Effect of niridazole in cellular immunity in vivo and in vitro.
The influence of niridazole, an anti-helminthic drug, on cell-mediated immune responses was investigated. Allograft rejection in mice as well as the in vitro induction of cytotoxic T lymphocytes (CTL) against murine alloantigen were used as the test system. Repeated daily oral treatment of host mice with niridazole (100 mg/kg) prior to and during allotransplantation resulte in the postponement of graft rejection, inducing a transitory functional state of allograft tolerance. The time interval between the termination of niridazole administration and onset of graft rejection was estimated to be 5-7 days. In order to test the effect of niridazole or its derivatives on the in vitro induction of alloreactive CTL, the serum or urine of mice which were treated with niridazole were added to the cultures, instead of adding niridazole directly to the cultures. Such serum and urine were found to be inhibitory for in vitro induction of CTL. The serum and urine had no effect on the effector phase of CTL.


Nasoseptal flap closure of traumatic cerebrospinal fluid leaks.
The vascularized nasoseptal flap has become a principal reconstructive technique for the closure of endonasal skull base surgery defects. Despite its potential utility, there has been no report describing the use of the modern nasoseptal flap to repair traumatic cerebrospinal fluid (CSF) leaks and documenting the outcomes of this application. Specific concerns in skull base trauma include septal trauma with disruption of the flap pedicle, multiple leak sites, and issues surrounding persistent leaks after traumatic craniotomy. We performed a retrospective case series review of 14 patients who underwent nasoseptal flap closure of traumatic CSF leaks in a tertiary academic hospital. Main outcome measures include analysis of clinical outcome data. Defect etiology was motor vehicle collision in eight patients (57%), prior sinus surgery in four (29%), and assault in two (14%). At the time of nasoseptal flap repair, four patients had failed prior avascular grafts and two had previously undergone craniotomies for repair. Follow-up data were available for all patients (mean, 10 months). The overall success rate was 100% (no leaks), with 100% defect coverage. The nasoseptal flap is a versatile and reliable local reconstructive technique for ventral base traumatic defects, with a 100% CSF leak repair rate in this series.


[Treatment of atypical absences with a combination of succinimide and dipropylacetate (author's transl)].
Fifteen epileptic patients with mild seizures of the narcolepsy type were treated with a combination of succinimide (average dose 750 mg) and dipropylacetate (average dose 1,200 mg), medication with each drug alone having brought no success. The combination of drugs stopped the seizures in eleven patients, in three they almost stopped and in one the frequency of seizures was halved. An E.E.G. was recorded in twelve, with improvement in each. Side effects occurred in five patients (nausea, vomiting, singultus and fatigue), but the drug had to be discontinued in only one instance.


Understanding the effects of solvate ionic liquids as solvents on substitution processes.
The effects of solvate ionic liquids as solvents have been considered for two substitution processes where the solvent effects of typical ionic liquids have been extensively investigated previously; the bimolecular nucleophilic substitution (SN2) reaction between pyridine and benzyl bromide and the nucleophilic aromatic substitution (SNAr) reaction between ethanol and 1-fluoro-2,4-dinitrobenzene. It was found that use of solvate ionic liquids gave rise to similar trends in the activation parameters for both substitution processes as typical ionic liquids, implying the microscopic interactions responsible for the effects were the same. However, different effects on the rate constants compared to typical ionic liquids were observed due to the changes in the balance of enthalpic and entropic contributions to the observed rate constants. From these data it is clear that the reaction outcome for both of these substitution reactions fall within the 'predictive framework' established in previous studies with a cautionary tale or two of their own to add to the general knowledge of ionic liquid solvent effects for these processes, particularly with respect to potential reactivity of the solvate ionic liquids themselves.


Effects of Intraoperative Intrawound Antibiotic Administration on Spinal Fusion: A Comparison of Vancomycin and Tobramycin in a Rat Model.
Local, intrawound use of antibiotic powder, such as vancomycin and tobramycin, in spinal fusion surgery has become an increasingly common prophylactic measure in an attempt to reduce rates of postsurgical infection. However, the effects of localized antibiotic delivery on fusion remain unclear. The objective of this study was to examine the in vivo effects of intraoperative local delivery of 2 antibiotics commonly used in bone-grafting surgery on spinal fusion outcomes in a rat model. Single-level (L4-L5), bilateral posterolateral intertransverse process lumbar fusion surgery was performed on 60 female Lewis rats (6 to 8 weeks of age) using syngeneic iliac crest allograft mixed with clinical bone-graft substitute and varying concentrations of antibiotics (n = 12 each): (1) control without any antibiotics, (2) low-dose vancomycin (14.3 mg/kg), (3) high-dose vancomycin (71.5 mg/kg), (4) low-dose tobramycin (28.6 mg/kg), and (5) high-dose tobramycin (143 mg/kg). Eight weeks postoperatively, fusion was evaluated via micro-computed tomography (µCT), manual palpation, and histological analysis, with blinding to treatment group. In the µCT analysis, fusion-mass volumes were measured for each rat. Each spine specimen (L4-L5) was rated (manual palpation score) on a scale of 2 to 0 (2 = fused, 1 = partially fused, and 0 = non-fused). The mean fusion-mass volume on µCT (mm) was as follows: control, 29.3 ± 6.2; low-dose vancomycin, 26.3 ± 8.9; high-dose vancomycin, 18.8 ± 7.9; low-dose tobramycin, 32.7 ± 9.0; and high-dose tobramycin, 43.8 ± 11.9 (control versus high-dose vancomycin, p < 0.05; and control versus high-dose tobramycin, p < 0.05). The mean manual palpation score for each group was as follows: control, 1.46 ± 0.58; low-dose vancomycin, 0.86 ± 0.87; high-dose vancomycin, 0.68 ± 0.62; low-dose tobramycin, 1.25 ± 0.71; and high-dose tobramycin, 1.32 ± 0.72 (control versus high-dose vancomycin, p < 0.05). The histological analyses demonstrated a similar trend with regard to spinal fusion volume. Intraoperative local application of vancomycin, particularly at a supraphysiological dosage, may have detrimental effects on fusion-mass formation. No inhibitory effect of tobramycin on fusion-mass formation was observed. When spine surgeons decide to use intraoperative intrawound antibiotics in spinal fusion surgery, they should weigh the reduction in surgical site infection against a possible inhibitory effect on fusion.


Diagnosis of acute nerve compression in the cat with high frequency nerve trains evoked responses.
High frequency nerve trains were evaluated from above and below the site of compression before, during, and after acute compression of the sciatic nerves of six adult cats. Acute nerve compression reduced the ability of axons to conduct high frequency impulse trains: the longer the compression, the lower the frequency of impulses that could be conducted through the region of compression without a decrement in latency and amplitude. Possible mechanisms for alterations of nerve trains and the possible clinical and experimental use of nerve trains analysis are discussed.


DomainFit: Identification of Protein Domains in cryo-EM maps at Intermediate Resolution using AlphaFold2-predicted Models.
Cryo-electron microscopy (cryo-EM) has revolutionized our understanding of macromolecular complexes, enabling high-resolution structure determination. With the paradigm shift to in situ structural biology recently driven by the ground-breaking development of cryo-focused ion beam milling and cryo-electron tomography, there are an increasing number of structures at sub-nanometer resolution of complexes solved directly within their cellular environment. These cellular complexes often contain unidentified proteins, related to different cellular states or processes. Identifying proteins at resolutions lower than 4 Å remains challenging because the side chains cannot be visualized reliably. Here, we present DomainFit, a program for automated domain-level protein identification from cryo-EM maps at resolutions lower than 4 Å. By fitting domains from artificial intelligence-predicted models such as AlphaFold2-predicted models into cryo-EM maps, the program performs statistical analyses and attempts to identify the proteins forming the density. Using DomainFit, we identified two microtubule inner proteins, one of them, a CCDC81 domain-containing protein, is exclusively localized in the proximal region of the doublet microtubule from the ciliate Tetrahymena thermophila . The flexibility and capability of DomainFit makes it a valuable tool for analyzing in situ structures.


Re-evaluating transarterial chemoembolization for the treatment of hepatocellular carcinoma: Consensus recommendations and review by an International Expert Panel.
Patients with unresectable hepatocellular carcinoma (HCC) usually receive transarterial chemoembolization (TACE) or systemic therapies with intermediate and advanced-stage disease. However, intermediate-stage HCC patients often have unsatisfactory clinical outcomes with repeated TACE and there is considerable uncertainty surrounding the criteria for repeating or stopping TACE treatment. In July 2012, an Expert Panel Opinion on Interventions in Hepatocellular Carcinoma (EPOIHCC) was re-convened in Shanghai in an attempt to provide a consensus on the practice of TACE, particularly in regard to evaluating TACE 'failure'. To that end, current clinical practice throughout Asia was reviewed in detail including safety and efficacy data on TACE alone as well as in combination with targeted systemic therapies for intermediate HCC. This review summarizes the evidence discussed at the meeting and provides expert recommendations regarding the use of TACE for unresectable intermediate-stage HCC. A key consensus of the Expert Panel was that the current definitions of TACE failure are not useful in differentiating between situations where TACE is no longer effective in controlling disease locally vs. systemically. By redefining these concepts, it may be possible to provide a clearer indication of when TACE should be repeated and more importantly, when TACE should be discontinued.


Effect of interleukin-1β on the expression of actin isoforms in cultured mouse astroglia.
Cytokines are soluble mediators that are thought to act as communication signals between astroglia and neighboring neural cells. They are both released by, and act on, astroglia. It is hypothesized that it is this effect on astroglia that may be important in widespread phenomena including traumatic brain injury, inflammation, and scar formation. In this article, we examine the effect of mouse recombinant interleukin-1β (IL-1β) on the morphology, organization, and expression of glial fibrillary acidic protein (GFAP) and actin isoforms in cultured mouse astroglia. This study shows that the majority of the astroglia treated with IL-1β acquire long processes. Immunofluorescence staining shows that there are no remarkable changes in the organization of GFAP, F-actin, α-smooth muscle (α-sm) actin, and β-actin isoforms. In fluorescent microplate assay, the short-term treated astroglia (range, 1-2 days) show an increase in the intensity of GFAP and β-actin isoform over the level observed in untreated control, whereas no remarkable changes are observed in the intensity of α-sm actin isoform. In the case of long-term treatment (range, 4-8 days), the intensity of GFAP and α-sm actin isoform progressively decreases below the level of untreated control. In addition, the intensity of β-actin isoform increases above the control level. These results have been confirmed by immunoblotting experiments. The upregulation of β-actin isoform may be important in limiting the noxious effects of an inflammatory reaction. This gives credence to the hypothesis that it might be possible to modulate astroglial effects on neuronal inflammation and scar formation with appropriate therapies.


