[Asthma attacks in low-dose preventive use of heparin in a male with femoral neck fracture and aortic aneurysm].
Hypersensitivity reactions to heparin preparations with a wide spectrum of clinical manifestations have been reported frequently in the past, but are a rarity now. A 88 year old man was admitted for physical therapy of a collum femoris fracture. Treatment with a diuretic, Reserpine and Verapamil was continued. Chest x-ray revealed a large thoracic aortic aneurysm. From the 12th to the 18th day of low dose heparin prophylaxis with calcium heparin, 7500 U twice daily, at least eight attacks of asthma or cyanosis were observed, starting about two hours after heparin injection. The last attack began suddenly with wheezing, tachypnoea and cough and was associated with apprehension, a sudden blood pressure increase and severe cyanosis. Ventilation improved with oxygen and a beta 2-stimulator, but hypertension and cyanosis lasted for three hours. After discontinuation of heparin no further attacks occurred. Causes other then heparin could not be found. Despite the use of porcine mucosa heparin, avoidance of preservatives and use of low doses a hypersensitivity reaction occurred in our case. The delayed onset after preceding subcutaneous application as well as difficulties in separating the reaction from complications of underlying disease may delay heparin discontinuation.


Age-related change in cortical thickness in adolescents at clinical high risk for psychosis: a longitudinal study.
Progression to psychosis has been associated with increased cortical thinning in the frontal, temporal and parietal lobes in individuals at clinical high risk for the disorder (CHR-P). The timing and spatial extent of these changes are thought to be influenced by age. However, most evidence so far stems from adult samples. Longitudinal studies are essential to understanding the neuroanatomical changes associated to transition to psychosis during adolescence, and their relationship with age. We conducted a longitudinal, multisite study including adolescents at CHR-P and healthy controls (HC), aged 10-17 years. Structural images were acquired at baseline and at 18-month follow-up. Images were processed with the longitudinal pipeline in FreeSurfer. We used a longitudinal two-stage model to compute the regional cortical thickness (CT) change, and analyze between-group differences controlling for age, sex and scan, and corrected for multiple comparisons. Linear regression was used to study the effect of age at baseline. A total of 103 individuals (49 CHR-P and 54 HC) were included in the analysis. During follow-up, the 13 CHR-P participants who transitioned to psychosis exhibited greater CT decrease over time in the right parietal cortex compared to those who did not transition to psychosis and to HC. Age at baseline correlated with longitudinal changes in CT, with younger individuals showing greater cortical thinning in this region. The emergence of psychosis during early adolescence may have an impact on typical neuromaturational processes. This study provides new insights on the cortical changes taking place prior to illness onset.


Temporal properties of spatial contrast vision.
The temporal characteristics of spatial contrast vision at and above threshold were assessed psychophysically using sinusoidal gratings and a contrast-matching method. Temporal frequency response curves became flatter as contrast level increased. An impulse response model was fitted to these flicker data, and used to make predictions about temporal integration and two-pulse summation. The predictions fitted the experimental data well, except under conditions where the Broca-Sulzer effect occurred. The latter was not predicted by the biphasic impulse response that otherwise worked well. Temporal filtering became moderately transient and operated over a shorter time-scale as contrast increased, and above threshold temporal properties varied little with spatial frequency. The data and modelling supported the idea that subjects exploited probability summation at threshold while using a peak detection criterion above threshold. Systematic visual field asymmetries in contrast perception are also described. Single- and multiple-channel models of temporal processing are discussed.


Chronic Memantine Treatment Ameliorates Behavioral Deficits, Neuron Loss, and Impaired Neurogenesis in a Model of Alzheimer's Disease.
Memantine, a non-competitive NMDA receptor antagonist possessing neuroprotective properties, belongs to the small group of drugs which have been approved for the treatment of Alzheimer's disease (AD). While several preclinical studies employing different transgenic AD mouse models have described beneficial effects with regard to rescued behavioral deficits or reduced amyloid plaque pathology, it is largely unknown whether memantine might have beneficial effects on neurodegeneration. In the current study, we assessed whether memantine treatment has an impact on hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. We demonstrate that a chronic oral memantine treatment for 4 months diminishes hippocampal CA1 neuron loss and rescues learning and memory performance in different behavioral paradigms, such as Morris water maze or a novel object recognition task. Cognitive benefits of chronic memantine treatment were accompanied by an amelioration of impaired adult hippocampal neurogenesis. Taken together, our results demonstrate that memantine successfully counteracts pathological alterations in a preclinical mouse model of AD.


Detection of homologous and heterologous malaria antibodies by application of Plasmodium falciparum merozoite antigen to an ELISA.
Sera of patients with anti-plasmodial antibodies determined by indirect fluorescence antibody test (IFAT) were used to evaluate an enzyme immunoassay (IgG ELISA) for determining antibodies to Plasmodium falciparum merozoite antigen. The two tests correlated well. Antibodies to species other than P. falciparum, however, were detected by P. falciparum merozoite antigen to a limited extent only.


MicroRNA regulation of murine trophoblast stem cell self-renewal and differentiation.
Proper placentation is fundamental to successful pregnancy. Placenta arises from differentiation of trophoblast stem (TS) cells during development. Despite being recognized as the counterpart of ES cells in placental development, the role of regulatory miRNAs in TS cell differentiation remains inadequately explored. Here, we have identified complete repertoire of microRNAs present in mouse trophoblast cells in proliferative and differentiated state. We demonstrated that two miRNA clusters, -290 and -322, displayed reciprocal expression during trophoblast differentiation. Loss of miR-290 cluster members or gain in miR-322 cluster members led to differentiation of TS cells. The trophoblast stemness factor, CDX2, transactivated the miR-290 cluster and Cyclin D1 MiR-290 cluster members repressed cell cycle repressors, P21, P27, WEE1, RBL2, and E2F7, in TS cells. MiR-322 cluster members repressed the cell cycle activators, CYCLIN D1, CYCLIN E1, CDC25B, and CDX2, to induce differentiation. Taken together, our findings highlight the importance of posttranscriptional regulation by conserved miRNA clusters that form a regulatory network with CDX2, cell cycle activators, and repressors in equipoising TS cell self-renewal and differentiation.


Rat strain differences in ethanol self-administration and taste aversion learning.
Taste aversion learning was investigated in two inbred strains of rats known to differ in amount of ethanol (EtOH) they will self-administer orally. The "low EtOH preference" strain, WKYs, acquired an aversion to an EtOH solution during self-administration; but a "high preference" strain, M520s, did not. It was shown that a lower dose of EtOH will condition saccharin aversion in WKYs than in M520s, suggesting EtOH is a more effective US in the low preference strain. Analysis of patterns of EtOH self-administration indicates the pattern of the low preference strain is more likely to result in taste aversion learning. The implications of these results for the presumed relation between EtOH preference and other EtOH-related phenotypes is discussed.


Lockdown in France: Impact on Families of Young Children With Special Needs.
Families with young children have faced serious challenges during the first lockdown as a result of the COVID-19 pandemic. In addition to remote working, parents have had to monitor their children's schoolwork and manage their daily lives. When one of the children also has neuro-developmental disorders, this results in an increased burden. We can therefore wonder how these families with one or more young children (under 6 years old) with special needs have experienced and dealt with this lockdown. In this context, the "COVJEUNENFANT" study focused more specifically on the subjective experience, as a parent, of those who cared for children with special needs (i.e., with developmental disorders, neurodevelopmental disorders, proven disabilities or chronic health conditions) compared to the general population. We wished to see if the consequences of the health crisis were significantly different from those perceived by respondents in the general population (n = 490) and if the sociodemographic structure of these families differed from those of other respondents. Ninety three French families with at least one child under 6 years old and one with developmental difficulties or a chronic illness, from a cohort of 490 control families, participated in a web-based survey during the first lockdown, from the 28th April 2020 to 29th May 2020. After presenting the participants' sociodemographic characteristics, the results show that these French families (n = 93) are less wealthy than the control population "without special needs" (n = 397), have felt more pressures originating from their environment (families, friends, colleagues, media, social networks…), have suffered from more health issues (other than COVID-19), have taken more measures to protect themselves (social-distancing), and were less likely to feel happy. A significantly larger number of them lamented the lack of free time and voiced a larger need for information regarding children's education. However, their parental role was felt as being more satisfying and their family relations strengthened more than in the general population of participants. It is apparent that urgent prioritisation is needed in order to support and care for these families by continuing to provide care for their children in one way or another, and by ensuring that their need to adapt again does not exceed their own abilities and resources, especially as young children, who have high levels of requirements, are present in the home.


CEP290 Mutation Spectrum and Delineation of the Associated Phenotype in a Large German Cohort: A Monocentric Study.
Gene therapy for Leber congenital amaurosis (LCA) is becoming available, and therefore it is crucial to identify eligible candidates. We report the spectrum and associated phenotype of CEP290 mutations in the largest German cohort observed by a single clinical site. Prospective cohort study. Twenty-three patients with mutations in CEP290 were included. Genomic DNA was analyzed by Sanger sequencing or high-throughput sequencing for all retinitis pigmentosa-associated genes in patients, and segregation analysis was done in family members. Patients underwent functional and morphologic examinations, including fundus autofluorescence and spectral-domain optical coherence tomography. The most frequent mutation was c.2991+1655A>G, found in 87% of patients (20/23). Thirty percent of patients (7/23) carried the mutation in an apparent homozygous state and 57% (13/23) in a likely compound heterozygous state. The most common clinical diagnosis was LCA and/or early onset severe retinal dystrophy in 82% (19/23), followed by retinitis pigmentosa in 14% (3/23) and cone-rod dystrophy (4%, 1/23). Best-corrected visual acuity was severely reduced to residual light perception and hand motion vision, with the exception of 3 patients with best-corrected visual acuity of 0.8 (Snellen). The visual field was severely decreased and electroretinogram was undetectable in most cases; however, retinal layers at the fovea appeared to be relatively well preserved. Systemic disorders were not noticed. c.2991+1655A>G is by far the most important CEP290 mutation, contributing to 87% of patients with the CEP290 mutation in Germany. In our cohort, a homozygous c.2991+1655A>G genotype presented with a more severe phenotype. National studies and further detailed phenotype analysis seem to be important to assess the need for and promise of specific gene therapies.


