Efficacy of class I and II vs class III histone deacetylase inhibitors in neuroblastoma.
Histone deacetylase (HDAC) inhibitors have shown promise in the treatment of resistant and refractory tumors including neuroblastoma. The goal of the study was to compare the efficacy of a class III HDAC inhibitor (cambinol) to a class I and II inhibitor (vorinostat). In vitro efficacy of vorinostat and cambinol, alone or in combination with doxorubicin, was assessed by 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide calorimetric assay using both wild-type (WT) and doxorubicin-resistant (DoxR) SK-N-SH neuroblastoma cells. In vivo efficacy was determined using the same drug combinations in nude mice bearing xenograft implants of WT and DoxR cells on opposite flanks. Vorinostat and cambinol were efficacious against WT and DoxR neuroblastoma cells in vitro. In WT cells, the potency of the doxorubicin itself overshadowed any effect of cotherapy with vorinostat or cambinol. The effect of vorinostat and/or cambinol on the DoxR cells was constant across progressively increasing doses of doxorubicin. In the in vivo model, the efficacy of doxorubicin itself (88% reduction in tumor volume) again overshadowed any effect of cotreatment with vorinostat or cambinol on the WT tumors. However, in the DoxR tumors, doxorubicin alone had no efficacy, but cotreatment with either cambinol or vorinostat suppressed tumor growth (70% and 91% reduction in tumor volume, respectively). Both the class III HDAC inhibitor cambinol and the class I/II HDAC inhibitor vorinostat have efficacy against SK-N-SH neuroblastoma cells, including those resistant to doxorubicin.


D-PSA-K: A Model for Estimating the Accumulated Potential Damage on Kiwifruit Canes Caused by Bacterial Canker during the Growing and Overwintering Seasons.
We developed a model, termed D-PSA-K, to estimate the accumulated potential damage on kiwifruit canes caused by bacterial canker during the growing and overwintering seasons. The model consisted of three parts including estimation of the amount of necrotic lesion in a non-frozen environment, the rate of necrosis increase in a freezing environment during the overwintering season, and the amount of necrotic lesion on kiwifruit canes caused by bacterial canker during the overwintering and growing seasons. We evaluated the model's accuracy by comparing the observed maximum disease incidence on kiwifruit canes against the damage estimated using weather and disease data collected at Wando during 1994-1997 and at Seogwipo during 2014-2015. For the Hayward cultivar, D-PSA-K estimated the accumulated damage as approximately nine times the observed maximum disease incidence. For the Hort16A cultivar, the accumulated damage estimated by D-PSA-K was high when the observed disease incidence was high. D-PSA-K could assist kiwifruit growers in selecting optimal sites for kiwifruit cultivation and establishing improved production plans by predicting the loss in kiwifruit production due to bacterial canker, using past weather or future climate change data.


[Laparoscopic cholecystectomy training on plastic mannequins].
The objective of this project is to offer for any Medical Education Institution an effective method of learning and developing the skills on this new surgery procedure that is necessary to improve the ability as consequence of technological innovations. Simple and low cost materials were used for doing and carrying on the laparoscopic cholecystectomy on plastic mannequins as if it were done in vivo. The results were shown through illustrated photographs from the surgery procedures. Laparoscopic cholecystectomy on plastic mannequins proved to be an alternative and a feasible method of training with Medical students.


Delivery of bacterial artificial chromosomes into mammalian cells with psoralen-inactivated adenovirus carrier.
Molecular biology has many applications where the introduction of large (>100 kb) DNA molecules is required. The current methods of large DNA transfection are very inefficient. We reasoned that two limits to improving transfection methods with these large DNA molecules were the difficulty of preparing workable quantities of clean DNA and the lack of rapid assays to determine transfection success. We have used bacterial artificial chromosomes (BACs) based on the Escherichia coli F factor plasmid system, which are simple to manipulate and purify in microgram quantities. Because BAC plasmids are kept at one to two copies per cell, the problems of rearrangement observed with YACs are eliminated. We have generated two series of BAC vectors bearing marker genes for luciferase and green fluorescent protein (GFP). Using these reagents, we have developed methods of delivering BACs of up to 170 kb into mammalian cells with transfection efficiency comparable to 5-10 kb DNA. Psoralen-inactivated adenovirus is used as the carrier, thus eliminating the problems associated with viral gene expression. The delivered DNA is linked to the carrier virus with a condensing polycation. Further improvements in gene delivery were obtained by replacing polylysine with low molecular weight polyethylenimine (PEI) as the DNA condensing agent.


Epidemiology of west nile in europe and in the mediterranean basin.
In the last 30 years several cases of West Nile (WN) virus infection were reported in horses and humans in Europe and in the Mediterranean Basin. Most of them were determined by strains of the Lineage 1 included in the European Mediterranean/Kenyan cluster. Strains of this cluster are characterised by a moderate pathogenicity for horses and humans and limited or no pathogenicity for birds. In recent years, however, WN cases determined by strains grouped in the Israeli/American cluster of Lineage 1 or in the lineage 2 have been reported in Hungary and Austria. The role of migrating birds in introducing new viruses to Europe has been often demonstrated. The migratory birds, which may be infected in their African wintering places, carry the virus northward to European sites during spring migrations. In the past, the virus introduction determined occasional cases of WN. In the recent years, new epidemiological scenarios are developing. In few occasions it has been evidenced the capability of WNV strains of overwintering by using local birds and mosquitoes. Species of Culex amongst mosquitoes and magpies (Pica pica), carrion crows (Corvus corone) and rock pigeons (Columba livia) amongst resident birds are the most probable species involved in this hypothetical WND endemic cycle.


Energy barriers for dipole moment flipping in PVDF-related ferroelectric polymers.
Energy barriers for flipping the transverse dipole moments in poly(vinylidene fluoride) (PVDF) and related copolymers and terpolymers are predicted using the nudged elastic band method. The dipole moments flip individually along the chain, with an order and energy barrier magnitudes (0.1-1.2 eV) that depend on the chain composition and environment. Trifluoroethylene (TrFE) and chlorofluoroethylene (CFE) monomers have larger energy barriers than VDF monomers, while a chain in an amorphous environment has a similar transition pathway as that of an isolated molecule. In a crystalline environment, TrFE and CFE monomers expand the lattice and lower the energy barriers for flipping VDF monomers. This finding is consistent with experimental observations of a large electrocaloric effect in P(VDF-TrFE-CFE) terpolymers.


Effects of Equine-Assisted Activities and Therapies on the Affective Network of Adolescents with Internet Gaming Disorder.
Internet gaming disorder (IGD) has been suggested to be a mental health disorder. Attachment and emotional status in IGD patients are important for understanding the etiology and progression of IGD because both parameters are considered to be associated with the affective network. Equine-assisted activities and therapies (EAAT) have been reported to improve emotional status and attachment in subjects. We hypothesized that EAAT would improve attachment in IGD adolescents with insecure attachment issues and increase functional connectivity (FC) within the affective network. Subjects completed a demographic questionnaire, the Korean Experiences in Close Relationships Scale Revised version (K-ECRS), the Child Depression Inventory, Young's Internet Addiction Scale, the Korean Attention-Deficit Hyperactivity Disorder Rating Scale, and resting-state functional magnetic resonance imaging at baseline at the end of EAAT. Fifteen IGD adolescents with insecure attachment issues and 15 healthy comparison adolescents with secure attachment agreed to participate in this study. After 7 days of EAAT, K-ECRS avoidance and anxiety scores improved in all adolescents. K-ECRS avoidance scores of the IGD group showed marked improvement compared with those of the healthy group. In all participants, FC from the left amygdala to the left parahippocampal gyrus, left medial frontal gyrus, and left inferior frontal gyrus, as well as from the right amygdala to the left caudate, right claustrum, and left inferior frontal gyrus increased. In IGD adolescents, FC from the left amygdala to the left frontal orbital gyrus, as well as from the right amygdala to the right corpus callosum also increased. These findings suggested that EAAT improves attachment, which could lead to a decrease in the severity of IGD symptoms in IGD patients with insecure attachment issues. In addition, EAAT increases FC within the affective network, which was associated with attachment not only in healthy adolescents but also in adolescents with IGD.


Receptors for beta-adrenergic agonists in cultured chick ventricular cells. Relationship between agonist binding and physiologic effect.
To determine if the two-state, guanine nucleotide-modulated beta-adrenergic receptor model elucidated in erythrocyte membranes accurately describes hormone binding to intact heart cells, and to determine the relationship of agonist binding to physiologic contractile response, we studied beta-adrenergic antagonist and agonist binding to intact cultured heart cells and homogenates of these cells from embryonic chick ventricle and related the binding observations to alterations in amplitude of contraction of intact cells under identical conditions. The levo isomer of the beta-adrenergic antagonist pindolol was radioiodinated, purified, and utilized to characterize the beta-adrenergic receptor in intact, beating heart cells under physiologic conditions. Computer analysis of iodopindolol-binding isotherms revealed a KD = 22 +/- 3 pM with Bmax = 10.3 fmol/mg of protein in intact cells; in homogenates of cells, the KD was 39 +/- 12 pM in the absence of exogenous guanine nucleotides and 19 +/- 7 pM in their presence. Estimation of the dissociation constant for iodopindolol binding to intact cells by kinetic methods yielded KD = 64 pM. Binding was stereospecific, saturable, and identified a beta 1-adrenergic receptor. Computer modeling of agonist competition curves indicated a single receptor state in intact cells with KD = 0.28 microM for isoproterenol. However, in cell homogenates, two receptor states for agonists were identified with the high affinity state of the receptor having a KD = 3 nM. Addition of guanine nucleotides to the cell homogenate reverted the receptor to a single state similar to that in intact cells. Under nonequilibrium binding conditions, a high affinity state for agonist was detected in intact cells with IC50 = 1.1 nM. The EC50 for isoproterenol-enhanced contractility was 6 nM and EC50 for cAMP response was 4 nM. At the isoproterenol concentration causing 50% maximal inotropic response, 67% occupancy of high affinity receptors occurs. Thus, there is a close relationship between high affinity receptor occupancy and augmentation of contractility in intact cells. These findings support the view that agonist interaction with the guanine nucleotide-sensitive, high affinity receptor state initiates the physiologic response of myocardial tissue to beta-adrenergic agonists.


