Effects of a calmodulin inhibitor on bleomycin-induced lung inflammation in hamsters. Biochemical, morphometric, and bronchoalveolar lavage data.
Previous studies have shown that bleomycin-induced pulmonary fibrosis is accompanied by elevated levels of calcium and calmodulin, which are important in the regulation of many biologic processes. The authors have further extended these observations and assessed the effect of a calmodulin inhibitor, trifluoperazine, on bleomycin-induced lung damage with biochemical, morphometric, and bronchoalveolar lavage techniques. The cumulative mortality due to bleomycin was not significantly reduced in animals receiving trifluoperazine. Trifluoperazine had no apparent effect on lung levels of collagen and DNA elevated by bleomycin. However, morphometric studies showed that the volume density of the lesion, the volume of amorphous material and interstitial inflammation, and the number of monocytes within lesions were less in the lungs of bleomycin-treated hamsters receiving trifluoperazine daily. When compared with hamsters treated with bleomycin alone, animals treated with both bleomycin and trifluoperazine had significantly fewer lymphocytes in their bronchoalveolar lavage fluid. The data suggest that trifluoperazine reduced the acute inflammation which accompanies bleomycin pneumotoxicity but did not affect the subsequent development of pulmonary fibrosis. It has been postulated that the observed antiinflammatory action of trifluoperazine may be due to inhibition of calmodulin-dependent leukocyte functions.


Single nucleotide polymorphisms (SNPs) at -238 and -308 positions in the TNFalpha promoter: clinical and bacteriological evaluation in leprosy.
Tumor necrosis factor alpha (TNFalpha) plays a key role in orchestrating the complex events involved in inflammation and immune response. The presence of single nucleotide polymorphisms (SNPs) within the promoter region of the TNFa gene has been associated with a number of diseases. The aim of this study was to investigate the distribution of polymorphisms at positions -238 (G/A) and -308 (G/A) at the TNFalpha promoter, and its association to the outcome of different clinical forms of leprosy. Furthermore, the bacteriological index (BI) was evaluated among genotyped multibacillary (MB) patients in order to investigate the possible influence of each polymorphism on the bacterial load. This study included a total of 631 leprosy patients being 401 MB and 230 paucibacillary (PB), that was further separated according to its ethnicity (Afro- and Euro-Brazilians). The combination of SNPs in haplotypes generated three different arrangements: TNFG-G, TNFG-A and TNFA-G. In spite of the marked differences observed in the frequency of the haplotypes along the ethnic groups, no statistical differences were observed in haplotype frequencies between MB and PB patients. The BI analyses showed a lower bacteriological index among the -308 carriers, while the BI of the -238 carriers was higher. Although no significance has been achieved in this analysis regarding the influence of the polymorphisms to the development of the clinical outcome, it seems that in a different stage (among the MB patients) the polymorphisms could contribute to the degree of severity observed.


Imbalance of SMC1 and SMC3 cohesins causes specific and distinct effects.
SMC1 and SMC3 form a high-affinity heterodimer, which provides an open backbone of the cohesin ring, to be closed by a kleisin protein. RNAi mediated knock-down of either one heterodimer partner, SMC1 or SMC3, is expected to cause very similar if not identical phenotypes. However, we observed highly distinct, protein-specific phenotypes. Upon knock-down of human SMC1, much of SMC3 remains stable, accumulates in the cytoplasm and does not associate with other cohesin proteins. Most of the excess nuclear SMC3 is highly mobile and not or only weakly chromosome-associated. In contrast, human SMC3 knock-down rendered SMC1 instable without cytoplasmic accumulation. As observed by differential protein extraction and in FRAP experiments the remaining SMC1 or SMC3 proteins in the respective SMC1 or SMC3 knock-down experiments constituted a cohesin pool, which is associated with chromatin with highest affinity, likely the least expendable. Expression of bovine EGFP-SMC1 or mouse EGFP-SMC3 in human cells under conditions of human SMC1 or SMC3 knock-down rescued the respective phenotypes, but in untreated cells over-expressed exogenous SMC proteins mis-localized. Paucity of either one of the SMC proteins causes RAD21 degradation. These results argue for great caution in interpreting SMC1 and SMC3 RNAi or over-expression experiments. Under challenged conditions these two proteins unexpectedly behave differently, which may have biological consequences for regulation of cohesin-associated functions and for human cohesin pathologies.


Decellularized periodontal ligament cell sheets with recellularization potential.
The periodontal ligament is the key tissue facilitating periodontal regeneration. This study aimed to fabricate decellularized human periodontal ligament cell sheets for subsequent periodontal tissue engineering applications. The decellularization protocol involved the transfer of intact human periodontal ligament cell sheets onto melt electrospun polycaprolactone membranes and subsequent bi-directional perfusion with NH4OH/Triton X-100 and DNase solutions. The protocol was shown to remove 92% of DNA content. The structural integrity of the decellularized cell sheets was confirmed by a collagen quantification assay, immunostaining of human collagen type I and fibronectin, and scanning electron microscopy. ELISA was used to demonstrate the presence of residual basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) in the decellularized cell sheet constructs. The decellularized cell sheets were shown to have the ability to support recellularization by allogenic human periodontal ligament cells. This study describes the fabrication of decellularized periodontal ligament cell sheets that retain an intact extracellular matrix and resident growth factors and can support repopulation by allogenic cells. The decellularized hPDL cell sheet concept has the potential to be utilized in future "off-the-shelf" periodontal tissue engineering strategies.


When MT1-MMP meets ADAMs.
MT1-MMP is a membrane-tethered enzyme capable of remodeling extracellular matrix. MT1-MMP-deficient mice exhibit systematic defects during development, especially in craniofacial development characterized by retarded calvarial bone formation. Recently, we identified MT1-MMP as a critical positive modulator of FGF signaling during intramembranous ossification. MT1-MMP cleaves ADAM9 to protect FGFR2 from ectodomain shedding. Depletion of ADAM9 in MT1-MMP-deficient mice significantly rescued the calvarial defects via restoring FGF signaling. Interestingly, this regulatory mechanism seems to be highly tissue-specific, as defective FGF2-induced corneal angiogenesis in Mmp14-/- mice could not be rescued by removal of ADAM9. In addition, MT1-MMP also cleaves another ADAM family member, ADAM15. Our current findings not only present a novel regulatory mechanism for FGF signaling but also reveal a functional crosstalk between MMP and ADAM families. Better understanding of the interplay between ADAMs and MT1-MMP and its consequences for signaling pathways will provide new insights into therapeutic approaches for the management of developmental disorders and various diseases, such as cancer.


Efficient singlet oxygen generation by luminescent 2-(2′-thienyl)pyridyl cyclometalated platinum(II) complexes and their calixarene derivatives.
Luminescent cyclometalated platinum(II) complexes, namely [Pt(Thpy)(PPh3)X]n+ (HThpy = 2-(2′-thienyl)pyridine; X = Cl− (1), n = 0; X = CH3CN (2), pyridine (3), n = 1) and [Pt(Thpy)(HThpy)Y]n+ (Y = Cl− (4), n = 0; Y = pyridine (5), n = 1), exhibit structured emission with peak maximum at ∼556 and 598 nm in degassed acetonitrile and with emission quantum yield and lifetime of up to 0.38 and 26 μs, respectively. These complexes are efficient photosensitizers of singlet oxygen with yields up to >90%. Complex 5 exhibited photocytotoxicity towards cancer cells and fluorescence microscopic images of cells incubated with 5 reveal substantial uptake at the nucleus and mitochondria.


Plasmid and chromosomal elements involved in the pathogenesis of attaching and effacing Escherichia coli.
Attaching and effacing (A/E) intestinal lesions are produced by enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and RDEC-1, a pathogen of weanling rabbits. We recently identified a chromosomal locus (eae[E. coli A/E]) which is required for A/E activity in a wild-type EPEC strain. Sequences homologous to those of an eae gene probe were detected in EPEC, RDEC-1, and EHEC isolates. We report here that the eae gene is chromosomally encoded in all EPEC and EHEC strains tested and in RDEC-1. In addition, the eae probe was found to be 100% sensitive and 98% specific in detecting E. coli of EPEC serogroups that demonstrate A/E activity. Ten percent of E. coli of EPEC serogroups that hybridized with the eae probe and produced A/E activity did not hybridize with the EAF (EPEC adherence factor) probe, a plasmid-associated diagnostic probe which is currently used to identify EPEC. In addition to A/E factors, plasmid-associated adhesins also contribute to the pathogenesis of EPEC and RDEC-1. To further investigate the role of plasmid-associated adherence, a hybrid RDEC-1-EPEC strain containing the adherence plasmid of an EPEC strain in the A/E background of RDEC-1 was constructed. This hybrid strain, unlike the parent RDEC-1 strain, produced A/E lesions on human tissue culture cells, which suggests that the EPEC adherence plasmid provides tissue specificity to the hybrid strain and that the A/E factors of RDEC-1 are not host restricted.


Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids.
Extensive data obtained in both experimental animals and humans demonstrate that steady-state plasma LDL-C concentrations are determined largely by the rate of LDL-C formation, Jt, and the level of LDL-R activity, Jm, located primarily in the liver. An increase in net cholesterol delivery to the liver suppresses Jm, slightly elevates Jt, and modestly raises the LDL-C level. Feeding lipids such as the 12:0, 14:0, and 16:0 saturated fatty acids further suppresses Jm, increases Jt, and markedly elevates the plasma LDL-C concentration. Feeding triacylglycerols containing the 18:1(c9) fatty acid restores hepatic receptor activity, decreases Jt, and modestly reduces the concentration of LDL-C in the plasma. The 18:2(c9, c12) compound has similar effects, although it is quantitatively less active than the monounsaturated fatty acid in restoring Jm. In contrast to these fatty acids that actively raise or lower hepatic receptor activity, a large group of compounds including the 4:0, 6:0, 8:0, 10:0, 18:0, and 18:1(t9) fatty acids have no demonstrable effect on any parameter of LDL-C metabolism. These fatty acids, therefore, can be added to animal and human diets with relative impunity. They will alter plasma LDL-C levels only to the extent that they replace the active saturated fatty acids (in which case they lower the LDL-C concentration) or unsaturated compounds (in which case they raise the plasma cholesterol level). All of these effects of cholesterol and the various fatty acids can be explained by the effects of these lipids in altering the size of the regulatory pool of cholesterol in the hepatocyte. However, many aspects of the cellular and molecular biology of these regulatory processes require additional investigation. In particular, new studies should focus on how the genetic background of an individual animal or human alters the quantitative response of its plasma LDL-C concentration to the dietary challenge of each of these types of lipids.


