Improved VO2max and time trial performance with more high aerobic intensity interval training and reduced training volume: a case study on an elite national cyclist.
The present study investigated to what extent more high aerobic intensity interval training (HAIT) and reduced training volume would influence maximal oxygen uptake (VO2max) and time trial (TT) performance in an elite national cyclist in the preseason period. The cyclist was tested for VO2max, cycling economy (C(c)), and TT performance on an ergometer cycle during 1 year. Training was continuously logged using heart rate monitor during the entire period. Total monthly training volume was reduced in the 2011 preseason compared with the 2010 preseason, and 2 HAIT blocks (14 sessions in 9 days and 15 sessions in 10 days) were performed as running. Between the HAIT blocks, 3 HAIT sessions per week were performed as cycling. From November 2010 to February 2011, the cyclist reduced total average monthly training volume by 18% and cycling training volume by 60%. The amount of training at 90-95% HRpeak increased by 41%. VO2max increased by 10.3% on ergometer cycle. TT performance improved by 14.9%. C(c) did not change. In conclusion, preseason reduced total training volume but increased amount of HAIT improved VO2max and TT performance without any changes in C(c). These improvements on cycling appeared despite that the HAIT blocks were performed as running. Reduced training time, and training transfer from running into improved cycling form, may be beneficial for cyclists living in cold climate areas.


Effect of gamma-irradiation on prenatal development of the tongue in CD-1 mice.
Development of the tongue in murine fetuses, in which the dams were exposed to whole body gamma-irradiation (400 rads) on the 12th day postcoitum, was studied and compared with unirradiated controls. Experimental and control groups were killed on day 18 of gestation and the fetuses were removed via laparotomy. The fetal heads were excised, fixed in Bouin's solution, prepared for paraffin sectioning, and stained with hematoxylin and eosin for light microscopic examination. Histologic examination of serial coronal sections demonstrated that all of the experimental fetuses possessed malformed, poorly developed tongues, when compared to those of the control group. It was concluded that gamma-irradiation has an adverse effect on tongue development in mouse fetuses.


Interaction ofEscherichia coli cytotoxic necrotizing factor type 1 (CNF1) with cultured cells.
The cytotoxic necrotizing factor type 1 (CNF1) fromE. coli causes necrosis in rabbit skin and multinucleation in cultured cells. Cells exposed to CNF1 were characterized by changes in actin organization, mainly consisting in the presence of well-developed stress fibers and membrane ruffles. The interaction of CNF1 with the cell cytoskeleton probably promotes the cell spreading and interferes with the cytokinesis, leading to the formation of giant multinucleated cells.


Referral centers and specialized care. Based on a presentation by Ronald P. Lesser, MD.
Appropriate diagnosis and treatment and the correct use of specialized services at epilepsy referral centers make it possible to control seizures relatively quickly in a large number of patients. Timeliness is extremely important, however, because delaying treatment decreases the likelihood of achieving complete remission from seizures. Epilepsy has a tremendous impact on quality of life. Concerns about concomitant illnesses, seizure-related injuries, and the psychosocial effects of seizures and anticonvulsants on patients are very real and should be addressed. An accurate diagnosis is the first step in effective seizure control, because not every patient with a seizure disorder has epilepsy. The second step is choosing an antiepileptic drug (AED) that is appropriate for the patient and using the correct dose and dosing schedule. When seizures remain uncontrolled or are poorly controlled despite medical therapy, the patient should be reevaluated to ascertain why the drug or drug combination is not working. The reason may be the wrong diagnosis, the wrong drug, or the wrong dose. If the seizures remain uncontrolled, the patient should be evaluated as a possible candidate for epilepsy surgery. If the patient is a good candidate, a presurgical work-up that includes monitoring and imaging studies should be performed, ideally at an epilepsy referral center. Quality care depends on access, communication, and knowledge, which involves patients who know how to achieve the best possible seizure control, doctors who are well informed and know what to do to ensure that their patients are receiving the best care, and mechanisms that permit consultation among everyone involved in caring for patients with epilepsy. Developing a system of quality, cost-effective care for the management of epilepsy also offers an excellent opportunity to apply such a system to the larger arena of medical care in general.


[Effects of polyene antibiotics and detergents on cell membranes of polyene-sensitive and polyene-resistant strains of Candida albicans].
Various detergents and EPR-probes of 4,4-dimethylspiro[5alpha-androstan-17beta-ol-3,2-(1,3-oxazolidin-3-oxyl)]2CH3OH; 2,2,6,6-tetramethylpalmitoyl-amidopiperidine-1-oxyl and 2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinoxyl were used to establish structural differences in the membrane of polyene-sensitive and polyene-resistant strains of C. albicans. It was shown that the type of protein-lipid interactions is modified by the changes in the sterol component of the polyene-resistant strain membranes. This manifests itself in a decrease in sensitivity of membrane alkaline phosphatase for levorin and the detergents, as well as in the alteration of the lipid fluidity pattern of the polyene-resistant strain membranes as compared to the membranes of original culture of C. albicans. Treatment of polyene-sensitive strain membranes with amphotericine B causes more intensive protein-lipid interactions, which is not observed in case of the polyene-resistant strain. It is assumed that C. albicans resistance to polyenes is due to the existence of strong protein-lipid interactions in the membrane coupled with ergosterol substitution by other sterol components.


Satellite cell characterization from aging human muscle.
Satellite cells (SCs) are skeletal muscle progenitor cells located between the basal lamina and the sarcolemma of muscle fibers. They are responsible for muscle growth and repair. In humans, aging results in the depletion of the SC population and in its proliferative activity, but not in its function. It has not yet been determined whether under conditions of massive muscle fiber death in vivo, the regenerative potential of SCs is totally or partially compromised in old muscle. No studies have yet tested whether advanced age is a factor that restrains the response of SCs to muscle denervation in humans; this is also due to difficulties in the isolation and in the culture of SCs from a small human surgery fragment. The aim of this study was to study in depth muscle regeneration analysing the SC ability of SCs to proliferate and differentiate in aging human patients. In order to study in more detail the molecular mechanism, the proliferative and differentiative ability of aging SCs, we isolated SCs from aging human muscle biopsies and analysed their morphology by transmission electron microscopy and immunocytochemical analysis (antibodies against desmin, N-CAM and M-cadherin) and their capacity to grow and to expand in vitro. Moreover, in order to evaluate gene expression of myogenic regulatory factors Myf5, MyoD and myogenin (Myf4), RT-PCR was performed. SCs isolated from aging human muscle biopsies and plated into favorable proliferation and differentiation conditions were able to proceed through the myogenic program and actively form myotubes, although taking longer than the young control sample. The RT-PCR analysis together with the ultrastructural SC features showed that the myogenic potential seemed to be compromised during the aging human muscle proliferation in vitro.


Bromine polycondensation in pristine and fluorinated graphitic carbons.
Despite decades of study the precise behavior of bromine in graphitic carbons remains unclear. In this report, using Raman spectroscopy, we reveal two types of bromine structure in graphitic carbon materials. Between fluorinated graphene layers with a composition close to C2F, Br2 molecules are intercalated in a form similar to liquid bromine. Bromination of pristine and low-fluorinated graphitic carbons behaves very differently with distinct Br-related Raman spectra. With the guidance of density functional theory (DFT) calculations, all Raman features are assigned to normal vibration modes of specific bromine species over graphene and fluorinated graphene. When intercalated between extended non-fluorinated sp2-hybridized carbon regions, physisorbed Br2 molecules move freely across the non-functionalized region toward the CF border. Multiple Br2 molecules then combine spontaneously into Br3-based chains, whose coupling activates otherwise Raman inactive modes. Significant charge transfer to bromine species occurs in this case. DFT calculated frequencies match precisely the experimental Br-related Raman bands observed in the intercalation carbon compounds. The fluorine-catalyzed bromine chain-formation process shown here is general and should also operate with edges and other defect species.


Impairment in renal medulla development underlies salt wasting in Clc-k2 channel deficiency.
The prevailing view is that the ClC-Ka chloride channel (mouse Clc-k1) functions in the thin ascending limb to control urine concentration, whereas the ClC-Kb channel (mouse Clc-k2) functions in the thick ascending limb (TAL) to control salt reabsorption. Mutations of ClC-Kb cause classic Bartter syndrome, characterized by renal salt wasting, with perinatal to adolescent onset. We studied the roles of Clc-k channels in perinatal mouse kidneys using constitutive or inducible kidney-specific gene ablation and 2D and advanced 3D imaging of optically cleared kidneys. We show that Clc-k1 and Clc-k2 were broadly expressed and colocalized in perinatal kidneys. Deletion of Clc-k1 and Clc-k2 revealed that both participated in NKCC2- and NCC-mediated NaCl reabsorption in neonatal kidneys. Embryonic deletion of Clc-k2 caused tubular injury and impaired renal medulla and TAL development. Inducible deletion of Clc-k2 beginning after medulla maturation produced mild salt wasting resulting from reduced NCC activity. Thus, both Clc-k1 and Clc-k2 contributed to salt reabsorption in TAL and distal convoluted tubule (DCT) in neonates, potentially explaining the less-severe phenotypes in classic Bartter syndrome. As opposed to the current understanding that salt wasting in adult patients with Bartter syndrome is due to Clc-k2 deficiency in adult TAL, our results suggest that it originates mainly from defects occurring in the medulla and TAL during development.


Handling of tracer bicarbonate by the liver. The relative impermeability of hepatocyte cell membranes to the ionic species.
The multiple indicator dilution technique was used to study transfer of labeled HCO3- across the hepatocyte membrane in the anesthetized mongrel dog. A bolus of H[14C]O3-, 51Cr-labeled erythrocytes, [36Cl-] and/or [3H]sucrose, and [3H]OH was injected through a catheter in the portal vein, and timed anaerobic blood samples were obtained from a catheter in the hepatic vein. Experiments were carried out in untreated controls and after intravenous infusion of acetazolamide (100 mg/kg). In the controls, the H[14C]O3- curve was very similar to the [3H]OH curve. The dilution curves were all linear transformations of each other, indicating that HCO3-, as had previously been shown for the other diffusible tracers, undergoes delayed-wave flow-limited distribution. The distribution space for H[14C]O3- in the control situation includes the blood plasma and interstitial spaces, the erythrocyte interior modified by a Donnan equilibrium, and the available liver cellular space. The calculated HCO3- concentration in the liver cells was somewhat lower than that in the plasma space; the difference implied a cellular pH lower than that of plasma by approximately 0.08 pH units. When the carbonic anhydrases were inhibited with acetazolamide, the dilution curve for H[14C]O3- changed radically, approaching that for [36Cl-], which does not enter the liver cells. The change indicates that although HCO3-, like Cl-, is rapidly exchanged between plasma and erythrocytes, it also does not readily penetrate hepatocytes unless previously transformed to carbon dioxide by the carbonic anhydrases.


