Tuberculous aneurysm of the descending thoracic aorta.
Tuberculous aneurysm of the descending thoracic aorta is a rare entity. To our knowledge the present case is the sixth on record to have been successfully treated surgically. These aneurysms present the usual difficulties of surgical therapy of the thoracic aorta: spinal cord and renal circulatory protection and the choice between distant or in situ revascularization. This case is of particular interest for its evolution and its treatment: resection of the aneurysm without shunting and insertion of a graft in situ covered by a flap of omentum.


Relevance of photocatalytic redox transformations of selected pharmaceuticals in a copper- and iron-rich Mediterranean intermittent river.
This work aimed at investigating specific attenuation pathways of pharmaceuticals in copper- and iron-rich Mediterranean intermittent and sunlit rivers by combining lab- and field-scale studies. Poorly photodegradable and biodegradable compounds such as fluconazole, oxazepam and venlafaxine attenuated in two river stretches with short hydraulic residence times (<3 h). This result was assumed to be related to their capacity to interact with photoreactive free Cu2+ and Fe3+ or their associated oxides. Lab-scale photodegradation experiments under simulated solar irradiation revealed the beneficial impact of a mixture Cu2+ and colloidal iron hydroxides at environmental concentrations and at neutral pH on the pharmaceuticals photodegradation kinetic rate constants. These latter were consistent with the in-stream attenuation rate constants of targeted contaminants which ranged from 0.104 to 0.154 h-1. Further identification of phototransformation products by LC-HRMS highlighted reductive transformation pathways including reductive dehalogenation and hydrogenation reactions. Several TPs were found to be stable under irradiation and were detected in field monitoring, accordingly. This was ascribed to the formation of a Cu/Fe composite material under solar irradiation with photocatalytic properties. The role of Cu was to trap the electron in the conduction band of the iron-based photocatalyst, which promoted separation efficiency of electron-hole pairs as well as enhanced photoreduction processes at the expense of oxidation ones. Even though, these mechanisms have been reported in water treatment field for organic micropollutants removal, their significance was demonstrated for the first time in natural settings.


Mechanistic considerations of enantiorecognition on novel Cinchona alkaloid-based zwitterionic chiral stationary phases from the aspect of the separation of trans-paroxetine enantiomers as model compounds.
The enantiomers of trans-paroxetine were separated on four chiral stationary phases (CSPs) based on chiral zwitterionic Cinchona alkaloids fused with (R,R)- or (S,S)-trans-2-aminocyclohexanesulfonic acid. The enantioseparations were carried out in polar-ionic or in hydro-organic mobile phases with MeOH/THF, MeCN/THF, MeCN/THF/H2O and MeOH/MeCN/THF containing organic acid and base additives, in the temperature range 0-50°C. The effects of the mobile phase composition, the natures and concentrations of the additives and temperature on the separations were investigated. Thermodynamic parameters were calculated from plots of ln α vs 1/T. Δ(ΔH°) ranged between -3.0 and +1.5 kJ mol(-1), and Δ(ΔS°) between -8.8 and +5.9 J mol(-1)K(-1). The enantioseparation was generally enthalpically controlled, the retention factor and separation factor decreasing with increasing temperature, but entropically controlled separation was also observed. The elution sequences of the paroxetine enantiomers on the two pairs of pseudo-enantiomeric CSPs were investigated, and an attempt was made to explain the observed anomalies in silico in order to gain an insight into the underlying molecular recognition events between the four chiral selectors and the analyte enantiomers.


Mental nerve invasion by basal cell carcinoma of the chin: a case report.
A case of perineural infiltration from recurrent cutaneous basal cell carcinoma of the chin is reported. Clinical presentation, surgical treatment, and pathological evidence are discussed. This report stresses the importance of a correct follow-up and an accurate clinical staging in order to identifying clinical signs highly suspicious for neoplastic perineural infiltration.


Structural and functional features of an NDP kinase from the hyperthermophile crenarchaeon Pyrobaculum aerophilum.
Nucleoside diphosphate (NDP) kinases are ubiquitous enzymes that transfer gamma-phosphates from nucleoside triphosphates to nucleoside diphosphates via a ping-pong mechanism. The important role of this large family of enzymes in controlling cellular functions and developmental processes along with their crystallizability has made them good candidates for structural studies. We recently determined the structure of an evolved version of an NDP kinase from Pyrobaculum aerophilum, an extreme thermophile. This NDP kinase has similarity to the 42 other NDP kinases deposited in the Protein Data Bank (PDB) but differs significantly in sequence, structure, and biophysical properties. The P. aerophilum NDP kinase sequence contains two unique segments not present in other NDP kinases, comprising residues 66-100 and 156-165. We show that deletion mutants of the P. aerophilum NDP kinase lacking either or both of these inserts have an altered substrate specificity, allowing dGTP as the phosphate donor. A structural analysis of the evolved NDP kinase in conjunction with mutagenesis experiments suggests that the substrate specificity of the P. aerophilum NDP kinase is related to the presence of these two inserts.


The first phylogenetic study of Mesembrinellidae (Diptera: Oestroidea) based on molecular data: clades and congruence with morphological characters.
The Mesembrinellidae (Diptera: Oestroidea) comprise a small group of strictly Neotropical calyptrate flies, with 36 described species. The group has often been treated as a subfamily of Calliphoridae, but there is growing evidence that it corresponds to a distinct Oestroidea lineage. Internal relationships have so far been addressed based only on morphology, with results lacking resolution and support. This is the first molecular phylogeny for the group, which is based on the analyses of 80 terminal taxa (22 mesembrinellid and 28 outgroup species) and 5 molecular markers (ITS2, 28S, COI, COII and 16S). Maximum-parsimony, maximum-likelihood and Bayesian inference methods were used, the latter two with partitioning strategies considering codon position and secondary structure information. Results corroborate the Mesembrinellidae as a monophyletic lineage inside Oestroidea. Three clades were consistently recovered: (1) (Laneella + Mesembrinella patriciae); (2) (Mesembrinella (excluding M. patriciae) + Eumesembrinella); and (3) (Huascaromusca + Giovanella). Re-examination of the female reproductive tract of M. patriciae revealed a Laneela-type spermatheca, which corroborates the position of the species recovered in the molecular phylogenetic analyses. Mesembrinella and Huascaromusca are in all cases paraphyletic with regards to Eumesembrinella and Giovanella, respectively. These latter two genera should, thus, be seen as subjective junior synonyms.


The effect of walking with reduced trunk motion on dynamic stability in healthy adults.
Most people with Parkinson's disease (PD) walk with a smaller mediolateral base of support (BoS) compared to healthy people, but the underlying mechanisms remain unknown. Reduced trunk motion in people with PD might be related to this narrow-based gait. Here, we study the relationship between trunk motion and narrow-based gait in healthy adults. According to the extrapolated center of mass (XCoM) concept, a decrease in mediolateral XCoM excursion would require a smaller mediolateral BoS to maintain a constant margin of stability (MoS) and remain stable. As proof of principle, we assessed whether walking with reduced trunk motion results in a smaller step width in healthy adults, without altering the mediolateral MoS. Fifteen healthy adults walked on a treadmill at preferred comfortable walking speed in two conditions. First, the 'regular walking' condition without any instructions, and second, the 'reduced trunk motion' condition with the instruction: 'Keep your trunk as still as possible'. Treadmill speed was kept the same in the two conditions. Trunk kinematics, step width, mediolateral XCoM excursion and mediolateral MoS were calculated and compared between the two conditions. Walking with the instruction to keep the trunk still significantly reduced trunk kinematics. Walking with reduced trunk motion resulted in significant decreases in step width and mediolateral XCoM excursion, but not in the mediolateral MoS. Furthermore, step width and mediolateral XCoM excursion were strongly correlated during both conditions (r = 0.887 and r = 0.934). This study shows that walking with reduced trunk motion leads to a gait pattern with a smaller BoS in healthy adults, without altering the mediolateral MoS. Our findings indicate a strong coupling between CoM motion state and the mediolateral BoS. We expect that people with PD who walk narrow-based, have a similar mediolateral MoS as healthy people, which will be further investigated.


Immediate reconstruction of massive cranio-orbito-facial defects with allogeneic and alloplastic matrices in baboons.
40 cranio-orbito-facial osseous defects were created in 20 adult male baboons (Papio ursinus) to test the effectiveness of an allogeneic and an alloplastic matrix implant for the functional and morphological repair of the disassembled craniofacial complex. In each animal, one defect was reconstructed with a craniofacial bone segment harvested from donor adult baboons, and processed so as to obtain autolysed antigen-extracted allogeneic (AAA) bone matrix, preserving the bone morphogenetic protein (BMP) activity essential for bone induction. The contralateral defect was implanted with spherical macrobeads of polymethylmethacrylate (PMMA) coated with poly-2-hydroxyethylmethacrylate (PHEMA), and sintered into a porous molded implant, replicating the structural anatomy of the avulsed osseous segment. Histological analysis was carried out on undecalcified and decalcified bone sections prepared from specimens harvested at 3, 6 and 12 months after surgery. In AAA bone, the morphogenetic response was characterized by vascular invasion and mesenchymal cell aggregation after partial resorption of the implanted matrix. This was followed by bone deposition at the osteotomy interfaces and within the medullary spaces of the implanted AAA bone. Although bone ingrowth did occur in some PMMA/PHEMA specimens, the majority of implants showed fibrous union at the recipient interfaces. The limited bone ingrowth may be related to narrow interconnections between larger porous spaces after chemical synthesis of the two polymeric components. Osteogenesis in AAA bone appeared consistent with osteoconductive invasion from the viable bone at the recipient interfaces. In addition, the finding of a delicate trabecular-like bone, appositional to the central areas of the implanted matrix, suggests bone formation by induction.