Laboratory diagnostics for human Leishmania infections: a polymerase chain reaction-focussed review of detection and identification methods.
Leishmania infections span a range of clinical syndromes and impact humans from many geographic foci, but primarily the world's poorest regions. Transmitted by the bite of a female sand fly, Leishmania infections are increasing with human movement (due to international travel and war) as well as with shifts in vector habitat (due to climate change). Accurate diagnosis of the 20 or so species of Leishmania that infect humans can lead to the successful treatment of infections and, importantly, their prevention through modelling and intervention programs. A multitude of laboratory techniques for the detection of Leishmania have been developed over the past few decades, and although many have drawbacks, several of them show promise, particularly molecular methods like polymerase chain reaction. This review provides an overview of the methods available to diagnostic laboratories, from traditional techniques to the now-preferred molecular techniques, with an emphasis on polymerase chain reaction-based detection and typing methods.


The tyrosine free radical in ribonucleotide reductase from Escherichia coli.
One of the two nonidentical subunits of ribonucleotide reductase from Escherichia coli, protein B2, contains an organic free radical required for enzyme activity. Earlier isotope subtitution experiments (Sjöberg, B.-M., Reichard, P. Gräslund, A., and Ehrenberg, A. (1977) J. Biol. Chem. 252, 536-541) demonstrated that the radical was localized to a tyrosine residue of the enzyme and suggested that the spin density of the radical was centered at the methylene carbon of tyrosine. However, additional isotope substitution experiments now show that the spin density of the radical must be delocalized over the aromatic ring of the tyrosine residue.


Management of acute extensive portal vein thrombosis: the complexity and morbidity.
A 62-year-old patient was admitted with an acute unprovoked portal vein thrombosis with splenic and mesenteric extension. His progress was complicated by progressive small bowel ischaemia and increasing clot burden despite systemic anticoagulation. This case report describes the use of catheter-directed thrombolysis via a transjugular intrahepatic portosystemic shunt, with the disease and its treatment complicated by a ruptured iatrogenic pseudoaneurysm, abdominal compartment syndrome and small bowel infarction necessitating extensive small bowel resection.


Nocardia asteroides brain abscess following mastoidectomy.
Nocardia asteroides brain abscess occurred after mastoidectomy and tympanoplasty in a previously healthy 10-year-old boy. Combined surgical excision and trimethoprim/sulfamethoxazole therapy resulted in significant improvement.


Epilepsy in the elderly.
Other than children under the age of 5 years, the highest incidence of new onset epilepsy occurs in the population over 65 years of age. Risk factors in this age group include stroke, head trauma, dementia, infection, alcoholism and aging. Clinically, seizure behavior may be confused with other neurological impairments, thus delaying accurate diagnosis. Concomitant drug therapy affects the choice of antiepileptic drugs. Neuroscience nurses need to identify high-risk patients, recognize and document seizure activity and adverse drug reactions and interactions, and modify traditional seizure first aid for the frail elderly. An understanding of the psychosocial impact of epilepsy is necessary when offering education and support to the patient and family.


Degradation of acrylamide during chlorination as a precursor of haloacetonitriles and haloacetamides.
Acrylamide is a monomer of polyacrylamide, which is widely used in the water treatment process as a flocculant. The degradation kinetics and formation of disinfection by-products (DBPs) during acrylamide chlorination were investigated in this study. The reaction between chlorine and acrylamide followed a pseudo-first-order kinetics. A kinetic model regarding acrylamide chlorination was established and the rate constants of each predominant elementary reaction (i.e., the base-catalyzed reaction of acrylamide with ClO- as well as the reactions of acrylamide with HOCl and ClO-) were calculated as 7.89×107M-2h-1, 7.72×101M-1h-1, and 1.65×103M-1h-1, respectively. The presence of Br- in water led to the formation of HOBr and accelerated the rate of acrylamide degradation by chlorine. The reaction rate constant of acrylamide with HOBr was calculated as 1.33×103M-1h-1. The degradation pathways of acrylamide chlorination were proposed according to the intermediates identified using ultra-performance liquid chromatography and electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Five chlorinated DBPs including chloroform (CF), dichloroacetonitrile (DCAN), trichloroacetonitrile (TCAN), dichloroacetamide (DCAcAm), and trichloroacetamide (TCAcAm) were identified during acrylamide chlorination. The formation of CF, DCAN, DCAcAm, and TCAcAm kept increasing, while that of TCAN increased and then decreased with increasing reaction time. As the chlorine dosage increased from 0.75 to 4.5mM, DCAN became the dominant DBP. Large amounts of CF, DCAN, and TCAN were formed at basic pHs. The hydrolysis of DCAN and TCAN led to the formation of DCAcAm and TCAcAm, respectively. The results of this study elucidated that acrylamide can be a precursor for the formation of haloacetonitriles (HANs) and haloacetamides (HAcAms) during drinking water treatment.


Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor.
LPS (lipopolysaccharide) is one of the major factors that induce acute lung injury. Recently, it was reported that LPS induced disseminated endothelial apoptosis, preceding nonendothelial tissue damage. Caspases play important roles in apoptosis, including tumor necrosis factor-alpha-induced apoptosis, in several systems. We therefore investigated whether the injection of a caspase inhibitor prevents LPS-induced apoptosis and acute lung injury in mice. LPS (30 mg/kg) was administered intravenously to Institute for Cancer Research mice. Electron microscopic findings demonstrated characteristic features of apoptosis in endothelial cells and alveolar epithelial cells. The caspase-3 activity and the number of terminal dUTP nick-end labeling-positive cells in lung tissues were significantly increased after LPS administration. Benzyloxycarbonil-Val-Ala-Asp fluoromethylketone (Z-VAD.fmk), which is a broad-spectrum caspase inhibitor, was injected before and after the administration of LPS. The injection of Z-VAD.fmk suppressed the caspase-3 activity in lung tissues, and significantly decreased the number of terminal dUTP nick-end labeling-positive cells. Furthermore, the survival rate of mice was prolonged significantly by the injection of Z-VAD.fmk. These results indicate that apoptosis may play an important role in acute lung injury, and thus that inhibition of caspase activity may constitute a new therapeutic approach for treatment of this disease.


Italian nivolumab Expanded Access Programme in melanoma adjuvant setting: patient outcomes and safety profile.
The CheckMate 238 randomised study demonstrated the relevant benefit in terms of recurrence-free survival (RFS) of nivolumab versus ipilimumab in resected stage IIIB-C or IV melanoma patients with a tolerable safety profile. From November 2018 to June 2019, 611 patients with stage III and IV resected melanoma were enroled to receive nivolumab as part of an Italian Expanded Access Programme (EAP). According to stages, 77% were stage III while 141 (23%) were stage IV with no evidence of disease (NED). Among stage III, 121 patients had IIIA (19.8%). After a median follow-up of 23 months, the RFS in the Intention-to-Treat (ITT) population was 76.6% at 1 year and 59.6% at 2 years; 1- and 2-year distant metastasis-free survival were 83.7% and 71.2%, respectively. The overall survival rate in the ITT population was 93.8% at 1 year and 85.5% at 2 years. No significant differences in RFS were observed according to BRAF status. Treatment-related adverse events of grades 3-4 occurred in 11.5% of patients. This paper reports the results of the Italian Nivolumab EAP in the adjuvant setting of stage III and IV NED melanoma patients. Our results confirm in a real-life setting the clinical activity and safety of nivolumab reported in the CheckMate238 registrative/pivotal. The enroled cohort of 611 patients highlights the relevant clinical need in this setting, also confirmed by the very short accrual time, representing one of the largest series reported as adjuvant EAP with the longest follow-up.


Genome-wide identification of Smad/Foxh1 targets reveals a role for Foxh1 in retinoic acid regulation and forebrain development.
Foxh1, a Smad DNA-binding partner, mediates TGFbeta-dependent gene expression during early development. Few Foxh1 targets are known. Here, we describe a genome-wide approach that we developed that couples systematic mapping of a functional Smad/Foxh1 enhancer (SFE) to Site Search, a program used to search annotated genomes for composite response elements. Ranking of SFEs that are positionally conserved across species yielded a set of genes enriched in Foxh1 targets. Analysis of top candidates, such as Hesx1, Lgr4, Lmo1, Fgf8, and members of the Aldh1a subfamily, revealed that Foxh1 initiates a transcriptional regulatory network within the developing anterior neuroectoderm. The Aldh1a family is required for retinoic acid (RA) synthesis, and, in Foxh1 mutants, expression of Aldh1a1, -2, and -3 and activation of a RA-responsive transgenic reporter is abolished in anterior structures. Integrated mapping of a developmental transcription factor network thus reveals a key role for Foxh1 in patterning and initiating RA signaling in the forebrain.


Impact of Cochlear Implant With Diametric Magnet on Imaging Access, Safety, and Clinical Care.
Review safety and effectiveness of magnetic resonance imaging (MRI) of patients implanted with a cochlear implant (CI) containing a diametric magnet housed within the undersurface of the device. Retrospective chart review with additional review of MRI at a tertiary-care children's hospital. Seven patients with mean age of 8.4 years (range = 1.3-19 years) with a diametric magnet in situ during MRI. The intervention comprised one or more sessions of 1.5 T or 3.0 T MRI without a head wrap. The main outcome measures were the occurrence of magnet-related complications including discomfort and magnet displacement, use of anesthesia or sedation, and clinical usefulness of MRI studies. Seven CI recipients underwent 17 episodes of 1.5 or 3.0 T MRI with an in situ diametric magnet. Thirteen of 17 (76%) MRI sessions were completed in awake patients. No patients had device-related discomfort. No magnet-related complications occurred. Thirteen of 14 (93%) brain studies were clinically useful despite artifacts. The diametric magnet enabled MRI with magnet in situ without the discomfort or magnet displacement associated with removable axial magnets. The reduction in MRI magnet-related complications occurred because torque is not directed perpendicular and outward from the plane of the magnet, and the magnet is securely contained within its housing. The design of this device increased access and reduced the need for sedation or anesthesia. 4 Laryngoscope, 131:E952-E956, 2021.


The influence of the extent of target organs on sensitivities of methods for screening rodent carcinogens.
Two hundred and thirty-three rodent carcinogens from the Carcinogenic Potency Database (CPDB) were analyzed with CASE (Computer Automated Structure Evaluation), and a comparison of the extents of target organs with the sensitivities for long-term carcinogenic bioassays in rats and mice, Salmonella assay (Sty), electrophilic substructure alert analysis (ESAA) and CASE was made. The carcinogenicity of 233 chemicals was evaluated in both rat and mouse bioassays. The present study showed that the sensitivities of the five methods for screening carcinogens were related to the extents of target organs of carcinogens. Among the carcinogens that did not induce tumors (extent = 0) in rats, the sensitivities of Sty and ESAA were 46 and 53, respectively. Among the carcinogens which induced tumors at a single organ (extent = 1) in rats, the sensitivities were 57 and 64 respectively; and 71 and 80 at multiple organs (extent > 1) respectively. The sensitivities of CASE were 76, 82, and 89 respectively at these three different extents. Similar results were obtained with these carcinogens in mice. The results indicate that mutagenic or electrophilic carcinogens are more likely to induce tumors at multiple target organs; in contrast, most carcinogens which induced tumors at only a single target organ in one species are rarely mutagenic or electrophilic. The sensitivities of Sty and ESAA were lower than that of the CASE method in these carcinogens. CASE analyzed chemical structures of many carcinogens and non-carcinogens and then established a database of key fragments, and its parameters are not only based on mutagenicity or electrophilicity of chemicals, and this resulted in a more exact detection of the carcinogenicity of chemicals with the CASE method.