[Regulation of lipid metabolism by the orphan nuclear receptors].
Lipids (cholesterol and fatty acids) are essential nutriments and have a major impact on gene expression. Hence cholesterol intracellular concentration is precisely controlled by some complex mechanisms involving transcriptional regulations. The excess of cholesterol in cells is converted into oxysterols. These cholesterol metabolites are important signalisation molecules that modulate several transcription factors involved in cholesterol homeostasis. Schematically, regulation of cholesterol homeostasis is achieved by three different but complementary pathways: 1) endogeneous biosynthesis, which corresponds to the de novo synthesis of cholesterol and is controlled by sterol response element binding proteins (SREBPs); 2) the transport, intracellular absorption and esterification of the cholesterol; 3) the metabolic conversion into bile acids and steroid hormones. These three pathways are closely linked, however we will schematically detail the role of the orphan nuclear receptors on the modulation of these three levels of regulation. Phenotype analyses of knock-out or transgenic mice pointed out the respective role of the "enterohepatic" orphan nuclear receptors LXRalpha, LXRB, FXR, LRH-1, the nuclear receptor PPARalpha, and their heterodimeric partner RXR, as well as the peculiar receptor SHP. Complex feed-backs have thus been demonstrated. These transciptional regulations have several targets: the P450 cytochromes involved in the bile acid synthesis Cyp7a1 and Cyp8b1; the intestinal bile acid binding protein IBABP; the cholesteryl ester transfert protein CETP and phospholipid transfert protein PLTP, both involved in the HDL catabolism; the ABC cholesterol transporters ABCG1/ABC8 and ABCAI/ABCI. At last it seems that polyunsaturated fatty acids could activate LXRalpha transcription through its activation by PPARalpha. In the near future, the identification and study of new target genes by transcriptomic or proteomic analyses will allow a better understanding of lipid homeostasis in physiological as well as pathophysiological conditions.


Medical Oncology Group of Australia position statement and membership survey on voluntary assisted dying.
The controversial topic of voluntary assisted dying (VAD) is receiving significant attention at state government levels and in the community. Acknowledging potential legalisation of VAD, the Medical Oncology Group of Australia (MOGA) undertook a survey of members to inform the development of a position statement on the subject. All MOGA members were invited to complete an anonymous online survey. The survey comprised 12 closed-response categorical questions. Descriptive statistics were used to summarise the survey data. Majority views expressed in the survey would form the basis of a MOGA position statement on VAD. A total of 362 members completed the questionnaire, representing 55% of the membership; 47% of respondents disagreed with VAD; 36% agreed with VAD and the remaining members (17%) were 'neutral'. A clear majority position was not established. Only 14% agreed that physicians involved in VAD should be required personally to administer the lethal medication; 94% supported conscientious objection of physicians to the VAD process; 95% agreed that a palliative care physician consultation should be required and 86% agreed with the need for the involvement of specialist psychiatry medical services before a patient can be deemed as suitable for VAD. The MOGA membership expressed a range of views on the topic of VAD. A clear majority-held view to support a MOGA position that either supports or opposes VAD was not established. The position statement that flows from the survey encourages informed debate on this topic and brings into focus important considerations.


Induction of tolerance in freshly isolated alloreactive T cells by activated T cell stimulators is not due to the absence of CD28-B7 interaction.
Human T cells express MHC class II molecules on activation, and this makes them potential APCs for responder CD4 T cells. We have shown earlier that MHC class II-expressing human T cell APCs induce specific tolerance in freshly isolated alloreactive responder CD4 T cells. In this study, we show that this induction of tolerance does not depend on the expression of a specific coreceptor on the stimulator T cell APCs, because both CD4 and CD8 T cell stimulators efficiently induce tolerance. Such a tolerant cell population responds significantly better to IL-2 than unprimed cells, indicating the physical presence of T cells expressing higher levels of IL-2 receptors. The addition of exogenous IL-2 during priming with activated T cell APCs effectively blocks the induction of tolerance and permits successful priming of alloreactive responder cells. We have investigated the possible role of the CD28/CTLA4-B7 family interaction in this model of induction of T cell anergy in T-T interactions. The freshly activated T cell APCs used in this study express CTLA4-binding ligand(s). Furthermore, cross-linking CD28 on responder T cells does not enable activated T cell APCs to elicit a primary proliferative alloresponse, nor does it prevent the induction of tolerance in responder T cells. The CD28/CTLA4-B7 family interaction is thus unlikely to be involved in the induction of T cell anergy by T cell APCs.


Chromatin structure and transcriptional regulation of human papillomavirus type 18 DNA in HeLa cells.
Mapping analysis of the nucleosomal organization of integrated human papillomavirus type 18 (HPV18) DNA in HeLa cells reveals a very prominent nuclease-hypersensitive site within the viral noncoding regulatory region that harbors transcriptional control sequences and coincides with most of the 5' ends of the cytoplasmic early mRNAs. Moreover, it is shown that the conserved coamplified 5' cellular flank, common to all HPV18 copies in HeLa cells and located close to the virus-cell integration site, also contains several distinct hypersensitive sites, accessible not only to DNase I but also to restriction enzymes. Nuclear run-on analysis in isolated HeLa nuclei demonstrates the occurrence of nascent transcripts covering the cellular flank (the late and the viral noncoding regulatory region), indicating that a cellular promoter, marked by the hypersensitive sites, cooperates with the viral control region in generating the HPV18 transcripts. Cycloheximide treatment of HeLa cells results in a reduction of the cytoplasmic steady-state level of the 3.5-kb mRNA corresponding to the viral E6, E7, and parts of the E1 open reading frames (ORFs), whereas the expression of the 1.6-kb transcript corresponding only to the E6 and E7 ORFs is not influenced. Nuclear run-on analysis carried out after the cycloheximide chase reveals that the distribution of nascent transcripts spanning the viral E6, E7, and parts of the E1 region is substantially decreased. In contrast to this finding, an even, pronounced increase of the elongation rate of those transcripts, which cover the cellular flank, the late and the viral noncoding regulatory region was noted indicating a different involvement of regulatory factors in the activity of both promoters.


The DCC gene: structural analysis and mutations in colorectal carcinomas.
DCC is a candidate tumor-suppressor gene encoding a protein with sequence similarity to cell adhesion molecules such as N-CAM. A set of overlapping YAC clones that contains the entire DCC coding region was isolated. Studies of this YAC contig showed that the DCC gene spans approximately 1.4 Mb. For elucidation of exon-intron structure, lambda phage clones containing all known coding sequences were isolated from a genomic library. These clones were used to demonstrate the existence of 29 DCC exons, and the sequences of the exon-intron boundaries were determined for each. Twenty-three polymorphic markers from chromosome 18 were then studied in a panel of primary colorectal tumors that had lost some, but not all, of chromosome 18. In most of these tumors, the region that was lost included DCC. Finally, Southern blot and PCR-based approaches were used to search for subtle mutations in several DCC exons. One tumor that had a point mutation in exon 28 was found, resulting in a proline to histidine substitution. A second tumor with a point mutation in intron 13 was also found. The regional map and genomic structure of DCC should provide the means to more extensively study DCC gene alterations and protein function in normal and neoplastic cells.


Efficient delivery of therapeutic small nucleic acids to prostate cancer cells using ketal nucleoside lipid nanoparticles.
A novel nucleoside lipid derived from dioleyl ketal was synthesized from uridine in three steps starting from dioleyl ketone. Electronic microscopy studies show that Ketals Nucleoside Lipids (KNL) self-assemble to form liposome-like structures in aqueous solutions. KNL is able to bind siRNA as demonstrated by electrophoresis experiment and standard ethidium bromide fluorescence displacement assay. Transfection assays of stable hepatic cell lines HupIRF, carrying a luciferase reporter gene demonstrate that KNL is able to transfect siRNA and exhibits protein knockdown more efficiently than its diester analog (DOTAU) and lipofectamine. Herein, we also report that KNLs are suitable transfecting reagents for the development of novel therapeutic approaches involving either siRNA or antisense oligonucleotide against human prostate cancer PC-3 cells resistant to chemotherapy.


The economic impact of moderate stage Alzheimer's disease in Italy: evidence from the UP-TECH randomized trial.
There is consensus that dementia is the most burdensome disease for modern societies. Few cost-of-illness studies examined the complexity of Alzheimer's disease (AD) burden, considering at the same time health and social care, cash allowances, informal care, and out-of-pocket expenditure by families. This is a comprehensive cost-of-illness study based on the baseline data from a randomized controlled trial (UP-TECH) enrolling 438 patients with moderate AD and their primary caregiver living in the community. The societal burden of AD, composed of public, patient, and informal care costs, was about €20,000/yr. Out of this, the cost borne by the public sector was €4,534/yr. The main driver of public cost was the national cash-for-care allowance (€2,324/yr), followed by drug prescriptions (€1,402/yr). Out-of-pocket expenditure predominantly concerned the cost of private care workers. The value of informal care peaked at €13,590/yr. Socioeconomic factors do not influence AD public cost, but do affect the level of out-of-pocket expenditure. The burden of AD reflects the structure of Italian welfare. The families predominantly manage AD patients. The public expenditure is mostly for drugs and cash-for-care benefits. From a State perspective in the short term, the advantage of these care arrangements is clear, compared to the cost of residential care. However, if caregivers are not adequately supported, savings may be soon offset by higher risk of caregiver morbidity and mortality produced by high burden and stress. The study has been registered on the website www.clinicaltrials.org ( NCT01700556).


Pre-operative analgesia for acute surgical patients: no place for complacency.
Pain is common in patients presenting with acute surgical conditions but there has been little discussion of the provision of pre-operative analgesia. This study analyses the pattern of pre-operative analgesic administration and questions the practices of the admitting medical officers in a district hospital. It shows that pre-operative analgesia is often omitted or that an unduly long time is taken to administer it. We suggest that this is an area worthy of audit.


