Polymorphs of a 1:1 salt of sulfadiazine and piperazine-relative stability, dissolution studies, pharmacokinetics and anti-meningitis efficiency.
Two new salt forms of sulfadiazine (SDZ) and piperazine (PIP) were synthesized and characterized. Out of the two polymorphs (SDZ-PIP Ⅰ and SDZ-PIP II), SDZ-PIP Ⅱ is the more stable form at low temperature, room temperature and high temperature. The solution-mediated phase transformation result shows that SDZ-PIP II can transform into pure SDZ within 15 s in phosphate buffer at 37 °C, which leads to a loss in solubility advantage. The addition of 2 mg/mL PVP K30, a polymeric crystallization inhibitor, maintains the solubility advantage and permits supersaturation for a longer period of time. SDZ-PIP II showed 2.5 times the solubility of SDZ alone. The area under the curve (AUC) of SDZ-PIP II with 2 mg/mL PVP K30 was approximately 165% of that of SDZ alone. Moreover, SDZ-PIP II with PVP K30 was more effective than SDZ alone in treating meningitis. Therefore, the SDZ-PIP II salt improves the solubility, bioavailability, and anti-meningitis activity of SDZ.


The diagnostic role of plasma circulating precursors of miRNA-944 and miRNA-3662 for non-small cell lung cancer detection.
microRNA (miRNA) seem to be most attractive cancer markers due their crucial role in tumor development and possibility of their analysis using liquid biopsy. To date there is little known about role of miRNA precursors (pri-miRNA) in carcinogenesis and their utility as tumor markers. miRNA-944 and miRNA-3662 precursors as potential non-small cell lung cancer (NSCLC) markers were analyzed in plasma samples of 56 patients in an early stage of NSCLC and 100 healthy individuals. Diagnostic test based on two studied markers for stage I-IIIA of the disease allowed to distinguish NSCLC from healthy individuals with 75.7% sensitivity and 82.3% specificity (AUC=0.898). pri-miRNA-944 distinguished SCC from AC with sensitivity of 78.6% and specificity of 91.7% (AUC=0.771), and pri-miRNA-3662 distinguished AC from SCC with 57.1% sensitivity and 90% specificity (AUC=0.845). Circulating pri-miRNA-944 and 3662 can improve non-invasive NSCLC detection of operable stages of SCC and AC. miRNA precursors could be considered as novel potential lung cancer biomarkers.


Monoclonal antibody TB-403: a first-in-human, Phase I, double-blind, dose escalation study directed against placental growth factor in healthy male subjects.
TB-403 (RO5323441) is a humanized monoclonal antibody directed against placental growth factor (PlGF). Preclinical studies have demonstrated that targeting PlGF can result in significant inhibition of tumor growth and metastasis. The purpose of this study was to assess the safety profile, tolerability, and pharmacokinetics of TB-403, developed for the treatment of solid tumors. Healthy male subjects were exposed to a single intravenous infusion of TB-403 or placebo. Blood samples for hematology, clinical chemistry, coagulation factors, and urinalysis were collected; vital signs and ECGs were recorded; and serial blood samples were drawn for pharmacokinetic and immunogenicity measurements and circulating levels of pharmacodynamics markers PlGF and (VEGF) vascular endothelial growth factor. Sixteen subjects received either placebo or TB-403 at doses ranging from 0.3 to 5.0 mg/kg. Mild (grade 1 or 2) nasopharyngitis, headache, neck pain, and joint pain were the most frequently reported adverse events (AEs). There were no serious AEs in the study, and none of the AEs led to withdrawal. None of the safety laboratory assessments was considered clinically significant, and none was reported as an AE. There were no apparent differences in terms of safety profiles among the 3 dose levels of active treatment compared with placebo. Clearance, volume of distribution, and terminal t(½) (mean values) for TB-403 in all 3 cohorts were in the range of 4.2 to 4.9 (mL/d/kg), 56 to 79 (mL/kg), and 8 to 13 (days), respectively. The highest dose of TB-403 (5.0 mg/kg) was well tolerated in this study of a single intravenous infusion to healthy males. This result allowed a higher starting dose level in a subsequent Phase I study in cancer patients, the patient population for which this antibody is developed.


Fitch diets in New Zealand: an analytical survey.
Fitch diets from 30 farms were surveyed and analysed for moisture, protein, carbohydrate, fibre, ash, fat and individual fatty acids, fat peroxide value, and infinity-tocopherol. The dietary raw materials most often used were mutton, fish, poultry, beef and cereals. Eight of the 30 breeders added no vitamin or other supplements. Analytical mean (range) values on a wet matter basis were: moisture, 66.3 (49.6-76.8)%; protein, 16.5 (12.4-21.2)%; carbohydrate, 2.5 (<0.1-8.7)%; fibre, 0.4 (0.1-1.0)%; ash, 3.7 (1.2-8.3)%; fat, 10.6 (1.4-26.1)%; peroxide value, 5.7 (0.3-110) m.equiv x /kg fat; infinity-tocopherol, 13 (0.6-103) mg/kg; calculated gross energy value, 7.2 (3.7-13.7) MJ/kg. Protein contributed 42 (20-79)% of the gross energy value; fat, 49 (15-74) %, and carbohydrate, 6 (0-20) %. Polyunsaturated fatty acids (PUFA's) comprised 10 (3.6-39) % of the total fatty acids. The ratio of infinity-tocopherol to PUFA was 2.1(0.1-10.5) mg/g. Results of the survey are discussed in the light of nutrient requirements for the fitch.


Cyclodextrin-assisted capillary electrophoresis for determination of the cyclic nitramine explosives RDX, HMX and CL-20 comparison with high-performance liquid chromatography.
A sulfobutyl ether-beta-cyclodextrin-assisted electrokinetic chromatographic method was developed to rapidly resolve and detect the cyclic nitramine explosives 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaaza-isowurtzitane (CL-20), octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and their related degradation intermediates in environmental samples. Development of the electrophoretic method required the measurement of the aqueous solubility of CL-20 which was determined to be 3.59 +/- 0.74 mg/l at 25 degrees C (95% confidence interval, n=3). The performance of the method was then compared to results obtained from existing high-performance liquid chromatography methods including US Environmental Protection Agency method 8330.


Vocal fold oscillation pattern changes related to loudness in patients with vocal fold mass lesions.
Vocal fold mass lesions can affect vocal fold oscillation patterns and therefore voice production. It has been previously observed that perturbation values from audio signals were lower with increased loudness. However, how much the oscillation patterns change with gradual alteration of loudness is not yet fully understood. Eight patients with vocal fold mass lesions were asked to perform a glide from minimum to maximum loudness on the vowel /i/, ƒo of 125 Hz for male or 250 Hz for female voices. During phonation the subjects were simultaneously recorded with transnasal high speed videoendoscopy (HSV, 20,000 fps), electroglottography (EGG), and an audio recording. Based on the HSV material the Glottal Area Waveform (GAW) was segmented and GAW parameters were computed. The greatest vocal fold irregularities were observed at different values between minimum and maximum sound pressure level. There was a relevant discrepancy between the HSV and EGG derived open quotients. Furthermore, the EGG derived sample entropy and GAW values also evidenced different behavior. The amount of vocal fold irregularity changes with varying loudness. Therefore, any evaluation of the voice should be performed under different loudness conditions. The discrepancy between EGG and GAW values appears to be much stronger in patients with vocal fold mass lesions than those with normal physiological conditions. 4.


HIV infection among female partners of seropositive men in Brazil. Rio de Janeiro Heterosexual Study Group.
A heterosexual partner study was carried out in Rio de Janeiro, Brazil, from August 1990 to December 1991. The main objectives were to determine the rate of male-to-female transmission of human immunodeficiency virus (HIV) and to determine risk factors. Male index cases were recruited according to the following criteria: 1) confirmed HIV positivity, 2) 18 years old or older; 3) heterosexual contact within the past year. Only female partners who reported not to have other risk factors but to have had sexual contact with the index case were invited to participate. Couples were interviewed for risk factors and had blood collected for laboratory studies. The overall prevalence of HIV infection was 45 percent among 204 female partners in the study. Using logistic regression, the authors found the following factors to be independently (p < 0.05) associated with HIV infection: 1) anal sex (odds ratio (OR) = 3.74, 95% confidence interval (CI) 1.87-7.45); 2) condom use during vaginal sex sometimes (OR = 1.45, 95% CI 1.07-1.96), rarely (OR = 2.10, 95% CI 1.15-3.83), or never (OR = 3.04, 95% CI 1.23-7.50) as compared with always; 3) frequency of sexual contacts in the year prior to interview (100+) (OR = 2.00, 95% CI 1.03-3.91); and 4) oral contraceptive use (OR = 2.04, 95% CI 0.97-4.29). In addition to a borderline significance of oral contraceptive use, there was a strong suggestion of an interaction with history of sexually transmitted diseases.


DNA methylation in promoter region as biomarkers in prostate cancer.
The prostate gland is the most common site of cancer and the second leading cause of cancer death in American men. Recent emerging molecular biological technologies help us to know that epigenetic alterations such as DNA methylation within the regulatory (promoter) regions of genes are associated with transcriptional silencing in cancer. Promoter hypermethylation of critical pathway genes could be potential biomarkers and therapeutic targets for prostate cancer. In this chapter, we updated current information on methylated genes associated with the development and progression of prostate cancer. Over 40 genes have been investigated for methylation in promoter region in prostate cancer. These methylated genes are involved in critical pathways, such as DNA repair, metabolism, and invasion/metastasis. The role of hypermethylated genes in regulation of critical pathways in prostate cancer is discussed. These findings may provide new information of the pathogenesis, the exciting potential to be predictive and to provide personalized treatment of prostate cancer. Indeed, some epigenetic alterations in prostate tumors are being translated into clinical practice for therapeutic use.


Nonclassical binding of formylated peptide in crystal structure of the MHC class Ib molecule H2-M3.
H2-M3 is a class Ib MHC molecule of the mouse with a 10(4)-fold preference for binding N-formylated peptides. To elucidate the basis of this unusual specificity, we expressed and crystallized a soluble form of M3 with a formylated nonamer peptide, fMYFINILTL, and determined the structure by X-ray crystallography. M3, refined at 2.1 A resolution, resembles class la MHC molecules in its overall structure, but differs in the peptide-binding groove. The A pocket, which usually accommodates the free N-terminus of a bound peptide, is closed, and the peptide is shifted one residue, such that the P1 side chain is lodged in the B pocket. The formyl group is coordinated by His-9 and a bound water on the floor of the groove.


