 patients with APA, 21 patients with BAH, and 2 patients with primary adrenal hyperplasia. Plasma aldosterone was significantly higher in patients with APA (46.3 +/- 8.5 ng/dL; 1284 +/- 235 pmol/L) than in those with BAH (29.3 +/- 2.4 ng/dL; 813 +/- 11 pmol/L; P < 0.05). Plasma potassium was significantly lower in patients with APA (3.1 +/- 0.1 mmol/L) than in patients with BAH (3.5 +/- 0.1 mmol/L; P < 0.02). There was considerable overlap in the other biochemical indices (e.g. PRA and urinary aldosterone) in patients with the different subtypes. In patients with APA proven by AVS, eight had concordant findings with CT imaging, four had discordant findings, and three had normal CT imaging. In patients with BAH proven by AVS, four had concordant findings with CT imaging, eight had discordant findings, and nine had normal CT imaging. Compared with AVS, CT imaging was either inaccurate or provided no additional information in 68% of the patients with primary aldosteronism. We conclude that adrenal CT imaging is not a reliable method to differentiate primary aldosteronism. Adrenal vein sampling is essential to establish the correct diagnosis of primary aldosteronism.


Pertussis in pregnancy.
During the period July 1979 to April 1980 four pregnant women in one general practice were found to be suffering from pertussis. The diagnosis was based on clinical and serological evidence. The paper gives a clinical and bacteriological account for their progress and that of their babies. The possibility of pertussis occurring in expectant mothers at the present time is stressed.


Memory for affixes in a long-lag priming paradigm.
Psycholinguistic research on the processing of morphologically complex words has largely focused on debates about how/if lexical stems are recognized, stored, and retrieved. Comparatively little processing research has investigated similar issues for functional affixes. In Word or Lexeme Based Morphology (Aronoff 1994), affixes are not representational units on par with stems or roots. This view is in stark contrast to the claims of linguistic theories like Distributed Morphology (Halle & Marantz 1993), which assign rich representational content to affixes. We conducted a series of eight visual lexical decision studies, evaluating effects of derivational affix priming along with stem priming, identity priming, form priming, and semantic priming at long and short lags. We find robust and consistent affix priming (but not semantic or form priming) with lags up to 33 items, supporting the position that affixes are morphemes, i.e., representational units on par with stems. Intriguingly, we find only weaker evidence for the long-lag stem priming effect found in other studies. We interpret this potential asymmetry in terms of the salience of different morphological contexts for recollection memory.


Ovarian cancer incidence in the United States in relation to manufacturing industry.
Ovarian cancer is primarily a disease of the industrialized world. However, few factors associated with industrialization that contribute to the etiology of ovarian cancer have been identified. We sought to explore factors potentially associated with ovarian cancer by correlating ovarian cancer incidence rates in US states with the distribution of US manufacturing. Data on age-adjusted incidence rates for ovarian cancer per state in the United States and manufacturing rates per state were analyzed using multiple linear regression controlling for access to ovarian cancer care, fertility rate, and other potential confounders. In univariate analyses, ovarian cancer incidence rates were positively correlated with the extent of manufacturing, with dairy production, and with the manufacturing of pulp and paper. Using multiple linear regression, only the correlation of ovarian cancer with pulp and paper manufacturing industry was significant. The correlation of ovarian cancer with pulp and paper manufacturing industry remained significant after adjusting for access to ovarian cancer care, fertility rates, and other potential confounders (P < 0.05). Pulp and paper mills are associated with exposures to known ovarian carcinogens. Further epidemiological study of exposures involved in the manufacturing of pulp and paper in relation to risk of ovarian cancer is warranted.