Molecular cloning and sequence analysis of mutant alleles of the fission yeast cdc2 protein kinase gene: implications for cdc2+ protein structure and function.
The cdc2+ gene function plays a central role in the control of the mitotic cell cycle of the fission yeast Schizosaccharomyces pombe. Recessive temperature-sensitive mutations in the cdc2 gene cause cell cycle arrest when shifted to the restrictive temperature, while a second class of mutations within the cdc2 gene causes a premature advancement into mitosis. Previously the cdc2+ gene has been cloned and has been shown to encode a 34 kDa phosphoprotein with in vitro protein kinase activity. Here we describe the cloning of 11 mutant alleles of the cdc2 gene using two simple methods, one of which is presented here for the first time. We have sequenced these alleles and find a variety of single amino acid substitutions mapping throughout the cdc2 protein. Analysis of these mutations has identified a number of regions within the cdc2 protein that are important for cdc2+ activity and regulation. These include regions which may be involved in the interaction of the cdc2+ gene product with the proteins encoded by the wee1+, cdc13+ and suc1+ genes.


(18)F-FDG and (18)F-FET uptake in experimental soft tissue infection.
The aim of this study was to compare the uptake of (18)F-fluoroethyl- L-tyrosine ((18)F-FET) with that of (18)F-fluorodeoxyglucose ((18)F-FDG) in activated inflammatory white blood cells. Unilateral thigh muscle abscesses were induced in 11 rats by intramuscular inoculation of 0.1 ml of a bacterial suspension ( S. aureus, 1.2 x 10(9) CFU/ml). Four animals were intraperitoneally injected with 130-180 MBq (18)F-FDG, four with 140-170 MBq (18)F-FET and three with a mixture of 140-170 MBq (18)F-FET and 1.8 MBq (14)C-deoxyglucose. Autoradiography (10 microm slice thickness) of the abscess and the contralateral muscle was performed and detailed spatial correlation of autoradiography and histopathology (haematoxylin-eosin staining) was obtained. Regions of interest were placed on the abscess wall and the grey values (digitised image intensities) measured were converted to kBq/cc per kBq injected activity per gram (SUV). Areas with increased (18)F-FDG uptake corresponded to cellular inflammatory infiltrates mainly consisting of granulocytes. The SUV was calculated to be 4.08+/-0.65 (mean+/-SD). The uptake of (18)F-FET in activated white blood cells was not increased: the SUV of the abscess wall, at 0.74+/-0.14, was even below that of contralateral muscle. The low uptake of (18)F-FET in non-neoplastic inflammatory cells promises a higher specificity for the detection of tumour cells than is achieved with (18)F-FDG, since the immunological host response will not be labelled and inflammation can be excluded.


Progressing neurological deficit secondary to acute ischemic stroke. A study on predictability, pathogenesis, and prognosis.
To identify predictors and possible pathogenetic mechanisms of early neurological deterioration in patients with acute ischemic strokes and to evaluate their impact on clinical outcome. Case series. University hospital's stroke unit. A continuous series of 152 patients with first-ever ischemic hemispheric strokes were hospitalized within 5 hours of onset, evaluated with the Canadian Neurological Scale, and underwent a computed tomographic (CT) scan. The initial subset of 80 patients also underwent angiography. A repeated CT scan or autopsy was performed within 5 to 9 days of a patient's stroke. Progressing neurological deficit was defined as a decrease of one point or more in the global neurological scale score during hospitalization, when compared with that at entry. The conditions of 39 patients (26%) deteriorated during the initial 4 days; 20 patients (51%) had an impaired level of consciousness, and 19 patients (49%) had impaired limb strength and/or speech. They had been hospitalized earlier and had higher serum glucose levels at admission; the baseline CT scans of these patients showed an early focal hypodensity and initial mass effect more frequently. On the repeated CT scan (144 patients) or at autopsy (eight patients), patients with a progressing course more frequently had large infarcts, severe mass effect, and hemorrhagic infarction. We found no differences with regard to demographic data, medical history, and treatments that were given; only subcutaneous heparin calcium was more frequently administered to patients with a progressing course. Twenty-two (27%) of the 80 patients who underwent angiography had a progressing course, of whom 20 (91%) had an intracranial and/or extracranial arterial occlusion, with collateral blood supply in seven patients (35%). Logistic regression analysis showed that the independent predictors of progression were the serum glucose levels at admission and the early focal hypodensity with cortical and corticosubcortical locations, with the positive predictive values of the latter being 34% (95% confidence interval [CI], 26% to 42%) and 57% (95% CI, 47% to 67%), respectively. Among patients who underwent angiography, logistic regression analysis showed a significant correlation between carotid siphon occlusion and a progressing course. The 30-day case-fatality ratio and disability (Barthel index, < 60) were higher in patients with a progressing course (36% and 54% vs 12% and 35%, respectively). Early stroke deterioration is still an event that is difficult to predict; it is largely determined by cerebral edema following an arterial occlusion, as indicated by an early focal hypodensity and initial mass effect on the baseline CT scan. Since early deterioration anticipates a bad outcome in 90% of patients, it might be used as an early surrogate end point in therapeutic trials.


IRF4 deficiency abrogates lupus nephritis despite enhancing systemic cytokine production.
The IFN-regulatory factors IRF1, IRF3, IRF5, and IRF7 modulate processes involved in the pathogenesis of systemic lupus and lupus nephritis, but the contribution of IRF4, which has multiple roles in innate and adaptive immunity, is unknown. To determine a putative pathogenic role of IRF4 in lupus, we crossed Irf4-deficient mice with autoimmune C57BL/6-(Fas)lpr mice. IRF4 deficiency associated with increased activation of antigen-presenting cells in C57BL/6-(Fas)lpr mice, resulting in a massive increase in plasma levels of TNF and IL-12p40, suggesting that IRF4 suppresses cytokine release in these mice. Nevertheless, IRF4 deficiency completely protected these mice from glomerulonephritis and lung disease. The mice were hypogammaglobulinemic and lacked antinuclear and anti-dsDNA autoantibodies, revealing the requirement of IRF4 for the maturation of plasma cells. As a consequence, Irf4-deficient C57BL/6-(Fas)lpr mice neither developed immune complex disease nor glomerular activation of complement. In addition, lack of IRF4 impaired the maturation of Th17 effector T cells and reduced plasma levels of IL-17 and IL-21, which are cytokines known to contribute to autoimmune tissue injury. In summary, IRF4 deficiency enhances systemic inflammation and the activation of antigen-presenting cells but also prevents the maturation of plasma cells and effector T cells. Because these adaptive immune effectors are essential for the evolution of lupus nephritis, we conclude that IRF4 promotes the development of lupus nephritis despite suppressing antigen-presenting cells.


Less head motion during MRI under task than resting-state conditions.
Head motion reduces data quality of neuroimaging data. In three functional magnetic resonance imaging (MRI) experiments we demonstrate that people make less head movements under task than resting-state conditions. In Experiment 1, we observed less head motion during a memory encoding task than during the resting-state condition. In Experiment 2, using publicly shared data from the UCLA Consortium for Neuropsychiatric Phenomics LA5c Study, we again found less head motion during several active task conditions than during a resting-state condition, although some task conditions also showed comparable motion. In the healthy controls, we found more head motion in men than in women and more motion with increasing age. When comparing clinical groups, we found that patients with a clinical diagnosis of bipolar disorder, or schizophrenia, move more compared to healthy controls or patients with ADHD. Both these experiments had a fixed acquisition order across participants, and we could not rule out that a first or last scan during a session might be particularly prone to more head motion. Therefore, we conducted Experiment 3, in which we collected several task and resting-state fMRI runs with an acquisition order counter-balanced. The results of Experiment 3 show again less head motion during several task conditions than during rest. Together these experiments demonstrate that small head motions occur during MRI even with careful instruction to remain still and fixation with foam pillows, but that head motion is lower when participants are engaged in a cognitive task. These finding may inform the choice of functional runs when studying difficult-to-scan populations, such as children or certain patient populations. Our findings also indicate that differences in head motion complicate direct comparisons of measures of functional neuronal networks between task and resting-state fMRI because of potential differences in data quality. In practice, a task to reduce head motion might be especially useful when acquiring structural MRI data such as T1/T2-weighted and diffusion MRI in research and clinical settings.


Comparison of oral midazolam with a combination of oral midazolam and nitrous oxide-oxygen inhalation in the effectiveness of dental sedation for young children.
To compare the effectiveness of 0.6 mg/kg oral midazolam sedation alone and a combination of 0.6 mg/kg oral midazolam plus nitrous oxide-oxygen inhalation sedation, in controlling the behavior of uncooperative children during dental treatment. The study had a crossover design where the same patient received two different sedation regimens, that is, oral midazolam 0.6 mg/kg and oral midazolam 0.6 mg/kg with nitrous oxide-oxygen inhalation during two dental treatment visits. Thirty children (17 males and 13 females) were randomly selected for the study, with a mean age of 55.07 (+/- 9.29) months, ranging from 48 - 72 months. A scoring system suggested by Houpt et al. (1985) was utilized for assessment of the children's behavior. There was no significant (p > 0.05) difference in the overall behavior assessment between the two sedation regimens, that is, oral midazolam alone and oral midazolam plus nitrous oxide-oxygen. However, the combination of midazolam and nitrous oxide-oxygen showed significantly (p < 0.05) superior results as compared to midazolam alone, in terms of controlling movement and crying during local anesthesia administration and restorative procedures. Compared to oral midazolam alone, a combination of oral midazolam and nitrous oxide inhalation sedation appears to provide more comfort to pediatric dental patients and operators during critical stages of dental treatment.


Hormonal imprinting in the unicellular Tetrahymena: the proto-model of epigenetics.
The unicellular ciliate, Tetrahymena has a complete hormonal system. It has receptors for receiving hormones, produces, stores and secretes hormones, similar to mammalian ones and has signal transduction pathways, for transmitting the information given by the hormones. The first encounter with a hormone provokes the hormonal imprinting under the effect of which the further encounters with the same hormone induces altered (usually enhanced) reaction (hormone binding, hormone synthesis, chemoattraction, movement, growth etc.). The effect of imprinting is durable, it can be observed also after 1000 generations, or after one year in non-dividing cells. Receptors of the nuclear envelope also can be imprinted. The plasma membrane receptors provoked by imprinting are similar to the receptors of mammals. Although steroid hormones are not present in Tetrahymena, the production of them and their receptors can be induced by imprinting. The hormonal imprinting is an epigenetic process and inhibition of DNA-methylation alters the imprinting. Hormonal imprinting in Tetrahymena was likely the first epigenetic phenomenon which was justified at cellular level. It is very useful for the unicells, as it helps to avoid dangerous molecules more easily or to find useful ones and by this contributes to the permanence of the population's life.