A Case Report of B-cell Lymphoblastic Leukemia/Lymphoma Presenting as Isolated Torticollis in a 2-year-old Female.
Malignancy is a rare cause of acquired torticollis in children, and spinal cord involvement from hematolymphoid malignancies is similarly unusual. Neurologic abnormalities may not be present on initial evaluation, and delayed diagnosis and treatment is associated with increased risk of permanent paralysis. The author describes a case of isolated torticollis in a 2-year-old evaluated multiple times in the emergency department (ED) and outpatient settings. For her first three presentations, the patient had no associated neurologic abnormalities. She was discharged with return precautions and a presumptive diagnosis of viral infection/lymphadenitis. She later developed weakness of her left arm and was diagnosed with a B-cell lymphoblastic leukemia/lymphoma causing spinal cord compression. This case highlights the importance of continued comprehensive and meticulous physical examination in patients with repeat ED visits, as well as the value of detailed discharge instructions in mitigating diagnostic delays in these patients.


Oxygen Level Modifies the Expression of Genes Involved in the Epigenetic Regulation of Multipotent Stromal Cells In Vitro.
Changes in the transcriptional activity of genes involved in the epigenetic regulation of adipose tissue multipotent mesenchymal stromal cells were analyzed in vitro at different O2 levels. DNA microarray study showed that the most pronounced changes in gene expression, including genes responsible for the epigenetic regulation of mesenchymal stromal cells, occurred at 3% O2. A lower number of genes changed the expression at 1% O2, and a minimum response was observed at 5% O2 in comparison with standard culturing conditions (20% O2). The greatest number of differentially expressed genes were genes responsible for the regulation of histones; the genes encoding products that regulate chromatin, DNA, and RNA constituted a lower part. Thus, the degree of hypoxia can modify the response of multipotent mesenchymal stromal cells at the level of epigenetic regulators.


Analysis of herbal dietary supplements for sexual performance enhancement: first characterization of propoxyphenyl-thiohydroxyhomosildenafil and identification of sildenafil, thiosildenafil, phentolamine and tetrahydropalmatine as adulterants.
Nine herbal dietary supplements intended to be beverages for enhancing sexual performance were analyzed before their possible launch on the market. Four of them contained a sildenafil analog reported for the first time as an adulterant. After isolation and characterization using NMR, MS, IR and UV, this analog was named propoxyphenyl-thiohydroxyhomosildenafil as the ethoxy chain on the phenyl ring of the already known analog thiohydroxyhomosildenafil was replaced by a propoxy moiety. One formulation was tainted with thiosildenafil, another unapproved PDE-5 inhibitor. Sildenafil along with the natural alkaloid tetrahydropalmatine that has no documented effect for enhancing erectile dysfunction were identified in two formulations. Another formulation was adulterated with phentolamine, a drug that is not approved for boosting male sexual performance when taken orally. The last formulation containing osthole, a bioactive natural coumarine improving sexual dysfunction, is most probably truly natural.


Miller-Fisher syndrome associated with unilateral cerebral white matter lesions.
Miller-Fisher syndrome (MFS) is characterized by classical triad of ophthalmoplegia, ataxia and areflexia. The involvement of cerebral white matter in MFS is very rare. We report a typical MFS patient whose brain MRI showed unilateral and extensive involvement in cerebral white matter. We also found mild pleocytosis and raised protein concentration in cerebrospinal fluid. Deficits resolved completely after treatment with intravenous immunoglobulins. Subsequent brain MRI shows cavity formation in involved white matter.


Flipped Classroom Versus Classroom Lecture: A Content Mapping Study in Undergraduate Nursing.
Educators face the ongoing difficulty of managing finite class time and limited instructor-student interactions to balance discourse and active learning. Complicating this is the growing expectation to incorporate technology into nursing curriculum. This study explored the differences of the traditional classroom lecture (TL) with the flipped classroom (FC) format and the effects on higher-order thinking. A content analysis was performed on previous work. Concept maps were used to evaluate data from transcripts of undergraduate nursing students' case study discussions in either a TL or FC format. FC groups had a more complex concept map morphology and identified more subcategories and links. They exhibited a greater number of higher-order thinking concepts compared with the TL groups. The emergence of discussion tangents across both the FC and the TL groups was unexpected. The FC approach enhances student learning and aids in the development of higher-order thinking. [J Nurs Educ. 2021;60(11):629-632.].


Computational psychiatry: the brain as a phantastic organ.
In this Review, we discuss advances in computational neuroscience that relate to psychiatry. We review computational psychiatry in terms of the ambitions of investigators, emerging domains of application, and future work. Our focus is on theoretical formulations of brain function that put subjective beliefs and behaviour within formal (computational) frameworks-frameworks that can be grounded in neurophysiology down to the level of synaptic mechanisms. Understanding the principles that underlie the brain's functional architecture might be essential for an informed phenotyping of psychopathology in terms of its pathophysiological underpinnings. We focus on active (Bayesian) inference and predictive coding. Specifically, we show how basic principles of neuronal computation can be used to explain psychopathology, ranging from impoverished theory of mind in autism to abnormalities of smooth pursuit eye movements in schizophrenia.


Epidermolysis Bullosa Patients' Perception of Surgical Wound and Scar Healing.
There is limited evidence to suggest patients with epidermolysis bullosa (EB) have more postoperative wound complications than the general population. Despite this, the authors have noted reluctance among some surgeons to operate on these patients. A cross-sectional study was designed to investigate postoperative wound and scar healing outcomes in patients with EB. Patients were asked to complete the "Surgical Wound and Scar Healing in EB" questionnaire, and data gathered were analyzed. Forty-six patients completed the questionnaire for a total of 94 different surgical procedures. Five patients reported blistering at the surgical wound site. All 5 had generalized forms of EB. Four patients reported wound infections, and 1 patient reported wound dehiscence. The postoperative scar healed with keloid or hypertrophic scarring after 26% of the reported surgical procedures. Blistering at the postoperative site seems to be uncommon and particularly unlikely to occur in localized forms of EB. Postoperative wound infections and dehiscence are uncommon. Patients with EB may have a propensity to develop keloid or hypertrophic scarring. With these data, the authors hope clinicians have greater confidence in referring patients with EB for surgery, and surgeons more reassured about postoperative wound healing.


Chiral analysis of neurotransmitters using cyclodextrin-modified capillary electrophoresis equipped with microfabricated interdigitated electrodes.
We present cyclodextrin-modified capillary electrophoresis equipped with a microfabricated chip consisting of an array of eight interdigitated microband platinum electrodes (IDs) for simultaneous analysis of three chiral models: epinephrine, norepinephrine and isoproterenol. The IDE chip, positioned very close to the capillary outlet, served as an amplification/detection system. Emerging neurotransmitters at the IDE surface were oxidized at +1.1 V by seven electrodes of the array and then detected by the remaining electrode, poised at +0.0 V. There was an amplification effect on the detecting electrode owing to the recycle between the reduced and oxidized forms of the optical isomers at the electrode surface. The detecting "amplification" current response was governed by the applied potential, the detecting electrode position, the number of adjacent electrodes used for recycling and the distance between the oxidative and reductive electrodes. The six chiral forms of the three neurotransmitters were resolved using 25 mM heptakis(2,6,di-o-methyl)-beta-cyclodextrin with a detection limit of approximately 5 microM. The scheme detected a reduced compound at a reducing potential instead of conventional oxidation detection to alleviate electrode fouling and electroactive interferences. The concurrent oxidation/reduction detection of compounds also facilitated and ascertained peak identification as interfering compounds were unlikely to have the same oxidative/reductive characteristics and mobilities as the analytes of interrogation.


Role of minimally invasive glaucoma surgery in the management of chronic open-angle glaucoma.
To compare the safety and efficacy of phacoemulsification combined with ab-interno trabeculectomy (Trabectome) and phacoemulsification combined with I-Stent inject in patients with medically uncontrolled primary open-angle glaucoma (POAG). A retrospective comparative case series. 70 eyes of 66 patients completed 2 years follow up after these treatments performed in 2017-2018. 35 eyes of 33 patients underwent combined Phaco-Trabectome (PT); and 35 eyes of 33 patients underwent combined Phaco-I-Stent inject (Pi). Patient demographics and preoperative characteristics are comparable. A 20% drop in IOP was achieved in 27 eyes (77.14%) in PT group and 28 eyes (80%) in Pi group (p = 0.77). Success rate (target IOP achieved and maintained for 2 years) in advance glaucoma was 25% in PT group and 30.7% in Pi group (p = 0.90). In mild to moderate glaucoma, success rate was 85.71% in PT group and 90% in Pi group (p = 0.67). There was no significant difference between two groups with regards to mean reduction in glaucoma medications and complication rates. Trabectome and I-Stent combined with phacoemulsification are equally efficacious and safe for treating patients with medically uncontrolled mild and moderate primary open-angle glaucoma (POAG). However, they are not an effective treatment for patients with advanced glaucoma.


Positional integration of lung adenocarcinoma susceptibility loci with primary human alveolar epithelial cell epigenomes.
To identify functional lung adenocarcinoma (LUAD) risk SNPs. Eighteen validated LUAD risk SNPs (p ≤ 5 × 10-8) and 930 SNPs in high linkage disequilibrium (r2 > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression. Forty-seven SNPs mapped to putative enhancers; 11 located to open chromatin. Of these, seven altered predicted transcription factor-binding motifs. Rs6942067 showed allele-specific luciferase expression and expression quantitative trait loci analysis indicates that it influences expression of DCBLD1, a gene that encodes an unknown membrane protein and is overexpressed in LUAD. Integration of candidate LUAD risk SNPS with epigenomic marks from normal alveolar epithelium identified numerous candidate functional LUAD risk SNPs including rs6942067, which appears to affect DCBLD1 expression. Data deposition: Data are provided in GEO record GSE84273.


Hereditary coproporphyria. Demonstration of the abnormalities in haem biosynthesis in peripheral blood.
Hereditary coproporphyria is biochemically distinct from the other porphyrias and is characterized by excessive excretion of coproporphyrin in faeces and usually in urine. The laboratory findings in 28 patients with this disease are presented and the clinical details of eight patients who have been in attack summarised. The remaining 20 patients were latent for the disease. In all patients studied the activity of delta-aminolaevulinic acid synthase was raised and coproporphyrinogen oxidase depressed in the leucocyte. This indicates the partial enzyme block in the haem biosynthetic pathway in this disease. The activities of the other enzymes in the pathway, leucocyte ferrochelatase and erythrocyte delta-aminolaevulinic acid dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase showed no consistent change. On review of 111 cases, 35 per cent presented in acute attack: 80 per cent had abdominal pain, 34 per cent vomiting, 29 per cent solar sensitivity, 23 per cent neurological involvement, 23 per cent psychiatric symptoms and 20 per cent severe constipation. Only two fatalities have been published, both from respiratory failure. There was a female preponderance of cases in attack of 2-5:1 and in the latent cases of 1-5:1 suggesting hormonal provocation in the uncovering of the disease. Drugs were implicated as precipitating 54 per cent of acute attacks and in 34 per cent of cases, these were barbiturates. This study demonstrates the reduction in activity of coproporphyrinogen oxidase in the haem biosynthetic pathway and the elevation of delta-aminolaevulinic acid synthase in the peripheral blood. These features, together with the typical abnormal porphyrin excretion pattern, appear to be diagnostic of hereditary coproporphyria whether in attack, remission, or in the latent form.


