Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys.
The neuropharmacological profile of the atypical antipsychotic, olanzapine, is consistent with a potentially useful medication for cocaine abuse. The present study utilized an i.v. drug self-administration paradigm in nonhuman primates to obtain definitive evidence regarding the effectiveness of olanzapine to modulate the reinforcing effects of cocaine. The effects of olanzapine were compared directly to those of the neuroleptic, haloperidol. Rhesus monkeys (n=7) were trained to self-administer cocaine (0.03-0.3 mg/kg/injection) under a second-order, fixed-interval 600-s schedule with fixed ratio 20 components. Experimental sessions comprised five consecutive fixed intervals, each followed by a 1-min timeout. In drug-interaction experiments, a single dose of olanzapine (0.03-0.3 mg/kg) or haloperidol (0.01-0.03 mg/kg) was administered i.v. 15 min presession for at least three consecutive sessions. In drug-substitution experiments, different doses of olanzapine (0.01-0.1 mg/kg/injection) were substituted for cocaine until responding stabilized. Olanzapine caused dose-related decreases in cocaine self-administration at pretreatment doses that had no overt behavioral effects indicative of sedation. A dose of 0.1 mg/kg eliminated cocaine self-administration in all subjects. In contrast, doses of haloperidol that suppressed cocaine self-administration induced marked sedation and catalepsy. Olanzapine failed to maintain self-administration behavior above saline extinction levels over a range of unit doses. In vivo microdialysis experiments in a second group of awake rhesus monkeys (n=3) confirmed previous reports in rodents that olanzapine effectively increases extracellular dopamine in ventral striatum. The dose of olanzapine that markedly suppressed cocaine self-administration behavior increased dopamine to approximately 190% of control values. Lastly, pretreatment with fluoxetine had no systematic effect on olanzapine-induced increases in striatal dopamine. The results indicate that olanzapine can effectively suppress cocaine self-administration behavior in nonhuman primates at doses that enhance dopamine release but do not maintain drug self-administration.


Limited value of interictal brain perfusion SPECT for detection of epileptic foci: high resolution SPECT studies in comparison with FDG-PET.
Accurate localization of epileptic foci is important for pre-surgical evaluation of patients with medically intractable epilepsy, and F-18 FDG PET has been proved to be a valuable method for this purpose. To examine the clinical value with interictal brain perfusion SPECT, we performed brain perfusion SPECT of Tc-99m HMPAO by means of a high resolution SPECT camera, and compared the results with F-18 FDG PET images and MRI in 10 patients with medically intractable epilepsy. In 9 of 10 patients (90%), FDG PET images showed focal hypo-metabolism in the area corresponding with the results of electroencephalography (EEG). SPECT images, however, demonstrated hypo-perfused lesions which corresponded with hypo-metabolic lesions on FDG PET images in only 6 cases (60%). Although MRI showed abnormal findings in 8 cases, the lesions were not directly related to epileptic foci in 2 cases. In conclusion, FDG PET is a valuable tool for accurate localization of epileptic foci. Brain perfusion SPECT, however, may not always be paralleled to metabolism visualized on FDG PET images.


Eggerthella lenta bloodstream infections: two cases and review of the literature.
Eggerthella lenta is an emerging and uncommon human pathogen that has been under recognized due to the limitations of phenotypic identification. Here we describe two cases of bacteremia caused by E. lenta and summarize the results of antimicrobial susceptibility testing according to some previous literatures, which illustrate the importance of identification and treatment of unusual organisms. The most reliable antibiotic treatment options to E. lenta appear to be metronidazole, amoxicillin-clavulanate, carbapenems, vancomycin, cefoxitin, chloramphenicol and clindamycin.


Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases.
This study was designed to determine the incidence and to quantitate aortic debris retrieved during placement of guiding catheters in patients undergoing percutaneous interventions. Studies have shown that atherosclerotic aortic debris predisposes patients to spontaneous or procedurally related ischemic events. In 1,000 consecutive percutaneous interventions, the amount of visible atheromatous material from large-lumen-guiding catheters was recorded. Clinical characteristics and in-hospital complications were prospectively collected and associated with debris production. Visible aortic debris (1+ to 3+) occurred more frequently with the Judkins left (JL) catheter, followed by the multipurpose (Multi) catheter compared to any other type of guiding catheter (65%, p = 0.001 and 60%, p = 0.01, respectively). Large debris (2+ and 3+) was observed most frequently with the Multi (odds ratio 3.79, C.I. = 2.32 to 6.21, p = 0.001), JL (odds ratio 2.83, C.I. = 1.98 to 4.05, p = 0.001) and voda left (VL) (odds ratio 2.73, C.I. = 1.51 to 4.95, p = 0.001) catheters. The Judkins right (JR) catheter type was least likely to produce any debris (24%, p = 0.001). A history of unstable angina (p = 0.05) or myocardial infarction (p = 0.003) was associated with a decreased incidence of debris production. The presence of debris was not found to be associated with in-hospital ischemic complications. Studies have shown that atherosclerosis of the aorta is a potential source of systemic embolism in patients undergoing cardiac catheterization. Our study shows that in more than 50% of percutaneous revascularization procedures, guiding catheter placement is associated with scraping debris from the aorta. Design characteristics of the JL, Multi and VL guiding catheters make them most likely to produce such debris. Meticulous attention to allow the debris to exit the back of the catheter is essential to prevent injecting atheromatous debris into the vascular bed.


Peptidyl chemosensors incorporating a FRET mechanism for detection of Ni(II).
Hexapeptides incorporating two fluorophores flanking a tripeptide sequence that binds Ni(II) and Cu(II) with high affinity have been synthesized. While Cu(II) quenches the fluorescence of the resulting peptides, coordination of Ni(II) enables enhanced FRET (fluorescent resonance energy transfer) from one fluorophore to the other.


Adding a diazo-transfer reagent to culture to generate secondary metabolite probes for click chemistry.
Converting discrete microbial metabolites into chemical probes for chemical biology and medicinal chemistry studies is typically preceded by lengthy purification and chemical derivatization processes. Standard practice involves purifying the target microbial metabolite from culture, followed by derivatization and/or conjugation chemistry to convert the pure metabolite into a tagged species. This multistep approach can pose difficulties in generating useful yields of chemical probes, particularly in the case of low-abundant metabolites, as common in metabolomes. This chapter describes a methodological approach to simplify the steps towards generating chemical probes from complex mixtures, that combines: (a) tailored purification processes; (b) compound identification using state-of-the-art tandem mass spectrometry and data-dependent fragmentation; and (c) in situ bioorthogonal bioconjugation chemistries. The combination of these methods, as illustrated by the conversion of a set of amine-bearing metabolites to the cognate azide analogs suitable for biotinylation through azide-alkyne cycloaddition, describes a powerful approach to access new chemical probes of low-abundant metabolites that might otherwise be inaccessible using traditional methods.


The effects of high-pressure treatment on the structure, physicochemical properties and digestive property of starch - A review.
High hydrostatic pressure (HHP) is a novel technology used in the food-processing industry. Starch is an important renewable natural resource. The applications of starch are determined by its properties, which in turn are determined by its structure. In this study, the effects of HHP treatment on starch structure (granular structure, crystalline structure, molecular structure, and molecular conformation) and properties (pasting, retrogradation, thermal, digestive, rheological, swelling, solubility, water absorption, and oil absorption properties) are summarised. Additionally, the mechanism of HHP-induced gelatinisation is discussed. First, the strong hydration ability of starch molecules under high pressure facilitates the binding of water molecules to starch molecules via hydrogen bonding. These bound water molecules may block the channels inside the starch granules, leading to the formation of a sealed space. Finally, the granules disintegrate because of the intra/extra pressure difference. This study provides a reference for the application of HHP to starch processing and modification.


Hypersequestration of 51Cr-labelled erythrocytes as a criterion for splenectomy in regular hemodialysis patients.
The splenic uptake of 51Cr-labelled autologous erythrocytes was studied by body surface counting in 20 hemodialysis patients. Evidence for splenic hypersequestration of erythrocytes was obtained in 7 patients. Splenectomy was performed in 6 of these and led to a reduction in transfusion requirements. One patient without evidence of splenic hypersequestration of red cells was also subjected to splenectomy but was not improved. The importance of following the splenic uptake of 51Cr for a sufficiently long time to detect a delayed uptake of 51Cr is pointed out.


Expression of the 3-fucosyl N-acetyllactosamine (CD 15) antigen in normal, metaplastic, dysplastic, and neoplastic squamous epithelia.
The 3-fucosyl N-acetyllactosamine residue is the antigen recognized by the monoclonal antibody MC2. Using MC2, we demonstrated the distribution of this antigen in a variety of squamous epithelia. The antigen is expressed to a variable degree on supra-basal cells in most normal non-keratinizing squamous mucosae, with a similar distribution in metaplastic squamous epithelia; antibody-labelled latex microspheres and immunogold electron microscopy show the antigen to form part of the glycocalyx. In dysplastic and neoplastic squamous lesions, expression is reduced or absent except in cells around areas of differentiation. Prior neuraminidase treatment of sections had little effect on the amount or distribution of demonstrable antigen. Expression of this antigen by cells in non-keratinizing squamous epithelia gives an indication of cell maturity and may provide a histological marker for the grading of dysplastic and malignant squamous mucosal lesions. A possible role for these carbohydrate residues in squamous mucosal defence is discussed.


Coordinate expression of alkali and DTNB myosin light chains during transformation of rabbit fast muscle by chronic stimulation.
Chronic nerve stimulation induces an almost complete exchange of the fast myosin light chains (LC) LC1f and LC2f to the slow light chains LC1s and LC2s. LC3f decreases only by 30%. The exchange of the DTNB LCs (LC2f to LC2s) precedes that of LC1f to LC1s. However, the equimolar ratio of total alkali to total DTNB LCs is maintained. This points to a hitherto unknown regulation that preserves this ratio independent of whether alkali and DTNB LCs are expressed in fast or slow isotypes.


Mimicry in psychotherapy - an actor partner model of therapists' and patients' non-verbal behavior and its effects on the working alliance.
Objective: The alliance between patient and therapist is central for therapeutic progress. Social mimicry, the automatic imitation of another person, has been linked to building relationships. This is the first preregistered study to systematically investigate mimicry and its effects on the working alliance in real psychotherapy sessions.Method: Sixty-four different patient-therapist dyads were filmed during a cognitive behavioral therapy (CBT) treatment for obsessive-compulsive disorder (OCD). By using actor-partner interdependence models, we analyzed the extent to which therapists' and patients' earlier mimicry predicted their own mimicry (actor effect), how they influenced each other in their mimicry (partner effect) and the effects of mimicry on the patients' alliance. Videos of 151 sessions were rated by two observers.Results: Patients showed stable low mimicry levels. Furthermore, the patients' mimicry predicted that of the therapists, indicating that therapists adapt their mimicry levels to patients. Only the patients' but not the therapists' mimicry at the beginning of treatment predicted the patients' alliance.Conclusion: The results suggest that the role of the active patient is underestimated. Furthermore, results offer new treatment targets by shedding light on low mimicry levels displayed by patients, which might lead to social costs.