Efficacy of superficial cervical plexus block versus cervical retrolaminar block both combined with auriculotemporal nerve block in parotid surgeries.
Regional techniques in parotid surgeries include superficial cervical plexus block (SCPB) and auriculotemporal nerve (ATN) block, which can be used as an anesthetic technique for awake parotidectomy. This study aimed to evaluate the efficacy of cervical retrolaminar block (RLB) as an alternative to SCPB both, used in combination with auriculotemporal nerve (ATN) block, in parotid surgery. A total of 40 patients undergoing parotid surgery were prospectively randomized into either the SCPB group (n = 20) or the cervical RLB group (n = 20) using 20 ml of 0.25% bupivacaine plus 5 mcg\mL epinephrine. Both were combined with ATN block using 5 ml of 0.25% bupivacaine plus 5 mcg\mL epinephrine. The time to first request for analgesia was longer in the RLB group than the SCPB group. Total intra operative fentanyl consumption and post-operative pethidine consumption in the first 24h were lower in group RLB. All patients (n = 20) in the SCPB group required rescue analgesia using pethidine, while only 40% of patients required pethidine in the RLB group. Visual analog scale was lower in the RLB group from 2 to 24-h post-operatively, but it was associated with hypotension and longer block technique time occurred with RLB than SCPB. There was no significant difference in side effects except for 20% Horner's syndrome in the SCPB group. Cervical RLB is more effective analgesic technique than SCPB, as the cervical RLB showed longer time to first analgesic request, lower intraoperative anesthetic consumption, lower total post-operative pethidine consumption and lower VAS.


Utility of Electrical Stimulation for Correct Placement and Neuromodulation of the Erector Spinae Plane Block for Total Shoulder Arthroplasty: A Case Report.
The role of neuromodulation in fascial plane blocks is unknown. This case report presents a complex patient who underwent shoulder arthroplasty with a high thoracic-erector spinae plane (HT-ESP) catheter that provided electrical and chemical neuromodulation, highlighting the potential of electrical stimulation in the identification of and therapy at the fascial plane level.


Regional expressions of Fos-like immunoreactivity in rat cerebral cortex after stress; restraint and intraperitoneal lipopolysaccharide.
To demonstrate regional activation in the rat cerebral cortex related to stress-evoked neuroendocrine response, Fos expression in both the cerebral cortex and hypothalamic paraventricular nucleus (PVN) was immunohistochemically examined in two experimental groups; a lipopolysaccharide (LPS) intraperitoneally injected group for inflammatory stress and a restraint group for emotional stress. The LPS injection (100 microg/100 g b.w.) and restraint (for 30 min) had similar effect on Fos-like immunoreactivity (Fos-LI) in PVN with regard to the number of immunoreactive nuclei and their distribution pattern, while the times to maximize Fos-LI were different. Numerical analysis of cortical Fos-LI in untreated rats showed a distinct region-specific pattern. Statistical analysis revealed no significant increase in Fos-LI density in any cortical regions in the LPS group, but restraint resulted in a dramatic and region-specific increase. A significant increase was detected in the prefrontal cortex (the cingulate, orbital and agranular insular cortex), the frontal area 2, the agranular retrosplenial cortex, the parietal cortex, and the medial and lateral occipital area 2. These results indicate that cortical activation relevant to specific functions may be involved in stress-specific neural circuitry.


A novel biophysical model on calcium and voltage dual dependent gating of calcium-activated chloride channel.
Ca(2+)-activated Cl(-) channels (CaCCs) are anion-selective channels and involved in physiological processes such as electrolyte/fluid secretion, smooth muscle excitability, and olfactory perception which critically depend on the Ca(2+) and voltage dual-dependent gating of channels. However, how the Ca(2+) and voltage regulate the gating of CaCCs still unclear. In this work, the authors constructed a biophysical model to illustrate the dual-dependent gating of CaCCs. For validation, we applied our model on both native CaCCs and exogenous TMEM16A which is thought to be the molecular basis of CaCCs. Our data show that the native CaCCs may share universal gating mechanism. We confirmed the assumption that by binding with the channel, Ca(2+) decreases the energy-barrier to open the channel, but not changes the voltage-sensitivity. For TMEM16A, our model indicates that the exogenous channels show different Ca(2+) dependent gating mechanism from the native ones. These results advance the understanding of intracellular Ca(2+) and membrane potential regulation in CaCCs, and shed new light on its function in aspect of physiology and pharmacology.


The clinical spectrum associated with ATP1A2 variants in Chinese pediatric patients.
To evaluate the clinical spectrum associated with ATP1A2 variants in Chinese children with hemiplegia, migraines, encephalopathy or seizures. Sixteen children (12 males and 4 females), including ten patients with ATP1A2 variants whose cases had been published previously, were identified using next-generation sequencing. Fifteen patients had FHM2 (familial hemiplegic migraine type 2), including three who had AHC (alternating hemiplegia of childhood) and one who had drug-resistant focal epilepsy. Thirteen patients had DD (developmental delay). The onset of febrile seizures, which occurred between 5 months and 2 years 5 months (median 1 year 3 months) was earlier than the onset of HM (hemiplegic migraine), which occurred between 1 year 5 months and 13 years (median 3 years 11 months). Disturbance of consciousness subsided first, at 40 h to 9 days (median 4.5 days); hemiplegia and aphasia were resolved slowly, taking 30 min to 6 months (median 17.5 days) for the former and 24 h to over 1 year (median 14.5 days) for the latter. Cranial MRI showed edema in the cerebral hemispheres, mainly the left hemisphereacute attacks. All thirteen FHM2 patients recovered to baseline in 30 min to 6 months. Fifteen patients had between 1 and 7 (median 2) total attacks between the baseline and follow-up timepoints. We report twelve missense variants, including a novel variant ATP1A2 variant, p.G855E. The known genotypic and phenotypic spectra of Chinese patients with ATP1A2-related disorders were further expanded. Recurrent febrile seizures and DD combined with paroxysmal hemiplegia and encephalopathy should raise the clinical suspicion of FHM2. The avoidance of triggers and thus the prevention of attacks may be the most effective therapy for FHM2.


Lead Poisoning and the Dangers of Pragmatism.
Drawing from ethnographic research on lead poisoning in Uruguay and secondary literature from lead poisoning cases around the world, the commentary argues that public health policy guided by pragmatism presents multiple dangers to effective health intervention.


Development and preliminary psychometric evaluation of the Self-Perceptions in Rehabilitation Questionnaire (SPIRQ) for brain injury rehabilitation.
The Self-Perceptions in Rehabilitation Questionnaire (SPIRQ) is a brief measure developed to monitor client self-perceptions, motivation, and emotional reactions throughout rehabilitation. We describe the SPIRQ's development and preliminary psychometric evaluation. One hundred five adults with traumatic brain injury attending two brain injury rehabilitation units completed the SPIRQ during occupational therapy sessions. A subset (n = 33) completed the SPIRQ twice over a 5- to 7-day interval to examine test-retest reliability. Exploratory factor analysis yielded three factors: Changes in Self and Life Plans, Self in Rehabilitation, and Emotional Reactions. Their internal consistency was sound (αs = .72-.83). Test-retest reliability was generally acceptable (rs = .67-.81), and scores did not significantly change between testing occasions (p > .05). We found preliminary support for the SPIRQ scales' reliability and construct validity. Future empirical evaluation and potential clinical applications of the SPIRQ in occupational therapy are discussed.


Inhibition of forskolin-stimulated cyclic AMP formation by 1-aminocyclopentane-trans-1,3-dicarboxylate in guinea-pig cerebral cortical slices.
The effects of the selective metabotropic glutamate receptor agonist 1-aminocyclopentane-trans-1,3-dicarboxylate (t-ACPD) on forskolin-stimulated cyclic AMP formation in guinea-pig cerebral cortex slices were determined. t-ACPD inhibited the accumulation of [3H]cyclic AMP by approximately 80%, with an IC50 value of 35 +/- 4 microM. The effect was reversible and stereoselective, with the 1S,3R isomer being approximately 400-fold more potent than the 1R,3S isomer. L-Glutamate (over a restricted concentration range) also partially inhibited the response to forskolin, but quisqualate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and N-methyl-D-aspartate (NMDA) were ineffective. The effect of t-ACPD was not blocked by antagonists of the phospholipase C-linked metabotropic glutamate receptor, the AMPA ionotropic glutamate receptor, or the NMDA receptor. In summary, our results indicate the presence of a glutamate receptor in guinea-pig brain that is activated selectively by t-ACPD and that is negatively linked to adenylyl cyclase.


Aspergillus terreus and its toxic metabolites as a food contaminant in some Egyptian Bakery products and grains.
A. terreus isolates isolated from some bakery products, corn and rice were found to be able to produce territrems. 90% of theA. terreus isolated from bakery products were able to produce territrem A, with a mean of 0.09 ppm, while 80% ofA. terreus isolates produce territrem B with a mean of 0.24 ppm. On the other hand 31.8% of the isolates ofA. terreus from corn were able to produce territrem A with a mean of 0.44 ppm. ConcerningA. terreus isolates from rice, 66.7% were found to produce territrem A, with a mean of 5.28 ppm, and 77.8% of the isolates produced territrem B with a mean of 1.79 ppm.