Infiltrative subcutaneous malignant fibrous histiocytoma: a comparative study with deep malignant fibrous histiocytoma and an observation of biologic behavior.
Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas of adulthood. Although it is usually intramuscular and pseudocapsulated, we have recently observed MFHs with extremely infiltrative growth margins, which are predominantly located in the subcutis. These lesions are often associated with incomplete primary surgical excision, the subsequent need for additional surgery or adjuvant therapy, and an increased risk for local recurrence. To further analyze the growth pattern and clinical implication of the subcutaneous infiltrative MFHs, we reviewed a series of 24 subcutis and 21 intramuscular MFHs of the extremities. Morphologically, we defined "infiltrative" as tumor extension along normal tissue planes for a minimum measurable distance of 2 mm from the edge of the main mass. Radiographic findings were correlated with pathologic findings. Of the 24 subcutis MFHs, 83% showed an infiltrative growth pattern, involving 5% to 90% (mean, 51%) of the evaluable margin. Fifty percent of patients with subcutaneous MFH had both an infiltrative growth pattern and positive surgical resection margin on initial resection. Only 25% noninfiltrative subcutaneous MFHs had a positive initial surgical resection margin. Of the 21 intramuscular MFHs, only 5 (24%) had an infiltrative growth pattern that involved 5% to 90% (mean, 40%) of the evaluable margin. One of the five tumors had 90% margin infiltration with multiple positive surgical resection margins. Of 16 noninfiltrative intramuscular MFHs, 3 (19%) had positive resection margins. Magnetic resonance imaging (MRI) and/or computed tomography (CT) scan correctly identified the growth pattern in 87% of subcutaneous and 88% of intramuscular MFHs. Patient follow-up evaluation showed that four (17%) patients with subcutaneous MFHs had resection-proven recurrences, 6 to 57 months after diagnosis. All four of these tumors had infiltrative growth patterns and positive margins on the original surgical resection. There were no local recurrences of the intramuscular MFHs. Two patients of 20 in the infiltrative subcutaneous MFH group and two patients of four in the well-circumscribed subcutaneous MFH group had biopsy-proven metastases, which developed within 5 years after diagnosis. Six patients had metastases in the intramuscular MFH group. A group of MFHs, predominantly subcutaneous, have an extremely infiltrative growth pattern. This growth pattern, documented by radiographic methods and/or light microscopic examination of biopsy specimens, should indicate that a wider margin on initial resection is necessary to entirely excise the lesion. The presence or absence of an infiltrative growth pattern is not predictive of the tumor's metastatic potential.


[Pathogenesis and surgical tactics in varicose ulcers of the lower limbs].
The character and specific features of the venous blood circulation in lower extremities were determined by clinico-angiographic studies in 358 patients with trophic ulcers resulting from varicose disease of lower extremities. Causes of the formation of the ulcer are analyzed, methods of correcting the disturbed venous hemodynamics are proposed in relation to the pathology revealed. Indications for dissection of the ulcer are developed.


Homology blocks of Plasmodium falciparum var genes and clinically distinct forms of severe malaria in a local population.
The primary target of the human immune response to the malaria parasite Plasmodium falciparum, P. falciparum erythrocyte membrane protein 1 (PfEMP1), is encoded by the members of the hyper-diverse var gene family. The parasite exhibits antigenic variation via mutually exclusive expression (switching) of the ~60 var genes within its genome. It is thought that different variants exhibit different host endothelial binding preferences that in turn result in different manifestations of disease. Var sequences comprise ancient sequence fragments, termed homology blocks (HBs), that recombine at exceedingly high rates. We use HBs to define distinct var types within a local population. We then reanalyze a dataset that contains clinical and var expression data to investigate whether the HBs allow for a description of sequence diversity corresponding to biological function, such that it improves our ability to predict disease phenotype from parasite genetics. We find that even a generic set of HBs, which are defined for a small number of non-local parasites: capture the majority of local sequence diversity; improve our ability to predict disease severity from parasite genetics; and reveal a previously hypothesized yet previously unobserved parasite genetic basis for two forms of severe disease. We find that the expression rates of some HBs correlate more strongly with severe disease phenotypes than the expression rates of classic var DBLα tag types, and principal components of HB expression rate profiles further improve genotype-phenotype models. More specifically, within the large Kenyan dataset that is the focus of this study, we observe that HB expression differs significantly for severe versus mild disease, and for rosetting versus impaired consciousness associated severe disease. The analysis of a second much smaller dataset from Mali suggests that these HB-phenotype associations are consistent across geographically distant populations, since we find evidence suggesting that the same HB-phenotype associations characterize this population as well. The distinction between rosetting versus impaired consciousness associated var genes has not been described previously, and it could have important implications for monitoring, intervention and diagnosis. Moreover, our results have the potential to illuminate the molecular mechanisms underlying the complex spectrum of severe disease phenotypes associated with malaria--an important objective given that only about 1% of P. falciparum infections result in severe disease.


Combined airway and oesophageal stenting in malignant airway-oesophageal fistulas: a prospective study.
Malignant airway-oesophageal fistulas (AEF) are a serious complication of advance oesophageal or lung cancer. The aim of this study was to assess the quality of life before and after stent insertion, and to examine the role of treatment and location of AEF as factors influencing survival in AEF patients managed with airway and/or oesophageal stent insertion. 112 patients with AEF were included prospectively. 83 (74%) patients had advanced lung cancer and 29 (26%) patients had oesophageal cancers. Airway stents were inserted in 65 (58%) patients, oesophageal stents in 37 (33%) patients, and both airway and oesophageal stents in 10 (9%) patients. Seven (6%) patients developed respiratory failure and required transient ventilator support in the intensive care unit (four patients with airway stenting, two patients with double stents and one patient in the oesophageal stenting group). None of the patients developed stent migration or needed stent repositioning. Overall, mean survival was 236.6 days (airway stent 219.1 days, oesophageal stent 262.8 days and combined airway-oesophageal stent 252.9 days). Backward, stepwise regression revealed the site of stent placement (airway and/or oesophagus; p < 0.028), exact location of the fistula in airway (p = 0.011) and additional treatment with chemotherapy and/or radiation (p < 0.001) as independent risk factors predicting increased survival. The mean quality of life score (QoL) was 81 prior to stent insertion and 72 post-stent insertion (p < 0.001). Airway and/or oesophageal stent insertion provides an effective approach to improve the QoL in patients with malignant AEF.


Effect of immunisation against vasoactive intestinal polypeptide on gastric corpus tone and motility in the ferret.
The role of vasoactive intestinal polypeptide in the control of gastric corpus tone and motility was investigated using auto-antibodies to neutralise endogenous vasoactive intestinal polypeptide. Six ferrets were immunised with vasoactive intestinal polypeptide thyroglobulin conjugate in Freund's complete adjuvant which resulted in a significant increase in plasma vasoactive intestinal polypeptide binding activity compared with unimmunised control animals. In acute experiments the level of spontaneous motility in the period immediately after completion of the surgical preparation was 15 times higher in immunised v control animals (p < 0.02). Surprisingly, however, there was no deficit in the ability of the corpus to accommodate fluid. Peak pressure at the end of a 20 ml ramp distension was not different in immunised animals (5.7 (0.6) cm H2O) compared with controls (4.8 (0.3) cm H2O). It is concluded that the non-adrenergic non-cholinergic inhibitory mechanisms regulating corpus tone and motility are different and that vasoactive intestinal polypeptide acts primarily to regulate phasic contractile activity. Alternatively, because of plasticity in the mechanisms controlling corpus tone, the effect of vasoactive intestinal polypeptide may have been superceded during the timecourse of the immunisation procedure.


High prevalence of CYP2C19*2 allele in Roma samples: study on Roma and Hungarian population samples with review of the literature.
The purpose of our study was to characterise the CYP2C19*2 and CYP2C19*3 alleles in healthy Roma and Hungarian populations. DNA of 500 Roma and 370 Hungarian subjects were genotyped for CYP2C19*2 (G681A, rs4244285) and CYP2C19*3 (G636A, rs4986893) by PCR-RFLP assay and direct sequencing. Significant differences were found comparing the Roma and Hungarian populations in CYP2C19 681 GG (63.6 vs. 75.9%), GA (31.8 vs. 23.0%), AA (4.6 vs. 1.1%), GA+AA (36.4 vs. 24.1%) and A allele frequencies (0.205 vs. 0.125) (p<0.004). Striking differences were found between Roma and Hungarian samples in CYP2C19*1 (79.5 vs. 87.4%) and CYP2C19*2 (20.5 vs. 12.6%) alleles, respectively (p<0.001). None of the subjects was found to carry the CYP2C19*3 allele. Frequencies of the intermedier metabolizer phenotype defined by the *1/*2 genotype (0.318 vs. 0.230, p<0.005) and poor metabolizer predicted by the *2/*2 genotype (0.046 vs. 0.011, p<0.005) was significantly higher in Roma than in Hungarians, respectively. Genotype distribution of the Roma population was similar to those of the population of North India, however, a major difference was found in the frequency of the CYP2C19*2 allele, which is likely a result of admixture with European lineages. In conclusion, the frequencies of the CYP2C19 alleles, genotypes and corresponding extensive, intermediate and poor metabolizer phenotypes studied here in the Hungarian population are similar to those of other European Caucasian populations, but display clear differences when compared to the Roma population.


In vitro immunization to KLH. II. Limiting dilution analysis of antigen-reactive cells in primary and secondary culture.
Limiting dilution analysis was used to estimate the frequency of human peripheral blood T lymphocytes that proliferate in response to in vitro immunization with keyhole limpet hemocyanin (KLH). Antigen-reactive cells (ARC) were estimated 9 days after primary immunization with KLH. The ARC frequency of lymphocytes from 12 subjects ranged from 1:23,800 to 1:52,631. Lymphocytes from five of these subjects were also primed for 12 days with KLH, rechallenged in secondary culture with fresh adherent cells and KLH, and assayed 4 days later. The ARC frequency increased to 1:1,123 to 1:7,247, indicating that T cell clones responsive to KLH had expanded during primary culture. In addition, we observed that the proliferative response of lymphocytes from 5 of the 12 subjects were inhibited at high cell concentrations. Depletion of OKT8+ T cells before culturing with KLH however did not alter the inhibitory effect of high concentrations of T cells.