Noninvasive evaluation of aortic stenosis severity utilizing Doppler ultrasound and electrical bioimpedance.
Aortic valve area was calculated noninvasively in 30 patients with aortic stenosis undergoing cardiac catheterization. Continuous wave Doppler ultrasound was employed to estimate the mean transvalvular pressure gradient. The mean left ventricular outflow tract flow velocity and cross-sectional area were determined from pulsed Doppler and two-dimensional ultrasound recordings. Electrical transthoracic bioimpedance cardiography performed simultaneously with the ultrasonic study and repeated at the time of catheterization measured heart rate, systolic ejection period and cardiac output. These noninvasive data permitted calculation of aortic valve area using the Gorlin equation (range 0.21 to 1.75 cm2) and the continuity equation (range 0.25 to 1.9 cm2). Subsequent cardiac catheterization showed valve area to range from 0.21 to 1.75 cm2. The mean Doppler pressure gradient estimate was highly predictive of the gradient measured at catheterization (r = +0.92, SEE = 10). Bioimpedance cardiac output measurements agreed with the average of Fick and indicator dye estimates (r = +0.90, SEE = 0.52). Valve area estimates utilizing continuous wave Doppler ultrasound and electrical bioimpedance were superior (r = +0.91, SEE = 0.12) to estimates obtained utilizing the continuity equation (r = +0.76, SEE = 0.29) and were more reliable in the detection of patients with severe aortic stenosis (9 of 11 versus 6 of 11). These data show that 1) electrical bioimpedance methods accurately estimate cardiac output in the presence of aortic stenosis; 2) the hybridized bioimpedance-Doppler ultrasound method yields accurate estimates of aortic stenosis area; and 3) the speed, accuracy and cost-effectiveness of aortic stenosis evaluation may be improved by this hybridized approach.


Outcome of SARS-CoV-2-Infected Polish Patients with Chronic Lymphocytic Leukemia.
The severe acute respiratory syndrome coronavirus (SARS-CoV-2) has become the cause of a worldwide pandemic, and its clinical infection course in patients with hematological malignancies may be severe. We performed a retrospective study on 188 chronic lymphocytic leukemia patients (CLL) with COVID-19 infection. At the time of infection 51 patients (27.1%) were treated with Bruton tyrosine kinase inhibitor (BTKi), 46 (24.5%) with anti-CD20 antibodies while 37 patients (19.7%) received venetoclax. In total, 111 patients (59.0%) required hospitalization and 50 patients (26.5%) died due to COVID-19. Patients with poor performance status (ECOG >1; p = 0.02), advanced age (>65 years; p = 0.04), low hemoglobin concentration (≤10 g/dl; p = 0.0001), low platelets (<100 × 109/L; p = 0.003), and elevated lactate dehydrogenase level (LDH; p = 0.014) had an increased risk of death due to COVID-19. Neither CLL treatment status (treatment naïve vs. treated) nor the type of CLL-directed treatment had impact on the SARS-CoV-2 related risk of death. The multivariate survival analysis showed that advanced age (p = 0.009) and low platelet count (p = 0.0001) were associated with significantly shorter patients' overall survival. SARS-CoV-2 infection in CLL patients is associated with poor outcome regardless of administered CLL-directed treatment.


Mitochondria, oxidative DNA damage, and aging.
Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan. It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, MnSOD -/+ mice incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence. A great deal of work remains before it will be known whether mitochondrial oxidative damage is a "clock" which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences. Measurements of damage need to focus more on distribution, both within tissues and within cells. In addition, study must be given to the incidence and repair of other DNA lesions, and to the possibility that repair varies from species to species, tissue to tissue, and young to old.


Cost-effectiveness of heart failure therapies.
Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Management of HF involves accurate diagnosis and implementation of evidence-based treatment strategies. Costs related to the care of patients with HF have increased substantially over the past 2 decades, partly owing to new medications and diagnostic tests, increased rates of hospitalization, implantation of costly novel devices and, as the disease progresses, consideration for heart transplantation, mechanical circulatory support, and end-of-life care. Not surprisingly, HF places a huge burden on health-care systems, and widespread implementation of all potentially beneficial therapies for HF could prove unrealistic for many, if not all, nations. Cost-effectiveness analyses can help to quantify the relationship between clinical outcomes and the economic implications of available therapies. This Review is a critical overview of cost-effectiveness studies on key areas of HF management, involving pharmacological and nonpharmacological clinical therapies, including device-based and surgical therapeutic strategies.


Epigenetic Control of NRF2-Directed Cellular Antioxidant Status in Dictating Life-Death Decisions.
In this issue of Molecular Cell, Chen et al. (2017) demonstrate that the tumor suppressor protein ARF sensitizes cancer cells to programmed death through a surprising mechanism: ARF physically interacts with and antagonizes activation by acetylation of the master redox regulator NRF2, providing an unusual mode of posttranslational NRF2 regulation.


Non-Linear Optical Properties of Biexciton in Ellipsoidal Quantum Dot.
We have presented a theoretical investigation of exciton and biexciton states for the ground and excited levels in a strongly oblate ellipsoidal quantum dot made from GaAs. The variational trial wave functions for the ground and excited states of the exciton and biexciton are constructed on the base of one-particle wave functions. The energies for the ground and excited levels, depending on the ellipsoidal quantum dot's geometrical parameters, are depicted in the framework of the variational method. The oscillator strength of the transition from exciton to biexciton states for ground and excited levels is investigated as a function of the ellipsoidal quantum dot's small and large semiaxes. The third-order optical susceptibilities of ground and excited biexcitons around one-photon and two-photon resonances are calculated as a function of the photon energy. The dependences of third-order optical susceptibilities for the ground and excited levels on the photon energy for different values of the ellipsoidal quantum dot's semiaxis are revealed. The absorption coefficients in the ellipsoidal quantum dot, both for ground and excited states of exciton and biexciton, are calculated. The absorption coefficients for the ground level of exciton and biexciton for the fixed value of the large semiaxis and for the different values of the small semiaxis are determined. Finally, the two-photon absorption coefficient of the biexciton in the GaAs ellipsoidal quantum dot is computed.


Facile synthesis, larvicidal activity, biological effects, and molecular docking of sulfonamide-incorporating quaternary ammonium iodides as acetylcholinesterase inhibitors against Culex pipiens L.
Insecticides participate with a vital role in our lives especially in preventing the spread of human diseases via controlling the dangerous pests. It is a challenge to identify alternatives to the ordinary insecticides with new mode of action to be used for mosquitoes' control in an environmentally sustainable manner. Using a facile two-step procedure, three novel series of sulfonamide-incorporating quaternary ammonium iodides (3a-i, 4a-i and 5a-i) were synthesized and their chemical structures were successfully characterized. The uncharged sulfonamide intermediates (2a-i) were constructed through simple amidation of the corresponding (hetero)aryl sulfonyl chlorides then the cationic target molecules were formed by quaternizing the tertiary nitrogen with methyl, ethyl, and allyl iodides. The larvicidal activities and biological effects of most synthesized compounds against Culex pipiens L. were extensively investigated and they exhibited good and comparable activities to temephos. Among these hybrids, 4a showed the most potent activity with LC50 = 26.71 ppm. Additionally, the developmental durations of larval and pupal stages were significantly prolonged after treatment with all concentrations of 4h. At high concentration (160 ppm) of 4a and 4b, no adults emerged due to the complete death of pupae, and consequently zero growth index. Moreover, the results of the molecular docking demonstrated that the activities of compounds correlate partially to their binding with acetylcholinesterase (AChE) and it is not the sole parameter for determining the activity.


The complete sequence of Oat mosaic virus and evidence for deletion and duplication in RNA2.
The complete nucleotide sequence of a UK isolate of oat mosaic virus (OMV) was determined. RNA1 was 7550 nt long with one large open reading frame potentially encoding a polyprotein of 262.8 kDa with features typical of bymoviruses. RNA2 was 2284 nt in length, substantially smaller than those of other bymoviruses sequenced. It appeared that most of the P2 region had been deleted during repeated mechanical transmission of the isolate. The 3'-UTR of RNA2 was very long (> 1.25 kb) and proved to have a 532 nt slightly overlapping repeat. Phylogenetic analysis confirmed that OMV is an independent member of the genus Bymovirus.


Docking unbound proteins using shape complementarity, desolvation, and electrostatics.
A comprehensive docking study was performed on 27 distinct protein-protein complexes. For 13 test systems, docking was performed with the unbound X-ray structures of both the receptor and the ligand. For the remaining systems, the unbound X-ray structure of only molecule was available; therefore the bound structure for the other molecule was used. Our method optimizes desolvation, shape complementarity, and electrostatics using a Fast Fourier Transform algorithm. A global search in the rotational and translational space without any knowledge of the binding sites was performed for all proteins except nine antibodies recognizing antigens. For these antibodies, we docked their well-characterized binding site-the complementarity-determining region defined without information of the antigen-to the entire surface of the antigen. For 24 systems, we were able to find near-native ligand orientations (interface C(alpha) root mean square deviation less than 2.5 A from the crystal complex) among the top 2,000 choices. For three systems, our algorithm could identify the correct complex structure unambiguously. For 13 other complexes, we either ranked a near-native structure in the top 20 or obtained 20 or more near-native structures in the top 2,000 or both. The key feature of our algorithm is the use of target functions that are highly tolerant to conformational changes upon binding. If combined with a post-processing method, our algorithm may provide a general solution to the unbound docking problem. Our program, called ZDOCK, is freely available to academic users (http://zlab.bu.edu/~rong/dock/).


Open-Source web-based Geographical Information System for health exposure assessment.
This paper presents the design and development of an open source web-based Geographical Information System allowing users to visualise, customise and interact with spatial data within their web browser. The developed application shows that by using solely Open Source software it was possible to develop a customisable web based GIS application that provides functions necessary to convey health and environmental data to experts and non-experts alike without the requirement of proprietary software.


A case report: verrucous carcinoma of the endometrium--the difficulty of diagnosis, and a review of the literature.
A verrucous carcinoma is a subtype of well-differentiated squamous-cell carcinomas, arising in the vagina, vulva, and uterine cervix. But a verrucous carcinoma very rarely arises in the uterine endometrium. The present paper presents a case of a verrucous carcinoma of the endometrium that is described in association with the tumor marker SCC; this paper also includes a review of the relevant literature.


Histologic chorioamnionitis in pregnancies of various gestational ages: implications in preterm rupture of membranes.
A retrospective review of placental material derived primarily from preterm deliveries was conducted and inflammatory changes graded on a scale of 0-3. Reviewers were blind as to the clinical outcomes. Other reviewers, unaware of the pathologic results, surveyed the clinical data, and results were combined for analysis. The findings suggest that placental and membrane inflammation probably precedes preterm spontaneous rupture of membranes in 8-30% of cases without labor. The duration of ruptured membranes and labor enhance the frequency of inflammation. Inflammation is not associated with significant puerperal infection unless cesarean delivery occurs. Perinatal morbidity and mortality were not significantly enhanced nor associated with conservative management of spontaneous preterm rupture of membranes in this population beyond the influence of fetal weight and gestational age.