Prescription medication burden in patients with newly diagnosed diabetes: a SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) study.
To understand the burden of medication use for patients with newly diagnosed diabetes both before and after diabetes diagnosis and to identify subpopulations of patients with newly diagnosed diabetes who face a relatively high drug burden. Retrospective cohort study. 11 integrated health systems in the United States. 196,654 insured adults 20 years of age or older newly diagnosed with type 1 or type 2 diabetes from January 2005 through December 2009. Number of unique therapeutic classes of drugs dispensed in the 12 months before and 12 months after diagnosis of diabetes in five categories: overall, antihypertensive agents, antihyperlipidemic agents, mental health agents, and antihyperglycemic agents (in the postdiagnosis period only). The mean number of drug classes used by newly diagnosed patients with diabetes is high before diagnosis (5.0) and increases significantly afterward (6.6). Of this increase, 81% is due to antihyperglycemic initiation and increased use of medications to control hypertension and lipid levels. Multivariate analyses showed that overall drug burden after diabetes diagnosis was higher in women, older, white, and obese patients, as well as among those with higher glycosylated hemoglobin concentrations and comorbidity levels (significant for all comparisons). The overall number of drug classes used by newly diagnosed patients with diabetes after diagnosis decreased slightly but significantly between 2005 and 2009. Patients newly diagnosed with diabetes face a substantially increased burden of medications used to control diabetes and other comorbidities. This study shows an increased focus on cardiovascular disease risk factor control after diagnosis of diabetes. However, total drug burden may be slightly decreasing over time.


Detection of gastrointestinal parasitism at recreational canine sites in the USA: the DOGPARCS study.
The rapid growth in off-leash dog parks provides opportunity for canine socialization activities but carries risk of exposure to intestinal parasites. This study assessed the prevalence of these infections in dogs visiting off-leash dog parks. Fresh defecations were collected from dogs visiting parks in 30 metropolitan areas across the USA. Samples were analyzed by coproantigen immunoassay (CAI) (Fecal Dx® and Giardia Test, IDEXX Laboratories, Inc.) and zinc sulfate centrifugal flotation (CF). Owners responded to a questionnaire on their dog's signalment and use of heartworm/intestinal parasite control medications (HWCM). Samples were examined from 3006 dogs, 87.9% aged at least 12 months, visiting 288 parks. At least one intestinal parasite was detected in 622 (20.7%) samples, nematodes in 263 (8.8%), with hookworms, whipworms and ascarids in 7.1, 1.9 and 0.6% of samples, respectively. A sample positive for one or more intestinal parasites was found in 245 (85.1%) parks, with nematodes found in 143 (49.7%). Combined, CAI and CF detected 78.4% more intestinal nematode infections than CF alone. Hookworm and whipworm infections were detected in all age groups, but ascarids were only detected in dogs less than 4 years-old. Approximately 42% of dogs aged less than 1 year were positive for nematodes or Giardia. Based on owner reports, HWCM was current for 68.8% of dogs, dogs previously diagnosed with intestinal parasitism were more likely to be receiving a HWCM than those without such history, and a significantly lower (P = 0.0003) proportion of dogs receiving a HWCM were positive for intestinal nematodes compared with those not on such medication. Intestinal parasites, the most common of which were Giardia, Ancylostoma caninum and Trichuris vulpis, were found in 20% of dogs and 85% of dog parks across the USA. Enhanced detection of canine intestinal parasitism was achieved by combining CF and CAI. Canine intestinal parasites are common across the USA and dog health can be improved by regular testing of fecal samples and routine administration of medications effective against the most common infections.


Ventilation control for airborne transmission of human exhaled bio-aerosols in buildings.
The emergence of respiratory diseases, i.e., severe acute respiratory syndrome (SARS) epidemic in 2003, H1N1 influenza epidemic in 2011 and Middle East respiratory syndrome (MERS) outbreak, reiterated the significance of ventilation in buildings. The role of ventilation in removing exhaled airborne bio-aerosols and preventing cross infections has been multidisciplinary extensively studied after the SARS outbreak in 2003. The characteristics of droplet-borne, short-range airborne and long-range airborne transmission of infectious diseases were identified. Increasing ventilation rate can effectively reduce the risk of long-range airborne transmission, while it may be of little useful in preventing the droplet-borne transmission. To maintain the airflow direction from clean cubicles to dirty cubicles is an effective way to prevent the cross infection between cubicles, which is widely used in hospital isolation rooms. Field measurements showed that wrong air flow direction was due to poor construction quality or maintenance. The impacts of different airflow patterns on removing large droplets and fine droplet nuclei were discussed. Some new concepts in general ventilation systems and local personalized equipment were also introduced. This review updates current knowledge of the airborne transmission of pathogens and the improvement of ventilation efficiency concerning the infection prevention.


A national survey of anthelmintic resistance in ascarid and strongylid nematodes in Australian Thoroughbred horses.
This study quantified the extent of anthelmintic resistance (AR) in ascarid and strongylid nematodes against commonly used anthelmintics in Australian Thoroughbred horses. Faecal egg count reduction tests (FECRTs, n = 86) and egg reappearance period (ERP) tests were conducted on 22 farms across Australia. Faecal egg counts (FECs) were determined using the modified McMaster technique, and percent faecal egg count reduction (%FECR) was calculated using the Bayesian hierarchical model and hybrid Frequentist/Bayesian analysis method. The results were interpreted using old (published in 1992) and new (2023) research guidelines of the World Association for the Advancement of Veterinary Parasitology (WAAVP). The species composition of strongylid nematodes was detected utilising a DNA-metabarcoding method using pre- and post-treatment samples. Resistance was observed in strongylid nematodes to commonly used single-active and combination anthelmintics, including ivermectin (IVM %FECR range: 82%-92%; 95% lower credible interval (LCI) range: 80%-90%), abamectin (ABM: 73%-92%; 65%-88%), moxidectin (MOX: 89%-91%; 84%-89%), oxfendazole (OFZ: 0%-56%; 0%-31%) and its combination with pyrantel (OFZ + PYR: 0%-82%; 0%-78%). Resistance in Parascaris spp. was observed to IVM (10%-43%; 0%-36%), ABM (0%; 0%) and MOX (0%; 0%). When the new thresholds recommended by the WAAVP were used, AR was detected in six additional FECRTs for strongylids and three more tests for Parascaris spp., introducing resistance to OFZ and OFZ + PYR in the latter. Shortened ERPs (4-6 weeks) of strongylids were observed in 31 FECRTs in which AR was not detected at 2 weeks post-treatment for all the anthelmintics tested. Among cyathostomins, Cylicocyclus nassatus, Cylicostephanus longibursatus and Coronocyclus coronatus were the most prevalent species at 2 weeks post-treatment, whereas the main species appearing at five weeks following treatments with macrocyclic lactones were Cylicocyclus nassatus, Cylicostephanus longibursatus and Cylicocyclus ashworthi. After treatment with OFZ + PYR, the latter three, plus Coronocyclus coronatus and Cyathostomum catinatum, were detected at 5 weeks post-treatment. Overall, the study highlights the prevalence of AR in both ascarids and strongylid nematodes against commonly used anthelmintic products to control worms in Australian horses. The results indicate that ML combination products provided acceptable efficacy at 2 weeks. However, ERP calculations suggest that products work less effectively than previously measured. It is suggested to regularly monitor the efficacy of the anthelmintics and consider changing the worm control practices to better manage worms and AR in Australian horses.


A physiologically realistic virtual patient database for the study of arterial haemodynamics.
This study creates a physiologically realistic virtual patient database (VPD), representing the human arterial system, for the primary purpose of studying the effects of arterial disease on haemodynamics. A low dimensional representation of an anatomically detailed arterial network is outlined, and a physiologically realistic posterior distribution for its parameters constructed through the use of a Bayesian approach. This approach combines both physiological/geometrical constraints and the available measurements reported in the literature. A key contribution of this work is to present a framework for including all such available information for the creation of virtual patients (VPs). The Markov Chain Monte Carlo (MCMC) method is used to sample random VPs from this posterior distribution, and the pressure and flow-rate profiles associated with each VP computed through a physics based model of pulse wave propagation. This combination of the arterial network parameters (representing a virtual patient) and the haemodynamics waveforms of pressure and flow-rates at various locations (representing functional response and potential measurements that can be acquired in the virtual patient) makes up the VPD. While 75,000 VPs are sampled from the posterior distribution, 10,000 are discarded as the initial burn-in period of the MCMC sampler. A further 12,857 VPs are subsequently removed due to the presence of negative average flow-rate, reducing the VPD to 52,143. Due to undesirable behaviour observed in some VPs-asymmetric under- and over-damped pressure and flow-rate profiles in left and right sides of the arterial system-a filter is proposed to remove VPs showing such behaviour. Post application of the filter, the VPD has 28,868 subjects. It is shown that the methodology is appropriate by comparing the VPD statistics to those reported in literature across real populations. Generally, a good agreement between the two is found while respecting physiological/geometrical constraints.


Legal implications of genetics and crime research.
Two controversial topics dominate discussions of the legal implications of genetics and crime research; (1) the viability and politics of such research, which has sparked fervent debate in the USA; and (2) the current status of new or atypical criminal law defences, which would include a genetic-defect defence to criminal behaviour. This chapter begins by examining the scientifically discredited XYY chromosome syndrome defence, the major genetic-defect defence that defendants have attempted, albeit unsuccessfully. It then focuses on attorneys' efforts to test for evidence of genetic abnormality in the recent and highly publicized case involving convicted murderer Stephen Mobley, whose family history reveals four generations of violent, aggressive and behaviourally disordered men and women. Mobley is currently appealing his death sentence before the Georgia Supreme Court on the basis that the trial court denied his request both to have genetic testing performed and to have such testing allowed as evidence into court. This chapter concludes by emphasizing that the question is not whether genetic evidence will ever be admitted into court, but when and under what kinds of circumstances. No doubt, genetic evidence, and comparable kinds of biological evidence, will have a major impact on juries when such evidence is more fully accepted by the legal and scientific communities.