The white-rot fungus Cerrena unicolor strain 137 produces two laccase isoforms with different physico-chemical and catalytic properties.
Cerrena unicolor secreted two laccase isoforms with different characteristics during the growth in liquid media. In a synthetic low-nutrient nitrogen glucose medium (Kirk medium), high amounts of laccase (4,000 U l(-1)) were produced in response to Cu2+. Highest laccase levels (19,000 U l(-1)) were obtained in a complex tomato juice medium. The isoforms (Lacc I, Lacc II) were purified to homogeneity with an overall yield of 22%. Purification involved ultrafiltration and Mono Q separation. Lacc I and II had M (w) of 64 and 57 kDa and pI of 3.6 and 3.7, respectively. Both isoforms had an absorption maximum at 608 nm but different pH optima and thermal stability. Optimum pH ranged from 2.5 to 5.5 depending on the substrate. The pH optima of Lacc II were always higher than those of Lacc I. Both laccases were stable at pH 7 and 10 but rapidly lost activity at pH 3. Their temperature optimum was around 60 degrees C, and at 5 degrees C they still reached 30% of the maximum activity. Lacc II was the more thermostable isoform that did not lose any activity during 6 months storage at 4 degrees C. Kinetic constants (K (m), k (cat)) were determined for 2,2'-azino-bis(3-ethylthiazoline-6-sulfonate) (ABTS), 2,6-dimethoxyphenol and syringaldazine.


MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2.
Understanding cell cycle regulation in postmitotic cardiomyocytes may lead to new therapeutic approaches to regenerate damaged cardiac tissue. We have demonstrated previously that microRNAs encoded by the Gtl2-Dio3 noncoding RNA locus function downstream of the MEF2A transcription factor in skeletal muscle regeneration. We have also reported expression of these miRNAs in the heart. Here we investigated the role of two Gtl2-Dio3 miRNAs, miR-410 and miR-495, in cardiac muscle. Overexpression of miR-410 and miR-495 robustly stimulated cardiomyocyte DNA synthesis and proliferation. Interestingly, unlike our findings in skeletal muscle, these miRNAs did not modulate the activity of the WNT signaling pathway. Instead, these miRNAs targeted Cited2, a coactivator required for proper cardiac development. Consistent with miR-410 and miR-495 overexpression, siRNA knockdown of Cited2 in neonatal cardiomyocytes resulted in robust proliferation. This phenotype was associated with reduced expression of Cdkn1c/p57/Kip2, a cell cycle inhibitor, and increased expression of VEGFA, a growth factor with proliferation-promoting effects. Therefore, miR-410 and miR-495 are among a growing number of miRNAs that have the ability to potently stimulate neonatal cardiomyocyte proliferation.


Genome-wide analyses of gene expression during mouse endochondral ossification.
Endochondral ossification is a complex process involving a series of events that are initiated by the establishment of a chondrogenic template and culminate in its replacement through the coordinated activity of osteoblasts, osteoclasts and endothelial cells. Comprehensive analyses of in vivo gene expression profiles during these processes are essential to obtain a complete understanding of the regulatory mechanisms involved. To address these issues, we completed a microarray screen of three zones derived from manually segmented embryonic mouse tibiae. Classification of genes differentially expressed between each respective zone, functional categorization as well as characterization of gene expression patterns, cytogenetic loci, signaling pathways and functional motifs both confirmed reported data and provided novel insights into endochondral ossification. Parallel comparisons of the microdissected tibiae data set with our previously completed micromass culture screen further corroborated the suitability of micromass cultures for modeling gene expression in chondrocyte development. The micromass culture system demonstrated striking similarities to the in vivo microdissected tibiae screen; however, the micromass system was unable to accurately distinguish gene expression differences in the hypertrophic and mineralized zones of the tibia. These studies allow us to better understand gene expression patterns in the growth plate and endochondral bones and provide an important technical resource for comparison of gene expression in diseased or experimentally-manipulated cartilages. Ultimately, this work will help to define the genomic context in which genes are expressed in long bones and to understand physiological and pathological ossification.


Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism: entosis without matrix detachment.
Cell-cell contact formation following cadherin engagement requires actomyosin contraction along the periphery of cell-cell contact. The molecular mechanisms that regulate myosin activation during this process are not clear. In this paper, we show that two polarity proteins, partitioning defective 3 homologue (Par3) and mammalian homologues of Drosophila Lethal (2) Giant Larvae (Lgl1/2), antagonize each other in modulating myosin II activation during cell-cell contact formation in Madin-Darby canine kidney cells. While overexpression of Lgl1/2 or depletion of endogenous Par3 leads to enhanced myosin II activation, knockdown of Lgl1/2 does the opposite. Intriguingly, altering the counteraction between Par3 and Lgl1/2 induces cell-cell internalization during early cell-cell contact formation, which involves active invasion of the lateral cell-cell contact underneath the apical-junctional complexes and requires activation of the Rho-Rho-associated, coiled-coil containing protein kinase (ROCK)-myosin pathway. This is followed by predominantly nonapoptotic cell-in-cell death of the internalized cells and frequent aneuploidy of the host cells. Such effects are reminiscent of entosis, a recently described process observed when mammary gland epithelial cells were cultured in suspension. We propose that entosis could occur without matrix detachment and that overactivation of myosin or unbalanced myosin activation between contacting cells may be the driving force for entosis in epithelial cells.


Deviations of the visual upright in three dimensions in disorders of the brainstem: a clinical exploration.
Deviations of the subjective visual vertical in the roll or fronto-parallel plane occur commonly in disorders of the brainstem and have been extensively explored. In contrast, little is known about deviations in other directions. The present retrospective study focused on deviations in the pitch (sagittal) direction in 176 patients with a wide variety of disorders. The test task was to set a self-illuminated rod in the apparent upright position, in total darkness. Abnormal results (outside ± 4°) were recorded in 58% of the subjects. Negative (top backward) deviations were the most common, particularly with mass lesions in the pineal region, obstructive hydrocephalus, cerebellar lesions and crowding at the craniocervical junction. Positive and negative deviations were about equally common with focal intra-axial lesions. Negative deviations appeared related to dorsal locations of lesions and vice versa. Normal pressure hydrocephalus, Parkinson's disease and progressive supranuclear palsy were associated with smaller deviations, without a clear directional preponderance, and a larger individual variability. Most subjects lacked overt clinical corollaries. The most common ocular signs were aqueduct syndromes (n = 17) and ocular tilt reactions (n = 12), which were associated with deviations in 47 and 92% of instances, respectively. Subjective corollaries of deviation were never reported, not even by those subjects who showed a dramatic improvement upon resolution of the underlying condition. Deviations were also assessed in roll in a subgroup of 40 patients with focal lesions. Thirty subjects returned abnormal results: 13% in roll, 47% in pitch and 40% in pitch and roll. The direction of roll deviation appeared primarily related to laterality, with clockwise deviations with right-sided lesions and vice versa. All subjects with ocular tilt reactions had combined pitch and roll deviations, implying a common neural substrate. Correlation analyses, geometrical modelling and experimental self-observations indicated that deviations in pitch were attributable to cyclotorsional asymmetries between the eyes. The frequent co-existence of abnormal pitch and roll results implies that the true axis of deviation in focal brainstem disorders commonly falls outside traditional reference planes. The term 'visual upright in three dimensions' is suggested to identify unrestricted measurements, preserving the established term 'visual vertical' for measurements confined to the roll plane. Assessment of the visual upright in three dimensions provides a new, quantitative angle on brainstem disorders. The test appears useful for identifying a ubiquitous yet clinically silent feature of brainstem disease and also for monitoring the evolution of underlying conditions. More detailed explorations appear well motivated.


Silicon antisite in 4H SiC.
Electron paramagnetic resonance spectrum with C(3V) symmetry and a spin S = 1/2 has been observed in p-type, electron-irradiated 4H SiC. Based on the observed 29Si hyperfine structures it is suggested that the defect is the isolated silicon antisite (Si(C)). The spin S = 1/2 and the observation of the defect only in p-type material suggest that the Si(C) is in the positive-charge state. A strong temperature dependence of the g value and hyperfine coupling constant of the Si(C)(+) center indicates a considerable lattice relaxation in the vicinity of the defect.


Genetic diseases: congenital central hypoventilation, Rett, and Prader-Willi syndromes.
The present review summarizes current knowledge on three rare genetic disorders of respiratory control, congenital central hypoventilation syndrome (CCHS), Rett syndrome (RTT), and Prader-Willi syndrome (PWS). CCHS is characterized by lack of ventilatory chemosensitivity caused by PHOX2B gene abnormalities consisting mainly of alanine expansions. RTT is associated with episodes of tachypneic and irregular breathing intermixed with breathholds and apneas and is caused by mutations in the X-linked MECP2 gene encoding methyl-CpG-binding protein. PWS manifests as sleep-disordered breathing with apneas and episodes of hypoventilation and is caused by the loss of a group of paternally inherited genes on chromosome 15. CCHS is the most specific disorder of respiratory control, whereas the breathing disorders in RTT and PWS are components of a more general developmental disorder. The main clinical features of these three disorders are reviewed with special emphasis on the associated brain abnormalities. In all three syndromes, disease-causing genetic defects have been identified, allowing the development of genetically engineered mouse models. New directions for future therapies based on these models or, in some cases, on clinical experience are delineated. Studies of CCHS, RTT, and PWS extend our knowledge of the molecular and cellular aspects of respiratory rhythm generation and suggest possible pharmacological approaches to respiratory control disorders. This knowledge is relevant for the clinical management of many respiratory disorders that are far more prevalent than the rare diseases discussed here.


Broken Sacral Neuromodulation Lead Migration Into the Sigmoid Colon: A Case Report.
Sacral neuromodulation is an effective treatment of urinary incontinence, fecal incontinence, and idiopathic urinary retention. The procedure is considered low risk with overall low complication rates. This report describes a 40-year-old woman who underwent sacral neuromodulation explant and full-system implant for weaning efficacy of her device. During device removal, the tined lead broke and was left in situ. Four months later, she was diagnosed as having a wound infection at the site of the retained lead. Imaging revealed lead fragment migration into the sigmoid colon. A colocutaneous fistula was noted soon thereafter. The retained lead was removed during a colonoscopy and the fistula healed. A retained lead can result in migration through the peritoneum and into the colon. This can be managed with assistance from colorectal or gastroenterology consultants.