Diversification of three TaSOS1 genes and their roles in sodium exclusion in bread wheat (Triticum aestivum L.).
The ability to exclude sodium from the shoot is a crucial feature of salinity tolerance in bread wheat (Triticum aestivum L.). The plasma membrane sodium/proton exchanger salt-overly-sensitive 1 (SOS1) is a critical Na+. efflux protein in plants. Here, we cloned three homologues of the TaSOS1 gene in bread wheat, designated TaSOS1-A1, TaSOS1-B1 and TaSOS1-D1, respectively, according to the location on group 3 chromosomes 3A, 3B and 3D. Sequence analysis demonstrated that the TaSOS1 deduced protein-contained domains similar to the SOS1 protein, including 12 membrane-spanning regions, a long hydrophilic tail in the C-terminus, the cyclic nucleotidebinding domain, the putative auto-inhibitory domain and the phosphorylation motif. Phylogenetic analysis established the evolutionary relationships between the different copies of this gene in bread wheat and its diploid progenitors, as well as with SOS1 genes from Arabidopsis, rice and Brachypodium distachyon. Analysis of transient TaSOS1-A1::green fluorescent protein expression demonstrated that TaSOS1 was exclusively localized to the plasma membrane. The yeast and Arabidopsis complementary test supported the sodium extrusion function of TaSOS1-A1. Virus-induced gene silencing technology was used to further examine the function of TaSOS1-A1 in bread wheat.


The effects of HIV and combination antiretroviral therapy on white matter integrity.
HIV preferentially affects white matter in the brain. Although combination antiretroviral therapy (cART) reduces HIV viral load within the brain, continued inflammation can persist. We investigated the effect of HIV and cART on white matter integrity. We used diffusion tensor imaging (DTI) to examine the effects of HIV and cART on white matter integrity within the corpus callosum and centrum semiovale (CSO). Neuropsychological testing and DTI measures (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity) were obtained from 21 HIV-uninfected controls, 21 HIV-infected patients naive to cART (HIV+/cART-), and 21 HIV+ patients receiving stable cART (HIV+/cART+). A subset of the HIV+/cART- individuals (n=10) was assessed before and 6 months after receiving medications. Differences among the cross-sectional groups were assessed using an analysis of variance, whereas paired t-tests evaluated longitudinal changes. HIV+/cART- participants had significantly lower mean diffusivity, axial diffusivity, and radial diffusivity for the corpus callosum and CSO compared to HIV- controls and HIV+/cART+ individuals. No significant difference existed between HIV- controls and HIV+/cART+ patients. cART initiation significantly improved mean diffusivity, radial diffusivity, and axial diffusivity, but not fractional anisotropy, in the corpus callosum and CSO in some HIV-infected patients. Observed decreases in DTI parameters between HIV+/cART+ and HIV+/cART- individuals could reflect the presence of inflammatory cells or cytotoxic edema in HIV+/cART- patients. Initiating cART could lead to a reduction in neuro-inflammation and improvement in DTI measures. Future DTI studies may be useful for evaluating the efficacy higher brain penetrating cART regimens.


Autogenous/reactive obsessions and their relationship with OCD symptoms and schizotypal personality features.
This study was conducted to examine the autogenous-reactive model of obsessions [Behav. Res. Ther. 41 (2003) 11-29]. A large number of college students (n=932) were administered a questionnaire battery assessing obsessional intrusions, schizotypal personality features, depressive symptoms, general anxiety and OCD symptoms. Hierarchical regression analyses revealed that autogenous obsessions were more strongly associated with schizotypal personality features than with OCD symptoms, general anxiety, or depression, whereas the relationship between reactive obsessions and schizotypal personality features was negligible. Moreover, autogenous obsessions were more strongly associated with covert OCD symptoms, whereas reactive obsessions were more strongly associated with overt OCD symptoms. These findings suggest that autogenous obsessions are more strongly associated with cognitive features (e.g., anomalous perception, obsessing), whereas reactive obsessions are more strongly associated with overt behavioral features (e.g., checking, washing, ordering). Theoretical and clinical implications are discussed.


Differences in the Association of Neighborhood Environment With Physical Frailty Between Urban and Rural Older Adults: The Korean Frailty and Aging Cohort Study (KFACS).
We examined the difference in the relationship between perceived neighborhood environments and physical frailty between urban and rural older adults. Cross-sectional study. Urban and rural community in South Korea; a total of 2593 community-dwelling older adults aged 70-84 years (mean age: 76.0 years, 51.0% women) in the Korean Frailty and Aging Cohort Study (KFACS). The neighborhood environment was assessed using the 17-item Environmental Module of the International Physical Activity Questionnaire (IPAQ-E). The IPAQ-E had 7 environmental factors (residential density, access to destinations, neighborhood infrastructure, neighborhood safety, social environment, aesthetic qualities, and street connectivity). Physical frailty was defined using the Fried frailty criteria with modified cutoffs. The number of participants residing in urban and rural areas was 1902 and 691, respectively. The prevalence of frailty was 5.3% and 12.0% in urban and rural areas, respectively. In urban areas, frailty was associated with the total IPAQ-E score (β = -0.007, P = .009) after adjusting for confounding factors. There was no association in the rural areas (β = -0.003, P = .535). In urban older adults, logistic regression showed that absence of destination [odds ratio (OR) 2.58, 95% confidence interval (CI) 1.36-4.90] and no crime safety at night (OR 2.00, 95% CI 1.12-3.57) were associated with a higher risk of frailty. In rural older adults, poor access to recreational facilities (OR 2.17, 95% CI 1.07-4.40) and no aesthetics (OR 2.49, 95% CI 1.22-5.10) were associated with frailty. Our study indicated that the presence of destination and crime safety at night was significantly associated with physical frailty among older adults living in urban areas, whereas aesthetics and recreational facilities were significantly associated with physical frailty in rural older adults.


Tissue Plasminogen Activator as a Possible Indicator of Breast Cancer Relapse: A Preliminary, Prospective Study.
(1) Background: The fundamental causes of breast cancer mortality are the cancer spread and hypercoagulability state. The study aimed to evaluate the prognostic efficacy of the fibrinolytic profile concerning 5-year follow-up. (2) Methods: We investigated the predictive potential of the plasma activity of urokinase plasminogen activator (u-PA) and plasminogen activator inhibitor type 1 (PAI-1) as well as antigen of tissue plasminogen activator (t-PA), u-PA, PAI-1, and PAI-1/t-PA and PAI-1/u-PA complexes in 41 breast cancer patients. The median follow-up was 66 months, with full evidence of the first event. (3) Results: A significantly lower level of PAI-1 antigen was noted in IBrC patients with lymph node involvement (N1) than in patients with free lymph node metastases (N0). According to ROC curve analysis, a t-PA antigen was the strongest predictor of disease relapse (the area under the curve, AUC = 0.799; p < 0.0006). Patients with PAI-1 activity < 3.04 U/mL had significantly better disease-free survival (DFS) compared to those with PAI-1 activity > 3.04 U/mL. Patients with both t-PA antigen lower than 1.41 ng/mL (cut-off according to median value) and lower than 1.37 ng/mL (cut-off according to ROC curve) had significantly shorter DFS (p = 0.0086; p = 0.0029). (4) Conclusions: The results suggest that a higher plasma t-PA antigen level or lower PAI-1 activity are linked to better outcomes in breast cancer patients.


Prospective screening for deep vein thrombosis in high risk patients.
In 257 patients undergoing total hip replacement, gastric bypass for morbid obesity, major abdominal surgery, and major leg amputation, Doppler ultrasonic screening revealed only five instances of deep vein thrombosis. The present study suggests that Doppler screening of high risk patients is a useful alternative to routine anticoagulant prophylaxis of venous thromboembolic disease.


Cutaneous pigmentation.
The color of an individual's skin is an inherited trait, poorly understood in any real genetic sense and likely to remain so in the outbred populace. Pigmentary anomalies are assignable either to hyperpigmentation (melanoderma, ceruloderma) or hypopigmentation (leukoderma). This article briefly reviews such anomalies.


CDK inhibitor SU9516 induces tetraploid blastocyst formation from parthenogenetically activated porcine embryos.
To examine the effect of SU9516, a cyclin-dependent kinase inhibitor, on the induction of tetraploid blastocyst formation in porcine embryos by parthenogenetic activation. Karyotype analysis of blastocysts showed that in the SU9516-treatment group 56% were tetraploid, whereas in the cytochalasin B (CB) group 67% were diploid. The level of maturation-promoting factor (MPF) in stimulated embryos treated with 10 µM SU9516 for 4 h was lower than in embryos treated with CB group (103 vs. 131 pg/ml). The mRNA expression levels of Nanog significantly increased in SU9516-treated embryos than CB group. SU9516 can induce tetraploid blastocyst formation at high efficiency. SU9516 can significantly influence the in vitro developmental competence of porcine parthenogenetically activated embryos by influencing the level of MPF and the gene related apoptosis and pluripotency.


Ultrasound in the changing approaches to breast cancer diagnosis and treatment.
Advances in ultrasound technology have not only refined this modality for diagnostic purposes, but have also extended its utility to the realm of treatment. Specific patient populations benefit from the addition of ultrasound to mammographic screening, such as those with BRCA-1 or BRCA-2 mutations or a personal or family history of breast cancer. Ultrasound is of particular benefit in guiding wire localization under sedation, as well as in guiding core biopsies and fine-needle aspirations. Current ablative techniques, including radiofrequency, cryoablation and laser, are now incorporating ultrasound guidance to maximize efficacy. Furthermore, ultrasound has been found to have significant utility in guiding preablative core biopsies for definitive diagnosis, estrogen receptor (ER)/progesterone receptor (PR), HER-2/neu, and other markers. As a result of its proven utility, ultrasound is now undergoing evaluation for use in the removal of malignant breast lesions.