Autoimmune Neutropenia Updates: Etiology, Pathology, and Treatment.
Autoimmune neutropenia (AIN) is defined as a neutrophil count <1.5 × 109/L caused by increased peripheral destruction of neutrophils from an underlying autoimmune mechanism in which autoantibodies are directed against a patient's own neutrophils. AIN has a multifactorial etiology ranging from an idiopathic primary phenomenon to secondary disorders associated with established autoimmune diseases. Primary AIN is more prevalent in children, generally self-limited, and typically manifests as a sole hematologic abnormality. Secondary AIN is more common in adults and often occurs in the setting of concurrent autoimmune diseases, infections, malignancies, or medications. It may be seen posttransplantation or occasionally with neurological diseases. Various laboratory modalities are used to detect anti-neutrophil antibodies. Although biologic agents such as rituximab and alemtuzumab (Campath-1H) have been used in the management of AIN, granulocyte colony-stimulating factor remains the first-line therapy. In this article we provide a review of the pathogenesis of AIN, its clinical presentation, and the current treatment options.


[Metabolic and renal changes in lymphoproliferative syndromes of childhood].
Authors report five patients with lymphoproliferative diseases who suffered from metabolic and renal disorders hyperuricemia, hyperphosforemia, hyperkaliemia, hypocalcemia and azotemia) during initial phase of chemotherapy. They comment on measures to prevent these disorders and the need of hemodialysis in some cases.


Impact of Early COVID-19 Pandemic on Common Ophthalmic Procedures Volumes: A US Claims-Based Analysis.
The COVID-19 pandemic has had a profound effect on the delivery of healthcare in the United States and globally. The aim of this study was to evaluate the impact of COVID-19 on common ophthalmic procedure utilization and normalization to pre-pandemic daily rates. Leveraging a national database, Clinformatics™ DataMart (OptumInsight, Eden Prairie, MN), procedure frequencies and daily averages, defined by Current Procedural Terminology codes, of common elective and non-elective procedures within multiple ophthalmology sub-specialties were calculated. Interrupted time-series analysis with a Poisson regression model and smooth spline functions was used to model trends in pre-COVID-19 (January 1, 2018-February 29, 2020) and COVID-19 (March 1, 2020-June 30, 2020) periods. Of 3,583,231 procedures in the study period, 339,607 occurred during the early COVID-19 time period. Anti-vascular endothelial growth factor injections (44,412 to 39,774, RR 1.01, CI 0.99-1.02; p = .212), retinal detachment repairs (1,290 to 1,086, RR 1.07, CI 0.99-1.15; p = .103), and glaucoma drainage implants/trabeculectomies (706 to 487, RR 0.93, CI 0.83-1.04; p = .200) remained stable. Cataract surgery (61,421 to 33,054, RR 0.77; CI 0.76-0.78; p < .001), laser peripheral iridotomy (1,875 to 890, RR 0.82, CI 0.76-0.88; p < .001), laser trabeculoplasty (2,680 to 1,753, RR 0.79, CI 0.74-0.84; p < .001), and blepharoplasty (1,522 to 797, RR 0.71, CI 0.66-0.77; p < .001) all declined significantly. All procedures except laser iridotomy returned to pre-COVID19 rates by June 2020. Most ophthalmic procedures that significantly declined during the COVID-19 pandemic were elective procedures. Among these, the majority returned to 2019 daily averages by June 2020.


Epstein syndrome: another renal disorder with mutations in the nonmuscle myosin heavy chain 9 gene.
Epstein syndrome (EPTS) is an autosomal dominant disease characterized by nephritis, mild hearing loss, and thrombocytopenia with giant platelets. Renal and hearing abnormalities are indistinguishable from those observed in Fechtner syndrome (FTNS), an Alport-like variant. EPTS macrothrombocytopenia is similar to that described in FTNS, May-Hegglin anomaly (MHA), and Sebastian syndrome (SBS), three disorders caused by mutations in the nonmuscle heavy chain myosin IIA ( MYH9). Unlike FTNS, MHA, and SBS, EPTS does not show inclusion bodies in the leukocytes. The clinical features of EPTS and the chromosomal localization of the respective gene in the same region as MYH9 suggest that this disorder is allelic with the other giant platelet disorders. We identified a MYH9 missense mutation in two EPTS familial cases. In both families, an R702H substitution was found, probably inducing conformational changes to the myosin head. A different amino acid substitution at the same codon (R702C) has been previously identified in FTNS. On the basis of predictions from molecular modeling of the X-ray crystallographic structure of chick smooth muscle myosin, the mutated thiol reactive group of R702C may lead to intermolecular disulfide bridges, with the consequent formation of the inclusions typical of FTNS. On the contrary, the R702H mutation does not allow the protein to aggregate and thus to generate "Döhle-like" bodies, which are indeed absent in EPTS. In conclusion, our results extend the allelic heterogeneity of MYH9 mutations to another clinical syndrome and contribute to the clarification of the pathogenesis of the various inherited giant platelet disorders.


Effect of Fasting on Contrast Sensitivity in Healthy Males.
To evaluate the effect of fasting on contrast sensitivity (CS) in healthy male individuals during the month of Ramadan. This study included 45 healthy male individuals, aged between 20 and 40 years, working in the same environment. Functional acuity contrast testing (F.A.C.T) was performed using the Optec 6500 vision testing system. Measurements taken during a state of satiety one week before Ramadan were compared with those taken a minimum of 12 hours after the start of fasting in the first and fourth weeks of Ramadan. Contrast sensitivity (CS) was increased at the spatial frequency of three cycles per degree (cpd) at the end of the first week of Ramadan in comparison to the CS measured before Ramadan ( P = 0.03). The mean CS values were increased at the spatial frequencies of 3 and 12 cpd at the end of the last week of Ramadan in comparison to the mean values measured before Ramadan ( P = 0.01 for both). Although we found statistically significant increases in CS at certain frequencies, we can conclude that Ramadan fasting has no negative effects on CS.


Determination of uromodulin in human urine: influence of storage and processing.
Uromodulin (Tamm-Horsfall protein) is the most abundant protein excreted in the urine under physiological conditions. It is exclusively produced in the kidney and secreted into the urine via proteolytic cleavage. The involvement of UMOD, the gene that encodes uromodulin, in rare autosomal dominant diseases, and its robust genome-wide association with the risk of chronic kidney disease suggest that the level of uromodulin in urine could represent a critical biomarker for kidney function. The structure of uromodulin is complex, with multiple disulfide bonds and typical domains of extracellular proteins. Thus far, the conditions influencing stability and measurement of uromodulin in human urine have not been systematically investigated, giving inconsistent results. In this study, we used a robust, in-house ELISA to characterize the conditions of sampling and storage necessary to provide a faithful dosage of uromodulin in the urine. The levels of uromodulin in human urine were significantly affected by centrifugation and vortexing, as well as by the conditions and duration of storage. These results validate a simple, low-cost ELISA and document the optimal conditions of processing and storage for measuring uromodulin in human urine.


Epilepsy in adults.
The past decade has seen advances in the management of patients with epilepsy. The development of practical long-term electroencephalographic techniques, with or without simultaneous video recording, has increased the accuracy of diagnosis of seizure types. The technique also provides clinicians and investigators with a method for establishing the clinical efficacy of antiepileptic drugs and determining their therapeutic serum concentrations. Computerized tomography has enhanced the identification of structural brain lesions. Most of the reported CT abnormalities consist of diffuse and focal atrophies, mild ventricular dilatations, and porencephalies. CT has detected tumors in 8 to 10% of the patients regardless of age or type of seizure involved. New concepts of antiepileptic drug therapy have developed from the recognition of pharmacological properties peculiar to each agent. Determination of serum antiepileptic drug levels has to be utilized to reduce the problem of pharmacokinetic variability from one patient to another and in the same patient at different times, so that dosage can be individualized to achieve maximum therapeutic effects with least toxicity. Review of the literature on pregnancy in epileptic women shows that a third to half experienced more seizures during gestation. Reduced serum levels of most antiepileptic drugs have recently been observed during gestation. Infants of epileptic women taking antiepileptic drugs have a two to three times greater risk for congenital anomalies than infants of nonepileptic women. However, with the exception of oxazolidinediones, evidence to date has not proved the teratogenicity of antiepileptic drugs. The role of genetic factors and the effect of seizures during pregnancy have not been determined. Modest progress has been made in epilepsy rehabilitation, but serious problems still remain. The unemployment rate of persons with epilepsy is twice the national average. Half of those who are successfully employed did not disclose their disorder at the time of employment. Several prognostic indicators have been reported, but the validity of many of these indicators is questionable. For example, does shorter life expectancy apply to all subgroups, or does it vary according to seizure type and cause? The life expectancy, treatment response, and probability of remission in epileptic persons must be reevaluated after consistent applications of current methods of epilepsy management.


Strong interactive growth behaviours in solution-phase synthesis of three-dimensional metal oxide nanostructures.
Wet-chemical synthesis is a promising alternative to the conventional vapour-phase method owing to its advantages in commercial-scale production at low cost. Studies on nanocrystallization in solution have suggested that growth rate is commonly affected by the size and density of surrounding crystals. However, systematic investigation on the mutual interaction among neighbouring crystals is still lacking. Here we report on strong interactive growth behaviours observed during anisotropic growth of zinc oxide hexagonal nanorods arrays. In particular, we found multiple growth regimes demonstrating that the diameter of the rod is dependent on its height. Local interactions among the growing rods result in cases where height is irrelevant to the diameter, increased with increasing diameter or inversely proportional to the diameter. These phenomena originate from material diffusion and the size-dependent Gibbs-Thomson effect that are universally applicable to a variety of material systems, thereby providing bottom-up strategies for diverse three-dimensional nanofabrication.


Biological neurons act as generalization filters in reservoir computing.
Reservoir computing is a machine learning paradigm that transforms the transient dynamics of high-dimensional nonlinear systems for processing time-series data. Although the paradigm was initially proposed to model information processing in the mammalian cortex, it remains unclear how the nonrandom network architecture, such as the modular architecture, in the cortex integrates with the biophysics of living neurons to characterize the function of biological neuronal networks (BNNs). Here, we used optogenetics and calcium imaging to record the multicellular responses of cultured BNNs and employed the reservoir computing framework to decode their computational capabilities. Micropatterned substrates were used to embed the modular architecture in the BNNs. We first show that the dynamics of modular BNNs in response to static inputs can be classified with a linear decoder and that the modularity of the BNNs positively correlates with the classification accuracy. We then used a timer task to verify that BNNs possess a short-term memory of several 100 ms and finally show that this property can be exploited for spoken digit classification. Interestingly, BNN-based reservoirs allow categorical learning, wherein a network trained on one dataset can be used to classify separate datasets of the same category. Such classification was not possible when the inputs were directly decoded by a linear decoder, suggesting that BNNs act as a generalization filter to improve reservoir computing performance. Our findings pave the way toward a mechanistic understanding of information representation within BNNs and build future expectations toward the realization of physical reservoir computing systems based on BNNs.