Multipoint assessment of demarcation line depth after standard and accelerated cross-linking in central and inferior keratoconus.
To determine the changes in the depth of the demarcation line in the central to peripheral cornea following accelerated compared to standard corneal cross-linking (CXL). In this prospective, non-randomized study, 60 eyes with progressive keratoconus underwent accelerated or standard CXL (30 in each group). Anterior segment optical coherence tomography (AS-OCT) was done one month later by two independent masked examiners to measure the depth of the demarcation line in the central cornea and on peripheral rings. The inter-examiner agreement (intra-class correlation coefficient) was >0.75 for all measured points, and average measurements were used in the analysis. The depth of the visualized demarcation line in the center was 223.4 ± 67.4 μm and 354.9 ± 79.0 μm in the accelerated and standard groups, respectively (P < 0.001). The depth significantly decreased from the center to the 7 mm ring in both groups (all P < 0.05). This change was 7.7-26.1% and 2.2%-11.1% in the accelerated and standard groups, respectively. In the accelerated group, the demarcation line was deeper in the central cone sub-group compared to the inferior cone sub-group, but in the standard group, the demarcation line was deeper in the inferior cone sub-group (all P < 0.05). Cases with an inferior cone showed greater inter-group differences in all studied points. The depth of the demarcation line with accelerated CXL is less than the standard protocol and decreases from the center towards the periphery. Demarcation lines are more homogenized with standard CXL. In cases with an inferior cone, demarcation line depth varies throughout the cornea.


Congenital Cervical Tethered Spinal Cord in Adults: Recognition, Surgical Technique, and Literature Review.
Recognition of congenital tethered cervical cord in adults and literature review. Retrospective review of adult onset tethered cervical cord patients (age >20 years). Three adults were identified; 2 women and 1 man, average age 47 years. The presenting symptoms were neck pain with restricted movement (3), quadriparesis (2), and sensory changes (2). Hyperreflexia was present in all three. Bony abnormalities were mainly bifid cervical spinous processes (3), with Klippel-Feil abnormalities in 1. The neurocutaneous stigmata was seen in 2. Magnetic resonance imaging revealed "limited dorsal myeloschisis" in all 3 patients. The dorsal aspect of the cervical cord extruded into the tract leading to the surface. Neurocutaneous stigmata should not be considered benign. A missed clinical diagnosis was apparent in all 3 patients; 2 of whom underwent surgery with excellent results. Magnetic resonance imaging can identify the abnormal cervical cord protruding towards the "sinus tract" and allow planning to avert injury to the spinal cord during release.


Cross-species screening platforms identify EPS-8 as a critical link for mitochondrial stress and actin stabilization.
The dysfunction of mitochondria is associated with the physiological consequences of aging and many age-related diseases. Therefore, critical quality control mechanisms exist to protect mitochondrial functions, including the unfolded protein response of the mitochondria (UPRMT). However, it is still unclear how UPRMT is regulated in mammals with mechanistic discrepancies between previous studies. Here, we reasoned that a study of conserved mechanisms could provide a uniquely powerful way to reveal previously uncharacterized components of the mammalian UPRMT. We performed cross-species comparison of genetic requirements for survival under—and in response to—mitochondrial stress between karyotypically normal human stem cells and the nematode Caenorhabditis elegans. We identified a role for EPS-8/EPS8 (epidermal growth factor receptor pathway substrate 8), a signaling protein adaptor, in general mitochondrial homeostasis and UPRMT regulation through integrin-mediated remodeling of the actin cytoskeleton. This study also highlights the use of cross-species comparisons in genetic screens to interrogate cellular pathways.


Occupations and the Risk of Bladder Cancer in Yazd Province: A Case-Control Study.
Bladder cancer is the most common cancer of the urinary tract, with known occupational causes. The most effective way to prevent occupational cancers of the urinary tract is to prevent exposure to known carcinogens. To examine the relationship between occupation and the risk of bladder cancer. This case-control study was performed on 200 patients with bladder cancer and 200 healthy individuals in Yazd. Data were collected using a researcher-made questionnaire and based on interviews with patients and controls. The mean age of cases and controls were 61.5 (SD 13.6) and 61.5 (13.3) years, respectively. Level of education, type of occupation, family history of bladder cancer in the first-degree relatives, and history of chronic and recurrent urinary tract infection, kidney and bladder stones, and using hair dye, were considered the main predictors for bladder cancer. There was a significant difference between cases and controls in terms of type of occupation. The risk of bladder cancer was higher among those working in high-risk occupations-metal working, textile, driving, farming, and construction.


Elevated systemic galectin-1 levels characterize HELLP syndrome.
Galectin-1 (gal-1), a member of a family of conserved β-galactoside-binding proteins, has been shown to exert a key role during gestation. Though gal-1 is expressed at higher levels in the placenta from HELLP patients, it is still poorly understood whether systemic gal-1 levels also differ in HELLP patients. In the present study, we evaluated the systemic expression of gal-1, together with the angiogenic factors, placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in conjunction with HELLP syndrome severity. Systemic levels of gal-1 and sFlt-1 were elevated in patients with both early- and late-onset HELLP syndrome as compared to healthy controls. In contrast, peripheral PlGF levels were decreased in early- and late-onset HELLP. A positive correlation between systemic gal-1 levels and sFlt-1/PlGF ratios was found in early onset HELLP patients. Our results show that HELLP syndrome is associated with increased circulating levels of gal-1; integrating systemic gal-1 measurements into the diagnostic analyses of pregnant women may provide more effective prediction of HELLP syndrome development.


New entity, definition and diagnostic criteria of cutaneous adult T-cell leukemia/lymphoma: human T-lymphotropic virus type 1 proviral DNA load can distinguish between cutaneous and smoldering types.
Adult T-cell leukemia/lymphoma (ATLL) has been divided into four subtypes up to now: (i) acute; (ii) lymphoma; (iii) chronic; and (iv) smoldering. Skin lesion(s) may be present and the cases showing less than 5% abnormal T-lymphocytes in peripheral blood without involvement of other organs, have been classified as smoldering ATLL. However, this type of ATLL with skin manifestations had a worse prognosis than that without skin lesions. This study aimed to define and distinguish cutaneous ATLL lacking nodal lymphoma and leukemic change from smoldering ATLL. We propose an entity of cutaneous ATLL, which has less than 5% abnormal T lymphocyte in peripheral blood, a normal lymphocyte count (i.e. <4 x 10(9)/L), no hypercalcemia and lactate dehydrogenase values of up to 1.5 times the normal upper limit. At least one of the histologically proven skin lesions should be present accompanying monoclonal integration of human T-cell lymphotropic virus type 1 (HTLV-1) proviral DNA in the skin lesion. Blood samples were collected from 41 HTLV-1-infected patients, 21 asymptomatic carriers, 16 patients with cutaneous ATLL and four patients with smoldering ATLL. HTLV-1 proviral loads, soluble interleukin-2 receptors and other parameters were examined in each case. HTLV-1 proviral DNA loads in smoldering ATLL group are significantly higher than those in asymptomatic carrier and cutaneous ATLL group. Cutaneous ATLL may be a distinct entity that should be separated from smoldering ATLL clinically and virologically.


Merosesquiterpenoids and ten-membered macrolides from a soft coral-derived Lophiostoma sp. fungus.
One new merosesquiterpenoid, craterellin D (1), along with one known analog, craterellin A (2), and five known ten-membered macrolides, 3-7, were isolated from a soft coral-derived Lophiostoma sp. fungus. The absolute configuration of 1 was established based on biogenetic consideration with the co-isolated analog 2, whose configuration was determined by modified Mosher's method and single-crystal X-ray diffraction analysis using CuKα radiation. The absolute configuration of 3 was determined by X-ray diffraction analysis using CuKα radiation. Compounds 2 and 3 showed antibacterial activities against Bacillus cereus with a MIC value of 3.12 μM.


Potential toxins of acute liver failure and their effects on blood-brain barrier permeability.
The effects of potentials toxins of hepatic coma on the blood-brain barrier (BBB) permeability of the rat have been examined using the Oldendorf technique. Classical toxins of hepatic failure such as ammonia, methyl octanoate, mercaptans, and phenol caused significant increases in BBB permeability. A slight increase in permeability occurred following infusion of peroxidized linoleic acid and unconjugated bilirubin but no increase after infusion of bile acids. E. coli endotoxin infused into rats following partial hepatectomy also increased the BBB permeability.


Uterine sarcoma vs adenocarcinoma: can MRI distinguish between them?
To analyze the MRI characteristics of uterine sarcomas (mainly carcinosarcomas) and to compare them with those of adenocarcinomas to define the findings that would be useful for the differential diagnosis. We retrospectively reviewed the MRI studies of 13 patients with histologically diagnosed uterine sarcoma. We analyzed tumor size, signal in T2-weighted, unenhanced and gadolinium-enhanced T1-weighted, and diffusion-weighted sequences. We compared the data obtained with those of another series of 30 consecutive cases of adenocarcinomas studied with MRI. The sarcomas (> 9cm in 77% of cases) were considerably larger than the adenocarcinomas (p<0.001). There were no differences in FIGO staging by MRI or surgery: both tumor types were diagnosed in early stages. The signal intensity in T2-weighted images differed significantly between the two tumor types: all the sarcomas were heterogeneous and predominantly hyperintense with respect to the myometrium in T2-weighted sequences (p<0.001). In postcontrast studies, all the sarcomas showed enhancement greater than or equal to the myometrium; this finding was significantly different from the adenocarcinomas (p<0.001). In diffusion-weighted sequences, we found no significant differences in ADC values in the areas with greatest restriction, but the ADC map was more heterogeneous in the sarcomas. Uterine sarcomas do not have specific characteristics on MRI, but some findings can indicate the diagnosis. In our study, we found significant differences between sarcomas and adenocarcinomas. Sarcomas were larger, had more hyperintense and heterogeneous signal intensity in T2-weighted sequences, and enhanced more than or at least as much as the myometrium.


