Microanatomical study of pyramidal neurons in the contralesional somatosensory cortex after experimental ischemic stroke.
At present, many studies support the notion that after stroke, remote regions connected to the infarcted area are also affected and may contribute to functional outcome. In the present study, we have analyzed possible microanatomical alterations in pyramidal neurons from the contralesional hemisphere after induced stroke. We performed intracellular injections of Lucifer yellow in pyramidal neurons from layer III in the somatosensory cortex of the contralesional hemisphere in an ischemic stroke mouse model. A detailed 3-dimensional analysis of the neuronal complexity and morphological alterations of dendritic spines was then performed. Our results demonstrate that pyramidal neurons from layer III in the somatosensory cortex of the contralesional hemisphere show selective changes in their dendritic arbors, namely, less dendritic complexity of the apical dendritic arbor-but no changes in the basal dendritic arbor. In addition, we found differences in spine morphology in both apical and basal dendrites comparing the contralesional hemisphere with the lesional hemisphere. Our results show that pyramidal neurons of remote areas connected to the infarct zone exhibit a series of selective changes in neuronal complexity and morphological distribution of dendritic spines, supporting the hypothesis that remote regions connected to the peri-infarcted area are also affected after stroke.


Altered oxyanion selectivity in mutants of UhpT, the Pi-linked sugar phosphate carrier of Escherichia coli.
In Escherichia coli, the UhpT transporter catalyzes the electroneutral accumulation of sugar 6-phosphate by exchange with internal inorganic phosphate (Pi). The substrate specificity of UhpT is regulated at least in part by constituents of an Asp388-Lys391 intrahelical salt bridge, and mutations that remove one but not both of these residues alter UhpT preference for organophosphate substrates. Using site-directed mutagenesis, we examined the role played by these two positions in the selection of the oxyanion countersubstrate. We show that derivatives having aliphatic or polar residues at positions 388 and 391 are gain-of-function mutants capable of transporting SO4 as well as Pi. These oxyanions share similar structures but differ significantly in the presence of a proton(s) on Pi. Our findings therefore lead us to suggest that the Asp388-Lys391 ion pair acts normally as a filter that prevents substrates lacking a proton that can be donated from occupying the UhpT active site.


The Influence of Mental Resilience on the Positive Coping Style of Air Force Soldiers: A Moderation- Mediation Model.
In this study, 697 air force soldiers from China were investigated with the Chinese Resilience Scale, Military Emotional Regulation Scale, Simple Coping Scale, and Social Support Rating Scale. Structural equation modeling revealed the following: (1) resilience had a positive predictive effect on active coping style; (2) the emotion regulation strategy of self-comfort mediated the relationship between resilience and positive coping style; and (3) social support moderated the latter half of the intermediary process, in which resilience influenced the active coping style of soldiers through self-comfort. The influence of resilience on air force soldiers was a mediating effect, in which resilience could not only directly predict the coping style of soldiers but also influence their coping style through self-comfort. Social support enhanced the influence of self-comfort on coping style. The study has great theoretical and empirical value for promoting the mental health of soldiers and using positive coping strategies.


Rigid external fixation and condylar remodeling.
Condylar fractures, instead of other mandibular fractures, play a primary importance role because their high incidence and the historic controversy existent in literature regarding their treatment. Recent studies prove that conservative treatment of condylar fractures, although not determining perfect alignment of the fractured segments, leads to a series of histologic and morphologic healing processes ending with consolidation of the fracture and functional recovery of the TMJ (temporo-mandibular joint). In this study, we observed long-term results of 2 cases of bicondylar fracture treated with surgical reduction and rigid external fixation. Rx orthopantomography control 1 year after surgery showed condylar remodeling bilaterally with good functional recovery. Our school affirms that semirigid fixation system allows optimal function between the articular head and the glenoid fossa, with good tridimensional repositioning of the fractured segments.


Clinical differences between children and adults with pulmonary hypertension and sickle cell disease.
Pulmonary hypertension (PHT) is an important co-morbidity in sickle cell disease (SCD). Despite increasing research in adults, the prevalence and implication of this condition in children is unknown. Charts of 362 SCD patients followed at the Children's Hospital & Research Center Oakland were reviewed to determine clinical variables associated with obtaining echocardiographic screening for PHT, clinical associations of PHT, and associated mortality following diagnosis in adults and children with SCD. In this cohort, patients with underlying lung abnormalities or those on chronic transfusions were more likely to have echocardiograms, however the diagnosis of PHT was often unrecognized. A different clinical phenotype for PHT in adults versus children was identified. Associations with PHT for adults included age, renal and lung disease, hepatitis C, chronic transfusions, and a history of acute chest syndrome (ACS), with ACS being protective. Surprisingly, for children, a history of sepsis, along with a history of ACS, or obstructive lung disease were associated with PHT. Survival analysis found significant mortality for PHT, with a hazard ratio of 17.3 (95% confidence interval 4.9-60.4). The divergent clinical spectrum for PHT between adults and children may point to different age-specific mechanisms or biological expression of PHT.


Prothrombin activation in eastern tiger snake bite.
To perform ex vivo studies in eastern tiger snake envenomation which define the haemostatic events associated with prothrombin activation. Serial studies were performed on plasma from six individuals with evidence of eastern tiger snake envenomation. These analyses were particularly directed to fibrinogen levels, F1 + 2, TAT and evidence of fibrinolysis. There was a substantial rise in F1 + 2 and thrombin-antithrombin (TAT) complexes in all cases, even with minimal evenomation. In some cases the molar ratio of F1 + 2 and TAT was reduced from the relationship normally seen in vitro and ex vivo in clinical thrombosis. There was a dramatic fall in factor V and VIII levels which occurred 4-6 hours before the decline in prothrombin and AT3. This related in time to a fall in alpha2AP and plasminogen. Protein C levels also declined dramatically but many hours after presentation. F1 + 2 and TAT are sensitive markers of tiger snake evenomation. In some patients with massive prothrombin activation, the common mechanism for TAT clearance may be altered or overwhelmed. Conversely, the renal clearance of the smaller F1 + 2 may be enhanced. In the absence of thrombocytopaenia, which is a very sensitive marker of DIC, the fall in labile factors with tiger snake envenomation is significantly contributed to by proteolytic digestion of clotting factors.


A new device for measurement of fibrin clot lysis: application to the euglobulin clot lysis time.
Determination of clot lysis times on whole blood, diluted whole blood, plasma or plasma fraction has been used for many years to assess the overall activity of the fibrinolytic system. We designed a completely computerised semi-automatic 8-channel device for measurement and determination of fibrin clot lysis. The lysis time is evaluated by a mathematical analysis of the lysis curve and the results are expressed in minute (range: 5 to 9999). We have used this new device for Euglobulin Clot Lysis Time (ECLT) determination, which is the most common test used in laboratories to estimate plasma fibrinolytic capacity. The correlation between ECLT and manual method is very tight : R = 0,99; p < 10(-6). The efficiency scores of the method are <4% in intra-assay and <7% in inter-assay. It allows to achieve the tests on hyperlipaemic samples. This new device has been easily integrated in laboratory routine and allows to achieve several ECLT every day without disturbance of laboratory workflow. The routine use of this new device could be useful in various situations such as assessment in atherosclerosis and arteriosclerosis associated diseases, coagulation survey of liver transplantations, cardiovascular surgery or pharmacological research.It has already provided highly promising results in preliminary studies on the relation between fibrinolysis and cardiovascular risk factors.