Serum levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α, renal function biochemical parameters and clinical outcomes in pediatric cardiopulmonary bypass surgery.
Cardiopulmonary bypass causes detrimental effects on remote organs due to inflammatory response. One of these organs is kidney that is frequently affected by cardiac surgery. Acute kidney injury is a post-cardiopulmonary bypass complication, which may result in increased post-operative morbidity and mortality. Post-cardiopulmonary bypass inflammatory response may contribute to remote organ dysfunction. In the present study, we investigated the relation between cytokines including interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α, and renal function tests such as creatinine and blood urea nitrogen (BUN). In total, 91 patients between the ages of 4 and 60 months were enrolled for elective cardiac surgery with cardiopulmonary bypass after informed consent. Data regarding renal function tests and clinical outcomes were carefully recorded until 24 hours after admission to intensive care unit and analyzed. Our findings support that there is a direct correlation between cytokines including interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α and cardiopulmonary bypass time, duration of operation, and intensive care unit stay. Longer cardiopulmonary bypass time was associated with higher interleukin-8 at cross-clamp removal and 24 hours post- intensive care unit as well as higher interleukin-10 at declamp time. Higher interleukin-6 at declamp time was directly correlated with higher post-operative BUN. Interleukin-8 level after anesthesia induction was directly correlated with intensive care unit stay duration. Higher blood interleukin-6 and tumor necrosis factor-α levels following 24 hours of admission to intensive care unit were associated with longer mechanical ventilation time. Higher circulatory pro-inflammatory cytokine level is associated with adverse outcomes such as increased intensive care unit stay and longer mechanical ventilation time in pediatric patients. It is also correlated with unfavorable biochemical parameter of renal function, BUN. Findings hint that proper control of the inflammatory response is vital for the control of unfavorable clinical and pathological outcomes.


Practical aspects of assessing and preparing pulmonary cripples for surgery.
The problems presented by patients with advanced pulmonary disease both during and after operation are reviewed. Proper evaluation of the degree of respiratory impairment by simple but systematic bedside and laboratory function tests and blood gas studies is essential. Preparing these patients for surgery by postural drainage, intermittent positive pressure breathing, humidification, bronchodilators, and mucokynetics will decrease postoperative morbidity and mortality.


Is metabolic syndrome associated to HIV infection per se? Results from the HERMES study.
HERMES is a prospective study, including all treatment-naïve patients attending scheduled visits at hospitals in the CISAI group in 2007. The present cross-sectional analysis aims to assess the baseline prevalence and characteristics of Metabolic Syndrome (MS) in a population of HIV-positive treatment-naïve patients. MS was diagnosed using the National Cholesterol Education Program (NCEP) definitions. A total of 292 subjects were enrolled, median age was 37 years, 75% of them were males. The prevalence of MS was 12.3%. The most frequent trio of abnormalities that led to the diagnosis of MS was high blood pressure, triglycerides and HDL. Univariate analysis showed that MS was associated with the following variables: age, education, physical activity, advanced HIV disease (CDC stage C or HIV-RNA >100,000 copies + CD4 <100 cells/mm(3)). Higher educational levels remained protectively associated with MS in multivariate analysis. A higher risk of MS was also associated with advanced HIV disease. Actually, treatment-naïve HIV-positive patients in an advanced stage of the disease have a higher prevalence of abnormal levels of triglycerides, HDL cholesterol and blood glucose than those at a less advanced stage. These findings of the HERMES study suggest, therefore, that HIV infection per se is associated to MS.


Is the incidence of motor neuron disease higher in French military personnel?
Objective: Previous studies, mostly from the United States, showed an increased risk of motor neuron disease (MND) in military personnel. We compared MND incidence rates in French military personnel to that in the general population. Methods: Among persons covered between 2010 and 2016 by the Caisse Nationale Militaire de Sécurité Sociale (CNMSS, military personnel) and the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés (CNAMTS, general population) aged ≥50 years, we identified incident MND cases and estimated populations at risk using national health insurance databases. We estimated relative risks (RRs) and 95% confidence intervals (CIs) separately for men and women using age-adjusted Poisson regression. Analyses were also stratified by 10-year age groups. We used the E-value approach and probabilistic bias analysis to assess robustness of the results regarding unmeasured confounding by smoking. Results: On average, 25 cases/year were newly diagnosed with MND among military personnel aged ≥50 years. The incidence rate was higher for male military personnel compared to the general population (RR = 1.16; 95% CI = 1.05-1.29) but was similar for women (RR = 1.02; 95% CI = 0.79-1.31). Although there were no significant interactions with age and sex, the association was mainly explained by men aged 70-79 years. The prevalence of ever-smoking should be at least 1.1-fold higher in male CNMSS compared to male CNAMTS members to make the association in male military personnel not significant. Conclusion: MND incidence was 16% higher in French male military personnel, in agreement with studies from other countries. Smoking may contribute to this finding. Further studies are needed to identify exposures that drive this association.


Cancer-disease associations: A visualization and animation through medical big data.
Cancer is the primary disease responsible for death and disability worldwide. Currently, prevention and early detection represents the best hope for cure. Knowing the expected diseases that occur with a particular cancer in advance could lead to physicians being able to better tailor their treatment for cancer. The aim of this study was to build an animated visualization tool called as Cancer Associations Map Animation (CAMA), to chart the association of cancers with other disease over time. The study population was collected from the Taiwan National Health Insurance Database during the period January 2000 to December 2002, 782 million outpatient visits were used to compute the associations of nine major cancers with other diseases. A motion chart was used to quantify and visualize the associations between diseases and cancers. The CAMA motion chart that was built successfully facilitated the observation of cancer-disease associations across ages and genders. The CAMA system can be accessed online at http://18.104.22.168/web/runq16.html. The CAMA animation system is an animated medical data visualization tool which provides a dynamic, time-lapse, animated view of cancer-disease associations across different age groups and gender. Derived from a large, nationwide healthcare dataset, this exploratory data analysis tool can detect cancer comorbidities earlier than is possible by manual inspection. Taking into account the trajectory of cancer-specific comorbidity development may facilitate clinicians and healthcare researchers to more efficiently explore early stage hypotheses, develop new cancer treatment approaches, and identify potential effect modifiers or new risk factors associated with specific cancers.


Autologous growth factors versus autogenous graft for anterior cervical interbody fusion: an in vivo caprine model.
Using an in vivo caprine model, authors in this study compared the efficacy of autologous growth factors (AGFs) with autogenous graft for anterior cervical interbody arthrodesis. Fourteen skeletally mature Nubian goats were used in this study and followed up for a period of 16 weeks postoperatively. Anterior cervical interbody arthrodesis was performed at the C3-4 and C5-6 vertebral levels. Four interbody treatment groups (7 animals in each group) were equally randomized among the 28 arthrodesis sites: Group 1, autograft alone; Group 2, autograft + cervical cage; Group 3, AGFs + cervical cage; and Group 4, autograft + anterior cervical plate. Groups 1 and 4 served as operative controls. Autologous growth factors were obtained preoperatively from venous blood and were ultra-concentrated. Following the 16-week survival period, interbody fusion success was evaluated based on radiographic, biomechanical, and histological analyses. All goats survived surgery without incidence of vascular or infectious complications. Radiographic analysis by 3 independent observers indicated fusion rates ranging from 9 (43%) of 21 in the autograft-alone and autograft + cage groups to 12 (57%) of 21 in the autograft + anterior plate group. The sample size was not large enough to detect any statistical significance in these observed differences. Biomechanical testing revealed statistical differences (p < 0.05) between all treatments and the nonoperative controls under axial rotation and flexion and extension loading. Although the AGF + cage and autograft-alone treatments appeared to be statistically different from the intact spine during lateral bending, larger variances and smaller relative differences precluded a determination of statistical significance. Histomorphometric analysis of bone formation within the predefined fusion zone indicated quantities of bone within the interbody cage ranging from 21.3 +/- 14.7% for the AGF + cage group to 34.5 +/- 9.9% for the autograft-alone group. The results indicated no differences in biomechanical findings among the treatment groups and comparable levels of trabecular bone formation within the fusion site between specimens treated with autogenous bone and those filled with the ultra-concentrated AGF extract. In addition, interbody cage treatments appeared to maintain disc space height better than autograft-alone treatments.


Effects of Tactical Periodization on Workload, Physical Fitness, and Well-Being in Professional Rugby Union Players During a Preseason Period.
Hu, X, Boisbluche, S, Philippe, K, Maurelli, O, Li, S, Xu, B, and Prioux, J. Effects of tactical periodization on workload, physical fitness, and well-being in professional rugby union players during a preseason period. J Strength Cond Res 38(1): 105-115, 2024-Tactical periodization (TP) emerged approximately 30 years ago and has recently gained considerable attention in rugby union (RU). It aims to develop specific physical fitness components with 3 acquisition days (strength, endurance, and speed). However, no study has investigated the effects of TP on workload, physical fitness, and well-being across an RU preseason. This study aimed to determine how RU players' workload response to TP focusing on positional differences, observe the influence of a TP preseason training program on aerobic fitness and neuromuscular performance between positions, and analyze the variation of well-being reported by forwards and backs from the 3 acquisition days. Thirty-two male players completed a 6-week TP protocol. External and internal workload variables were recorded through global positioning systems and session rating of perceived exertion (s-RPE) separately. Fitness assessments included Bronco and countermovement jump (CMJ) tests. The sum of well-being indices was measured using the Hooper index. Kruskal-Wallis H tests revealed that the highest values of PlayerLoad slow, PlayerLoad slow percentage, and s-RPE were found on endurance day and the lowest on speed day. Mann-Whitney U tests showed that 15 external workload parameters were higher in backs than forwards for each acquisition day. Small improvements were observed on the Bronco test. No differences were observed in CMJ performance during the preseason period and well-being values between acquisition days. This study provides unique insights into external and internal workload variables during each acquisition day. Furthermore, it highlights TP as an efficient theoretical concept to use in an RU context.