Projected diagnosis, anticipatory medicine, and uncertainty: How medical providers 'rule out' potential pregnancy in contraceptive counseling.
This article builds on theories of anticipatory medicine and diagnostic uncertainty using the critical case of ruling out pregnancy. Through discourse analysis of 224 patient visits from the Patient-Provider Communication about Contraception Study in which medical providers assess the probability of pregnancy, this article compares cases with and without material evidence and reliable tests. This article demonstrates that in cases in which providers do not currently have access to the tests and tools to which they are accustomed, they continue to reach for additional versions of the potential pregnancy. As part of this, providers may mobilize a version of potential pregnancy using unseen or anticipated events inside the patient's body. Thus, the practice of diagnosis not only involves oscillating between observed material and known categories, but also between habituated practices and projected possibilities. This article expands our understanding of anticipatory medicine, diagnostic uncertainty, and medical authority by considering the role of the missing and unseen.


[Prognostic factors and the effect of radiotherapy in the treatment of differentiated thyroid carcinomas].
In the treatment of differentiated thyroid carcinomas the indication for adjuvant radiotherapy is discussed contradictory. The following study analyzes the long-term survival rates of patients with follicular and papillar thyroid carcinomas after percutaneous radiotherapy. Records of 178 patients with differentiated thyroid carcinomas (132 female, median age 46 years; 46 male, median age 47 years) were evaluated. Following thyroid-resection and radioiodine therapy external beam irradiation was performed with a telecobalt device and high energy electrons (mean reference dose 54.7 Gy). Hundred and twenty patients (67.4%) had a histologically confirmed papillary carcinoma, 58 (32.6%) patients had follicular carcinoma. In the group with papillary carcinoma 57 patients (47.5%) were classified as stage I, 11 patients (9.2%) as stage II, 48 patients (40.0%) as stage III, 4 patients (3.3%) as stage IV, respectively, in the group with follicular carcinoma 21 patients (36.2%) were classified as stage I, 4 patients (6.9%) as stage II, 28 patients (48.3%) as stage III and 5 patients (8.6%) as stage IV. Survival, recurrence rate and prognostic factors were analyzed.


CENP-T provides a structural platform for outer kinetochore assembly.
The kinetochore forms a dynamic interface with microtubules from the mitotic spindle during mitosis. The Ndc80 complex acts as the key microtubule-binding complex at kinetochores. However, it is unclear how the Ndc80 complex associates with the inner kinetochore proteins that assemble upon centromeric chromatin. Here, based on a high-resolution structural analysis, we demonstrate that the N-terminal region of vertebrate CENP-T interacts with the 'RWD' domain in the Spc24/25 portion of the Ndc80 complex. Phosphorylation of CENP-T strengthens a cryptic hydrophobic interaction between CENP-T and Spc25 resulting in a phospho-regulated interaction that occurs without direct recognition of the phosphorylated residue. The Ndc80 complex interacts with both CENP-T and the Mis12 complex, but we find that these interactions are mutually exclusive, supporting a model in which two distinct pathways target the Ndc80 complex to kinetochores. Our results provide a model for how the multiple protein complexes at kinetochores associate in a phospho-regulated manner.


Cyclohexyl-linked tricyclic isoxazoles are potent and selective modulators of the multidrug resistance protein (MRP1).
Structure-activity relationship (SAR) studies on the tricyclic isoxazole series of MRP1 modulators have resulted in the identification of potent and selective inhibitors containing cyclohexyl-based linkers. These studies ultimately identified compound 21b, which reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.093microM), while showing no inherent cytotoxicity. Additionally, 21b inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=0.064microM) and shows selectivity (1115-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, 21b showed tumor regression and growth delay in MRP1-overexpressing tumors in vivo.


Clinical predictors of non-response to any tumor necrosis factor (TNF) blockers: a retrospective study.
Anti-tumor necrosis factor (TNF)-α therapies represent a significant innovation in therapy for psoriasis. However, a significant number of psoriasis patients do not respond well to TNF blockers or show an insufficient control of disease activity on a long-term basis. The aim of this study was to recognize specific clinical factors that could be associated with a non-response to any available TNF blockers in patients with moderate-to-severe plaque psoriasis. The authors reviewed the medical records of all patients who had started etanercept, infliximab, adalimumab and had achieved a minimum of 24 months follow-up. The authors identified subjects who were not responsive to all available anti-TNF agents, whatever the chronology of their use. A total of 110 patients were retrospectively examined. Thirteen patients were identified as "non-responders" to all available TNF-α blockers. Current smoking at the start of anti-TNF therapy was associated with non-response to TNF blockers. The group of "non-responders" presented a high mean body mass index and a high baseline PASI score with respect to the group of responders. The data showed that the majority of non-responder patients were smokers, overweight or obese and had a high baseline PASI score. Concomitant arthritis was not significantly associated with non-response.


Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation.
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA. Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment. Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m2, and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity. This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.


A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy.
Some breast cancer survivors report cognitive difficulties greater than 1 year after chemotherapy. Acetylcholinesterase inhibitors (AChEI) may improve cognitive impairment. We conducted a randomized, placebo-controlled, pilot study to assess the feasibility of using the AChEI, donepezil, to improve subjective and objective measures of cognitive function in breast cancer survivors. Women who received adjuvant chemotherapy 1-5 years prior with current cognitive dysfunction symptoms were randomized to 5 mg of donepezil/day vs placebo for 6 weeks and if tolerated 10 mg/day for 18 weeks for a total of 24 weeks. A battery of validated measures of attention, memory, language, visuomotor skills, processing speed, executive function, and motor dexterity and speed was administered at baseline and at 24 and 36 weeks. Subjective cognitive function, fatigue, sleep, mood, and health-related quality of life were evaluated at baseline and at 12, 24, and 36 weeks. Sixty-two patients were enrolled, 76 % completed the study, self-reported compliance was 98 %, and toxicities were minimal. At the end of treatment, the donepezil group performed significantly better than the control group on two parameters of memory-the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall (p = 0.033) and HVLT-R Discrimination (p = 0.036). There were no significant differences on other cognitive variables or in subjective cognitive function or quality of life. Accrual to this feasibility trial was robust, retention was good, compliance was excellent, and toxicities were minimal. Randomized clinical trials in breast cancer survivors to improve cognitive dysfunction are feasible. A phase III trial testing the efficacy of donepezil is warranted given these pilot results.


Multiple ganciclovir-resistant strains in a newborn with symptomatic congenital human cytomegalovirus infection.
A case of human cytomegalovirus (HCMV) drug-resistance in a congenitally infected newborn is described. Unusual aspects of this case include: (i) the detection of an extremely complex virus population, composed of a mixture of wild-type (wt) and multiple mutant ganciclovir (GCV) and valganciclovir (val-GCV) resistant strains carrying a variety of known mutations in UL97; (ii) the identification of novel UL97 mutations and (iii) the first time detection of combined UL97 drug resistance mutations in the same viral strain. In detail, four known UL97 single-nucleotide mutations (A594T/V, M460V/I, C592G), a new amino-acid substitution (C607S), and a new deletion (597-600) in one of the three UL97 hot spots for GCV/val-GCV resistance (codons 460, 520 and 590-607) were detected. In addition, the combination of M460V+A594V and M460V+C592G was observed for the first time. The emergence of HCMV drug-resistance in symptomatic congenital infections chronically treated with GCV or val-GCV should be taken into account. The immaturity of the neonatal immune system may contribute to selection of complex virus populations in these patients.


Immune checkpoint gene VSIR predicts patient prognosis in acute myeloid leukemia and myelodysplastic syndromes.
Immune checkpoint proteins play critical functions during the immune response to cancer and have been targeted by immune checkpoint blockade therapy. V-domain Ig suppressor of T cell activation (VSIR) is one of these immune checkpoint genes and has been investigated extensively in recent years due to its conflicting roles in cancer immunity. Specifically, in acute myeloid leukemia (AML), the prognostic value of VSIR is debated. In both patient tumor samples and cancer cell lines we find that VSIR has the highest expression in AML out of all cancer types and, in AML, has the highest expression out of all other immune checkpoint genes. Survival analysis indicated that AML patients with higher VSIR expression have significantly shorter survival than those patients with lower expression, even within established AML subgroups (e.g., FAB subtypes). Importantly, VSIR expression is predictive of progression from myelodysplastic syndromes (MDS) patients into AML, suggesting its potential role during the very early stage of AML development and progression. In addition to AML, VSIR also demonstrates prognostic values in other cancer types, including multiple myeloma and mesothelioma. In summary, our analyses revealed the prognostic value of VSIR and its potential as a target for immunotherapy, especially in AML.


Semi-automatic magnetic resonance imaging based orbital fat volumetry: reliability and correlation with computed tomography.
Post-processing analysis can provide valuable information for diagnosis and planning of orbital disorders. This cross-sectional study aims to evaluate the reliability of semi-automatic, orbital fat volumetry using magnetic resonance imaging (MRI). Two observers assessed the orbital fat volume using a standard MRI protocol (3T, T1w sequence) in 12 orbits diagnosed with Graves' orbitopathy (GO) and 10 healthy control orbits. MRI and computed tomography (CT) based analysis were compared. Intra-observer variability was good (intraclass correlation coefficient (ICC) 0.88; 95% confidence interval (CI) [0.70, 0.95]) and interobserver agreement was moderate (ICC 0.55; 95% CI [-0.09, 0.81]), which corresponds to a mean percentage difference of 1.3% and 17.9% of the total orbital fat volume. Mean differences between MRI and CT measurements were, respectively, 1.1 cm3 (P= 0.064, 95% CI [-0.20, 2.43]) and 1.4 cm3 (P=0.016, 95% CI [0.21, 2.56]) for the control and the GO group. MRI volumetry was strongly correlated with CT (Pearson's r= 0.7, P<0.001). We conclude that orbital fat volumetry is feasible with a semi-automatic segmentation procedure and standard MRI protocol. Correlation with CT volumetry is good, but considerable bias may derive from observer variability and these errors should be taken into account for the purpose of volumetric analysis. Better definition of error sources may increase measurement accuracy.