Management and prevention of brachial plexus injury caused by surgical suture of neck dissection induced chylous fistula.
The complication of brachial plexus injury (BPI) after surgical suture of chylous fistula caused by neck dissection is extremely rare. For the first time, we investigated the treatment and prevention strategy of BPI caused by surgical suture of neck dissection induced chylous fistula. Forty-two patients undergoing surgical suture of neck dissection induced chylous fistula were identified between January 2015 to March 2022 at a single tertiary academic center. All patients were divided into two groups, medial anterior scalene muscle (MASM) group (24 patients) and lateral anterior scalene muscle (LASM) group (18 patients), according to the location of fistula regarding scalene muscle described in the surgical records. The incidence of BPI between the two groups after surgical suture was summarized and compared. There was significant difference in the incidence of different degrees of BPI between the two groups. In the MASM group, the incidence of BPI was 0 % (0/24), while in the LASM group, 6 cases suffered different degrees of BPI immediately after operation and the incidence of BPI was 33.3 % (6/18) (p < 0.05). The neurological function of all BPI cases recovered within 1-3 months after the suture was removed in time. The incidence of BPI in patients of LASM group was significantly higher than that of MASM group. When suturing this kind of fistula, the depth of the needle should be properly controlled to avoid BPI. In case of BPI, the suture should be removed as soon as possible to promote the recovery of neurological function.


Neurovascular unit: a focus on pericytes.
The blood-brain barrier (BBB) is a highly specialized system that controls the exchanges between the blood and the central nervous system (CNS). This barrier shields the CNS from toxic substances in the blood and provides nutrients to CNS, thus playing an essential role in the maintenance of homeostasis. The anatomical basis of the BBB is formed by the endothelial cells of brain microvasculature, with elaborated tight and adherens junctions, which together with pericytes, the basement membrane, and astrocytes, as well as neurons, microglia and oligodendrocytes form the neurovascular unit. The interaction between all these components guarantees a proper environment for neural function and a restricted permeability and transport. Pericytes were initially reported by Rouget in 1873 and since then they have been recognized as an important component of the BBB, despite the difficulty of their identification. Diverse functions have been assigned to pericytes, including a role in BBB properties, hemostasis, and angiogenesis, as well as a contractile, immune, and phagocytic function. These cells are also seen like multipotent cells and so with a great potential for therapy. Here, we review the neurovascular unit composition and the interplay between the diverse components, addressing pericytes with a particular detail.


Perceiver bias in the processing of deliberately asymmetric emotional expressions.
Posers were requested to produce happy and sad emotional expressions, deliberately accentuated on the left and right sides of the face. Raters judged the emotional intensity of expressions when presented in original and mirror-reverse orientation. Left-side-accentuated sad expressions were rated as more intense than right-side-accentuated sad expressions. Raters were biased to judge expressions as more intense when the accentuated side was to their left. The findings indicated that the perceiver bias in weighting information from the side of the face in left hemispace extends to judgments of emotional intensity.


Antigenic sites of coxsackie A9 virus inducing neutralizing monoclonal antibodies protective in mice.
A panel of murine IgG monoclonal antibodies (MAbs) was produced against coxsackievirus A9 (CAV9). Fifty-nine MAbs reactive in ELISA with purified CAV9 were identified. Eighteen of them could efficiently inhibit infection by CAV9 but not coxsackieviruses B. Neutralization-resistant CAV9 variants to four different MAbs were isolated and tested for resistance to neutralization by other MAbs of the panel. Three groups of reactivity including 10, 7, and 1 MAbs were thus identified. Sequencing of neutralization-escape virus mutants showed that neutralization by one MAb group was affected by change of VP3 amino acids 62 or 69. For the second group of reactivity, mutations included amino acids 154 or 165 of VP2. The only MAb of the third group selected for a change at residue 70 of VP2. Protection studies in a newborn mouse model of myositis suggested that either epitopes in VP2 or in VP3 mediate protection from CAV9 infection in vivo.


Use of a brief steroid trial before initiating OKT3 therapy for renal allograft rejection.
OKT3 (Ortho Pharmaceutical, Raritan, NJ) has been employed in a protocol where all patients received cyclosporine as part of their baseline immunosuppressive regimen and, after the diagnosis of rejection was established, were treated with up to three pulses of methylprednisolone before monoclonal antibody therapy was initiated. Use of this protocol has allowed 46% of rejection episodes encountered to be treated on an outpatient basis without resorting to inpatient use of OKT3, but has avoided delaying OKT3 therapy until after all other methods of rejection treatment were found to be ineffective. Of 83 rejection episodes treated with OKT3 between March 1985 and May 1987, 78 (94%) were reversed. Overall graft survival is 84% and patient survival is 96% in OKT3-treated patients. Of the 17 rejection episodes where OKT3 treatment was a second or third exposure to the drug, rejection was successfully reversed in 15 (88%). In cadaver donor allograft recipients transplanted between March 1985 and May 1986, actual 1-year graft survival is 80% for 30 patients requiring no rejection therapy, 80% for 20 patients with rejection episodes responding quickly to steroids, and 82% for 28 patients with OKT3-treated, steroid-insensitive rejections. Mean serum creatinine at 1 year posttransplant is 1.5 +/- 0.5; 1.9 +/- 0.7; and 2.1 +/- 0.8, respectively, for these groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Globin gene expression in MSV-transformed fibroblasts.
The activation of globin gene expression on viral transformation of 3T3 cells was investigated. Globin mRNA was determined using a radioactive complementary DNA probe. No difference was found between 3T3 and transformed 3T3 cells. There does not therefore appear to be a random activation of extensive regions of the cellular genome.


Cooperative unit size in the gel-liquid crystalline phase transition of dipalmitoyl phosphatidylcholine-water multilayers: an estimate from Raman spectroscopy.
The temperature dependence of the Raman spectral transitions assigned to the acyl chain C-C stretching modes of dipalmitoyl phosphatidylcholine was determined for the gel, phase transition and liquid crystalline states of the lipid multilayers. The van't Hoff enthalpy differences delta HVH between trans and gauche rotational isomers were obtained from the Raman spectral data for the temperature region characteristic of each bilayer state. An average size for the cooperative unit undergoing the chain melting process during the phase transition was estimated from the ratio of the appropriate van't Hoff enthalpy to an adjusted calorimetric enthalpy.


The thiol group of bovine serum albumin. High reactivity at acidic pH as measured by the reaction with 2,2'-dipyridyl disulphide.
The reaction between 2,2'-dipyridyl disulphide and the thiol group in bovine serum albumin has been studied at pH 1.1-7.9. At pH 5.5-7.9 the reaction rate was second order in dipyridyl disulphide and thiolate ion, as expected for an aliphatic thiol compound. Below pH 5.5 the reaction rate increased and became maximum at pH 2.6. The observed rate constant (110 M-1-s-1) was comparable with that at pH 6.6, although the thiolate ion concentration should be 10(4) times less at the lower pH. The increase in reactivity seemed to be correlated with the conformational change in serum albumin at pH 3.6-4.0. Increased nucleophilicity due to interaction with some suitable functional group might explain the high reactivity of the SH group at acidic pH.


Phylogenetic relationships and genetic polymorphisms in wild Indian mice.
Randomly amplified polymorphic DNA (RAPD) analysis was used to examine the extent of variability in 11 Indian wild derived commensal house mice (Mus musculus) populations and compared with inbred strains of musculus and domesticus subspecies as well as commonly used laboratory inbred strains C57BL/6J and DBA/2J. Arbitrary designed 10 mer oligonucleotide primers with 60-70% (G+C) content were used to amplify DNA template. Out of 52 primers screened initially on the laboratory strains, 20 were selected for analysis on the basis of amplification product in the size range of 200-1400 bp. Among 353 total polymorphic bands, 220 bands (64%) were found to be polymorphic in Indian wild mice, 85 bands (25%) in wild derived inbred strains and 37 bands (11%) in laboratory mice strains. The amplification patterns produced by primers were statistically analysed by Jaccard's similarity coefficient the value of which ranged from 0.56 to 0.80. High level of genetic diversity was seen in the Indian wild mice populations as compared to the controls. The UPGMA phenogram grouped mice population into two major clusters except Bikaner [BIK], Bilaspur [BIL] and Ranikhet [RK] populations which were placed outside the close-knit clusters. Inspite of low values of bootstrap estimates obtained by Wagner and Dollo parsimony analysis, the results were comparable with UPGMA phenogram when constitution of the populations in the major cluster was considered. Indian mice populations appeared to be diverse from laboratory inbred mice strains.


Photodynamic therapy for choroidal metastasis in 8 cases.
To determine the efficacy of photodynamic therapy (PDT) in the treatment of choroidal metastasis. Retrospective, interventional case series. Nine tumors in 8 eyes of 8 patients. Photodynamic therapy using verteporfin at a dose of 6 mg/m(2) body surface area and 689 nm diode laser at an intensity of 600 mW/cm(2) for 83 seconds (50 J/cm(2)). Tumor control and best-corrected visual acuity. Nine choroidal metastases in 8 eyes were treated with 1 (8 tumors) or 2 (1 tumor) sessions of PDT. The mean tumor basal diameter was 7 mm (median, 7 mm [range, 2-13 mm]), and mean tumor thickness was 2.9 mm (median, 2.9 mm [range, 1.6-4 mm]). All 9 tumors were associated with shallow subretinal fluid. After PDT, complete control with resolution of subretinal fluid was achieved in 7 tumors (78%), with mean tumor thickness reduction of 39% (median, 43% [range, 6%-61%]). Two tumors failed to respond to PDT, both requiring plaque radiotherapy. Improvement or stabilization of vision was achieved in 7 eyes. Photodynamic therapy-related complications included intraretinal hemorrhage in 1 eye. Photodynamic therapy can be an effective alternative for the treatment of choroidal metastasis. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


The effect of age on the nucleic acid content of slow- and fast-twitch muscle in normal and dystrophic mice and their litter mates.
RNA, DNA, and NCP content were measured in fast- and slow-twitch skeletal muscle of normal and dystrophic mice (HDM) and their littermates at ages 4 through 29 weeks. In normal and litter mate mice RNA and DNA content were far greater in the soleus than in the gastrocnemius while the RNA/DNA ratio and NCP content were greater in the gastrocnemius. In dystrophic mice, however, the differences between nuleic acid content of the 2 muscles were far less, apparently due to a proportionately higher content in the dystrophic gastrocnemius. Due to a proportionately lower ratio in the gastrocnemius, dystrophic RNA/DNA ratios for the 2 muscles were essentially the same. Age had a marked effect on the nucleic acid content of both muscles in all 3 mice types but to varying degrees. In the soleus, RNA and DNA content rapidly decreased until 9 to 10 weeks of age followed by a gradual decline. Soleus RNA/DNA ratios showed little change with age except in the HDM mice in which there was a significant overall decline. In the gastrocnemius, RNA content followed the same pattern but with a smaller decline in the younger ages. Age had no affect on DNA content in the normal gastrocnemius, but there was significant decline in the HDM gastrocnemius. RNA/DNA gastrocnemius ratios showed marked fluctuations in both normal and dystrophic mice but did not appear to be affected by age.