Short-term outcome of adrenalectomy in dogs with adrenal gland tumours that did not receive pre-operative medical management.
Review medical records of dogs that underwent adrenalectomy without pre-operative medical management, to examine the peri-operative morbidity and mortality. Case series of 65 dogs. Medical records were reviewed. Features recorded included the histologic diagnosis, intra-operative hypertension or tachycardia, requirement for cavotomy, administration of intra- and post-operative corticosteroids, performance of additional surgery and the occurrence of peri-operative complications. Dogs requiring emergency surgery were excluded. Of the 65 dogs, 49 had adrenocortical tumours (11 bilateral), 13 had pheochromocytomas (one bilateral) and three dogs had tumours in both adrenal glands of a different tumour type. Five dogs had caudal vena cava invasion and 33 had additional procedures performed at the same time. Mortality occurred in 1/65 dogs (1.5%; 95% CI 0.03%-8.2%), major complications were identified in 1/65 dogs (1.5%; 95% CI 0.03%-8.2%) and minor complications occurred in 10/53 dogs (15%; 95% CI 8.6%-26%). Based on the limited peri-operative complications and low mortality in this pre-operatively untreated cohort, and based on critique of the available literature, the added value afforded by pre-operative treatment is questioned. With appropriate management, adrenal tumours can be removed with few peri-operative complications and low mortality.


Modeling the implementation of population-level isoniazid preventive therapy for tuberculosis control in a high HIV-prevalence setting.
We model the epidemiological impact of providing isoniazid preventive therapy (IPT) to South African adolescents, among whom HIV prevalence is low, latent tuberculosis (TB) prevalence is high, and school-based programs may enable population-level coverage. We simulate a dynamic compartmental model of age-structured HIV and TB coepidemics in South Africa. HIV dynamics are modeled by infection status, CD4 cell count, and antiretroviral therapy; TB dynamics are modeled by disease stage, diagnosis, treatment, and IPT status. We analyze the effects of continuous IPT coverage among adolescents from 5 (baseline) to 90%. Our model is calibrated to WHO and the Joint United Nations Programme on HIV/AIDS epidemiological estimates. In simulations, increasing IPT coverage to 50% among adolescents reduced active TB incidence by 5-34%. Increasing coverage to 90% led to a 9-40% reduction in active TB incidence. Expanded IPT access causes TB incidence to decline in the general population of HIV-positive individuals, as well as in adult HIV-positive individuals. Targeting IPT to a secondary school population with high latent TB prevalence and low-HIV prevalence, in which risk of false-negative diagnosis of active TB is low and IPT benefits are more established, could have substantial benefits to adolescents and spillover benefits to the adult population.


Loss of correction after medial opening wedge high tibial osteotomy: a comparison of locking plates without bone grafts and non-locking compression plates with bone grafts.
A loss of correction is one of the common complications after medial opening wedge high tibial osteotomy (MOWHTO) and can lead to deteriorate outcomes. The technique of fixation plays an important role in maintaining the correction angle until union. The present study aims to compare the amount of correction loss between two different fixation techniques after MOWHTO. Between 2005 and 2007, 67 knees from 54 patients who underwent MOWHTO were reviewed and classified into the following groups: group A, treated with T-buttress plate fixation and autologous tricortical iliac bone graft, and group B, operated upon with a locking compression medial high tibial plate without any augmentation. Preoperatively and at 1, 12 and 24 months postoperatively, medial proximal tibial angles (MPTA) were measured and the loss of correction angle was determined by measuring the decrease in MPTAs at 1 and 2 years after the operation. The differences in clinical and radiographic outcomes were analyzed using Student's t-test and the Chi-squared test. The overall loss of correction at 2 years in group A (2.0 +/- 2.7 degrees) was higher than in group B (0.3 +/- 3.3 degree) (p = 0.026). The majority of correction loss occurred in the first year (1.6 +/- 2.6 and 0.4 +/- 2.6 degrees in groups A and B, respectively). During the second year, there was slightly more loss in group A (0.4 +/- 1.3 degree), while a stable angle was found in group B (-0.1 +/- 2.5 degree). All osteotomies were united and a 7.5% incidence of overall complications was reported. Maintenance of the correction angle after MOWHTO depended on the fixation technique. The authors recommend that 2 degrees more than the planned overcorrection point is required in the non-locking plate system, with no need for such a measure in the locking plate system.


CAENOGENESIS, DEVELOPMENTAL VARIABILITY, AND EVOLUTION IN THE CARPUS AND TARSUS OF THE MARBLED NEWT TRITURUS MARMORATUS.
In this paper, after a comparative analysis of the development of Triturus marmoratus, we explore the existence of caenogenetic events and their ontogenetic and phylogenetic consequences. The adult morphology of the Triturus marmoratus limb, in terms of number and spatial arrangement of skeletal elements, agrees with the general pattern of urodeles. The congruence in the typical pattern of adult morphology does not hint at the striking differences in embryonic development. These differences can be summarized as follows: 1) Presence of a "central axis" that develops in a distal-to-proximal direction. It originates in the basale commune giving rise to the centrale and the intermedium. Thus, there is no postaxial branching as found in Ambystoma mexicanum. 2) Again, unlike in Ambystoma mexicanum, we find a postaxial structure composed of the ulnare (fibulare)-distal carpal (tarsal) 4-metacarpal (metatarsal) 4 which is independent of the "digital arch." 3) The (forelimb) digits, in particular, digits 1, 2, and 3, undergo disproportionate elongation. For example, the second digit, composed of a thin continuous, cartilaginous rod, becomes longer than the rest of the limb. Our study of the patterns of embryonic connectivity suggests the coexistence of three directions of growth and morphogenesis in the development of the Triturus marmoratus limb. 1) A proximo-distal one that gives rise to the preaxial axis, "primary axis," and individual digits. 2) An anterio-posterior axis of development that gives rise to the "digital arch" and determines the number of digits. 3) A disto-proximal central axis that originates in the basale commune and sequentially generates the centrale and the intermedium. We speculate that heterochronic interspecific variation in the time of onset of limb bud formation is related to the degree of precocious digital elongation. Selection for long extremities in early larval stages, associated with functional demands for locomotion and balancing, may be the cause for the above listed changes in developmental pattern. Thus, the reported system is an example of how selection during ontogeny can result in the evolution of the developmental process.


Safety and immunogenicity of influenza A H1N1 vaccines.
Evaluation of: Liang XF, Wang HQ, Wang JZ et al. Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 375(9708), 56-66 (2009). The novel swine-origin influenza A H1N1 2009 virus was first identified in April 2009 in Mexico. Since then, it has caused a worldwide pandemic with more than 10,000 deaths documented by December 2009. While many countries adopted pandemic plans and border controls to try to control the spread of the virus, it was quickly realized that the virus was unstoppable. The virus was initially largely susceptible to oseltamivir and zanamivir, and various strategies that included treatment of severe cases, all cases or targeted chemoprophylaxis were used to try to limit the mortality and morbidity due to the virus. However, predictably, resistance to neuraminidase inhibitors has increasingly appeared in different settings and outbreaks of resistant virus have been reported. Mass vaccination is the most economic and effective measure to reduce infection and mortality from influenza. Before this pandemic, several studies were conducted using H5N1 prepandemic vaccines to try to determine the optimal composition and dose of vaccine for a novel strain of influenza. Most of these studies found significantly higher doses required for novel influenza strains and all previous studies showed the need for two doses of vaccine to achieve protective levels of antibody. Once it became apparent that the pandemic was due to H1N1 2009 instead, efforts were redirected to finding the optimal antigen dose and composition including the use of adjuvant combinations. This unique study conducted in ten centers across the People's Republic of China found that a single-dose, 7.5-microg, nonadjuvanted, split-virion vaccine was sufficiently immunogenic for adults and adolescents aged 12 years and above to meet regulatory requirements for registration. The vaccine was relatively well tolerated with serious adverse reactions--mainly high-grade fever in only 0.6% of vaccine recipients. This large, unique study conducted in a developing country using vaccine manufactured in that developing country shows a high degree of seroprotection and has had a major impact on pandemic vaccination strategies worldwide.