All metacyclic variable antigen types of Trypanosoma congolense identified using monoclonal antibodies.
Vaccination against the tsetse-borne trypanosomiases has proved impossible because of the trypanosome's ability to generate a seemingly inexhaustible number of variable antigen types in the blood or tissues of the host. Each variable antigen is a glycoprotein which forms a surface coat on the trypanosome and each glycoprotein is the product of a single gene. The full repertoire of such antigens has not been identified for any trypanosome serodeme (genotype) as yet, but the number of genes coding for variable antigen glycoproteins is estimated to be between 100 and 1,000. We have previously postulated that for Trypanosoma brucei the antigen repertoire of the infective metacyclic stage trypanosomes inoculated by the tsetse fly may be considerably smaller than that expressed in the mammalian host. If this is so then protection against infection by the vector becomes an easier proposition, but the actual scale of the metacyclic repertoire is also unknown. We present here evidence that the metacyclic repertoire of a stock of T. congolense, the most important of the pathogenic cattle trypanosomes, is limited to 12 variable antigen types.


Immunostimulation by a formula-defined diet.
A formula-defined diet (diet 3, table 1) acted as an adjuvant as an adjuvant in the response of the immune system to SRBC in the rat. Similar minimum and maximum antibody levels were measured in both males and females. In the males, the maximum was reached with diet 3 alone while females required the complementary action of diet 3 and LPS mR 595.


Predictors of unfavourable tuberculosis treatment outcome in Bilene District, Gaza Province, Mozambique: A retrospective analysis, 2016 - 2019.
Tuberculosis (TB) is a serious public health problem and remains one of the leading causes of death from an infectious agent globally. Mozambique is one of 30 countries considered to have a high TB burden. To describe the clinical characteristics of TB in children and adults in Bilene District in Gaza Province, Mozambique, over 43 months and to assess determinants of unfavourable treatment outcomes. This retrospective cohort study took place from 1 January 2016 to 31 July 2019 in Bilene District, Gaza. We included patients in the TB register at the Centro de Saúde de Macia TB unit with available data on final treatment outcome. Predictors of unfavourable outcomes were determined using multivariable logistic regression models. A total of 3 012 TB-infected patients were registered in the TB unit of the Macia health facility during the study period: 358 (11.9%) were children (<14 years), 1 522 (50.5%) were male, and 2 581 (85.7%) were new TB cases. No bacteriological test was performed at diagnosis in 1 250 patients (41.5%). Treatment was successful in 2 863 patients (95.1%), with better outcomes in children than in adults (98.0% v. 94.6%; p=0.005). Although mortality (n=97; 3.2%) was low in both groups, the proportion who died was lower in children compared with adults (1.4% v. 3.5%; p=0.035). Multivariable logistic regression analysis showed that unfavourable outcomes were more likely in men compared with women (adjusted odds ratio (aOR) 1.48; 95% confidence interval (CI) 1.04 - 2.12; p=0.029), in patients with recurrent TB infection compared with newly infected patients (aOR 1.63; 95% CI 1.05 - 2.50; p=0.027), and in patients co-infected with TB and HIV compared with HIV-negative TB-infected patients (aOR 2.17; 95% CI 1.43 - 3.29; p<0.001). The factor conferring the most risk for an unfavourable outcome was positive microbiological sputum results (aOR 5.27; 95% CI 3.25 - 8.54; p<0.001). Factors independently associated with an unfavourable TB treatment outcome were male sex, recurrent TB infection, having positive microbiology, and co-infection with HIV. It remains crucial to improve data quality and adherence to TB screening and diagnostic algorithms.


Heterogeneous platelet-activating factor (PAF) receptors and calcium increase in platelets and macrophages.
We used the increase in cytosolic Ca2+ levels, [Ca2+]i, as a way to characterize PAF (platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) receptors in human platelets and rat and human macrophages. [Ca2+] was measured by means of the fluorescent probe fura-2/acetoxymethylester. PAF recognized heterogeneous receptors in human macrophages only (curve slope <1). The PAF antagonist SCH 37370 (1-acetyl-4(8-chloro-5,6-dihydro-11H-benzo[5.6]cyclohepta[1,2-b]pyridine -11-ylidine)piperidine) abolished [Ca2+]i elevation in human platelets, while in rat and human macrophages the maximal inhibition was 76% and 85%, respectively. On the contrary, the antagonist WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6Hthieno[3,2-f] [1,2,4]triazolo-[4,3-a] [1,4]-diazepin-2-yl]-1-(4-morpholiny)-1-propanon, apafant) totally inhibited the effect of PAF in both platelets and macrophages. The WEB 2086 concentration-response curves had a slope <1 in the three cell types, indicating interaction with heterogeneous receptors. Accordingly, 3H-WEB 2086 bound to two different classes of sites. Both phases of [Ca2+]i elevation (influx or release) were equally affected by the antagonists. These data support the notions that: 1) PAF receptors are heterogeneous; 2) the two antagonists have a different selectivity toward the receptor subtypes: WEB 2086 recognizes two different receptors both in platelets and in macrophages, while SCH 37370 does not discriminate between receptor subtypes in platelets, and only interacts with one subtype in macrophages; and 3) both SCH 37370 and WEB 2086 display different potencies in rat and human macrophages.


Dietetic intervention in psoriatic arthritis: the DIETA trial.
To evaluate whether dietary pattern changes, antioxidant supplementation or 5-10% weight loss could improve disease activity (skin and joint) in patients with psoriatic arthritis (PsA). A total of 97 PsA patients were enrolled in this 12-week randomized, double-blinded, placebo-controlled trial. Patients were randomized into three groups: Diet-placebo (hypocaloric diet + placebo supplementation); Diet-fish (hypocaloric diet + 3 g/day of omega-3 supplementation; and Placebo. Food intake (3-day registry, Healthy Eating Index (HEI), and the Dietary Inflammatory Index (DII)), body composition (whole-body dual-energy X-ray absorptiometry (DXA), weight and waist circumference) and disease activity (PASI, BSA, BASDAI, DAS28-ESR, DAS28-CRP and MDA) were evaluated at baseline and after the 12-week intervention. Statistical analysis used the intention-to-treat approach. The P value was considered to indicate significance when below 0.05. After 12 weeks, DAS28-CRP and BASDAI scores improved, especially in the Diet-placebo group (- 0.6 ± 0.9; p = 0.004 and - 1.39 ± 1.97; p = 0.001, respectively). In addition, a higher proportion of patients achieved minimal disease activity (MDA) in all groups. The Diet-fish group showed significant weight loss (- 1.79 ± 2.4; p = 0.004), as well as waist circumference (- 3.28 ± 3.5, p < 0.001) and body fat (- 1.2 ± 2.2, p = 0.006) reductions. There was no significant correlation between weight loss and disease activity improvement. Each 1-unit increase in the HEI value reduced the likelihood of achieving remission by 4%. Additionally, each 100-cal daily intake increase caused a 3.4-fold DAS28-ESR impairment. A 12-week hypocaloric intervention provided suitable control of joint disease activity in patients with PsA, regardless of weight loss. Adding omega-3 supplementation caused relevant body composition changes but not disease activity improvement. The study was recorded on Clinicaltrials.gov (NCT03142503).


Deletion 12p12 involving SOX5 in two children with developmental delay and dysmorphic features.
The SOX5 gene encodes a transcription factor involved in the regulation of nervous system development and chondrogenesis. This article reports on two cases of 12p12.1 deletion involving SOX5 presenting with global developmental delay, intellectual disability, expressive language delay, mild motor impairment, distinct features, and multiorgan involvement. The first case involves a 32-month-old boy with de novo 53-kilobase interstitial deletion at 12p12.1, representing the smallest deletion reported, and presents with severe symptomatology. The second case is a 31-month-old girl with 3.2-megabase deletion at 12p12.2 p12.1 with severe neurodevelopmental disability and minimal organ involvement. These patients bear many of the characteristics previously reported in patients with SOX5 mutations. We propose a neurodevelopmental approach to a novel syndrome with dose- and location-sensitive SOX5 gene expression.


Cultures of Dinophysis sacculus, D. acuminata and pectenotoxin 2 affect gametes and fertilization success of the Pacific oyster, Crassostrea gigas.
Harmful algal blooms (HABs) of toxic species of the dinoflagellate genus Dinophysis are a threat to human health as they are mainly responsible for diarrheic shellfish poisoning (DSP) in the consumers of contaminated shellfish. Such contamination leads to shellfish farm closures causing major economic and social issues. The direct effects of numerous HAB species have been demonstrated on adult bivalves, whereas the effects on critical early life stages remain relatively unexplored. The present study aimed to determine the in vitro effects of either cultivated strains of D. sacculus and D. acuminata isolated from France or their associated toxins (i.e. okadaic acid (OA) and pectenotoxin 2 (PTX2)) on the quality of the gametes of the Pacific oyster Crassostrea gigas. This was performed by assessing the ROS production and viability of the gametes using flow cytometry, and fertilization success using microscopic counts. Oocytes were more affected than spermatozoa and their mortality and ROS production increased in the presence of D. sacculus and PTX2, respectively. A decrease in fertilization success was observed at concentrations as low as 0.5 cell mL-1 of Dinophysis spp. and 5 nM of PTX2, whereas no effect of OA could be observed. The effect on fertilization success was higher when both gamete types were concomitantly exposed compared to separate exposures, suggesting a synergistic effect. Our results also suggest that the effects could be due to cell-to-cell contact. These results highlight a potential effect of Dinophysis spp. and PTX2 on reproduction and recruitment of the Pacific oyster.


Investigation of the mechanisms and experimental verification of Cuscuta-Salvia in the treatment of polycystic ovary syndrome (PCOS) via network pharmacology.
Polycystic ovary syndrome (PCOS) is an endocrine disease associated with reproduction. The Cuscuta-Salvia formula has been widely used to treat for PCOS in clinic. However, its chemical and pharmacological properties remain unclear. We identified the active components and related targets of Cuscuta-Salvia using UHPLC-ESI-Q-TOF-MS and TCMSP database. Disease targets were obtained from the DisGeNET and GeneCards databases. Subsequently, common targets between Cuscuta-Salvia and PCOS were identified using a Venn diagram. PPI network was established. Core genes were selected using a Cytoscape software plugin. GO and KEGG enrichment analyses were performed for common targets using the "pathview" package in R. Several core targets were verified using molecular and Immunological methods. By combining UHPLC-ESI-Q-TOF-MS with a network pharmacology study, 14 active components and a total of 80 common targets were obtained. Ten core genes were regulated by Cuscuta-Salvia in PCOS, including IL6, AKT1, VEGFA, TP53, TNF, MAPK1, JUN, EGF, CASP3, and EGFR. GO results showed that cellular response to drugs, response to oxygen levels, response lipopolysaccharides, and response to molecule of bacterial origin in BP category; membrane, transcription regulator complex, nuclear chromatin, postsynaptic membrane, and vesicle lumen in CC category; DNA-binding transcription factor binding, RNA polymerase II-specific DNA-binding transcription factor binding, DNA-binding transcription activator activity, RNA polymerase II-specific, DNA-binding transcription activator activity, and cytokine receptor binding in MF terms. The KEGG enrichment pathway was mainly involved in the PI3K - Akt, MAPK, TNF, IL-17 signalling pathways, and in cellular senescence. Furthermore, the results of the experimental study showed that Cuscuta-Salvia ameliorated the pathological changes in the ovaries, liver and adipose tissue. And it improved the expressions of the genes or proteins. Our results demonstrate that Cuscuta-Salvia may provide a novel pharmacological basis in an experimental model of PCOS by regulating gene expression. This study provides a basis for future research and clinical applications.