[Morphometric study of the adrenal medulla of rats in long-term hypokinesia].
Using Wood's differential staining, norepinephrine- and epinephrine-secreting cells of the adrenal medulla of 36 Wistar male rats exposed to 1 to 5.5-month hypokinesia were measured karyometrically. After 2 month hypokinesia the nuclear volume of norepinephrine-secreting cells increased significantly. After 5.5-month hypokinesia no dystrophic changes were seen in the adrenal medulla.


Novel therapy for anaplastic thyroid carcinoma cells using an oncolytic vaccinia virus carrying the human sodium iodide symporter.
Anaplastic thyroid carcinoma (ATC) is fatal with resistance to radiotherapy because of the loss of intrinsic human sodium iodine symporter (hNIS). We determined whether vaccinia virus carrying hNIS kills and induces hNIS reexpression in ATC cells, facilitating deep-tissue imaging. Vaccinia virus (GLV-1h153) carrying hNIS was tested against ATC lines for killing and replication via cytotoxicity and viral plaque assays. Cellular radiouptake was determined using radiouptake assays. GLV-1h153-infected ATC xenografts were imaged via (99m)Tc-pertechnetate. GLV-1h153 infected, replicated in, and killed all ATC cell lines. GFP expression confirmed viral infection by 24 hours. At a multiplicity of infection (MOI) of 1.0, GLV-1h153 reached near 100% cytotoxicity in 8305c and FRO by day 5 and 70% in the least sensitive cell line, 8505c. GLV-1h153-infected ATC cells had a 14-fold increase of hNIS-specific radiouptake compared with uninfected control 24 hours after infection at an MOI of 1.0. In vivo, GLV-1h153 facilitated imaging of hNIS expression in 8505c tumors using (99m)Tc-pertechnetate. GLV-1h153 is an effective oncolytic agent against ATC. The results show hNIS-specific radiouptake in infected ATC cells, facilitating deep-tissue imaging. GLV-1h153 is a promising candidate for treatment and imaging, and potentially enhancing susceptibility to radioiodine therapy by converting non-hNIS-expressing cells into hNIS-expressing ATC cells.


Prevalence and treatment of atherogenic dyslipidemia in the primary prevention of cardiovascular disease in Europe: EURIKA, a cross-sectional observational study.
Atherogenic dyslipidemia is associated with poor cardiovascular outcomes, yet markers of this condition are often ignored in clinical practice. Here, we address a clear evidence gap by assessing the prevalence and treatment of two markers of atherogenic dyslipidemia: elevated triglyceride levels and low levels of high-density lipoprotein cholesterol. This cross-sectional observational study assessed the prevalence of two atherogenic dyslipidemia markers, high triglyceride levels and low high-density lipoprotein cholesterol levels, in the study population from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA; N = 7641; of whom 51.6% were female and 95.6% were White/Caucasian). The EURIKA population included European patients, aged at least 50 years with at least one cardiovascular risk factor but no history of cardiovascular disease. Over 20% of patients from the EURIKA population have either triglyceride or high-density lipoprotein cholesterol levels characteristic of atherogenic dyslipidemia. Furthermore, the proportions of patients with one of these markers were higher in subpopulations with type 2 diabetes mellitus or those already calculated to be at high risk of cardiovascular disease. Approximately 55% of the EURIKA population who have markers of atherogenic dyslipidemia are not receiving lipid-lowering therapy. A considerable proportion of patients with at least one major cardiovascular risk factor in the primary cardiovascular disease prevention setting have markers of atherogenic dyslipidemia. The majority of these patients are not receiving optimal treatment, as specified in international guidelines, and thus their risk of developing cardiovascular disease is possibly underestimated. The present study is registered with ClinicalTrials.gov (ID: NCT00882336).


Effects of IBMX on norepinephrine-induced vasoconstriction in small mesenteric arteries.
The present study assesses the effects of the phosphodiesterase inhibitor IBMX on norepinephrine (NE)-induced constriction of small mesenteric arteries. Arteries ( approximately 150 micrometer) were dissected from rats and mounted on a wire myograph for isometric force measurement. NE concentration effect curves were generated after exposure to 500 microM IBMX for 60 min. IBMX significantly reduced NE-induced tension development. Studies were also conducted following sarcoplasmic reticulum (SR) depletion (ryanodine, 10 microM) or L-type Ca2+ channel blockade [(+)-BAY K 8644, 10 microM] in the presence and absence of IBMX. Both SR depletion and L-channel blockade reduced NE-induced tension generation, consistent with incomplete Ca2+ mobilization. IBMX significantly attenuated NE responses in ryanodine and (+)-BAY K 8644-treated vessels. Finally, treatment of NE-stimulated vessels with IBMX (500 microM) caused a reduction in vascular tension that was greater than the concomitant reduction in cytosolic Ca2+ concentration ([Ca2+]i), indicating that a portion of the IBMX-mediated relaxation is Ca2+-independent. These data suggest that IBMX attenuation of NE responsiveness not only involves a reduction in [Ca2+]i but also a significant decrease in Ca2+ sensitivity.


Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial.
Patients and clinicians share concerns that generic drug substitution might lead to loss of efficacy or emergence of adverse events. In this trial, we assessed US Food and Drug Administration (FDA) bioequivalence standards by studying the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy. The Equivalence among Generic Antiepileptic Drugs (EQUIGEN) chronic-dose study was a randomised, double-blind, crossover study that enrolled adults (aged ≥18 years) with epilepsy from six epilepsy centres at academic institutions across the USA who were receiving immediate-release lamotrigine dosed at 100 mg, 200 mg, 300 mg, or 400 mg twice daily. Eligible patients were randomly allocated (1:1) to one of two treatment sequences (sequence 1 or sequence 2), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 h (200-800 mg total, identical to lamotrigine dose prior to study enrolment); after each 14-day period, patients were crossed over to receive the other generic product. Computer-based randomisation was done using random permuted blocks of size two or four for each site to prevent sequence predictability. Both patients and study personnel were masked to the generic products selected, their predicted exposure (ie, "high" vs "low"), and their group allocation. The primary outcome of this trial was bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) for each product in the analysis population (all patients who completed all four treatment periods). Bioequivalence was established if the 90% CIs of the ratios of these two parameters for the two products were within equivalence limits (80-125%) in the analysis population. This study is registered with ClinicalTrials.gov\, number NCT01713777. Between April 25, 2013, and Aug 12, 2014, 35 eligible patients were enrolled and randomly assigned to treatment sequence 1 (n=15) or treatment sequence 2 (n=20). 33 patients completed all four treatment periods and were included in the primary outcome analysis. The 90% CIs of the ratios of both Cmax and AUC were within equivalence limits (AUC 90% CI 98-103, Cmax 90% CI 99-105), showing that lamotrigine exposures were equivalent between the generic products. No significant changes in seizure frequency or adverse events were recorded. No deaths, study-related serious adverse events, or changes in clinical laboratory values or vital signs occurred during this study. Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate. American Epilepsy Society, Epilepsy Foundation, and US Food and Drug Administration.


Inhibition of Myc-induced cell transformation by brain acid-soluble protein 1 (BASP1).
Cell transformation by the Myc oncoprotein involves transcriptional activation or suppression of specific target genes with intrinsic oncogenic or tumor-suppressive potential, respectively. We have identified the BASP1 (CAP-23, NAP-22) gene as a novel target suppressed by Myc. The acidic 25-kDa BASP1 protein was originally isolated as a cortical cytoskeleton-associated protein from rat and chicken brain, but has also been found in other tissues and subcellular locations. BASP1 mRNA and protein expression is specifically suppressed in fibroblasts transformed by the v-myc oncogene, but not in cells transformed by other oncogenic agents. The BASP1 gene encompasses 2 exons separated by a 58-kbp intron and a Myc-responsive regulatory region at the 5' boundary of untranslated exon 1. Bicistronic expression of BASP1 and v-myc from a retroviral vector blocks v-myc-induced cell transformation. Furthermore, ectopic expression of BASP1 renders fibroblasts resistant to subsequent cell transformation by v-myc, and exogenous delivery of the BASP1 gene into v-myc-transformed cells leads to significant attenuation of the transformed phenotype. The inhibition of v-myc-induced cell transformation by BASP1 also prevents the transcriptional activation or repression of known Myc target genes. Mutational analysis showed that the basic N-terminal domain containing a myristoylation site, a calmodulin binding domain, and a putative nuclear localization signal is essential for the inhibitory function of BASP1. Our results suggest that down-regulation of the BASP1 gene is a necessary event in myc-induced oncogenesis and define the BASP1 protein as a potential tumor suppressor.


Indocyanine Green Perfusion Imaging-Guided Laparoscopic Pancreaticoduodenectomy: Potential Application in Retroperitoneal Margin Dissection.
During laparoscopic pancreaticoduodenectomy (LPD), dissecting uncinate process from the superior mesenteric artery (SMA) will determine one of the important surgical margins (retroperitoneal margin) for predicting oncological outcomes and the quality of LPD. However, clear identification of the division line for retroperitoneal margin is not easy as the uncinate process of the pancreas is anatomically very close to SMA and intermingled with the nerve plexus and soft tissues around SMA. In this study, we present data regarding the potential usefulness of indocyanine green (ICG)-enhanced approach in obtaining retroperitoneal margin during LPD. From January to September 2017, medical records of patients who underwent LPD for periampullary pathological conditions were retrospectively reviewed. ICG (5 mg/2 cm3) was prepared and intravenously injected when dissecting uncinate process of the pancreas. Perioperative outcomes, including gender, age, diagnosis, body mass index, operation time, estimated blood loss, transfusion, presence of postoperative pancreatic fistulas (POPFs), and length of hospital stay, were evaluated. During the study period, a total of 37 patients underwent LPD for periampullary pathological lesions. Among them, ICG-enhanced dissection of uncinate process of the pancreas was applied in 10 patients (27%). All patients were able to obtain margin-negative resection. There were no significant differences between the perioperative outcomes of patients who did and did not undergo ICG-enhanced approach. ICG perfusion-based laparoscopic dissection of retroperitoneal margin is feasible and safe in LPD. This intraoperative visual difference can provide the surgeon with very helpful real-time visual information. Further study is mandatory.