Long-acting {beta}2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD.
The objective of this study was to describe risks of death and asthma outcomes with prescription of long-acting β(2)-agonists (LABA), short-acting β(2)-agonists (SABA) or inhaled corticosteroids (ICS) in general practice. The study population included β(2)-agonist users aged ≥18 yrs, who were in the UK General Practice Research Database (GPRD), which is linked to the national registry of hospitalisations. The study included 507,966 patients with 5.5 million SABA, 4.0 million ICS and 1.3 million LABA prescriptions. Rates of asthma outcome increased with more severe treatment steps. The mortality rate was increased with least and most severe treatment steps. Higher relative rates (RR) of outcomes were found in recent starters and heavy long-term users with LABA, SABA and ICS. The RRs in heavy long-term users were 1.9 for all-cause mortality and 3.0 for asthma death with SABA, 1.4 and 1.6, respectively, with LABA and 1.7 and 2.2, respectively, with ICS. The RR of death was statistically similar over time between LABA and ICS despite changes in exposure. Risks for death and asthma outcomes varied substantially with exposure characteristics. The statistical power for detecting increases in asthma death was low. The results of this study did not indicate that LABA exposure was associated with an increased risk for all-cause mortality.


A study of use of low dose aspirin in prevention of pregnancy induced hypertension.
Forty-six nulliparous women in third trimester of pregnancy with a raised blood pressure of 30 mm Hg (systolic) or/and 15 mm Hg (diastolic) or both, over baseline values were treated with 75 mg of aspirin per day. The results are compared with another 48 age, height, weight, and gestational period matched nulliparaous women with similar condition for trial selection, who were treated as control. There is considerable more number of cases in the control group than in aspirin treated group showing subsequent rise of BP, appearance of proteinuria, and severe pre-eclamptic toxaemia. The aspirin treated group showed increased mean gestational age at termination 39.4 +/- 2.6 weeks as against 38.2 +/- 3.4, increased foetal weight 2860 +/- 552 g as against 2540 +/- 720 g. No case of neonatal haemorrhagic manifestations or congenital malformations were seen. However not much result is obtained with aspirin therapy in cases with established pregnancy induced hypertension or with proteinuria. Hence it is concluded that aspirin therapy should be given to prevent pregnancy induced hypertension. As predictability of other screening tests are not unequivocal, criterion used in this series for screening may be used.


Rheology based estimates of self- and collective diffusivities in viscous liquids.
The self-diffusion coefficient of viscous liquids is estimated on the basis of a simple analysis of their rheological shear spectra. To this end, the Almond-West approach, previously employed to access single-particle diffusivities in ionic conductors, is generalized for application to molecular dynamics in supercooled liquids. Rheology based estimates, presented for indomethacin, ortho-terphenyl, and trinaphthylbenzene, reveal relatively small, yet systematic differences when compared with diffusivity data directly measured for these highly viscous liquids. These deviations are discussed in terms of mechanical Haven ratios, introduced to quantify the magnitude of collective translational effects that have an impact on the viscous flow.


Phenotypic diversity of smooth muscle cells isolated from human intracranial basilar artery.
The present work examined heterogeneity of vascular smooth muscle cells cultured from human cerebral arteries that has not been previously reported. Primary smooth muscle cell cultures were isolated from human intracranial basilar arteries. Using a ring isolation method, multiple clones were generated from the cell cultures. These clones had two distinctly different morphologies: (1) fusiform; and (2) stellate. At confluence the fusiform-shaped clones grew in compact clusters with overlapping cells while the stellate-shaped clones were contact-inhibited growing in a monolayered pattern. The smooth muscle differentiation markers, alpha-smooth muscle-actin, calponin and smooth muscle-myosin heavy chains were expressed in all these clones. In response to serum stimulation, the stellate-shaped clones had a higher growth rate than the fusiform clones. This study reports that smooth muscle cells derived from human basilar arteries are heterogeneous.


Infrared thermography: a graphic interpretation of exitance as a function of surface temperature, emittance, and background.
Calorimetrio and radiation balance equations for an object in thermal equilibrium with its environment are combined to yield a graphic interpretation of exitance as a function of surface temperature, emittance, and background factors. In a monochromatic image of a scene, errors in interpreting the same shade-of-gray as being isothermal are immediately apparent from the graph. Relative effects on exitance of fractional changes in the experimental variables, internal power dissipation through the surface and emittance of the surface are derived and illustrated graphically. Modifications of the simple model move toward real world imagery.


Influence of process variables on extraction of Cefalexin in a novel biocompatible ionic liquid based-aqueous two phase system.
Despite the fact that ionic liquid-based aqueous two phase systems (ATPSs) have been widely studied for extraction purposes, the adequacy of biodegradable organic salts as salting out agents has been left unexploited. In this study, we investigated the ability of sodium-based organic salts in the formation of ATPS in the presence of a common ionic liquid, [C4mim]BF4. In the pioneering aspect of this work, Response Surface Methodology (RSM) based on three-variable central composite design (CCD) was employed for determination of the effect of pH and the initial concentration of phase components on the partition coefficient of Cefalexin. Consequently, regression model equations and contour plots were applied to evaluate the effect of system's parameters on biomolecule's extraction. The tie-line (TL) data were determined for each experimental run and their reliability was confirmed by Othmer-Tobias and Bancroft correlations. In order to investigate the salting-out ability the effective excluded volume (EEV) was determined from the binodal data. Furthermore, FTIR spectra confirmed no chemical interactions between Cefalexin and [C4mim]BF4 in the extraction process. The microscopic structure of the top phase was analyzed by DLS, conductivity and TEM in order to investigate the mechanism of extraction. Hydrophobic interaction, the salting-out effect and the aggregation phenomena played the dominant role in the study of the extraction process.


Charge-transfer complexes of 4-(dimethylamino)pyridine with 2,4-, 3,4- and 3,5-dinitrobenzoic acid.
In the three title crystal structures 4-(dimethylamino)pyridinium 2,4-dinitrobenzoate, (I), 4-(dimethylamino)pyridinium 3,4-dinitrobenzoate, (II), and 4-(dimethylamino)pyridinium 3,5-dinitrobenzoate, (III), all C(7)H(11)N(2)(+).C(7)H(3)N(2)O(6)(-), the ions are connected by an N-H.O hydrogen bond. Dihedral angles between the pyridine and phenyl rings are 69.9 (1), 26.7 (1) and 56.2 (1) degrees in (I), (II) and (III), respectively. Donor-acceptor pi-pi stacking is observed in (II) and (III), but not in (I).


Cost-effectiveness and safety of the molecular targeted drugs afatinib, gefitinib and erlotinib as first-line treatments for patients with advanced EGFR mutation-positive non-small-cell lung cancer.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib and afatinib are standard first-line treatments for EGFR gene mutation-positive non-small cell lung cancer. The present study aimed to compare the cost-effectiveness of using erlotinib, afatinib or gefitinib. The safety of EGFR-TKIs was also investigated. Expected costs were calculated based on data from patients with advanced EGFR mutation-positive non-small-cell lung cancer who were treated with gefitinib, erlotinib or afatinib. Literature was collected to obtain the necessary clinical information for calculating the probability and the validity of each chemotherapy. Median survival time (MST) was used to evaluate the therapeutic effect of the regimens. The cost-effectiveness ratio was calculated using expected costs and MSTs for the three regimens. The cost-effectiveness ratio per month was JPY 386,859.4/MST for afatinib, JPY 264,788.7/MST for gefitinib and JPY 397,039.9/MST for erlotinib. Significant differences were observed between the three groups (p<0.001). The incremental cost-effectiveness ratio (ICER) of gefitinib compared with afatinib per month was JPY 122,070.7/MST. The ICER of gefitinib compared with erlotinib was JPY -69,605.9/MST. Adverse effects of Grade 3 and higher, including diarrhoea (28.6%) and paronychia (14.3%) were observed in the afatinib treatment group. Paronychia (23.1%) was observed in the erlotinib treatment group, while none were observed in the gefitinib treatment group. These findings demonstrate that gefitinib is more cost effective in comparison with the afatinib and erlotinib regimens, although the afatinib and erlotinib regimens were well-tolerated and produce sufficient effects.