The role of hiatus hernia in GERD.
Increased esophageal acid exposure in gastroesophageal reflux disease has several potential causes, some related primarily to physiological dysfunction of the LES and others related to anatomic distortion of the gastroesophageal junction as occurs with hiatus hernia. One attractive feature of implicating hiatal hernias in the pathogenesis of reflux disease is that, like reflux disease, axial hernias become more common with age and obesity. However, the importance of hiatus hernia is obscured by imprecise definition and an all-or-none conceptualization that has led to wide variation in estimates of prevalence among normal or diseased populations. There are at least three potentially significant radiographic features of a hiatus hernia: axial length during distention, axial length at rest, and competence of the diaphragmatic hiatus. Although any or all of these features may be abnormal in a particular instance of hiatus hernia, each is of different functional significance. Grouping all abnormalities of the gastroesophageal junction as "hiatus hernia" without detailing the specifics of each case defies logic. Mechanistically, the gastroesophageal junction must protect against reflux both in static and dynamic conditions. During abrupt increases in intra-abdominal pressure, the crural diaphragm normally serves as a "second sphincter," and this mechanism is substantially impaired in individuals with a gaping hiatus. Large, non-reducing hernias also impair the process of esophageal emptying, thereby prolonging acid clearance time following a reflux event (especially while in the supine posture). These anatomically-determined functional impairments of the gastroesophageal junction lead to increased esophageal acid exposure. Thus, although hiatus hernia may or may not be an initiating factor at the inception of reflux disease, it clearly can act as a sustaining factor accounting for the frequently observed chronicity of the disease.


Dopaminergic Balance between Reward Maximization and Policy Complexity.
Previous reinforcement-learning models of the basal ganglia network have highlighted the role of dopamine in encoding the mismatch between prediction and reality. Far less attention has been paid to the computational goals and algorithms of the main-axis (actor). Here, we construct a top-down model of the basal ganglia with emphasis on the role of dopamine as both a reinforcement learning signal and as a pseudo-temperature signal controlling the general level of basal ganglia excitability and motor vigilance of the acting agent. We argue that the basal ganglia endow the thalamic-cortical networks with the optimal dynamic tradeoff between two constraints: minimizing the policy complexity (cost) and maximizing the expected future reward (gain). We show that this multi-dimensional optimization processes results in an experience-modulated version of the softmax behavioral policy. Thus, as in classical softmax behavioral policies, probability of actions are selected according to their estimated values and the pseudo-temperature, but in addition also vary according to the frequency of previous choices of these actions. We conclude that the computational goal of the basal ganglia is not to maximize cumulative (positive and negative) reward. Rather, the basal ganglia aim at optimization of independent gain and cost functions. Unlike previously suggested single-variable maximization processes, this multi-dimensional optimization process leads naturally to a softmax-like behavioral policy. We suggest that beyond its role in the modulation of the efficacy of the cortico-striatal synapses, dopamine directly affects striatal excitability and thus provides a pseudo-temperature signal that modulates the tradeoff between gain and cost. The resulting experience and dopamine modulated softmax policy can then serve as a theoretical framework to account for the broad range of behaviors and clinical states governed by the basal ganglia and dopamine systems.


Hypoxia promotes etoposide (VP-16) resistance in neuroblastoma CHP126 cells.
Hypoxia is widespread in solid tumors as a consequence of poorly structured tumor-derived neovasculature, which is recognized to play a role in the resistance of cancer cells to chemotherapy. Etoposide (VP-16), a drug commonly used in chemotherapy, leads to enhanced accumulation of cell populations in G2/M phase and increases levels of apoptosis as a topoisomerase II inhibitor. We evaluated the effects of hypoxia on the response of the neuroblastoma cell line CHP126 to VP-16, in order to delineate the mechanisms responsible for the hypoxia-induced chemoresistance of this clinically conventional anti-cancer agent, with an insight to determining potential indications in neuroblastoma therapy. In this study, physiological hypoxia was shown to attenuate G2/M arrest and apoptosis induced in CHP126 cells by VP-16. It suppressed drug-related Cdk1 activity with a less elevation of regulator proteins such as cyclin B1, Cdk7 and reduced caspase activation and PARP cleavage compared to the efficiency observed in normoxic condition, which were significantly relative with hypoxia-driven inhibition of p53 and p-ERK1/2 activation. These results clearly demonstrated that hypoxia had a protective effect against VP-16-induced cytotoxicity, which is likely to provide a further therapeutic knowledge in neuroblastomas.