Comparison of radar and raingauge measurements during heavy rainfall.
Five heavy small-scale rainfall events in North Rhine-Westphalia (Germany) were investigated with radar and raingauge data. Special attention was paid to quality check and adjustment of radar data. Attenuation effects could be observed on both, C-Band and on X-Band radar. Adjustment of radar data to raingauge values turned out to be very difficult in the vicinity of heavy local rain cells. For the five affected regions the precipitation was quantified in the form of areal time series and cumulated radar images. As further result of this project, the spatial extent of the precipitation fields was identified and compared with radar and raingauge data.


A long-term maternal diet intervention is necessary to avoid the obesogenic effect of maternal high-fat diet in the offspring.
Although a pre-pregnancy dietary intervention is believed to be able to prevent offspring obesity, research evidence is absent. We hypothesize that a long period of pre-pregnancy maternal diet transition from a high-fat (HF) diet to a normal-fat (NF) diet effectively prevents offspring obesity, and this preventive effect is independent of maternal body weight change. In our study, female mice were either continued on an NF diet (NF group) or an HF diet (HF group) until weaning, or switched from an HF to an NF for 1 week (H1N group), 5 weeks (H5N group) or 9 weeks (H9N group) before pregnancy. After weaning, the offspring were given the HF diet for 12 weeks to promote obesity. The mothers, regardless of which group, did not display maternal body weight change and glucose intolerance either before pregnancy or after weaning. Compared to the HF group, the H1N and H5N, but not the H9N, offspring developed glucose intolerance earlier, with more severely imbalanced glucose homeostasis. These offspring also displayed hepatocyte degeneration and significant adipocyte hypertrophy associated with higher expression of lipogenesis genes. The molecular mechanistic study showed blunted insulin signaling, overactivated adipocyte Akt signaling and hepatic AMPK signaling with enhanced lipogenesis genes in the H1N and H5N versus the NF offspring. However, maternal H9N diets normalized glucose and lipid metabolism of the offspring via resensitized insulin signaling and normalized Akt and AMPK signaling. In summary, we showed that a long-term maternal diet intervention effectively released the intergenerational obesogenic effect of maternal HF diet independent of maternal weight management.


An efficient approach to obtaining water-compatible and stimuli-responsive molecularly imprinted polymers by the facile surface-grafting of functional polymer brushes via RAFT polymerization.
A new and efficient approach to obtaining molecularly imprinted polymers (MIPs) with both pure water-compatible (i.e., applicable in the pure aqueous environments) and stimuli-responsive binding properties is described, whose proof-of-principle is demonstrated by the facile modification of the preformed MIP microspheres via surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization of N-isopropylacrylamide (NIPAAm). The presence of poly(NIPAAm) (PNIPAAm) brushes on the obtained MIP microspheres was confirmed by FT-IR as well as the water dispersion and static contact angle experiments, and some quantitative information including the molecular weights and polydispersities of the grafted polymer brushes, the thickness of the polymer brush layers, and their grafting densities was provided. In addition, the binding properties of the ungrafted and grafted MIPs/NIPs in both methanol/water (4/1, v/v) and pure water solutions were also investigated. The introduction of PNIPAAm brushes onto the MIP microspheres has proven to significantly improve their surface hydrophilicity and impart stimuli-responsive properties to them, leading to their pure water-compatible and thermo-responsive binding properties. The application of the facile surface-grafting approach, together with the versatility of RAFT polymerization and the availability of many different functional monomers, makes the present methodology a general and promising way to prepare water-compatible and stimuli-responsive MIPs for a wide range of templates.


[Effect of succinate- and methionine-containing drug runihol on reparative regeneration processes in liver under experimental hepatectomy conditions].
The effect of runihol and ademethionine on the processes of reparative regeneration in the liver has been experimentally studied in a group of 78 white male rats subjected to partial hepatectomy, in comparison to intact and drug-untreated operated control animals. The administration of ademethionine and runihol within the first four days after operation led to a decrease in the relative area of discomplexation in liver beams and the appearance of prerequisites of the activation of regeneration processes. A morphometric investigation showed that ademethionine stimulated intracellular regeneration reactions on all terms after the partial extirpation of liver, the most pronounced effect being observed on the 4th and 10th days, while the administration of runihol led to comparable effects only on the 14th day. The activation of regeneration processesin the liver parenchyma is retained after cancellation of the preparations.


Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon.
In the last 6 years, following the first pathological description of presumed amyloid-beta (Aβ) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)-attributed to the transmission of Aβ seeds-have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.


Cannabidiol efficiently suppressed the acquisition and expression of methamphetamine-induced conditioned place preference in the rat.
Methamphetamine (MET) is one of the most prevalently abused psychostimulants in the world with drastic repercussions. Several studies emphasized the inhibitory effect of Cannabidiol (CBD) on the reward properties of psychostimulants. The current investigation utilized conditioned place preference (CPP) to assay CBD's impact on MET's reward characteristic, including acquisition and expression phases of MET-induced CPP. Like our prior researches, animals received MET (1 mg/kg; sc) in a five-day schedule to induce CPP. The rats were given intracerebroventricular (ICV) microinjection of CBD (2, 10, and 50 μg/5 μL DMSO) during the 5-day conditioning phase in the CPP paradigm to highlight the CBD's impact on the development (acquisition) of MET-induced place preference. Furthermore, animals were treated with CBD (2, 10 and 50 μg/5 μL) in the lateral ventricle on the post-conditioning day to elucidate the effect of ICV injection of CBD on the expression of MET-induced CPP. It was revealed that CBD (10 and 50 μg/5 μL) microinjection profoundly inhibited both phases of MET-induced CPP without any side effect on the locomotion in animals were treated by MET injection over conditioning phase. Also, CBD's inhibitory impact was more potent in the acquisition phase than the expression phase of MET-induced CPP. Ultimately, the current research reported that CBD could be a beneficial compound to treat drug abuse however more investigations are needed.


Recommendations for handling of pediatric liver biopsy specimens.
Pediatric liver disease may require specialized evaluation with abstruse techniques. We present suggestions to permit pathologists who do not work at pediatric referral hospitals to handle liver biopsy specimens from pediatric patients so that information will not be lost.


3D Cell Models in Radiobiology: Improving the Predictive Value of In Vitro Research.
Cancer is intrinsically complex, comprising both heterogeneous cellular composition and extracellular matrix. In vitro cancer research models have been widely used in the past to model and study cancer. Although two-dimensional (2D) cell culture models have traditionally been used for cancer research, they have many limitations, such as the disturbance of interactions between cellular and extracellular environments and changes in cell morphology, polarity, division mechanism, differentiation and cell motion. Moreover, 2D cell models are usually monotypic. This implies that 2D tumor models are ineffective at accurately recapitulating complex aspects of tumor cell growth, as well as their radiation responses. Over the past decade there has been significant uptake of three-dimensional (3D) in vitro models by cancer researchers, highlighting a complementary model for studies of radiation effects on tumors, especially in conjunction with chemotherapy. The introduction of 3D cell culture approaches aims to model in vivo tissue interactions with radiation by positioning itself halfway between 2D cell and animal models, and thus opening up new possibilities in the study of radiation response mechanisms of healthy and tumor tissues.


Effects of Sulcus Vocalis Depth on Phonation in Three-Dimensional Fluid-Structure Interaction Laryngeal Models.
Sulcus vocalis is an indentation parallel to the edge of vocal fold, which may extend into the cover and ligament layer of the vocal fold or deeper. The effects of sulcus vocalis depth d on phonation and the vocal cord vibrations are investigated in this study. The three-dimensional laryngeal models were established for healthy vocal folds (0 mm) and different types of sulcus vocalis with the typical depth of 1 mm, 2 mm, and 3 mm. These models with fluid-structure interaction (FSI) are computed numerically by sequential coupling method, which includes an immersed boundary method (IBM) for modelling the glottal airflow, a finite-element method (FEM) for modelling vocal fold tissue. The results show that a deeper sulcus vocalis in the cover layer decreases the vibrating frequency of vocal folds and expands the prephonatory glottal half-width which increases the phonation threshold pressure. The larger sulcus vocalis depth makes vocal folds difficult to vibrate and phonate. The effects of sulcus vocalis depth suggest that the feature such as phonation threshold pressure could assist in the detection of healthy vocal folds and different types of sulcus vocalis.


The Candida boidinii peroxisomal membrane protein Pmp30 has a role in peroxisomal proliferation and is functionally homologous to Pmp27 from Saccharomyces cerevisiae.
The mechanism of peroxisome proliferation is poorly understood. Candida boidinii is a methylotrophic yeast that undergoes rapid and massive peroxisome proliferation and serves as a good model system for this process. Pmp30A and Pmp30B (formerly designated Pmp31 and Pmp32, respectively) are two closely related proteins in a polyploid strain of this yeast that are strongly induced by diverse peroxisome proliferators such as methanol, oleate, and D-alanine. The function of these proteins is not understood. To study this issue, we used a recently described haploid strain (S2) of C. boidinii that can be manipulated genetically. We now report that strain S2 contains a single PMP30 gene very similar in sequence (greater than 93% identity at the DNA level) to PMP30A and PMP30B. When PMP30 was disrupted, cell growth on methanol was greatly inhibited, and cells grown in both methanol and oleate had fewer, larger, and more spherical peroxisomes than wild-type cells. A similar phenotype was recently described for Saccharomyces cerevisiae cultured on oleate in which PMP27, which encodes a protein of related sequence that is important for peroxisome proliferation, was disrupted. To determine whether Pmp27 is a functional homolog of Pmp30, gentle complementation was performed. PMP30A was expressed in the PMP27 disruptant of S. cerevisiae, and PMP27 was expressed in the PMP30 disruptant of C. boidinii S2. Complementation, in terms of both cell growth and organelle size, shape, and number, was successful in both directions, although reversion to a wild-type phenotype was only partial for the PMP30 disruptant. We conclude that these proteins are functional homologs and that both Pmp30 and Pmp27 have a direct role in proliferation and organelle size rather than a role in a specific peroxisomal metabolic pathway of substrate utilization.