Government capacities and stakeholders: what facilitates ehealth legislation?
Newly established high-technology areas such as eHealth require regulations regarding the interoperability of health information infrastructures and data protection. It is argued that government capacities as well as the extent to which public and private organizations participate in policy-making determine the level of eHealth legislation. Both explanatory factors are influenced by international organizations that provide knowledge transfer and encourage private actor participation. Data analysis is based on the Global Observatory for eHealth-ATLAS eHealth country profiles which summarizes eHealth policies in 114 countries. Data analysis was carried out using two-component hurdle models with a truncated Poisson model for positive counts and a hurdle component model with a binomial distribution for zero or greater counts. The analysis reveals that the participation of private organizations such as donors has negative effects on the level of eHealth legislation. The impact of public-private partnerships (PPPs) depends on the degree of government capacities already available and on democratic regimes. Democracies are more responsive to these new regulatory demands than autocracies. Democracies find it easier to transfer knowledge out of PPPs than autocracies. Government capacities increase the knowledge transfer effect of PPPs, thus leading to more eHealth legislation. All international regimes--the WHO, the EU, and the OECD--promote PPPs in order to ensure the construction of a national eHealth infrastructure. This paper shows that the development of government capacities in the eHealth domain has to be given a higher priority than the establishment of PPPs, since the existence of some (initial) capacities is the sine qua non of further capacity building.


Stem Cells: Innovative Therapeutic Options for Neurodegenerative Diseases?
Neurodegenerative diseases are characterized by the progressive loss of structure and/or function of both neurons and glial cells, leading to different degrees of pathology and loss of cognition. The hypothesis of circuit reconstruction in the damaged brain via direct cell replacement has been pursued extensively so far. In this context, stem cells represent a useful option since they provide tissue restoration through the substitution of damaged neuronal cells with exogenous stem cells and create a neuro-protective environment through the release of bioactive molecules for healthy neurons, as well. These peculiar properties of stem cells are opening to potential therapeutic strategies for the treatment of severe neurodegenerative disorders, for which the absence of effective treatment options leads to an increasingly socio-economic burden. Currently, the introduction of new technologies in the field of stem cells and the implementation of alternative cell tissues sources are pointing to exciting frontiers in this area of research. Here, we provide an update of the current knowledge about source and administration routes of stem cells, and review light and shadows of cells replacement therapy for the treatment of the three main neurodegenerative disorders (Amyotrophic lateral sclerosis, Parkinson's, and Alzheimer's disease).


Mucinous cystadenocarcinoma arising from mucinous cystadenoma of the lung: case report and review of the literature.
Mucinous cystadenoma is a benign tumor commonly found in the pancreas, the ovaries or the appendix. Only very few cases of these tumors originating from the lungs have been reported worldwide, with even less cases describing malignant transformation. We present the case of a 58-year-old woman with a history of recurrent pulmonary infections who underwent left upper lobectomy for lung abscess and was initially diagnosed with pulmonary mucinous cystadenoma (PMCA). Upon thorough immunohistochemical workup, especially due to carcinoembryonic antigen (CEA) positivity, intramucinous singlet cells were eventually diagnostic for invasive carcinoma, in this case a mucinous cystadenocarcinoma arising from a PCMA. PMCA is a rare benign tumor whose potential for malignant transformation has not yet been fully understood. Due to the low number of cases further studies are needed to evaluate if there is a benefit of complete oncologic resection, provided the general condition of the patient allows it. A review of the currently available literature serves to better understand the clinical, radiological and histological features of this rare tumor.


Tail and Center Rounding of Probabilistic Expectations in the Health and Retirement Study.
We study rounding of numerical expectations in the Health and Retirement Study (HRS) between 2002 and 2014. We document that respondent-specific rounding patterns across questions in individual waves are quite stable across waves. We discover a tendency by about half of the respondents to provide more refined responses in the tails of the 0-100 scale than the center. In contrast, only about five percent of the respondents give more refined responses in the center than the tails. We find that respondents tend to report the values 25 and 75 more frequently than other values ending in 5. We also find that rounding practices vary somewhat across question domains and respondent characteristics. We propose an inferential approach that assumes stability of response tendencies across questions and waves to infer person-specific rounding in each question domain and scale segment and that replaces each point-response with an interval representing the range of possible values of the true latent belief. Using expectations from the 2016 wave of the HRS, we validate our approach. To demonstrate the consequences of rounding on inference, we compare best-predictor estimates from face-value expectations with those implied by our intervals.


Serpin Signatures in Prion and Alzheimer's Diseases.
Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the serpin-protease equilibrium can lead to severe consequences. SERPINA3 dysregulation has been associated with Alzheimer's disease (AD) and prion diseases. In this study, we investigated the differential expression of serpin superfamily members in neurodegenerative diseases. SERPIN expression was analyzed in human frontal cortex samples from cases of sporadic Creutzfeldt-Jakob disease (sCJD), patients at early stages of AD-related pathology, and age-matched controls not affected by neurodegenerative disorders. In addition, we studied whether Serpin expression was dysregulated in two animal models of prion disease and AD.Our analysis revealed that, besides the already observed upregulation of SERPINA3 in patients with prion disease and AD, SERPINB1, SERPINB6, SERPING1, SERPINH1, and SERPINI1 were dysregulated in sCJD individuals compared to controls, while only SERPINB1 was upregulated in AD patients. Furthermore, we analyzed whether other serpin members were differentially expressed in prion-infected mice compared to controls and, together with SerpinA3n, SerpinF2 increased levels were observed. Interestingly, SerpinA3n transcript and protein were upregulated in a mouse model of AD. The SERPINA3/SerpinA3nincreased anti-protease activity found in post-mortem brain tissue of AD and prion disease samples suggest its involvement in the neurodegenerative processes. A SERPINA3/SerpinA3n role in neurodegenerative disease-related protein aggregation was further corroborated by in vitro SerpinA3n-dependent prion accumulation changes. Our results indicate SERPINA3/SerpinA3n is a potential therapeutic target for the treatment of prion and prion-like neurodegenerative diseases.


Mass spectrometry of intracellular and membrane proteins using cleavable detergents.
Detergents have been used to enhance the solubility of hydrophobic biomolecules for decades. Despite the widespread use of detergents in biochemistry, the presence of these molecules often complicates further analysis by mass spectrometry. This study presents a solution to this problem by outlining a method utilizing a novel cleavable detergent, 3-[3-(1,1-bisalkyloxyethyl)pyridin-1-yl]propane-1-sulfonate (PPS). This detergent can be used to extract protein contained within the interior of the cell by disrupting cell membranes. Once the proteins are free from the cell, PPS also assists in protein solubilization by shielding the hydrophobic regions of the newly extracted protein from unfavorable interactions with water. The added advantage of PPS over conventional detergents such as sodium dodecyl sulfate or n-octylglucoside is that the detergent properties that interfere with MALDI mass spectrometry can be eliminated prior to analysis. PPS was found to improve sensitivity in MALDI analyses of both soluble proteins and membrane proteins without degrading spectral quality. The virtues of this strategy were applied to whole cell extracts. Analysis of these extracts resulted in an overall increase in both the number of peaks observed and overall signal intensity.


Prevalence and incidence of enuresis before puberty.
A mixed study of the prevalence and incidence of enuresis addressed to the schools of the province of Sassari was planned over a 2-year period. School children aged between 3 and 11 years were considered. 734 children aged 3, 6, and 9, of 3 schools representative of the urban, suburban and rural areas of Sassari were selected by "cluster" sampling. In this first stage of the project a study of prevalence in children aged 3, 6, and 9 years was carried out. The second stage encompasses a 1-year longitudinal study of the cohort selected in the first stage and provides incidence data pertinent to children aged 4, 7 and 10 years. Cross sectional study: In the 73 children aged 3 years who attended nursery schools, 7 cases of enuresis (9.6%) were identified. In the 306 6-year old children of the first year of primary school, 22 cases of enuresis (7.2%) were observed. In the 355 9-year-old students of the fourth year of primary school, 10 cases (2.8%) were reported. Follow up: No case of enuresis was observed among children of the nursery school (aged 4 years); 2 new cases (0.7%) were identified in the 7 year-old group and only 1 new case (0.57%) was encountered in the group of children aged 10. Prevalence of enuresis reached 5.3% in the overall sample and showed a progressive decrease from the younger to the older age group.


Traumatic spinal cord injury in Uganda: a prevention strategy and mechanism to improve home care.
In low- and middle-income countries (LMICs), the burden of traumatic spinal cord injury (TSCI) is largely unknown. The estimated incidence of TSCI in LMICs is 25.5/million/year, and the impact on affected patients and their families is presumed to be immense due to the social structure, limited health system resources and reliance on family to care for those that survive injury to return home. In sub-Saharan Africa, extrapolated regional figures for incidence range from 21 - 29/million/year, and the occurrence of a spinal injury is likely to be fatal within a year.


Physical activity and colon cancer prevention: a meta-analysis.
Although an inverse association between physical activity and risk of colon cancer is well established, a formal estimate of the magnitude of this risk reduction that includes recent studies is not available. This analysis examines the association by sex and study design, restricting analyses to studies where data for colon cancer alone were available. The authors reviewed published studies through June 2008 examining the association between physical activity and risk of colon cancer. Heterogeneity and publication bias were evaluated and random effects models used to estimate relative risks (RR). Differences by sex and study design were evaluated. A total of 52 studies were included. An inverse association between physical activity and colon cancer was found with an overall relative risk (RR) of 0.76 (95% confidence interval (CI): 0.72, 0.81). For men, the RR was 0.76 (95% CI: 0.71, 0.82); for women, this was little different, (RR=0.79, 95% CI: 0.71, 0.88). The findings from case-control studies were stronger (RR=0.69, 95% CI: 0.65, 0.74) than for cohort studies (RR=0.83, 95% CI: 0.78, 0.88). This study confirms previous studies reporting an inverse association between physical activity and colon cancer in both men and women, and provides quantitative estimates of the inverse association.