Metformin reduces asymmetric dimethylarginine and prevents hypertension in spontaneously hypertensive rats.
Elevated asymmetric dimethylarginine (ADMA) levels and nitric oxide (NO) deficiency are associated with the development of hypertension. Metformin, an antidiabetic agent, is a structural analog of ADMA. We examined whether metformin can prevent the development of hypertension in spontaneously hypertensive rats (SHRs) by restoration of ADMA-NO balance. SHRs and control normotensive Wistar-Kyoto (WKY) rats were assigned to 4 groups (N = 8 for each group): untreated SHRs and WKY rats, metformin-treated SHRs and WKY rats. Metformin-treated rats received metformin 500 mg/kg per day via oral gavage for 8 weeks. All rats were sacrificed at the age of 12 weeks. We found an increase in the blood pressure of SHRs was prevented by metformin. ADMA levels in the plasma and lung were elevated in SHRs, which metformin prevented. Lung dimethylarginine dimethylaminohydrolase (DDAH, ADMA-metabolizing enzyme) activity was lower in SHRs than WKY rats. Next, metformin had no effect on protein arginine methyltransferase 1 (ADMA-synthesizing enzyme), DDAH-1, DDAH-2, NO synthase enzymes, and DDAH activity in the kidney. Moreover, metformin increased the levels of NO in kidney. Conclusively, the observed antihypertensive effect of metformin in SHRs is because of the restoration of the ADMA-NO pathway. Our findings support the consideration of metformin as an antihypertensive agent for diabetic patients with prehypertension.


Antibody-targeted paclitaxel loaded nanoparticles for the treatment of CD20+ B-cell lymphoma.
We developed a nano-antibody targeted chemotherapy (nATC) delivery strategy in which tumor specific and clinically relevant antibodies (rituximab, anti-CD20) are non-covalently bound to the albumin scaffold of nab-paclitaxel (ABX). We define the nanoparticle formed when the 2 drugs are bound (AR160). The newly created nATC retains the cytotoxicity of ABX and CD20 affinity of rituximab in vitro. We describe the binding characteristics of the ABX and rituximab in AR160 using peptide mapping/Biacore approach. Flow-based methods, including ImageStream and nanoparticle tracking, were used to characterize the AR160 particles in vitro. A mouse model of human B-cell lymphoma was utilized to test in vivo efficacy of AR160 therapy, which suggested improved tumor targeting (biodistribution) as the most likely mechanism of AR160 therapeutic superiority over ABX or rituximab alone. These data suggest a novel platform for nATC delivery using a slight modification of existing cancer drugs with significantly improved treatment efficacy.


CuO/C nanocomposite: Synthesis and optimization using sucrose as carbon source and its antifungal activity.
The synthesis of bioactive CuO/C nano composite using sucrose as a capping agent is achieved through simple green approach via Response Surface Methodology. The synthesis process was done in a green environment which prevents aggregation of sucrose and promotes nanoparticles formation. The innovative approach produces sucrose as a carbon source mediated copper oxide nanocomposites (CuO/C nanocomposite) with the particle size of 50 nm. Additionally, the produced CuO/C nanocomposite were characterized using microscopic techniques like SEM, TEM and spectroscopic techniques like UV-vis and X-ray diffraction. The antifungal activities of CuO/C nanocomposite were tested against Aspergillus niger and Aspergillus flavus species. At 1000 ppm of CuO/C nanocomposite, it showed 70% restraint on A. flavus and 90% hindrance on A. niger. The fungal inhibition mechanism of bioactive CuO/C nanocomposite was discussed in this research article. The particular high antifungal performance of CuO/C nanocomposite was found against Aspergillus niger while compare to Aspergillus flavus fungal strain.


Identification and Coexposure of Neonicotinoid Insecticides and Their Transformation Products in Retail Cowpea (Vigna unguiculata).
There is growing evidence that the transformation products of emerging contaminants in foodstuffs may pose a health risk to humans. However, the exact identities, levels, and estimated dietary intake (EDI) of neonicotinoid transformation products in crops remain poorly understood. We established an extended suspect screening strategy to investigate neonicotinoid insecticides and their transformation products in retail cowpea from 11 cities in Hainan Province, China. Forty-nine transformation products were identified in retail cowpea, of which 22-36 were found in 98.6% of the samples. Notably, 31 new transformation products were derived from new processes or a combination of different transformation processes. The mean concentrations of neonicotinoids and nine of the transformation products (with authentic standards) were in the ranges of 0.0824-5.34 and 0.0636-1.50 ng/g, respectively. The cumulative EDIs of the quantified transformation products were lower than those of parent neonicotinoids with the exception of clothianidin desmethyl, which had a ratio of 1157%. However, the coexistence of the other 40 transformation products (without authentic standards) in cowpea suggested that the exposure risk from all of the transformation products might be higher. This study demonstrated that pesticide transformation products should be considered in food chain risk assessments and included in future regulatory management.


Frequency and pattern of rhythmic leg movement in humans after fatiguing exercises.
In the current study we investigated changes in voluntary rhythmic leg movement frequency (freely chosen cycling cadence) and rhythmic movement pattern (tangential pedal force profile) after fatiguing hip flexion and hip extension exercises. Nine healthy individuals performed ergometer cycling at freely chosen cadence and at a cadence of 1 Hz before and after fatiguing hip flexion and hip extension exercises. The freely chosen cadence was not affected after fatiguing exercises. An alteration of key characteristics of the tangential pedal force profile was found during cycling at a cadence of 1 Hz after hip flexion exercise. Thus, minimum tangential pedal force decreased by 12.0 ± 11.3% (p = .006), while maximum tangential pedal force increased by 4.6 ± 4.2% (p = .011), and the phase with negative tangential pedal force increased by 2.6 ± 3.2% (p = .040). In conclusion, novel information was obtained on aspects of rhythmic leg movement behavior in form of pedaling after fatiguing exercise.


Determination of elastin-antielastin circulating immune complexes in serum of normal subjects and atherosclerotic patients.
Healthy subjects of different ages and a group of atherosclerotic patients were tested for the presence of elastin-antielastin circulating immune complexes (CIC) in their sera. For the purpose the authors used a method based on sequential precipitation with rising concentrations of polyethylene glycol (PEG), dissociation of the precipitated CIC and further analysis of the resuspended precipitates for the presence of elastin derived peptides by an enzyme-linked immunosorbent assay (ELISA). Elastin-antielastin CIC were detected only in the serum of atherosclerotic patients and that of healthy subjects over 60. The elastin-antielastin CIC obtained from the serum of atherosclerotic patients were precipitated by higher PEG concentrations mainly and had a higher elastin content in comparison with those isolated from the serum of healthy persons over 60.


Is there a connection between perivascular space and subarachnoid space?
Perivascular spaces (PVSs) surrounding the walls of arteries, arterioles, and venules do not directly communicate with subarachnoid spaces. There are a few reports exhibiting subarachnoid hemorrhage (SAH) and intracerebral hematomas extending to the PVSs by leakage of the leptomeninges that surround arteries. In this report, we present 4 patients of whom 3 had SAH extending into the PVSs in the bilateral basal ganglia and 1 had extension of contrast medium to the PVSs after injection of the contrast medium into the lumbar subarachnoid space. The hemorrhage extending to the PVSs in our 3 patients with SAH could be explained by leakage of the leptomeninges surrounding the arteries. However, how the contrast medium extends to the PVSs is not clear. We think that, although speculative, incomplete or complete defect at the leptomeninges surrounding the arteries resulting in direct continuity between the subarachnoid space and the PVS allows that blood or contrast media to extend to the PVSs.


A new framework for childhood health promotion: the role of policies and programs in building capacity and foundations of early childhood health.
Although the connection between early life experiences and later health is becoming increasingly clear, what is needed, now, is a new organizing framework for childhood health promotion, grounded in the latest science. We review the evidence base to identify the steps in the overall pathway to ensuring better health for all children. A key factor in optimizing health in early childhood is building capacities of parents and communities. Although often overlooked, capacities are integral to building the foundations of lifelong health in early childhood. We outline a framework for policymakers and practitioners to guide future decision-making and investments in early childhood health promotion.


Natural killer cells in viral arthritis.
Changes in natural killer (NK) cell activity were studied in patients with polyarthritis associated with rubella or Ross River virus infections. In 30 of 32 Ross River virus patients, peripheral NK cell activity was depressed at some stage of the disease but returned to normal levels as patients recovered from arthritic symptoms. Similar changes did not occur in rubella patients and no difference was found between changes in peripheral NK activity and serum interferon (IFN) levels in rubella patients with arthritis and those without. Neither the peak of NK cell activity in peripheral blood lymphocytes (PBL) recovered early in Ross River virus and rubella infections, nor the depression of NK cell activity late in Ross River virus infections could be correlated with changes in serum IFN levels. The decrease in PBL-NK cell activity in epidemic polyarthritis (EPA) patients could not be attributed solely to loss of NK cells from the peripheral circulation because limiting-cell-dilution (LCD) analyses indicated changes in peripheral NK cell activity were due to changes in both the number and lytic activity of NK cells. Despite the association between HLA-DR7 and EPA no differences were found in levels of peripheral NK cell activity in DR7+ and DR7- EPA patients. The demonstration that peripheral NK cells could kill autologous synovial cells suggested that NK cells in joints of EPA patients may contribute to the arthritis associated with Ross River virus infection.


[Outcome assessment methods in nursing care].
This review study aimed at the theoretical and methodological assessment of nursing care outcome. The study focused on the element outcome as a means to assess the nursing care service quality as well as on the nursing care classification and on the main methods and strategies used for assessing the outcome of nursing care, provided by health services.