Evolution: revenge of the clones!
Recent work on ants shows both extraordinary patterns of reproduction and a new type of sexual conflict, leading to the remarkable scenario where females have no father and males have no mother.


A newly designed plastic stent for EUS-guided hepaticogastrostomy: a prospective preliminary feasibility study (with videos).
There are currently no dedicated plastic stents for EUS-guided hepaticogastrostomy (EUS-HGS). We prospectively evaluated the feasibility and the technical and functional success rates of our newly designed plastic stent for EUS-HGS. Prospective preliminary feasibility study. A tertiary-care referral center. Twenty-three consecutive patients were treated. The reasons for requiring EUS-HGS were periampullary tumor invasion (n=9), altered anatomy (n=7), failed duodenal intubation (n=3), and previous ERCP failure (n=4). An 8F single-pigtail plastic stent with 4 flanges was placed for EUS-HGS. Technical success, clinical success, and adverse events according to the American Society for Gastrointestinal Endoscopy lexicon. All stents were successfully deployed without procedural adverse events (100% technical success rate). Bleeding from the punctured gastric wall occurred in 1 patient 3 days postoperatively. We exchanged the plastic stent for a fully covered self-expandable metal stent. A mild adverse event of self-limited abdominal pain occurred in 3 patients. Treatment success was achieved in all patients. The occlusion rate was 13.7% (3/22) during the median follow-up period (5.0 months, range 0.5-12.5 months). The median duration of stent patency was 4.0 months (range 0.5-9.0 months). There was no stent migration or dislocation during the follow-up period. Small number of patients and lack of a control group. This newly designed single-pigtail plastic stent dedicated for EUS-HGS was technically feasible and can possibly be used for highly selected patients with advanced malignancy or benign stricture. ( http://www.umin.ac.jp/english/: UMIN000012993.).


Nitrogen budget of a shortgrass prairie ecosystem.
A N budget is presented for a shortgrass prairie ecosystem. The grassland was ungrazed by domestic herbivores. The quantities of N in various plant, animal, microorganism, and soil components of the ecosystem are estimated for the date when aboveground living biomass was at its maximum for the growing season of 1973. Annual transfers of N between the various compartments were also estimated.Of the total N, 99.5% was in organic forms. The relatively inert heteropolycondensate fraction of the organic matter in the soils contained 88.8% of the N. Living organisms contained 4.2% and dead but recognizable organisms or part thereof contained 6.5% of the total N. Belowground animals contained more than 10 times as much N as abovegroud animals, but combined, animals contained less than 0.1% of the total in the system. Living plant material contained 2.5% of the total N. Seventy-two percent of the living plant N was below ground. Microorganisms contained 1.4% of the total N.Total N uptake by plants from soil solution was 2.9 g·m-2·yr-1. Aerial portions of plants were allocated 1.9 N·m-2·yr-1 although apparently 26% of this amount came from internally recycled sources. The heteropolycondensate fraction of the soil contributed 0.7 g N·m-2·yr-1 to mineral forms, but these components of the system were assumed to be in steady state; thus an equal amount of mineral N was allocated back to the source. Mineralization of N from plant residues was sufficient to account for all of the N taken up by plants from soil solution. Soil animals immobilized about 0.4 g N·m-2·yr-1 while the amount shunted to aboveground animals was trivial.


Effect of norepinephrine on ouabain-sensitive, K+-dependent p-nitrophenylphosphatase activity in strial marginal cells of the cochlea in normal and reserpinized guinea pigs.
On the basolateral infoldings of the strial marginal cells in the cochlea, Na K ATPase activity is abundant. To clarify the humoral control by norepinephrine, K-NPPase activity of strial marginal cells in the cochlea was investigated in normal, reserpine, norepinephrine (NE), reserpine plus NE-treated guinea pigs using a cerium-based method. K-NPPase activity was almost completely decreased 3-20 days after reserpine administration. At 10 days after reserpinization and following NE repeated treatment, enzyme activity was detectable. These results suggested that norepinephrine might restore and regulate strial K-NPPase activity.


Expression of base excision DNA repair genes as a biomarker of oxidative DNA damage.
Oxidative stress induced DNA damage is considered to be the most common insult affecting the genome. Moreover, it is recognized as a common pathway to mutations and is suggested to play a major role in the development of chronic diseases such as cancer. However, current analytical methods used to detect oxidative DNA damage have been hampered by both technical and biological obstacles. These include spurious oxidation during DNA isolation and processing, and the inherent removal of damaged bases by numerous operating DNA repair systems. The removal of oxidized bases is performed predominantly by the base excision repair (BER) pathway and it has been shown that induction of DNA repair genes occurs in response to oxidative stress. Here, we demonstrate the utility of measuring changes in expression of BER genes as a sensitive in vivo biomarker for oxidative DNA damage.


Corneal ectasia associated with massage of dacryocystoceles.
To report a patient with corneal ectasia and bilateral dacryocystoceles. Case report, review of medical literature. The patient experienced gradual bilateral worsening of visual acuity caused by increasing corneal ectasia. Vigorous and frequent massaging of the lacrimal sacs and globes preceded development of symptomatic corneal ectasia. The timing of the development of this patient's corneal ectasia suggests an association between the dacryocystoceles massage and the ectasia.


Elevated serum neopterin levels and adverse cardiac events at 6 months follow-up in Mediterranean patients with non-ST-segment elevation acute coronary syndrome.
Little information exists regarding the prognostic role of biomarkers of inflammation in Mediterranean patients. High C-reactive protein and neopterin levels - a marker of macrophage activation - predict cardiovascular events in stable angina patients and patients with acute coronary syndromes (ACS). We sought to assess whether plasma neopterin levels predict adverse clinical outcomes in Mediterranean patients with non-ST elevation (NSTE) ACS, i.e. unstable angina (UA) and NSTE myocardial infarction (MI). We prospectively assessed 397 patients (74% men) admitted with NSTEACS, 147 (37%) had unstable angina and 250 (63%) NSTEMI. Blood samples for neopterin and CRP assessment were obtained at admission. The study endpoint was the composite of cardiac death, acute myocardial infarction and unstable angina at 180 days. Baseline neopterin concentrations (nmol/L) were similar in unstable angina and NSTEMI patients (8.3 [6.6-10.7] vs. 7.9 [6.2-10.9]; p=0.4). Fifty-nine patients (14.9%) had events during follow-up. Twenty-nine (21.5%) patients with neopterin levels in the highest third experienced the combined endpoint, compared to 30 (11.5%) patients with neopterin levels in the second and the lowest thirds (log-rank 7.435, p=0.024). On multivariable hazard Cox regression, neopterin (highest vs. 1st and 2nd thirds, HR 1.762, 95% CI [1.023-3.036]) was independently associated with the combined endpoint. Increased neopterin levels are an independent predictor of 180-day adverse cardiac events in Mediterranean patients with NSTEACS.


The Equine Neonatal Central Nervous System: Development and Diseases.
Neonatal encephalopathy is the most common neurologic condition affecting newborn foals and shares similarities with perinatal asphyxia syndrome of human infants. In many cases of neonatal encephalopathy there is no obvious episode of acute or chronic hypoxia and other mechanisms likely play a role in the pathogenesis. Increased concentrations of neuroactive progestagens are found in affected foals; whether these molecules are protective, as has been suggested, or play a role in the pathogenesis is unknown. Neurologic diseases other than neonatal encephalopathy affect foals occasionally and should be considered when evaluating sick foals with clinical signs of neurologic dysfunction.


Current Recommendations on the Management of Pediatric Asthma and Allergic Rhinitis during the COVID-19 Pandemic versus Real-Life Practice.
Several statements and position papers on the management of childhood asthma and allergies during the COVID-19 pandemic have been published of late. The aim of this study was to evaluate the knowledge and awareness of pediatricians and family physicians regarding the management of asthma and allergic rhinitis during the pandemic according to recently published updated guidelines. We conducted an online survey among pediatricians and family physicians in Turkey, using a questionnaire designed to evaluate 4 items: (1) the relationship between COVID-19 infection risk and pediatric asthma/allergic rhinitis and medications used in treatment; (2) the follow-up and management of asthma/allergic rhinitis according to published updated recommendations; (3) pediatricians' and family physicians' observations and perceptions of treatment compliance and the attitudes of their pediatric asthma patients; and (4) pediatricians and family physicians' attitudes to using telehealth in the follow-up and management of pediatric asthma patients during the pandemic. A total of 346 participants responded to the survey. The relationship between the risk of COVID-19 and asthma was known by less than 25% of the participants. More than 33% of family physicians and 20% of pediatricians were unaware that asthma medication does not lead to a susceptibility to COVID-19 infection; 55% of family physicians and 48% of pediatricians thought that patients showed better compliance with asthma controller medication; over 33% of pediatricians and approximately 50% of family physicians stated that they could not distinguish between an asthma attack and lung involvement in COVID-19 infection; of the respondents, over 75% stated that they prefer face-to-face visits with patients, even in situations that do not require a physical examination. The overall knowledge and awareness of pediatricians and, especially, family physicians regarding the management of pediatric asthma/allergic rhinitis during the pandemic is not at a satisfactory level. There is an urgent need to inform them about updated recommendations appearing in recent guidelines published by allergy organizations.


Structure-Activity Relationships in Nucleic-Acid-Templated Vectors Based on Peptidic Dynamic Covalent Polymers.
The use of nucleic acids as templates, which can trigger the self-assembly of their own vectors represent an emerging, simple and versatile, approach toward the self-fabrication of tailored nucleic acids delivery vectors. However, the structure-activity relationships governing this complex templated self-assembly process that accompanies the complexation of nucleic acids remains poorly understood. Herein, the class of arginine-rich dynamic covalent polymers (DCPs) composed of different monomers varying the number and position of arginines were studied. The combinations that lead to nucleic acid complexation, in saline buffer, using different templates, from short siRNA to long DNA, are described. Finally, a successful peptidic DCP featuring six-arginine repeating unit that promote the safe and effective delivery of siRNA in live cancer cells was identified.