Combination of PARP and WEE1 inhibitors in vitro: Potential for use in the treatment of SHH medulloblastoma.
Medulloblastoma (MB), grouped as either WNT‑activated, Sonic hedgehog (SHH)‑activated, or non-WNT/non-SHH group 3, accounts for almost 20% of all childhood brain cancers. In spite of current intensive treatments, not all patients are cured and survivors suffer from severe side‑effects. The present study therefore examined the effects of the poly‑ADP‑ribose polymerase (PARP) and WEE1‑like protein kinase (WEE1) inhibitors, BMN673 and MK‑1775, respectively, alone or in combination on four MB cell lines. More specifically, the MB cell lines, DAOY, UW228‑3, MED8A and D425, were tested for their sensitivity to BMN673 and MK‑1775 alone or in combination, using cell viability, cell confluency and cytotoxicity assays. The effects on the cell cycle phases were also examined using FACS analysis. Monotherapy with BMN673 and MK‑1775 exerted dose‑dependent inhibitory effects on the viability of almost all MB cell lines. Notably, when BMN673 and MK‑1775 were used in combination, synergistic effects were noted in the SHH group cell lines (DAOY and UW228‑3), but not in the already WEE1‑sensitive group 3 (MED8A and D425) lines. Moreover, the combination treatment decreased the percentage of cells in the G1 phase and induced the novel distribution of both DAOY and UW228‑3 cells in the S and G2/M phases, with the UW228‑3 cells exhibiting a greater delay. To conclude, MK‑1775 was efficient in all and BMN673 in most cell lines, and their combined use exerted synergistic effects on the SHH, but not the group 3 cell lines. These data suggest that MK‑1775 alone may be of interest for all MB cell lines, and that the combination of PARP/WEE1 inhibitors may provide possible therapeutic opportunities for the therapy of SHH MBs. Their use warrants further investigations in the future.


Note: A compact external-cavity diode laser, using feedback from an optical fiber.
We demonstrate a simple and compact external cavity diode laser (ECDL), where light reflected from the tip of an optical fiber provides feedback, and an interference filter provides frequency selection. The ECDL combines ease of construction with robust operation and exhibits a linewidth of 50 kHz.


Hydrodynamic characterization and DNA-binding properties of the liganded and unliganded forms of the retinoic-acid receptor alpha from human HL-60 cells.
The hydrodynamic parameters of the retinoic-acid receptor from human myeloblastic leukemia HL-60 cells were accurately investigated. The ligand-bound retinoic-acid receptor (RAR) has a Stokes radius of 3.5 nm when analyzed by size-exclusion chromatography. A 53-kDa protein was detected by Western blot analysis using a polyclonal antibody directed against the F domain of hRAR alpha, in the fractions containing the 3.5-nm complex. Fractionation of a crude nuclear extract from HL-60 cells, untreated with retinoic acid, yielded antibody-revealed material with Stokes radii ranging from 3.5 nm to 6 nm. From the hydrodynamic data, a molecular mass of 52 kDa was calculated for the liganded receptor, whereas no precise value could be deduced for the unliganded receptor form, since it dissociates rapidly into the 3.5-nm form. Gel-retardation experiments showed that the 3.5-nm form of hRAR alpha bound specifically to DNA, whereas binding of the unliganded receptor form was sharply reduced. These findings suggest that the unliganded inactive receptor form dissociates upon ligand binding and acquires a ligand-dependent DNA-binding activity.


Antileishmanial activity of Riparin structural analogs of Aniba riparia: Biological evaluation, in silico Adme-Tox, and molecular docking.
We performed a biological evaluation of antileishmanial activity, in silico ADME-Tox profile, and molecular docking of riparins A-F. The antileishmanial activity was evaluated in Leishmania major promastigotes, whereas the cytotoxic activity was tested on murine macrophages. Computational parameters were predicted by in silico analysis. Molecular docking was performed with 18 L. major molecular targets. Riparins, especially RipC and RipE, showed cytotoxic activity in vitro toward L. major promastigotes and a high selectivity index. Riparins showed small differences in their physicochemical properties, such as polarity and aqueous solubility. LogP was an important parameter for the differences in the antileishmanial activity between the molecules. In molecular docking, the ligands displayed Ki < 1 μM for LmNMT and LmLEI. Significant molecular interactions were observed with residues from the active site and adjacent regions of such enzymes. Thus, riparins have the potential for application in antileishmanial therapy.


Reliability of orbital diagnostic tests: ultrasonography, computerized tomography, and radiography.
A series of 342 patients with unilateral exophthalmos underwent orbital diagnostic studies including ultrasonography, computerized tomography, radiographic studies, and vascular contrast studies. Each test was found to have diagnostic capabilities that complemented other studies depending upon the specific disease process involved. No one test was entirely adequate without supplementary information from the other tests. Radiographic studies demonstrated bony abnormality in 50% of the tumor cases, but in only 28% of the entire series of exophthalmos cases. Computerized tomography demonstrated diagnostic soft tissue abnormality in 86% of tumors, 43% of inflammatory diseases, and an overall yield of 62% positive results. Ultrasonography proved the most versatile test for evaluation of orbital soft tissues, with 80% positive results for tumors, 87% for inflammatory disorders, and 78% overall accurate orbital diagnosis. Erroneous tumor diagnosis of 7% with computerized tomography and 3% with ultrasonography were corrected by combining these two studies, because they tend to err in opposite directions. Combination of ultrasound and CT scan resulted in a 98% correct diagnosis of all types of orbital diseases.


Kallistatin treatment attenuates lethality and organ injury in mouse models of established sepsis.
Kallistatin levels in the circulation are reduced in patients with sepsis and liver disease. Transgenic mice expressing kallistatin are resistant to lipopolysaccharide (LPS)-induced mortality. Here, we investigated the effect of kallistatin on survival and organ damage in mouse models of established sepsis. Mice were rendered septic by cecal ligation and puncture (CLP), or endotoxemic by LPS injection. Recombinant human kallistatin was administered intravenously six hours after CLP, or intraperitoneally four hours after LPS challenge. The effect of kallistatin treatment on organ damage was examined one day after sepsis initiation, and mouse survival was monitored for four to six days. Human kallistatin was detected in mouse serum of kallistatin-treated mice. Kallistatin significantly reduced CLP-induced renal injury as well as blood urea nitrogen, serum creatinine, interleukin-6 (IL-6), and high mobility group box-1 (HMGB1) levels. In the lung, kallistatin decreased malondialdehyde levels and HMGB1 and toll-like receptor-4 (TLR4) synthesis, but increased suppressor of cytokine signaling-3 (SOCS3) expression. Moreover, kallistatin attenuated liver injury, serum alanine transaminase (ALT) levels and hepatic tumor necrosis factor-α (TNF-α) synthesis. Furthermore, delayed kallistatin administration improved survival in CLP mice by 38%, and LPS-treated mice by 42%. In LPS-induced endotoxemic mice, kallistatin attenuated kidney damage in association with reduced serum creatinine, IL-6 and HMGB1 levels, and increased renal SOCS3 expression. Kallistatin also decreased liver injury in conjunction with diminished serum ALT levels and hepatic TNF-α and TLR4 expression. In cultured macrophages, kallistatin through its active site increased SOCS3 expression, but this effect was blocked by inhibitors of tyrosine kinase, protein kinase C and extracellular signal-regulated kinase (ERK), indicating that kallistatin stimulates a tyrosine-kinase-protein kinase C-ERK signaling pathway. This is the first study to demonstrate that delayed human kallistatin administration is effective in attenuating multi-organ injury, inflammation and mortality in mouse models of polymicrobial infection and endotoxemia. Thus, kallistatin therapy may provide a promising approach for the treatment of sepsis in humans.


Tetrakis(dimethoxyphenyl)adamantane (TDA) and its inclusion complexes in the crystalline state: a versatile carrier for small molecules.
Molecular storage solutions for incorporating small molecules in crystalline matrices are of interest in the context of structure elucidation, decontamination, and slow release of active ingredients. Here we report the syntheses of 1,3,5,7-tetrakis(2,4-dimethoxyphenyl)adamantane, 1,3,5,7-tetrakis(4-methoxyphenyl)adamantane, 1,3,5,7-tetrakis(4-methoxy-2-methylphenyl)adamantane, and 1,3,5,7-tetrakis(4-methoxy-2-ethylphenyl)adamantane, together with their X-ray crystal structures. All four compounds crystallize readily. Only the octaether shows an unusual level of (pseudo)polymorphism in its crystalline state, combined with the ability to include a number of different small molecules in its crystal lattices. A total of 20 different inclusion complexes with guest molecules as different as ethanol or trifluorobenzene were found. For nitromethane and benzene, schemes for uptake and release are presented.


Guided tissue regeneration combined with bone allograft in infrabony defects: Clinical outcomes and assessment of prognostic factors.
Clinical data on the outcomes of guided tissue regeneration (GTR) is scarce. The aim of this retrospective cohort study was to evaluate the outcomes after GTR, their stability and the survival of the treated teeth with periodontal infrabony defects. Infrabony defects treated with GTR using a bioabsorbable membrane and a bone graft substitute with at least 1-year follow-up were included. Survival and regression analyses were conducted to evaluate the outcomes, their stability, and the retention of the teeth. The effect of recorded variables on clinical attachment gain (CAL) and tooth survival were assessed via Cox proportional-hazards models and multivariate generalized linear models. One hundred seventy-five treated defects were selected from a total of 641 charts. The average follow-up was 5.75 ± 4.6 years. At baseline, the mean CAL was 9.56 ± 1.93 mm with a mean pocket depth (PD) of 8.41 ± 1.42 mm. At the 1-year post-surgical recall, 3.55 ± 1.85 mm of CAL gain and 3.87 ± 1.87 mm PD reduction were observed (P < 0.05). The 5- and 10-year survival rates of the treated teeth were 85.0% and 72.7%, respectively. Baseline PD, smoking, and membrane exposure were significantly related to CAL gain, whereas baseline CAL, age, frequency in maintenance visits significantly affected tooth survival. Within the limitations of this study, data suggests GTR is a good option for the treatment of infrabony defects because it can improve both tooth retention rate and overall clinical outcomes.