Complex regional pain syndrome, alexithymia, and psychological distress.
This study aims to elucidate the relationships between alexithymia, psychological distress, and pain in persons with complex regional pain syndrome (CRPS). Participants were 60 Israeli adults ages 19-65. This is a cross sectional study with a comparison group. Alexithymia, psychological distress, and pain were assessed in 30 individuals with CRPS in comparison to 30 gender- and age-matched persons with lower back pain (LBP). Assessments included the Toronto Alexithymia Scale, Hospital Anxiety and Depression Scale, and two subscales of the McGill Pain Questionnaire. Persons with CRPS had significantly higher ratings of psychological distress and of alexithymia when compared to LBP controls. Pain severity was significantly associated with higher levels of alexithymia and psychological distress among persons with CRPS, but not among controls. Alexithymia and pain severity correlations were significantly different between the two groups. In persons with CRPS, the relationships between alexithymia and pain severity and between difficulty identifying feelings and pain were not confounded by psychological distress. To our knowledge, this is the first cross sectional study providing empirical evidence on the relationship between alexithymia and CRPS. From the perspective of conceptualizing alexithymia as an outcome of CRPS, findings highlight the importance of early CRPS diagnosis and support the provision of care that addresses pain-related psychological distress and alexithymia among CRPS patients. Also, findings underscore the need to generate alternative, non-physical avenues, such as learning to identify feelings for processing pain, in order to reduce pain among persons with CRPS.


Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases.
Hypoxia has been identified as one of the hallmarks of tumor environments and a prognosis factor in many cancers. The development of ideal chemical probes for imaging and sensing of hypoxia remains elusive. Crucial characteristics would include a measurable response to subtle variations of pO2 in living systems and an ability to accumulate only in the areas of interest (e.g., targeting hypoxia tissues) whilst exhibiting kinetic stabilities in vitro and in vivo. A sensitive probe would comprise platforms for applications in imaging and therapy for non-communicable diseases (NCDs) relying on sensitive detection of pO2. Just a handful of probes for the in vivo imaging of hypoxia [mainly using positron emission tomography (PET)] have reached the clinical research stage. Many chemical compounds, whilst presenting promising in vitro results as oxygen-sensing probes, are facing considerable disadvantages regarding their general application in vivo. The mechanisms of action of many hypoxia tracers have not been entirely rationalized, especially in the case of metallo-probes. An insight into the hypoxia selectivity mechanisms can allow an optimization of current imaging probes candidates and this will be explored hereby. The mechanistic understanding of the modes of action of coordination compounds under oxygen concentration gradients in living cells allows an expansion of the scope of compounds toward in vivo applications which, in turn, would help translate these into clinical applications. We summarize hereby some of the recent research efforts made toward the discovery of new oxygen sensing molecules having a metal-ligand core. We discuss their applications in vitro and/or in vivo, with an appreciation of a plethora of molecular imaging techniques (mainly reliant on nuclear medicine techniques) currently applied in the detection and tracing of hypoxia in the preclinical and clinical setups. The design of imaging/sensing probe for early-stage diagnosis would longer term avoid invasive procedures providing platforms for therapy monitoring in a variety of NCDs and, particularly, in cancers.


'It's Not Like in the Films': Bereaved People's Experiences of the Deathbed Vigil.
This paper explores how people enact and experience the deathbed vigil when someone close to them is dying. It draws on qualitative interviews with 34 bereaved people carried out as part of a wider study exploring public perceptions of death and dying. Participants were aware of the expectation that they would attend the deathbed and did their best to do so. Findings are reported using four themes: gathering, enacting the deathbed vigil, experiencing the deathbed vigil and moment of death. Participants' experiences varied. Some families kept vigil as a group, while others established a shift system or waited alone. Activities at the bedside included reading to the dying person, talking amongst themselves, sharing memories, saying goodbye. The covid-19 pandemic highlighted families' wish to accompany their dying relatives.


Novel Real-time Digital Pressure Sensor Reveals Wide Variations in Current Nerve Crush Injury Models.
Peripheral nerve crush injury (PNCI) models are commonly used to study nerve damage and the potential beneficial effects of novel therapeutic strategies. Current models of PNCI rely on inter-device and operator precision to limit the variation with applied pressure. Although the inability to accurately quantify the PNCI pressure may result in reduced reproducibility between animals and studies, there is very limited information on the standardization and quantification of applied pressure with PNCI. To address this deficit, we constructed a novel device comprised of an Arduino UNO microcontroller board and Force Sensitive Resistor capable of reporting the real-time pressure applied to a nerve. Two forceps and two needle drivers were used to perform 30-second PNCIs to the sciatic nerves of mice (n = 5/group). Needle drivers were set to the first notch, and a jig was used to hold the forceps pinch at a reproducible pressure. The Force Sensitive Resistor was interposed in-series between the nerve and instrument during PNCI. Data collected from these procedures displayed average needle driver pressures an order of multitude greater than forceps pressures. Additionally, needle driver inter- and intra-procedure pressure remained more consistent than forceps pressure, with needle driver coefficient of variation equal to 14.5% vs. a forceps coefficient of variation equal to 45.4%. This is the first demonstration of real-time pressure measurements in PNCI models and it reveals that the applied pressures are dependent on the types of device used. The large disparity in pressure represents an inability to apply graded accurate and consistent intermediate pressure gradients in PNCI. These findings indicate a need for documentation of pressure severity as a screening for PNCI in animals, and the real-time pressure sensor could be a useful tool in monitoring and applying consistent pressure, reducing the outcome variability within the same experimental model of PNCI.


The Effect of Age, Accommodation, and Refractive Error on the Adult Human Eye.
To quantify changes in ocular dimensions associated with age, refractive error, and accommodative response, in vivo, in 30- to 50-year-old human subjects. The right eyes of 91 adults were examined using ultrasonography, phakometry, keratometry, pachymetry, interferometry, anterior segment optical coherence tomography, and high-resolution magnetic resonance imaging. Accommodation was measured subjectively with a push-up test and objectively using open-field autorefraction. Regression analyses were used to assess differences in ocular parameters with age, refractive error, and accommodation. With age, crystalline lens thickness increased (0.03 mm/yr), anterior lens curvature steepened (0.11 mm/yr), anterior chamber depth decreased (0.02 mm/yr), and lens equivalent refractive index decreased (0.001/yr) (all p < 0.01). With increasing myopia, there were significant increases in axial length (0.37 mm/D), vitreous chamber depth (0.34 mm/D), vitreous chamber height (0.09 mm/D), and ciliary muscle ring diameter (0.10 mm/D) (all p < 0.05). Increasing myopia was also associated with steepening of both the cornea (0.16 mm/D) and anterior lens surface (0.011 mm/D) (both p < 0.04). With accommodation, the ciliary muscle ring diameter decreased (0.08 mm/D) and the muscle thinned posteriorly (0.008 mm/D), allowing the lens to shorten equatorially (0.07 mm/D) and thicken axially (0.06 mm/D) (all p < 0.03). Refractive error is significantly correlated with not only the axial dimensions but also the anterior equatorial dimension of the adult eye. Further testing and development of accommodating intraocular lenses should account for differences in patients' preoperative refractive error.


[Acupuncture randomized controlled trials: comparing China-based vs. Western-based studies].
With the worldwide spread of acupuncture as a therapeutic modality and the rapid development of acupuncture clinical research, the number of acupuncture randomized controlled trial (RCT) studies is steadily increasing in China and around the world. However, the results of these studies seem to come from two different worlds indeed. Chinese RCT studies overwhelmingly demonstrate positive outcomes from acupuncture, whereas Western-based studies generally conclude that there is no discernible difference between acupuncture and a placebo. Why should there be such different outcomes when the same scientific method is being used? This paper analyzes factors that may be contributing to the different outcomes between China-based and Western-based RCT studies by considering and comparing starting points, purpose, study design, investigators, acupuncture treatment regimen, methodological quality, results, conclusions, and deficiencies in acupuncture RCT. Based on these comparisons, this paper examines the value of acupuncture RCT in general, and the methodological confusion which seems to have propagated from study to study. We propose the following suggestions to remediate the acupuncture clinical research paradigm: First, acupuncture clinical researches should be carried out step-by-step according to universal, agreed-upon research protocols. Second, norms for reporting outcome metrics need to be standardized for each stage of a study.


[II. Validity and sensitivity to change of the Musculoskeletal Functional Assessment Questionnaire in primary gonarthrosis and total endoprosthetic joint replacement].
Scoring systems used so far in total knee arthroplasty are limited by their non-fulfillment of basic test criteria. The aim of the study was to demonstrate the validity and responsiveness of a German version of the new short musculoskeletal function assessment questionnaire (SMFA-D) in patients with primary osteoarthritis and total knee arthroplasty. 66 patients with a tricompartmental cemented PFC-Sigma total knee arthroplasty completed the SMFA-D and the WOMAC questionnaire preoperatively and at 12 to 16 weeks follow-up. Preoperatively, physicians' rating of function of the leg, patients' self-selected walking speed, pain and arthritis severity score were registered for demonstration of criterion validity. Construct validity was evaluated with the WOMAC. Discriminant validity was assessed by comparing patients with or without previous surgery at the knee, use of pain medication and use of walking aids. The function and bother indexes of the SMFA-D were correlated with these parameters. Standardized response means were calculated. The function index correlated with physicians' rating (r = 0.51), walking speed (r = 0.61), pain (r = 0.36) and the arthritis severity index (r = 0.36). The bother index correlated with pain (r = 0.37) and the arthritis severity index (r = 0.25). The function and bother index correlated with the WOMAC (r = 0.77) and (r = 0.81), respectively. Patient groups with or without walking aids (p = 0.02) and with or without pain medication (p = 0.001) differed in the function index. The bother index of patients with or without pain medication (p < 0.001) and with or without walking aids (p < 0.006) differed. Function and bother index improved from 46 (SD 17) to 34 (SD 19, p < 0.001) and 43 (SD 18) to 33 (SD 22 p < 0.001), respectively. The standardized response mean was 0.86 for the function index and 0.53 for the bother index. The SMFA-D questionnaire is valid and responsive in patients with primary osteoarthritis of the knee and total knee arthroplasty. It measures function and bother from the perspective of these patients.