Immune cells in residual disease and recurrence.
Tumor recurrence following potentially curative therapy constitutes a major obstacle to achieving cures in patients with cancer. Recurrent tumors frequently arise from a population of residual cancer cells - also referred to as minimal residual disease (RD) or persister cells - that survive therapy and persist for prolonged periods prior to tumor relapse. While there has been significant recent progress in deciphering tumor-cell-intrinsic pathways that regulate residual cancer cell survival and recurrence, much less is known about how the tumor microenvironment (TME) of residual tumors impacts persister cancer cells or tumor recurrence. In this review, we highlight recent studies exploring the regulation and function of immune cells in RD and discuss therapeutic opportunities to target immune cells in residual tumors.


A case of recurrent hyperreactio luteinalis.
Hyperreactio luteinalis (HL) in normal pregnancy has been reported previously. However, only a few cases of HL recurrence have been reported. The present report describes HL in a normal singleton pregnancy presenting with an acute abdomen requiring surgical intervention. In a subsequent normal singleton pregnancy, HL recurred and was treated conservatively.


Vitamin K-dependent oxygenase/carboxylase; differential inactivation by sulfhydryl reagents.
Inhibition of vitamin K-dependent carboxylase and oxygenase by sulfhydryl reagents was compared. Formation of vitamin K epoxide and vitamin K-dependent carboxylation are both strongly (greater than 90%) inhibited by l mM p-hydroxy-mercuribenzoate, and this inhibition is reversed by dithiothreitol. Both activities are also effectively inhibited by N-ethylmaleimide (NEM). Preincubation with vitamin K hydroquinone prevents NEM inhibition of epoxide formation but not of carboxylation. These data argue that separate active sites are required to support vitamin K-dependent epoxide formation and carboxylation and that the binding site vitamin K oxygenase contains an active thiol group.


Laparoscopic adjustable gastric banding for massive superobesity ( > 60 body mass index kg/m2).
Surgery for massive super obesity is a formidable challenge. No existing open or laparoscopic procedure reduces BMI below 30 from a starting point above 55. Laparoscopic adjustable gastric banding has been used to treat 76 massive super obese patients with a BMI > 60 kgs/m2. Median weight was 193 kgs +/-34.7 kgs (154-335 kgs). Five patients had a BMI > 100 kgs/m2. There was neither mortality nor pulmonary emboli. hospital stay was 3 days (1-6 days). Excess weight loss was 46.69 +/-10.5 at 1 year; 59.14 +/- 11.7% at 3 years and 61 +/- 15.1% at 5 years. At 2 years, 84% of the patients had greater than 50% excess weight loss and this was maintained at 3, 4, and 5 years. BMI fell from 69 +/- 6.2 to 49 +/- 7.73 at 1 year to 37 +/- 4.45 at 3 years and this was maintained at 4 and 5 years. BMI in 13 patients with > 5 year follow up was 35.09 +/- 53 kgs/m2 (27-44). Weight loss with laparoscopic adjustable gastric banding in this group of massive super obese patients has been similar to all other surgical techniques with reduction of BMI from 69 to 33 kgs/m2 at 3 years. The relative safety of the Lapband avoids bowel surgery in these very big patients, suggesting that laparoscopic adjustable gastric banding is a valid surgical approach to these difficult patients.


Validation of the ECHS non trauma cranial CT rule in Australia: A prospective cohort study.
Computed tomography (CT) is a commonly used imaging modality in Emergency Departments (EDs), however its use is questionable in many low yield settings. The Emergency CT Head score (ECHS) is a recently published clinical tool that assists in stratifying the need for CT brain (CTB) for patients presenting without a history of trauma. We sought to validate this tool in an Australian ED setting. We prospectively evaluated 412 patients who received CTB without a history of trauma at a large Australian ED. We assessed them for the 4 main ECHS data points: focal neurological deficit on physical examination, new acute onset headache, transient neurological deficit, and a combination of new onset seizures with an altered conscious state. We examined their association with acute and chronic CTB findings. We then applied the ECHS to our data, calculating its sensitivity and its appropriateness at this single site via the calculation of a receiver operating curve (ROC). 10.2% of all CTB performed were positive for an acute or chronic abnormality. Only sex (male) and focal motor deficit were independent predictors of positive CTB at univariate analysis. The ECHS did not perform as anticipated in our population, with a ROC area under the curve of 0.498. An ECHS score of >0, which has been proposed as the threshold to not require imaging, had sensitivity of only 83.3% in our population. Further research and validation is required in order to safely implement the ECHS clinical score in the Australian ED setting.


Behavior of human periodontal ligament cells on dentin surfaces ablated with an ultra-short pulsed laser.
This study aimed to evaluate the effects of an ultrashort pulsed laser (USPL) (1064 nm, 20 ps, 100 kHz) with different laser fluences (F, 4, 6, 8 J/cm2) and pulse overlaps (PO, 0, 50%) on human periodontal ligament cells (hPDLs) behavior. Dentin samples were ablated with USPL with different combinations of fluences and pulse overlaps; some samples were ablated with an Er:YAG laser (2940 nm, 150 µs, 100 mJ/pulse, 5 J/cm2) and some samples were ground with a carbide bur. Then hPDLs were grown on the samples after different treatments. Dentin morphology and cell adhesion were observed with SEM and gene expressions were measured by RT-PCR. The results showed dentin surfaces ablated with USPL when F = 4 J/cm2, PO = 0, and F = 6 J/cm2, PO = 0 were partially intact with obvious ridges and valleys and cells on these surfaces grew mostly along the valleys. USPL ablated surfaces in other groups were entirely ablated and cell cluster formation was observed. The RT-PCR results showed an upregulation of osteocalcin of cells grown on the dentin after some laser treatment. It can be concluded that USPL could improve the attachment and differentiation of hPDLs and thus potentially promote periodontal tissue regeneration.


Ionic effects on adrenal steroidogenic electron transport. The role of adrenodoxin as an electron shuttle.
We have shown (Seybert, D., Lambeth, D., and Kamin, H. (1978), J. Biol. Chem. 253, 8355-8358) that, whereas the 1:1 complex between adrenodoxin reductase and adrenodoxin is the active species for cytochrome c reduction, the complex is not sufficient to allow cytochrome P-45011 beta-mediated hydroxylations;adrenodoxin in excess of reductase is required. In the present studies, reduction by NADPH of excess adrenodoxin is shown to occur at a rate sufficient to support both cytochrome P-450 11 beta-mediated hydroxylation of deoxycorticosterone, and cytochrome P-450sec-mediated side chain cleavage of cholesterol. Oxidation-reduction potential and ion effect studies indicate that the mechanism of steroidogenic electron transport involves an adrenodoxin electron "shuttle" rather than a macromolecular complex of reductase, adrenodoxin, and cytochrome. The oxidation-reduction potential of adrenodoxin is shifted about -100 mV when bound to reductase, and reduction of the iron-sulfur protein thus promotes dissociation of the complex. The rate of adrenodoxin reduction is first stimulated, then inhibited by increasing salt; the effect is ion-specific, with Ca2+ approximately Mg2+ greater than Na+ greater than NH/+. Similar ion-specific rate effects are observed for both of the cytochrome P-450-mediated hydroxylations, indicating that the same reduction mechanism is required for these reactions. Increasing salt concentrations caused dissociation of the complex; dissociation of the form of the complex containing reduced adrenodoxin occurred at lower salt concentrations than that containing oxidized adrenodoxin. The order of effectiveness of ions in causing dissociation is the same as the order for stimulation of adrenodoxin reduction, suggesting a dissociation step in the mechanism. This proposed model, together with dissociation constants for the form of the complex containing either oxidized or reduced adrenodoxin, allows accurate prediction of the salt rate effects curve. For all ions, an activity maximum is seen at the ion concentration which produces the largest molar difference between associated-oxidized and dissociated-reduced states, and the model predicts the positions of the maxima for adrenodoxin reduction, 11 beta-hydroxylation, and side chain cleavage. Thus reduction-induced dissociation of adrenodoxin from adrenodoxin reductase appears to be a required step in steroidogenic electron transport by this system, and a role for adrenodoxin as a mobile electron shuttle is proposed.


Rice body formation characterized by the chronic non-specific tenosynovitis in the tibialis anterior tendon.
In this case report a 38-year-old woman who presented with swelling and pain on her right ankle for two years is presented. Physical and radiological examinations revealed a soft, lobulated and fixed mass in the ankle. During surgical resection shiny, whitish bodies were removed from the tendon sheath of tibialis anterior and synovectomy was performed. Histopathological diagnosis was rice body formation and syovitis. There was no recurrence at the 5th year follow-up. Magnetic resonance imaging was effective in the diagnosis of this rare case of extra articular rice body formation presenting with tenosynovitis and full recovery was achieved with surgical treatment.


The effect of 1alpha-hydroxyvitamin D3 in pre-dialysis renal bone disease.
Assessment of 18 azotaemic patients treated with long-term 1alpha-hydroxyvitamin D3 (1alpha-OHD3) confirms the generally favourable effect of this analogue of 1,25-dihydroxyvitamin D3 in azotaemic osteodystrophy. Growing children with radiological rickets respond very well as do adults showing mild hyperparathyroidism with or without osteomalacia. However, patients with severe 'pure' hyperparathyroidism and features of autonomy do not respond well and in such patients 1alpha-OHD3 alone should be avoided. Phosphate restriction and occasionally a sub-total parathyroidectomy may be indicated in these patients.


Efficacy of Cranial Electrotherapy Stimulation Combined with Biofeedback Therapy in Patients with Functional Constipation.
A large number of studies have shown that function constipation (FC) has an extremely high incidence of mental and psychological disorders. Cranial electrotherapy stimulation (CES) was applied to the treatment of psychological disorders such as anxiety and depression. We explored the effects of CES combined with biofeedback therapy (BFT) on the psychological state, clinical symptoms, and anorectal function in patients with FC. A total of 74 patients with FC were randomly divided into 2 groups. The control group received BFT. CES combined with BFT was carried out in the experiment group. All patients were assessed using the self-rating anxiety scale (SAS), self-rating depression scale (SDS), and Wexner constipation score at baseline and the end of each course. Anorectal manometry and balloon expulsion tests were performed before and after treatment. After treatment, the participants in the experiment group had significantly lower score SAS, SDS, and Wexner constipation scores than the control group (all P < 0.05). The number of successful expulsion in the experiment group was larger than the control group (P = 0.016). CES combined with BFT was effective in improving the psychological status of anxiety, depression, and bowel symptoms in patients with FC.