Knowledge, Attitudes, and Practices of Speech Language Pathologists in India about Telerehabilitation Services during the COVID-19 pandemic.
The global impact of the COVID-19 pandemic has opened opportunities for service providers and patients to continue with clinical services in certain extraordinary settings and circumstances. Telerehabilitation in the field of speech language pathology in India is still at its infancy, with a majority of the Speech Language Pathologists (SLP) accustomed with the conventional face-to-face system of service delivery. The present study aims to gather the knowledge, attitudes, and practices (KAP) of SLPs in India regarding telerehabilitation services during the pandemic. The study was conducted in three phases: phase I involved the development and validation of a questionnaire to explore the KAP of SLPs regarding telerehabilitation services. The items were framed based on a Likert rating scale (strongly agree, agree, neutral, disagree, and strongly disagree), yes-no-maybe format, open-ended, and multiple-choice format. Phase II involved data collection, while phase III involved data analysis. Descriptive statistics was done to derive the frequency and percentage for discrete variables and mean and SD for continuous variables. Many SLPs feel underprepared in their technical knowledge and skills needed for telerehabilitation. Furthermore, a majority of the SLPs also did report patients to be relatively lesser motivated and satisfied with tele practices due to issues that are discussed in the paper. This study is an initial attempt to touch upon the fabric of telerehabilitation services delivered by SLPs of India. Future studies are directed to study the technical, professional, and personal issues encountered during telerehabilitation services specifically pertaining to specific communication disabilities.


[Energy-dispersive X-ray analysis of pharmaceutical formulations].
Energy-dispersive X-ray analysis (EDS) coupled to a scanning electron microscopy (SEM) could represent a valuable tool in the study of solid dosage forms. In particular, EDS can be useful in the control of conventional pharmaceutical formulations by determining the presence and the distribution of characteristic compounds. More recently, the growth in the development of modified release dosage forms needed the determinations of parameters affecting the drug delivery. Among these, drug distribution, elements involved in crosslinking procedures and coatings of "reservoir" systems could easily and rapidly evaluated by EDS analysis. In this paper, we report the theoretical aspects and some applications of the EDS technique especially concerning controlled release dosage forms in order to show the versatility of such an analytical method which could be widely used in the future.


Premises and evidence in the rhetoric of assisted suicide and euthanasia.
In debates about euthanasia and assisted suicide, it is rare to find an article that begins with an expression of neutral interest and then proceeds to examine the various arguments and data before drawing conclusions based upon the results of a scholarly investigation. Although authors frequently give the impression of being impartial in their introduction, they invariably reach their prior conclusions. Positions tend to be clearly dichotomized: either one believes that the practice of euthanasia or assisted suicide is totally acceptable or completely unacceptable in a just and moral society. Where there is some admission of a gray zone of incertitude, authors attempt to persuade us that their beliefs (preferences) are the only sensible way to resolve outstanding dilemmas. The practice of vehemently promoting a "pro" or "con" position may be useful when societies must decide to either legalize certain practices or not. Although only a handful of countries have thus far accepted the legal practice of euthanasia or assisted suicide (Belgium, Luxembourg, The Netherlands, the U.S. states of Montana, Oregon, Vermont and Washington, and Switzerland), scholarly articles in recent trends mainly promote legalization, to the point of recommending expansion of the current practices. Is this a case of the philosophers being ahead of their time in promoting and rationalizing the wave of the future? Alternatively, does the small number of countries that have legalized these practices indicate a substantial gap between the beliefs and desires of common citizens and the universe of the 'abstracted realm'? For the time being, what we do know is that more countries and states are debating legalization of euthanasia or assisted suicide, the nature of laws and legal practices vary greatly and both ethical and empirical assessments of current practices are the subject of much controversy. This article presents an examination of the premises and evidence in the rhetoric of assisted suicide and euthanasia. Inasmuch as any analysis cannot be totally impartial, we do not contend that our analysis is without influence from our experiences and philosophical affinities. Notwithstanding this caveat, we venture to propose that our scrutiny of the arguments and empirical data may offer some guidance to individuals who are attempting to reach practical conclusions based upon the available evidence, whether empirical or rationalized.


The anti-La response of a single MRL/Mp-lpr/lpr mouse: specificity for DNA and VH gene usage.
Autoantibodies to ribonucleoproteins (RNP) occur prominently in human systemic lupus erythematosus and murine lupus models. In previous studies we demonstrated a relationship in MRL/Mp-lpr/lpr (MRL/lpr) mice between antibodies to Sm, an RNP autoantigen, and antibodies to DNA. Thus, many anti-Sm monoclonals bound DNA and expressed the same V region genes as anti-DNA. In addition, many had multiple VHCDR3 Arg residues suggestive of selection by DNA, and some had somatic mutations suggesting selection for mutant B cells by DNA. To determine whether autoantibodies to other RNP antigens are also associated with the anti-DNA response, we have analyzed the response to the La RNP. Six anti-La B cell hybridomas were generated from a single MRL/lpr mouse. Southern blot analysis of Ig V gene rearrangements and V gene sequences indicated two clonally related pairs, suggesting an oligoclonal response. Antibodies from all six hybridomas bound single-stranded DNA, while antibodies from five hybridomas bound double-stranded DNA. Two hybridomas expressed a VH7183 gene which is used by members of two previously reported anti-DNA clones and two anti-Sm/DNA clones of MRL/lpr origin. These data demonstrate an association between the anti-La and anti-DNA responses in MRL/lpr mice, suggesting that cross-reactive anti-RNP and anti-DNA responses are a general feature of autoimmunity in this lupus model.


Perforin-dependent nuclear entry of granzyme B precedes apoptosis, and is not a consequence of nuclear membrane dysfunction.
Killer lymphocytes utilize the synergy of a membranolytic protein, perforin, and the serine protease granzyme B (grB) to induce target cell apoptosis, however the mechanism of this synergy remains incompletely defined. We have previously shown that perforin specifically induces the redistribution of cytoplasmic grB into the nucleus of dying cells, however a causal role for nuclear targeting of grB in cell death has not been demonstrated. In the present study, we used confocal laser scanning microscopy (CLSM) to determine whether the nuclear accumulation of fluoresceinated (FITC-) grB precedes or is a consequence of apoptosis. Two distinct and mutually exclusive cellular responses were observed in FDC-P1 cells: (i) up to 50% of the cells rapidly accumulated FITC-grB in the nucleus (maximal at 7 min; t1/2 of 2 min) and underwent apoptosis; (ii) the remaining cells took up FITC-grB only into the cytoplasm, and escaped apoptosis. Under these conditions, DNA fragmentation was not observed for at least 13 min, indicating nuclear accumulation of grB preceded the execution phase of apoptosis. Furthermore, nuclear import of grB proceeded through an intact nuclear membrane, as the nuclei of cells whose cytoplasm was pre-loaded with 70 kDa FITC-dextran excluded dextran for up to 90 min while still undergoing apoptosis in response to perforin and grB. These findings indicated that perforin-induced nuclear accumulation of grB precedes apoptosis, and is not a by-product of caspase-induced nuclear membrane degradation. The cell membrane lesions formed by perforin in these experiments were not large enough to permit a 13 kDa protein (yeast cdk p13suc) access into the cytoplasm, but an 8 kDa protein (bacterial azurin) was able to equilibrate between the cytosol and the exterior. Therefore, transmembrane pores large enough to allow passive diffusion of grB (32 kDa) into the cell are not necessary for apoptosis. Rather, a perforin-dependent signal results in a redistribution of grB from the cytoplasm to the nucleus, where it may contribute to the nuclear changes associated with apoptosis.


Therapeutic effect of green tea extract on advanced glycation and cross-linking of collagen in the aorta of streptozotocin diabetic rats.
1. The therapeutic effect of green tea extract (GTE) on the aortic collagen content and its characteristics were investigated in streptozotocin diabetic rats. 2. Diabetes was induced in rats by a single intra peritoneal injection of streptozotocin (60 mg/kg bodyweight). Six weeks after diabetes induction, GTE was administered orally for four weeks (300 mg/kg bodyweight daily). Systolic blood pressure, blood glucose, anti-oxidant status, collagen content, extent of glycation, collagen linked fluorescence and aortic collagen solubility pattern were determined in experimental rats. 3. At the end of the experimental period, there was a significant increase in the systolic blood pressure and blood glucose in diabetic rats. The lipid peroxides increased whereas glutathione and vitamin C levels were decreased in the serum of diabetic rats. The collagen content, extent of glycation, the advanced glycation end products (AGEs) and degree of cross-linking were increased in the aorta of diabetic rats. 4. The oral administration of GTE to diabetic rats significantly reduced the systolic blood pressure and blood glucose. The level of lipid peroxides reduced and the content of glutathione and vitamin C increased in the serum of GTE treated diabetic rats. Green tea extract also impede the accumulation of aortic collagen, extent of glycation, formation of AGEs and cross-linking of collagen in diabetic rats. The antihyperglycemic, anti-oxidant and antiglycating effects of GTE ascribed for these beneficial effects. In conclusion, green tea may have therapeutic effect in the treatment of cardiovascular complications characterized by increased AGE accumulation and protein cross-linking associated with diabetes.


Does substance P comediate with acetylcholine in nerves of opossum esophageal muscularis mucosa?
In opossum esophagus the highest density of varicose substance P-like immunoreactive deposits was in the muscularis mucosa, and this muscle layer, which is thick and prominent, was the most sensitive in contracting to exogenous substance P. On field stimulation, a tetrodotoxin-sensitive biphasic contraction was produced; an initial phasic component was followed after cessation of stimulation by a prolonged tonic component. This contractile response was unaffected by guanethidine or antagonists to several nerve mediators and to histamine and serotonin antagonists. Each component showed a different frequency dependence. The phasic component was abolished by atropine and potentiated by physostigmine; the tonic component was reduced or abolished after carbachol or physostigmine and potentiated by atropine. The tonic component was inhibited after substance P tachyphylaxis or by the substance P antagonist [D-Pro2, D-Trp7,9]substance P. On electron microscopic examination, the majority of nerve varicosities contained a mixture of small agranular and large granular vesicles. We postulate that acetylcholine and substance P may coexist in and be coreleased from nerves of this muscle and that the acetylcholine release occurs first, causing an initial phasic response and delaying and diminishing the release of substance P. The two mediators cause muscle contraction by actions on independent receptors.