Predictors of Plasmodium vivax malaria-induced nephropathy in young Korean men.
Plasmodium vivax malaria accounts for more than half of all malaria cases in Asia and Latin America. Despite the high prevalence of disease caused by this parasite, research into its effects (especially its renal effect) has lagged disproportionately. To investigate predictors of vivax malaria-induced nephropathy, we analyzed the cases of vivax malaria-induced nephropathy in young Korean men. This was a retrospective analysis of P. vivax patients with acute nephropathy (all males, n = 75), defined by an absolute increase in serum creatinine of 0.3 mg/dl or more (equal to an estimated glomerular filtration rate (eGFR) <80 ml/min) (group 1, n = 31) or proteinuria (group 2, n = 44), between January 2004 and December 2007. The eGFR was calculated using a simplified Modification of Renal Disease (MDRD) equation. None of the patients had a history of traveling abroad, drug abuse or blood transfusion. The clinical manifestations, laboratory abnormalities and predictors of nephropathy were reviewed. Out of 398 cases of vivax malaria, 75 patients (all males) suffered from to vivax malaria-induced acute nephropathy. The mean age of the patients who were divided into two groups was 22.8 +/- 3.7 and 21.6 +/- 1.8 years, respectively (p = 0.089). In group 1, the total serum bilirubin significantly correlated with serum creatinine and eGFR (p = 0.004 and 0.035, correlation coefficient = 0.508 and -0.387, respectively). In group 2, 24-hour proteinuria significantly correlated with hemoglobin (p = 0.004, correlation coefficient = -0.424). Total serum bilirubin (group 1, an absolute increase in serum creatinine of 0.3 mg/dl or more (equal to an eGFR <80 ml/min)) and hemoglobin (group 2, proteinuria) are useful to predict vivax-induced nephropathy.


RNAi-dependent Polycomb repression controls transposable elements in Tetrahymena.
RNAi and Polycomb repression play evolutionarily conserved and often coordinated roles in transcriptional silencing. Here, we show that, in the protozoan Tetrahymena thermophila, germline-specific internally eliminated sequences (IESs)-many related to transposable elements (TEs)-become transcriptionally activated in mutants deficient in the RNAi-dependent Polycomb repression pathway. Germline TE mobilization also dramatically increases in these mutants. The transition from noncoding RNA (ncRNA) to mRNA production accompanies transcriptional activation of TE-related sequences and vice versa for transcriptional silencing. The balance between ncRNA and mRNA production is potentially affected by cotranscriptional processing as well as RNAi and Polycomb repression. We posit that interplay between RNAi and Polycomb repression is a widely conserved phenomenon, whose ancestral role is epigenetic silencing of TEs.


Familial oculopharyngeal muscular dystrophy with distal spread.
An Italian male aged 50 years with oculopharyngeal muscular dystrophy is reported. Eleven of his relatives, over a period of three generations, had ptosis, dysphagia, nasal voice and difficulty in walking. The distribution of muscle weakness in the propositus and in one of his sisters was proximal in the upper, but distal in the lower limbs, confirming the existence of a relationship between oculopharyngeal dystrophy and distal myopathy. The first muscle biopsy appeared normal except for some round-cell collections, whereas the second one, 5 years later, showed marked dystrophic changes. Some patients with oculopharyngeal dystrophy may apparently pass through a secondary muscular inflammatory stage.


Frequency of occurrence and habitat selection shape the spatial variation in the antibiotic resistome in riverine ecosystems in eastern China.
Riverine ecosystems are one of the most important reservoirs of antibiotic resistance genes (ARGs) in the environment, but the occurrence and controlling factors of ARG distribution in different habitats of riverine ecosystems remain poorly understood. In this study, a metagenomic approach was used to characterize ARG types and their abundance in different habitats (rhizosphere soil, surface bulk soil, bottom bulk soil, and sediment) of riverine ecosystems in eastern China. Sampling sites were located along different rivers of eastern China, which are geographically isolated. Differences in bacterial communities, mobile genetic elements (MGEs), pattern and intensity of human activities, climate, and other environmental factors at the sampling sites and habitats were expected to affect ARG occurrence. ARGs were observed with high variations in diversity (44-206 subtypes) and abundance (6.85-105.68 ×/Gb). There were significant south-north differences in ARG occurrence in the same habitat, except for surface bulk soil. And the significant difference was found in ARGs among four southern habitats. South-north differences in ARGs of the same habitat were mainly attributed to the combination of different occurrence frequencies and habitat selections of ARGs. Differences in ARG profiles among the four habitats in the south and the north were both mainly attributed to the different occurrence frequencies of ARGs. Bacterial communities and MGEs (Mobile genetic elements) could account for the observed variance in the resistome of riverine ecosystems across eastern China. The co-occurrences of specific ARGs with bacterial communities and MGEs were more frequent at the northern sampling sites than in the south, and co-occurrence patterns (i.e. ARGs and bacterial communities or ARGs and MGEs) varied between the habitats. Moreover, building land in all habitats, except bulk soils, showed significant positive correlations with ARG abundance. This study reveals a high variance in the resistome of riverine ecosystems in eastern China and its controlling factors. We appeal to the importance of assessment of ARGs in the riverine ecosystem and the need for future prevention and intervention of ARG spread.


Prevention of venous thromboembolism in patients with cancer: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET)(1).
Prevention of venous thromboembolism (VTE) in cancer patients remains controversial in most clinical settings. The Italian Society for Haemostasis and Thrombosis (SISET) commissioned a project to develop clinical practice guidelines for the prevention of VTE in patients with malignancy. Key questions concerning the prevention of VTE in patients with malignancy were formulated by a multidisciplinary working group consisting of experts in clinical medicine and research. After a systematic review and discussion of the literature, recommendations were formulated and graded according to the supporting evidence. For those questions for which the literature search did not find any definitive answers (due to absence of evidence, low quality evidence and/or contradictory evidence), a formal consensus method was used instead to issue clinical recommendations. The search for "VTE prevention" resulted in 1021 citations; 69 articles were selected and 24 were used for drafting clinical recommendations. Four areas were graded A to C: 1) Need of prevention (pharmacological and/or mechanical) in cancer patients undergoing major abdominal or pelvic surgery and in 2) those with an acute medical disease requiring hospitalization and who are bedridden. Avoid prevention in 3) cancer patients with a central venous catheter and 4) those on chemotherapy, radiotherapy or hormonal therapy, except patients with multiple myeloma treated with thalidomide/lenalidomide plus high-dose dexamethasone, and those with gastrointestinal or lung cancer. Six areas were considered to be clinically important, but lacked evidence from the literature and thus required a formal consensus (grade D): 1) need of prevention during chemo- radiotherapy or hormonal therapy in patients with previous VTE; 2) optimal duration of pharmacological prevention in patients who are hospitalized/bedridden for acute medical illness; 3) optimal duration of pharmacological prevention in patients undergoing major surgery other than abdominal and pelvic; 4) optimal duration of pharmacological prevention in myeloma patients receiving thalidomide plus dexamethasone; 5) presence of cerebral metastasis as a contraindication to pharmacological prevention; 6) prevention in cancer patients undergoing surgery by laparoscopic procedures lasting>30min. Results of the systematic literature review and an explicit approach to consensus techniques have led to recommendations for the most clinically important issues in the prevention of VTE in cancer patients.


Extracellular-matrix mechanics regulate cellular metabolism: A ninja warrior behind mechano-chemo signaling crosstalk.
Mechanical forces are the indispensable constituent of environmental cues, such as gravity, barometric pressure, vibration, and contact with bodies, which are involved in pattern and organogenesis, providing mechanical input to tissues and determining the ultimate fate of cells. Extracellular matrix (ECM) stiffness, the slow elastic force, carries the external physical force load onto the cell or outputs the internal force exerted by the cell and its neighbors into the environment. Accumulating evidence illustrates the pivotal role of ECM stiffness in the regulation of organogenesis, maintenance of tissue homeostasis, and the development of multiple diseases, which is largely fulfilled through its systematical impact on cellular metabolism. This review summarizes the establishment and regulation of ECM stiffness, the mechanisms underlying how ECM stiffness is sensed by cells and signals to modulate diverse cell metabolic pathways, and the physiological and pathological significance of the ECM stiffness-cell metabolism axis.


Low-Intensity Pulsed Ultrasound Treatment Accelerates Angiogenesis by Activating YAP/TAZ in Human Umbilical Vein Endothelial Cells.
As a non-invasive method, low-intensity pulsed ultrasound (LIPUS) can accelerate fracture healing. The mechanisms responsible for the enhanced fracture healing need to be studied further. Activation of YAP/TAZ, key mediators of the Hippo signaling pathway, could promote angiogenesis and vascular remodeling. The purpose of this study was to determine whether LIPUS treatment can activate YAP/TAZ. Human umbilical vein endothelial cells (HUVEC) were used. After LIPUS treatment, Western blot and immunofluorescence staining were used for YAP/TAZ activation. Small interfering RNA (siRNA) of YAP and short hairpin LATS1/2 (shLATS1/2) were used to check whether there is cross-talk with the Hippo pathway. The phosphorylated YAP (p-127 and p-397) protein increased more than 3-fold 0.5 h after LIPUS treatment (p < 0.05). TAZ protein increased 3.0-, 2.0- and 1.5-fold 0.5, 6 and 12 h after LIPUS treatment. We found that LIPUS treatment activates YAP/TAZ, which is translocated into the cell nucleus to activate target genes. This process can be inactivated by siYAP and activated by shLATS1/2. The cross-talk with the Hippo pathway can initiate angiogenesis so as to accelerate fracture healing by LIPUS.


Resource allocation in ICU: ethical considerations.
Increasing scarcity of resources on the background of ever improving medical care and prolonged life expectancy has placed a burden on all aspects of health care. In this article we examine the current problems with resource allocation in intensive care and question whether we can find guidance on appropriate resource allocation through ethical models. The problem of fair and ethical resource allocation has perpetually plagued health care. Recent work has looked at value for money, benefits of therapies and how we define futility, but these still fall victim to the same problems that classical schools of ethical thought have tried to tackle. Many ethical principles provide a framework on which to allocate resources to certain cohorts of patients, however, most appear too rigid to be fully and primarily utilized for intensive care admission. We suggest a collaboration of principles be applied to achieve a moral, ethical and common sense approach to this issue. Over resourcing and under resourcing is also suggested to be problematic for patients and healthcare workers alike.


Exclusion of emphysematous lung from dose-volume estimates of risk improves prediction of radiation pneumonitis.
The risk factors for radiation pneumonitis (RP) in patients with chronic obstructive pulmonary disease (COPD) are unclear. Mean lung dose (MLD) and percentage of irradiated lung volume are common predictors of RP, but the most accurate dosimetric parameter has not been established. We hypothesized that the total lung volume irradiated without emphysema would influence the onset of RP. We retrospectively evaluated 100 patients who received radiotherapy for lung cancer. RP was graded according to the Common Terminology Criteria for Adverse Events (version 4.03). We quantified low attenuation volume (LAV) using quantitative computed tomography analysis. The association between RP and traditional dosimetric parameters including MLD, volume of the lung receiving a dose of ≥2 Gy, ≥ 5 Gy, ≥ 10 Gy, ≥ 20 Gy, and ≥30 Gy, and counterpart measurements of the lung without LAV, were analyzed by logistic regression. We compared each dosimetric parameter for RP using multiple predictive performance measures including area under the receiver operating characteristic curve (AUC) and integrated discrimination improvement (IDI). Of 100 patients, RP of Grades 1, 2, 3, 4, and 5 was diagnosed in 24, 12, 13, 1, and 1 patients, respectively. Compared with traditional dosimetric parameters, counterpart measurements without LAV improved risk prediction of symptomatic RP. The ratio of the lung without LAV receiving ≥30 Gy to the total lung volume without LAV most accurately predicted symptomatic RP (AUC, 0.894; IDI, 0.064). Irradiated lung volume without LAV predicted RP more accurately than traditional dosimetric parameters.