Sleep disorders in elderly population suffering from TB and respiratory diseases.
Sleep disorders (SD) are more frequent in the elderly population than younger counterparts. The underlying SD has a more severe impact on cardiorespiratory fitness. In elderly population with respiratory disorders, incidence and baneful influence of sleep disorders are extremely high. Insomnia in elderly is very common probably due to age related changes, underlying co morbidities and multiple medications. With aging there is decrease in duration of slow wave sleep and increase in NREM stage 1 and 2 sleep, which increases number of spontaneous arousals. Compared to younger people, elderly individuals tend to sleep earlier and wake up earlier due to changes in their normal circadian rhythm. Poor sleep quality and restless leg syndrome are higher in Tuberculosis patients. Disturbances in immune regulation due to chronic insomnia may exacerbate chronic infections like TB. Because many respiratory diseases and medications are known to cause sleep disturbances, it is important to assess treatable medical conditions and insomnia inducing medications before initiating hypnotics. Diagnosing sleep disordered breathing (SDB) in ILD patients is particularly important as nocturnal oxygen desaturation is associated with poor prognosis and could possibly be a cause of pulmonary hypertension. In patients with pulmonary hypertension (PH) and underlying obstructive sleep apnoea, CPAP therapy may help to reduce the PH. Addressing sleep disorders will be highly beneficial in elderly COPD patients with sleep disorders. This article reviews different SD, its effects and the treatment benefits in improving the quality of life and reducing the risk of progression of respiratory dysfunction in elderly population with TB and respiratory diseases.


Prognostic factors and staging for soft tissue sarcomas: an update.
Soft tissue sarcoma (STS) staging is a constantly evolving process. Grading is still of utmost importance and has been adapted into a three-tier system. The STS most difficult to categorize are those with uncertain malignant potential, such as solitary fibrous tumors, gastrointestinal stromal tumors, and glomus tumors, some of which have developed completely separate staging systems and may not even be considered sarcomas. Beyond the current TNM staging system, a multitude of prognostic factors for STS will continue to be discovered and ultimately incorporated into future revisions of the staging system.


Investigation of Novel Pesticides with Insecticidal and Antifungal Activities: Design, Synthesis and SAR Studies of Benzoylpyrimidinylurea Derivatives.
In order to find pesticides with insecticidal and antifungal activities, a series of novel benzoyl pyrimidinylurea derivatives were designed and synthesized. All target compounds were identified by ¹H-NMR spectroscopy and HRMS. Insecticidal and antifungal activity of these compounds were evaluated and the structure-activity relationships (SAR) were clearly and comprehensively illustrated. Compound 7, with low toxicity to zebrafish (LC50 = 378.387 µg mL-1) showed 100% inhibition against mosquito (Culex pipiens pallens) at 0.25 µg mL-1. Both compounds 19 and 25 exhibited broad-spectrum fungicidal activity (>50% inhibitory activities against 13 phytopathogenic fungi), which were better than those of the commercial pesticide pyrimethanil (>50% inhibitory activities against eight phytopathogenic fungi). Furthermore, compounds 19 and 25 exhibited protective activity against Sclerotinia sclerotiorum on leaves of Brassica oleracea L. during in vivo experiments.


Profile of dyslipidemia in Psammomys obesus, an animal model of the metabolic syndrome.
To investigate lipid profiles in Psammomys obesus and relationships between lipid profile and other components of the Metabolic Syndrome. A total number of 49 adults with a wide range of body weight and glucose tolerance were studied in a cross-sectional analysis. Plasma cholesterol distribution profiles were measured by size exclusion lipid chromatography. Blood glucose was measured using an enzymatic glucose analyser, and plasma insulin was determined by radioimmunoassay. Obese diabetic Psammomys obesus had elevated plasma cholesterol (P=0.003) and triglyceride levels (p>0.001) compared to their lean littermates. The hypercholesterolemia was mainly due to increased circulating levels of VLDL-cholesterol (P=0.003) and LDL-cholesterol (P=0.003) in these animals. Multiple linear regression analyses revealed that body weight was independently associated with plasma cholesterol (P=0.011) and LDL concentration (P=0.009), while plasma insulin was associated with VLDL-cholesterol concentration (P=0.005). All of the variables measured exhibited continuous distributions across a wide range of phenotypes, from a normal rodent lipid profile to profound dyslipidemia. These data suggest that the dyslipidemia in obese, diabetic Psammomys obesus is closely associated with other components of the Metabolic Syndrome, including obesity and insulin resistance.


Aspects on the benefit-risk balance of felodipine in hypertension.
This review attempts to evaluate the benefit-risk balance of felodipine in the treatment of hypertension. Known positive and negative properties of felodipine are considered. Although accurate benefit-risk statements may be difficult even for old, well-established drugs it is concluded that felodipine appears to be an effective and well tolerated new antihypertensive drug. The reduction in blood pressure during felodipine treatment has been superior to that seen with established antihypertensive drugs in controlled studies.


Phosphorylation and nitration levels of photosynthetic proteins are conversely regulated by light stress.
Using a label-free mass spectrometric approach, we investigated light-induced changes in the distribution of phosphorylated and nitrated proteins within subpopulations of native photosynthetic complexes in the thylakoid membrane of Arabidopsis thaliana leaves adapted to growth light (GL) and subsequently exposed to high light (HL). Eight protein phosphorylation sites were identified in photosystem II (PSII) and the phosphorylation level of seven was regulated by HL as determined based on peak areas from ion chromatograms of phosphorylated and non-phosphorylated peptides. Although the phosphorylation of PSII proteins was reported in the past, we demonstrated for the first time that two minor antenna LHCB4 isoforms are alternately phosphorylated under GL and HL conditions in PSII monomers, dimers and supercomplexes. A role of LHCB4 phosphorylation in state transition and monomerization of PSII under HL conditions is proposed. We determined changes in the nitration level of 23 tyrosine residues in five photosystem I (PSI) and nine PSII proteins and demonstrated for the majority of them a lower nitration level in PSI and PSII complexes and supercomplexes under HL conditions, as compared to GL. In contrast, the nitration level significantly increased in assembled/disassembled PSI and PSII subcomplexes under HL conditions. A possible role of nitration in (1) monomerization of LHCB1-3 trimers under HL conditions (2) binding properties of ferredoxin-NADP+ oxidoreductase to photosystem I, and (3) PSII photodamage and repair cycle, is discussed. Based on these data, we propose that the conversely regulated phosphorylation and nitration levels regulate the stability and turnover of photosynthetic complexes under HL conditions.


Prostaglandin F2α-induced Prostate Transmembrane Protein, Androgen Induced 1 mediates ovarian cancer progression increasing epithelial plasticity.
The role of prostaglandin (PG) F2α has been scarcely studied in cancer. We have identified a new function for PGF2α in ovarian cancer, stimulating the production of Prostate Transmembrane Protein, Androgen Induced 1 (PMEPA1). We show that this induction increases cell plasticity and proliferation, enhancing tumor growth through PMEPA1. Thus, PMEPA1 overexpression in ovarian carcinoma cells, significantly increased cell proliferation rates, whereas PMEPA1 silencing decreased proliferation. In addition, PMEPA1 overexpression buffered TGFβ signaling, via reduction of SMAD-dependent signaling. PMEPA1 overexpressing cells acquired an epithelial morphology, associated with higher E-cadherin expression levels while β-catenin nuclear translocation was inhibited. Notwithstanding, high PMEPA1 levels also correlated with epithelial to mesenchymal transition markers, such as vimentin and ZEB1, allowing the cells to take advantage of both epithelial and mesenchymal characteristics, gaining in cell plasticity and adaptability. Interestingly, in mouse xenografts, PMEPA1 overexpressing ovarian cells had a clear survival and proliferative advantage, resulting in higher metastatic capacity, while PMEPA1 silencing had the opposite effect. Furthermore, high PMEPA1 expression in a cohort of advanced ovarian cancer patients was observed, correlating with E-cadherin expression. Most importantly, high PMEPA1 mRNA levels were associated with lower patient survival.


Is it possible to detect ulcerative colitis-related respiratory syndrome early?
Obstructive airway disease, bronchiectasis, non-specific parenchymal infiltration and bronchiolitis obliterans organizing pneumonia are seen occasionally in patients with inflammatory bowel disease. In the present study, we evaluated ulcerative colitis (UC) patients for latent pulmonary involvement. Fifteen patients (nine females, six males, mean age 44 years) were admitted into the study. All patients were free of respiratory symptoms. Ulcerative colitis was active in nine patients and all patients were using anti-inflammatory treatment. Pulmonary function tests (PFT), high resolution computed tomography of thorax (HRCT) and bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy (TBLB) were carried out in all subjects. Mild airways obstruction was found in 1 of 13 patients. High resolution CT was abnormal in 4 of 15 patients. Ground glass appearance suggestive of an interstitial lung disease was present in three patients. Radiolucency and pneumocysts were present in the fourth patient suggesting obstructive small airway disease. High resolution CT findings correlated with disease activity (P < 0.05). Fiberoptic bronchoscopy was performed in 10 patients. A mixed type alveolitis was detected in BAL fluid in five patients. In eight patients, TBLB showed alveolar septal thickening by connective tissue, lymphocytic accumulation in the septal area and minimal septal fibrosis, suggesting subclinical pulmonary parenchymal involvement linked to UC. Our data suggest that latent interstitial pulmonary involvement may occur during the course of UC, despite an absence of symptoms of lung disease.