Burkitt's like lymphoma in patients with and without HIV infection. A report of 33 patients from north-east Italy.
With the aim of comparing the clinical features of Burkitt's like lymphoma (BL) in HIV-infected patients and in the general population, we retrospectively analyzed 35 patients with HIV-positive non-Hodgkin's lymphoma (NHL) and 535 patients with HIV-negative NHL, from 1985 to 1990. A total of 33 patients with BL were diagnosed at our institute: 18 without and 15 with HIV infection; 3.3% and 43% of all HIV-seronegative and HIV-seropositive NHL respectively. No significant differences were found between these two series concerning clinical features, with the exception of peripheral adenopathy that was more common in the HIV infected patients (p = 0.05). In both groups BL was characterized by advanced stage and high incidence of bone marrow and gastrointestinal involvement. Response rate was lower in the HIV-positive patients, but the difference was not significant. No relevant differences in the toxicity after chemotherapy were observed. The median survival in the HIV-infected patients was lower (7 months) than in the other group (14 months), with borderline statistical significance (p = 0.06).


Snoring and breathing pauses during sleep: telephone interview survey of a United Kingdom population sample.
To determine the prevalence of snoring, breathing pauses during sleep, and obstructive sleep apnoea syndrome and determine the relation between these events and sociodemographic variables, other health problems, driving accidents, and consumption of healthcare resources. Telephone interview survey directed by a previously validated computerised system (Sleep-Eval). United Kingdom. 2894 women and 2078 men aged 15-100 years who formed a representative sample of the non-institutionalised population. Interview responses. Forty per cent of the population reported snoring regularly and 3.8% reported breathing pauses during sleep. Regular snoring was significantly associated with male sex, age 25 or more, obesity, daytime sleepiness or naps, night time awakenings, consuming large amounts of caffeine, and smoking. Breathing pauses during sleep were significantly associated with obstructive airways or thyroid disease, male sex, age 35-44 years, consumption of anxiety reducing drugs, complaints of non-restorative sleep, and consultation with a doctor in the past year. The two breathing symptoms were also significantly associated with drowsiness while driving. Based on minimal criteria of the International classification of Sleep Disorders (1990), 1.9% of the sample had obstructive sleep apnoea syndrome. In the 35-64 year age group 1.5% of women (95% confidence interval 0.8% to 2.2%) and 3.5% of men (2.4% to 4.6%) had obstructive sleep apnoea syndrome. Disordered breathing during sleep is widely underdiagnosed in the United Kingdom. The condition is linked to increased use of medical resources and a greater risk of daytime sleepiness, which augments the risk of accidents. Doctors should ask patients and bed partners regularly about snoring and breathing pauses during sleep.


Folium Sennae and emodin reverse airway smooth muscle contraction.
The objective of this project was to find a bronchodilatory compound from herbs and clarify the mechanism. We found that the ethanol extract of Folium Sennae (EEFS) can relax airway smooth muscle (ASM). EEFS inhibited ASM contraction, induced by acetylcholine, in mouse tracheal rings and lung slices. High-performance liquid chromatography assay showed that EEFS contained emodin. Emodin had a similar reversal action. Acetylcholine-evoked contraction was also partially reduced by nifedipine (a selective inhibitor of L-type voltage-dependent Ca2+ channels, LVDCCs), YM-58483 (a selective inhibitor of store-operated Ca2+ entry, SOCE), as well as Y-27632 (an inhibitor of Rho-associated protein kinase). In addition, LVDCC- and SOCE-mediated currents and cytosolic Ca2+ elevations were inhibited by emodin. Emodin reversed acetylcholine-caused increases in phosphorylation of myosin phosphatase target subunit 1. Furthermore, emodin, in vivo, inhibited acetylcholine-induced respiratory system resistance in mice. These results indicate that EEFS-induced relaxation results from emodin inhibiting LVDCC, SOCE, and Ca2+ sensitization. These findings suggest that Folium Sennae and emodin may be new sources of bronchodilators.


Sphingosine-1-phosphate receptor-3 signaling up-regulates epidermal growth factor receptor and enhances epidermal growth factor receptor-mediated carcinogenic activities in cultured lung adenocarcinoma cells.
Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions. However, the role of S1P signaling in tumorigenesis remains to be elucidated. In this study, we show that S1P receptor subtype 3 (S1P₃) is markedly up-regulated in a subset of lung adenocarcinoma cells compared to normal lung epithelial cells. Specific knockdown of S1P₃ receptors inhibits proliferation and anchorage-independent growth of lung adenocarcinoma cells. Mechanistically, we demonstrate that S1P₃ signaling increases epidermal growth factor receptor (EGFR) expression via the Rho kinase (ROCK) pathway in lung adenocarcinoma cells. Nuclear run-off analysis indicates that S1P/S1P₃ signaling transcriptionally increases EGFR expression. Knockdown of S1P₃ receptors diminishes the S1P-stimulated EGFR expression in lung adenocarcinoma cells. Moreover, S1P treatment greatly enhances EGF-stimulated colony formation, proliferation and invasion of lung adenocarcinoma cells. Together, these results suggest that the enhanced S1P₃-EGFR signaling axis may contribute to the tumorigenesis or progression of lung adenocarcinomas.


Resolution and contrast enhancement in coherent anti-Stokes Raman-scattering microscopy.
We implement switching laser mode coherent anti-Stokes Raman-scattering (SLAM-CARS) microscopy to enhance the spatial resolution and contrast in label-free vibrational microscopy. The method, based on the intensity difference between two images obtained with Gaussian and doughnut-shaped modes, does not depend on the specimen and relies on minimal modifications of the typical CARS setup. We demonstrate subdiffraction resolution imaging of myelin sheaths in a mouse brainstem. A lateral resolution of 0.36λ(p) is achieved.


Baseline Vulnerability and Inpatient Frailty Status in Relation to Adverse Outcomes in a Surgical Cohort.
This study aimed to derive measures of baseline vulnerability and inpatient frailty in elderly surgical patients and to study their association with adverse post-operative outcomes. Data from comprehensive geriatric assessment of 208 general surgical and orthopaedic patients aged 70 and over admitted to four acute hospitals in Queensland, Australia, were analysed to derive a baseline and inpatient Frailty Index (FI). The association of these indices with adverse outcomes was examined in logistic regression. The mean (SD) baseline FI was 0.19 (0.09) compared to 0.26 (0.12) on admission, with a predominant increase in domains related to functional status. Both baseline and inpatient FI were significant predictors of one year mortality, inpatient delirium, and a composite adverse outcome, after adjusting for age, sex and acuity of surgery. In summary, detecting baseline frailty pre-hospitalisation may be useful to trigger the implementation of supportive and preventative measures in hospital.


A randomized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrhea-predominant IBS.
Alosetron is indicated for women with chronic, severe diarrhea-predominant IBS (d-IBS) who have not responded adequately to conventional therapy. Constipation is the most common adverse event with alosetron treatment. Multiple dosing regimens were assessed in a randomized, double-blind, placebo-controlled study (S3B30040) to determine efficacy, tolerability, and evaluate constipation rate. 705 women with severe d-IBS were randomized to placebo, alosetron 0.5 mg once daily, 1 mg once daily, or 1 mg twice daily for 12 wk. The primary end point was the proportion of week 12 responders (patients with moderate or substantial improvement in IBS symptoms) on the 7-point Likert Global Improvement Scale (GIS). Secondary end points were average rate of adequate relief of IBS pain and discomfort, and bowel symptom improvements. The proportion of GIS responders at week 12 (primary time point) was significantly greater in all alosetron groups compared with placebo (54/176 [30.7%], 90/177 [50.8%], 84/175 [48%], and 76/177 [42.9%] for placebo, 0.5, 1 mg once daily, and 1 mg twice daily alosetron groups, respectively; P< or = 0.02). Results were similar for the average adequate relief rate (treatment effects > or =12%, P< or = 0.038). Bowel symptoms were improved in all alosetron groups. Constipation was the most common adverse event (9%, 16%, and 19% patients in the 0.5 mg, 1 mg once daily, and 1 mg twice daily groups, respectively). One event of intestinal obstruction and one of ischemic colitis occurred in the 0.5 mg group, and one event of fecal impaction occurred in the 1 mg twice-daily group. All were self-limited and resolved without sequelae. Alosetron 0.5 mg and 1 mg once daily as well as 1 mg twice daily are effective in providing global improvement in IBS symptoms, adequate relief of IBS pain and discomfort, and improvement in bowel symptoms in women with severe d-IBS. Lower dosing regimens resulted in a decreased constipation rate.


Timing of hot spot--related volcanism and the breakup of madagascar and India.
Widespread basalts and rhyolites were erupted in Madagascar during the Late Cretaceous. These are considered to be related to the Marion hot spot and the breakup of Madagascar and Greater India. Seventeen argon-40/argon-39 age determinations reveal that volcanic rocks and dikes from the 1500-kilometer-long rifted eastern margin of Madagascar were emplaced rapidly (mean age = 87.6 +/- 0.6 million years ago) and that the entire duration of Cretaceous volcanism on the island was no more than 6 million years. The evidence suggests that the thick lava pile at Volcan de l'Androy in the south of the island marks the focal point of the Marion hot spot at approximately 88 million years ago and that this mantle plume was instrumental in causing continental breakup.


The development of a pilot telemedicine network in Scotland: lessons learned.
A pilot telemedicine network was established in 11 sites using funding provided by the Department of Trade and Industry in the UK. The main purpose of the project was to develop and evaluate clinical and educational links between central and peripheral sites in Scotland. The results were very encouraging, and clinical services were established in accident and emergency medicine, tele-ultrasound and clinical psychology. An undergraduate medical teaching service was also successfully established. All of these services are to be continued after the completion of the project. Many lessons were learned during the establishment of this network which will be useful in future projects. These included the importance of training for telemedicine users, the importance of identifying a telemedicine champion, the pitfall of health economics and the fact that services must be needs driven.