Evaluation of midwifery pelvic floor education and Training across the UK and Spain.
The aim of this study was to evaluate current education and training of student and registered midwives across the UK and Spain; analysing both pelvic floor teaching and practical experience. A cross-sectional survey was carried out by 711 student and 384 registered midwives across different universities and regions in the UK and Spain. The vast majority (91.5 % n = 382) of UK students complete training without ever cutting or repairing an episiotomy. This compares to 39.4 % (n = 85) of registered midwives who did not cut an episiotomy during training. Only 20 % (n = 9) of Spanish and 10 % (n = 45) of UK registered midwives felt confident undertaking these techniques. In Spain just 15 % (n = 6) of students, compared to 54.8 % (n = 80) of registered midwives had received teaching on longer-term pelvic floor complications. There is a considerable deficit in the current training practices for midwives regarding episiotomies. This lack of practice and confidence may be impacting on the increased rates of perineal tears and pelvic dysfunction in post-partum women. Across registered midwives there are gaps in education regarding longer-term pelvic floor complications. Our study was limited by a smaller sample size from Spain compared to the UK. Our results show practical assessment of skills during training is desirable and could improve both the confidence and competence of midwives upon registration.


A cyclic AMP binding protein pattern useful as a biochemical differentiation marker of erythroleukemic cell lines and normal cloned erythroblasts.
Previous study of a variety of a human hemopoietic cell lines and normal samples with 8-N3-[32P]-cAMP photoaffinity labelling, SDS-polyacrylamide gel electrophoresis and autoradiography revealed five distinct cAMP binding protein patterns, each of which were restricted to cells of particular lineages. One pattern unique to K562 cells was characterized by the presence of three bands designated a, b and d. In order to ascertain the significance of this finding, we studied by the same methods normal human erythroblasts harvested from methylcellulose cultures of fetal liver and adult blood, and murine and human erythroleukemic cells (MEL and HEL) as well as K562, cultured with and without chemical inducers of erythrodifferentiation. Three band patterns recognizable as similar to that of K562, but distinctive from those of myeloid and lymphoid cells, were noted of cells of erythroblastic origin. Both HEL and MEL, as well as the normal erythroblasts, exhibited heaviest labeling of band a in contrast to K562, which exhibited heaviest labelling of band d. Relative labelling of band b and d of HEL and MEL increased following treatment with 50 mu hemin or 4 mM hexamethylenebisacetamide (HMBA), respectively. Treatment of K562 with hemin, however, resulted in increased band a. Thus, among hemopoietic cells, an isozymic cAMP binding protein pattern has been identified which is characteristic of the erythroid lineage. The relative abundances of the three components (a, b and d) have been furthermore noted to undergo a series of shifts during induced differentiation. Cyclic AMP binding proteins may thus prove useful as a biochemical marker system in the recognition and analysis of erythroid differentiation.


Analytical methodologies for the quantitation of platinum anti-cancer drugs and related compounds in biological media.
The methods for analysis of platinum-based anti-cancer drugs in biological media are reviewed in this paper. Although emphasis is placed on cisplatin, attention is also given to several of its analogues (carboplatin, iproplatin) and their degradation and biotransformation products. In an introductory section a short description is given of the historical background and the clinical applications of cisplatin. Reactions occurring in the body and in aqueous solutions are discussed because of their implications for the design of analytical procedures. After a detailed description of sample preparation and storage, attention is focussed on the analytical techniques used for the determination of either total platinum levels or individual platinum-containing compounds. The techniques discussed include atomic absorption and emission spectrometry, derivatization reactions and several chromatographic techniques with different detection methods. The specific advantages and disadvantages of these techniques are discussed.


International variations in AAA screening.
Abdominal aortic aneurysm (AAA) screening programmes reduce AAA-related mortality and are cost-effective. This study aims to assess the state and variability of AAA screening programmes worldwide. Data were obtained from an international expert group convened at the 34th Charing Cross Symposium as well as government websites and published reports on screening programmes. Six countries are in the process of implementing national AAA screening programmes, with Italy still performing screening trials. There is wide variability in inclusion criteria between countries with the majority screening only men in their 65th year, however 3 programmes include women, 2 programmes only include patients with high cardiovascular risk, and 2 trials are also screening for hypertension and lower limb atherosclerosis. Surveillance intervals vary between screening programmes, with the most common regimen being to vary the surveillance interval depending upon aneurysm size, however the optimum surveillance interval in terms of decreasing mortality and cost effectiveness remains uncertain. International dissemination of current AAA screening programme outcomes is required to inform developing programmes about optimum screening intervals, benefits of surveillance of the subaneurysmal aorta, and screening for other cardiovascular disease.


Assessment of skin dose and its relation to cosmesis in the conservative treatment of early breast cancer.
A conservation technique has been developed for the treatment of early breast cancer which involved removal of the tumor, axillary clearance, tumor site implantation with Iridium-192 wires for a boost dose and subsequent treatment of the breast with radical megavoltage external beam therapy. Although the cosmetic results were satisfactory in the majority of the patients, for some it was rated as fair or poor. One variable factor which could have carried some morbidity was the dose of radiation received by the skin. In 51 patients, doses were measured at several points over the treated breast using Thermoluminescent Dosimetry (TLD) at the time of the iridium implant and during the subsequent external beam therapy. Development of skin pigmentation, oedema, and fibrosis were unrelated to the dose received by the skin but the findings suggested that doses greater than 50 Gy to the skin increased the possibility of late (greater than 24 months) telangiectasia over the boosted area. Treatment of tumors in the lower half of the breast, or in large breasts, was associated with a higher incidence of poor cosmesis. This may have been the result of varying posture on the interstitial dose distribution from the Iridium-192 wires and comparison of dose distribution in both supine and erect positions was carried out.


Predicting success in psychiatric training for foreign medical graduates: II. Patterns in course.
Faculty ratings of 22 foreign medical graduates ('FMGs'), all of whom entered psychiatric residency training at the University of Missouri-Columbia from 1966 through 1973, were compared with those of a similar group of North American medical graduates ('AMGs'). An on-going evaluation programme provided data for a variety of parameters ranging from 'theoretical knowledge' to 'clinical skills'. Results indicated that in most of performance the median FMG started at a level substantially lower than that of the median AMG and very slowly caught up. When achievement criteria were utilized it became apparent that, at least by the third year of training, 'superior' FMGs could equal or surpass the median performance of 'superior' AMGs, whereas 'marginal' residents, whether foreign or native-born, seldom attained even competence in most major spheres of functioning. Implications of these findings and those in related studies are discussed.


Prevalence and genotype distribution of cytomegalovirus UL55 sequence in renal transplant recipients in north west of Iran.
Cytomegalovirus (CMV) is one of the most important infections in renal transplant recipients. Kidney transplant is the last hope for the patients with end stage renal diseases. Cytomegalovirus infection can threaten patients and graft survival after transplantation. Four hundred and thirty-four renal transplant recipients contributed to this study. PCR and RFLP analyses were performed in order to determine CMV viremia and its genotypes. CMV viremia was detected in 68 (15.9%) recipients. The mean post-transplantation time in our recipients was 50 months, ranging from 1 to 354 months. Viremia was detected in 31.2%, 30.7%, 17.5%, 10.2%, and 6.4% of the recipients in 0-3, 4-6, 7-12, 13-24, and more than 24 months post-transplantation, respectively. The distribution of gB1, gB2, gB3, and gB4 genotypes was detected as 26.5%, 20.5%, 17.6%, and 5.9%, respectively. Mixed genotype infection was observed in 29.4% of the recipients. Incidence of viremia was higher in the first 6 months after the transplantation compared with the later stages. Moreover, CMV gB1 and mixed genotype infection were more common in our recipients. J. Med. Virol. 88:1622-1627, 2016. © 2016 Wiley Periodicals, Inc.


Refundoplication for recurrent gastroesophageal reflux.
Reoperation after a failed antireflux procedure is a surgical challenge. Many operative techniques have been proposed, but reports on systematic follow-up with endoscopy and esophageal function tests are few. The purpose of the present study was to evaluate the results of repeated fundoplication in cases of recurrent reflux, including assessment of esophageal function. Of the 18 cases of repeat fundoplication performed for recurrent reflux during 1970-1991 at Tampere University Hospital, 15 were evaluated a median of 18 (range 5-152) months after reoperation. Follow-up studies included endoscopy in all and esophageal function tests (esophageal 24-hour pH recording, manometry, and radionuclide transit) in 14 cases. All the patients had defective fundic wrap before reoperation, whereas at follow-up 12 of the 15 wraps were intact. Reflux symptoms were diminished in all 15. Six patients (40%), however, had objective recurrence of reflux (esophagitis or pathologic pH recording). Three of the recurrences were due to slipped fundic wrap, but the others were probably caused by impaired esophageal function. By repeat fundoplication the wrap could be repaired as reliably as in primary operation. Symptomatic outcome and objective results were reasonable. The results were, however, not as good as after primary operation, which was due to more impaired esophageal motility caused by prolonged reflux or repeated surgery (or both).


Stroke and COVID19: Not only a large-vessel disease.
Recent evidence has underlined the association between large-vessel stroke and COVID-19, probably due to a proinflammatory and prothrombotic microenvironment induced by SARS-CoV-2. Here, we report the case of a young fit woman affected by COVID-19 without any flu-like symptom, who suffered from speech disorder and left hemiparesis. Brain magnetic resonance evidenced two small acute brain infarctions in right perirolandic cortex without signs of previous ischemic lesions and hemorrhagic infarction. Diagnostic workup excluded cardiac embolic sources, acquired and inherited thrombophilia or autoimmune diseases. Two positive nasopharyngeal swab tests and high titers of serum specific IgA/IgM confirmed COVID-19 diagnosis. In our case stroke seems to be the only manifestation of SARS-COV-2 infection. Therefore the hypothesis of an underlying viral infection, as COVID-19, should be investigated in all the cases of small vessel cryptogenic stroke.