Expression of mixed lineage kinase 2 in germ cells of the testis.
Mixed Lineage Kinase 2 is a mammalian protein kinase that activates stress-activated protein kinases/c-jun N-terminal kinases (SAPK/JNKs) through direct phosphorylation of their upstream activator, SEK1/JNKK. We have examined expression of both MLK2 and SEK1/JNKK RNAs in the rat testis at various times during postnatal development and in isolated testicular cell populations. We also have used immunohistochemistry to examine MLK2 protein expression and localization in adult rat and mouse testis. In these analyses, we found rat MLK2 mRNA expression was first evident at a very low level on day 25 after birth and present from day 35 at much higher levels that continue into adulthood. In RNA from isolated cell types, a MLK2 transcript was detected in primary spermatocytes and round spermatids, but not in Leydig or Sertoli cells. MLK2 RNA was also absent from the testis of rats after induced cryptorchidism. SEK1/JNKK transcripts, on the other hand, were present at all stages of testicular development and in all cell types tested. In tissue sections from both adult rat and mouse testis, MLK2 immunoreactivity was present in the nucleus of primary and secondary spermatocytes and round spermatids within seminiferous tubules, but was absent from spermatogonia. These findings indicate the JNK pathway is most likely ubiquitous in rodent testicular cells, while the cell-specific pattern of MLK2 expression suggests that it may be involved in the regulation of processes specific to post-mitotic germ cells. Furthermore, the finding of MLK2 protein in the nucleus of spermatocytes and round spermatids indicates a role for MLK2 in regulation of nuclear events specific to germ cell development.


Retinal vessel diameter in bilateral glaucoma suspects: comparison between the eye converted to glaucoma and the contralateral non-converted eye.
To investigate retinal vessel diameter in patients classified as bilateral glaucoma suspects who showed unilateral glaucomatous conversion. This retrospective study included 21 patients who had initially been diagnosed as bilateral glaucoma suspects but showed unilateral glaucomatous conversion during a follow-up period of more than 2 years. Conversion to glaucoma was determined either by documentation of a new retinal nerve fiber layer defect on red-free photography or a reproducible glaucomatous visual field defect. The central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were measured from fundus photographs taken at baseline and at the point of glaucoma conversion. The mean CRAE of the converted eyes was significantly lower than that of the non-converted eyes at baseline (164.9 ± 13.2 μm vs 175.2 ± 15.6 μm; p = 0.001), but no significant difference was observed in the mean CRVE (p = 0.108). The mean CRAE of the converted eyes was also lower than in the non-converted eyes at the point of glaucoma conversion (158.6 ± 13.5 μm vs 168.0 ± 17.2 μm; p = 0.011). In bilateral glaucoma suspects, there was a significant inter-eye difference in CRAE at baseline between eyes that converted to glaucoma and those that did not. These findings suggest that measurement of retinal arteriolar diameter may help clinicians when evaluating the risk of conversion in glaucoma suspects.


Specific detection of the pesticide chlorpyrifos by a sensitive genetic-based whole cell biosensor.
The Sinorhizobium meliloti chpA promoter is highly induced in the presence of the pesticide chlorpyrifos (CPF) through the action of the transcriptional activator, ChpR. A whole-cell biosensor for the detection of CPF was developed and is composed of an Escherichia coli strain carrying a chpR expression vector and a chpA promoter-atsBA transcriptional fusion plasmid encoding sulfatase (atsA) and formylglycine generating enzyme (atsB) from Klebsiella sp. The sulfatase is posttranslationally activated by formylglycine generating enzyme (FGE) and then converts 4-methylumbelliferyl sulfate (4-MUS) to the fluorescent product, 4-methyllumbelliferone (4-MU). This biosensor system exhibited a linear response range from 25 to 500 nM CPF.


Growth hormone deficiency short stature in a third world adult endocrine clinic: usefulness of clonidine test in its diagnosis.
Short stature (SS) can be treatable; yet the diagnostic value of a simple test in correctly identifying the two common etiologies in developing countries, viz., growth hormone deficiency (GHD) and normal variant short stature (NVSS), has not been reported in a typical third world population. The aim of the study was to evaluate the reliability of clonidine test in differentiating short stature caused by GHD from NVSS. Data of subjects evaluated for growth hormone deficiency SS at a Saudi Arabian university hospital were retrospectively reviewed. Clonidine and insulin tolerance tests (ITT) were conducted on 60 subjects aged 12 years and above with SS, while peak stimulated growth hormone cut off value of < 10 microg/l was used to diagnose GHD. Sensitivity and specificity for clonidine test and ITT were computed, while receiver operator characteristic (ROC) curves were constructed from the results in order to assess the diagnostic usefulness of the two tests. Mann-Whitney test was used to determine level of significance. Clonidine test showed superior sensitivity and specificity, viz., 81% and 82%, as against 65% and 59% for ITT respectively. Overall, the efficiency of clonidine test in correctly differentiating short stature caused by GHD from NVSS was higher, viz., 90%, compared to ITT's 77%. Clonidine test proved to be an excellent test for initial assessment of GHD and may be used as a screening test for short stature in third world countries.


Detection of Mycoplasma pneumoniae by loop-mediated isothermal amplification (LAMP) assay and serology in pediatric community-acquired pneumonia.
Rapid diagnosis of Mycoplasma pneumoniae pneumonia is required for treatment with effective antimicrobial agents without delay; however, this capacity has not yet been established in clinical practice. Recently, a novel nucleic acid amplification method termed loop-mediated isothermal amplification (LAMP) has been used to rapidly diagnose various infectious diseases. In this study, we prospectively evaluated the efficacy of the LAMP assay to rapidly diagnose M. pneumoniae pneumonia in clinical practice. Three hundred sixty-eight children (median age, 3.8 years; range, 0.1-14.3 years) admitted to our hospital between April 2009 and March 2010 for community-acquired pneumonia were enrolled in this study. We obtained throat swabs on admission to detect M. pneumoniae DNA and paired serum samples on admission and at discharge to assay M. pneumoniae antibody titers. M. pneumoniae pneumonia was diagnosed by either a positive LAMP assay or a fourfold or greater increase in antibody titer. Overall, 46 children (12.5% of the patients with pneumonia) were diagnosed with M. pneumoniae pneumonia; of these, 27 (58.7%) were aged less than 6 years. Of the aforementioned 46 children, 38 (82.6%) and 37 (80.4%) were identified by LAMP and serology, respectively. When the results of serology were taken as the standard, the sensitivity and specificity and positive and negative predictive values of the LAMP assay were 78.4%, 97.3%, 76.3%, and 97.6%, respectively. We concluded the LAMP assay may be useful for rapid diagnosis of M. pneumoniae pneumonia.


Fluoride enrichment mechanisms and related health risks of groundwater in the transition zone of geomorphic units, northern China.
Although groundwater is the primary drinking water source in northern of China, little is known about generation mechanisms and related health risks of high fluoride groundwater at the geomorphic transition zones. Thus, 419 groundwater samples were collected from Zhangjiakou region, where is a typically geomorphic transition zone of the North China Plain and the Inner Mongolia Plateau, to conduct the hydrochemical analysis, geochemical modeling, multivariate statistical analysis, and health risks assessment. From the results, F- concentration in groundwater had a range of 0.05-9.71 mg L-1. About 37.1% and 26.2% of groundwater samples from Bashang region (BSR) and Baxia region (BXR), respectively, were over the 1.50 mg L-1, which were mainly distributed in the groundwater flow retardation area and/or evaporation discharge area. Thermodynamic simulations demonstrated that F-bearing minerals dissolution and Ca2+/Mg2+ removal via calcite/dolomite precipitation primarily governed high-F- groundwater formation in the whole study area. Competitive adsorption, evaporation, evaporites dissolution and salt-effect also affected F- enrichment in BSR. Desorption in alkaline environment, ion exchange and human activities played a vital role in F- enrichment at BXR. The multivariate statistical analysis revealed that the origin of F- contamination was geogenic in BSR; whereas, it was geogenic and anthropogenic in BXR. Besides, more than 71.8%, 51.0%, 36.1% and 25.5% of the study area exceeded the acceptable level (health index>1) for infants, children, adult males, and females, respectively. The health risks for different groups of people varied significantly and ranked: infants > children > males > females, suggesting that younger people were more susceptible to fluoride contamination. Meanwhile, females were more resistant to fluoride contamination than males. These findings are vital to providing insights on high-F- groundwater formation, investigate the situation of health risks, and conduct the integrated management for high fluoride groundwater in geomorphic transition zones at northern China.


Ultrasound-triggered reactive oxygen species effector nanoamplifier for enhanced combination therapy of mutant p53 tumors.
Reactive oxygen species (ROS) damage is a crucial method with which to inhibit tumor cell proliferation; however, tumor cells can reduce ROS damage by modulating multiple repair mechanisms, thus, reducing the efficacy of ROS damage in tumor therapy. In this study, we built an ultrasound-triggered ROS damage nanoamplifier using a synergistic strategy consisting of ROS damage and decreased tumor self-protection capability to enhance the treatment efficacy of mutant p53 tumors. A ROS damage nanoamplifier (PT@PTGA) was fabricated using amphiphilic polyglutamic acid (PTGA) to load with a sonosensitizer (protoporphyrin IX, PpIX) and an MTH1 inhibitor (TH287). Under ultrasonic excitation, PpIX catalyzes oxygen to produce singlet oxygen and release TH287 to inhibit MTH1 activity, thereby causing the accumulation of 8-oxo-dGTP, which enhances DNA damage and further induces cell apoptosis. In addition, TH287 allies with ROS to eliminate the mutated p53 protein in tumor cells, thus reducing the self-protective capacity of tumor cells. As a result, the "internal and external" aspects were combined to enhance sensitization for mutant p53 tumor therapy. The construction of a ROS nanoamplifier not only provides an effective strategy for the treatment of mutant p53 tumors but also supplies an integrated platform for tumor diagnosis and therapy.


Synthesis of Beta/MCM-41 composite molecular sieve with high hydrothermal stability in static and stirred condition.
Beta/MCM-41 micro/mesoporous composite materials have been prepared through assembly of zeolite Beta nanoclusters and their hydrolysis products in the presence of CTAB under static or stirred conditions. The resulting materials were characterized by powder XRD, TEM and nitrogen adsorption-desorption. Hydrothermal stability of the obtained Beta/MCM-41 composites was evaluated by boiling in distilled water for different periods of time under refluxing. All materials exhibit very high hydrothermal stability.


Bronchopleural fistula resulting from the use of a thoracic vent: a case report and review.
Pneumothorax is defined as the presence of gas or air within the pleural space. Standard treatment is usually based on the evacuation of the gas by various methods. The thoracic vent is a relatively new device used in the treatment of pneumothorax. This report focuses on the first major complication, as far as is known, associated with the use of a thoracic vent.