Cellular expression and subcellular localization of diacylglycerol kinase γ in rat brain.
Gq protein-coupled receptors lead to activation of phospholipase C, which triggers phosphoinositide signaling. Diacylglycerol (DG) is one of the phosphoinositide metabolites and serves as a second messenger. Diacylglycerol kinase (DGK) phosphorylates DG to produce another second messenger phosphatidic acid. Of the DGK family, DGKγ is predominantly expressed in the brain at the mRNA level. Recent studies have shown the expression of DGKγ in vascular endothelial cells and adrenal medullary cells at the protein level, although its detailed cellular expression pattern and subcellular localization in the brain remain to be determined. In the present study, we addressed this point using specific DGKγ antibody. DGKγ was expressed in both projection neurons and interneurons in the cerebral cortex, hippocampal formation, and cerebellum. In cerebellar Purkinje cells, DGKγ was distributed to the soma and dendrites. Fractionation study revealed that DGKγ was enriched in the internal membranes containing the endoplasmic reticulum and Golgi complex. In immunoelectron microscopy, DGKγ was localized throughout the smooth endoplasmic reticulum system. These findings suggest that DGKγ shows unique cellular expression pattern in the brain and distinct subcellular localization different from other DGK isozymes.


Is Machine Learning a Better Way to Identify COVID-19 Patients Who Might Benefit from Hydroxychloroquine Treatment?-The IDENTIFY Trial.
Therapeutic agents for the novel coronavirus disease 2019 (COVID-19) have been proposed, but evidence supporting their use is limited. A machine learning algorithm was developed in order to identify a subpopulation of COVID-19 patients for whom hydroxychloroquine was associated with improved survival; this population might be relevant for study in a clinical trial. A pragmatic trial was conducted at six United States hospitals. We enrolled COVID-19 patients that were admitted between 10 March and 4 June 2020. Treatment was not randomized. The study endpoint was mortality; discharge was a competing event. Hazard ratios were obtained on the entire population, and on the subpopulation indicated by the algorithm as suitable for treatment. A total of 290 patients were enrolled. In the subpopulation that was identified by the algorithm, hydroxychloroquine was associated with a statistically significant (p = 0.011) increase in survival (adjusted hazard ratio 0.29, 95% confidence interval (CI) 0.11-0.75). Adjusted survival among the algorithm indicated patients was 82.6% in the treated arm and 51.2% in the arm not treated. No association between treatment and mortality was observed in the general population. A 31% increase in survival at the end of the study was observed in a population of COVID-19 patients that were identified by a machine learning algorithm as having a better outcome with hydroxychloroquine treatment. Precision medicine approaches may be useful in identifying a subpopulation of COVID-19 patients more likely to be proven to benefit from hydroxychloroquine treatment in a clinical trial.


[Doping control in race horses].
Doping in performance horses is defined as the "illegal application of any substance, except normal diet, that might modify the natural and present capacities of the horse at the time of the race." The prohibition of doping is mainly based on the protection of animals. Doping can be performed with various aims: "doping to win" can be regarded as the classical method by mobilization of overphysiological capacities. Such positive doping may be classified as an acute form using psychomotoric stimulants, as a chronic form using anabolic hormones, and as a paradoxical form using small doses of neuroleptics or tranquilizers in excitable horses. In larger doses these sedatives are acting for "doping to loose" in a more subtle manner as compared to hypnotics. According to the doping regulations there is no difference between therapy and doping at the time of the race. Thus at the race all medications to restore normal performance have to be regarded as doping. This fact especially concerns the therapy of lamenesses with non-steroidal antiinflammatory drugs or local anesthetics. A particular problem is "inadvertent" doping due to unknown side effects, combinations of drugs, galenic supplements or food additives. Accidental doping may further be caused by the unawareness of elimination times. At the moment no exact withdrawing times can be defined due to the manifold interindividual variations at different levels of the pharmacokinetics. As a border-line case of doping the application of endogenous substances, like electrolytes or glucose, may be regarded. Though their parenteral application is prohibited prior to the race, only bicarbonate or "blood doping" may be considered to be effective as positive doping. Special doping methods are the use of "masking" substances or diuretics in order to make more difficult the detection of illegal drugs as well as physical doping procedures which are often hardly to define and which thus are only in part included in the doping regulations.