Six additional systematic lateral cores enhance sextant biopsy prediction of pathological features at radical prostatectomy.
We evaluated the contribution of 6 additional systematically obtained, laterally directed biopsy cores to traditional sextant biopsy for the prediction of final pathological findings in the radical prostatectomy specimen. We studied 178 consecutive patients with no history of prostate biopsy in whom prostate cancer was diagnosed during an initial systematic 12 core biopsy and who subsequently underwent radical prostatectomy. Of the systematic 12 cores we compared the subset of the 6 traditional sextant cores (S6C), the set of 6 laterally directed cores (L6C) and the complete 12 core set, which included the 6 traditional sextant and the 6 laterally directed cores. Biopsy Gleason score, number of positive cores, total cancer length and percent of tumor in the biopsy sets were examined for their ability to predict extracapsular extension, total tumor volume and pathological Gleason score. On univariable analyses the biopsy parameters of the complete 12 core set correlated more strongly with extracapsular extension and total tumor volume than the biopsy parameters of S6C or L6C. On multivariable analyses S6C and L6C were independent predictors of pathological features at prostatectomy. The addition of 6 systematically obtained, laterally directed cores to traditional sextant biopsy improved the ability to predict pathological features at prostatectomy by a statistically and prognostically significant margin. Preoperative nomograms that use data from a full complement of 12 systematic cores, specifying sextant and laterally directed biopsy cores, should demonstrate improved performance in predicting prostatectomy pathology.


Central contribution to hypoventilation during severe inspiratory resistive loads.
Recent observations suggest that central hypoventilation with slowing of respiratory frequency contributes to hypoventilation during severe inspiratory resistive loads. We carried out a study to further characterize this bradypneic response. Prospective, controlled laboratory study. Basic science laboratory of a university hospital. Anesthetized adult cats (loading experiment n = 7, nonloaded hypercapnic controls n = 11). Experimental inspiratory loads increased transdiaphragmatic pressure to 75% of the maximum for each animal. Respiratory responses were observed at midrun or moderate conditions of respiratory insufficiency (defined as PaCO2 > or = 60 torr [> or = 8.0 kPa]) and failure (PaCO2 > or = 80 torr [> or = 10.6 kPa]). Nonloaded hypercapnic controls were studied with similar durations of exposure to CO2 in the same CO2 range. Inspiratory airflow, tidal volume, respiratory frequency, airway pressure, transdiaphragmatic pressure, transdiaphragmatic pressure response to phrenic nerve electrical stimulation, blood gas analysis. Severe inspiratory loads were applied to anesthetized adult cats to determine whether bradypnea could be observed in an anesthesized model that eliminated conscious responses. Experiments were performed in hyperoxic conditions to determine whether bradypnea develops in the absence of hypoxia. An additional control group was studied under hypercapnic conditions without loading to determine whether comparable hypercapnia is a sufficient stimulus to elicit bradypnea. From midrun until failure, minute ventilation decreased by 16% in loaded animals. Hypoventilation was associated with a decrease in respiratory frequency from 40.1 to 29.9 breaths/min, whereas tidal volume, spontaneous transdiaphragmatic pressure, and transdiaphragmatic pressure response to phrenic nerve electrical stimulation remained unchanged. Control animals had no significant reduction in ventilation or respiratory frequency over similar levels and durations of hypercapnia. Centrally mediated bradypnea contributed to hypoventilation in respiratory failure associated with inspiratory loading. Bradypnea preceded evidence of muscle fatigue. This change in respiratory cycle timing occurred under anesthesia, and thus, did not depend on conscious perception of dyspnea. Bradypnea does not depend on either hypercapnia or hypoxia.


Dual acting anti-inflammatory drugs.
Drugs able to inhibit both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory drugs) have been designed in order to obtain compounds that retain the activity of classical nonsteroidal anti-inflammatory drugs (NSAIDs) while avoiding their main drawbacks. The classical NSAIDs display their anti-inflammatory action mainly through inhibition of COX and one of their main drawbacks is the curtailed production of gastroprotective prostaglandins (PGs) being associated with the concurrent increased production of the gastro-damaging and bronchoconstrictive leukotrienes (LTs). Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory and increase microvascular permeability. One of the leukotrienes (LTB(4)) is the most potent chemotactic agent and it induces chemotaxis of eosinophils, neutrophils and monocytes in the inflamed tissue, increases superoxide generation and proinflammatory cytokines production. It is further advantageous for a drug to have both COX and 5-LOX inhibiting activities because prostaglandins enhance leukotriene-mediated inflammation. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing clinical development. In the post-COX-2 selective inhibitors era, these dual acting inhibitors may turn out to be promising new drugs to treat inflammatory diseases and possibly other diseases. Indeed, both COX-2 and 5-LOX are also involved in the development and progression of several types of cancer; in these conditions, selective inhibition of COX-2 alone may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway, and therefore the blockade of both COX-2 and 5-LOX may produce a better anticancer response. In addition, the dual inhibition of both COX and 5-LOX is neuroprotective by suppressing toxic actions of reactive microglia and macrophages, that are increased in aging brain and in age-related degenerative conditions, particularly Alzheimer's and Parkinson's diseases. Finally, the blockade of 5-LOX does not impair the synthesis of lipoxins (LXs), which are mainly produced by further lipoxygenation of 15-HPETE, and which have potent anti-inflammatory properties and can be considered as stop-signal mediators. Leukocyte 15-LOX and platelet 12-LOX by intercellular mechanism via leukocyte/platelet cell-cell interaction convert 15-HPETE into lipoxins.


Predicting the scope of practice of family physicians.
To identify factors that are associated with the scope of practice of FPs and GPs who have office-based practices. Secondary univariable and multivariable analyses of cross-sectional data from the 2001 National Family Physician Workforce Survey conducted by the College of Family Physicians of Canada. Canada. General community of FPs and GPs who spent most of their clinical time in office settings. Demographic characteristics and scope of practice score (SPS), which was the number of 12 selected medical services provided by office-based FPs and GPs. The multivariable model explained 35.1% of the variation in the SPS among participants. Geographic factors of provincial division and whether or not the population served was rural explained 30.5% of the variation in the SPS. Male physician sex, younger physician age, being in group practice, greater access to hospital beds, less access to specialists, main practice setting of an academic teaching unit, mixed method physician payment, additional structured postresidency training, and greater number of different types of allied health professionals in the main practice setting were also associated with higher SPSs. Geographic factors were the strongest determinants of scope of practice; physician-related factors, availability of health care resources to the main practice setting, and practice organization factors were weaker determinants. It is important to understand how and why geographic factors influence scope of practice, and whether a broad scope of practice independent of population needs benefits the population. This study supports primary care renewal efforts that use mixed payment systems, incorporate allied health care professionals into family and general practices, and foster group practices.


Phospholipase D activity is required for dimorphic transition in Candida albicans.
Candida albicans is an opportunistic pathogen that causes significant morbidity and mortality in immunocompromised patients. In this report, the presence of a phospholipase D (PLD) activity in C. albicans, designated CaPLD1, is demonstrated. This is the first description of PLD activity in this organism. CaPLD1 activity was stimulated by inducers of dimorphic transition. Furthermore, transition was stimulated by the addition of exogenous PLD to cells. The addition of 1-propanol to the medium, which resulted in the production of phosphatidylpropanol by CaPLD1 at the expense of the usual product phosphatidic acid, delayed the yeast to hypha transition. These results suggest that CaPLD1 may be an important regulator of dimorphic transition in C. albicans.


Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin.
Lesions in the gene for frataxin, a nuclear-encoded mitochondrial protein, cause the recessively inherited condition Friedreich's ataxia. It is thought that the condition arises from disregulation of mitochondrial iron homeostasis, with concomitant oxidative damage leading to neuronal death. Very little is, as yet, known about the biochemical function of frataxin. Here, we show that the mature form of recombinant frataxin behaves in solution as a monodisperse species that is composed of a 15-residue-long unstructured N terminus and an evolutionarily conserved C-terminal region that is able to fold independently. The structure of the C-terminal domain consists of a stable seven-stranded antiparallel beta sheet packing against a pair of parallel helices. The structure is compact with neither grooves nor cavities, features that are typical of iron-binding modules. Exposed evolutionarily conserved residues cover a broad area and all cluster on the beta-sheet face of the structure, suggesting that this is a functionally important surface. The effect of two clinically occurring mutations on the fold was checked experimentally. When the mature protein was titrated with iron, no tendency to iron-binding or to aggregation was observed. Knowledge of the frataxin structure provides important guidelines as to the nature of the frataxin binding partner. The absence of all the features expected for an iron-binding activity, the large conserved area on its surface and lack of evidence for iron-binding activity strongly support an indirect involvement of frataxin in iron metabolism. The effects of point mutations associated with Friedreich's ataxia can be rationalised by knowledge of the structure and suggest possible models for the occurrence of the disease in compound heterozygous patients.


Quantitative analysis of surfactant deposits on human skin by liquid chromatography/electrospray ionisation tandem mass spectrometry.
Surfactants are commonly used as cleansing agents and yet there are concerns that they may also have a role in skin irritation. The lack of suitable methods for the quantitative and qualitative analysis of surfactant deposition on skin has hindered the in-depth investigation of such effects. Here, we report the application of reversed-phase liquid chromatography/electrospray ionisation tandem mass spectrometry (LC/ESI-MS/MS) assays for two surfactants commonly used in consumer products, namely sodium lauryl ether sulfate (SLES) and laurylamidopropyl betaine (LAPB), to a baseline study aiming to assess deposition levels on human skin. The linearity of the assays was established at 3-20 ng, with coefficient of variation below 5%. The detection limits were 100 pg for LAPB and 1 ng for SLES; quantitation limits were 500 pg for LAPB and 2.5 ng for SLES. The baseline study was conducted using a panel of 40 healthy volunteers. Skin extract samples were taken in triplicate from forearms, using ethanol. SLES was detected on most volunteers, with 75% of them having SLES deposits in the range of 100-600 ng/cm(2). LAPB was detected on the skin of all volunteers with 85% of them having deposit levels within the concentration range of 1-100 ng/cm(2). These results demonstrate the extent to which commonly used surfactants remain on the skin during the day. The analytical methods reported here can be applied to the investigation of surfactants in relation to general skin condition and to the development and optimisation of new consumer wash products.


Trendelenburg versus PASG application in moderate hemorrhagic hypoperfusion.
In hemorrhagic hypoperfusion one of the therapeutic goals of pneumatic antishock garment (PASG) application is to increase cardiac output, presumably by augmenting venous return from below the diaphragm, an effect expected to be similar to Trendelenburg positioning. The purpose of this study was to compare the hemodynamic response of these two common therapeutic interventions in hemorrhagic hypoperfusion. Five anesthetized dogs were bled over 10 minutes 24% of measured blood volume on two separate days. At the beginning of hemorrhage, they randomly received either PASG application or Trendelenburg positioning. PASG pressures of 30 +/- 5 mm Hg were applied to produce an inferior vena cava pressure of 10-15 mm Hg. Such PASG pressure had been shown previously to not diminish cardiac output from PASG application. Mean arterial pressure was maintained throughout the experiment with both therapies. With PASG application, cardiac index was depressed and systemic vascular resistance was elevated at 10, 20, and 30 minutes following hemorrhage. In contrast, Trendelenburg therapy maintained cardiac index and produced no significant increase in systemic vascular resistance index. Thus Trendelenburg therapy preserved mean arterial pressure primarily by maintaining cardiac output, probably by increasing venous return, whereas PASG application preserved mean arterial pressure primarily by increasing systemic vascular resistance. For treatment of moderate hemorrhagic hypoperfusion, Trendelenburg positioning may be superior therapy to PASG application.