Evaluation of the role of 8-iso-PGF levels at multiple sites during intracranial hemorrhage in pediatric patients.
The present study was planned to explore the role of 8-isomeric-prostaglandinF2α (8-iso-PGF2α) levels at the multiple sites of cerebrospinal fluid in children with intracranial hemorrhage. 90 children with intracranial hemorrhage were admitted to Surgery Intensive Care Unit (SICU) of our hospital from January to December 2013 and were selected as study subjects. They were divided into group A (n=30), group B (n=30) and group C (n=30). The group A was given conventional treatment, the group B was treated with minimally invasive puncture and the group C was treated with cerebrospinal fluid decompression. After 1 d, 2 d, 3 d, and 7 d of hospitalization, enzyme-linked immunosorbent assay (ELISA) was used to detect the 8-iso-PGF2α levels in peripheral blood of children in all groups. On the day of admission and 10 d after treatment, 3 groups of children were implemented with brain nuclear magnetic resonance spectroscopy for metabolite analyses. On the day of admission there were no significant differences in the 8-iso-PGF2α levels among group A, B and C. Further, after 1 d, 3 d, 7 d of hospital stay, the 8-iso-PGF2α levels in peripheral blood showed a gradual downward trend, and decline range of the group C was greater than that of group A and B (p < 0.05). After 10 days of treatment, there were significant differences in the bilateral temporal lobe and hippocampal NAA/Creatinine (Cr), Cho/Cr, mI/Cr and NAA/mI among group A, B, and C. The survival rate of group C was higher than that of group A and B (p < 0.05). On the other hand, the prevalence of sequelae was significantly lower than that of group A and B (p < 0.05). The amount of blood loss in children with intracranial hemorrhage was positively correlated with the levels of 8-iso-PGF2α in peripheral blood (r = 0.546, p < 0.05) as observed by Spearman correlation analysis. 8-iso-PGF2α plays an important role in the pathogenesis of intracranial hemorrhage, and could be utilized as a biomarker of oxidative stress in children with intracranial hemorrhage. Further, cerebrospinal fluid decompression is a better method of treatment for intracranial hemorrhage.


Abbreviated MRI and Accelerated MRI for Screening and Diagnosis of Breast Cancer.
Although published studies have revealed that magnetic resonance imaging (MRI) is by far the most effective imaging modality for cancer detection, it is currently considered cost-ineffective for screening women at an intermediate risk for breast cancer. The concept of an "abbreviated MRI" protocol has recently emerged as a possible solution for reducing the cost of MRI. The abbreviated MRI is a shortened version of the standard MRI, consisting of a single early phase dynamic contrast enhanced (DCE) series. Several clinical studies have shown that this MRI protocol would not affect sensitivity or specificity for breast MRI screening purposes. In clinical practice, morphologic evaluation and kinetic assessment are 2 major components of the interpretation process. However, kinetic assessment cannot be performed with the abbreviated protocol, because multiple sets of post-contrast images are necessary for the generation of kinetic curves. "Accelerated MRI" is a collective term for imaging techniques that acquire DCE-MR images in a very short time. Published studies suggest that the kinetic assessment during the very early post-contrast phase obtained with the accelerated MRI techniques is comparable to that with the standard MRI techniques. Applying accelerated MR techniques could potentially enhance the abbreviated MRI protocol in terms of diagnostic potential, while maintaining the shorter study time. Thus, the abbreviated MRI protocol associated with accelerated MRI techniques may provide value for screening and for diagnostic purposes.


Population genetics of the potentially invasive African fruit fly species, Ceratitis rosa and Ceratitis fasciventris (Diptera: Tephritidae).
A set of 10 microsatellite markers was used to survey the levels of genetic variability and to analyse the genetic aspects of the population dynamics of two potentially invasive pest fruit fly species, Ceratitis rosa and C. fasciventris, in Africa. The loci were derived from the closely related species, C. capitata. The degree of microsatellite polymorphism in C. rosa and C. fasciventris was extensive and comparable to that of C. capitata. In C. rosa, the evolution of microsatellite polymorphism in its distribution area reflects the colonization history of this species. The mainland populations are more polymorphic than the island populations. Low levels of differentiation were found within the Africa mainland area, while greater levels of differentiation affect the islands. Ceratitis fasciventris is a central-east African species. The microsatellite data over the Uganda/Kenya spatial scale suggest a recent expansion and possibly continuing gene flow within this area. The microsatellite variability data from C. rosa and C. fasciventris, together with those of C. capitata, support the hypothesis of an east African origin of the Ceratitis spp.


Preliminary characterization of an organism isolated from a case of Viluy encephalomyelitis indicates a protozoal, rather than viral, aetiology.
A microbial agent was isolated previously from a case of Viluy encephalomyelitis and named the 'KPN agent' after the initials of the patient. Here a detailed characterization of nucleic acids extracted from the purified KPN agent is presented. The agent contains both DNA and RNA, and has its own tRNAs and some other low-Mr RNAs, including 5S RNA. These findings, and the isolation of eukaryotic-type ribosomes, suggest that the KPN agent is not a virus, as believed before, but a more complex micro-organism, with protein-synthesizing capacity. The nucleotide sequence of the 5S RNA in the ribosomes of the KPN agent is identical with the sequence of 5S RNA of Acanthamoeba castellanii. The novel protozoan nature of the KPN agent is discussed in relation to other unusual properties of this micro-organism. Some implications of these results for the aetiology of Viluy encephalomyelitis are also discussed.


Antifungal and antiaflatoxigenic activities of coumarinyl thiosemicarbazides against Aspergillus flavus NRRL 3251.
The antifungal and antiaflatoxigenic effects of two series of coumarinyl thiosemicarbazides on Aspergillus flavus NRRL 3251 were studied. Fungi were grown in YES medium for 72 h at 29 °C in the presence of 0, 0.1, 1, and 10 μg mL-1 of coumarinyl thiosemicarbazides: one series with substitution in position 7 and another with substitution in position 4 of the coumarin core. Dry mycelia weight determination was used for antifungal activity estimation, while the aflatoxin B1 content in YES media, determined by the dilute and shoot LC-MS/MS technique, was used for the antiaflatoxigenic effect estimation. Standard biochemical assays were used for oxidative status marker (TBARS, SOD, CAT, and GPX) determination in A. flavus NRRL 3251 mycelia. Results show that 7-substituted-coumarinyl thiosemicarbazides possess a better antifungal and antiaflatoxigenic activity than 4-substituted ones. The most prominent substituted compound was the compound 3, N-(4-chlorophenyl)-2-(2-((4-methyl-2-oxo-2H-chromen-7-yl)oxy)acetyl)hydrazine-1-carbothioamide, which completely inhibited aflatoxin production at the concentration of 10 μg mL-1. Oxidative stress response of A. flavus exposed to the selected compounds points to the modulation of oxidative stress as a possible reason of aflatoxin production inhibition.


Differential permeability of the blood-testis barrier during reinitiation of spermatogenesis in adult male rats.
The blood-testis barrier (BTB) sequesters meiotic spermatocytes and differentiating spermatids away from the vascular environment. We aimed to assess whether meiosis and postmeiotic differentiation could occur when the BTB is permeable. Using a model of meiotic suppression and reinitiation, BTB function was assessed using permeability tracers of small, medium, and large (0.6-, 70-, and 150-kDa) sizes to emulate blood- and lymphatic-borne factors that could cross the BTB. Adult rats (n = 9/group) received the GnRH antagonist acyline (10 wk) to suppress gonadotropins, followed by testosterone (24cm Silastic implant), for 2, 4, 7, 10, 15, and 35 days. In acyline-suppressed testes, all tracers permeated the seminiferous epithelium. As spermatocytes up to diplotene stage XIII reappeared, both the 0.6- and 70-kDa tracers, but not 150 kDa, permeated around these cells. Intriguingly, the 0.6- and 70-kDa tracers were excluded from pachytene spermatocytes at stages VII and VIII but not in subsequent stages. The BTB became progressively impermeable to the 0.6- and 70-kDa tracers as stages IV-VII round spermatids reappeared in the epithelium. This coincided with the appearance of the tight junction protein, claudin-12, in Sertoli cells and at the BTB. We conclude that meiosis can occur when the BTB is permeable to factors up to 70 kDa during the reinitiation of spermatogenesis. Moreover, BTB closure corresponds with the presence of particular pachytene spermatocytes and round spermatids. This research has implications for understanding the effects of BTB dynamics in normal spermatogenesis and also potentially in states where spermatogenesis is suppressed, such as male hormonal contraception or infertility.


Glycosylation of GIRK1 at Asn119 and ROMK1 at Asn117 has different consequences in potassium channel function.
GIRK (G protein-gated inward rectifier K(+) channel) proteins play critical functional roles in heart and brain physiology. Using antibodies directed to either GIRK1 or GIRK4, site-directed mutagenesis, and specific glycosidases, we have investigated the effects of glycosylation in the biosynthesis and heteromerization of these proteins expressed in oocytes. Both GIRK1 and GIRK4 have one extracellular consensus N-glycosylation site. Using chimeras between GIRK1 and GIRK4 as well as a GIRK1 N-glycosylation mutant, we report that GIRK1 was glycosylated at Asn(119), whereas GIRK4 was not glycosylated at Asn(132). GIRK1 membrane-spanning domain 1 was required for optimal glycosylation at Asn(119) because a chimera that contained GIRK4 membrane-spanning domain 1 significantly reduced the addition of a carbohydrate structure at this site. This finding may partly account for the reason that GIRK4 is not glycosylated at Asn(132), either as a homomer or when coexpressed with GIRK1. When the GIRK1(N119Q) mutant was coexpressed with GIRK4, the biophysical properties of the heteromeric channel and the magnitude of the agonist-induced currents were similar to those of controls. Thus, N-glycosylation of GIRK1 at Asn(119) does not appear to affect its physical association with GIRK4, the routing of the heteromer to the cell surface, or heteromeric channel function, unlike the dramatic functional effects of N-glycosylation of ROMK1 at Asn(117) (Schwalbe, R. A., Wang, Z., Wible, B. A., and Brown, A. M. (1995) J. Biol. Chem. 270, 15336-15340).


Isotropy of Angular Frequencies and Weak Chimeras with Broken Symmetry.
The notion of a weak chimeras provides a tractable definition for chimera states in networks of finitely many phase oscillators. Here, we generalize the definition of a weak chimera to a more general class of equivariant dynamical systems by characterizing solutions in terms of the isotropy of their angular frequency vector-for coupled phase oscillators the angular frequency vector is given by the average of the vector field along a trajectory. Symmetries of solutions automatically imply angular frequency synchronization. We show that the presence of such symmetries is not necessary by giving a result for the existence of weak chimeras without instantaneous or setwise symmetries for coupled phase oscillators. Moreover, we construct a coupling function that gives rise to chaotic weak chimeras without symmetry in weakly coupled populations of phase oscillators with generalized coupling.