Remarks on GIAO-DFT predictions of 13C chemical shifts.
Predicting (13)C chemical shifts by GIAO-DFT calculations appears to be more accurate than frequently expected provided that: (a) the comparison between experimental and theoretical data is performed using the linear regression method, (b) a sufficiently high level of theory [e.g. B3LYP/6-311 + + G(2d,p)//B3LYP/6-311 + + G(2d,p) or PBE1PBE/6-311 + G(2df,p)//B3LYP/6-311 + + G(2d,p)] is used, (c) the experimental data originate from the measurements performed in one solvent whose influence is taken into account at the molecular geometry optimization step and, first of all, during the shielding calculation, (d) the experimental data are free of heavy atom effects or such effects are appropriately treated in calculations, and finally (e) the conformational compositions of the investigated objects are known.


Label-free imaging of 3D pluripotent stem cell differentiation dynamics on chip.
Massive, parallelized 3D stem cell cultures for engineering in vitro human cell types require imaging methods with high time and spatial resolution to fully exploit technological advances in cell culture technologies. Here, we introduce a large-scale integrated microfluidic chip platform for automated 3D stem cell differentiation. To fully enable dynamic high-content imaging on the chip platform, we developed a label-free deep learning method called Bright2Nuc to predict in silico nuclear staining in 3D from confocal microscopy bright-field images. Bright2Nuc was trained and applied to hundreds of 3D human induced pluripotent stem cell cultures differentiating toward definitive endoderm on a microfluidic platform. Combined with existing image analysis tools, Bright2Nuc segmented individual nuclei from bright-field images, quantified their morphological properties, predicted stem cell differentiation state, and tracked the cells over time. Our methods are available in an open-source pipeline, enabling researchers to upscale image acquisition and phenotyping of 3D cell culture.


Environmental pollution, energy import, and economic growth: evidence of sustainable growth in South Africa and Nigeria.
Simultaneous achievement of sustainable development goals (SDGs), especially energy efficiency (SDG 7), economic growth (SDG 8), and pollution reduction (SDG 13), has been a major challenge among the developing countries. Besides, there is absence of a study which quantifies clean production (net growth-emission effects) and energy import efficiency (net growth-energy import effects) as indicators of sustainable growth. Thus, this current study examines this issue for South Africa and Nigeria at aggregate and sectoral levels between 1981 and 2015 using simultaneous equation models and threshold regression analysis. Evidence of the sustainable growth cannot be established for South Africa and Nigeria with and without structural break. Further, the analysis shows that, with respect to Nigeria, keeping petroleum import per capita above the respective threshold enhances the environmental quality as aggregate and sectoral outputs increase. However, the CO2 emission can only induce increased GDP per capita when the petroleum import is below the threshold level. In South Africa's case, although maintaining petroleum import beyond the threshold may increase CO2 emission per capita associated with high aggregate output per capita, such emission exhibits a negligible reverse impact on output per capita. Results are found to vary across both lower and upper threshold regimes for sectors. Policy recommendations are discussed in the conclusion.


Epigenetic regulation of cardiac fibrosis.
Cardiac fibrosis is characterized by excessive extracellular matrix accumulation that ultimately destroys tissue architecture and eventually abolishes normal function. In recent years, despite the underlying mechanisms of cardiac fibrosis are still unknown, numerous studies suggest that epigenetic modifications impact on the development of cardiac fibrosis. Epigenetic modifications control cell proliferation, differentiation, migration, and so on. Epigenetic modifications contain three main processes: DNA methylation, histone modifications, and silencing by microRNAs. We here outline the recent work pertaining to epigenetic changes in cardiac fibrosis. This review focuses on the epigenetic regulation of cardiac fibrosis.


Increase of creatine kinase and lactate dehydrogenase in the serum of rats submitted to experimental intestinal infarction.
Acute intestinal ischemia is a severe condition for which no early biochemical index exists at present. We have investigated the effect of experimental intestinal infarction in the rat on the serum concentration of total creatine kinase, creatine kinase BB and total lactate dehydrogenase. Suppression of blood supply from the superior mesenteric artery resulted in marked increases of total creatine kinase, of its BB isoenzyme, and of total lactate dehydrogenase. Whereas total creatine kinase and total lactate dehydrogenase cannot be regarded as specific markers of the intestine, creatine kinase BB could prove to be more specific in view of its limited tissue distribution.


Clinical pharmacology of sodium butyrate in patients with acute leukemia.
Since cancer may be regarded as a disease of differentiation and sodium butyrate induces differentiation of malignant cells in vitro, a study of the clinical pharmacology of sodium butyrate was undertaken. Nine patients with acute myeloid (n = 1), acute monocytic (n = 1), acute myelomonocytic (n = 6) and acute undifferentiated (n = 1) leukemia were treated. Their median age was 52 (range, 27-78) years. Six of the nine patients were pretreated with cytostatic agents. Sodium butyrate was administered i.v. at a dosage of 500 mg/kg/day as continuous infusion over 10 days. A sensitive and reproducible high-performance liquid chromatographic separation was developed after derivatization of sodium butyrate with 2,4'-dibromoacetophenone employing crown ether catalysis. Plasma concentrations and urinary excretion of sodium butyrate were monitored during the 10 days of continuous infusion and for 2 days thereafter. During infusion, plasma concentrations increased 6-fold over the endogenous butyrate level and reached 39-59 microM. The area under the curve of the exogenous butyrate was 384 +/- 50 microM X day (mean +/- S.D.). After the end of infusion, concentrations declined rapidly with a half-life of 6.1 +/- 1.4 min, and reached pretreatment values within 1 hr. The total clearance rate was 83 +/- 12 ml/kg/min and the volume of distribution 738 +/- 245 ml/kg. The excreted amounts of butyrate in the urine were minimal as compared to the infused dose. Although excretion by other organs was not ruled out, it is suggested that the infused sodium butyrate was rapidly metabolized. A significant increase in peripheral blast cells was observed, whereas bone marrow cytologies before and after treatment did not reveal a significant change in blasts. Differential counts of peripheral white blood cells did not show significant changes. No toxicity was encountered. The apparent lack of clinical efficacy may be explained by the low plasma levels of sodium butyrate due to its short half-life in vivo. In comparison, concentrations reported for in vitro studies were at least 10 times higher.


The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers.
This study was performed in a sample of the Dutch population to estimate the prevalence of noncoding mutations of CYP2D6 and CYP2C19 as obtained by genotyping. In addition, the predictability of the genotyping strategy was assessed. The CYP2D6 and CYP2C19 status of 765 unrelated healthy volunteers was evaluated. Dextromethorphan and mephenytoin were used for determining the phenotypes. Genotyping was performed by PCR on the most common null alleles for CYP2D6 (except for CYP2D6*5) and CYP2C19. For CYP2D6, the most frequently observed null allele was CYP2D6*4, which accounted for 89% of all null alleles. The prevalence of poor metabolizers (PMs) in healthy volunteers was 5.5%, which was lower than that found previously by phenotyping (8.0%; chi2 test P = 0.009). For CYP2C19*2 and CYP2C19*3, the frequencies were 13.3% and 0.2%, respectively. The S:R ratio was significantly higher in heterozygous subjects (S:R ratio 0.22) than in homozygous wild type subjects (S:R ratio 0.11). Comparison of all subjects below 45 years showed a significantly higher S:R ratio in the female ones compared to the male ones, especially in heterozygous subjects (S:R ratio 0.39 vs. 0. 19; P < 0.001). The frequencies of CYP2D6 and CYP2C19 allelic variants were in accordance with other European populations. Assessment of *3, *4, *6, *7, and *8 alleles for CYP2D6, and *2 and *3 for CYP2C19, predicted the phenotype with an accuracy of over 98.6%. A gene-dose effect was found for CYP2C19. CYP2C19 heterozygous female subjects had a decreased CYP2C19 activity that may be at least partly due to the use of oral contraceptives.


Influence of acute moderate- to high-intensity aerobic exercise on markers of immune function and microparticles in renal transplant recipients.
Renal transplant recipients (RTRs) and patients with nondialysis chronic kidney disease display elevated circulating microparticle (MP) counts, while RTRs display immunosuppression-induced infection susceptibility. The impact of aerobic exercise on circulating immune cells and MPs is unknown in RTRs. Fifteen RTRs [age: 52.8 ± 14.5 yr, estimated glomerular filtration rate (eGFR): 51.7 ± 19.8 mL·min-1·1.73 m-2 (mean ± SD)] and 16 patients with nondialysis chronic kidney disease (age: 54.8 ± 16.3 yr, eGFR: 61.9 ± 21.0 mL·min-1·1.73 m-2, acting as a uremic control group), and 16 healthy control participants (age: 52.2 ± 16.2 yr, eGFR: 85.6 ± 6.1 mL·min-1·1.73 m-2) completed 20 min of walking at 60-70% peak O2 consumption. Venous blood samples were taken preexercise, postexercise, and 1 h postexercise. Leukocytes and MPs were assessed using flow cytometry. Exercise increased classical (P = 0.001) and nonclassical (P = 0.002) monocyte subset proportions but decreased the intermediate subset (P < 0.001) in all groups. Exercise also decreased the percentage of platelet-derived MPs that expressed tissue factor in all groups (P = 0.01), although no other exercise-dependent effects were observed. The exercise-induced reduction in intermediate monocyte percentage suggests an anti-inflammatory effect, although this requires further investigation. The reduction in the percentage of tissue factor-positive platelet-derived MPs suggests reduced prothrombotic potential, although further functional assays are required. Exercise did not cause aberrant immune cell activation, suggesting its safety from an immunological standpoint (ISRCTN38935454).


Prevalence of overweight in north Florida elementary and middle school children: effects of age, sex, ethnicity, and socioeconomic status.
The number of overweight children has been rapidly increasing, although its prevalence varies by age, sex, ethnicity, and socioeconomic (SES) status. Height and weight assessments were used to calculate body mass index (BMI) and BMI percentile on more than 17,000 children in 1 north Florida school district's elementary and middle schools. Based on the child's BMI percentile, each child was placed into 1 of 4 groups: underweight, normal, at risk for overweight, and overweight. Logistic regression was used to test the relative contribution of sex, ethnicity, school (elementary vs middle), age, and SES (indicated by free/reduced vs full-pay lunch status) to a child's weight classification. Overall, 36.2% of the children were either overweight (18.9%) or at risk for overweight (17.4%). Approximately 30% of the kindergarten children were overweight (14.0%) or at risk for overweight (15.5%). African American children were most likely to begin kindergarten overweight. The prevalence of overweight increased for all ethnic groups during the elementary school years. However, African American girls and Hispanic boys were more likely to be overweight than any other ethnic group; Asian girls were least likely to be overweight. These findings could not be readily explained by the effects of SES. Higher SES appeared to be protective but only for white and Hispanic children. These results confirm the increasing prevalence of overweight in US school children, especially among African American girls and Hispanic boys.