Do people attending a same day testing clinic discuss their need for a HIV test with their GP?
In the United Kingdom, people with HIV infection present with advanced disease and general practitioners (GPs) are currently an underused resource for HIV testing. We describe the reasons for using an open-access clinic rather than primary care for testing for HIV. People attending the clinic were asked to complete a questionnaire asking about GP registration, access, and whether HIV testing was discussed in primary care. Despite access to GPs, HIV testing in primary care was rarely discussed. If HIV testing is to move to a general practice setting, GPs could address the issues, such as the recording of sensitive information in notes, future life insurance, and confidentiality, which this report identifies as the main barriers for using primary care.


Investigations of the impact of altered auditory feedback in-the-ear devices on the speech of people who stutter: initial fitting and 4-month follow-up.
Self-contained ear-level devices delivering altered auditory feedback (AAF) for the application with those who stutter have only been recently developed. The paper examines the first therapeutic application of self-contained ear-level devices in three experiments. The effect of the device on the proportion of stuttered syllables and speech naturalness was investigated following initial fitting and at 4 months post-fitting. Three experiments were undertaken: In Experiment 1, the effect of a self-contained in-the-ear device delivering AAF was investigated with those who stutter during reading and monologue. Two adolescents and five adults who stuttered read and produced monologue with and without a device fit monaurally. The device provided a frequency shift of +500 Hz in combination with a delayed auditory feedback of 60 ms. Custom-made ITC and CIC devices were fabricated for four adults and four youths in Experiment 2. The effect of group (i.e. youth versus adult), time (i.e. initial fitting versus 4-month follow-up), speech task (i.e. reading versus monologue), and device (i.e. present versus absent) on stuttering rate was examined. In Experiment 3, 15 naïve listeners rated the speech naturalness of speech produced by the participants in Experiment 2. Speech samples from six conditions were rated: reading and monologue without the device at the initial visit, reading and monologue with the device at the initial visit, and reading and monologue with the device at 4 months. In Experiment 1, the proportion of stuttered syllables was significantly (p=0.011) reduced by approximately 90% during reading and 67% during monologue with the device relative to no device. Only a significant main effect of device (p=0.0028) was found in Experiment 2. That is, stuttering rate was significantly reduced with the device in place regardless of speech task or group and remained so 4 months later. In Experiment 3, speech samples generated while wearing the device were judged to be more natural sounding than those without the device (p<0.0001) for reading and monologue with both adults and youths. There was no significant difference between the mean naturalness ratings of speech samples generated during the initial fitting with the device relative to that at 4 months with the device (p>0.05) in all cases except with the youths while engaged in monologue. For that condition, raters judged the speech produced at the initial fitting as more natural. These findings support the notion that a self-contained in-the-ear device delivering AAF assists those who stutter. With the device in place, stuttering is reduced and speech produced is judged to be more natural than with out the device.


Three-dimensional finite element analyses of all-ceramic posterior fixed partial dentures with different designs.
The aim was to evaluate the influence on the stress distribution patterns in and the magnitude of stresses on fixed partial dentures (FPDs) under different anatomic and design conditions. Three-dimensional finite element models of posterior 3-unit all-ceramic FPDs were created with and without periodontal ligaments, with different radii of curvature at the embrasure area, and in a curve shape with a periodontal ligament. The model with a periodontal ligament showed 40% higher stress values compared to the no-ligament model. A smaller radius of curvature resulted in 20% to 40% higher stress values. The curved model increased stress values at the distal connector by 65% compared to the straight model. Support by teeth, occlusal curvature, and a small radius of curvature at the embrasure area negatively affect stress distribution patterns in the connector area of all-ceramic FPDs.


KCNE4 is an inhibitory subunit to the KCNQ1 channel.
KCNE4 is a membrane protein belonging to a family of single transmembrane domain proteins known to have dramatic effect on the gating of certain potassium channels. However, no functional role of KCNE4 has been suggested so far. In the present paper we demonstrate that KCNE4 is an inhibitory subunit to KCNQ1 channels. Co-expression of KCNQ1 and KCNE4 in Xenopus oocytes completely inhibited the KCNQ1 current. This was reproduced in mammalian CHO-K1 cells. Experiments with delayed expression of mRNA coding for KCNE4 in KCNQ1-expressing oocytes suggested that KCNE4 exerts its effect on KCNQ1 channels already expressed in the plasma membrane. This notion was supported by immunocytochemical studies and Western blotting, showing no significant difference in plasma membrane expression of KCNQ1 channels in the presence or absence of KCNE4. The impact of KCNE4 on KCNQ1 was specific since no effect of KCNE4 could be detected if co-expressed with KCNQ2-5 channels or hERG1 channels. RT-PCR studies revealed high KCNE4 expression in embryos and adult uterus, where significant expression of KCNQ1 channels has also been demonstrated.


iGEMS: an integrated model for identification of alternative exon usage events.
DNA microarrays and RNAseq are complementary methods for studying RNA molecules. Current computational methods to determine alternative exon usage (AEU) using such data require impractical visual inspection and still yield high false-positive rates. Integrated Gene and Exon Model of Splicing (iGEMS) adapts a gene-level residuals model with a gene size adjusted false discovery rate and exon-level analysis to circumvent these limitations. iGEMS was applied to two new DNA microarray datasets, including the high coverage Human Transcriptome Arrays 2.0 and performance was validated using RT-qPCR. First, AEU was studied in adipocytes treated with (n = 9) or without (n = 8) the anti-diabetes drug, rosiglitazone. iGEMS identified 555 genes with AEU, and robust verification by RT-qPCR (∼90%). Second, in a three-way human tissue comparison (muscle, adipose and blood, n = 41) iGEMS identified 4421 genes with at least one AEU event, with excellent RT-qPCR verification (95%, n = 22). Importantly, iGEMS identified a variety of AEU events, including 3'UTR extension, as well as exon inclusion/exclusion impacting on protein kinase and extracellular matrix domains. In conclusion, iGEMS is a robust method for identification of AEU while the variety of exon usage between human tissues is 5-10 times more prevalent than reported by the Genotype-Tissue Expression consortium using RNA sequencing.


Highly sensitive detection of cancer cells using femtosecond dual-wavelength near-IR two-photon imaging.
We describe novel imaging protocols that allow detection of small cancer cell colonies deep inside tissue phantoms with high sensitivity and specificity. We compare fluorescence excited in Styryl-9M molecules by femtosecond pulses at near IR wavelengths, where Styryl-9M shows the largest dependence of the two-photon absorption (2PA) cross section on the local environment. We show that by calculating the normalized ratio of the two-photon excited fluorescence (2PEF) intensity at 1200 nm and 1100 nm excitation wavelengths we can achieve high sensitivity and specificity for determining the location of cancer cells surrounded by normal cells. The 2PEF results showed a positive correlation with the levels of MDR1 proteins expressed by the cells, and, for high MDR1 expressors, as few as ten cancer cells could be detected. Similar high sensitivity is also demonstrated for tumor colonies induced in mouse external ears. This technique could be useful in early cancer detection, and, perhaps, also in monitoring dormant cancer deposits.


Protein biochips patterned by microcontact printing or by adsorption-soft lithography in two modes.
Patterning of proteins is critical to protein biochips. Printing of layers of proteins is well established, as is adsorption of proteins to surfaces properly modified with surface chemical functionalities. The authors show that simple methods based on soft lithography stamps can be used to prepare functional antibody chips through both these routes. Both methods incorporate transfer of the stamp material poly(dimethylsiloxane) (PDMS) to the biochip, whether intended or not intended. The results indicate that microcontact printing of proteins always includes PDMS transfer, thereby creating a possibility of unspecific adsorption to a hydrophobic domain.


DPYSL4 is a Prognostic Indicator Linked to Immune Infiltration in Gastric Cancer.
Dihydropyrimidinase like 4 (DPYSL4), expressed little in normal tissues, was reported as one of the gene family members to predict prognosis in melanoma; however, there are no reports about the link between DPYSL4 expression in gastric cancer and the tumor immune microenvironment. In our research, we first evaluated the differential expression level of DPYSL4 between gastric cancer tissues and paracancerous tissues, as well as the prognostic value of DPYSL4 expression in gastric cancer through the databases, such as Timer, UALCAN, Kaplan-Meier plotter database, accompanied with the validation of clinical specimens by immunohistochemistry. Then, we also looked for the functional pathway of DPYSL4 by analyzing the GO and KEGG enrichment analysis based on DPYSL4 co-expression genes. Last but not least, the Timer database was also applied to analyze the correlation between DPYSL4 expression and immune cells, as well as signature molecules, in order to provide a theoretical basis for assessing the relationship between DPYSL4 expression and immune infiltration in gastric cancer. The results of databases and immunohistochemistry showed that the expression level of DPYSL4 in gastric cancer was higher than that in adjacent tissues, and DPYSL4 overexpression was associated with poor prognosis of gastric cancer patients. The analysis of Go and KEGG revealed that DPYSL4 expression was enriched in pathways involved in "immune responses". Furthermore, by the application of an immunoinfiltration database, DPYSL4 overexpression was strongly related to immune cell infiltration and their corresponding star molecules in gastric cancer. Our study implied that DPYSL4 may be regarded as a prognostic indicator in gastric cancer and is associated with immune infiltration.