Activated coagulation test in normal and heparinized ponies and horses.
Activated coagulation test (ACT) was performed in 37 adult ponies and 31 adult horses. The mean ACT time of all ponies and horses was 2 minutes 38 seconds, with a standard deviation (SD) of 29 seconds. The ACT was compared with the Lee-White clotting test in heparinized ponies. The correlation of ACT with the Lee-White test was 0.95. Anticoagulation heparinized ponies during prolonged cardiopulmonary bypass was successfully monitored with the ACT. The ACT is simple and reproducible, has a definite end point, and would seem to be an ideal screening test for hemorrhagic diathesis in equine animals.


In vitro inhibition of Cryptosporidium parvum infection by human monoclonal antibodies.
Cryptosporidium parvum infection of the small epithelial intestine causes unremitting diarrhea and malabsorption that can lead to chronic and sometimes fatal illness in patients with AIDS. The illness may be ameliorated by passive oral immunoglobulin therapy. The objective of this study was to produce anti-Cryptosporidium human monoclonal antibodies for evaluation as potential therapy. All human monoclonal cell lines that produced C. parvum antibodies were originally generated from the peripheral blood lymphocytes of a human immunodeficiency virus-seronegative woman. She had recovered from C. parvum infection and had a high specific antibody titer. Hybridization of these lymphocytes with a tumor cell line was accomplished by hypo-osmolar electrofusion. Twelve clones were identified by enzyme-linked immunosorbent assay (ELISA) as secreting anti-Cryptosporidium antibodies after the initial hybridization. From the 12 positive clones, two high antibody-secreting clones, 17A and 17B, were maintained in long-term culture. A second hybridization produced two other human monoclonal cell lines, EC5 and BB2. Human monoclonal antibody from the first two cell lines bound to C. parvum sporozoites and oocysts by immunofluorescence. The ability of human monoclonal antibodies to inhibit C. parvum infection in vitro was assessed by using a human enterocyte cell line, HT29.74. The antibodies of the four different human hybridomas inhibited infection by 35 to 68% (P < 0.05) compared to a control irrelevant human monoclonal antibody derived in a similar fashion. Human monoclonal antibodies are candidate molecules for immunotherapy of C. parvum infection.


Radical resection of upper right lung under thoracoscopic guidance.
In recent years, thoracoscopic lobectomy has been rapidly developing and applied in China with an ever growing list of indications as the resectable range has been evolving from the peripheral type to the central type, from a diameter less than 3 cm to greater than 5 cm, and from lobectomy to pneumonectomy and segmental lung resection. This technique has become a routine option in our department. This video shows one case of thoracoscopic lobectomy with lymph node dissection for upper right lung cancer of 6 cm in diameter.


Reconstruction of conductivity and current density images using only one component of magnetic field measurements.
Magnetic resonance current density imaging (MRCDI) is to provide current density images of a subject using a magnetic resonance imaging (MRI) scanner with a current injection apparatus. The injection current generates a magnetic field that we can measure from MR phase images. We obtain internal current density images from the measured magnetic flux densities via Ampere's law. However, we must rotate the subject to acquire all of the three components of the induced magnetic flux density. This subject rotation is impractical in clinical MRI scanners when the subject is a human body. In this paper, we propose a way to eliminate the requirement of subject rotation by careful mathematical analysis of the MRCDI problem. In our new MRCDI technique, we need to measure only one component of the induced magnetic flux density and reconstruct both cross-sectional conductivity and current density images without any subject rotation.


Body mass index, underweight and overweight in children 3 to 5 years of age from Skopje.
The aim of this research is to present body mass index (BMI) data in children 3-5 years of age from Skopje and provide the information on the prevalence of different categories of nutritional status during the early childhood. The study included 420 preschool children (210 boys and 210 girls). Stature and body weight were measured, and the BMI value was calculated. Twelve anthropometric parameters were measured using standard equipment and measurement technique according to the International Biological Programme. The majority of anthropometrical parameters have shown significant age and sex specific differences in favor of male subjects. Values at the 50(th) percentile in our male subjects aged 3, 4 and 5 years for the weight-for-age index were 19 kg, 19.1 and 21 kg, respectively whereas in the female subjects the corresponding values were 16.8 kg, 20 kg and 21 kg. The height-for-age index values corresponding to the 50(th) percentile showed slightly higher values in our male subjects (100 cm, 109.5 cm and 116 cm) than those in our female subjects (102 cm, 108.5 cm and 116 cm). The values of 50(th) percentile of BMI in our males subjects were 18.1 kg/m(2), 16.2 kg/m(2) and 16 kg/m(2) whereas in our females were 16.5 kg/m(2), 16.7 kg/m(2) and 16.4 kg/m(2). These results show that underweight is a health problem of the rising generation in Skopje and needs to be considered along with the problem of overweight. It is recommended that the detected values could be applied for evaluation of deviations in growth and nutritional status in children aged 3-5.