Tissue-Specific Ablation of the LIF Receptor in the Murine Uterine Epithelium Results in Implantation Failure.
The cytokine leukemia inhibitory factor (LIF) is essential for rendering the uterus receptive for blastocyst implantation. In mice, LIF receptor expression (LIFR) is largely restricted to the uterine luminal epithelium (LE). LIF, secreted from the endometrial glands (GEs), binds to the LIFR, activating the Janus kinase-signal transducer and activation of transcription (STAT) 3 (Jak-Stat3) signaling pathway in the LE. JAK-STAT activation converts the LE to a receptive state so that juxtaposed blastocysts begin to implant. To specifically delete the LIFR in the LE, we derived a line of mice in which Cre recombinase was inserted into the endogenous lactoferrin gene (Ltf-Cre). Lactoferrin expression in the LE is induced by E2, and we demonstrate that Cre recombinase activity is restricted to the LE and GE. To determine the requirement of the LIFR in implantation, we derived an additional mouse line carrying a conditional (floxed) Lifrflx/flx gene. Crossing Ltf-Cre mice with Lifrflx/flx mice generated Lifrflx/Δ:LtfCre/+ females that were overtly normal but infertile. Many of these females, despite repeated matings, did not become pregnant. Unimplanted blastocysts were recovered from the Lifrflx/Δ:LtfCre/+ uteri and, when transferred to wild-type recipients, implanted normally, indicating that uterine receptivity rather than the embryo's competency is compromised. The loss of Lifr results in both the failure for STAT3 to translocate to the LE nuclei and a reduction in the expression of the LIF regulated gene Msx1 that regulates uterine receptivity. These results reveal that uterine expression of the LIFR is essential for embryo implantation and further define the components of the LIF signaling pathway necessary for effective implantation.


Development of a national Zoom-based lectureship for pediatric transplant hepatology trainees.
Previous publications identified a gap in standard education on topics related to advanced hepatology and liver transplantation for pediatric transplant hepatology trainees. The Society of Pediatric Liver Transplantation (SPLIT) Education Committee designed a Zoom-based lectureship series for all advanced pediatric transplant hepatology trainees. We aim to describe the educational series and feedback from fellow participants. Pediatric transplant hepatology trainees from across the United States and Canada were invited to attend 25 Zoom-based lectures on a broad list of topics pertaining to pediatric transplant hepatology. At the completion of the lectureship, a 53-item REDcap survey using single-answer, Likert-scale, and open-ended questions was distributed via email to all participants. A total of 16 fellows from broad geographic areas responded to the survey. Nineteen percent (n = 3/16) of fellows attended all 25 lectures and 31% (n = 5/16) attended 16-20 lectures. Majority of fellows (88%, n = 14/16) reported the lecture series increased knowledge of liver disease, increased confidence in managing children with liver disease, and aided with board preparation. Additionally, over half of the fellows (81%, n = 13/16) reported the series served as a platform for networking and mentoring from peers and experts in the field. All fellows recommended the lecture series for future fellows. The SPLIT educational lectureship for advanced pediatric transplant hepatology trainees provided a national education curriculum that not only led to increased knowledge and confidence in the diagnosis and management of common conditions encountered in pediatric transplant hepatology but also provided a unique networking and mentorship environment.


Association study of IL2RA and CTLA4 Gene Variants with Type I Diabetes Mellitus in children in the northwest of Iran.
Introduction: A variety of genetic predisposing factors and environmental factors are known to influence the pathogenesis of type-1 diabetes (T1D). This study intended to investigate the association of cytotoxic T-lymphocyte associated protein 4 (CTLA4) and interleukin 2 receptor subunit alpha (IL2RA) gene polymorphisms with type 1 diabetes in children of northwest of Iran. Methods: Genomic DNA was extracted by salting-out method. PCR amplification and direct sequencing methods were used for genotyping of CTLA4 (exon 1) and IL2RA (intron 1) genes in all patients and controls. SNPStats was used to calculate odds ratios (ORs), 95% confidence intervals (CIs), and p values. Results: In this study, the frequency of G allele and GG genotype of CTLA-4 (+49A/G) polymorphism in T1D patients were significantly different from those in the controls (26% vs. 11%, p = 0.006). Moreover, a significant difference was observed between patients and control group in the allele frequencies of the new SNP (chr2:203868145) that was identified in exon one of CTLA4 (14% vs. 3%, p = 0.006). The results showed that the GG homozygous genotype of +49 A>G was associated with increased glycemic level in T1D patients in the study population (95% CI = 10.47, p = 0.0067). However, no significant association was found between IL2RA (ss52580101C>A) polymorphism and T1D patients (2% vs. 4%, p = 0.41). Conclusion: The results further support the association of T1D with +49A>G SNP in the CTLA4 gene in the population of northwest of Iran. However, no significant relationship was observed between ss52580101C>A polymorphism of IL2RA gene and T1D in this study.


An amidolytic assay for determination of alpha 1-antitrypsin in serum and in cerebrospinal fluid.
An amidolytic assay using the chromogenic substrate tosyl-glycyl-prolyl-lysine-4-nitranilide acetate (Chromozym PL) has been studied for the determination of alpha 1-antitrypsin in serum and in cerebrospinal fluid (CSF). It was found that binding of trypsin to alpha 2-macroglobulin has to be taken into consideration when alpha 1-antitrypsin is determined by an amidolytic assay. In serum this accounts for 7.4 +/- 3.2% and in CSF 2.8 +/- 1.8% of the total antitrypsin capacity. The reference range of alpha 1-antitrypsin in sera was found to be x = 60.3 +/- 20.8 kIU/l, and in CSF mean = 186 +/- 99 IU/l. Within-run precision showed a C.V. of 1.36% in sera, and a C.V. of 1.86% in CSF. There was a good correlation with immunochemical methods: r = 0.946 in 65 sera (p less than 0.001) and r = 0.986 in 55 samples of CSF (p less than 0.001).


Interleukin (IL)-2 deficiency aggravates the defect of natural killer cell activity in AIDS patients.
A decrease in natural killer (NK) cell activity is a common feature of the immune dysfunction found in patients with human immunodeficiency virus (HIV)-induced acquired immune deficiency syndrome (AIDS). The present study was aimed at exploring the NK and the lymphokine-activated killer (LAK) cell activities of lymphocytes from HIV-seropositive subjects. The in vitro production of interleukins (IL-2 and IL-10) in response to mitogens was also studied. Two groups of HIV-seropositive subjects were studied: asymptomatic and AIDS patients. Controls were normal blood donors. The NK cell activity in peripheral blood mononuclear cells (PBMC) from AIDS patients was significantly lower than that in PBMC from both HIV-seronegative subjects and asymptomatic patients. There was no significant difference between asymptomatic patients and controls. Exposure of PBMC from all three groups of individuals to an optimal dose of IL-2 in vitro enhanced LAK cell activity. At all three effector: target cell ratios, the LAK activity in AIDS patients remained below that in normal subjects. However, the proportional increase of lytic activity with IL-2 was slightly higher in AIDS patients than in HIV-seronegative subjects. The mitogen-induced production of IL-2 was especially reduced in AIDS patients. In contrast, very high levels of mitogen-induced production of IL-10 were found in the AIDS group, as compared to asymptomatic subjects or to controls. We therefore conclude that the alteration of NK cell activity occurs at an advanced stage of HIV infection, that the reduction of cytotoxic activity is partially restored by exogenous IL-2, and that decreased production of IL-2 and increased production of IL-10 may account for part of this reduction in cytotoxicity.