Discovery of novel chloropyramine-cinnamic acid hybrids as potential FAK inhibitors for intervention of metastatic triple-negative breast cancer.
To search for novel focal adhesion kinase (FAK) inhibitors for intervention of metastatic triple-negative breast cancer (TNBC), a series of hybrids 7a-s from chloropyramine and cinnamic acid analogs were designed, synthesized and biologically evaluated. The most active compound 7d could potently inhibit the proliferation, invasion and migration of TNBC cells in vitro. The docking analysis of 7d was performed to elucidate its possible binding modes to focal adhesion targeting (FAT) domain of FAK scaffold. Further mechanism studies indicated the ability of 7d in disrupting Y925 autophosphorylation of FAK, reducing formation of focal adhesions (FAs) and stress fibers (SFs) as well as inducing apoptosis of TNBC cells. Together, 7d is a novel FAK inhibitor to inhibit the essential nonkinase scaffolding function of FAK via binding FAT domain and may be worth studying further for intervention of TNBC.


Ethnic differences in narcotics addiction. I. Characteristics of Chicano and Anglo methadone maintenance clients.
This paper reviews the research literature comparing Chicano (Mexican American) to Anglo heroin addicts. In addition, characteristics of 546 Chicano and Anglo men and women who had been clients of southern California methadone maintenance programs in 1978 are compared. Background factors examined include nativity, family socioeconomic status (SES) and family interpersonal relationships, education, and gang membership. Lifetime characteristics and status at follow-up interview are reported with particular attention to legal status, criminality, employment, and interpersonal relationships. Drug experimentation history and circumstances surrounding narcotics initiation are also compared. Most observed differences prior to addiction are similar to ethnic differences found in the general population. Part II analyzes ethnic differences progressing through five stages of the addiction career.


Outcomes of parenteral vs enteral ketogenic diet in pediatric super-refractory status epilepticus.
Super-refractory status epilepticus (SRSE) is extremely difficult to control and associated with poor outcomes. Ketogenic diet (KD) has been increasingly used for SRSE treatment. Enteral ketosis induction in SRSE is sometimes unfeasible, leading to the use of parenteral KD which has limited data among children. To assess the effectiveness of KD and compare parenteral and enteral ketosis induction as treatment options in pediatric SRSE patients. This study is a retrospective medical record review of children < 15 years old diagnosed with SRSE who received KD as one of the treatment modalities during 2007-2021 at King Chulalongkorn Memorial Hospital, Thailand. KD was used in 14 (77.8%) of the 18 pediatric SRSE cases whose age ranged from 2 months to 13.5 years. The leading etiologies of SRSE were immune-mediated encephalitis, infectious encephalitis, and epilepsy. Ketosis was induced via enteral route (kEN) in 8/14 and parenteral route (kPN) in 6/14 cases. The median time from the onset of SRSE to KD initiation was 6 days (IQR 4.8-9.3) with no demonstrable difference between groups. The median time to achieve significant ketosis was significantly shorter in the kPN (2 days; IQR 1.8-4) compared to the kEN group (5 days (3.3-7.8)). Nonetheless, the median time after ketosis induction to SRSE termination when anesthetic infusion was stopped was not statistically difference between the kPN (14 days; IQR 8.5-18) and the kEN group (10.5 days (5.5-15.3)). Hypertriglyceridemia was found more in the kPN (6/6, 100%) compared to the kEN group (3/8, 37.5%). All survivors (12/14) were seizure free at discharge. Parenteral ketosis induction achieved the target ketosis quicker than enteral induction but showed no difference in efficacy and duration for SRSE termination in our study. The adverse effects were minimal and controllable. Both parenteral and enteral KD could be considered early during SRSE treatment.


Optimization of an assay for studying the effects of agents on cyclooxygenase and lipoxygenase metabolism of arachidonic acid in washed human platelets.
Before one can examine the effects of substances on the metabolism of arachidonic acid (AA) by the cyclooxygenase and lipoxygenase pathways, an assay system which allows one to detect increases or decreases in both pathways in needed. In order to develop such a system, we have examined nonaggregating washed human platelets (10(8) platelets/0.5 ml) incubated for various times with 2 microCi 3H-AA and increasing concentrations of AA. T/B2, HHT, 12-HETE, and AA were extracted and separated using reverse phase-HPLC. We first calculated the mass of AA products formed with 10(-7) to 10(-4) M AA and found that the cyclooxygenase was saturated with 10(-5) M AA whereas the lipoxygenase was not saturated with 10(-4) M AA. Cyclooxygenase products were more prevalent than 12-HETE below 10(-5) M AA, while lipoxygenase products predominated at 3 x 10(-5)-10(-4) M AA. Using 3 microM AA, which does not saturate the cyclooxygenase, we examined the effect of 0.25-10 minute incubation durations on the distribution of AA metabolites and found AA product formation to increase throughout this period without completely depleting the substrate. Since substrate depletion does not occur and further metabolism could be detected for both pathways with a 5 minute incubation with 3 microM AA, these incubation parameters were chosen in order to further test the assay system. Using these parameters, we found that 10(-4) M 5-hydroxytryptamine enhanced platelet 12-HETE formation and decreased T/B2 and HHT formation, thus demonstrating the capacity of this system to simultaneously detect changes in cyclooxygenase and lipoxygenase enzyme metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)


Spontaneous fracture and embolization of a central venous catheter: prevention and early detection.
Central venous catheters are used increasingly in oncology patients. Spontaneous fracture and embolization of a catheter is a rare complication. This report illustrates such a case, in which the fragment was retrieved percutaneously. Impending line fracture may be detected by the 'pinch-off sign' on a chest radiograph. Prevention may be possible by inserting the catheter more laterally.


Treatment of a syngeneic rat tumor with magnetically responsive albumin microspheres labeled with doxorubicin or protein A.
The tumoricidal activity of magnetically responsive albumin microspheres tagged with either doxorubicin or Staphylococcal protein A was tested against an induced mammary adenocarcinoma, 13762, implanted subcutaneously in the tail of female Fischer-344 rats. Magnetically responsive albumin microspheres containing Fe3O4 particles were prepared by an emulsion polymerization method incorporating either doxorubicin or protein A into the albumin matrix. Microspheres were produced with an average diameter of 1 micron (0.2 to 1.5 micron) in a concentration of 10(9) microspheres/mg. Microspheres were injected either directly into the tail artery and localized to the implanted tumor using a permanent bipolar adjustable gap magnet with a field strength of 8000 Oe, or directly into the femoral vein with no magnetic localization. Control groups consisted of animals treated with intravenously or intraarterially administered microspheres containing no active agent, and a no-treatment group. Survival was significantly greater in both the doxorubicin- and protein A-treated animals than in the control groups. First appearance of local metastases was prolonged in only the intraarterial magnetically localized doxorubicin-treated group of animals. Tumor growth rate was significantly depressed in both intraarterially magnetically localized treatment groups when compared to intravenously administered nonlocalized treatment groups. Magnetically responsive albumin microspheres appear to be an effective delivery system for cytotoxic agents and biologic response modifiers. Significant tumoricidal activity can be produced with a one-time administration of these agents utilizing this drug delivery system.


Role of glyoxalase 1 in methylglyoxal detoxification-the broad player of psychiatric disorders.
Methylglyoxal (MG) is a highly reactive α-ketoaldehyde formed endogenously as a byproduct of the glycolytic pathway. To remove MG, various detoxification systems work together in vivo, including the glyoxalase system, which enzymatically degrades MG using glyoxalase 1 (GLO1) and GLO2. Recently, numerous reports have shown that GLO1 expression and MG accumulation in the brain are involved in the pathogenesis of psychiatric disorders, such as anxiety disorder, depression, autism, and schizophrenia. Furthermore, it has been reported that GLO1 inhibitors may be promising drugs for the treatment of psychiatric disorders. In this review, we discuss the recent findings of the effects of altered GLO1 function on mental behavior, especially focusing on results obtained from animal models.


Prognostic Importance of Impaired Systolic Function in Heart Failure With Preserved Ejection Fraction and the Impact of Spironolactone.
Impairment in left ventricular systolic function has been described in heart failure (HF) with preserved ejection fraction (HFpEF), but its prognostic relevance is not known. We determined whether left ventricular longitudinal strain (LS) is predictive of cardiovascular outcomes in HFpEF beyond clinical and conventional echocardiographic measures. LS was assessed by 2-dimensional speckle-tracking echocardiography at baseline in 447 patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. At a median follow-up of 2.6 years (interquartile range, 1.5-3.9 years), 115 patients experienced the primary composite outcome of cardiovascular death, HF hospitalization, or aborted cardiac arrest. Impaired LS, defined as an absolute LS <15.8%, was present in 52% of patients and was predictive of the composite outcome (adjusted hazard ratio, 2.14; 95% confidence interval, 1.26-3.66; P=0.005), cardiovascular death alone (adjusted hazard ratio, 3.20; 95% confidence interval, 1.44-7.12; P=0.004), and HF hospitalization alone (adjusted hazard ratio, 2.23; 95% confidence interval, 1.16-4.28; P=0.016) after adjustment for clinical and conventional echocardiographic variables. LS was the strongest echocardiographic predictor of the composite outcome. Exploratory analysis in a subset of 131 patients with follow-up LS assessed after 12 to 18 months demonstrated a trend toward improvement in LS associated with spironolactone in patients enrolled in the Americas but not in Russia or Georgia. Impaired left ventricular systolic function is a powerful predictor of HF hospitalization, cardiovascular death, or aborted cardiac arrest in HFpEF independent of clinical predictors. Impaired LS represents a novel imaging biomarker to identify patients with HFpEF at particularly high risk for cardiovascular morbidity and mortality. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.


Magnetic resonance diagnosis of intramedullary tumors of the spinal cord.
Fifty patients with intramedullary space occupying lesions were studied with MR from October 1983. Of these 32 were operated on and histological diagnosis together with gross morphological description was available. MR findings were reviewed in search for morphological and signal characteristics capable of providing a better preoperative diagnosis. There were 11 astrocytomas, 10 ependymomas, 5 vascular lesions and 6 "gliomas". All lesions usually had signal characteristics different from those of the normal cord, mainly because of prolonged T1 and T2 relaxation times. No specific patterns related either to morphology or signal were found, capable of differentiating the two main histological types. Vascular malformations may be suspected from the presence of serpiginous areas without signal. Tumor nodules within cysts can however be well recognized, thus providing the neurosurgeon with very useful preoperative information. Some characteristics of signal and morphology, are more common for one or the other of the two main groups of tumors. A tumor involving all the cord with a homogeneously prolonged T2 relaxation time is most likely to be an astrocytoma. A small nodule with signal close to normal parenchyma, associated with extensive cysts, is most likely to be an ependymoma.