Development of brain-wide connectivity architecture in awake rats.
Childhood and adolescence are both critical developmental periods, evidenced by complex neurophysiological changes the brain undergoes and high occurrence rates of neuropsychiatric disorders during these periods. Despite substantial progress in elucidating the developmental trajectories of individual neural circuits, our knowledge of developmental changes of whole-brain connectivity architecture in animals is sparse. To fill this gap, here we longitudinally acquired rsfMRI data in awake rats during five developmental stages from juvenile to adulthood. We found that the maturation timelines of brain circuits were heterogeneous and system specific. Functional connectivity (FC) tended to decrease in subcortical circuits, but increase in cortical circuits during development. In addition, the developing brain exhibited hemispheric functional specialization, evidenced by reduced inter-hemispheric FC between homotopic regions, and lower similarity of region-to-region FC patterns between the two hemispheres. Finally, we showed that whole-brain network development was characterized by reduced clustering (i.e. local communication) but increased integration (distant communication). Taken together, the present study has systematically characterized the development of brain-wide connectivity architecture from juvenile to adulthood in awake rats. It also serves as a critical reference point for understanding circuit- and network-level changes in animal models of brain development-related disorders. Furthermore, FC data during brain development in awake rodents contain high translational value and can shed light onto comparative neuroanatomy.


A 6-month follow-up of disability, quality of life, and depressive and anxiety symptoms in pediatric migraine with magnesium prophylaxis.
Magnesium is frequently used for pediatric migraine prophylaxis. The aim of this study was to evaluate to which extent the disability levels, quality of life (QOL), and anxiety and depressive symptoms change after 6-month magnesium prophylaxis in pediatric migraine. This is a follow-up study of 34 children aged 7-17 years with migraine treated with oral magnesium. Disability due to migraine was assessed by the Pediatric Migraine Disability Assessment tool (PedMIDAS), QOL was assessed by the KIDSCREEN-27, and anxiety and depressive symptoms were assessed by the Revised Child Anxiety and Depression Scale (RCADS). PedMIDAS scores significantly decreased from baseline to end-point (F(df, dferror) = 11.10 (1.63, 50.49), p<0.001), as well as anxiety (F(df, dferror) = 8.95 (1.64, 50.67), p = 0.001) and depressive symptoms (F(df, dferror) = 8.91 (1.59, 49.29), p = 0.001). Considering the KIDSCREEN-27, scores for physical and psychological well-being and social support domain significantly increased from baseline to end-point (p≤0.01). After 6 months of magnesium prophylaxis, disability due to migraine significantly decreased, whereas physical and psychosocial well-being improved. Children also reported fewer anxiety and depressive symptoms. More follow-up and randomized controlled clinical trials are needed to propose clinical recommendations for magnesium prophylaxis in pediatric migraine.


Parental perception of contrast enhanced voiding ultrasonography urodynamics vs fluoroscopic urodynamics.
Contrast enhanced voiding ultrasonography (ceVUS) has not been widely reported to be used during video urodynamics (UDS). We previously reported on the feasibility of this. In this study, we aimed to understand how parents perceived their child's experience of undergoing ceVUS during UDS compared to fluoroscopic (fluoro) UDS. Children who underwent both fluoro UDS and ceVUS UDS were recruited. Parents were asked to complete a questionnaire to evaluate their experience with both studies. Demographics including gender, age at study, and diagnosis were collected to account for differences in perception. Statistical analysis was performed. 53 patients were included: 31 girls, 22 boys. Diagnoses included myelomeningocele (67.9%), low/tethered cord (13.2%), closed spinal dysraphism (9.4%), posterior urethral valve (1.9%), cloacal anomaly (1.9%), caudal regression (1.9%), myeloschisis (1.9%), and cerebral palsy (1.9%). There was no statistical difference in mean age at fluoro UDS and ceVUS UDS (77.3 months vs 99.7 months respectively, p = 0.09). All 53 parents (100%) were satisfied/very satisfied with their ceVUS experience; 48 parents (90.6%) preferred ceVUS, 3 parents (5.7%) preferred fluoro UDS, and 2 (3.8%) were neutral. On average, parents perceived ceVUS to be more comfortable (72.7%) and produce better results (67.4%) than fluoro UDS. The majority felt that both studies allowed the same contact with their child (52.3%) and took the same amount of time (50.0%). However 29.5% felt ceVUS was faster and 34.1% felt ceVUS allowed more contact with their child (Fig. 1). 26 parents (49.1%) specifically noted no radiation as the reason why they preferred ceVUS over fluoro. The average age at ceVUS UDS was younger in those who preferred ceVUS UDS compared to those who preferred fluoro UDS (94.6 months vs 180.0 months, p = 0.03). The average age at fluoro UDS was younger in those who preferred ceVUS UDS vs fluoro UDS (73.1 months vs 144 months, p = 0.03). Gender's influence on preference approached significance (p = 0.07); all 3 parents who preferred fluoro UDS had male children. The majority of parents preferred ceVUS over fluoro UDS. ceVUS was perceived to be more comfortable and provide better results. Many parents highlighted no radiation and no fluoroscopic machinery as factors in preference of ceVUS over fluoro. The parents who preferred ceVUS UDS had children who had both studies done at an earlier age compared to the parents who preferred fluoro UDS.


[Fiber bronchoscopy with artificial pulmonary ventilation by an injection method in ambulatory practice].
The experience of 800 bronchoscopies with the help of fibrobronchoscopes under anesthesia in the outpatient clinic is generalized. An original method of the artificial ventilation of the lungs with the aid of a specially elaborated by the authors attachment-injector to an ordinary endotracheal tube is described. According to the authors' data, fibrobronchoscopy under anesthesia with the injectional artificial ventilation of the lungs is a little-traumatic measure which permits obtaining a complete information on the character of changes in the tracheobroncheal tree of the patients.


The tyrosine kinase receptors Ron and Sea control "scattering" and morphogenesis of liver progenitor cells in vitro.
The mammalian RON and the avian sea genes encode tyrosine kinase receptors of poorly characterized biological functions. We recently identified macrophage-stimulating protein as the ligand for Ron; no ligand has yet been found for Sea. In this work we investigated the biological response to macrophage-stimulating protein in mouse liver progenitor cells expressing Ron. These cells were also transfected with a chimeric cDNA encoding the cytoplasmic domain of Sea, fused to the extracellular domain of Trk (nerve growth factor receptor). In the presence of nanomolar concentrations of the respective ligands, both receptors induced cell "scattering", extracellular matrix invasion, and DNA synthesis. When liver progenitor cells were grown in a tri-dimensional type-I collagen matrix, ligand-induced stimulation of either Ron or Sea induced sprouting of branched cell cords, evolving into ductular-like tubules. The motogenic, mitogenic, and morphogenic responses were also elicited by triggering the structurally related hepatocyte growth factor receptor (Met) but not epidermal growth factor or platelet-derived growth factor receptors. These data show that Ron, Sea, and Met belong to a receptor subfamily that elicits a distinctive biological response in epithelial cells.


Active morbidity surveillance after Hurricane Andrew--Florida, 1992.
To describe the health status of and to detect disease outbreaks in the population affected by Hurricane Andrew in south Dade County, Florida. The Florida Department of Health and Rehabilitative Services and the US Army conducted active surveillance for gastrointestinal illness, respiratory illness, injury, and other index conditions by monitoring civilian and service member visits to care sites (civilian and military free care sites and hospital emergency departments) from August 30 (1 week after the hurricane's landfall) through September 30, 1992. South Dade County, Florida. Proportional morbidity: the number of daily visits for each index condition divided by the total number of visits, expressed as a percentage. Morbidity rate: the total number of daily visits by service members divided by the total number of service members, expressed as a percentage. Six index conditions accounted for 41.3% of visits to civilian free care sites: diarrhea (4.7%), cough (4.7%), other infection (9.6%), rash (5.4%), animal bite (1.2%), and injury (15.7%). At military free care sites, five index conditions accounted for 75.7% of civilian visits: injury (23.7%), dermatologic illness (12.4%), respiratory illness (9.9%), gastrointestinal illness (5.3%), and other medical conditions (24.4%). Two index conditions accounted for 54.1% of service member visits: injury (36.2%) and dermatologic illness (17.9%). During the 5 weeks after the hurricane, proportional morbidity from injury decreased; proportional morbidity from respiratory illness increased; and proportional morbidity from diarrhea was stable. No infectious disease outbreaks occurred. Injuries were an important source of morbidity throughout the surveillance period, especially among service members. Enteric and respiratory agents did not cause disease outbreaks, despite alarming rumors to the contrary.


Desensitization of glutamate dehydrogenase by reaction of tyrosne residues.
1. The reaction of glutamate dehydrogenase with N-acetylimidazole and with tetranitromethane leads to modification of tyrosine residues. 2. Modification of 1 tyrosine residue/subunit does not affect the enzymic activity but decreases the response of the enzyme to the allosteric inhibitor, GTP. 3. The physical properties of the enzyme (sedimentation coefficient and optical rotatory dispersion) remain unaltered. 4. GTP partially protects against desensitization. 5. The diminished responses of the modified enzymes to GTP are also detected by using the fluorescence of 1-anilinonaphthalene-8-sulphonate as a conformational probe. 6. Difficulties that generally arise in chemical modifications from inhomogeneous distributions of products are discussed.