Effect of gastric bubble as a weight reduction device: a controlled, crossover study.
In spite of the widespread use of the Garren-Edwards gastric bubble as an adjuvant device in weight reduction, its efficacy has not been established. Therefore, our purpose was to conduct a randomized, double-blind, crossover study of this device in the management of exogenous obesity. The study group consisted of 23 patients, 21 women and 2 men, ranging in age from 21 to 53 yr. Patients were 25%-111% above their ideal body weight. They were studied for 24 wk, consisting of two separate 12-wk evaluation periods. Patients were randomly assigned either to receive the gastric bubble or to have a sham procedure. After the first 12-wk evaluation period, the gastric bubble and sham were administered in crossover fashion, so that those who had received the gastric bubble initially received the sham later and vice versa. The study coordinator remained blind to the kind of treatment, weighed each patient biweekly, enforced dietary counseling, and provided behavior modification. Those who had passed or were found to have a deflated bubble at the end of the treatment period were excluded from the study. Mean weight reduction in the two evaluation periods did not differ significantly. Patients lost 5.4 +/- 1.7 kg (mean +/- SE) during the gastric bubble period and 5.20 +/- 0.8 kg during the sham period. The order of administration of the gastric bubble and sham did not significantly affect the result. The time-course of mean biweekly values, however, revealed that with the gastric bubble, weight loss was significantly greater only during first (p less than 0.005) and second (p less than 0.025) 2-wk evaluation periods. This difference, however, disappeared after the initial 4 wk of treatment. These observations suggest that although gastric bubble implantation reduced weight significantly more than the sham procedure initially, the mean weight loss during 12 wk of evaluation was not different between the two periods. In our opinion, the gastric bubble is of no value as an adjuvant device in weight reduction.


Enhancement of fluoride release in glass ionomer cements modified with titanium dioxide nanoparticles.
Several efforts have been made to improve the glass ionomer cements (GICs) properties with nanotechnology. Fluoride release in once of most beneficial properties of GICs. The purpose of this study was to evaluate the fluoride release, recharge, and cytotoxicity in GICs reinforced with titanium dioxide nanoparticles (TiO2N). Evaluate the fluoride release, recharge, and cytotoxicity in GICs reinforced with TiO2N. Four GICs, FUJI IX EXTRA (G1c), KETAC MOLAR (G2c), IONOFILL MOLAR (G3c), and FUJI IX (G4c) were combined with TiO2N (G1e, G2e, G3e, and G4e) and divided into blocks of 5-mm width and 1-mm thickness 10 each. A total of 80 samples were arranged as follows: GICs alone as negative control (n = 40) and GICs + TiO2N as experimental groups (n = 40). The fluoride release was determined for periods of 1, 2, 6, 10, 31, 90, 180, 240, and 300 days. On days 30 and 179, samples were recharged by submerging in 1 mL of 20,000 ppm sodium fluoride gel. Cytotoxic activity was carried out with gingival fibroblasts, using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide cell viability assay. The experimental groups obtained the highest and more constant fluoride released when compared to control groups. After the first recharge, experimental groups (G1e, G3e, and G4e) showed statistically significant results (P = .001, 0.010, and 0.001 respectively) enhancing their recharge ability regarding control groups. The second recharge showed better results in G1e concerning the rest of the groups. No cytotoxic activity was observed in all experimental groups, although significant differences were observed in G3e and G4e regarding control group. The incorporation of TiO2N enhance the fluoride release in glass ionomers with a noncytotoxic effect on human gingival fibroblasts.


Considerable deficits in the detection performance of the cat after lesion of the suprasylvian visual cortex.
The ability of two cats to discriminate between two geometrical outline patterns in the presence of superimposed structured background was tested before and after bilateral removal of the lateral suprasylvian visual areas (PMLS, PLLS, AMLS, ALLS, part of area 7). There were mild deficits when patterns and background were kept stationary; these deficits may be due to a partial undercutting of areas 17, 18 and 19. However, there was a severe impairment in performance when the patterns were moving on a stationary background which may be due to loss of the suprasylvian visual areas. Movement of the background relative to the figure resulted in an intermediate detection deficit.


Three-dimensional convolutional neural network model to identify clinically significant prostate cancer in transrectal ultrasound videos: a prospective, multi-institutional, diagnostic study.
Identifying patients with clinically significant prostate cancer (csPCa) before biopsy helps reduce unnecessary biopsies and improve patient prognosis. The diagnostic performance of traditional transrectal ultrasound (TRUS) for csPCa is relatively limited. This study was aimed to develop a high-performance convolutional neural network (CNN) model (P-Net) based on a TRUS video of the entire prostate and investigate its efficacy in identifying csPCa. Between January 2021 and December 2022, this study prospectively evaluated 832 patients from four centres who underwent prostate biopsy and/or radical prostatectomy. All patients had a standardised TRUS video of the whole prostate. A two-dimensional CNN (2D P-Net) and three-dimensional CNN (3D P-Net) were constructed using the training cohort (559 patients) and tested on the internal validation cohort (140 patients) as well as on the external validation cohort (133 patients). The performance of 2D P-Net and 3D P-Net in predicting csPCa was assessed in terms of the area under the receiver operating characteristic curve (AUC), biopsy rate, and unnecessary biopsy rate, and compared with the TRUS 5-point Likert score system as well as multiparametric magnetic resonance imaging (mp-MRI) prostate imaging reporting and data system (PI-RADS) v2.1. Decision curve analyses (DCAs) were used to determine the net benefits associated with their use. The study is registered at https://www.chictr.org.cn with the unique identifier ChiCTR2200064545. The diagnostic performance of 3D P-Net (AUC: 0.85-0.89) was superior to TRUS 5-point Likert score system (AUC: 0.71-0.78, P = 0.003-0.040), and similar to mp-MRI PI-RADS v2.1 score system interpreted by experienced radiologists (AUC: 0.83-0.86, P = 0.460-0.732) and 2D P-Net (AUC: 0.79-0.86, P = 0.066-0.678) in the internal and external validation cohorts. The biopsy rate decreased from 40.3% (TRUS 5-point Likert score system) and 47.6% (mp-MRI PI-RADS v2.1 score system) to 35.5% (2D P-Net) and 34.0% (3D P-Net). The unnecessary biopsy rate decreased from 38.1% (TRUS 5-point Likert score system) and 35.2% (mp-MRI PI-RADS v2.1 score system) to 32.0% (2D P-Net) and 25.8% (3D P-Net). 3D P-Net yielded the highest net benefit according to the DCAs. 3D P-Net based on a prostate grayscale TRUS video achieved satisfactory performance in identifying csPCa and potentially reducing unnecessary biopsies. More studies to determine how AI models better integrate into routine practice and randomized controlled trials to show the values of these models in real clinical applications are warranted. The National Natural Science Foundation of China (Grants 82202174 and 82202153), the Science and Technology Commission of Shanghai Municipality (Grants 18441905500 and 19DZ2251100), Shanghai Municipal Health Commission (Grants 2019LJ21 and SHSLCZDZK03502), Shanghai Science and Technology Innovation Action Plan (21Y11911200), and Fundamental Research Funds for the Central Universities (ZD-11-202151), Scientific Research and Development Fund of Zhongshan Hospital of Fudan University (Grant 2022ZSQD07).


Three-Dimensional Imaging of Fibrinogen and Neurovascular Alterations in Alzheimer's Disease.
Cerebrovascular dysfunction is a hallmark of Alzheimer's disease (AD) that is linked to cognitive decline. However, blood-brain barrier (BBB) disruption in AD is focal and requires sensitive methods to detect extravasated blood proteins and vasculature in large brain volumes. Fibrinogen, a blood coagulation factor, is deposited in AD brains at sites of BBB disruption and cerebrovascular damage. This chapter presents the methodology of fibrinogen immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs (iDISCO) which, when combined with immunolabeling of amyloid β (Aβ) and vasculature, enables sensitive detection of focal BBB vascular abnormalities, and reveals the spatial distribution of Aβ plaques and fibrin deposits, in large tissue volumes from cleared human brains. Overall, fibrinogen iDISCO enables the investigation of neurovascular and neuroimmune mechanisms driving neurodegeneration in disease.


An international comparability study on quantification of total methyl cytosine content.
Various methods have been developed for quantitative analysis of DNA methylation. However, there is currently no reference analysis system regarding DNA methylation with which other analytical approaches can be compared and evaluated. A standard measurement system that includes reference methods and reference materials may improve comparability and credibility of data obtained from different analytical environments. In an effort to establish a standard system for measurement of DNA methylation, the Korea Research Institute of Standards and Science (KRISS) coordinated an international comparison study among different national metrology institutes. An initial stage of the study involved an intercomparison regarding quantitative measurement of total methyl cytosine contents in artificially constructed DNA samples. The measurement principle involved measurement of dNMP contents following enzymatic hydrolysis of DNA samples. Results of the study showed good comparability among four of five participants and close agreement with reference values assigned by the coordinating laboratory. Conflicting data from one participant may have resulted from incomplete hydrolysis of samples due to use of insufficient amounts of enzymes. These results indicate that comparable and accurate results can be obtained from different measurement environments if digestion conditions are controlled appropriately and valid calibration systems are employed.


Missing value imputation in a data matrix using the regularised singular value decomposition.
Some statistical analysis techniques may require complete data matrices, but a frequent problem in the construction of databases is the incomplete collection of information for different reasons. One option to tackle the problem is to estimate and impute the missing data. This paper describes a form of imputation that mixes regression with lower rank approximations. To improve the quality of the imputations, a generalisation is proposed that replaces the singular value decomposition (SVD) of the matrix with a regularised SVD in which the regularisation parameter is estimated by cross-validation. To evaluate the performance of the proposal, ten sets of real data from multienvironment trials were used. Missing values were created in each set at four percentages of missing not at random, and three criteria were then considered to investigate the effectiveness of the proposal. The results show that the regularised method proves very competitive when compared to the original method, beating it in several of the considered scenarios. As it is a very general system, its application can be extended to all multivariate data matrices. •The imputation method is modified through the inclusion of a stable and efficient computational algorithm that replaces the classical SVD least squares criterion by a penalised criterion. This penalty produces smoothed eigenvectors and eigenvalues that avoid overfitting problems, improving the performance of the method when the penalty is necessary. The size of the penalty can be determined by minimising one of the following criteria: the prediction errors, the Procrustes similarity statistic or the critical angles between subspaces of principal components.