Comparison of reproductive development in triploid and diploid female rainbow trout Oncorhynchus mykiss.
The diploid rainbow trout Oncorhynchus mykiss reached sexual maturity 3 years after hatching and its oogenesis underwent four stages, which were oogonia, primary oocyte, secondary oocyte and egg. Reproductive development and hormone changes of 4 to 35 month-old female O. mykiss were investigated using histological and radioimmunoassay methods in order to provide a theoretical and practical basis for the use of triploid female O. mykiss. The oogonium of the triploid female could develop into the oocytes of the prophase with abortion occurring later; the oogonium was surrounded by stroma cells to form the oogonium cluster and the gonads showed a virilescent tendency when the oogonium clusters were gradually replaced by spermatogenic-like cytocysts. After 13 months, amounts of gonadotropic hormone (GtH-I, GtH-II) and oestradiol (17beta-E(2)) in triploid females were lower than in diploid fish at corresponding time periods, but the amounts of testosterone (T) increased consistently after 21 months and were more than in diploid fish in the corresponding time periods (P > 0.05). The infertility of triploid females resulted from meiosis failure, which caused developmental abortion of oocytes and oogonium formed cytocysts before the prophase oocytes. The cytocyst formation was due to the lack of the normal interaction of ovum and follicular cells, the development of follicular cells producing steroids were inhibited, the arylate path from T to 17beta-E(2) was interrupted, concentration of 17beta-E(2) decreased and concentration of T increased in the blood, the content of vitellogenin (Vg) decreased in the liver with a low 17beta-E(2) and high T caused to ovaries to show a tendency to be virilescent.


A reference air kerma rate calibration protocol for a 370 GBq 192Ir high dose rate brachytherapy source.
A suggested protocol for the in-air calibration of 192Ir High Dose Rate (HDR) Brachytherapy sources is presented. The protocol was constructed using Nucletron-Oldelft HDR brachytherapy equipment and should be transportable to any High Dose Rate Brachytherapy Afterloader system.


The enigma of cobalamin (Vitamin B12) biosynthesis in Porphyromonas gingivalis. Identification and characterization of a functional corrin pathway.
The ability of Porphyromonas gingivalis to biosynthesize tetrapyrroles de novo has been investigated. Extracts of the bacterium do not possess activity for 5- aminolevulinic-acid dehydratase or porphobilinogen deaminase, two key enzymes involved in the synthesis of uroporphyrinogen III. Similarly, it was not possible to detect any genetic evidence for these early enzymes with the use of degenerate polymerase chain reaction. However, the bacterium does appear to harbor some of the enzymes for cobalamin biosynthesis since cobyric acid, a pathway intermediate, was converted into cobinamide. Furthermore, degenerate polymerase chain reaction with primers to cbiP, which encodes cobyric-acid synthase, produced a fragment with a high degree of identity to Salmonella typhimurium cbiP. Indeed, the recently released genome sequence data confirmed the presence of cbiP together with 14 other genes of the cobalamin pathway. A number of these genes were cloned and functionally characterized. Although P. gingivalis harbors all the genes necessary to convert precorrin-2 into cobalamin, it is missing the genes for the synthesis of precorrin-2. Either the organism has a novel pathway for the synthesis of precorrin-2, or more likely, it has lost this early part of the pathway. The remainder of the pathway may be being maintained to act as a salvage route for corrin synthesis.


Quantification of renal function following stereotactic body radiotherapy for pancreatic cancer: secondary dosimetric analysis of a prospective clinical trial.
This is the first known study examining renal function following stereotactic body radiotherapy (SBRT) for pancreatic head adenocarcinoma. Thirty-eight borderline-resectable/unresectable patients, part of an ongoing prospective trial, underwent 3 cycles of gemcitabine/5-fluorouracil followed by SBRT (5 daily fractions of 5/6/7/8 Gy) and concurrent nelfinavir. Thereafter, in resectable cases, surgery was performed within 4-8 weeks. The last available pre-SBRT creatinine was recorded, along with the highest post-SBRT value. Glomerular filtration rate (GFR) was calculated by the commonly-utilized Modification of Diet in Renal Disease formula. GFR decline was defined as the post-SBRT nadir GFR minus the pre-SBRT GFR. Correlations with the V5-V30, and mean/maximum kidney doses was performed. Statistics included Pearson correlation, Mann-Whitney, and Fisher's exact tests. The median total kidney volume was 355 cm3. Median dosimetric values were as follows: V5 (209 cm3), V10 (103 cm3), V15 (9 cm3), V20 (0 cm3), V25 (0 cm3); and mean (6.7 Gy) & maximum kidney dose (18.3 Gy). Median GFR change was -23 (range, -105 to 25) mL/min/1.73 cm2. Of all dosimetric parameters, only V5 was significantly associated with changes in GFR (Pearson r = -0.40, p = 0.012). In patients with V5 < 210 cm3, median GFR change was -11.8 mL/min/1.73 cm2, as compared with -37.1 mL/min/1.73 cm2 change in those with V5 ≥ 210 cm3 (p = 0.02). A GFR change < -23 mL/min/1.73 cm2 was observed in 6/20 (30%) patients with V5 < 210 cm3, versus 15/18 (83%) of those with V5 ≥ 210 cm3. Patients with V5 ≥ 210 cm3 were over ten times as likely to have GFR change < -23 mL/min/1.73 cm2 (p = 0.003). Using linear regression, GFR change ≈ -0.1748 × V5(cm3) + 8.63. In the first known analysis of renal function after pancreatic SBRT, evaluating patients on a prospective study, V5 ≥ 210 cm3 was associated with a post-SBRT GFR decline of >23 mL/min/1.73 cm2. If V5 is kept <210 cm3, median GFR decline was only 11.8 mL/min/1.73 cm2. Further validation is needed to ascertain definite dose-volume parameters and examine late renal decline.


ACTION OF ERYTHROMYCIN ON "PROTOPLASTS" IN VIVO.
Bacteria may persist in "protoplast" form in kidneys after treatment of experimental enterococcal pyelonephritis with penicillin. Erythromycin, while ineffective against the bacterial form of infection, was able to kill "protoplasts" in vivo. This finding is consistent with the hypothesis that intact cell wall interferes with the ingress of erythromycin into the cellular area in which it acts.


Interaction between Streptococcus pneumoniae and Staphylococcus aureus Generates ·OH Radicals That Rapidly Kill Staphylococcus aureus Strains.
Streptococcus pneumoniae rapidly kills Staphylococcus aureus by producing membrane-permeable hydrogen peroxide (H2O2). The mechanism by which S. pneumoniae-produced H2O2 mediates S. aureus killing was investigated. An in vitro model that mimicked S. pneumoniae-S. aureus contact during colonization of the nasopharynx demonstrated that S. aureus killing required outcompeting densities of S. pneumoniae Compared to the wild-type strain, isogenic S. pneumoniae ΔlctO and S. pneumoniae ΔspxB, both deficient in production of H2O2, required increased density to kill S. aureus While residual H2O2 activity produced by single mutants was sufficient to eradicate S. aureus, an S. pneumoniae ΔspxB ΔlctO double mutant was unable to kill S. aureus A collection of 20 diverse methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains showed linear sensitivity (R2 = 0.95) for S. pneumoniae killing, but the same strains had different susceptibilities when challenged with pure H2O2 (5 mM). There was no association between the S. aureus clonal complex and sensitivity to either S. pneumoniae or H2O2 To kill S. aureus, S. pneumoniae produced ∼180 μM H2O2 within 4 h of incubation, while the killing-defective S. pneumoniae ΔspxB and S. pneumoniae ΔspxB ΔlctO mutants produced undetectable levels. Remarkably, a sublethal dose (1 mM) of pure H2O2 incubated with S. pneumoniae ΔspxB eradicated diverse S. aureus strains, suggesting that S. pneumoniae bacteria may facilitate conversion of H2O2 to a hydroxyl radical (·OH). Accordingly, S. aureus killing was completely blocked by incubation with scavengers of ·OH radicals, dimethyl sulfoxide (Me2SO), thiourea, or sodium salicylate. The ·OH was detected in S. pneumoniae cells by spin trapping and electron paramagnetic resonance. Therefore, S. pneumoniae produces H2O2, which is rapidly converted to a more potent oxidant, hydroxyl radicals, to rapidly intoxicate S. aureus strains.IMPORTANCEStreptococcus pneumoniae strains produce hydrogen peroxide (H2O2) to kill bacteria in the upper airways, including pathogenic Staphylococcus aureus strains. The targets of S. pneumoniae-produced H2O2 have not been discovered, in part because of a lack of knowledge about the underlying molecular mechanism. We demonstrated that an increased density of S. pneumoniae kills S. aureus by means of H2O2 produced by two enzymes, SpxB and LctO. We discovered that SpxB/LctO-produced H2O2 is converted into a hydroxyl radical (·OH) that rapidly intoxicates and kills S. aureus We successfully inhibited the toxicity of ·OH with three different scavengers and detected ·OH in the supernatant. The target(s) of the hydroxyl radicals represents a new alternative for the development of antimicrobials against S. aureus infections.


Multivariate QST-FST comparisons: a neutrality test for the evolution of the g matrix in structured populations.
Neutrality tests in quantitative genetics provide a statistical framework for the detection of selection on polygenic traits in wild populations. However, the existing method based on comparisons of divergence at neutral markers and quantitative traits (Q(st)-F(st)) suffers from several limitations that hinder a clear interpretation of the results with typical empirical designs. In this article, we propose a multivariate extension of this neutrality test based on empirical estimates of the among-populations (D) and within-populations (G) covariance matrices by MANOVA. A simple pattern is expected under neutrality: D = 2F(st)/(1 - F(st))G, so that neutrality implies both proportionality of the two matrices and a specific value of the proportionality coefficient. This pattern is tested using Flury's framework for matrix comparison [common principal-component (CPC) analysis], a well-known tool in G matrix evolution studies. We show the importance of using a Bartlett adjustment of the test for the small sample sizes typically found in empirical studies. We propose a dual test: (i) that the proportionality coefficient is not different from its neutral expectation [2F(st)/(1 - F(st))] and (ii) that the MANOVA estimates of mean square matrices between and among populations are proportional. These two tests combined provide a more stringent test for neutrality than the classic Q(st)-F(st) comparison and avoid several statistical problems. Extensive simulations of realistic empirical designs suggest that these tests correctly detect the expected pattern under neutrality and have enough power to efficiently detect mild to strong selection (homogeneous, heterogeneous, or mixed) when it is occurring on a set of traits. This method also provides a rigorous and quantitative framework for disentangling the effects of different selection regimes and of drift on the evolution of the G matrix. We discuss practical requirements for the proper application of our test in empirical studies and potential extensions.