Classification of low-grade neuroendocrine tumors of midgut and unknown origin.
Metastasized neuroendocrine tumors of the gastrointestinal tract and of unknown origin show a highly variable clinical course. Within this group, low-grade and high-grade malignant tumors can be recognized based on the revised classification of neuroendocrine tumors of the lung, pancreas, and gut published by Capella et al in 1995. The present study investigated whether fine-tuning the prediction of prognosis was possible by dividing the group of low-grade malignant tumors of the midgut and of unknown origin into typical and atypical carcinoids by grading them according to the World Health Organization (WHO) classification criteria for neuroendocrine tumors of the lung. Moreover, the prognostic value of immunohistochemical stainings and clinical parameters was evaluated. The study group comprised patients diagnosed between 1983 and 1999 with liver metastases of a neuroendocrine tumor of the midgut n = 40) or of unknown origin (n = 16). As a control for the consistency of grading, 10 patients with metastasized neuroendocrine tumors of the lung also were evaluated. Immunohistochemical stainings for chromogranin A, synaptophysin, Leu 7/CD57, neural cell adhesion molecule/CD56, cytokeratin 8, bcl-2, p53, ki67, and HER2/neu were performed. The clinical parameters age, gender, urinary 5-HIAA level, and presence or absence of the carcinoid syndrome were evaluated. Tumors of the midgut and of unknown origin were evaluated together, because they were clinically similar. In this group of 56 patients, both the Capella and the WHO classification systems recognized the high-grade malignant tumors with a bad prognosis. When the low-grade malignant tumors (Capella) were divided into typical and atypical carcinoids (WHO), no difference in survival was observed, but when the dichotomy into typical and atypical was based on mitotic count alone, the difference became borderline significant (P =.072). Of the immunohistochemical stainings used, synaptophysin, cytokeratin 8, and ki67 had limited prognostic value. Age above 60 was the only clinical parameter of unfavorable prognostic significance. We conclude that high-grade malignant neuroendocrine tumors of the midgut and of unknown origin are recognized by both the Capella classification and the WHO classification of neuroendocrine tumors of the lung. Further subdividing low-grade malignant tumors at this location appears to be of less value than in the lung, but assessing the mitotic activity of these tumors might be of prognostic value.


Relationship between prognosis of papillary thyroid carcinoma patient and age: a retrospective single-institution study.
Age is an important prognostic factor in papillary thyroid carcinoma (PTC). In this study, we investigated the difference in prognosis of 7 subsets of PTC patients without distant metastasis at presentation or a history of radiation exposure (20 years or younger, 21-30 years, 31-40 years, 41-50 years, 51-60 years, 61-70 years, and older than 70 years). The lymph node recurrence rate was high in patients 20 years or younger and those older than 60 years. Distant recurrence and carcinoma death rates significantly elevated in patients older than 60 years. The incidence of significant extrathyroid extension markedly increased with age, although that of large node metastasis or extranodal tumor extension did not differ much among the 7 subsets. With the Kaplan-Meier method, lymph node recurrence rate was poor in patients 20 years or younger and in those older than 60 years. Poor distant recurrence-free and cause specific survivals of patients older than 60 years were identified in the series of PTC patients with and without these aggressive features. It is therefore suggested that 1) Lymph node recurrence rate was high in patients 20 years or younger and those older than 60 years and 2) prognosis, including distant recurrence-free survival and cause-specific survival, of patients older than 60 years was poor regardless of clinicopathological features of PTC at initial surgery.


Multiplexed digital mRNA profiling of the inflammatory response in the West Nile Swiss Webster mouse model.
The ability to track changes in gene expression following viral infection is paramount to understanding viral pathogenesis. This study was undertaken to evaluate the nCounter, a high throughput digital gene expression system, as a means to better understand West Nile virus (WNV) dissemination and the inflammatory response against WNV in the outbred Swiss Webster (SW) mouse model over the course of infection. The nCounter Mouse Inflammation gene expression kit containing 179 inflammation related genes was used to analyze gene expression changes in multiple tissues over a nine day course of infection in SW mice following intraperitoneal injection with WNV. Protein expression levels for a subset of these cytokine/chemokine genes were determined using a multiplex protein detection system (BioPlex) and comparisons of protein/RNA expression levels made. Expression analysis of spleen, lung, liver, kidney and brain of SW mice infected with WNV revealed that Cxcl10 and Il12b are differentially expressed in all tissues tested except kidney. Data stratification of positively confirmed infected (WNV (+)) versus non-infected (WNV (-) tissues allowed differentiation of the systemic inflammatory gene response from tissue-specific responses arising from WNV infection. Significant (p<0.05) decrease in C3ar1 was found in WNV (-) spleen. Il23a was significantly upregulated, while Il10rb was down-regulated in WNV (-) lung. Il3 and Mbl2 were down-regulated in WNV (-) liver. In WNV (+) livers, Stat1, Tlr2, chemokines Cxcl1, Cxcl3, Cxcl9, Cxcl10, cytokines Il6, Il18, cytokine-related gene Il1r and cytokine agonist Ilrn were significantly upregulated. In WNV (-) brain tissues, Csf2 and Cxcl10 were significantly upregulated. Similar gene and protein expression kinetics were found for Ccl2, Ccl3, Ccl4 and Ccl5 and correlated with the presence of infectious virus. In summary, the utility of the nCounter platform for rapid identification of gene expression changes in SW mice associated with WNV infection was demonstrated.


[Intradiploic dermoid cyst of the skull: report of a case].
A case of intradiploic dermoid cyst of the skull in a female child with seizures is reported. The authors emphasize diagnostic aspects and the surgical procedure. The characteristics of the tumor were cleared at the surgical procedure, and its nature was confirmed by histological examination. The importance of the skull biopsy when radiological aspects are not definite and the benign characteristics of the process are discussed. Good results of surgical treatment and the infrequency of the tumor justify the report.


Impact of nocturnal hypoxemia on the recurrence of atrial tachyarrhythmia after catheter ablation of atrial fibrillation.
Factors causing atrial tachyarrhythmia recurrence after catheter ablation (CA) of atrial fibrillation (AF) remain undetermined. This study aimed to investigate the effect of nocturnal hypoxemia on the recurrence of atrial tachyarrhythmia after CA of AF. Among 594 patients with AF who underwent an ambulatory sleep study at the National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (2014-2019), 365 underwent CA of AF; 290 patients who underwent CA were followed up for > 3 months. Multivariate Cox regression analysis was used to calculate hazard ratios (HRs) using clinical variables, to identify the independent predictors of atrial tachyarrhythmia recurrence after the final CA. Atrial tachyarrhythmia recurred in 45 of 290 (15.5%) patients during the median follow-up period of 479 days (interquartile range 225-1002). On the performing multivariate analysis of the data of patients who did not receive continuous positive airway pressure (CPAP), severe nocturnal hypoxemia [defined as the percentage of sleep time spent with SaO2 of < 90% (T90) over 20%] [HR 8.53, 95% confidence interval (CI) 1.872-38.814; P < 0.01] and an 1 mL/m2 increase in the left atrial volume index (HR 1.02, 95% CI 1.004-1.044; P = 0.02) were found to be independently associated with the recurrence of atrial tachyarrhythmia. In addition, the rates of freedom from atrial tachyarrhythmia after the final AF ablation with CPAP were significantly lower in the group with more severe nocturnal hypoxemia (Log-rank P = 0.03). In conclusion, it is necessary to consider both, AHI and nocturnal hypoxia while performing an ambulatory sleep apnea study. CA may be less effective in patients with more severe nocturnal hypoxia, despite the administration of CPAP.


Long-term effects of nutritional programming of the embryo and fetus: mechanisms and critical windows.
The maternal nutritional and metabolic environment is critical in determining not only reproduction, but also long-term health and viability. In the present review, the effects of maternal nutritional manipulation at defined stages of gestation coinciding with embryogenesis, maximal placental or fetal growth will be discussed. Long-term outcomes from these three developmental windows appear to be very different, with brain and cardiovascular function being most sensitive to influences in the embryonic period, the kidney during placental development and adipose tissue in the fetal phase. In view of the similarities in fetal development, number and maturity at birth, there are close similarities in these outcomes between findings from epidemiological studies in historical human cohorts and nutritional manipulation of large animals, such as sheep. One key nutrient that may modulate the long-term metabolic effects is the supply of glucose from the mother to the fetus, because this is sensitive to both global changes in food intake, maternal glucocorticoid status and an increase in the carbohydrate content of the diet. The extent to which these dietary-induced changes may reflect epigenetic changes remains to be established, especially when considering the very artificial diets used to induce these types of effects. In summary, the maintenance of a balanced and appropriate supply of glucose from the mother to the fetus may be pivotal in ensuring optimal embryonic, placental and fetal growth. Increased or decreased maternal plasma glucose alone, or in conjunction with other macro- or micronutrients, may result in offspring at increased risk of adult diseases.


[The elimination of extended defects of the ductus deferens].
Based on their own experience gained in 12 reconstructive surgeries performed for iatrogenic lesions of the deferent duct in 8 patients the authors came to the conclusion that in the majority of patients an immediate vasovasostomy would be a failure or incompetence because of a significant tension of the tissues. To solve the faced problem, the authors proposed a technique of extra-anatomical (supra- and subpubic) anastomosis which enabled one to reduce the length of the duct by 9-19 cm. Transplantation of the duct's segments in the rat failed to demonstrate any benefit in case of homotransplantation of the duct's segments whereas autotransplants survived in 70 per cent of the cases and provided a 40 per cent recovery of the duct's patency. No signs of endoprosthetic effect on the transplantation outcomes were evident.


Performance of mNGS in bronchoalveolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in non-neutropenic patients.
The diagnosis of invasive pulmonary aspergillosis (IPA) diseases in non-neutropenic patients remains challenging. It is essential to develop optimal non-invasive or minimally invasive detection methods for the rapid and reliable diagnosis of IPA. Metagenomic next-generation sequencing (mNGS) in bronchoalveolar lavage fluid (BALF) can be a valuable tool for identifying the microorganism. Our study aims to evaluate the performance of mNGS in BALF in suspected IPA patients and compare it with other detection tests, including serum/BALF galactomannan antigen (GM) and traditional microbiological tests (BALF fungal culture and smear and lung biopsy histopathology). Ninety-four patients with suspicion of IPA were finally enrolled in our study. Thirty-nine patients were diagnosed with IPA, and 55 patients were non-IPA. There was significance between the IPA and non-IPA groups, such as BALF GM (P < 0.001), history of glucocorticoid use (P = 0.004), and pulmonary comorbidities (P = 0.002), as well as no significance of the other demographic data including age, sex, BMI, history of cigarette, blood GM assay, T-SPOT.TB, and NEUT#/LYMPH#. The sensitivity of the BALF mNGS was 92.31%, which was higher than that of the traditional tests or the GM assays. The specificity of BALF mNGS was 92.73%, which was relatively similar to that of the traditional tests. The AUC of BALF mNGS was 0.925, which presented an excellent performance compared with other traditional tests or GM assays. Our study demonstrated the important role of BALF detection by the mNGS platform for pathogen identification in IPA patients with non-neutropenic states, which may provide an optimal way to diagnose suspected IPA disease.


Depression and fatigue in the primary care physician.
Fatigue is a symptom that is found in a variety of psychiatric disorders. The nature of a physician's life may foster such symptoms that can be either a reaction to work or a sign of an emotional disorder. This article summarizes various developmental stages that can lead to such problems. These difficulties may also be found in the physician's family and can be easily overlooked.