Influences of Obesity on Job Demands and Worker Capacity.
Evidence suggests that the growing prevalence of obesity in the workforce has resulted in an increase in the incidence and cost of musculoskeletal injuries. Obesity can modify job demands and affect worker capacity in terms of anthropometry and occupational biomechanics, which may place workers at greater risk of injury. This paper presents a review of studies quantifying the work-relevant impacts of obesity, specifically related to work task demands, capacities, and their potential imbalance. The increased body fat that accompanies obesity leads to larger anthropometric dimensions and inertial parameters, particularly in the trunk and thigh areas. Consequently, individuals who are obese adjust their work postures and motions as an accommodation. These changes may affect the biomechanical demands on the joints and increase the burden on the musculoskeletal system. Independent of job demands, obesity-related differences also occur with respect to strength, fatigue, and task performance. Directions for future research are provided, focusing on the need for workplace redesign to account for changing workforce demographics.


Adenomatoid tumor of the uterus.
A case of adenomatoid tumor of the uterus of a 49-year-old woman is described. The tumor was unusually large and atypically located in the fundus of the uterus. Adenomatoid tumors in genitals are benign but may macroscopically resemble a malignant tumor. As recurrence does not occur simple excision is sufficient.


Neutrophil dysfunction in steroid-overdosed patients with ulcerative colitis: potential relevance of macrophage migration inhibitory factor to increased postoperative morbidity.
We studied macrophage migration inhibitory factor (MIF)-related neutrophil dysfunction in patients with ulcerative colitis (UC), under conditions of surgical stress, focusing in particular on total preoperative steroid dosages. Neutrophils were isolated from peripheral blood samples obtained from 21 UC patients soon after radical surgery for UC. The patients were divided into two subgroups according to their total preoperative prednisolone dosages. The neutrophil phagocytosis, viable cell, and cell necrosis rates after exposure to Escherichia coli were evaluated by flow cytometry. The supernatant concentrations of mediators after exposure to E. coli were evaluated by enzyme-linked immunosorbent assay. There was a significant positive correlation between the levels of MIF and the total preoperative dosage of prednisolone. More viable neutrophils from the high-dosage steroid group patients than from the low-dosage steroid group patients tended to undergo necrosis, followed by the release of neutrophil elastase after exposure to E. coli. The levels of anti-inflammatory cytokines were not enhanced after E. coli stimulation, but the levels of proinflammatory cytokines in the supernatants of neutrophils from the high-dosage steroid group patients were increased significantly. Steroid-overdosed UC patients with MIF-related neutrophil dysfunction may be at increased risk of destructive local inflammation following surgery.


Development of an assay to screen for inhibitors of tau phosphorylation by cdk5.
A high-throughput assay for tau phosphorylation by cdk5/p25 is described. Full-length recombinant tau was used as a substrate in the presence of saturating adenosine triphosphate (ATP). Using PHF-1, an antibody directed specifically against 2 tau phosphorylation epitopes (serine 396 and serine 404), an enzyme-linked immunosorbent assay (ELISA)-based colorimetric assay was formatted in 384-well plates. The assay was validated by measuring kinetic parameters for cdk5/p25 catalysis and known inhibitors. Rate constants for the site-specific phosphorylations at the PHF-1 epitopes were determined and suggested preferential phosphorylation at these sites. The performance of this assay in a high-throughput format was demonstrated and used to identify inhibitors of tau phosphorylation at specific epitopes phosphorylated by cdk5/p25.


The mitochondrial carnitine/acylcarnitine carrier is regulated by hydrogen sulfide via interaction with C136 and C155.
The carnitine/acylcarnitine carrier (CAC or CACT) mediates transport of acylcarnitines into mitochondria for the β-oxidation. CAC possesses Cys residues which respond to redox changes undergoing to SH/disulfide interconversion. The effect of H2S has been investigated on the [(3)H]carnitine/carnitine antiport catalyzed by recombinant or native CAC reconstituted in proteoliposomes. Site-directed mutagenesis was employed for identifying Cys reacting with H2S. H2S led to transport inhibition, which was dependent on concentration, pH and time of incubation. Best inhibition with IC50 of 0.70 μM was observed at physiological pH after 30-60 min incubation. At longer times of incubation, inhibition was reversed. After oxidation of the carrier by O2, transport activity was rescued by H2S indicating that the inhibition/activation depends on the initial redox state of the protein. The observed effects were more efficient on the native rat liver transporter than on the recombinant protein. Only the protein containing both C136 and C155 responded to the reagent as the WT. While reduced responses were observed in the mutants containing C136 or C155. Multi-alignment of known mitochondrial carriers, highlighted that only the CAC possesses both Cys residues. This correlates well with the absence of effects of H2S on carriers which does not contain the Cys couple. Altogether, these data demonstrate that H2S regulates the CAC by inhibiting or activating transport on the basis of the redox state of the protein. CAC represents a specific target of H2S among mitochondrial carriers in agreement with the presence of a reactive Cys couple.


SERCA2a gene therapy restores microRNA-1 expression in heart failure via an Akt/FoxO3A-dependent pathway.
Impaired myocardial sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) activity is a hallmark of failing hearts, and SERCA2a gene therapy improves cardiac function in animals and patients with heart failure (HF). Deregulation of microRNAs has been demonstrated in HF pathophysiology. We studied the effects of therapeutic AAV9.SERCA2a gene therapy on cardiac miRNome expression and focused on regulation, expression, and function of miR-1 in reverse remodelled failing hearts. We studied a chronic post-myocardial infarction HF model treated with AAV9.SERCA2a gene therapy. Heart failure resulted in a strong deregulation of the cardiac miRNome. miR-1 expression was decreased in failing hearts, but normalized in reverse remodelled hearts after AAV9.SERCA2a gene delivery. Increased Akt activation in cultured cardiomyocytes led to phosphorylation of FoxO3A and subsequent exclusion from the nucleus, resulting in miR-1 gene silencing. In vitro SERCA2a expression also rescued miR-1 in failing cardiomyocytes, whereas SERCA2a inhibition reduced miR-1 levels. In vivo, Akt and FoxO3A were highly phosphorylated in failing hearts, but reversed to normal by AAV9.SERCA2a, leading to cardiac miR-1 restoration. Likewise, enhanced sodium-calcium exchanger 1 (NCX1) expression during HF was normalized by SERCA2a gene therapy. Validation experiments identified NCX1 as a novel functional miR-1 target. SERCA2a gene therapy of failing hearts restores miR-1 expression by an Akt/FoxO3A-dependent pathway, which is associated with normalized NCX1 expression and improved cardiac function.


Hypoglycaemia incidence with a simple, low-dose insulin protocol for adult diabetic ketoacidosis.
The objective of this study is to validate the glycaemic safety of a simple insulin protocol using weight-based insulin rates adapted from American guidance for the management of adult diabetic ketoacidosis. Measures of hypoglycaemia were retrospectively assessed in a single cohort of inpatient adults. The primary outcome was incidence of hypoglycaemia during insulin infusion. Hypoglycaemia during infusion occurred in 6/81 patients (7% [95% CI 3-16%]). Five of these occurrences were associated with protocol nonadherence. The glycaemic safety of a novel, variable-rate insulin protocol directly incorporating weight-based infusion rates is supported by this single-centre study.


Boosting native promoter activities with non-adjacent response-element multimers.
Effective gene therapy requires regulated gene expression and vector safety. We developed a strategy to exponentially increase native promoter activity while retaining inherent regulation by inserting multi-copy response elements (REs) into non-adjacent locations. For the hepatocyte nuclear factor (HNF) 4α-dependent Hnf1a (MODY3) gene, HNF4α stimulation increased from 5- to 90-fold by inserting 3 additional HNF4α REs (H4REs). Constructing a promoter with two 4xH4REs 0.25kb apart by duplicating the 4xH4RE fragment increased stimulation to >1000-fold. HNF4α-induced protein expression by the duplicate 4xH4RE Hnf1a promoter was comparable to a viral promoter. Converting the two Apolipoprotein C3 (ApoC3) H4REs spaced 0.61kb apart to 4xH4REs achieved a similar result. Increasing spacing to 2.1kb with non-promoter DNA abolished the augmentation. Finally, converting the HNF1α RE of the HNF4A (MODY1) P2 promoter to 4xH1RE and adding a second 4xH1RE 0.84kb upstream increased HNF1α stimulation from 26- to >200-fold. Deleting intervening DNA to produce 0.23-kb spacing increased stimulation to >500-fold. Spaced multi-copy RE motifs is a novel strategy for engineering promoters that boosts activity far beyond other techniques. Augmentation of three promoters suggests that this approach is potentially applicable to other promoters for gene therapy and might obviate the need for viral promoters.


Prevalence of cerebral palsy in The Netherlands (1977-1988).
Children with cerebral palsy (CP) and their families often make strong demands on diagnostic, therapeutic, technical and social facilities. Prevalence estimates are needed to improve treatment and services. As recent Dutch data are not available, the present study aimed to assess the population prevalence of CP in the Netherlands. A representative Dutch area with 1.2 million inhabitants of which 172,000 were born between 1977 and 1988 was studied. To ascertain the children with CP from these birth years, medical practices (such as rehabilitation centres, paediatric and child neurological departments) were consecutively asked to contact their (supposed) CP cases. Next, a parents' organisation and finally regional news media assisted in the ascertainment. In total, 170 'supposed' CP cases underwent an expert examination. Of these 170, 127 children proved to be definite CP-cases, yielding a 'crude' average prevalence of 0.74 per 1,000 inhabitants (95% CI: 0.61-0.87). Under-ascertainment was recognised and quantified. Accordingly, the population prevalence of CP over the birth year period 1977-1988 was calculated as 1.51 per 1,000 inhabitants (average over the 12 birth years). The calculated CP prevalence rose significantly over time: from 0.77 (1977-1979) to 2.44 (1986-1988). This trend is in accordance with other studies.


Medial Septal NMDA Glutamate Receptors are Involved in Modulation of Blood Natural Killer Cell Activity in Rats.
The purpose of the present study was to determine the specific role of the medial septal (MS) NMDA glutamate receptors on peripheral blood natural killer cell cytotoxicity (NKCC) and their (large granular lymphocyte, LGL) number, as well as the plasma concentration of tumor necrosis factor α (TNF-α) and corticosterone in male Wistar rats exposed to elevated plus maze (EPM) stress or non-stress conditions. The NMDA groups were injected with NMDA glutamate receptor agonist (N-methyl-D-aspartate; 0.25 μg/rat), the D-AP7 group was injected with DL-2-amino-7-phosphoheptanoate (0.1 μg/rat), an antagonist of NMDA glutamate receptors, and the control Sal group with saline (0.5 μl/rat) via previously implanted cannulae into the MS. There was an increase in the NKCC, NK/LGL number and plasma TNF-α concentration after the NMDA injections, being much stronger within the rats under non-stress conditions rather than the rats exposed to EPM stress. These parameters were decreased in the D-AP7 rats, suggesting receptor/ion channel specificity. Moreover, a lower plasma corticosterone concentration within the NMDA rather than the Sal and D-AP7 groups was found. The obtained results suggest that activation of the NMDA glutamate receptors in the MS, accompanied by changes in the corticosterone and cytokine responses, may be involved in modulation of the blood natural anti-tumor response, under EPM stress and non-stress conditions.