Autosomal dominant vitreoretinochoroidopathy.
Autosomal dominant vitreoretinochoroidopathy is a newly described fundus dystrophy characterized by abnormal chorioretinal hypopigmentation and hyperpigmentation, usually lying between the vortex veins and the ora serrata for 360 degrees. In this zone, there are a discrete posterior boundary, preretinal punctate white opacities, retinal arteriolar narrowing and occlusion, and, in some cases, choroidal atrophy. Most affected family members have diffuse retinal vascular incompetence, cystoid macular edema, and presenile cataracts. The vitreous is characterized by fibrillar condensation and a moderate number of cells. Electroretinograms are normal in younger affected individuals and are only moderately abnormal in older ones. Preretinal neovascularization, present in the posterior pole, is progressive in the proband. There are no identifiable systemic or skeletal abnormalities, high myopia, optically empty vitreous, lattice degeneration, areas of white-without-pressure, retinal breaks, or retinal detachment; thus, previously described vitreoretinopathies can be excluded from diagnostic consideration. Progression of this diagnostic seems to be extremely slow in most family members.


Visual Network Asymmetry and Default Mode Network Function in ADHD: An fMRI Study.
A growing body of research has identified abnormal visual information processing in attention-deficit hyperactivity disorder (ADHD). In particular, slow processing speed and increased reliance on visuo-perceptual strategies have become evident. The current study used recently developed fMRI methods to replicate and further examine abnormal rightward biased visual information processing in ADHD and to further characterize the nature of this effect; we tested its association with several large-scale distributed network systems. We examined fMRI BOLD response during letter and location judgment tasks, and directly assessed visual network asymmetry and its association with large-scale networks using both a voxelwise and an averaged signal approach. Initial within-group analyses revealed a pattern of left-lateralized visual cortical activity in controls but right-lateralized visual cortical activity in ADHD children. Direct analyses of visual network asymmetry confirmed atypical rightward bias in ADHD children compared to controls. This ADHD characteristic was atypically associated with reduced activation across several extra-visual networks, including the default mode network (DMN). We also found atypical associations between DMN activation and ADHD subjects' inattentive symptoms and task performance. The current study demonstrated rightward VNA in ADHD during a simple letter discrimination task. This result adds an important novel consideration to the growing literature identifying abnormal visual processing in ADHD. We postulate that this characteristic reflects greater perceptual engagement of task-extraneous content, and that it may be a basic feature of less efficient top-down task-directed control over visual processing. We additionally argue that abnormal DMN function may contribute to this characteristic.


Biosynthesis of subunits of the soybean 7S storage protein.
Biosynthesis of the alpha', alpha, and beta subunits of the soybean 7S storage protein (conglycinin) was studied by in vivo and in vitro experiments. One hour in vivo labeling produced polypeptides of 72 kilodaltons (kD) and 78 kD which, in a subsequent 1-h chase period, gave rise to a heterodisperse band of polypeptides of 76-83 kD, the apparent molecular weights of mature alpha and alpha', respectively. After a 3-h chase period only mature alpha and alpha' were labeled. The pre-alpha' (80 kD) and pre-alpha (78 kD) polypeptides produced by in vitro translation of total seed poly(A)+ RNA did not coelectrophorese with polypeptides labeled in vivo. The mature beta-subunit (53 kD), produced in vivo during the 1-h chase period, apparently was translated as a 50 kD polypeptide in vitro. The data suggest that, in vivo, primary translation products undergo both cotranslational and posttranslational modifications during the formation of mature subunits. cDNA clones complementary to soybean seed poly(A)+ RNA were prepared and subsequently identified by hybrid-release and immunoprecipitation experiments. Clone pGmc 236 (550 base pairs) (bp) was shown to contain sequences complementary to mRNAs for the alpha', alpha, and beta subunits on the basis of hybrid-release experiments, corroborating tryptic fingerprints that demonstrate that these subunits are closely related to each other. Although selected by a single cDNA clone, the mRNAs are not identical because the alpha' mRNA was eluted from the filter-bound cDNAs at a lower temperature than were the alpha beta mRNAs, pGmc 236 hybridized on Northern blots to mRNAs of approximately 2500 nucleotides, sufficient size to code for the alpha' or alpha subunit of the 7S storage protein.


Protein Hydroxylation by Hypoxia-Inducible Factor (HIF) Hydroxylases: Unique or Ubiquitous?
All metazoans that utilize molecular oxygen (O2) for metabolic purposes have the capacity to adapt to hypoxia, the condition that arises when O2 demand exceeds supply. This is mediated through activation of the hypoxia-inducible factor (HIF) pathway. At physiological oxygen levels (normoxia), HIF-prolyl hydroxylases (PHDs) hydroxylate proline residues on HIF-α subunits leading to their destabilization by promoting ubiquitination by the von-Hippel Lindau (VHL) ubiquitin ligase and subsequent proteasomal degradation. HIF-α transactivation is also repressed in an O2-dependent way due to asparaginyl hydroxylation by the factor-inhibiting HIF (FIH). In hypoxia, the O2-dependent hydroxylation of HIF-α subunits by PHDs and FIH is reduced, resulting in HIF-α accumulation, dimerization with HIF-β and migration into the nucleus to induce an adaptive transcriptional response. Although HIFs are the canonical substrates for PHD- and FIH-mediated protein hydroxylation, increasing evidence indicates that these hydroxylases may also have alternative targets. In addition to PHD-conferred alterations in protein stability, there is now evidence that hydroxylation can affect protein activity and protein/protein interactions for alternative substrates. PHDs can be pharmacologically inhibited by a new class of drugs termed prolyl hydroxylase inhibitors which have recently been approved for the treatment of anemia associated with chronic kidney disease. The identification of alternative targets of HIF hydroxylases is important in order to fully elucidate the pharmacology of hydroxylase inhibitors (PHI). Despite significant technical advances, screening, detection and verification of alternative functional targets for PHDs and FIH remain challenging. In this review, we discuss recently proposed non-HIF targets for PHDs and FIH and provide an overview of the techniques used to identify these.


Elevated miR-200a and miR-141 inhibit endocrine gland-derived vascular endothelial growth factor expression and ciliogenesis in preeclampsia.
Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is a critical factor that facilitates trophoblast invasion in placenta. Plasma miR-141 and miR-200a levels were elevated, while EG-VEGF was decreased in peripheral blood and placenta of preeclamptic patients. Furthermore, numbers of cilia in the placenta from preeclamptic women were significantly decreased. Elevated miR-141 and miR-200a inhibited the expression of EG-VEGF, downstream extracellular signal-regulated kinase (ERK)/matrix metalloproteinase 9 signalling and cilia formation, thus leading to defective trophoblast invasion. The growth of the primary cilium, which transduced ERK signalling upon EG-VEGF induction for proper trophoblast invasion, was also inhibited by miR-141 and miR-200a upregulation. Preeclampsia is a severe gestational complication, and inadequate trophoblast invasion during placental development is an important pathoaetiology. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is a critical factor that facilitates trophoblast invasion in placenta. By binding to the primary cilium, EG-VEGF initiates the signalling cascade for proper embryo implantation and placental development. The miR-200 family was predicted to target the EG-VEGF 5'-untranslated region, and its specific binding site was confirmed using a dual luciferase and a co-transfection assay. In the peripheral blood and placenta of preeclamptic patients, EG-VEGF showed significantly lower expression, whereas plasma miR-141 and miR-200a had higher expression compared with the controls. The biological significance of miR-141 and miR-200a was verified using an overexpression method in a trophoblast cell line (HTR-8/SVneo). Elevated miR-141 and miR-200a inhibited the expression of EG-VEGF, matrix metalloproteinase 9 (MMP9) and downstream extracellular signal-regulated kinase (ERK) signalling, thus leading to defective trophoblast invasion. Additionally, the growth of the primary cilium, which transduces ERK/MMP9 signalling upon EG-VEGF induction, was inhibited by miR-141 and miR-200a upregulation. Furthermore, the number of cilia in the human placenta of preeclamptic women was significantly decreased compared to normal placenta. In conclusion, the study uncovers the clinical correlations among the miR-200 family, EG-VEGF and the primary cilium in preeclampsia and the underlying molecular mechanisms. The results indicate that miR-141 and miR-200a directly targeted EG-VEGF, suppressed primary cilia formation and inhibited trophoblast invasion. Thus, miR-141 and miR-200a could be explored as promising miRNA biomarkers and therapeutic targets in preeclampsia.


Gravitational lens optics.
Several instances of multiple imaging of cosmologically distant sources by intervening galaxies and galaxy clusters have been discovered over the past decade. These "gravitational lenses" have distinctive optical properties. Pointlike sources such as quasars generally produce two or four images when lensed, whereas extended sources such as galaxies produce spectacular arcs and rings. The salient features of most of the observations can be reproduced with the use of simple elliptical lens models that approximate the lenses made by ellipsoidal mass distributions such as are common in the universe. In addition to illustrating simple optics in operation on a cosmological scale, multiple images and arcs provide useful probes of the lensing galaxies and clusters. Also, gravitational lenses can make magnified images of cosmologically distant sources and may eventually furnish important cosmographic data such as the Hubble constant.


An epidemiologic study of the relationship between postural asymmetry in the teen years and subsequent back and neck pain.
This epidemiologic study examined the relationship between postural discrepancies in the posterior plane and the subsequent development of back and neck pain. The study population comprised women who were members of the graduating classes of 1957, 1958, and 1959 of an eastern U.S. women's college. Information on postural asymmetry was gathered from two sources: (1) measurements made from posture pictures taken early in the freshman year of college and obtained from each woman in the study, and (2) subjective evaluations made by the physical education department faculty at the time of examination. Information on the development of back and neck disorders and associated risk factors during the subsequent 25 years was obtained by a postal questionnaire. Three parameters of postural asymmetry were examined from the posture picture measurements: elevation of one shoulder, elevation of one hip, and deviation of the spine from the midline of the body. None of these parameters nor the physical education department evaluations was associated with a subsequent report of low-back pain, mid-back pain, or neck pain.