Proliferating trichilemmal cyst in an organoid nevus.
An unusual tumor mass of the scalp found in an elderly woman is presented. This lesion had many features simulating a verrucous squamous cell carcinoma of the scalp. Pathologic findings eventually revealed the tumor mass to be a proliferating trichilemmal cyst. Differentiation between a benign and malignant process in these lesions can sometimes be difficult. Clinical as well as histopathologic evaluation is necessary to make an accurate diagnosis.


Cardiovascular risks before myocardial infarction differences between men and women.
Prodromal cardiac symptoms are warning signals preceding cardiac disease. Previous studies have shown some gender differences in prodromal symptoms as well as established risk factors for MI. This study aims to map possible gender differences in social factors and established risk factors preceding myocardial infarction (MI). The study includes data of N = 213 middle-aged men and women, all diagnosed with myocardial infarction (ICD-10 I21.9) from the region of south-east Sweden. They answered a questionnaire at discharge from the cardiologic clinic and additional clinical data from medical records were merged from the National Swedeheart Register. The dominant prodromal symptom for both sexes were experience of chest pain at the onset of MI. The major gender differences were that significantly more females (p = 0.015) had a hyperlipidemia diagnose. Females also reported to have experienced higher stress load the year preceding myocardial infarction with serious life events (p = 0.019), strained economy (p = 0.003), and reports of sadness/depression (p < 0.001). Females reported higher perceived stress load than men (p = 0.006). Men had higher systolic blood pressure than women at hospital admission and a higher systolic- and diastolic blood pressure at discharge. Influences of the social environment, such as serious life events, strained economy, depression, stress, and sleep deprivation were stronger as potential risk factors for myocardial infarction in women than among men. Of the traditional risk factors only, hyperlipidemia was more frequent among women. These findings could contribute to a deeper understanding of diagnostic differences between gender, as well as a more gender-oriented cardiovascular preventive work.


Cutaneous immune-related phenomena in patients with inflammatory arthritides treated with biological therapies: Clinical and pathophysiological considerations.
In recent years, identifying the pathophysiologic mechanisms underlying autoimmune arthritides and systematic diseases has led to the use of biological drugs. The primary targets of those biological therapies are cytokines, B cells, and co-stimulation molecules. So far, these targeted therapies have shown good clinical improvement and an acceptable toxicity profile. However, by blocking components of an intact immune system, autoimmune phenomena and paradoxical inflammation have emerged, and among them many cutaneous immune-related adverse events (irAEs). In this article, we review the current state of knowledge on the clinical features and mechanisms of specific cutaneous irAEs observed during treatment with biological therapies. Among those, psoriatic skin lesions are the most commonly observed. Herein, we also report new cases of cutaneous irAEs recently seen in our clinic to help physicians treating inflammatory arthritides recognize cutaneous irAEs early and better manage patients receiving biologic therapies.


Placement of a covered expandable metallic stent to treat nonanastomotic malignant jejunal obstructions after total gastrectomy with esophagojejunostomy.
The objective of our study was to assess the technical feasibility and clinical effectiveness of expandable metallic stent placement in patients with nonanastomotic malignant jejunal obstruction after total gastrectomy with esophagojejunostomy. We retrospectively analyzed data from 21 patients with malignant jejunal obstruction after total gastrectomy with esophagojejunostomy who received one of two types of expandable metallic stent. Clinical effectiveness was assessed using the following variables: technical and clinical outcomes, complications, dysphagia scores before and after stent placement, patient survival, and stent patency. Complications with related interventions were evaluated and compared between the two stent types. Stent placement was technically successful in 20 of the 21 patients (95%) with 19 of 20 patients (95%) showing symptomatic improvement. Type A stents were used in 10 patients and type B stents in the remaining 10 patients. Complications occurred with seven of 20 stents (35%) and involved stent migration (n = 3), tumor overgrowth (n = 3), or pain (n = 1). The dysphagia score before stent placement (mean ± SD, 3.2 ± 0.5) had improved by 3 days after stent placement (1.3 ± 0.9, p < 0.001) and was maintained compared with the initial score up to 1 month (1.7 ± 1.1, p < 0.001) and 3 months (2.1 ± 1.5, p = 0.021) after stent placement. The median patient survival and stent patency were 114 and 46 days, respectively. The type of stent was not significantly related to complications (p = 0.350). Placement of expandable metallic stents to treat nonanastomotic malignant jejunal obstruction in patients who have undergone total gastrectomy with esophagojejunostomy is feasible and clinically effective.


Chiropractic scope of practice: what the law allows--update 1993.
To determine on a state by state, province by province basis what diagnostic and treatment procedures are allowed by statute in the various practice acts. A survey administered by mail. All state and provincial licensing boards. The response rate to the survey was 90%. More than 50% of the responding licensing boards allow chiropractors to order or perform clinical lab procedures, conduct components of a routine physical exam, examine the female pelvis, perform rectal exams, and conduct electromyographic, electrocardiographic and nerve conduction studies. More than 80% can perform a variety of X-ray procedures, use thermography, administer a vascularizer (Doppler) and order CT or MRI studies. More than 90% of the respondents permit chiropractors to employ some form of physiotherapy, adjust soft tissue or extremities, supplement with vitamins and conduct impairment ratings. These findings demonstrate that the chiropractic profession offers a broad range of diagnostic and treatment procedures.


[Acute and subacute catatonic syndromes with weight loss. Its favorable development with electroconvulsive therapy].
When following a malignant course, acute, sub-acute catatonias generally tend to cause bed-sores, loss of weight, and, within a few months, cachexia, ematiation, and marasmus. In general, they develop a periodical character provided they are adequately treated. What is more noteworthy in cachectic catatonias is a favorable reaction to electro convulsive therapy (ECT) which may be thus considered a principal indication for treatment. This paper presents the case of four catatonic patients with severe loss of weight, that remarkably improved with ECT.


Copper and cobalt recovery from pyrite ashes of a sulphuric acid plant.
The pyrite ashes formed as waste material during the calcination of concentrated pyrite ore used for producing sulphuric acid not only has a high iron content but also contains economically valuable metals. These wastes, which are currently landfilled or dumped into the sea, cause serious land and environmental pollution problems owing to the release of acids and toxic substances. In this study, physical (sulphation roasting) and hydrometallurgical methods were evaluated for their efficacy to recover non-iron metals with a high content in the pyrite ashes and to prevent pollution thereby. The preliminary enrichment tests performed via sulphation roasting were conducted at different roasting temperatures and with different acid amounts. The leaching tests investigated the impact of the variables, including different solvents, acid concentrations and leach temperatures on the copper and cobalt leaching efficiency. The experimental studies indicated that the pre-enrichment via sulphation roasting method has an effect on the leaching efficiencies of copper and cobalt, and that approximate recoveries of 80% copper and 70% cobalt were achieved in the H2O2-added H2SO4 leaching tests.


Immunologic hypo- or non-responder in natural dengue virus infection.
Serologically defined primary dengue virus infection and/or subsequent homologous serotype infection is known to be associated with less severe disease as compared with secondary subsequent heterologous serotype infection. In geographical locales of high dengue endemicity, almost all individuals in the population are infected at some point in time and should therefore are at high risk of secondary infection. Interestingly, dengue viremia in healthy blood donors whose sera apparently lack detectable levels of specific antibody to dengue viral antigens has been reported. The incidence rate of potential immunologic hypo- or non-responders following natural primary dengue virus infection in dengue endemic regions, who do become immune responders only after repeated exposure, has not been described. These are the patients who may be diagnosed as primary infection in the subsequent infection, but actually are secondary infection. This concept has important implications with regards to the hypothesis of immunological enhancement of dengue pathogenesis, which has largely been advanced based on empirical observations and/or from in vitro experimental assays. The fact that dengue naïve travelers can suffer from severe dengue upon primary exposure while visiting dengue endemic countries underscores one of the major problems in explaining the role of immune enhancement in the pathogenesis of severe dengue virus infection. This evidence suggests that the mechanism(s) leading to severe dengue may not be associated with pre-existing enhancing antibody. Consequently, we propose a new paradigm for dengue virus infection classification. These include a) patients with naïve primary infection, b) those that are serologically defined primary in dengue endemic zones and c) those who are serologically defined secondary dengue virus infection. We submit that clarity with regards to such definitions may help facilitate the delineation of the potential mechanisms of severe dengue virus infection.


The functional architecture of axonal actin.
The cytoskeleton builds and supports the complex architecture of neurons. It orchestrates the specification, growth, and compartmentation of the axon: axon initial segment, axonal shaft, presynapses. The cytoskeleton must then maintain this intricate architecture for the whole life of its host, but also drive its adaptation to new network demands and changing physiological conditions. Microtubules are readily visible inside axon shafts by electron microscopy, whereas axonal actin study has long been focused on dynamic structures of the axon such as growth cones. Super-resolution microscopy and live-cell imaging have recently revealed new actin-based structures in mature axons: rings, hotspots and trails. This has caused renewed interest for axonal actin, with efforts underway to understand the precise organization and cellular functions of these assemblies. Actin is also present in presynapses, where its arrangement is still poorly defined, and its functions vigorously debated. Here we review the organization of axonal actin, focusing on recent advances and current questions in this rejuvenated field.


Doxycycline Prophylaxis for Skin and Soft Tissue Infections in Naval Special Warfare Trainees, United States1.
In 2015, several severe cases of skin and soft tissue infection (SSTI) among US Naval Special Warfare trainees prompted the introduction of doxycycline prophylaxis during the highest-risk portion of training, Hell Week. We performed a retrospective analysis of the effect of this intervention on SSTI incidence and resulting hospital admissions during 2013-2020. In total, 3,371 trainees underwent Hell Week training during the study period; 284 SSTIs were diagnosed overall, 29 of which led to hospitalization. After doxycycline prophylaxis was introduced, admission rates for SSTI decreased from 1.37 to 0.64 admissions/100 trainees (p = 0.036). Overall SSTI rates remained stable at 7.42 to 8.86 SSTIs/100 trainees (p = 0.185). Hospitalization rates per diagnosed SSTI decreased from 18.4% to 7.2% (p = 0.009). Average length of hospitalization decreased from 9.01 days to 4.33 days (p = 0.034). Doxycycline prophylaxis was associated with decreased frequency and severity of hospitalization for SSTIs among this population.