CD146 as a promising therapeutic target for retinal and choroidal neovascularization diseases.
Blood vessel dysfunction causes several retinal diseases, including diabetic retinopathy, familial exudative vitreoretinopathy, macular degeneration and choroidal neovascularization in pathological myopia. Vascular endothelial growth factor (VEGF)-neutralizing proteins provide benefits in most of those diseases, yet unsolved haemorrhage and frequent intraocular injections still bothered patients. Here, we identified endothelial CD146 as a new target for retinal diseases. CD146 expression was activated in two ocular pathological angiogenesis models, a laser-induced choroid neovascularization model and an oxygen-induced retinopathy model. The absence of CD146 impaired hypoxia-induced cell migration and angiogenesis both in cell lines and animal model. Preventive or therapeutic treatment with anti-CD146 antibody AA98 significantly inhibited hypoxia-induced aberrant retinal angiogenesis in two retinal disease models. Mechanistically, under hypoxia condition, CD146 was involved in the activation of NFκB, Erk and Akt signalling pathways, which are partially independent of VEGF. Consistently, anti-CD146 therapy combined with anti-VEGF therapy showed enhanced impairment effect of hypoxia-induced angiogenesis in vitro and in vivo. Given the critical role of abnormal angiogenesis in retinal and choroidal diseases, our results provide novel insights into combinatorial therapy for neovascular fundus diseases.


Subepididymal orchiectomy: the acceptable alternative.
Orchiectomy remains the standard of therapeutic efficacy in the treatment of advanced prostatic cancer. It also is cost-effective and compliance is assured. Any stigma of a mutilating procedure may be avoided by subepididymal orchiectomy, which offers an acceptable cosmetic result.


In vitro precipitation of calcium oxalate in the presence of whole matrix or lipid components of the urinary stones.
Organic matrix of human calcium oxalate urinary stones was obtained by demineralizing with EDTA. Lipids were extracted from the EDTA-insoluble matrix by chloroform methanol treatment. The whole matrix and its total lipid extract were then incubated in a metastable solution of calcium oxalate and depletion of calcium and oxalate ions from the calcifying solution was determined. Results of our studies described here show that urinary calcium oxalate stone matrix and its total lipid contents were capable of binding calcium and oxalate ions and of catalysing calcium oxalate crystal formation from a metastable calcium oxalate solution.


Secondary structure prediction for complete rDNA sequences (18S, 5.8S, and 28S rDNA) of Demodex folliculorum, and comparison of divergent domains structures across Acari.
According to base pairing, the rRNA folds into corresponding secondary structures, which contain additional phylogenetic information. On the basis of sequencing for complete rDNA sequences (18S, ITS1, 5.8S, ITS2 and 28S rDNA) of Demodex, we predicted the secondary structure of the complete rDNA sequence (18S, 5.8S, and 28S rDNA) of Demodex folliculorum, which was in concordance with that of the main arthropod lineages in past studies. And together with the sequence data from GenBank, we also predicted the secondary structures of divergent domains in SSU rRNA of 51 species and in LSU rRNA of 43 species from four superfamilies in Acari (Cheyletoidea, Tetranychoidea, Analgoidea and Ixodoidea). The multiple alignment among the four superfamilies in Acari showed that, insertions from Tetranychoidea SSU rRNA formed two newly proposed helixes, and helix c3-2b of LSU rRNA was absent in Demodex (Cheyletoidea) taxa. Generally speaking, LSU rRNA presented more remarkable differences than SSU rRNA did, mainly in D2, D3, D5, D7a, D7b, D8 and D10.


Posttraumatic stress disorder-type behaviors in streptozotocin-induced diabetic rats can be prevented by prolonged treatment with vitamin E.
Anxiety and stress disorders, such as posttraumatic stress disorder (PTSD) have been described as debilitating comorbidities of diabetes. In the present study, we aimed to investigate anxiety-like behavior and the extinction and generalization of aversive memories in fear conditioning using a streptozotocin-induced model of diabetes (DBT). Moreover, considering that DBT animals present increased oxidative stress in brain areas related to anxiety and memory, we aimed to evaluate the effect of prolonged treatment with antioxidant vitamin E on behavioral parameters of anxiety and fear memory and on the diabetic condition. It was observed that DBT animals showed a deficiency in extinguishing the aversive memory in a fear conditioning test, along with a generalization of the fear memory. They also present a more pronounced anxiety-like behavior in the elevated plus maze test. VIT E treatment (300 mg/kg, p.o.) was not able to reduce hyperglycemia; however, it was able to block the anxiogenic-like behavior, also improving the deficit in the extinction of the aversive memory as well as blocking the generalization of such memory in a different context. Taken together, our data suggest that DBT animals are prone to extinction deficits and generalization of fear memories, behaviors which are observed in models of PTSD. Lastly, prolonged VIT E supplementation may be effective in the treatment of anxiety, extinction deficit and generalization of fear memories induced by the diabetic condition.


Perioperative Mortality in Nonelderly Adult Patients With Cancer: A Population-based Study Evaluating Health Care Disparities in the United States According to Insurance Status.
The purpose of this study was to evaluate whether insurance status predicts for perioperative mortality (death within 30 d of cancer-directed surgery) for the 20 most common surgically treated cancers. The SEER database was examined for the 20 most common surgically resected cancers and included nonelderly adults, aged 18 to 64 years. The database was queried from 2007 to 2011, with a total of 506,722 patients included in the analysis. Insurance status for all patients were the following: non-Medicaid insurance (83%), any Medicaid (10%), uninsured (4%), and unknown (3%). In univariate analyses, predictors for perioperative mortality included insurance status (P<0.001), age (P=0.015), race (P<0.001), marital status (P<0.001), residence (P=0.002), percent of county below the federal poverty level (P<0.001), and median county-level income (P<0.001). Perioperative mortality was also associated with advanced disease (P<0.001). Under multivariate analysis, patients with either Medicaid (Cochran-Mantel-Haenszel odds ratio [CMH OR], 1.21; 95% confidence interval [CI], 1.14-1.29; P<0.001) or uninsured status (CMH OR, 1.56; 95% CI, 1.44-1.70; P<0.001) were more likely to die within 30 days of surgery compared with patients with non-Medicaid insurance. When comparing Medicaid with the uninsured, Medicaid patients had significantly lower rates of perioperative mortality when compared with the uninsured (CMH OR, 0.80; 95% CI, 0.73-0.89, P<0.001). In the largest reported analysis of perioperative mortality evaluating the 20 most common surgically treated malignancies, patients with Medicaid coverage or without health insurance were more likely to die within 30 days of surgery, with the uninsured having the worst outcomes.


Reliability of the Effect of Artificial Anterior Chamber Pressure and Corneal Drying on Corneal Graft Thickness.
To investigate the effect of artificial anterior chamber (AAC) pressure and corneal drying on the graft thickness in preparation for Descemet stripping automated endothelial keratoplasty. Twenty-seven corneoscleral discs were placed in an AAC. The AAC pressure (15, 45, 92, 109, and 198 mm Hg) was controlled using the height of an infusion bottle and a roller clamp. The endothelium was removed in 1 subgroup. Corneas were exposed to room air or repeatedly dried using cellulose spears. Central corneal thickness was measured every 90 seconds for the first 15 minutes and again at 20 minutes using an ultrasound pachymeter (SP-100, Tomey). There was a significant linear relationship between the corneal thickness and both AAC pressure and corneal drying. Very high coefficients of determination and narrow 95% confidence intervals were present, in particular for high pressures and drying. The rate of thinning increased with increasing pressure and drying to 1.6% per minute. At the maximum rate of thinning, a 10% reduction in corneal thickness occurred in 6 minutes or 100 μm in 8.8 minutes. Removal of the corneal endothelium reduced the rate of thinning to 0.3% per minute (R = 0.72). Increasing AAC pressure and corneal drying reduced the graft thickness at a very predictable rate. Adequate corneal thinning can be achieved by increasing the pressure in the AAC by closing the clamp followed by removal of the residual corneal epithelium and repeated drying with a cellulose spear for 5 to 10 minutes, depending on the initial corneal thickness. This method is simple and is both suitable for use in the eye bank and by the surgeon.


Immunoglobulin therapy in the treatment of multifocal motor neuropathy.
Multifocal motor neuropathy (MMN) is a chronic immune-mediated disorder leading to slowly progressive muscle weakness and wasting. Current treatments are aimed at modulating the immune system in order to avoid further decline and to maintain functional status. Intravenous immunoglobulin (IVIg) is widely used in the treatment of immune-mediated disorders and is the only treatment approved for MMN. While patients do remain stable with maintenance IVIg treatment, most patients will slowly deteriorate over many years. The use of subcutaneous immunoglobulin (ScIg) is also gaining acceptance in this disease. The amount of axonal loss and the number of years without immunoglobulin (Ig) treatment appear to be associated with the permanence of weakness. We summarize the key literature to date that supports Ig use in the treatment of MMN.


Brain distribution of idebenone and its effect on local cerebral glucose utilization in rats.
To investigate the possible action sites of a cerebral metabolism activator, idebenone, (6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone), its distribution in the brain and effect on local cerebral glucose utilization (LCGU) were studied in normal (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions. 14C-Idebenone distributed rapidly into the brain after intravenous administration (10 mg/kg), and the total 14C contents in the brain at peak time corresponded to 0.45-0.56% of the dosages. An autoradiographic study showed that the 14C levels were higher in the white than in the gray matter. When 14C-idebenone was administered orally (100 mg/kg) and intraperitoneally (30 mg/kg), the total 14C levels were not markedly different among the brain regions of the rats. The concentration of unchanged idebenone was higher in the cerebral cortex, thalamus, and cerebellum than that in the other brain regions. Studies on LCGU demonstrated that idebenone (30 mg/kg/day, i.p., for 3 days) improved the reduction of LCGU in SHRSP with stroke, especially in the temporal cortex, thalamus dorsomedial nucleus, subthalamic nucleus, mamillary body, hippocampus dentate gyrus, caudate-putamen, inferior colliculus, and cerebellar nucleus. Based on these results, possible action sites of idebenone for its main pharmacologic effects are discussed.