In vitro effects of a beer-foam stabilizer on the activities of three pancreatic hydrolases.
The chemical composition of a foam stabilizer and its in vitro effects on the activities of trypsin, amylase and lipase in the pancreatic extract of male albino Wistar rats have been studied. Activities of two of the three hydrolases (amylase and trypsin) were stimulated while that of lipase was inhibited. Lineweaver--Burk reciprocal plot indicates non-competitive inhibition of lipase.


Studies on structural and physical characteristics of a novel exopolysaccharide from Pseudozyma sp. NII 08165.
The aim of this work was to study the production of exopolysaccharide (EPS) from a novel ustilaginomycetes yeast strain Pseudozyma sp. NII 08165. The culture produced 3.5g/l EPS on fourth day of fermentation in a glucose-based medium. The structural characterization revealed that the EPS was a polymer of glucose, galactose and mannose in the ratio of 2.4:5.0:2.6 with a molecular weight of 1.7MDa. The pseudoplastic behaviour of aqueous EPS with a thermal stability up to 220°C indicated its potential utility as a thickening or gelling agent in food industry. SEM studies of the EPS showed that it had compact film-like structure, which could make it a useful in preparing plasticized films. The AFM studies showed that EPS had spike-shaped microstructure. Physical properties of the exopolysaccharide determined further indicated its possible potential in different industrial applications.


PCSK9 Knockdown Can Improve Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy.
This study investigates the effect and mechanism of proprotein convertase subtilisin/Kexin type 9 (PCSK9) on myocardial ischemia-reperfusion injury (MIRI) and provides a reference for clinical prevention and treatment of acute myocardial infarction (AMI). We established a rat model of myocardial ischemia/reperfusion (I/R) and AC16 hypoxia/reoxygenation (H/R) model. A total of 48 adult 7-week-old male Sprague-Dawley rats were randomly assigned to three groups (n = 16): control, I/R, and I/R + SiRNA. In I/R and I/R + siRNA groups, myocardial ischemia was induced via occlusion of the left anterior descending branch (LAD) of the coronary artery in rats in I/R group for 30 min and reperfused for 3 days. To assess the myocardial injury, the rats were subjected to an electrocardiogram (ECG), cardiac function tests, cardiac enzymes analysis, and 2,3,5-triphenyl tetrazolium chloride (TTC)/Evan Blue (EB) staining. Meanwhile, differences in the expression of autophagy-level proteins and Bcl-2/adenovirus E1B 19-kDa interacting protein (Bnip3) signaling-related proteins were determined by protein blotting. In vitro and in vivo experimental studies revealed that siRNA knockdown of PCSK9 reduced the expression of autophagic protein Beclin-1, light chain 3 (LC3) compared to normal control-treated cells and control-operated groups. Simultaneously, the expression of Bnip3 pathway protein was downregulated. Furthermore, the PCSK9-mediated small interfering RNA (siRNA) group injected into the left ventricular wall significantly improved cardiac function and myocardial infarct size. In ischemic/hypoxic circumstances, PCSK9 expression was dramatically increased. PCSK9 knockdown alleviated MIRI via Bnip3-mediated autophagic pathway, inhibited inflammatory response, reduced myocardial infarct size, and protected cardiac function.


Nucleic acid detection technologies and marker molecules in bacterial diagnostics.
There is a growing need for quick and reliable methods for microorganism detection and identification worldwide. Although traditional culture-based technologies are trustworthy and accurate at a relatively low cost, they are also time- and labor-consuming and are limited to culturable bacteria. Those weaknesses have created a necessity for alternative technologies that are capable for faster and more precise bacterial identification from medical, food or environmental samples. The most common current approach is to analyze the nucleic acid component of analyte solution and determine the bacterial composition according to the specific nucleic acid profiles that are present. This review aims to give an up-to-date overview of different nucleic acid target sequences and respective analytical technologies.


Comparative survival of viruses during thermophilic and mesophilic anaerobic digestion.
Micro-scale technology was used to obtain survival data for three animal viruses and two bacteriophages during anaerobic digestion. The data for adenoviruses, MS2 and Φ6 provide the first published reports for survival of these viruses during mesophilic anaerobic digestion. Data were also obtained for thermophilic digestion, which showed greater inactivation of viruses at the higher temperature. Data on the survival of Φ6 are of particular interest since it is a lipid-based virus which has been suggested as a surrogate for the Ebola virus. In contrast, MS2 was found to be an inappropriate surrogate for Ebola.


Calculating the futureQuantum Supremacy: How the Quantum Computer Revolution Will Change Everything Michio Kaku Doubleday, 2023. 352 pp.
A quantum computing primer offers insights into the technology's most promising potential applications.


Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway.
Trop2 is a cell-surface glycoprotein overexpressed by a variety of epithelial carcinomas with reported low to restricted expression in normal tissues. Expression of Trop2 has been associated with increased tumor aggressiveness, metastasis and decreased patient survival, but the signaling mechanisms mediated by Trop2 are still unknown. Here, we studied the effects murine Trop2 (mTrop2) exerted on tumor cellular functions and some of the signaling mechanisms activated by this oncogene. mTrop2 expression significantly increased tumor cell proliferation at low serum concentration, migration, foci formation and anchorage-independent growth. These in vitro characteristics translated to increased tumor growth in both subcutaneous and orthotopic pancreatic cancer murine models and also led to increased liver metastasis. mTrop2 expression also increased the levels of phosphorylated ERK1/2 mediating cell cycle progression by increasing the levels of cyclin D1 and cyclin E as well as downregulating p27. The activation of ERK was also observed in human pancreatic ductal epithelial cells and colorectal adenocarcinoma cells overexpressing human Trop2. These findings demonstrate some of the pathogenic effects mediated by mTrop2 expression on cancer cells and the importance of targeting this cell surface glycoprotein. This study also provides the first indication of a molecular signaling pathway activated by Trop2 which has important implications for cancer cell growth and survival.


Determination of zonisamide (3-sulphamoylmethyl-1,2-benzisoxazole) in plasma at therapeutic concentrations by high-performance liquid chromatography.
A selective and sensitive liquid chromatographic method for the determination of zonisamide in small (0.1 ml) plasma samples is described. After adding internal standard, a direct solvent extract of the sample is examined by reversed-phase liquid chromatography with ultra-violet spectrophotometric detection. The method is rapid, simple and capable of determining plasma levels after therapeutic ingestion of zonisamide. Some results from a dose-ranging clinical trial are presented.


A new reality: achieving cholesterol-lowering goals in clinical practice.
Physicians often fail to achieve recommended low-density lipoprotein (LDL) cholesterol goals for their patients using lipid-lowering therapies in the primary care setting. A variety of factors may contribute to this failure, including inadequate effectiveness of lipid-lowering drugs in reducing LDL cholesterol at commonly used doses. In the Lipid Assessment Treatment Project (L-TAP), for example, the success rates for lipid-regulating therapies and treatments according to National Cholesterol Education Program (NCEP) Adult Treatment Panel II (ATP II) LDL cholesterol goals were 43% for bile acid sequestrants, 39% for niacin, 32% for gemfibrozil, 28% for psyllium fiber, 40% for statins, and 40% for combination therapy. Rosuvastatin is a new statin that has been shown to achieve significantly greater reductions in LDL cholesterol compared with pravastatin, simvastatin, and atorvastatin in primary hypercholesterolemia and enabled greater proportions of patients to achieve LDL cholesterol goals. Similarly, rosuvastatin proved superior to atorvastatin in lowering LDL cholesterol in patients with familial hypercholesterolemia, with more patients achieving LDL cholesterol goals. Data from these trials suggest that rosuvastatin is as safe and well tolerated as other statins. The availability of lipid-lowering drugs with greater LDL cholesterol-lowering effects could simplify the approach to coronary heart disease risk reduction in primary care.


Effects of clofilium on ischemic subendocardial Purkinje fibers 1 day postinfarction.
One day after ligation of the canine anterior descending coronary artery, clofilium, a long-acting class III antiarrhythmic agent, was studied for its effects on normal and ischemic Purkinje fibers. In normal Tyrode's solution (4 mM potassium, 2.7 mM calcium) clofilium (10(-7) to 10(-5) M) increased action potential duration. Although only 2 of 10 normal Purkinje fibers developed early after depolarizations and early afterdepolarization-initiated triggered activity, 10 of 11 ischemic Purkinje fibers developed these features. Consequently, action potentials in ischemic fibers were prolonged to durations greater than 10 s. The triggered activity in the ischemic Purkinje fibers produced repetitive activity in adjacent normal ventricular muscle. In vivo, 3 days after ligation, the administration of 3 to 10 mg/kg clofilium induced grouped beating. Action potentials recorded subsequently from these same hearts in vitro showed early afterdepolarizations, triggered activity and a similar grouping of responses. Therefore, clofilium differentially produced early afterdepolarizations in ischemic Purkinje fibers. This is a mechanism by which clofilium could be arrhythmogenic in an ischemic heart.


Weather and the first episode of schizophrenia.
To emphasize the effect of weather on the occurrence of the first episode of Schizophrenia. The relationship between weather and the first episode of schizophrenia was investigated at Ibn Sina Psychiatric Hospital, Damascus, Syria, from 1997 to 1999. Schizophrenia in developing countries affects men at a higher rate than women. The highest rates are found in lower socioeconomic classes, and the first episode of the disease usually occurs in May or June, and after weather changes. High temperature (equal or exceeding body temperature) is considered one of the outside factors of schizophrenia, however, as yet the etiology of the disease is still unknown.


Advancing from a "hemodynamic model" to a "mechanistic disease-modifying model" of cardiogenic shock.
Emerging clinical evidence has suggested that short-term mechanical augmentation of cardiac output (CO) may not consistently improve mortality in patients with cardiogenic shock (CS), despite improvements in hemodynamics. Such failures could reflect the underlying complexity of the mechanisms that contribute to malperfusion and organ dysfunction in CS. Distinct molecular and physiologic shock endophenotypes likely exist among patients with CS, with hemodynamic aberrations as the inciting insult but not necessarily the primary drivers of clinical outcomes. We propose that building a framework that moves away from the current "hemodynamic model" in preference for a "mechanistic disease-modifying model" of CS may facilitate progress toward reducing the stagnant mortality rates in this population. Such a therapeutic paradigm shift in patients with chronic systolic heart failure-the shift away from strategies that augment CO to those that modulate the systemic responses to low CO-has been one of the single most important shifts in contemporary cardiovascular medicine.