Regulatory domains of myosins: influence of heavy chain on Ca(2+)-binding.
Light chain binding domains of rabbit skeletal, turkey gizzard and scallop myosin comprised of equimolar amounts of a short heavy chain fragment, essential light chain, and regulatory light chain have been obtained following extensive tryptic digestion. These complexes that are analogous to the regulatory domain prepared previously from scallop myosin by digestion with clostripain resist proteolysis due to the mutual protection of the heavy chain and the light chains, and are common structural features of the myosins studied. Specific Ca(2+)-binding by the regulatory domains reflects the behaviour of intact myosin; only scallop regulatory domain has a specific Ca(2+)-binding site. The heavy chain fragments of the different regulatory domains have been isolated under denaturing conditions and reconstituted with scallop essential light chain and scallop regulatory light chain or turkey gizzard regulatory light chain to yield regulatory domain hybrids. Hybrids containing the turkey gizzard regulatory light chain were used in Ca(2+)-binding studies since they were far more stable than their counterparts with the scallop regulatory light chain. The gizzard hybrid binds Ca2+ with a comparable specificity but somewhat lower affinity than native scallop regulatory domain. The rabbit regulatory domain hybrid also binds Ca2+, although with a reduced affinity and specificity. The results indicate that Ca(2+)-binding ability is determined by the light chains and modified by the heavy chains.


Mitochondrial biology and disease in Dictyostelium.
The cellular slime mold Dictyostelium discoideum has become an increasingly useful model for the study of mitochondrial biology and disease. Dictyostelium is an amoebazoan, a sister clade to the animal and fungal lineages. The mitochondrial biology of Dictyostelium exhibits some features which are unique, others which are common to all eukaryotes, and still others that are otherwise found only in the plant or the animal lineages. The AT-rich mitochondrial genome of Dictyostelium is larger than its mammalian counterpart and contains 56kb (compared to 17kb in mammals) encoding tRNAs, rRNAs, and 33 polypeptides (compared to 13 in mammals). It produces a single primary transcript that is cotranscriptionally processed into multiple monocistronic, dicistronic, and tricistronic mRNAs, tRNAs, and rRNAs. The mitochondrial fission mechanism employed by Dictyostelium involves both the extramitochondrial dynamin-based system used by plant, animal, and fungal mitochondria and the ancient FtsZ-based intramitochondrial fission process inherited from the bacterial ancestor. The mitochondrial protein-import apparatus is homologous to that of other eukaryote, and mitochondria in Dictyostelium play an important role in the programmed cell death pathways. Mitochondrial disease in Dictyostelium has been created both by targeted gene disruptions and by antisense RNA and RNAi inhibition of expression of essential nucleus-encoded mitochondrial proteins. This has revealed a regular pattern of aberrant mitochondrial disease phenotypes caused not by ATP insufficiency per se, but by chronic activation of the universal eukaryotic energy-sensing protein kinase AMPK. This novel insight into the cytopathological mechanisms of mitochondrial dysfunction suggests new possibilities for therapeutic intervention in mitochondrial and neurodegenerative diseases.


Fasting Interventions for Stress, Anxiety and Depressive Symptoms: A Systematic Review and Meta-Analysis.
Fasting interventions have shown effectiveness in alleviating stress, anxiety and depressive symptoms. However, no quantitative analysis has been carried out thus far. The objective was to determine the effectiveness of fasting interventions on stress, anxiety and depression and if these interventions were associated with increased or decreased fatigue/energy. Overall, 11 studies and 1436 participants were included in the quantitative analyses. After limiting analyses to randomized controlled trials with low risk of bias, we found that fasting groups had lower anxiety (b = -0.508, p = 0.038), depression levels (b= -0.281, p = 0.012) and body mass index compared to controls without increased fatigue. There was no publication bias and no heterogeneity for these results. These interventions were safe, even in patients with type 2 diabetes. These results should be taken with a caveat. These results are preliminary and encouraging and fasting appears to be a safe intervention. Data are not sufficient to recommend one fasting intervention more than the others. No study was carried out in psychiatric populations and further trials should be carried out in these populations that may be good candidates for fasting interventions.


[Early x-ray diagnosis of hip dysplasia in children].
The author proposes a method of differential diagnosis of hip dislocations and hip joint dysplasia in infants aged 3 months. The alpha-angle of hip dislocation with relation to trochanteric space is determined on an anteroposterior radiogram of the hip joints; 64 degrees means hip dysplasia, 65-69 degrees and more mean dislocation. This method was tested in 75 children (150 joints) aged 3 months. A mean diagnostic accuracy was 90.1%.


Demonstration of Borrelia burgdorferi DNA in urine samples from healthy humans whose sera contain B. burgdorferi-specific antibodies.
Since the possibility of asymptomatic infection with Borrelia burgdorferi has been suggested by a positive serology found in healthy subjects, we hypothesized that these subjects might excrete borrelial DNA sequences in urine as happens in patients with Lyme borreliosis. We found borrelial sequences by nested PCR in the urine samples from 3 of 13 healthy B. burgdorferi antibody-positive adults but not in urine samples from 79 antibody-negative healthy controls. After therapy with doxycycline, the urine samples were repeatedly negative for B. burgdorferi DNA. We conclude that urinary excretion of borrelial DNA sequences may occur in seropositive healthy subjects during asymptomatic infection. Demonstration of such sequences in urine must be interpreted cautiously and may not necessarily prove a borrelial cause of disease.


Electrokinetics of diffuse soft interfaces. III. Interpretation of data on the polyacrylamide/water interface.
Streaming potential measurements were carried out on a family of polyacrylamide-co-sodium acrylate gels cross-linked with N,N'-methylenebisacrylamide in a homemade electrokinetic cell. Measurements of the ionic conductivity within thin films of these gels allowed the equilibrium Donnan potential difference between the bulk gel and the bulk electrolyte environments to be estimated at various ionic strengths. The resulting Donnan potential data were combined with the directly measurable streaming potential data and used to evaluate the diffuse soft interface model of electrokinetics (Langmuir 2004, 20, 10324). The model introduces the concept of a gradual decay of polymer density and fixed charge density within a narrow inter-phase at the gel/solution interface. The nature of the decay at the interface has a dramatic effect on the magnitude of the streaming potential as predicted by the diffuse soft interface model. In this investigation, the gradual decay of polymer density within the inter-phase is described with a hyperbolic tangent function. For the gels mentioned, the characteristic length scale of the decay, alpha, as calculated from the fit to the model, increases significantly with decreasing ionic strength, suggesting an osmotically driven swelling of the loosely cross-linked polymer chains at the interface. The experimental data and the results of the fitting are discussed in terms of the physical picture of the interface and compared to fitting results for a model which assumes a simple step function at the gel-solution interface.


Predictors of failure of high-frequency oscillatory ventilation in term infants with severe respiratory failure.
To identify clinical factors in term neonates with severe respiratory failure that predict which neonates are unlikely to respond to high-frequency oscillatory ventilation (HFOV). This was a retrospective review of patient charts and medical records. We studied 190 newborns treated with HFOV between July 1985 and December 1992. All patients were at least 35 weeks' estimated gestational age and had severe respiratory failure, defined as arterial to alveolar oxygen ratio (a/A ratio) of less than 0.2 or the need for peak inspiratory pressure greater than 35 cm H2O on conventional ventilation. Of the 190 patients, 111 (58%) responded to HFOV (HFOV responders), and 79 (42%) were placed on extracorporeal membrane oxygenation (ECMO) after HFOV failed to improve gas exchange (nonresponders). The two groups were similar in gender and birth weight. Factors associated with failure of HFOV to produce a sustained improvement in gas exchange were a diagnosis of congenital diaphragmatic hernia and more severe respiratory compromise as assessed by admission blood gas. Stepwise logistic regression analysis showed that a diagnosis of congenital diaphragmatic hernia/lung hypoplasia (CDH/LH) and the a/A ratio at initiation of and after 6 hours of HFOV were the only significant independent predictors of the need for ECMO. Among all the patients, the presence of CDH/LH or an initial a/A ratio of 0.05 or lower yielded a sensitivity of 74% and specificity of 77% in correctly identifying neonates in whom HFOV failed to produce a sustained improvement in oxygenation. When neonates with CDH/LH were excluded from analysis, the most significant predictor of failure of HFOV was the a/A ratio after 6 hours of HFOV. In neonates without CHD/LH, a 6-hour a/A ratio of 0.08 or lower discriminated responders from nonresponders (ie, treatment with ECMO) with a sensitivity of 77% and specificity of 92%. In our patients, the presence of CDH/LH, severe respiratory failure (a/A ratio 0.05 or lower) at initiation of HFOV, and lack of improvement in oxygenation (a/A ratio 0.08 or lower after 6 hours of HFOV) were associated with failure of HFOV and treatment with ECMO. This information should help other centers to identify neonates who are at the greatest risk for requiring ECMO support and thus allow prompt transfer to an ECMO center.


Peroxidase and fluorescein isothiocyanate as antibody markers. A quantitative comparison of two peroxidase conjugates prepared with glutaraldehyde or periodate anda fluorescein conjugate.
Batches of rabbit anti-human immunoglobulin G antibodies were labeled either with horseradish peroxidase, using the two-step glutaraldehyde method or the periodate method, or with fluorescein isothiocyanate (FITC). The peroxidase conjugates were isolated by chromatography using two different gel types. The five types of conjugates thus obtained were standardized to the same amount of rabbit immunoglobulin G. The antibody activity, as estimated by means of single radial immunodiffusion and passive hemagglutination, and the enzyme activity, determined with orthodianisidine, were compared. The ultimate dilutions and absolute amounts of the five conjugates giving positive reactions were determined in direct and indirect immunohistochemical tests, using both cryostat sections of skin and the agarose bead model system. It appeared that during the peroxidase conjugation procedures there was a considerable loss of abtibody and enzyme activity, whereas in the FITC conjugation procedure the antibody activity remained intact. Neverthe less, peroxidase conjugates prepared with glutaraldehyde still gave positive staining reactions in equal or somewhat higher dilutions than the fluorescin conjugate did. The peroxidase conjugates prepared with periodate could not be diluted to the same extent. For the detection of antibodies by indirect immunohistochemical methods, the peroxidase conjugate, prepared with glutaraldehyde, was comparable to the FITC conjugate. The peroxidase conjugate, prepared with periodate, was less effective.


In Vitro Evaluation of Bis-3-Chloropiperidines as RNA Modulators Targeting TAR and TAR-Protein Interaction.
After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem-bulge-loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabilizing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analytical approaches for the study of multicomponent RNA-based interactions.