Inhaled corticosteroids and risk of tuberculosis-How bad is the risk?
Inhaled corticosteroids (ICS) have a central role in the management of obstructive airway diseases. Use of ICS in asthma and chronic obstructive pulmonary disease (COPD) is associated with a small but clear increase in incidence of pneumonia and tuberculosis. Since ICS use in obstructive airway diseases has beneficial effects with regard to symptoms, lung function, quality of life and exacerbations, denying the benefit of ICS solely based on this small elevated risk of pneumonias and tuberculosis is not justified. The present article attempts to elucidate mechanisms contributing to the increased risk, assesses the magnitude and risk factors of tuberculosis in patients using ICS and provides practical suggestions for practising clinicians.


Prediction of fetal distress and poor outcome in intrauterine growth retardation--a comparison of fetal heart rate monitoring combined with stress tests and Doppler ultrasound.
One hundred and three intrauterine growth retardation (IUGR) pregnancies were scheduled for pulsed Doppler ultrasound of the common carotid and the umbilical artery, nonstress and contraction stress tests (NST/CST) as well as vibroacoustic stimulation tests (VAST). The last examinations < 3 days before birth were compared by receiver-operator characteristics: Results of the resistance indices of fetal common carotid/umbilical artery and NST were more predictive of later fetal distress during labour, compared to CST and VAST (p < 0.001/< 0.01). Similar results were found for the prediction of low pH and Apgar values, though differences were less pronounced. Our results suggest that stressful examinations should be abolished from mother and fetus in the supervision of IUGR.


Regulatory mechanisms of the immune response to heterologous insulins. I. Development and regulation of plaque-forming cell responses in vitro.
We, as well as many other investigators, have been studying the regulation of immune responses to insulin as a model system of H-2 linked immune response (Ir) gene control. Although antibody responses by mice to heterologous insulins are qualitatively controlled, antibodies that are generated to one species of heterologous insulin cross react extensively with other species. The exquisite control of responsiveness is regulated by T cells that appear to recognize differences in the amino acid sequences of the A-chain loop of insulin. Our previous studies of the mechanism(s) by which Ir genes regulate T cell activity to insulin have been confined to an adoptive transfer model because traditional cell culture techniques using normal or insulin-primed spleen cells have failed to generate insulin-specific plaque-forming cell responses in vitro. In this communication we demonstrate that more vigorous immunization protocols and the use of lymph node T cells as a source of helper T cells can circumvent this problem. More importantly, all of the major features of the regulation of responses to insulin that have been observed in vivo are reflected in this in vitro system. Thus, these experiments provide the essential foundation for future dissection of the mechanism of Ir gene control of responses to insulin.


Fifteen-year single-center experience with the Norwood operation for complex lesions with single-ventricle physiology compared with hypoplastic left heart syndrome.
The Norwood procedure, the first surgical step of staged palliation for hypoplastic left heart syndrome, is also applied for other complex single-ventricle lesions with systemic outflow tract obstruction or aortic arch hypoplasia. We reviewed our 15-year institutional experience with the Norwood procedure for patients with and without hypoplastic left heart syndrome. A total of 41 patients without hypoplastic left heart syndrome and 212 patients with hypoplastic left heart syndrome who underwent a Norwood procedure between January 1996 and December 2010 were enrolled. Full medical records were reviewed to assess the determinants of outcome. Early failure (death or cardiac transplantation) was 7% in patients without hypoplastic left heart syndrome and 13% in patients with hypoplastic left heart syndrome (P = .29). Frequency of postoperative complications, duration of postoperative ventilation, and length of vasoactive drug treatment were not different between groups. Transplant-free survival until the second operative step trended to be higher for patients without hypoplastic left heart syndrome (92% vs 80%, P = .067). Recurrent aortic arch obstruction was more common in patients without hypoplastic left heart syndrome (15/39 vs 32/171, P = .008), but there were 4 patients with stenosis of the proximal aortic arch. In subsequent procedures, 31 patients without hypoplastic left heart syndrome underwent superior cavopulmonary anastomosis and 5 biventricular repair. Overall transplant-free survival was not different between groups (P = .119) but trended to be higher in patients with a systemic or substantial left ventricle remnant contributing to cardiac output (P = .082). Early and long-term survivals and postoperative complications were similar between patients with and without hypoplastic left heart syndrome undergoing a Norwood operation. Recurrent aortic arch obstruction was common in both groups but more prevalent in patients without hypoplastic left heart syndrome.


Dental fluorosis in cohorts born before, during, and after the national salt fluoridation program in a community in Mexico.
To determine the prevalence and severity of dental fluorosis, as well as factors associated with its occurrence, in seven cohorts of children before and after the implementation of a fluoridated salt program in 1991. A cross-sectional study was carried out in 1,373 children aged from 6 to 12 years in Campeche, Mexico. Data were collected by means of a questionnaire administered to mothers and a dental examination of the children. Modified Dean's criteria were used to diagnose dental fluorosis. A multivariate logistic regression model was used to evaluate the relationship between dental fluorosis and independent variables. The prevalence of dental fluorosis was 51.9%. The most common degree of dental fluorosis was very mild, with 84.7%, followed by mild, moderate, and severe with 13.1%, 1.7%, and 0.6%, respectively. The multivariate model adjusted by number of additional sources of fluoride, age at the beginning of use of toothpaste, and level of schooling of the mother, showed that children born in 1990 (OR = 1.74; CI 95% = 1.36-2.22), 1991 (OR = 4.03; CI 95% = 2.58-6.28), and 1992 (OR = 10.41; CI 95% = 5.77-18.78) were more likely to have dental fluorosis than those born in the period 1986-1989. The frequency of toothbrushing (OR = 1.63; CI 95% = 1.37-1.95) was also associated with dental fluorosis. A close relationship was found between exposure to toothpaste and dental fluorosis. Implementation of the fluoridated salt program greatly increased the risk of fluorosis.


Cranial nerve monitoring in endoscopic endonasal surgery of skull base tumors (observing of 23 cases).
Preservation of anatomic integrity and function of the cranial nerves during the removal of skull base tumors is one of the most challenging procedures in endoscopic endonasal surgery. It is possible to use intraoperative mapping and identification of the cranial nerves in order to facilitate their preservation.The purpose of this study was to evaluate the effectiveness of intraoperative trigger electromyography in prevention of iatrogenic damage to the cranial nerves. Twenty three patients with various skull base tumors (chordomas, neuromas, pituitary adenomas, meningiomas, cholesteatomas) underwent mapping and identification of cranial nerves during tumor removal using the endoscopic endonasal approach in Department of Neurooncology of Federal State Autonomous Institution "N.N. Burdenko National Medical Research Center of Neurosurgery" of the Ministry of Health of the Russian Federation from 2013 to 2018. During the surgical interventions, mapping and identification of the cranial nerves were carried out using electromyography in triggered mode. The effectiveness of the method was evaluated based on a comparison with a control group (41 patients). In the main group of patients, 44 nerves were examined during surgery using triggered electromyography. During the study, the III, V, VI, VII, and XII cranial nerves were identified intraoperatively. Postoperative cranial nerve deficiency was observed in 5 patients in the study group and in 13 patients in the control group. The average length of hospitalization was 9 days. We did not receive statistically significant data supporting the fact that intraoperative identification of cranial nerves using trigger electromyography reduces the incidence of postoperative complications in the form of cranial nerve deficits (p = 0.56), but the odds ratio (0.6) suggests a less frequent occurrence of complications in the study group.Based on our experience, the trigger electromyography methodology appears quite promising and requires further research.


Effect of ambient temperature increase on intestinal mucosa amylolytic activity in freshwater fish.
The relationship between the level of the intestinal mucosa amylolytic activity (AA) of juvenile goldfish Carassius auratus, carp Cyprinus carpio, roach Rutilus rutilus and perch Perca fluviatilis and the rate of water temperature increase was studied. Increase in water heating rate significantly influences AA and the level of upper lethal temperatures defined by critical thermal maximum (CTM) during different seasons. At a low rate of water temperature increase, 0.04 °C/h, AA and the level of CTM are maximal during all seasons. More rapid rates of heating, 4-50 °C/h, increase the AA during the summer and usually decrease it by 2- to 7.5-fold during other seasons. Rapid increase in ambient temperature in the autumn-winter period, unnatural for seasonal dynamics, produces a negative impact upon the fish's carbohydrate hydrolysis rate and thermal resistance.


[Study on establishing animal model of myocardial infarction of blood-stasis and Xin-qi deficiency syndrome or blood-stasis and Xin-yang deficiency syndrome type].
To investigate the method for establishing animal model of integrative medical disease/ syndrome and its evaluation. Rat myocardial (heart failure) model was established by anterio-descending coronary arterial ligation, and treated by nitric oxide synthase inhibitor 9-12 weeks after operation to induce hypertension and aggravate heart failure. The model rat was observed 12 weeks to collect the information of four-diagnosis, for visceral qi-blood and excess-deficiency syndrome differentiation in combining with the eight-principal syndrome differentiation according to the standard of deficiency syndrome and blood-stasis syndrom issued by Chinese Association of integrative medicine. After modeling, the model rats revealed ascended ST segment and abnormal Q-wave in ECG, with the visceral ratio, left ventricular area and myocardial collagen content significantly more than those in the sham-operative group (P < 0.01), showing a blood-stasis syndrome. Besides, Xin-qi deficiency syndrome, exhibiting as quickened heart rate, shortened swimming time and lowered cardiac function, appeared in the model rats (P < 0.01), which was aggravated in the late stage due to the increased blood pressure and deteriorated cardiac function, even revealed the manifestation of Yang-deficiency syndrome as low body temperature and polyuria. The basic thinking path of TCM animal disease/syndrome model establishment and evaluation should adopt the normative, mature and unified standard and methods formed in clinical and experimental study of integrative medicine.