Reflections on the Brain Conference 2023.
Our acting Scientific Editor, Elizabeth Simzer, highlights a session from the third annual Brain Conference held on 16 March 2023.


A blend of Withania somnifera (L.) Dunal root and Abelmoschus esculentus (L.) Moench fruit extracts relieves constipation and improves bowel function: A proof-of-concept clinical investigation.
Withania somnifera (L.) Dunal (WS) and Abelmoschus esculentus (L.) Moench (AE) are known as Ashwagandha and Okra, respectively, important herbs in traditional medicine for their diverse therapeutic values. WS root is an adaptogen that relieves stress and anxiety and promotes sleep. AE fruit or Okra is widely consumed as a vegetable and is traditionally used to treat diabetes, gastric irritations, ulcers, and obesity. The present randomized, double-blind, placebo-controlled study aimed to establish a proof-of-concept evaluating the efficacy and tolerability of a proprietary blend of standardized extracts of WS root and AE fruit, CL18100F4 in relieving constipation and improving quality of life in adults. Forty-eight male and female participants (age: 25-60 years) with functional constipation (following Rome-III criteria) were randomized into placebo, 300 or 500 mg of CL18100F4 groups, and supplemented for fourteen consecutive days. CL18100F4 supplementation significantly (p < 0.0001) reduced the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), and Gastrointestinal Symptom Rating Scale (GSRS) scores. CL18100F4 supplementation improved sleep quality and reduced stress (p < 0.0001). At the end of the study, CL18100F4-500 subjects showed significant increases in serum serotonin, gastrin, and interleukin-10 and decrease in interleukin-6 and cortisol levels. Participants' hematology, total blood chemistry, vital signs, and urinalysis parameters were within the normal ranges. No adverse events were reported. This short-duration, single-site clinical investigation demonstrates that CL18100F4 supplementation is tolerable, helps relieve constipation, reduces stress, and improves gastrointestinal function, sleep quality, and general wellness in adults. Clinical Trials Registry- India (CTRI/2020/11/029320); Registered on 24/11/2020. Available at: http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=49391&EncHid=&userName=CL18100F4.


Using the Internet for research.
(1) To give an overview of research tools, techniques, and resources that are available on the Internet; and (2) to identify valid, pharmacy-related information that will reduce uncertainty in the problem-solving activities of practitioners. The World Wide Web. Examples cited in the article were evaluated according to the criteria offered in the text as a prerequisite for their inclusion. Functional aspects of the Internet include communication, commerce, and content. Because a lack of control has led to mixed information quality, the use of Internet-based information for patient care and professional decision making should be subject to rigorous screening criteria. Pharmacists can use Web browsers combined with excellent search engines and search techniques to identify quality resources, including primary, secondary, and tertiary literature, either fee-based or free, and that can be sought actively or distributed on a schedule directly to the desktop of the pharmacist. The Internet can be an immensely helpful research tool, if used appropriately. Whether actively searching or passively receiving useful updates, the Internet can function as a value-added asset to any pharmacy practice.


MRI is unnecessary for diagnosing acute Achilles tendon ruptures: clinical diagnostic criteria.
Achilles tendon ruptures are common in middle-aged athletes. Diagnosis is based on clinical examination or imaging. Although MRI is commonly used to document ruptures, there is no literature supporting its routine use and we wondered whether it was necessary. We (1) determined the sensitivity of physical examination in diagnosing acute Achilles ruptures, (2) compared the sensitivity of physical examination with that of MRI, and (3) assessed care delays and impact attributable to MRI. We retrospectively compared 66 patients with surgically confirmed acute Achilles ruptures and preoperative MRI with a control group of 66 patients without preoperative MRI. Clinical diagnostic criteria were an abnormal Thompson test, decreased resting tension, and palpable defect. Time to diagnosis and surgical procedures were compared with those of the control group. All patients had all three clinical findings preoperatively and complete ruptures intraoperatively (sensitivity of 100%). MR images were read as complete tears in 60, partial in four, and inconclusive in two patients. It took a mean of 5.1 days to obtain MRI after the injury, 8.8 days for initial evaluation, and 12.4 days for surgical intervention. In the control group, initial evaluation occurred at 2.5 days and surgical intervention at 5.6 days after injury. Nineteen patients in the MRI group had additional procedures whereas none of the control group patients had additional procedures. Physical examination findings were more sensitive than MRI. MRI is time consuming, expensive, and can lead to treatment delays. Clinicians should rely on the history and physical examination for accurate diagnosis and reserve MRI for ambiguous presentations and subacute or chronic injuries for preoperative planning. Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.


Survival improvement of patients with chronic lymphocytic leukemia (CLL) in routine care 1995-2017.
Seven hundred and twenty-four CLL-outpatients with a median age of 67 (35-92) were analyzed. Four hundred and twenty-seven (59%) were male, 297 (41%) female. At diagnosis 556 (77%) were in Binet stage A, 91 (13%) stage B and 36 (5%) stage C. Forty-six percent received treatment during the evaluation period. Treatment consisted of purine analogs in 38%, alkylating agents in 96%, chemoimmunotherapy with anti-CD20 monoclonal antibodies in 63%, ibrutinib in 9%, venetoclax in 1% and idelalisib in 3%. 3% received allogeneic hematopoietic stem cell transplantation. Overall survival (OS) according to Binet stage was: A 13.9 years (0.1-37.4), B 9.2 years (1.4-29.3) and C 7.9 years (0.5-19.4) respectively. Median OS from the start of therapy improved over time; 1995-2001: 5.8 years, 2002-2008: 6.1 years and 2009-2017: median not reached. Survival of patients with CLL has improved in routine care and was strongly related to active disease, disease stage, performance status and whether therapy included an anti-CD20 monoclonal antibody.


New filter for iodine applied in nuclear medicine services.
In Nuclear Medicine, radioiodine, in various chemical forms, is a key tracer used in diagnostic practices and/or therapy. Medical professionals may incorporate radioactive iodine during the preparation of the dose to be administered to the patient. In radioactive iodine therapy doses ranging from 3.7 to 7.4 GBq per patient are employed. Thus, aiming at reducing the risk of occupational contamination, we developed a low cost filter to be installed at the exit of the exhaust system (where doses of radioiodine are handled within fume hoods, and new filters will be installed at their exit), using domestic technology. The effectiveness of radioactive iodine retention by silver impregnated silica [10%] crystals and natural activated carbon was verified using radiotracer techniques. The results showed that natural activated carbon and silver impregnated silica are effective for I2 capture with large or small amounts of substrate but the use of activated carbon is restricted due to its low flash point (423 K). Besides, when poisoned by organic solvents, this flash point may become lower, causing explosions if absorbing large amounts of nitrates. To hold the CH3I gas, it was necessary to use natural activated carbon since it was not absorbed by SiO2+Ag crystals. We concluded that, for an exhaust flow range of (145 ± 2)m(3)/h, a double stage filter using SiO2+Ag in the first stage and natural activated carbon in the second stage is sufficient to meet radiological safety requirements.


In chronic low back pain, low level laser therapy combined with exercise is more beneficial than exercise alone in the long term: a randomised trial.
Is low level laser therapy an effective adjuvant intervention for chronic low back pain? Randomised trial with concealed allocation, blinded assessors and intention-to-treat analysis. Sixty-one patients who had low back pain for at least 12 weeks. One group received laser therapy alone, one received laser therapy and exercise, and the third group received placebo laser therapy and exercise. Laser therapy was performed twice a week for 6 weeks. Outcomes were pain severity measured using a 10-cm visual analogue scale, lumbar range of motion measured by the Schober Test and maximum active flexion, extension and lateral flexion, and disability measured with the Oswestry Disability Index on admission to the study, after 6 weeks of intervention, and after another 6 weeks of no intervention. There was no greater effect of laser therapy compared with exercise for any outcome, at either 6 or 12 weeks. There was also no greater effect of laser therapy plus exercise compared with exercise for any outcome at 6 weeks. However, in the laser therapy plus exercise group pain had reduced by 1.8 cm (95% CI 0.1 to 3.3, p = 0.03), lumbar range of movement increased by 0.9 cm (95% CI 0.2 to 1.8, p < 0.01) on the Schober Test and by 15 deg (95% CI 5 to 25, p < 0.01) of active flexion, and disability reduced by 9.4 points (95% CI 2.7 to 16.0, p = 0.03) more than in the exercise group at 12 weeks. In chronic low back pain low level laser therapy combined with exercise is more beneficial than exercise alone in the long term.


Evidence that ATP and noradrenaline are released during electrical field stimulation of the rat isolated seminal vesicle.
The effects of electrical field stimulation (at 1-100 Hz with 20-25 V, supramaximal, and 0.2 ms pulse duration, for 10-20 s), on tone and contractility of rat isolated seminal vesicle was studied, in the absence and presence of specific antagonists (phentolamine, 1 microM, alpha, beta-Me-ATP, 10 microM, and verapamil, 1 microM). The aim was to provide pharmacological evidence of the release of ATP, alongside NA, during electrical stimulation of the rat seminal vesicle. Electrical field stimulation of the rat seminal vesicle produced frequency-dependent contractions. At low rates of stimulation (1-20 Hz), only small tonic contractions were observed (0.3 g tension), whereas at high rates of stimulation (80-100 Hz), only phasic contractions (2-3 g) were seen. However, at intermediate rates of stimulation (e.g. 50 Hz), a biphasic response was produced: an initial fast, twitch-like response (phasic), followed by a slow tonic contraction. The phasic contraction was blocked by the stable analogue of ATP (alpha, beta-Me-ATP), which desensitizes P2-purinoceptors. The tonic contraction is adrenergic and was blocked by phentolamine. Verapamil reduced both types of contractions in this preparation and the block was unselective on tonic versus phasic contraction. It was concluded that electrical field stimulation produced frequency-dependent contractions tonic and phasic in the rat seminal vesicle. These responses were blocked by specific antagonists, suggesting the presence of different types of neurotransmitters released during electrical stimulation of the rat seminal vesicle.