Residual stresses in thin polymer films cause rupture and dominate early stages of dewetting.
In attempting to reduce the size of functional devices, the thickness of polymer films has reached values even smaller than the diameter of the unperturbed molecule. However, despite enormous efforts for more than a decade, our understanding of the origin of some puzzling properties of such thin films is still not satisfactory and several peculiar observations remain mysterious. For example, under certain conditions, such films show negative expansion coefficients or show undesirable rupture although energetically they are expected to be stable. Here, we demonstrate that many of these extraordinary effects can be related to residual stresses within the film, resulting from the preparation of these films from solution by fast evaporation of the solvent. Consequently, depending on thermal history and ageing time, such films show significant changes even in the glassy state, which we quantify by dewetting experiments and corresponding theoretical studies. Identifying the relevance of frozen-in polymer conformations gives us a handle for manipulating and controlling properties of nanometric thin polymer films.


Cleaning crew: Soluble TREM2 mops up complement.
Whether soluble TREM2 has a functional role in the central nervous system has been unclear. In this issue of Immunity, Zhong et al. show that soluble TREM2 inhibits aberrant synaptic pruning by sopping up the complement factor C1q to protect neurons and mitigate neurodegeneration.


Prevalence and determinants of low plasma zinc levels in adult peritoneal dialysis patients.
Zinc is an essential trace element, being a cofactor for almost 300 enzymes. As zinc is widely available in the diet, the European Best Practice Guidelines do not recommend routine supplementation in dialysis patients. However, some medicines prescribed to dialysis patients may potentially reduce absorption, and there may be increased losses with dialysis. As older and co-morbid patients are now treated by peritoneal dialysis (PD) we wished to determine the prevalence of patients with low plasma zinc levels. We prospectively measured plasma zinc in 550 PD patients attending for their first peritoneal membrane assessment using atomic absorption spectroscopy. Body composition was determined by bioimpedance. Plasma zinc was measured in 550 patients, mean age 58.7 years, 60.6% male, mean value 10.8 ± 2.2 umol/L, with 66.5% having low zinc levels (<11.5 umol/L). Normal plasma zinc was associated with haemoglobin (odds ratio (OR) 1.41 (95% confidence limits (95%CL) 1.22-1.63), serum albumin (OR 1.04 (95%CL 1.002-1.087), higher glucose dialysates L/day (OR 1.06 (1.001-1.129), and negatively with 24-hour urinary protein losses (OR 0.786 (95%CL 0.673-0.918) and age (OR 0.985 (95%CL 0.972-1.0). There was no association with dialysis adequacy, original renal disease or dietary protein estimation. Prescription of phosphate binders had no effect on zinc levels (10.7 ± 2.2 vs 10.8 ± 2.3 umol/L). Most PD patients had low plasma zinc levels, associated with older age, probably reflecting reduced intake, urinary protein losses, and lower albumin and haemoglobin most likely linked to greater co-morbidity, low grade inflammation and volume expansion requiring higher glucose dialysates.


Osteoplastic opening of the sellar floor in transsphenoidal surgery: technical note.
The authors propose a technique of opening the sellar floor during a transsphenoidal approach by means of two small bone flaps hinged sideward. Both opening and reconstruction of the sellar floor may be improved by this method, which may be used when the floor is paper-like.


Geometrical properties of mechanically annealed systems near the jamming transition.
Geometrical properties of two-dimensional mixtures near the jamming transition point are numerically investigated using harmonic particles under mechanical training. The configurations generated by the quasi-static compression and oscillatory shear deformations exhibit anomalous suppression of the density fluctuations, known as hyperuniformity, below and above the jamming transition. For the jammed system trained by compression above the transition point, the hyperuniformity exponent increases. For the system below the transition point under oscillatory shear, the hyperuniformity exponent also increases until the shear amplitude reaches the threshold value. The threshold value matches with the transition point from the point-reversible phase where the particles experience no collision to the loop-reversible phase where the particles' displacements are non-affine during a shear cycle before coming back to an original position. The results demonstrated in this paper are explained in terms of neither of universal criticality of the jamming transition nor the nonequilibrium phase transitions.


Longitudinal stability of inter-eye differences in optical coherence tomography measures for identifying unilateral optic nerve lesions in multiple sclerosis.
Optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell+inner plexiform layer (GCIPL) thickness inter-eye differences (IEDs) are robust measurements for identifying clinical history acute ON in people with MS (PwMS). This study investigated the utility and durability of these measures as longitudinal markers to identify optic nerve lesions. Prospective, multi-center international study of PwMS (with/without clinical history of ON) and healthy controls. Data from two sites in the International MS Visual System Consortium (IMSVISUAL) were analyzed. Mixed-effects models were used to compare inter-eye differences based on MS and acute ON history. Average age of those with MS (n = 210) was 39.1 ± 10.8 and 190 (91%) were relapsing-remitting. Fifty-nine (28.1%) had a history of acute unilateral ON, while 9/210 (4.3%) had >1 IB episode. Median follow-up between OCT scans was 9 months. By mixed-effects modeling, IEDs were stable between first and last visits within groups for GCIPL for controls (p = 0.18), all PwMS (p = 0.74), PwMs without ON (p = 0.22), and PwMS with ON (p = 0.48). For pRNFL, IEDs were within controls (p = 0.10), all PwMS (p = 0.53), PwMS without ON history (p = 0.98), and PwMS with history of ON (p = 0.81). We demonstrated longitudinal stability of pRNFL and GCIPL IEDs as markers for optic nerve lesions in PwMS, thus reinforcing the role for OCT in demonstrating optic nerve lesions.


Tissue-specific regulation of cell-cycle responses to DNA damage in Arabidopsis seedlings.
DNA damage-induced cell-cycle "checkpoint" responses reduce the mutagenic effects of this damage. However, the maintenance of genomic stability comes at a price: the slowing of growth and a delay in the development of critical tissues. In mammals, every mutated cell has the potential to become cancerous and therefore lethal. In plants, the risk of lethal cancers is essentially nil and the costs of delays in development are very high. Here, we investigate DNA damage checkpoint responses in meristematic (root and shoot tip) versus strictly somatic (stomatal and endoreduplicating) tissues in plants. We find that the ionizing radiation (IR)-induced cell-cycle responses observed in the root and shoot tip meristems do not apply to more differentiated tissues.


Testing a model of excitatory interactions between oscillators.
The experimentally observed influence of regularly arriving tugs upon the AP discharge of the slowly-adapting stretch receptor organ (SAO) of crayfish was compared to a model of pacemaker excitatory synaptic interactions (Segundo and Kohn 1981). Criteria for compliance referred to facets as A) the excitation, B) the postulates, and C) the behavior. A) Excitation was implied primarily by the tug initially increasing the AP rate (it subsequently decreased it). B) The pacemaker AP discharges, and with more reason the electronically driven tugs, were considered acceptably regular sequence (postulate i). Tugs advanced the next AP (postulate ii); the "delay function" plots of delays vs. phases, i.e. interval shortenings vs. the time from the last AP to the tug, were close to the V of postulate iii, even though the shortest phases tended to postpone the next AP and the longest ones did not trigger immediately but with an around 5 ms latency. These effects were displayed also as "old phase vs. new phase" plots. The interval following that with the tug tended to be lengthened, but the pre-tug timing was not recovered. C) Behavior during a train of excitatory events, both in model and experiments, went through very similar initial settlings and eventual steady-states. The latter were characterized in the model by 1. an average excitatory vs. excited rate display formed by an endless number of segments with all positive rational slopes separated by negative-going discontinuities, 2. locking in the sense of preferential phases, and 3. periodic repetition of the same phases and inter-AP intervals. Experimental results were compatible with this. Such behavior was absent when the tug sequence was highly irregular. The initial settling, in the SAO as in the model, depended jointly on the first phase phi 1 and the intertug interval E. If the former was under lambda, it went through one or two monotonic phase-decreasing stages (one smaller, the other larger, than lambda), or through a single increasing one, depending on E being smaller or greater than, respectively, an estimated but never actually observed E leading to unstable lockings. If the initial phase was greater than lambda, settling with E's under rN + lambda involved jumps between larger than and smaller than lambda phases; with E's over rn + lambda, it involved an intermediate stable locking with phi = E-rN.(ABSTRACT TRUNCATED AT 400 WORDS)


Inferring limb coordination strategies from trajectory kinematics.
This paper discusses the method of kinematic modeling and matching to human arm trajectories in order to ascertain the motor control system's coordination strategy. The planning variables of joint angles and endpoint Cartesian coordinates are contrasted, under linear and staggered interpolation strategies. It is shown that distinguishing the two variable planning sets depends critically on the region of the workspace in which movement takes place.


Characterization of currently marketed heparin products: analysis of molecular weight and heparinase-I digest patterns.
We evaluated polyacrylamide gel electrophoresis (PAGE) and size exclusion chromatography coupled with multi-angle laser light scattering (SEC-MALLS) approaches to determine weight-average molecular weight (M(w)) and polydispersity (PD) of heparins. A set of unfractionated heparin sodium (UFH) and low-molecular-weight heparin (LMWH) samples obtained from nine manufacturers which supply the US market were assessed. For SEC-MALLS, we measured values for water content, refractive index increment (dn/dc), and the second virial coefficient (A(2)) for each sample prior to molecular weight assessment. For UFH, a mean ± standard deviation value for M(w) of 16,773 ± 797 was observed with a range of 15,620 to 18,363 (n = 20, run in triplicate). For LMWHs by SEC-MALLS, we measured mean M(w) values for dalteparin, tinzaparin, and enoxaparin of 6,717 ± 71 (n = 4), 6,670 ± 417 (n = 3), and 3,959 ± 145 (n = 3), respectively. PAGE analysis of the same UFH, dalteparin, tinzaparin, and enoxaparin samples showed values of 16,135 ± 643 (n = 20), 5,845 ± 45 (n = 4), 6,049 ± 95 (n = 3), and 4,772 ± 69 (n = 3), respectively. These orthogonal measurements are the first M(w) results obtained with a large heparin sample set on product being marketed after the heparin crisis of 2008 changed the level of scrutiny of this drug class. In this study, we compare our new data set to samples analyzed over 10 years earlier. In addition, we found that the PAGE analysis of heparinase digested UFH and neat LMWH samples yield characteristic patterns that provide a facile approach for identification and assessment of drug quality and uniformity.