Conserved interactions required for inhibition of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
The COVID-19 pandemic caused by the SARS-CoV-2 requires a fast development of antiviral drugs. SARS-CoV-2 viral main protease (Mpro, also called 3C-like protease, 3CLpro) is a potential target for drug design. Crystal and co-crystal structures of the SARS-CoV-2 Mpro have been solved, enabling the rational design of inhibitory compounds. In this study we analyzed the available SARS-CoV-2 and the highly similar SARS-CoV-1 crystal structures. We identified within the active site of the Mpro, in addition to the inhibitory ligands' interaction with the catalytic C145, two key H-bond interactions with the conserved H163 and E166 residues. Both H-bond interactions are present in almost all co-crystals and are likely to occur also during the viral polypeptide cleavage process as suggested from docking of the Mpro cleavage recognition sequence. We screened in silico a library of 6900 FDA-approved drugs (ChEMBL) and filtered using these key interactions and selected 29 non-covalent compounds predicted to bind to the protease. Additional screen, using DOCKovalent was carried out on DrugBank library (11,414 experimental and approved drugs) and resulted in 6 covalent compounds. The selected compounds from both screens were tested in vitro by a protease activity inhibition assay. Two compounds showed activity at the 50 µM concentration range. Our analysis and findings can facilitate and focus the development of highly potent inhibitors against SARS-CoV-2 infection.


PoSSuM v.3: A Major Expansion of the PoSSuM Database for Finding Similar Binding Sites of Proteins.
Information on structures of protein-ligand complexes, including comparisons of known and putative protein-ligand-binding pockets, is valuable for protein annotation and drug discovery and development. To facilitate biomedical and pharmaceutical research, we developed PoSSuM (https://possum.cbrc.pj.aist.go.jp/PoSSuM/), a database for identifying similar binding pockets in proteins. The current PoSSuM database includes 191 million similar pairs among almost 10 million identified pockets. PoSSuM drug search (PoSSuMds) is a resource for investigating ligand and receptor diversity among a set of pockets that can bind to an approved drug compound. The enhanced PoSSuMds covers pockets associated with both approved drugs and drug candidates in clinical trials from the latest release of ChEMBL. Additionally, we developed two new databases: PoSSuMAg for investigating antibody-antigen interactions and PoSSuMAF to simplify exploring putative pockets in AlphaFold human protein models.


Partial purification and characterization of the ribonucleotide reductase induced by herpes simplex virus infection of mammalian cells.
In this report we confirm and further characterize the induction of a novel ribonucleotide reductase after herpes simplex virus infection of mammalian cells. Induction of the enzyme was observed at a multiplicity of infection of 1 PFU/cell or greater and was found to be maximal (three- to sixfold the activity in mock-infected controls at 6 to 8 h postinfection at a multiplicity of infection of 10 PFU/cell. Partial purification and subsequent characterization of the reductase activity from infected cells demonstrated the existence of two enzymes which could be separated by precipitation with ammonium sulfate. One of the activities precipitated at between 35 and 55% salt saturation, as did the enzyme from control cells, whereas the novel activity precipitated at 0 to 35% saturation. This latter enzyme was similar to the herpes simplex virus-induced reductase described by others in its lack of requirement for Mg2 and its resistance to inhibition by dTTP and dATP; in addition, we found that it was inhibited by ATP, whereas the enzyme from control cells displayed an absolute requirement for the nucleotide. Both enzymes were equally inhibited by pyridoxal phosphate and showed similar cold and heat stability. The enzyme induced by herpes simplex virus infection, however, was much more labile than the control enzyme upon purification.


In vitro selection of a sodium-specific DNAzyme and its application in intracellular sensing.
Over the past two decades, enormous progress has been made in designing fluorescent sensors or probes for divalent metal ions. In contrast, the development of fluorescent sensors for monovalent metal ions, such as sodium (Na(+)), has remained underdeveloped, even though Na(+) is one the most abundant metal ions in biological systems and plays a critical role in many biological processes. Here, we report the in vitro selection of the first (to our knowledge) Na(+)-specific, RNA-cleaving deoxyribozyme (DNAzyme) with a fast catalytic rate [observed rate constant (ko(bs)) ∼ 0.1 min(-1)], and the transformation of this DNAzyme into a fluorescent sensor for Na(+) by labeling the enzyme strand with a quencher at the 3' end, and the DNA substrate strand with a fluorophore and a quencher at the 5' and 3' ends, respectively. The presence of Na(+) catalyzed cleavage of the substrate strand at an internal ribonucleotide adenosine (rA) site, resulting in release of the fluorophore from its quenchers and thus a significant increase in fluorescence signal. The sensor displays a remarkable selectivity (>10,000-fold) for Na(+) over competing metal ions and has a detection limit of 135 µM (3.1 ppm). Furthermore, we demonstrate that this DNAzyme-based sensor can readily enter cells with the aid of α-helical cationic polypeptides. Finally, by protecting the cleavage site of the Na(+)-specific DNAzyme with a photolabile o-nitrobenzyl group, we achieved controlled activation of the sensor after DNAzyme delivery into cells. Together, these results demonstrate that such a DNAzyme-based sensor provides a promising platform for detection and quantification of Na(+) in living cells.


Using Market Research to Characterize College Students and Identify Potential Targets for Influencing Health Behaviors.
Marketing campaigns, such as those developed by the tobacco industry, are based on market research, which defines segments of a population by assessing psychographic characteristics (i.e., attitudes, interests). This study uses a similar approach to define market segments of college smokers, to examine differences in their health behaviors (smoking, drinking, binge drinking, exercise, diet), and to determine the validity of these segments. A total of 2,265 undergraduate students aged 18-25 years completed a 108-item online survey in fall 2008 assessing demographic, psychographic (i.e., attitudes, interests), and health-related variables. Among the 753 students reporting past 30-day smoking, cluster analysis was conducted using 21 psychographic questions and identified three market segments - Stoic Individualists, Responsible Traditionalists, and Thrill-Seeking Socializers. We found that segment membership was related to frequency of alcohol use, binge drinking, and limiting dietary fat. We then developed three messages targeting each segment and conducted message testing to validate the segments on a subset of 73 smokers representing each segment in spring 2009. As hypothesized, each segment indicated greater relevance and salience for their respective message. These findings indicate that identifying qualitatively different subgroups of young adults through market research may inform the development of engaging interventions and health campaigns targeting college students.


[Early fundus changes caused by repeated small crises in the Posner-Schlossman syndrome: a model for glaucoma simplex].
In Posner-Schlossman syndrome a repeated crisis of intraocular pressure (IOP) elevation to 25-45 mmHg continues for 3-10 days. During the relapses glaucomatous damage often occurs. The IOP and its variation during the crisis are similar to those in glaucoma simplex. Therefore, the syndrome can be considered as a natural model for investigations into glaucoma simplex. By analyzing five cases of Posner-Schlossman syndrome in which the glaucomatous lesions ranged from the earliest to advanced stages, the development and progression of glaucomatous damage of the optic nerve at varying chronically elevated IOP levels became evident. The earliest evident fundus change is a nerve fiber layer defect (NFLD) in the Bjerrum tangent, and not the enlargement of the physiologic excavation. The latter does not develop before stage IV. The slit-like NFLD shows a decrease in sensitivity of 0.2-0.4 log ND unit, which is thus easily overlooked. As the disease progresses the NFLD becomes more pronounced, its width increases and it becomes wedge-shaped. Due to a considerable loss of nerve fibers at the wedge-shaped defect, a small notch which develops in the direction of NFLD is not observed until stage IV. Goldmann perimetry demonstrated a certain abnormality at stages IV-V; in addition to the wedge-shaped NFLD, diffuse thinning of the NFLD begins around the optic disk and develops into a large, concentric excavation. For identification of the most delicate NFLDs, stereo fundus photography in color with 8-fold magnification, on 6 x 6 film is recommended.


Formation of ethylenethiourea from 5,6-dihydro-3H-imidazo[2,1-c]-1,2,4-dithiazole-3-thione by microorganisms and reducing agents.
Microorganisms formed readily ethylenethiourea (ETU) from 5,6-dihydro-3H-imidazo[2,1-c]-1,2,4-dithiazole-3-thione (DIDT), a spontaneous decomposition product of ethylenebisdithiocarbamates. This conversion also takes place after addition of reducing compounds like cysteine, glutathione or ascorbic acid. It consists of two steps: reduction of the S-S bond of DIDT with subsequent release of CS2 to form ETU. DIDT was reduced by NADH in the presence of enzyme extracts from Pseudomonas fluorescens or Asperigillus niger, or by commercial glutathione reductase or lipoamide dehydrogenase. ETU was formed as a result of this enzymatic reduction. The flavin compounds FMN and FAD were also able to promote the reduction of DIDT by NADH.


[The epidemiological aspects of a pseudotuberculosis polyclonal infection].
The plasmid profile of 489 Y. pseudotuberculosis strains, serovar 1b, isolated from patients during 23 outbreaks and in sporadic cases of the disease were studied. As revealed in this study, in foci with the heterogeneous population of Y. pseudotuberculosis, serovar 1b, outbreaks and sporadic cases of the disease were caused by the polyclonal population of the microorganism. The study showed that three types of outbreaks could be differentiated, depending on the clonal characteristics of the microorganism causing these outbreaks and the presence of the dominating clone of the causative agent. Y. pseudotuberculosis infection caused by the combination of several clones of the microorganism was designated as polyclonal infection.


Effect of supplementing different concentrations of organic trace minerals on performance, antioxidant activity, and bone mineralization in Vanaraja chickens developed for free range farming.
An experiment was conducted to determine the performance, antioxidation activity, and bone mineral content in Vanaraja chickens fed diet supplemented with organic trace minerals (oTM) at reduced levels. A total of 360 day-old chicks were selected and distributed randomly into 60 battery brooder pens. A maize-soybean meal-based control diet was supplemented with inorganic trace minerals (iTM), i.e., Mn, Zn, Fe, and Cu at 50, 45, 40, and 7.5 mg/kg, respectively, and varying concentration of oTM, i.e., Zn, Mn, Cu, Fe, I, Se, and Cr at 45, 50, 7.5, 40, 2, 0.30, and 0.25 mg/kg (diet II); 33.75, 37.50, 5.63, 30.0, 1.50, 0.23, and 0.19 mg/kg (diet III); 22.5, 25.0, 3.75, 20.0, 1.0, 0.15, and 0.13 mg/kg (diet IV); 18.0, 20.0, 3.0, 16.0, 0.80, 0.12, and 0.10 mg/kg (diet V); and 13.5, 15.0, 2.25, 12.0, 0.60, 0.09, and 0.08 mg/kg (diet VI), respectively. Each diet was allotted randomly to ten replicates and fed ad libitum from 1 to 42 days of age. The body weight at 14, 28, and 42 days was not affected by reducing the supplementation of oTM concentration in the diets. Similarly, feed intake at 14 days of age was not affected but reduced significantly (P < 0.05) in the group fed diet IV (50% oTM) compared to that in the other groups. The higher feed conversion ratio and increased concentration of Ca, P, and trace minerals in tibia were evident in the group fed oTM-supplemented diets compared to the diet containing iTM. Activities of glutathione peroxidase and ferric reducing ability in plasma did not differ in the groups fed on lower concentration of oTM compared to those fed on diet I (control diet). Therefore, it is concluded that the dietary supplementation of trace minerals can be reduced greatly when supplemented as organic form without affecting growth and antioxidant status in Vanaraja chickens.