Epigenetic variation and inheritance in mammals.
What determines phenotype is one of the most fundamental questions in biology. Historically, the search for answers had focused on genetic or environmental variants, but recent studies in epigenetics have revealed a third mechanism that can influence phenotypic outcomes, even in the absence of genetic or environmental heterogeneity. Even more surprisingly, some epigenetic variants, or epialleles, can be inherited by the offspring, indicating the existence of a mechanism for biological heredity that is not based on DNA sequence. Recent work from mouse models, human monozygotic twin studies, and large-scale epigenetic profiling suggests that epigenetically determined phenotypes and epigenetic inheritance are more common than previously appreciated.


Early local and systemic fibrinolytic response to high energy missile trauma.
In dogs, tissue and blood fibrinolysis was studied after a high velocity missile injury to one hind leg. Plasminogen activator activity in skeletal muscle at different distances from the wound was estimated with a histochemical method. Samples from venous blood draining both the injured and the not injured leg were regularly analysed for fibrinogen, plasminogen, alpha 2-antiplasmin, alpha 2-macroglobulin, fibrinolysis on fibrin plates and fibrin(ogen) degradation products. Tissue close to the bullet track judged as devitalized displayed a significant and persistent reduction of plasminogen activator activity. The same pattern of reaction was observed in muscle without apparent lesions 3 cm from the wound but no uniform pattern could be discerned at a distance of 10 cm. In the blood a very early activation of fibrinolysis took place. There was no difference between the two sides, thus the trauma induced a general activation of fibrinolysis in the organism. Towards the end of the experiments a continuous decrease of fibrinolysis in the euglobulin fraction of plasma on fibrin plates was noted. Concomitantly an increase of plasmin inhibitors took place. It was concluded that a high velocity missile injury to skeletal muscle induced a reduction of plasminogen activator activity in the tissue surrounding the wound. A very early and general activation of systemic fibrinolysis was followed by a decreased fibrinolysis within a few hours.


Novel insights into the role of acetyl-CoA producing enzymes in epigenetic regulation.
Inflammation-dependent changes in gene expression programs in innate immune cells, such as macrophages, involve extensive reprogramming of metabolism. This reprogramming is essential for the production of metabolites required for chromatin modifications, such as acetyl-CoA, and regulate their usage and availability impacting the macrophage epigenome. One of the most transcriptionally induced proinflammatory mediator is nitric oxide (NO), which has been shown to inhibit key metabolic enzymes involved in the production of these metabolites. Recent evidence indicates that NO inhibits mitochondrial enzymes such as pyruvate dehydrogenase (PDH) in macrophages induced by inflammatory stimulus. PDH is involved in the production of acetyl-CoA, which is essential for chromatin modifications in the nucleus, such as histone acetylation. In addition, acetyl-CoA levels in inflamed macrophages are regulated by ATP citrate lyase (ACLY) and citrate transporter SLC25A1. Interestingly, acetyl-CoA producing enzymes, such as PDH and ACLY, have also been reported to be present in the nucleus and to support the local generation of cofactors such as acetyl-CoA. Here, we will discuss the mechanisms involved in the regulation of acetyl-CoA production by metabolic enzymes, their inhibition by prolonged exposure to inflammation stimuli, their involvement in dynamic inflammatory expression changes and how these emerging findings could have significant implications for the design of novel therapeutic approaches.


Enhancing effect of thoracotomy on tumor growth in rats.
To indicate the influence of operative stress on tumor growth, thoracotomy and/or laparotomy were performed 48 hr after intraperitoneal or intravenous inoculation of Sato lung cancer into Donryu rats. Survival period, number of metastatic nodules on the surface of the lungs, and the percentage-area of metastases in the frontal section through pulmonary hilus were examined. By thoracotomy and laparothoracotomy the survival period of the tumor-inoculated rats was reduced significantly compared with that of the control but difference between these two test groups was not significant. Also there was no significant difference between the laparotomy group and the control. The results obtained in the number and percentage-area of metastatic nodules were quite similar to that observed in the survival period. Correlation between the number and the percentage-area of metastatic nodules was highly significant. The meaning of the stress of thoracotomy in cancer treatment is discussed.


[Experimental studies of carcino-embryonic antigen immunosensor based on piezoelectric resonate technology of quartz crystal].
In order to construct a new type of piezoelectric quartz immunosensor for the determination of carcino-embryonic antigen (CEA), the sensor detection pools were consisted of plastic loops and crystals that were 10 MHz quartz AT-cut with gold coated electrodes and the immobilization of the monoclonal antibody against CEA onto gold electrode surface of the quartz crystal was accomplished via Thiol method. Then the immunosensors were used in clinical laboratory. The experimental results showed that the piezoelectric immunosensor had good response to CEA, the frequency shifts were linearly dependent on CEA concentration in the range of 1.56 to approximately 50.00 ng/ml, other antigens such as alpha fetoprotein (AFP), prostate specific antigen (PSA), human chorionic gonadotropin (hCG) did not interfere with the sensor's response. The results obtained from this method were in satisfactory accordance with those obtained by radio immunoassay(P>0.05), The correlation coefficient was 0.90. Piezoelectric immunosensor for determination of CEA has the advantage of high sensitivity, high specificity, unnecessary labeling, simple performing, rapid analysis, low cost, real-time detection and repeated use, etc. It can be used for detecting serum CEA in clinical laboratory.


Markers of bone metabolism in multiple myeloma patients switched from zoledronic acid to denosumab.
To date, intravenous drip infusion of zoledronic acid (ZA) has mainly been used for the treatment and prevention of skeletal-related events (SRE) in patients with multiple myeloma (MM). Recently, denosumab, a fully humanized monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL), has also become available for the same purpose, but little is known about the impact of switching from ZA to denosumab. Herein, we present a retrospective study on bone metabolic markers in 10 MM patients initially treated with ZA and then switched to denosumab. Consequently, the levels of bone resorption markers, tartrate-resistant acid phosphatase 5b (TRACP-5b) and serum type-I collagen crosslinked N-telopeptide (sNTX), significantly decreased after denosumab treatment, while the levels of bone formation markers, osteocalcin (OC) and bone-specific alkaline phosphatase (BAP), showed no apparent changes. No patient developed severe hypocalcemia with denosumab treatment. In one patient not given chemotherapy, the M-protein level increased after switching from ZA to denosumab and plateaued when ZA was restarted. Based on this finding, we anticipate that switching from ZA to denosumab would exert a stronger suppressive effect on osteoclasts, but the anti-myeloma activity of ZA must be taken into consideration.


Bioinformatics analysis of mRNA and miRNA microarray to identify the key miRNA‑gene pairs in small‑cell lung cancer.
Small‑cell lung cancer (SCLC) is a type of lung cancer with early metastasis, and high recurrence and mortality rates. The molecular mechanism is still unclear and further research is required. The aim of the present study was to examine the pathogenesis and potential molecular markers of SCLC by comparing the differential expression of mRNA and microRNA (miRNA) between SCLC tissue and normal lung tissue. A transcriptome sequencing dataset (GSE6044) and a non‑coding RNA sequence dataset (GSE19945) were downloaded from the Gene Expression Omnibus (GEO) database. In total, 451 differentially expressed genes (DEGs) and 134 differentially expressed miRNAs (DEMs) were identified using the R limma software package and the GEO2R tool of the GEO, respectively. The Gene Ontology function was significantly enriched for 28 terms, and the Kyoto Encyclopedia of Genes and Genomes database had 19 enrichment pathways, mainly related to 'cell cycle', 'DNA replication' and 'oocyte meiosis mismatch repair'. The protein‑protein interaction network was constructed using Cytoscape software to identify the molecular mechanisms of key signaling pathways and cellular activities in SCLC. The 1,402 miRNA‑gene pairs encompassed 602 target genes of the DEMs using miRNAWalk, which is a bioinformatics platform that predicts DEM target genes and miRNA‑gene pairs. There were 19 overlapping genes regulated by 32 miRNAs between target genes of the DEMs and DEGs. Bioinformatics analysis may help to better understand the role of DEGs, DEMs and miRNA‑gene pairs in cell proliferation and signal transduction. The related hub genes may be used as biomarkers for the diagnosis and prognosis of SCLC, and as potential drug targets.