Indolo-pyrido-isoquinolin based alkaloid inhibits growth, invasion and migration of breast cancer cells via activation of p53-miR34a axis.
The tumor suppressor p53 plays a critical role in suppressing cancer growth and progression and is an attractive target for the development of new targeted therapies. We synthesized several indolo-pyrido-isoquinolin based alkaloids to activate p53 function and examined their therapeutic efficacy using NCI-60 screening. Here, we provide molecular evidence that one of these compounds, 11-methoxy-2,3,4,13-tetrahydro-1H-indolo[2',3':3,4]pyrido[1,2-b]isoquinolin-6-ylium-bromide (termed P18 or NSC-768219) inhibits growth and clonogenic potential of cancer cells. P18 treatment results in downregulation of mesenchymal markers and concurrent upregulation of epithelial markers as well as inhibition of migration and invasion. Experimental epithelial-mesenchymal-transition (EMT) induced by exposure to TGFβ/TNFα is also completely reversed by P18. Importantly, P18 also inhibits mammosphere-formation along with a reduction in the expression of stemness factors, Oct4, Nanog and Sox2. We show that P18 induces expression, phosphorylation and accumulation of p53 in cancer cells. P18-mediated induction of p53 leads to increased nuclear localization and elevated expression of p53 target genes. Using isogenic cancer cells differing only in p53 status, we show that p53 plays an important role in P18-mediated alteration of mesenchymal and epithelial genes, inhibition of migration and invasion of cancer cells. Furthermore, P18 increases miR-34a expression in p53-dependent manner and miR-34a is integral for P18-mediated inhibition of growth, invasion and mammosphere-formation. miR-34a mimics potentiate P18 efficacy while miR-34a antagomirs antagonize P18. Collectively, these data provide evidence that P18 may represent a promising therapeutic strategy for the inhibition of growth and progression of breast cancer and p53-miR-34a axis is important for P18 function.


Keratin 9 is required for the structural integrity and terminal differentiation of the palmoplantar epidermis.
Keratin 9 (K9) is a type I intermediate filament protein whose expression is confined to the suprabasal layers of the palmoplantar epidermis. Although mutations in the K9 gene are known to cause epidermolytic palmoplantar keratoderma, a rare dominant-negative skin disorder, its functional significance is poorly understood. To gain insight into the physical requirement and importance of K9, we generated K9-deficient (Krt9(-/-)) mice. Here, we report that adult Krt9(-/-)mice develop calluses marked by hyperpigmentation that are exclusively localized to the stress-bearing footpads. Histological, immunohistochemical, and immunoblot analyses of these regions revealed hyperproliferation, impaired terminal differentiation, and abnormal expression of keratins K5, K14, and K2. Furthermore, the absence of K9 induces the stress-activated keratins K6 and K16. Importantly, mice heterozygous for the K9-null allele (Krt9(+/-)) show neither an overt nor histological phenotype, demonstrating that one Krt9 allele is sufficient for the developing normal palmoplantar epidermis. Together, our data demonstrate that complete ablation of K9 is not tolerable in vivo and that K9 is required for terminal differentiation and maintaining the mechanical integrity of palmoplantar epidermis.


How do the physicochemical properties of nanoliposomes affect their interactions with the hCMEC/D3 cellular model of the BBB?
Nanosized liposomes composed of 1,2-distearoyl-sn-glycerol-3-phosphatidylcholine (DSPC), cholesterol and polyethylene glycol-conjugated phospholipid (PEG), incorporating FITC-dextran (FITC) and in some cases also Rhodamine-conjugated phospholipid (RHO) (as labels) were constructed by the thin film hydration method, followed by extrusion; membranes with pore diameters from 50 to 400nm were used, while charged vesicles were produced by partially replacing DSPC with 1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DSPG). The uptake of liposomes by hCMED/D3 cells was evaluated by measuring FITC in cells, and their permeability across cell monolayers was evaluated, by measuring the FI of liposome associated-FITC and RHO in the receiving side of a monolayer-transwell system. Results prove that liposome size has a significant effect on their uptake and permeability (for both charged and non-charged vesicles). The effect of liposome charge on cell uptake was slight (but significant), however charge (in the range from -2 to -16mV) did not significantly affect vesicle permeability; a significant decrease was only demonstrated for the liposome with the highest charge.


Low-dose tocilizumab is associated with improved outcome and a low risk of secondary infection in severe COVID-19 pneumonia.
Respiratory failure and death are the leading causes of severe Coronavirus disease 2019 (COVID-19). Hyper-inflammation and cytokine storm cause lung damage. This study aimed to compare the low-dose and high-dose effects of tocilizumab, an IL-6 receptor antagonist. Patients with severe pneumonia and hyper-inflammation signs because of COVID-19 were included in this retrospective study. Patients receiving tocilizumab <200 mg intravenously were classified as the low-dose group, and receiving ≥200 mg as the high-dose group, and those not treated with tocilizumab as the control group. Demographic and clinical data of patients who died and survived in both low-high dose and control patients were compared. According to symptom day and radiological infiltration, patients with tocilizumab were also evaluated in two groups as early and late periods at tocilizumab administration time. A total of 160 patients were included in the study; 70 were treated with a low dose and 50 with high-dose tocilizumab. Forty patients were in the control group. Age, comorbidity and clinical features were similar in the control, low-dose tocilizumab and high-dose tocilizumab groups. The mortality rate (12.9%, 30.0%, 37.5, P = .008) was less in the low-dose tocilizumab group. The secondary infection rate was higher in the high-dose group than in the low-dose tocilizumab and control groups (44.0%, 10.0%, 10.0%, P < .001). Distinguishing between those patients who died and survived, age (OR: 1.1589, P < .001), higher APACHE II scores (OR: 1.225, P = .001) and needs for non-invasive mechanical ventilation (OR: 14.469, P < .001) were the most critical risk factors. Low-dose tocilizumab was associated with a lower mortality rate (OR: 0.244, P = .012). The use of tocilizumab at a low dose is associated with lower secondary infections and mortality.


Predator-induced transgenerational plasticity in animals: a meta-analysis.
There is growing evidence that the environment experienced by one generation can influence phenotypes in the next generation via transgenerational plasticity (TGP). One of the best-studied examples of TGP in animals is predator-induced transgenerational plasticity, whereby exposing parents to predation risk triggers changes in offspring phenotypes. Yet, there is a lack of general consensus synthesizing the predator-prey literature with existing theory pertaining to ecology and evolution of TGP. Here, we apply a meta-analysis to the sizable literature on predator-induced TGP (441 effect sizes from 29 species and 49 studies) to explore five hypotheses about the magnitude, form and direction of predator-induced TGP. Hypothesis #1: the strength of predator-induced TGP should vary with the number of predator cues. Hypothesis #2: the strength of predator-induced TGP should vary with reproductive mode. Hypothesis #3: the strength and direction of predator-induced TGP should vary among offspring phenotypic traits because some traits are more plastic than others. Hypothesis #4: the strength of predator-induced TGP should wane over ontogeny. Hypothesis #5: predator-induced TGP should generate adaptive phenotypes that should be more evident when offspring are themselves exposed to risk. We found strong evidence for predator-induced TGP overall, but no evidence that parental predator exposure causes offspring traits to change in a particular direction. Additionally, we found little evidence in support of any of the specific hypotheses. We infer that the failure to find consistent evidence reflects the heterogeneous nature of the phenomena, and the highly diverse experimental designs used to study it. Together, these findings set an agenda for future work in this area.


Prodromal schizophrenia in primary care: a randomised sensitisation study.
GPs are often the first point of contact for patients with prodromal schizophrenia. Early intervention, and therefore early detection, of schizophrenia is pivotal for the further disease course. However, recent studies have revealed that, due to its low prevalence in general practice and its insidious features, prodromal schizophrenia often remains unnoticed. To test whether a repeated sensitisation method using clinical vignettes can improve diagnostic knowledge of GPs. Postal survey using anonymous questionnaires. Repeated sensitisation model using clinical vignettes. GPs in three distinct regions in Switzerland covering a general population of 1.43 million. The study was conducted between September 2008 and October 2009. Questionnaires were sent to 1138 GPs at baseline, and at 6 and 12 months. After randomisation, 591 GPs were sensitised at 1, 3, and 5 months, while no sensitisation was carried out in the remaining 547 GPs. The overall response rate was 66% (750 GPs). Sensitised GPs demonstrated a highly significant increase in diagnostic knowledge at 6 and at 12 months when compared to their own baseline knowledge scores and also to non-sensitised GPs (P<0.001). In particular, awareness of insidious features, such as functional decline and social withdrawal as signs of prodromal schizophrenia, accounted for this effect. Theoretical knowledge of prodromal schizophrenia among GPs can successfully be increased by repeated sensitisation models using clinical vignettes.


Effective Treatment of Knee Osteoarthritis Using a Nano-Enabled Drug Acupuncture Technology in Mice.
A nano-enabled drug delivery acupuncture technology (nd-Acu) is developed that is based on traditional acupuncture needles where the stainless-steel surface is designed to deliver various payload molecules. To create the nd-Acu platform, an electrochemistry procedure is used to attach methyl salicylate-modified cyclodextrin in which the sugar rings allow the encapsulation of structurally defined single or multiple payload molecules via an inclusion complexation process. Drug loading and release profile are first studied using fluorescent dyes abiotically and at intact animal level. nd-Acu allows more efficient dye loading and time-dependent release compared to pristine needles without cyclodextrin modification. Subsequently, a proof-of-principle efficacy study is conducted using the platform to load a local anesthetic, lidocaine, for the treatment of knee osteoarthritis (KOA) in mice. It is demonstrated that lidocaine-laden nd-Acu can effectively alleviate pain, reduce inflammation, and slow down KOA development biochemically and histologically. Hypothesis-driven and proteomic approaches are utilized to investigate the working mechanisms of lidocaine nd-Acu, indicating that the therapeutic outcome is attributed to the in vivo modulation of the HMGB1/TLR4 signaling pathway. The study also obtained preliminary evidence suggesting the involvement of mitochondria as well as small GTPase such as cdc42 during the treatment by lidocaine nd-Acu.


Impact of the COVID-19 Pandemic on Food Safety Inspection Outcomes in Toronto, Canada: A Bayesian Interrupted Time Series Analysis.
The coronavirus (COVID-19) pandemic resulted in major disruptions to the food service industry and regulatory food inspections. The objective of this study was to conduct an interrupted time series analysis to investigate the impact of the COVID-19 pandemic on food safety inspection trends in Toronto, Canada. Inspection data for restaurants and take-out establishments were obtained from 2017 to 2022 and summarized as weekly counts of inspections, pass ratings, and total infractions. Bayesian segmented regression was conducted to evaluate the impact of the pandemic on weekly infraction and inspection pass rates. On average, a 0.31-point lower weekly infraction rate (95% credible interval [CI]: 0.23, 0.40) and a 2.0% higher probability of passing inspections (95% CI: 1.1%, 3.0%) were predicted in the pandemic period compared to prepandemic. Models predicted lower infraction rates and higher pass rates immediately following the pandemic, with additional variability compared to the prepandemic period, that were regressing back toward pre-pandemic levels in 2022. Seasonal effects were also identified, with infraction rates highest in April and pass rates lowest in August. The COVID-19 pandemic resulted in an initial positive effect on food safety outcomes in restaurants and take-out food establishments in Toronto, but this effect appears to be temporary. This finding could be due to the beneficial impact of COVID-19 protection measures in these establishments or other factors such as less volume of customers. Additional research is needed to investigate causes of the identified differences as well as seasonal and long-term inspection trends postpandemic. Results can inform future food safety inspection planning, outreach, and pandemic preparedness.