Extrinsic local regression on manifold-valued data.
We propose an extrinsic regression framework for modeling data with manifold valued responses and Euclidean predictors. Regression with manifold responses has wide applications in shape analysis, neuroscience, medical imaging and many other areas. Our approach embeds the manifold where the responses lie onto a higher dimensional Euclidean space, obtains a local regression estimate in that space, and then projects this estimate back onto the image of the manifold. Outside the regression setting both intrinsic and extrinsic approaches have been proposed for modeling i.i.d manifold-valued data. However, to our knowledge our work is the first to take an extrinsic approach to the regression problem. The proposed extrinsic regression framework is general, computationally efficient and theoretically appealing. Asymptotic distributions and convergence rates of the extrinsic regression estimates are derived and a large class of examples are considered indicating the wide applicability of our approach.


Major histocompatibility complex and mate choice in sand lizards.
In mice and man, females prefer males with a major histocompatibility complex (MHC) genotype different to their own. We tested whether this phenomenon also occurs in the Swedish sand lizard (Lacerta agilis). Females in a laboratory experiment preferred to associate with odour samples obtained from more distantly related males at the MHC class 1 loci. Data on free-ranging lizards suggest that associations between males and females are nonrandom with respect to MHC genotype. However, male spatial distribution and mobility during the mating season suggest that the non-random pairing process in the wild may also be driven by corresponding genetic benefits to males pairing with less related females.


[Periodic variations in motor endplate potentials].
The amplitudes of motor end-plate potentials in the Frog have been measured during repetitive stimulations of the motor nerve at frequencies between 0,5 and 30 Hz. A serial analysis showed that cyclic variations of these amplitudes were superimposed on the random fluctuation of epp due to the quantal nature of transmitter release. The period of these cyclic variations varied between 3 and 10 stimulations. This period was not significantly related to the frequency of the stimulation. The frequency spectrum analysis of the epp amplitudes showed similar values for the period of the cyclic variation of epp. The same kind of analysis applied to a binomial series of random numbers did not significantly present periodic fluctuations. The same analysis was applied to mean amplitudes of groups of 5 to 120 successive epps at the same end-plate. Periodic fluctuations were identified with periods of about 10 to 180 sec. It is suggested that periodic failures of nerve spike propagation in nerve terminals at sites of low safety factor, as at branchings, are responsible for the observed cyclic variation of epp.


In Situ Alloying of Thermally Conductive Polymer Composites by Combining Liquid and Solid Metal Microadditives.
Room-temperature liquid metals (LMs) are attractive candidates for thermal interface materials (TIMs) because of their moderately high thermal conductivity and liquid nature, which allow them to conform well to mating surfaces with little thermal resistance. However, gallium-based LMs may be of concern due to the gallium-driven degradation of many metal microelectronic components. We present a three-component composite with LM, copper (Cu) microparticles, and a polymer matrix, as a cheaper, noncorrosive solution. The solid copper particles alloy with the gallium in the LM, in situ and at room temperature, immobilizing the LM and eliminating any corrosion issues of nearby components. Investigation of the structure-property-process relationship of the three-component composites reveals that the method and degree of additive blending dramatically alter the resulting thermal transport properties. In particular, microdispersion of any combination of the LM and Cu additives results in a large number of interfaces and a thermal conductivity below 2 W m-1 K-1. In contrast, a shorter blending procedure of premixed LM and Cu particle colloid into the polymer matrix yields a composite with polydispersed filler and effective intrinsic thermal conductivities of up to 17 W m-1 K-1 (effective thermal conductivity of up to 10 W m-1 K-1). The LM-Cu colloid alloying into CuGa2 provides a limited, but practical, time frame to cast the uncured composite into the desired shape, space, or void before the composite stiffens and cures with permanent characteristics.


Neurological complications of extracorporeal membrane oxygenation in children.
Extracorporeal membrane oxygenation (ECMO) is a potentially life-saving treatment for patients in refractory cardiorespiratory failure. Neurological complications that result from ECMO treatment are known to significantly impact patient survival and quality of life. The purpose of this study was to review the incidence of neurological complications of ECMO in the pediatric population and the role of neurosurgery in the treatment of these patients. Data were obtained from the national Extracorporeal Life Support Organization (ELSO) Registry for the years 1990 to 2009. The neurological complications recorded by the registry include CNS hemorrhage, CNS infarction, and seizure. The ECMO Registry at the authors' institution was then searched, and 3 pediatric patients who had undergone craniotomy during ECMO treatment were identified. Children in the ELSO Registry who were treated with ECMO survived to hospital discharge in 65% of cases. Intracranial hemorrhage occurred in 7.4% of the ECMO-treated patients, with 36% of those surviving to hospital discharge. Hemorrhage was more likely in patients younger than 30 days old and in those requiring ECMO for cardiac indications. Cerebral infarction occurred in 5.7% of all ECMO-treated patients. Clinically diagnosed seizures occurred in 8.4% of all ECMO-treated patients. The ECMO Registry at the authors' institution revealed that 1898 patients were treated there. Intracranial hemorrhage was diagnosed in 81 patients (5.8%), and 3 of these patients were treated with craniotomy. Two of the patients were alive with minimal neurological impairment and normal school performance at 10 and 16 years of follow-up. Intracranial hemorrhage is a serious complication of ECMO treatment. While the surgical risk is substantial, there may be a role for surgical evacuation of hemorrhage in well-selected patients.


Functional subtyping of neurokinin receptors on canine proximal colonic mucosa.
Functional subtyping of the receptors responsible for the neural and nonneural effects of substance P (SP) on the canine proximal colon were studied. Selective agonists and antagonists were used with two different in vitro preparations. The mucosa contained the muscularis mucosa and attendant submucosal plexuses, whereas the epithelium was devoid of both. We obtained the following results: [Sar9,Met(O2)11]SP (Sar9SP), a neurokinin-1 receptor agonist, stimulated both preparations; senktide, a neurokinin-3 agonist, evoked a response only on the mucosal preparation; [beta-Ala8]NKA4-10, a neurokinin-2 agonist, was ineffective on both preparations; tetrodotoxin completely inhibited the mucosal responses to senktide, but the inhibitory effects on Sar9SP were only partial; CP-96,345, a neurokinin-1-selective antagonist, inhibited both epithelial and mucosal responses to Sar9SP and R487 [Trp7,beta-Ala8]NKA4-10, a neurokinin-3 antagonist, inhibited mucosal responses to senktide. Thus, the neural effects involved both neurokinin-1 and neurokinin-3 receptors, whereas the nonneural effects were mediated by neurokinin-1 receptors alone. Neurokinin-2 receptors were functionally absent.


Sense of coherence predicts uncomplicated delivery: a prospective observational study.
The present study aimed to investigate factors predicting uncomplicated deliveries and specifically whether a sense of coherence (SOC) and perceived stress can predict such deliveries. A prospective observational study was conducted employing self-administered SOC and perceived stress scale (PSS) questionnaires with pregnant women attending the outpatient clinic for routine surveillance. Following delivery, data regarding maternal and fetal delivery complications were collected from the participants' medical records. Of one hundred forty-five women completing the study, 43.4% completed the delivery process without complications. Women experiencing delivery complications, on average, had lower SOC scores (67.7 +/- 1.19 vs. 72.2 +/- 1.32, p = 0.014). Maternal complications (as opposed to fetal complications) accounted for this divergence and were related to lower SOC scores (67.74 +/- 1.19 vs. 72.18 +/- 1.32, p = 0.01). PSS was not associated with uncomplicated delivery (18.82 +/- 0.59 vs. 17.98 +/- 0.62, p = 0.341). Nulliparity, however, was associated with higher occurrence of complicated delivery (31.9% of complicated vs. 13.2% of uncomplicated deliveries, p = 0.007). Multivariable analysis demonstrated that high SOC (OR = 1.042; 95% CI = 1.004-1.08; p = 0.03) and nulliparity (OR = 0.293; 95% CI = 0.113-0.758; p = 0.011) both were independent predictors of uncomplicated delivery, directly and inversely, respectively. In conclusion, higher SOC scores are an independent protective factor for the prediction of uncomplicated delivery.


An outbreak of rat mite dermatitis in an animal research facility.
We describe an outbreak of rat mite dermatitis that affected 15 employees of an animal research facility. Cases of rat mite dermatitis are infrequently reported, and outbreaks are reported even less. Our case series demonstrates that in contrast to most prior outbreaks, rat mite dermatitis may occur even in modern, well-maintained physical surroundings and thus remains a relevant diagnosis today.


Treatment-seeking college students with disabilities: Presenting concerns, protective factors, and academic distress.
Students with disabilities are a growing population on college campuses and have unique challenges that put them at risk for early departure, creating complexity in efforts to address their personal and academic needs. The purpose was to explore academic and other sources of distress among college students with disabilities to identify possible areas where enhanced supports might benefit this population. Research Method and Design: Researchers analyzed cross-sectional data from the Center for Collegiate Mental Health to compare subsamples of students with (n = 1,774) and without disabilities (n = 1,774) on presenting concerns, and to determine significant predictors of academic distress among students with disabilities. Results indicated that students with disabilities have many similar treatment concerns with their peers, but showed greater concerns in depression and self-harm; academic performance; anxiety and obsessions/compulsions; and fewer concerns in relationship problems. Significant predictors of academic distress for students with disabilities included attention deficit-hyperactivity disorder (ADHD), depression and self-harm, trauma or victimization, stress and academic performance, and social support from family and peers. These results suggest the importance of several factors in understanding the presenting concerns of treatment-seeking students with disabilities and mitigating academic distress for this population. Additional areas for research are presented. (PsycINFO Database Record


COVID-19 Pandemic: Impact on Admission, Diagnosis, and Treatment of Non-COVID-19 Patients Admitted to SARI ICU.
Background: Coronavirus disease 2019 (COVID-19) pandemic has caused a huge burden on healthcare services worldwide, severely affecting the management of non-COVID-19 patients as well. The Government of India has updated guidelines for the clinical management of COVID-19 illness, including severe acute respiratory infections (SARI) definition for triaging suspected COVID-19 cases in an isolated intensive care unit (ICU). The aim of this study was to estimate the adherence of clinicians in triaging COVID-19 suspects as per SARI definition to SARI ICU. This study also observed the impact of such triaging on admission, diagnosis, and treatment process of non-COVID-19 patients admitted to SARI ICU. Patients and methods: This cross-sectional study was conducted in a designated SARI ICU of two tertiary care medical college hospitals involving 78 patients from the month of June to July 2020. Data related to demographics, the severity of illness, advanced life supports, delay in diagnosis, intervention, and treatment of patients in SARI ICU due to suspected COVID-19 status were documented. Results: Adherence to SARI definition for triaging COVID-19-suspect cases was 19.2%. Despite hindrance in diagnosis (17.9%) and treatment (12.8%), mortality among patients in SARI ICU was limited to 14.10%. Results were insignificant when checked for various factors associated with mortality. Conclusion: Nonadherence to SARI definition may lead to undue delay in diagnosis, intervention, and treatment of non-COVID-19 cases. This may result in increased morbidity, mortality, and economic burden on patients and the healthcare system. key message: A rationale and just utilization of healthcare resources are need of the hour in the face of an enormous volume of SARI cases during COVID-19 pandemic. SARI criteria as implemented by the Ministry of Health and Family Welfare (MOHFW), Government of India, are a very important tool in triaging of COVID-19-suspect cases. Adequate measures should be in place in order to mitigate the inadequacies and deficiencies in the treatment of non-COVID-19 cases, which have occurred as a result of COVID-19 pandemic. How to cite this article: Arunachala S, Venkatesh BT, Bhatt MT, Puranik A, Rao S, Ravindranath S. COVID-19 Pandemic: Impact on Admission, Diagnosis, and Treatment of Non-COVID-19 Patients Admitted to SARI ICU. Indian J Crit Care Med 2021;25(8):853-859.