The use of ultrasonic tools in revision arthroplasty procedures.
Cemented and uncemented prostheses removed from bone using ultrasonic tools were evaluated grossly, microscopically, and microradiographically. The findings in this study indicate that application of an ultrasonic tool to the intramedullary canal is a safe method for removal of a variety of components. In addition, when the energy is coupled directly to the metallic component, it can be separated from the cement-bone or prosthesis-bone interface instantly.


Reflecting on our practice: an evaluation of Balint groups for medical students in psychiatry.
This paper qualitatively evaluates a one-year trial of Balint clinical reflection groups for medical students in psychiatry at a large Australian tertiary referral hospital. The trial considered whether clinical reflection groups following the Balint process would be perceived as useful and relevant to the learning needs of the student participants. A grounded theory approach was undertaken. This included survey data, thematic analysis of written feedback, and facilitator reflection on the process. Facilitators adapted the group process in response to participants' needs. These modifications included: increased education regarding the Balint process; the introduction of co-presenters; and the inclusion of a didactic summary following each session. The evaluation suggested that fidelity of the Balint group experience was achieved and that student attitudes were neutral to mildly positive regarding the educational experience. Balint groups are potentially useful to medical students in the Australian context. We suggest that Balint groups may be more useful when applied in less alienating learning environments, such as during general practice rotations. Emphasis is placed on the need to maintain a dynamic approach by adapting the group and the educational processes as the work unfolds.


Insights Into the Impacts of BRCA Mutations on Clinicopathology and Management of Early-Onset Triple-Negative Breast Cancer.
Little is known regarding the clinicopathologic characteristics, oncologic outcomes, and treatment strategies that could be ascribed to BRCA mutation in early-onset triple-negative breast cancer (eTNBC). eTNBC patients who underwent BRCA genetic testing were derived from our clinical database between 2012 and 2018. Differences in clinical features and pathologic characteristics were examined in groups divided by BRCA mutation status, and the contribution of germline mutations in conjunction with treatment modalities to survival outcomes was determined. Of the 355 qualifying eTNBC patients, 67 (18.87%) were BRCA mutated and 288 (81.13%) were BRCA wild. Overall, median age at diagnosis was 34 years (range, 24-40 years) in the BRCA mutated subgroup and 35 years (range, 21-40 years) in BRCA wild. The majority of clinicopathologic parameters were parallel; however, tumor size (P = 0.07) and nuclear grade (P =0.08) tend to be more aggressive in the BRCA mutated subgroup. Compared with BRCA wild patients, BRCA mutated patients had a higher likelihood of receiving anthracyclines and taxane-based combination chemotherapy (P = 0.04) and tend to be lower tumor burden (P =0.01). After approximately 5-year median follow-up, the overall survival (OS) (P = 0.021) and breast cancer-specific survival (BCSS) (P = 0.004) in BRCA mutated patients were superior to those in their BRCA wild counterparts. Intriguingly, the clinical outcomes were comparable in patients with breast conserving surgery (BCS) regardless of BRCA mutations and in patients with BRCA mutations in spite of surgical schedules. These results suggest that eTNBC patients with BRCA mutations are prone to better OS and BCSS, which might be largely attributed to more benefit from anthracyclines and taxane-based chemotherapy. The BCS procedure could be a safe alternative surgical option for eTNBC patients with BRCA mutations. Future studies with substantial numbers of participants are urgently needed to validate whether BRCA mutation eTNBC patients are more sensitive to chemotherapy.


Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3.
Forty-six patients suffering from autosomal dominant cerebellar ataxia type I (ADCA I) underwent to a genotype-phenotype correlation analysis by molecular genetic assignment to the spinocerebellar ataxia type 1, 2, or 3 (SCA1, SCA2, SCA3) genetic locus and electro-oculography. Oculomotor deficits that are attributed to dysfunction of cerebellar structures occurred in all three mutations without major differences between the groups. Gaze-evoked nystagmus, however, was not found to be associated with SCA2. Square wave jerks were exclusively observed in SCA3. The gain in vestibulo-ocular reflex was significantly impaired in SCA3 and SCA1. In SCA3 the severity of vestibular impairment increased with CAG repeat length. Severe saccade slowing was a highly characteristic feature of SCA2. In SCA3 saccade velocity was normal to mildly reduced while SCA1 fell into an intermediate range. The present data show that each mutation is associated with a distinct syndrome of oculomotor deficits. Reduced saccade velocity and the absence of both square-wave jerks and gaze-evoked nystagmus allow one SCA2 to be distinguished from SCA3 patients in almost all cases. The eye movement disorder of SCA1 patients, however, overlaps with both SCA2 and SCA3.


The estimation of N2O emissions from municipal solid waste incineration facilities: The Korea case.
The greenhouse gases (GHGs) generated in municipal solid waste (MSW) incineration are carbon dioxide (CO(2)), methane (CH(4)), and nitrous oxide (N(2)O). In South Korea case, the total of GHGs from the waste incineration facilities has been increasing at an annual rate 10%. In these view, waste incineration facilities should consider to reduce GHG emissions. This study is designed to estimate the N(2)O emission factors from MSW incineration plants, and calculate the N(2)O emissions based on these factors. The three MSW incinerators examined in this study were either stoker or both stoker and rotary kiln facilities. The N(2)O concentrations from the MSW incinerators were measured using gas chromatography-electron capture detection (GC-ECD) equipment. The average of the N(2)O emission factors for the M01 plant, M02 plant, and M03 plant are 71, 75, and 153g-N(2)O/ton-waste, respectively. These results showed a significant difference from the default values of the intergovernmental panel on climate change (IPCC), while approaching those values derived in Japan and Germany. Furthermore, comparing the results of this study to the Korea Energy Economics Institute (KEEI) (2007) data on waste incineration, N(2)O emissions from MSW incineration comprised 19% of the total N(2)O emissions.


D-ribose, a metabolic substrate for congestive heart failure.
The incidence of congestive heart failure continues to escalate worldwide, taxing health care systems. Current therapies focus on clinical management. Current accepted regimens have provided some success; however, most patients show progression of their disease. Because of this failure, research continues to explore therapies directed at stabilization of their disease and hopefully to improve the downward spiral. Publications have asserted that the failing heart is energy starved. D-ribose, a naturally occurring pentose carbohydrate and a key component in the adenosine triphosphate (ATP) molecule, has demonstrated an ability to replenish ATP levels and improve diastolic dysfunction following myocardial ischemia, which has been shown to improve the clinical state of patients afflicted with congestive heart failure. D-ribose may provide the necessary metabolic substrate to benefit this energy-deficient state found in heart failure.


Recent lung cancer mortality trends in Europe: effect of national smoke-free legislation strengthening.
The impact of smoke-free legislation within European Union (EU) countries on lung cancer mortality has not been evaluated to date. We aimed to determine lung cancer mortality trends in the EU-27 by sex, age, and calendar year for the period of 1994 and 2012, and relate them with changes in tobacco legislation at the national level. Deaths by Eurostat in each European country were analyzed, focusing on ICD-10 codes C33 and C34 from the years 1994 to 2012. Age-standardized mortality rates (ASR) were estimated separately for women and men in the EU-27 total and within country for each one of the years studied, and the significance of changing trends was estimated by joinpoint regression analysis, exploring lag times after initiation of smoke-free legislation in every country, if any. From 1994 to 2012, there were 4 681 877 deaths from lung cancer in Europe (3 491 607 in men and 1 190 180 in women) and a nearly linear decrease in mortality rates because of lung cancer in men from was observed1994 to 2012, mirrored in women by an upward trend, narrowing the sex gap during the study period from 5.1 in 1994 to 2.8 in 2012. Joinpoint regression analysis identified a number of trend changes over time, but it appears that they were unrelated to the implementation of smoke-free legislations. A few years after the introduction of smoke-free legislations across Europe, trends of lung cancer mortality trends have not changed.


Novel renal injury markers in dogs with ehrlichiosis.
Canine monocytic ehrlichiosis (CME) has been observed to impact renal function. Currently, the recognition of acute kidney injury is through the nonspecific biomarker serum creatinine (sCr). Novel markers of renal injury such as urinary clusterin (uClust) and urinary cystatin B (uCysB) may increase our understanding of the relationship between ehrlichiosis and renal cellular injury. The aim of this study was to evaluate novel renal injury biomarkers in dogs with acute CME. Twenty healthy dogs were enrolled in the control group (CG), and 16 dogs naturally infected with Ehrlichia canis were included in the Ehrlichia Group (EG). All dogs were followed for 45 days. EG dogs were treated with doxycycline twice daily for the first 30 days. Urine and serum were collected at: 0, 0.5, 1, 15, 30, and 45 days after start of treatment. Urine concentrations of uClust and uCysB were determined using a research ELISA immunoassay. A linear mixed model was used to estimate population mean of renal injury markers with patient as the random effect, and day and treatment as fixed effects. EG was observed to have higher uClust values compared to CG (estimated population mean EG: 213 ng/dL vs. CG: 84 ng/dL, P < 0.001). EG was observed to have higher uCysB values compared to CG (estimated population mean EG: 248 ng/dL vs. CG: 38 ng/dL, P < 0.001). Increases in uCysB and uClust suggest the presence of renal injury and a possible mechanism for the observed predisposition to chronic kidney disease in dogs with ehrlichiosis.