When to Consider Stand-Alone Lateral Lumbar Interbody Fusion: Is There a Role for a Comeback With New Implants?
To perform a comprehensive review of the literature about the role of stand-alone lateral lumbar interbody fusion (LLIF). A MEDLINE review was conducted including studies about stand-alone LLIF for any condition. The opinions of the authors were also considered. Studies that included biomechanical, cadaveric, or clinical aspects of stand-alone cages were revised to obtain data about the pros, cons, and limitations of the technique. Comparative studies with 360° (lateral + posterior) fusions were also analyzed. A total of 36 studies were identified. After reviewing the abstracts, 18 full articles of interest for the objective of this review were analyzed. Recommendations based on the literature were made. Although most of the recommendations in the literature were about augmentation with pedicle screws, there may be a role for stand-alone LLIF in some particular cases. Specific technical aspects should be considered to reduce the failure rate. Although there might be some specific indications for stand-alone LLIF, it should be considered an exception rather than the rule.


Simulated seasonal oceanographic changes and their implication for the small pelagic fisheries in the Java Sea, Indonesia.
Small pelagic fisheries in the Java Sea (JS) contributes to about 26.6% of the total marine fisheries resources, where their spatial-temporal variation is controlled by seasonal oceanographic changes. This study aims to investigate a relationship between seasonal reversal circulation and number of light-fishing vessels (VBD) dispersion that capture small pelagic fishes, using multi-datasets from a regional ocean circulation model, satellite-derived datasets, and pelagic fish landing datasets between 2010 and 2020. The model demonstrates that main axis of eastward (westward) monsoon current that brings warmer and fresher (cooler and saltier) water, confines much closer along the northern Java (southern Kalimantan) during the northwest (southeast) monsoon period. These changes are followed unprecedentedly by southward (northward) shift of VBD and high abundance of euryhaline (stenohaline) fish species. This new evidence implies that reversal monsoon current and surface component of Makassar Throughflow play a significant role on delineating potential small pelagic fishing ground and fish productions.


Ionization chamber measurements of the half-lives of 24Na, 42K, 76As and 198Au.
Samples of 24Na, 42K, 76As and 198Au were produced by irradiation in the National Institute of Standards and Technology (NIST) reactor, and examined for impurities before and after measurement. Half-life measurements were carried out in the NIST 4pigamma pressurized ionization chamber. The results are compared to presently accepted values and previous NIST measurements.


Possible interaction between phenobarbital, carbamazepine and itraconazole.
We report a case of a possible interaction between itraconazole, phenobarbital and carbamazepine. The first plasma itraconazole concentration, measured when the patient had been taking phenobarbital for 2 months, was very low. The second measurement, 2 months after withdrawing phenobarbital, was higher but below the therapeutic range. However, carbamazepine, a well known enzyme inducer, had been initiated 15 days before. 20 days after carbamazepine was withdrawn, the itraconazole concentration 4 hours after administration was near the lower end of the therapeutic range. The mechanism of this possible interaction is probably the same for phenobarbital and carbamazepine, involving hepatic microsomal enzyme system induction.


Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4-/- Mice.
The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4-/- mice. After weaning, male Abcb4-/- mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age. Liver tissue and serum were isolated and examined by means of serum analysis, quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4-/- and Bagg Albino Mouse/c wild-type mice served as controls. Cholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved Phosphoenolpyruvat-Carboxykinase expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated cellular-Jun N-terminal kinase/cellular-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4-/- mice were reduced to wild-type level by CB1 antagonization. We showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4-/- model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis.


Low molecular weight polysialic acid binds to properdin and reduces the activity of the alternative complement pathway.
Sialic acids as the terminal caps of the cellular glycocalyx play an essential role in self-recognition and were shown to modulate complement processes via interaction between α2,3-linked sialic acids and complement factor H. Previously, it was suggested that low molecular weight α2,8-linked polysialic acid (polySia avDP20) interferes with complement activation, but the exact molecular mechanism is still unclear. Here, we show that soluble polySia avDP20 (molecular weight of ~ 6 kDa) reduced the binding of serum-derived alternative pathway complement activator properdin to the cell surface of lesioned Hepa-1c1c7 and PC-12 neuroblastoma cells. Furthermore, polySia avDP20 added to human serum blocked the alternative complement pathway triggered by plate-bound lipopolysaccharides. Interestingly, no inhibitory effect was observed with monosialic acid or oligosialic acid with a chain length of DP3 and DP5. In addition, polySia avDP20 directly bound properdin, but not complement factor H. These data show that soluble polySia avDP20 binds properdin and reduces the alternative complement pathway activity. Results strengthen the previously described concept of self-recognition of sialylation as check-point control of complement activation in innate immunity.


Optimization of hydrolysis conditions for the production of glucomanno-oligosaccharides from konjac using β-mannanase by response surface methodology.
Glucomanno-oligosaccharides (GMO), usually produced from hydrolysis of konjac tubers with a high content of glucomannan, have a positive effect on Bifidobacterium as well as a variety of other physiological activities. Response surface methodology (RSM) was employed to optimize the hydrolysis time, hydrolysis temperature, pH and enzyme to substrate ratio (E/S) to obtain a high GMO yield from konjac tubers. From the signal-factor experiments, it was concluded that the change in the direct reducing sugar (DRS) is consistent with total reducing sugar (TRS) but contrary to the degree of polymerization (DP). DRS was used as an indicator of the content of GMO in the RSM study. The optimum RSM operating conditions were: reaction time of 3.4 h, reaction temperature of 41.0°C, pH of 7.1 and E/S of 0.49. The results suggested that the enzymatic hydrolysis was enhanced by temperature, pH and incubation time. Model validation showed good agreement between experimental results and the predicted responses.


Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women.
Obesity has become a recognized global epidemic that is associated with numerous comorbidities including type II diabetes, cardiovascular disease, hypertension, and cancer incidence and progression. Ovarian cancer (OvCa) has a unique mechanism of intra-peritoneal metastasis, already present in 80% of women at the time of diagnosis, making it the fifth leading cause of death from gynecological malignancy. Meta-analyses showed that obesity increases the risk of OvCa progression, leads to enhanced overall and organ-specific tumor burden, and adversely effects survival of women with OvCa. Recent data discovered that tumors grown in mice fed on a western diet (40% fat) have elevated lipid levels and a highly increased expression level of sterol regulatory element binding protein 1 (SREBP1). SREBP1 is a master transcription factor that regulates de novo lipogenesis and lipid homeostasis, and induces lipogenic reprogramming of tumor cells. Elevated SREBP1 levels are linked to cancer cell proliferation and metastasis. This review will summarize recent findings to provide a current understanding of lipid regulatory proteins in the ovarian tumor microenvironment with emphasis on SREBP1 expression in the obese host, the role of SREBP1 in cancer progression and metastasis, and potential therapeutic targeting of SREBPs and SREBP-pathway genes in treating cancers, particularly in the context of host obesity.


Medical diagnostics with mobile devices: Comparison of intrinsic and extrinsic sensing.
We review the recent development of mobile detection instruments used for medical diagnostics, and consider the relative advantages of approaches that utilize the internal sensing capabilities of commercially available mobile communication devices (such as smartphones and tablet computers) compared to those that utilize a custom external sensor module. In this review, we focus specifically upon mobile medical diagnostic platforms that are being developed to serve the need in global health, personalized medicine, and point-of-care diagnostics.


A comparison of the serum protein electrophoretic patterns of young and adult animals.
Samples of serum from both young and adult normal cattle, sheep and horses were subjected to protein electrophoresis on agarose gel films. After processing, the stained electrophoretic patterns and densitometric traces of each species exhibited certain specific characteristics. The separations also revealed differences between young and adult animals of the same species. These age-related differences are described here.


Histone chaperone FACT FAcilitates Chromatin Transcription: mechanistic and structural insights.
The histone chaperone FACT (FAcilitates Chromatin Transcription) modulates nucleosome structure during many processes requiring access to chromatinized DNA. Here, we review recent biochemical and structural insight into how FACT acts in both nucleosome assembly and disassembly, to maintain chromatin structure while DNA is being worked on by polymerases.


Screening and characterization of a chemical regulator for plant disease resistance.
Plants activate systemic acquired resistance (SAR), a form of long-lasting induced defense, to confer protection against a broad spectrum of pathogens. SAR induction is associated with the salicylic acid (SA)-mediated defense signaling networks. For detailed understandings of the SA-mediated signaling of SAR induction, we screened chemical inhibitors that block SA-mediated signaling from a 9600-compound chemical library. As a result, we identified one candidate chemical, 4-phenyl-2-{[3-(tri-fluoromethyl)anilino]methylidene}cyclohexane-1,3-dione (PAMD), that suppresses the expression of pathogenesis-related (PR) gene. PAMD also down-regulates SA-induced gene expression and enhances susceptibility to pathogen.


Patient factors that affect quality of colonoscopy preparation.
Optimal colonoscopy preparation requires patients to adhere to written instructions and be activated to complete the task. Among patients with chronic disease, health literacy and patient activation have been associated with outcome, but these factors have not been studied for colonoscopy. We examined the association between health literacy, patient activation, and quality of bowel preparation. We analyzed outpatient colonoscopy results from 462 adults, 55-74 years old (mean, 62 ± 6 years), who previously completed extensive neurocognitive assessments as part of a prospective study (Health Literacy and Cognitive Function in Older Adults). We collected information on cecal intubation, polyp detection, bowel preparation quality, and histopathology. One-third of the patients (n = 134) had suboptimal quality of bowel preparation; 15% (n = 62) had fair quality, and 17% (n = 72) had poor quality. Limited health literacy was associated with a lower level of education (P < .001), diabetes (P < .001), and a higher number of chronic conditions (P < .001), but not quality of colonoscopy preparation. No baseline characteristics were associated with patient activation. In multivariable analysis, after adjusting for demographics and clinical characteristics, diabetes (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.14-5.25) and patient activation (OR, 2.12; 95% CI, 1.30-3.45) were independent predictors of suboptimal bowel preparation quality, but limited health literacy was not (OR, 0.76; 95% CI, 0.38-1.52). We investigated the relationship between health literacy, patient activation, and colonoscopy preparation quality. Lower patient activation was an independent predictor of suboptimal bowel preparation quality. Interventions to improve colonoscopy preparation quality should consider the importance of patient activation within their design.