The tryptic peptides of rabbit muscle triose phosphate isomerase.
1. The peptides obtained by tryptic digestion of S-[(14)C]carboxymethylated rabbit muscle triose phosphate isomerase have been studied. 2. The first step in the fractionation of the tryptic digest was gel filtration on coupled columns of Sephadex G-25 and G-50. Further fractionation was carried out by paper electrophoresis and paper chromatography. 3. The digest contained 26 peptides and three free amino acids. The sizes of the peptides ranged from two to 29 residues. 4. The sequences of the peptides have been determined. 5. The length of the polypeptide chains is about 250 amino acid residues. 6. The variant sequences encountered were due to partial deamidation; this may be one of the reasons for multiple forms of the enzyme. 7. The chicken and rabbit enzymes are compared. 8. Detailed evidence for the sequences of the tryptic peptides has been deposited as Supplementary Publication SUP 50024 at the British Library, Lending Division (formerly the National Lending Library for Science and Technology), Boston Spa, Yorks. LS23 7BQ, U.K., from whom copies can be obtained on the terms given in Biochem. J. (1973) 131, 5.


Bone geometry according to menstrual function in female endurance athletes.
Athletes have higher bone mineral density (BMD) relative to nonathletes. In amenorrheic athletes BMD may be compromised by estrogen deficiency, but it is unknown whether this is accompanied by structural differences. We compared femoral neck bone geometry and density of a-/oligomenorrheic athletes (AAs), eumenorrheic athletes (EAs), and eumenorrheic controls (ECs). We recruited 156 women: (68 endurance athletes and 88 controls). Femoral neck BMD, section modulus (Z), and width were measured using dual-energy X-ray absorptiometry. Menstrual function was assessed by questionnaire and classified as EA (≥10 periods/year) or AA (≤9 periods/year): 24 athletes were AA and 44 EA. Femoral neck BMD was significantly higher in EA than AA (8 %, difference) and EC (11 % difference): mean [SE] 1.118 [0.015], 1.023 [0.020] and 0.999 [0.014] g cm(-2), respectively; p < 0.001. Z was significantly higher in EA than EC (11 % difference): EA 667 [19], AA 625 [21], and EC 592 [10] cm(3); p < 0.001. Femoral neck width did not differ between groups. All differences persisted after adjustment for height, age, and body mass. The higher femoral neck Z and BMD in athletes, despite similar width, may indicate that exercise-related bone gains are endosteal rather than periosteal. Athletes with amenorrhea had smaller increments in bone mass rather than structural adaptation. The maintained femoral neck width in controls may be an adaptive mechanism to conserve bone strength in bending despite inactivity-related bone decrement.