Structural Characterization of Covalently Stabilized Human Cystatin C Oligomers.
Human cystatin C (HCC), a cysteine-protease inhibitor, exists as a folded monomer under physiological conditions but has the ability to self-assemble via domain swapping into multimeric states, including oligomers with a doughnut-like structure. The structure of the monomeric HCC has been solved by X-ray crystallography, and a covalently linked version of HCC (stab-1 HCC) is able to form stable oligomeric species containing 10-12 monomeric subunits. We have performed molecular modeling, and in conjunction with experimental parameters obtained from atomic force microscopy (AFM), transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) measurements, we observe that the structures are essentially flat, with a height of about 2 nm, and the distance between the outer edge of the ring and the edge of the central cavity is ~5.1 nm. These dimensions correspond to the height and diameter of one stab-1 HCC subunit and we present a dodecamer model for stabilized cystatin C oligomers using molecular dynamics simulations and experimentally measured parameters. Given that oligomeric species in protein aggregation reactions are often transient and very highly heterogeneous, the structural information presented here on these isolated stab-1 HCC oligomers may be useful to further explore the physiological relevance of different structural species of cystatin C in relation to protein misfolding disease.


Successful endovascular treatment of a ruptured mycotic intracavernous carotid artery aneurysm in an AIDS patient.
As the medical treatment for human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) continues to advance, the HIV-related aneurysms may pose a clinical problem of increasing magnitude. The authors report on a successfully treated ruptured mycotic intracavernous carotid artery aneurysm case in an AIDS patient. This 41-year-old AIDS patient presented with severe epistaxis. His head CT revealed acute blood in the left sphenoid sinus with bony erosion of the lateral wall (Fig. 1). The cerebral angiogram demonstrated a quite irregularly shaped intracavernous carotid artery aneurysm with proximal arterial stenosis (Fig. 2). After balloon test occlusion, this aneurysm was trapped endovascularly with detachable balloons (Fig. 3). The blood culture was positive for Aspergillus. The patient died 2 years later from other AIDS-related causes. The cerebral aneurysms in HIV/AIDS patients can be generally categorized into two groups: the mycotic aneurysms from bacterial or fungal infections and the HIV-associated aneurysms as a distinct entity. To plan appropriate interventions, a high degree of clinical suspicion must be exercised to promptly recognize the mycotic nature of many HIV-related aneurysms.


BMP-2 induced early bone formation in spine fusion using rat ovariectomy osteoporosis model.
Bone morphogenetic proteins (BMPs) enhance bone formation. Numerous animal studies have established that BMPs can augment spinal fusion. However, there is a lack of data on the effect of BMP-2 on spinal fusion in the osteoporotic spine. To investigate whether recombinant human BMP-2 (rhBMP-2) enhances spine fusion in an ovariectomized rat model. In vivo animal study. Female Sprague-Dawley rats (n=60) were ovariectomized or sham operated and randomized into three groups: Sham (sham operated+fusion), ovariectomy (OVX) (OVX+fusion), and BMP (OVX+fusion+BMP-2). Six weeks after ovariectomy, unilateral lumbar spine fusion was performed using autologous iliac bone with/without rhBMP-2 delivered on a collagen matrix. For each group, gene expression and histology were evaluated at 3 and 6 weeks after fusion, and bone parameters were measured by microcomputed tomography at 3, 6, 9, and 12 weeks. Real-time reverse-transcription polymerase chain reaction at 3 weeks showed markedly increased expression of osteoblast-related markers (namely alkaline phosphatase, osteocalcin, Runx2, Smad1, and Smad5) in the BMP group compared with the other groups (p=.0005, .0005, .003, .009 and .012, respectively). Although the Sham and OVX groups showed both sparse and compacted bones between transverse processes at 6 weeks, the BMP group had a significantly larger bone mass within the fusion bed at 3 weeks and later. All rats in the BMP group had bridging bone at 3 weeks; at 12 weeks, bridging bones in the Sham and OVX groups were about 50% and 25%, respectively, of that in the BMP group. Recombinant human BMP-2 enhances spinal fusion in OVX rats and acts during early bone formation. Therapeutic BMP-2 may therefore improve the outcome of spinal fusion in the osteoporotic patient.


The Stereo-Electroencephalography Methodology.
The stereo-electroencephalography (SEEG) methodology and technique was developed almost 60 years ago in Europe. The efficacy and safety of SEEG has been proven. The main advantage is the possibility to study the epileptogenic neuronal network in its dynamic and 3-dimensional aspect, with optimal time and space correlation, with the clinical semiology of the patient's seizures. The main clinical challenge for the near future remains in the further refinement of specific selection criteria for the different methods of invasive monitoring, with the ultimate goal of comparing and validating the results (long-term seizure-free outcome) obtained from different methods of invasive monitoring.


Predictors for major in-hospital complications after catheter ablation of ventricular arrhythmias: validation and modification of the Risk in Ventricular Ablation (RIVA) Score.
Catheter-based treatment of patients with ventricular arrhythmias (VA) reduces VA and mortality in selected patients. With regard to potential risks of catheter ablation, a benefit-risk assessment should be carried out. This can be performed with risk scores such as the recently published "Risk in Ventricular Ablation (RIVA) Score". We sought to validate this score and to test for possible additional predictors in a large database of VT ablations. We analyzed 1964 catheter ablations for VA in patients with (1069; 54.4%) and without (893, 45.6%) structural heart disease (SHD) and observed an overall major adverse event rate of 4.0% with an in-hospital mortality of 1.3% with significantly less complications occurring in patients without structural heart disease (6.5% vs. 1.1%; p ≤ 0.01). The RIVA Score demonstrated to be a valid predictive tool for major in-hospital complications (OR 1.18; 95% CI 1.12, 1.25; p ≤ 0.001). NYHA Class ≥ III (OR 2.5; 95% CI 1.5, 4.2; p < 0.001) and age (OR 1.04; 95% CI 1.02, 1.07; p ≤ 0.001) proved to be additional predictive parameters. Hence, a modified RIVA Score (mRIVA) model was analyzed with a subset of established predictors (SHD, eGFR, epicardial puncture) as well as new predictive parameters (age, NYHA Class ≥ III), that achieved a higher predictive value for major complications compared with the model based on all RIVA variables. Adding age and functional heart failure status (NYHA class) as simple clinical parameters to the recently published RIVA Score increases the predictive value for ablation-associated complications in a large VT ablations registry.


Role of Flow Cytometry in the Diagnosis and Prognosis of Plasma Cell Myeloma.
This article provides an overview of the role of flow cytometry in the diagnosis and follow-up of plasma cell myeloma. A brief introduction to the general immunophenotypic features of normal and myeloma plasma cells is provided, followed by a discussion of technical issues as they relate to the application of flow cytometry in this entity. The prognostic and therapeutic utility of flow cytometric immunophenotyping in myeloma is also analyzed, with an emphasis on the growing role of minimal residual analysis as potential biomarker for evaluating treatment efficacy and for tailoring risk-adapted treatment, in prospective clinical trials.


Ploidy changes between diagnosis and relapse in childhood renal tumours.
Ploidy patterns, analysed by flow cytometry (FCM) and image analysis (IA), were investigated at relapse in a group of six children with renal tumours [five Wilms' tumour (WT) and one bone metastasizing renal tumour of childhood (BMRTC)] and results compared with diagnostic profiles. IA detected one or more aneuploid populations in five of 12 tumours which were diploid on FCM. Patterns in three of six patients [two with unfavourable histology (UH) and one with favourable histology (FH)] were aneuploid at diagnosis and relapse, two patients (one FH, one BMRTC) developed aneuploid features at relapse and one patient with a tetraploid tumour was diploid at relapse. Histology patterns were similar at diagnosis and relapse in all patients. Three of six patients (two UH, one BMRTC) have died of disease. This report highlights (1) the superiority of IA over FCM in detecting aneuploid populations and (2) changes in ploidy status which have not previously been reported in these tumours. Overinterpretation of DNA status at relapse may prove misleading.


Group therapy in primary care settings for the treatment of posttraumatic stress disorder: A systematic literature review.
This systematic review aims to summarize existing literature on group therapy for the treatment of post-traumatic stress disorder (PTSD) in primary care. A PRISMA systematic literature review was performed through February 26, 2022 identifying existing studies of group trauma therapy in primary care. Articles were included if they discussed group trauma therapy for primary care patients. Bias was assessed based on sample sizes and presence of control groups. Results are presented as a weighted average of the engagement rate and a qualitative description of overlapping study traits. Four studies of group PTSD treatment within primary care were identified with 70 total patients completing group treatment. The weighted treatment engagement rate was 65%. Each utilized distinct group trauma treatment models and reported significant patient improvements in PTSD symptoms on standardized trauma symptom scales. Group trauma therapy models are available and can be disseminated within primary care settings. Limitations include both the small number of studies and participants. There have been few studies of group therapy for PTSD in primary care, but these could represent a promising and scalable approach to meet the high need for trauma treatment. Further research is needed regarding implementation feasibility and impact.


A potential sanitary sewer overflow treatment technology: fixed-media bioreactors.
Under certain conditions, sanitary sewer overflows (SSOs) containing raw wastewater may be discharged to public land and can contribute to environmental and public health issues. Although this problem has attracted the attention of local, state, and federal government and regulators, relatively little SSO abatement research has been published. This study used fixed-media bioreactors, a proven onsite technology in rural areas, to treat wet weather SSO wastewater and reduce its effects on the receiving water environment. The results of this 32-month laboratory study showed that fixed-media bioreactors, especially sand bioreactors, efficiently removed organic matter, solids, and nutrients during six-hour simulated SSO peak flows. Five-day biochemical oxygen demand (BODs) of the simulated SSO varied between 40 and 125 mg/L. The average effluent concentration of BOD5 was 13 mg/L in sand bioreactors at a hydraulic loading rate of 20.4 cm/h. In addition to having high hydraulic loadings, SSO events occur infrequently. This irregularity requires that treatment systems quickly start up and effectively treat wastewater after a period of no flow. This research found that an interval up to six months between two SSO peak flows did not affect the bioreactor performance. Based on this work, fixed-media bioreactors have the potential to reduce the effects of SSOs on the water environment by following proper design parameters and operation strategies. The pollution loading of approximately 18 g BODs/m2 x h is recommended for the efficient performance of sand bioreactors in the SSO treatment.


Bypassing a dilemma: intraoperative coronary angiography in acute aortic dissection.
Untreated coronary artery disease may complicate the clinical course of patients with Stanford type A acute aortic dissection. In these patients the role of coronary angiography for the assessment of coronary circulation is controversial and it is considered by some time consuming thus increasing the risk of rupture. We describe a case of acute type A aortic dissection that illustrates our approach to this problem.


Leukocyte integrins: structure, function and regulation of their activity.
Adhesion is a crucial requirement for the correct regulation of immune and inflammatory responses. In the immune system, leukocytes can interact with each other and with vascular endothelium as well as with extracellular matrix components, changing rapidly and transiently from circulating non-adherent to adherent states. Most of these interactions are mediated by integrins. This review will focus mainly on the structure and function of integrins expressed by leukocytes. The mechanisms for regulating the functional activity of these adhesion receptors, as well as the intracellular signals transduced through integrins, are described.