Health risk assessment for air pollutants: alterations in lung and cardiac gene expression in mice exposed to Milano winter fine particulate matter (PM2.5).
Oxidative stress, pulmonary and systemic inflammation, endothelial cell dysfunction, atherosclerosis and cardiac autonomic dysfunction have been linked to urban particulate matter exposure. The chemical composition of airborne pollutants in Milano is similar to those of other European cities though with a higher PM2.5 fraction. Milano winter fine particles (PM2.5win) are characterized by the presence of nitrate, organic carbon fraction, with high amount of polycyclic aromatic hydrocarbons and elements such as Pb, Al, Zn, V, Fe, Cr and others, with a negligible endotoxin presence. In BALB/c mice, we examined, at biochemical and transcriptomic levels, the adverse effects of repeated Milano PM2.5win exposure in lung and heart. We found that ET-1, Hsp70, Cyp1A1, Cyp1B1 and Hsp-70, HO-1, MPO respectively increased within lung and heart of PM2.5win-treated mice. The PM2.5win exposure had a strong impact on global gene expression of heart tissue (181 up-regulated and 178 down-regulated genes) but a lesser impact on lung tissue (14 up-regulated genes and 43 down-regulated genes). Focusing on modulated genes, in lung we found two- to three-fold changes of those genes related to polycyclic aromatic hydrocarbons exposure and calcium signalling. Within heart the most striking aspect is the twofold to threefold increase in collagen and laminin related genes as well as in genes involved in calcium signaling. The current study extends our previous findings, showing that repeated instillations of PM2.5win trigger systemic adverse effects. PM2.5win thus likely poses an acute threat primarily to susceptible people, such as the elderly and those with unrecognized coronary artery or structural heart disease. The study of genomic responses will improve understanding of disease mechanisms and enable future clinical testing of interventions against the toxic effects of air pollutant.


Synchronous metastatic gastric cancer-molecular background and clinical implications with special attention to mismatch repair deficiency.
Current guidelines recommend that metastatic gastric cancer should not be treated with surgery unless this is required for symptom control. We hypothesized that patients with mismatch repair deficiency (MMRd) gastric cancer and metastatic disease detected at the timepoint of surgical resection would have superior survival compared to patients with MMRd cancers in the same setting. Clinicopathological details and survival data were collected from prospective databases at two large European centers on patients who had undergone surgery and were diagnosed with synchronous stage IV gastric cancer (distant lymph nodes, positive peritoneal cytology, peritoneal, and distant metastases) at the timepoint of surgery. Resection specimens were tested for the presence of microsatellite instability using a standard 5 mononucleotide repeat panel. One hundred and seventy six patients with resected stage IV gastric cancer were identified. 14/176 (8.0%) had MSI-H (high) disease. There was no significant difference between the clinical and pathological characteristics of MSI and microsatellite stable (MSS) patients. No differences in the type of metastases were observed between MSI and MSS groups. Patients who were MSI-H had superior OS compared to MSS patients (median OS 15.9 vs. 8 months, p = 0.023). However, in Cox regression multivariate analysis only liver and peritoneal metastases were independent predictors of survival. Surgically treated patients with MSI-H stage IV gastric cancer have a better survival than patients with MSS gastric cancer. Further analysis of the role of surgery in MSI stage IV GC is required.


Two-dimensional metal-organic surfaces for efficient hydrogen evolution from water.
Hydrogen production through the reduction of water has emerged as an important strategy for the storage of renewable energy in chemical bonds. One attractive scenario for the construction of efficient devices for electrochemical splitting of water requires the attachment of stable and active hydrogen evolving catalysts to electrode surfaces, which remains a significant challenge. We demonstrate here the successful integration of cobalt dithiolene catalysts into a metal-organic surface to generate very active electrocatalytic cathode materials for hydrogen generation from water. These surfaces display high catalyst loadings and remarkable stability even under very acidic aqueous solutions.


Agile Teams and Lean Methods in a Tertiary Care Hospital During COVID-19 Pandemic.
To share the experience of Agile Teams using Lean Method to facilitate improvement projects during the COVID-19 pandemic. A tertiary hospital in Oman mobilized agile teams using lean methods to streamline the workflow during the early stages of COVID-19 pandemic in year 2020. The collaborative network generated by the agile teams increased interdepartmental engagement within the hospital and trimmed workflows, thus improving patient care despite the pandemic. Agile teams using lean methods demonstrably enhance collaboration and efficiency in healthcare, leading to improved patient care.


Anti-oxidant properties of high-density lipoprotein and atherosclerosis.
1. High-density lipoprotein (HDL) is one of the major carriers of cholesterol in the blood. It attracts particular attention because, in contrast with other lipoproteins, many physiological functions of HDL influence the cardiovascular system in favourable ways unless HDL is modified pathologically. 2. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport. The functions of HDL that have recently attracted attention include anti-inflammatory and anti-oxidant activities. High anti-oxidant and anti-inflammatory activities of HDL are associated with protection from cardiovascular disease. 3. Atheroprotective activities, as well as a functional deficiency of HDL, ultimately depend on the protein and lipid composition of HDL. Conversely, these activities are compromised in many pathological states associated with inflammation. 4. The focus of the present review is on the anti-oxidant and anti-inflammatory functions of HDL and its individual components in relation to protection from atherosclerosis.


The Promising Frontier of Cardiometabolic Syndrome: A New Paradigm in Cardiology.
Cardiometabolic syndrome (CMS) is a complex interplay of metabolic dysregulation, cardiovascular disease (CVD), and diabetes risk factors. It encompasses obesity, insulin resistance, dyslipidemia, hyperuricemia, and hypertension, with obesity triggering metabolic disturbances. The global prevalence of CMS, driven by rising obesity rates and sedentary lifestyles, varies across regions. Underlying CMS mechanisms intertwine genetics, sedentary behaviors, poor diets, and hormonal imbalances. Genetic predisposition interacts with environmental factors, while sedentary lifestyles and poor diets amplify obesity and insulin resistance. Hormonal disruptions further complicate the syndrome's development. CMS has far-reaching clinical implications, extending beyond CVD and diabetes to conditions such as non-alcoholic fatty liver disease, cancer, and sleep apnea. Innovative CMS approaches revolve around biomarkers, personalized medicine, lifestyle interventions, and pharmacological breakthroughs. Emerging biomarkers offer early insights, while personalized medicine tailors interventions based on genetic profiles. Lifestyle modifications, encompassing dietary changes and tailored exercise, foster metabolic recalibration. The pharmaceutical frontier targets CMS facets, promising more precise treatments.


Anxiety and self-care behaviour in patients with chronic systolic heart failure: A multivariate model.
While comprehensive evidence exists regarding negative effects of depression on self-care behaviours in patients with chronic heart failure (CHF), the relation between anxiety and self-care behaviours in patients with CHF is not clear. The aim of this study was to analyse the interactions between anxiety, depression and self-care behaviours in patients with CHF. The self-care behaviour of CHF outpatients was measured using the European Heart Failure Self-care Behaviour Scale (EHFScBS). The Patient Health Questionnaire (PHQ) was used to assess anxiety, the PHQ-9 was used to measure depression severity. Differences between patients with and without anxiety were assessed with the respective tests. Associations between anxiety, self-care and other predictors were analysed using linear regressions. Of the 308 participating patients, 35 (11.4%) fulfilled the PHQ criteria for an anxiety disorder. These patients took antidepressants more frequently (11.8% versus 2.3%, p = .02), had had more contacts with their general practitioner within the last year (11.8 ± 16.1 versus 6.7 ± 8.6, p = .02), and had a higher PHQ-9 depression score (12.9 ± 5.7 versus 6.5 ± 4.7, p < .01) than patients without anxiety disorder. Anxiety and self-care were negatively associated (ß = -0.144, r2 = 0.021, p = 0.015). The explanation of variance was augmented in a multivariate regression with the predictors age, sex, education, living with a partner, and New York Heart Association (NYHA) class ( r2 = 0.098) when anxiety was added ( r2 = 0.112). Depression further increased the explanation of variance (ß = -0.161, r2 = 0.131, p = 0.019). Anxiety is negatively associated with self-care behaviour in patients with CHF. However, this effect disappears behind the stronger influence of depression on self-care. The consideration of mental comorbidities in patients with CHF is important.