Effectiveness of statins on outcomes of patients with Embolic Stroke of Undetermined Source (ESUS).
Statins are highly recommended as a secondary prevention strategy after a stroke. Embolic Stroke of Undetermined Source (ESUS) accounts for up to one fifth of cases of ischemic stroke. There is a lack of studies investigating the effectiveness of statins in this subgroup of patients. We designed a longitudinal cohort study involving patients properly diagnosed with ESUS. Data about statin therapy included information about the time of initiation of the treatment, pre-stroke statin use, statin withdrawal, and the type and dosage of the statin prescribed. Patients were followed for 48 months after the index stroke. The primary endpoints included stroke recurrence, major cardiovascular events, and death from all causes. The secondary endpoint was the functional outcome, assessed in a standardized and systematic way using the modified Rankin Scale (mRS). Patients who were not taking any statin after ESUS have significantly increased odds of stroke recurrence (OR = 3.29, 95% CI 1.27 - 8.55) or presenting the composite outcome of stroke recurrence, major cardiovascular events, and death (OR = 3.70, 95% CI 1.44 - 9.50) in the multivariate analysis. No statin therapy was directly associated with the functional outcome as well (OR = 3.32, 95% CI = 1.58 - 6.96). The early initiation of the statin therapy was estimated to reduce the risk of a second stroke and the composite outcome by 89% and 87%. Our pioneering study provides evidence that patients with ESUS may benefit from statin therapy, especially if prescribed early and at higher dosages.


Diversity oriented synthesis of a vinblastine-templated library of 7-aryl-octahydroazonino[5,4-b]indoles via a three-component reaction.
A vinblastine-templated library of 7-aryl-octahydroazonino[5,4-b]indoles was prepared by a three-component reaction from indolizino[8,7-b]indoles, chloroformates, and activated arenes via a chloroformate mediated fragmentation of the indolizinoindole nucleus followed by insertion of an activated arene. In addition to N3-carbamoyl-7-aryl-octahydroazonino[5,4-b]indoles prepared in one step, a wide range of N3-substituted substrates were synthesized in one pot via the derivatization of a versatile N3-H-azonino[5,4-b]indole intermediate generated in situ by application of the same strategy. A subset of 308 compounds out of a virtual library of 3216, representing 13 different chemotypes, was prepared by high throughput solution-phase synthesis and subsequently purified by mass-triggered high performance liquid chromatography (HPLC). A total of 188 compounds with a minimum purity of 80% by UV214 nm and 85% by evaporative light scattering detection (ELSD) was isolated for primary screening.


Platonin, a cyanine photosensitizing dye, inhibits pyrogen release and results in antipyresis.
Intravenous injection of the supernatant fluids from human peripheral blood mononuclear cells (PBMC) incubated with lipopolysaccharide (LPS) caused fever in rabbits. The fever was in parallel with the levels of either interleukin-1 beta (IL-1 beta), IL-6, or tumor necrosis factor-alpha (TNF-alpha) in supernatant fluids. When incubating the platonin with the LPS-human PBMC, both the levels of IL-1 beta, IL-6, or TNF-alpha in supernatant fluids and the pyrogenicity of supernatant fluids were significantly suppressed. The febrile response to supernatant fluids from the LPS-stimulated PBMC was attenuated almost completely by adding anti-IL-1 beta, but not anti-IL-6 or anti-TNF-alpha, monoclonal antibody to supernatant fluids. In addition, both the fever and the increased levels of either IL-1 beta, IL-6, or TNF-alpha in rabbit serum following an intravenous administration of LPS were significantly attenuated by pretreatment with an intravenous dose of platonin. Furthermore, the fever induced by intravenous injection of IL-1 beta was reduced by pretreatment of rabbits with intravenous injection of platonin. The data indicate that platonin inhibits production of pyrogenic cytokines (in particular, IL-1 beta) from PBMC and results in antipyresis.


The use of non-invasive instruments in characterizing human facial and abdominal skin.
The skin is highly variable. This variation, although helpful for function, causes inconsistencies when assessed using subjective scales. The purpose of this study is to measure differences in skin on the face and abdomen using non-invasive, objective devices as a method to eliminate subjective error and help reduce intra- and inter-observer variability in clinical analysis. Eighty-eight subjects between the ages of 18 and 61 were enrolled in this study. These subjects varied in age, ethnicity, and Fitzpatrick score. Facial analysis was performed by clinical evaluation and utilizing non-invasive objective devices which included the DermaScan C 20 MHz HFUS (Cyberderm, Broomall, PA), Tru Vu (Johnson and Johnson), BTC 2000 (SRLI Technologies, Nashville, TN), Derma Unit SSC3 (CK Electronic, Köln, Germany), and the Chromometer. Non-invasive devices were shown to be consistent and accurate through repeated measurement at each of the anatomical points with error rates of less than 5%. Chromometer measurements were able to categorize patients into Fitzpatrick level. DermaScan measurements demonstrated decreasing skin thicknesses associated with increasing age, smoking, and female gender. Derma Unit SSC 3 showed gender and sun exposure related differences in sebum concentration, pH, and moisture content. The Derma Unit SSC 3 sebum concentration also showed correlation with Tru Vu readings for clogged pores and bacterial activity. The skin assessment scales that are in use today are often prone to variability and inaccuracy due to their subjectivity. Use of the described objective non-invasive facial analysis method provides an accurate, objective analysis of human skin which can be used to measure changes pre- and post-operatively, or even screen patients prior to procedure to identify non-responders or those prone to adverse events. Utilization of these devices introduces a foundation on which a strong evidence-based approach to aesthetic medicine can be built.


Interaction between maropitant and carprofen on sparing of the minimum alveolar concentration for blunting adrenergic response (MAC-BAR) of sevoflurane in dogs.
Maropitant, a neurokinin-1 receptor antagonist, may provide analgesic effects by blocking pharmacological action of substance P. Carprofen is a non-steroidal anti-inflammatory drug commonly used for pain control in dogs. The purpose of this study was to evaluate the effect of a combination of maropitant and carprofen on the minimum alveolar concentration for blunting adrenergic response (MAC-BAR) of sevoflurane in dogs. Six healthy adult beagle dogs were anesthetized with sevoflurane four times with a minimum of 7-day washout period. On each occasion, maropitant (1 mg/kg) alone, carprofen (4 mg/kg) alone, a combination of maropitant (1 mg/kg) and carprofen (4 mg/kg), or saline (0.1 ml/kg) was subcutaneously administered at 1 hr prior to the first electrical stimulation for the sevoflurane MAC-BAR determination. The sevoflurane MAC-BAR was significantly reduced by maropitant alone (2.88 ± 0.73%, P=0.010), carprofen alone (2.96 ± 0.38%, P=0.016) and the combination (2.81 ± 0.51%, P=0.0003), compared with saline (3.37 ± 0.56%). There was no significant difference in the percentage of MAC-BAR reductions between maropitant alone, carprofen alone and the combination. The administration of maropitant alone and carprofen alone produced clinically significant sparing effects on the sevoflurane MAC-BAR in dogs. However, the combination of maropitant and carprofen did not produce any additive effect on the sevoflurane MAC-BAR reduction. Anesthetic premedication with a combination of maropitant and carprofen may not provide any further sparing effect on anesthetic requirement in dogs.


Chitosan film enriched with an antioxidant agent, taurine, in fenestration defects.
A natural polysaccharide, chitosan (poly-N-acetyl glucosaminoglycan), which is a nontoxic and bioabsorbable polymer, has been shown to have hemostatic and antibacterial effects. An amino acid, taurine, is considered to be beneficial for regulating the inflammation process. The purpose of this study was to investigate the synergistic effects of taurine and chitosan in the experimental defects at the vestibular bone of maxillary canine teeth in six dogs. Chitosan films were prepared as delivery system with or without taurine and placed in the randomly chosen defects. Biopsies were performed on the postoperative seventh day and routine histological procedures were performed for light and electron microscopic evaluations. For each group, 30 different microscopic areas were examined and the numbers of macrophages and neutrophils in these areas were counted. The mean numbers of both macrophages and neutrophils were found statistically different between the chitosan film incorporated with taurine and free chitosan groups (p < 0.0001 p > 0.05). In addition to the increase in cell counts in both groups, the cytological alterations were more obvious in the chitosan film group incorporated with taurine. Accordingly, taurine appears to enhance the acceleration effect of chitosan on wound healing at early periods. This effect could be considered beneficial in tissue repair in destructive diseases like periodontitis.


[Rearrangement of the morphological structure and degradation of the extracellular matrix in amphibian embryos after short-term disruption of cell contacts].
The changes in cell structure of explants of presumptive early gastrula mesoderm of Xenopus laevis and dynamics of extracellular matrix formation has been studied for 6 h after their isolation. After 6 h, control explants of any dorsoventral level turned into dense spheric homogeneous cell clusters. Explants of dorsal and lateral sectors, treated with medium without Ca2+ and Mg2+ for 30 s, bent and separated into several layers, and in ventral sector explants, cavities, surrounded by polarized cells, arose. In control explants, the amount of extracellular matrix on the surface and in intercellular spaces increased, and in the experimental explants, extracellular matrix disappeared and was not observed for several hours. Previously described differential transformations of the treated explants (Georgiev, Belousov, 1986) are supposed to be determined by extracellular matrix degradation and the degradation-associated complications of cell structure of the explant.


Predicting binocular visual field sensitivity from monocular visual field results.
To compare methods of predicting binocular visual field sensitivity of patients with glaucoma from monocular visual field data. Monocular and binocular visual fields were obtained for 111 patients with varying degrees of glaucomatous damage in one or both eyes, using the Humphrey 30-2 full-threshold procedure. Four binocular sensitivity prediction models were evaluated: BEST EYE, predictions based on individual values for the most sensitive eye, defined by mean deviation (MD); AVERAGE EYE, predictions based on the average sensitivity between eyes at each visual field location; BEST LOCATION, predictions based on the highest sensitivity between eyes at each visual field location; and BINOCUIAR SUMMATION, predictions based on binocular summation of sensitivity between eyes at each location. Differences between actual and predicted binocular sensitivities were calculated for each model. The average difference between predicted and actual binocular sensitivities was close to zero for the BINOCULAR SUMMATION and BEST LOCATION models, with 95% of all predictions being within +/-3 dB of actual binocular sensitivities. The best eye (MD) prediction had an average error of 1.5 dB (95% confidence limits [CL], +/-3.7 dB). The average eye prediction was the poorest, with an average error of 3.7 dB (95% CL, +/-4.6 dB). The BINOCULAR SUMMATION and BEST LOCATION models provided better predictions of binocular visual field sensitivity than the other two models, with a statistically significant difference in performance. The small difference in performance between the BINOCULAR SUMMATION and BEST LOCATION models was not statistically significant. For evaluations of functional visual field influences on task performance, daily activities, and related quality-of-life issues, either the BINOCULAR SUMMATION or BEST LOCATION model provides good estimates of binocular visual field sensitivity.