Lung Injury Is Induced by Abrupt Increase in Respiratory Rate but Prevented by Recruitment Maneuver in Mild Acute Respiratory Distress Syndrome in Rats.
Gradually changing respiratory rate (RR) during time to reduce ventilation-induced lung injury has not been investigated. The authors hypothesized that gradual, compared with abrupt, increments in RR would mitigate ventilation-induced lung injury and that recruitment maneuver before abruptly increasing RR may prevent injurious biologic impact. Twenty-four hours after intratracheal administration of Escherichia coli lipopolysaccharide, 49 male Wistar rats were anesthetized and mechanically ventilated (tidal volume, 6 ml/kg; positive end-expiratory pressure, 3 cm H2O) with RR increase patterns as follows (n = 7 per group): (1) control 1, RR = 70 breaths/min for 2 h; (2) and (3) abrupt increases of RR for 1 and 2 h, respectively, both for 2 h; (4) shorter RR adaptation, gradually increasing RR (from 70 to 130 breaths/min during 30 min); (5) longer RR adaptation, more gradual increase in RR (from 70 to 130 breaths/min during 60 min), both for 2 h; (6) control 2, abrupt increase of RR maintained for 1 h; and (7) control 3, recruitment maneuver (continuous positive airway pressure, 30 cm H2O for 30 s) followed by control-2 protocol. At the end of 1 h of mechanical ventilation, cumulative diffuse alveolar damage scores were lower in shorter (11.0 [8.0 to 12.0]) and longer (13.0 [11.0 to 14.0]) RR adaptation groups than in animals with abrupt increase of RR for 1 h (25.0 [22.0 to 26.0], P = 0.035 and P = 0.048, respectively) and 2 h (35.0 [32.0 to 39.0], P = 0.003 and P = 0.040, respectively); mechanical power and lung heterogeneity were lower, and alveolar integrity was higher, in the longer RR adaptation group compared with abruptly adjusted groups; markers of lung inflammation (interleukin-6), epithelial (club cell secretory protein [CC-16]) and endothelial cell damage (vascular cell adhesion molecule 1 [VCAM-1]) were higher in both abrupt groups, but not in either RR adaptation group, compared with controls. Recruitment maneuver prevented the increase in VCAM-1 and CC-16 gene expressions in the abruptly increased RR groups. In mild experimental acute respiratory distress syndrome in rats, gradually increasing RR, compared with abruptly doing so, can mitigate the development of ventilation-induced lung injury. In addition, recruitment maneuver prevented the injurious biologic impact of abrupt increases in RR.


Treatment of retinoblastoma with cryotherapy.
The authors report their personal experience and review the pertinent literature on cryotherapy in the treatment of selected patients with retinoblastoma. Tumor destruction with cryotherapy can generally be achieved with one or more treatments if the tumor is no greater than 2.5 mm in diameter and 1.0 mm in thickness and the tumor is confined to the sensory retina without seeding into the adjacent vitreous. Cryotherapy generally fails for larger tumors, particularly if there is clinical evidence of vitreous seeding by tumor cells. The authors define their current indications and contraindications for cryotherapy of retinoblastoma.


Outcomes of ZB5M angle-supported anterior chamber phakic intraocular lenses at 12 years.
To evaluate the visual and refractive stability and the potential long-term risks associated with ZB5M phakic intraocular lens (PIOL) implantation. A retrospective, non-randomized, cumulative clinical study was performed over 12 years in a consecutive group of 225 eyes implanted with the ZB5M PIOL. The main analyzed variables were visual and refractive outcomes (best spectacle-corrected visual acuity [BSCVA], uncorrected visual acuity [UCVA], and spherical equivalent), endothelial cell density, and postoperative complications. Mean preoperative spherical equivalent refraction was -17.23 +/- 7.69 diopters (D) and 12 years postoperatively it was -1.80 +/- 0.80 D. Mean BSCVA at 1- and 12-year follow-up was 0.38 +/- 0.19 and 0.57 +/- 0.18, respectively (Wilcoxon test, P < .001). At 12 years postoperatively, 3.5% of eyes lost > or = 2 lines of BSCVA. An initial 10.6% reduction in endothelial cell density was noted in the first year, followed by a mean annual rate of decrease of 1.78%. The cumulative incidence of pupil ovalization was 34.7% (78 eyes), and there was no statistical correlation with endothelial cell impairment. Bilateral hypertensive uveitis was diagnosed in 3 (1.33%) eyes. The ZB5M PIOL offers good refractive outcomes and stability in the long-term; however, endothelial cell loss increases over 12 years, requiring annual endothelial cell counts.