Serum procalcitonin for discrimination between septic and non-septic arthritis.
Early differentiation between septic and non-septic arthritis is difficult. A previous study showed promising diagnostic accuracy of serum Procalcitonin (PCT) in septic arthritis, limited by a low sensitive PCT test kit. To investigate the diagnostic value of PCT in patients with septic and non-septic arthritis using a novel test with low detection limit. Forty-two patients, 28 with non-septic and 14 with septic arthritis were prospectively included. For each patient, gram stain, culture and polarization microscopy of synovial fluid was done and PCT, C-reactive protein (CRP), white blood cell count, uric acid and blood cultures were taken. Patients with septic arthritis, patients with non-septic arthritis with and without concomitant infection were compared. Patients with septic arthritis had a significant higher PCT concentration than patients with non-septic arthritis (p<0.0001). At a cut-off of 0.1 (0.25) ng/ml, sensitivity for septic arthritis was 100(93)% and specificity 46(75)%. Specificity rose to 93% after exclusion of patients with non-septic arthritis and concomitant infection. Both sensitivity and specificity for the diagnosis of septic arthritis were higher for PCT than CRP. Our data suggest that PCT seems to be a highly sensitive and specific marker for septic arthritis, depending on the clinical setting. Further studies are warranted.


Nonmolecular treatment for muscular dystrophies.
This review highlights emerging evidence on the management of patients with muscular dystrophies. New diagnostic modalities based on muscle biopsy and DNA analysis mean that diagnoses within the heterogeneous group of muscular dystrophies can be much more precise; also, as the phenotypes associated with these different disorders are clarified, new management implications can be recognized. At the same time, the spread of evidence based medicine into this area has led to an increase in clinical trial activity and the development of evidence based guidelines. Because many if not all muscular dystrophies are multisystem disorders, these guidelines relate not only to the limited number of interventions aimed at improving strength but also to the management of potentially life threatening complications. Because specific diagnoses carry specific management implications in many areas for these hitherto rather neglected disorders, a more proactive approach to patients with muscular dystrophies is needed. Complications involving, for example, the cardiovascular, respiratory and gastrointestinal systems may need to be sought and actively managed, whereas caution for complications of anaesthesia and other interventions may also be necessary. However, areas remain where there is little evidence from which practice guidelines can be developed and these will need to be addressed with well planned clinical trials.


Dynamics of biological molecules irradiated by short x-ray pulses.
Very short and intense x-ray pulses can be used for diffraction imaging of single biological molecules. Inevitably, x-ray absorption initiates damage that degrades the molecule's image. This paper presents a continuum model of the physics that leads to damage when a small particle absorbs a large x-ray dose. The main processes are found to be ionization and Coulomb-force driven atomic motion. Trapping of electrons, Debye shielding, and nonuniform collisional ionization all have a significant effect on the overall damage kinetics.


Monoclonal antibodies to stromal cell types of the mouse thymus.
Seven hybridoma cell lines secreting monoclonal antibodies (mAb) to nonlymphoid cells of the mouse thymus have been prepared. These mAb clearly demonstrate the heterogeneity of the thymic stroma. Based on their anatomical distribution patterns observed with the immunoperoxidase technique on frozen tissue sections, they were subdivided into four groups. The first group of mAb, ER-TR1, 2 and 3, detects antigens encoded for by the I region of the major histocompatibility complex. These antigens are expressed on both stromal and lymphoid cells in lymphoid organs. mAb of the second category, ER-TR4, react with epithelial cells in the thymic cortex. mAb of the third group detect stromal cells of the thymic medulla. One antibody of this group, ER-TR5, exclusively reacts with medullary epithelial cells. ER-TR6, the other antibody of this group, reacts with medullary interdigitating cells and macrophages. The fourth type of antibodies, ER-TR7, detects the reticular fibroblasts of the thymus. The possible role of the thymic cell types detected by the present antibodies in T cell differentiation is discussed.


Researches on Mathematical Relationship of Five Elements of Containing Notes and Fibonacci Sequence Modulo 5.
Considering the five periods and six qi's theory in TCM almost shares a common basis of stem-branch system with the five elements of containing notes, studying the principle or mathematical structure behind the five elements of containing notes can surely bring a novel view for the five periods and six qi's researches. By analyzing typical mathematical rules included in He tu, Luo shu, and stem-branch theory in TCM as well as the Fibonacci sequence especially widely existent in the biological world, novel researches are performed on mathematical relationship between the five elements of containing notes and the Fibonacci sequence modulo 5. Enlightened by elementary Yin or Yang number grouping principle of He tu, Luo shu, the 12534 and 31542 key number series of Fibonacci sequence modulo 5 are obtained. And three new arrangements about the five elements of containing notes are then introduced, which have shown close relationship with the two obtained key subsequences of the Fibonacci sequence modulo 5. The novel discovery is quite helpful to recover the scientific secret of the five periods and six qi's theory in TCM as well as that of whole traditional Chinese culture system, but more data is needed to elucidate the TCM theory further.


The protective action of taurine and L-arginine in radiation pulmonary fibrosis.
Taurine has the ability to resist the action of oxygen-free radicals by protecting cytomembranes. L-arginine increases the nitric oxide in the organism, inhibiting some types of abnormal cell proliferation. We examined the actions and protective mechanisms of these two substances against radiation pulmonary fibrosis. The mRNA transcription and the distribution of pulmonary types I and III procollagen were measured by in situ hybridization. Type I and type III collagen in the interalveolar septa and the change ratio between the two types were assayed using Sirius Red staining and polarizing microscopy. Angiotensin converting enzyme (ACE), hydroxyproline (Hyp), malondialdehyde (MDA), and nitric oxide (NO) were measured in lung tissue after irradiation. We found that, following administration of taurine or arginine, the mRNA transcription of procollagen types I and III significantly decreased in the pulmonary tissue 3 months after irradiation and the Hyp content was lower, especially after the administration of arginine. The extent of the radiation-induced decrease in ACE activity was markedly attenuated. As a substrate of NO production, arginine can significantly increase the pulmonary NO content. We conclude that the administration of taurine or arginine can significantly decrease the mRNA transcription of procollagen and the synthesis of type I collagen in the interalveolar septa and can decrease the Hyp content of the pulmonary tissue. Following irradiation, NO can attenuate the radiation-induced decrease in ACE activity. Our study suggests that exogenous NO and taurine significantly protect against radiation pulmonary injury.


Temperature-driven narrowing of the insulating gap as a precursor of the insulator-to-metal transition: Implications for the electronic structure of solids.
We present a microscopic picture rationalizing the surprisingly steep decrease in the bandgap with temperature in insulators, crystalline or otherwise. The gap narrowing largely results from fluctuations of long-wavelength optical phonons-when the latter are present-or their disordered analogs if the material is amorphous. We elaborate on this notion to show that possibly with the exception of weakly bound solids made of closed-shell electronic configurations, the existence of an insulating gap or pseudogap in a periodic solid implies that optical phonons must be present, too. This means that in an insulating solid, the primitive cell must have at least two atoms and/or that a charge density wave is present, with the possible exception of weakly bonded solids such as rare-gas or ferromagnetic Wigner crystals. As a corollary, a (periodic) elemental solid held together by nonclosed shell interactions and whose primitive unit contains only one atom will ordinarily be a metal, consistent with observation. Consequences of the present picture for Wigner solids are discussed. A simple field theory of the metal-insulator transition is constructed that directly ties long-wavelength optical vibrations with fluctuations of an order parameter for the metal-insulator transition. The order parameter is shown to have at least two components, yet no Goldstone mode arises as a result of the transition.