No effect of B vitamins on ADMA levels in patients at increased cardiovascular risk.
Asymmetric dimethylarginine (ADMA) is a recently identified potent cardiovascular risk factor. ADMA levels are increased in hyperhomocysteinaemia and the metabolism of ADMA is linked with that of homocysteine in several ways. Treatment with B vitamins effectively reduces homocysteine levels, but studies investigating the effect on ADMA levels are scarce and show conflicting results. In this study we evaluated the effect of treatment with B vitamins on ADMA levels in two high cardiovascular risk populations. In study I, 110 siblings of patients with clinical atherosclerotic disease and postmethionine hyperhomocysteinaemia were treated with 5 mg of folic acid and 250 mg of pyridoxine or placebo, and were analysed after 1 year. In study II, 41 patients with type 2 diabetes and mild hyperhomocysteinaemia were analysed after 6 months treatment with 5 mg of folic acid or placebo. A correlation between baseline homocysteine and ADMA levels was found, which was partly due to confounding by renal function. Homocysteine levels decreased by 43% in study I and by 28% in study II. In both studies, treatment with B vitamins had no effect at all on ADMA, arginine/ADMA ratio and SDMA levels. This result was confirmed in multiple linear regression analyses with adjustment for baseline values and gender. Our studies indicate that B vitamins, despite causing a substantial reduction in plasma homocysteine levels, have no beneficial effect on ADMA levels.


Abiotic degradation of glyphosate into aminomethylphosphonic acid in the presence of metals.
Glyphosate [N-phosphono-methylglycine (PMG)] is the most used herbicide worldwide, particularly since the development of transgenic glyphosate-resistant (GR) crops. Aminomethylphosphonic acid (AMPA) is the main glyphosate metabolite, and it may be responsible for GR crop damage upon PMG application. PMG degradation into AMPA has hitherto been reckoned mainly as a biological process, produced by soil microorganisms (bacteria and fungi) and plants. In this work, we use density functional calculations to identify the vibrational bands of PMG and AMPA in surface-enhanced Raman spectroscopy (SERS) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra experiments. SERS shows the presence of AMPA after glyphosate is deposited from aqueous solution on different metallic surfaces. AMPA is also detected in ATR-FTIR experiments when PMG interacts with metallic ions in aqueous solution. These results reveal an abiotic degradation process of glyphosate into AMPA, where metals play a crucial role.


[Pathological anatomy of defects of the prosencephalic group].
Morphological changes in the brain were studied in 14 observations of defects of the prosencephalic group. These defects were shown to be of three kinds: prosencephaly, alobar prosencephaly, and holoprosencephaly, and to be due to partial or complete undivision of the cranial part of the medullary tube. The nature of these defects is heterogeneous. Most frequently prosencephalitic defects are due to autosomal aberrrations (trisomy 13 and 18, 13-q-, 18p-, triploidy), and may also be due to gene mutations. In cases of trisomy 13 these defects are regularly accompanied by structural disorders of cytoarchitectonics of the cortex of the end brain, cerebellum, and medulla, which may be important for differential diagnosis of prosencephaly of various etiologies.


Inhibition of ethionine pancreatitis in the rabbit by DL-BETA-3 thienylalanine pretreatment.
Beta-3 thienylalanine, an inhibitor of zymogen formation, was studied in the experimental model of ethionine pancreatitis in the rabbit. Beta-3TA pretreated and nonpretreated rabbits were given ethionine for six days and controls were given chow only. Animals were killed and serum amylase values determined. Pancreatic tissue was studied by light and electron microscopy. Beta-3TA pretreated rabbits on ethionine showed normal amylase values, while those receiving only ethionine showed high values. Microscopic examination showed severe pancreatitis in the nonpretreated group but only mild vacuolization of cells in the Beta-3TA pretreated animals. Electron microscopy demonstrated integrity of rough endoplasmic reticulum in pretreated animals and severe distortion of cytoplasmic organelles in nonpretreated animals.


Validation of a New Method for 2D Fusion Imaging Registration in a System Prepared Only for 3D.
Purpose: To validate a new 2D-3D registration method of fusion imaging during aortic repair in a system prepared only for 3D-3D registration and to compare radiation doses and accuracy. Materials and Methods: The study involved 189 patients, including 94 patients (median age 70 years; 85 men) who underwent abdominal endovascular aneurysm repair (EVAR) with 2D-3D fusion on an Artis zee imaging system and 95 EVAR patients (median age 70 years; 81 men) from a prior study who had 3D-3D registration done using cone beam computed tomography (CBCT). For the 2D-3D registration, an offline CBCT of the empty operating table was imported into the intraoperative dataset and superimposed on the preoperative computed tomography angiogram (CTA). Then 2 intraoperative single-frame 2D images of the skeleton were aligned with the patient's skeleton on the preoperative CTA to complete the registration process. A digital subtraction angiogram was done to correct any misalignment of the aortic CTA volume. Values are given as the median [interquartile range (IQR) Q1, Q3]. Results: The 2D-3D registration had an accuracy of 4.0 mm (IQR 3.0, 5.0) after bone matching compared with the final correction with DSA (78% within 5 mm). By applying the 2D-3D protocol the radiation exposure (dose area product) from the registration of the fusion image was significantly reduced compared with the 3D-3D registration [1.12 Gy∙cm2 (IQR 0.41, 2.14) vs 43.4 Gy∙cm2 (IQR 37.1, 49.0), respectively; p<0.001). Conclusion: The new 2D-3D registration protocol based on 2 single-frame images avoids an intraoperative CBCT and can be used for fusion imaging registration in a system originally designed for 3D-3D only. This 2D-3D registration protocol is accurate and leads to a significant reduction in radiation exposure.


Intranasal exposure to staphylococcal enterotoxin B elicits an acute systemic inflammatory response.
Staphylococcus aureus produces a variety of superantigen exotoxins, including staphylococcal enterotoxin B (SEB). Little is known regarding the pathogenesis of SEB entering through the intranasal route. Intranasal exposure to SEB might occur because of nasal packing following surgical procedure, biologic warfare, or even S. aureus colonization. We evaluated the local and systemic effects of intranasally delivered SEB using a series of human leukocyte antigen (HLA) class II transgenic mice as conventional mice expressing endogenous class II molecules mount a poor immune response to SEB. Gene expression profiling using microarrays showed robust up-regulation of genes involved in several proinflammatory pathways as early as 3 h post-intranasal challenge with SEB in HLA class II transgenic mice. This was accompanied by a several hundred-fold increase in serum levels of pro-inflammatory cytokines such as IL-12, IL-6, TNF-alpha, IFN-gamma, as well as MCP-1 in HLA class II transgenic mice but not in C57BL/6 mice; CD4 or CD8 T-cells independently contributed to the systemic cytokine response. Defective IL-12 or IL-4 receptor signaling significantly decreased or increased serum IFN-gamma, respectively. Intranasal exposure to SEB resulted in neutrophil influx into bronchoalveolar lavage fluid and caused expansion of both CD4 and CD8 T-cells expressing TCR V beta 8 in the spleen. This was accompanied by mononuclear cell infiltration in the liver reminiscent of the systemic inflammatory response syndrome. Thus, we have shown, for the first time, that intranasal administration of SEB can cause systemic immune activation.


[Status of central hemodynamics in patients with hypertension and secondary arterial hypertension].
A study was undertaken to examine 285 patients with hypertensive disease and 187 with secondary arterial hypertension. Their hemodynamic parameters were assessed by a radionuclide method. It was found that there were various blood circulatory types at each stage, no matter what the clinical type of the disease. The state of central hemodynamics was demonstrated to be associated with interaction of cardiac and peripheral mechanisms responsible for blood circulatory regulation.


Growth of neomucosa after intestinal resection.
The growth of neomucosa over patched intestinal defects may prove useful in the short-bowel syndrome. This study was done to determine if the timing of intestinal patching with respect to intestinal resection affects neomucosal growth. Twelve dogs underwent 75% intestinal resection, with intestinal patching done either simultaneously or 12 weeks later. Energy intake, final body weight, albumin level, and length of remnant patched were similar in both groups. Forty weeks after patching, neomucosal coverage of the defect (95.2% +/- 2.0% vs 94.2% +/- 1.6%), neomucosal surface area (36.2 +/- 4.5 vs 31.8 +/- 2.9 cm2), and patch size (56.2% +/- 6.8% vs 51.9% +/- 9.7%) were similar in both the simultaneous and delayed groups, as were villus height of neomucosa and disaccharidase activity. Neomucosal growth is similar whether intestinal patching is performed simultaneously or 12 weeks after resection. Intestinal patching is not indicated at the initial intestinal resection.


Reflex sympathetic dystrophy syndrome: a longitudinal study.
Reflex sympathetic dystrophy syndrome is a multi-symptom, multi-system syndrome which affects all age groups with the common, overriding complaint of severe, unrelenting, burning pain. Affecting millions worldwide, the illness trajectory is poorly understood. A large longitudinal patient study has yielded important preliminary findings, which have implications for nurses caring for a variety of patients in pain.