Harvey Cushing's Treatment of Skull Base Infections: The Johns Hopkins Experience.
Objectives In this report, we review Dr. Cushing's early surgical cases at the Johns Hopkins Hospital, revealing details of his early operative approaches to infections of the skull base. Design Following institutional review board (IRB) approval, and through the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896 to 1912. Setting The Johns Hopkins Hospital, 1896 to 1912. Participants Eleven patients underwent operative treatment for suspected infections of the skull base. Main Outcome Measures The main outcome measure was operative approach, postoperative mortality, and condition recorded at the time of discharge. Results Eleven patients underwent operative intervention for infections of the skull base. The mean age was 30 years (range: 9 to 63). Of these patients, seven (64%) were female. The mean length of stay was 16.5 days (range: 4 to 34). Postoperatively eight patients were discharged in "well" or "good" condition, one patient remained "unimproved," and two patients died during their admission. Conclusion Cushing's careful preoperative observation of patients, meticulous operative technique, and judicious use of postoperative drainage catheters contributed to a remarkably low mortality rate in his series of skull base infections.


Predicting ecological consequences of marine top predator declines.
Recent studies document unprecedented declines in marine top predators that can initiate trophic cascades. Predicting the wider ecological consequences of these declines requires understanding how predators influence communities by inflicting mortality on prey and inducing behavioral modifications (risk effects). Both mechanisms are important in marine communities, and a sole focus on the effects of predator-inflicted mortality might severely underestimate the importance of predators. We outline direct and indirect consequences of marine predator declines and propose an integrated predictive framework that includes risk effects, which appear to be strongest for long-lived prey species and when resources are abundant. We conclude that marine predators should be managed for the maintenance of both density- and risk-driven ecological processes, and not demographic persistence alone.


Vaccination of Urological Cancer Patients With WT1 Peptide-Pulsed Dendritic Cells in Combination With Molecular Targeted Therapy or Conventional Chemotherapy Induces Immunological and Clinical Responses.
The prognosis of metastatic or relapsed renal cell carcinoma (RCC) or bladder cancer (BC) remains poor despite the introduction of immune checkpoint blockade agents. We aimed to investigate the safety and the feasibility of a vaccination with WT1 peptide-loaded dendritic cells (DCs) and OK-432 adjuvant combined with molecular targeted therapy or conventional chemotherapy. Five eligible patients with metastatic or relapsed RCC and five eligible patients with BC were enrolled. No severe adverse events related to a vaccination were observed. Seven patients with RCC or non-muscle invasive BC had durable stable disease and three other patients had disease progression after DC vaccination. DC vaccination augmented WT1 specific immunity and the reduction of regulatory T cells which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a molecular targeted therapy or a conventional chemotherapy is safe and feasible for patients in advanced stage of RCC or BC.


Study on workers exposed to cadmium in alkaline storage battery manufacturing and PVC compounding.
The extent of cadmium exposure was studied in a cadmium-nickel battery factory and 8 PVC factories using cadmium stabilisers in the compounding of PVC. A total of 101 cadmium-exposed workers and 21 control subjects matched by sex, age, ethnic group and smoking history was investigated. Blood and urine cadmium levels were considerably elevated in the battery workers but were not raised in the PVC workers. These findings were consistent with the results of cadmium-in-air assessments. Among the female battery workers, urine cadmium excretion increased significantly with employment time. There was good correlation between blood and urine cadmium levels among the female subjects. A significant association between blood cadmium levels and prevalence of chest pain was also noted among the females. No low molecular weight proteinuria was detected, but two female battery workers had slight albuminuria and one male PVC worker had glucosuria but had abnormal GTT results.


The role of fear and expectancies in capture of covert attention by spiders.
Fear-related stimuli are often prioritized during visual selection but it remains unclear whether capture by salient objects is more likely to occur when individuals fear those objects. In this study, participants with high and low fear of spiders searched for a circle while on some trials a completely irrelevant fear-related (spider) or neutral distractor (butterfly/leaf) was presented simultaneously in the display. Our results show that when you fear spiders and you are not sure whether a spider is going to be present, then any salient distractor (i.e., a butterfly) grabs your attention, suggesting that mere expectation of a spider triggered compulsory monitoring of all irrelevant stimuli. However, neutral stimuli did not grab attention when high spider fearful people knew that a spider could not be present during a block of trials, treating the neutral stimuli just as the low spider fearful people do. Our results show that people that fear spiders inspect potential spider-containing locations in a compulsory fashion even though directing attention to this location is completely irrelevant for the task. Reduction of capture can only be accomplished when people that fear spiders do not expect a spider to be present.