[Clinical experiences with noxiptilin].
Noxiptilin (Elronon) proved to be a good bipolar thymoleptic agent in the clinical test at 3 special clinics. Its stimulating effect on the psychomotor function is more pronounced than its sedative action. Therefore, in cases with the anxious, agitated depressive syndrome the additional therapy with a neuroleptic agent or a sedative tranquilizer may be favourable. N. is well tolerated even at a higher age. The side effects are the same as those of other known thymoleptics.


Drosophila females trade off good nutrition with high-quality oviposition sites when choosing foods.
Animals, from insects to humans, select foods to regulate their acquisition of key nutrients in amounts and balances that maximise fitness. In species in which the nutrition of juveniles depends on parents, adults must make challenging foraging decisions that simultaneously address their own nutrient needs as well as those of their progeny. Here, we examined how the fruit fly Drosophila melanogaster, a species in which individuals eat and lay eggs in decaying fruits, integrate feeding decisions (individual nutrition) and oviposition decisions (offspring nutrition) when foraging. Using cafeteria assays with artificial diets varying in concentrations and ratios of protein to carbohydrates, we show that D. melanogaster females exhibit complex foraging patterns, alternating between laying eggs on high carbohydrate foods and feeding on foods with different nutrient contents depending on their own nutritional state. Although larvae showed faster development on high protein foods, both survival and learning performance were higher on balanced foods. We suggest that the apparent mismatch between the oviposition preference of females for high carbohydrate foods and the high performances of larvae on balanced foods reflects a natural situation where high carbohydrate ripened fruits gradually enrich in proteinaceous yeast as they start rotting, thereby yielding optimal nutrition for the developing larvae. Our findings that animals with rudimentary parental care uncouple feeding and egg-laying decisions in order to balance their own diet and provide a nutritionally optimal environment to their progeny reveal unsuspected levels of complexity in the nutritional ecology of parent-offspring interactions.


Effects of in vivo administration of epidermal growth factor (EGF) on uterine contractility, prostaglandin production and timing of parturition in rats.
Prostaglandins synthesized by cyclooxygenases elicit uterine contractions during labour. Nitric oxide synthases (NOS) produce nitric oxide (NO), which maintains uterine quiescence during pregnancy. Epidermal growth factor (EGF) interacts with prostaglandins and NO in many biological systems. The aim of this work was to study the effect of the in vivo administration of EGF on uterine contractility, prostaglandin production and timing of parturition in rats. EGF was injected into the uterine lumen of pregnant rats on day 20, 21 or 22 of gestation. Intra-uterine administration of 500 ng EGF on day 21 of gestation delayed parturition for 18 h compared with control rats. Administration of EGF was able to: (i) reduce cyclooxygenase expression in the uterus (determined by western blot analysis) and production of prostaglandins by the uterus (evaluated by conversion of [(14)C]arachidonate to labelled prostaglandins); (ii) decrease prostaglandin concentrations in amniotic fluid (radioimmunoassay); (iii) increase NO production (evaluated by conversion of [(14)C]arginine into [(14)C]citrulline); (iv) increase serum progesterone concentrations to more than control concentrations (P<0.05; radioimmunoassay); and (v) reduce the amplitude of the uterine contractions. The overall effect was a delay in the onset of delivery. This in vivo effect raises the question of whether exogenous EGF plays a role in the initiation of parturition.


Heterogeneity of a tumor antigen TA-4 of squamous cell carcinoma in relation to its appearance in the circulation.
The heterogeneity of a tumor antigen TA-4 of squamous cell carcinoma was studied by using isoelectric focusing (IEF). IEF of squamous cell carcinoma tissue of the uterine cervix showed 2 major peaks of TA-4 with pI values of 5.9 to 6.2 (acidic TA-4) and 6.3 to 6.6 (neutral TA-4). The non-malignant squamous epithelium of the uterine cervix showed a major TA-4 peak at pI 6.3 to 6.6 (neutral TA-4), while TA-4 in the blood of patients with squamous cell carcinoma was mainly eluted at pI 5.9 to 6.2 (acidic TA-4). These results indicated that acidic TA-4 is implicated in the appearance of this antigen in the circulation of patients with squamous cell carcinoma.


[Doctor, know that your patient has Googled: Internet and reason for medical consultation].
The internet is increasingly used as a source of medical information, not only by healthcare professionals but by patients as well. We describe the case of Patient A, a 32-year-old male with symptoms of sinusitis. He found a treatment on the internet and was informed when to consult a general practitioner. We also describe Patient B, a 31-year-old female with symptoms of fatigue after the delivery of her second child. Her search on the internet led to several referrals to a medical specialist due to her conviction that her symptoms were caused by a hormonal imbalance. We conclude that medical information on the internet can support both the doctor and the patient, or it can present an obstacle to proper communication during a consultation. Awareness by medical professionals of the Googling behaviour of their patients may be helpful in detecting the underlying question and worries of the patient.


Metallurgical considerations in the wear of metal-on-metal hip bearings.
Metal-on-metal bearings offer one possible solution to problems of osteo-lysis associated with ultra high molecular weight polyethylene (UHMWPE) wear debris generated during articulation in total joint replacements. Designs using larger bearing diameters are also possible with associated improvements in both range of motion and stability. There has been considerable debate as to the optimum metallurgical structure of the cobalt chrome alloys used in these metal-on-metal bearings. This review addresses the main metallurgical design issues in metal-on-metal bearing design and reviews some recent studies from two independent academic centres. Cobalt chrome alloys with a low carbon content, when paired against themselves, have been shown to have poor wear properties under both simple configuration and simulator testing. Other cobalt chrome alloy couples with higher carbon content, whether wrought, cast or cast and heat-treated, appear to have similar performance in clinically relevant wear simulation studies. (Hip International 2004; 14: 1-10).


A risk calculator to inform the need for a prostate biopsy: a rapid access clinic cohort.
Prostate cancer (PCa) represents a significant healthcare problem. The critical clinical question is the need for a biopsy. Accurate risk stratification of patients before a biopsy can allow for individualised risk stratification thus improving clinical decision making. This study aims to build a risk calculator to inform the need for a prostate biopsy. Using the clinical information of 4801 patients an Irish Prostate Cancer Risk Calculator (IPRC) for diagnosis of PCa and high grade (Gleason ≥7) was created using a binary regression model including age, digital rectal examination, family history of PCa, negative prior biopsy and Prostate-specific antigen (PSA) level as risk factors. The discrimination ability of the risk calculator is internally validated using cross validation to reduce overfitting, and its performance compared with PSA and the American risk calculator (PCPT), Prostate Biopsy Collaborative Group (PBCG) and European risk calculator (ERSPC) using various performance outcome summaries. In a subgroup of 2970 patients, prostate volume was included. Separate risk calculators including the prostate volume (IPRCv) for the diagnosis of PCa (and high-grade PCa) was created. IPRC area under the curve (AUC) for the prediction of PCa and high-grade PCa was 0.6741 (95% CI, 0.6591 to 0.6890) and 0.7214 (95% CI, 0.7018 to 0.7409) respectively. This significantly outperforms the predictive ability of cancer detection for PSA (0.5948), PCPT (0.6304), PBCG (0.6528) and ERSPC (0.6502) risk calculators; and also, for detecting high-grade cancer for PSA (0.6623) and PCPT (0.6804) but there was no significant improvement for PBCG (0.7185) and ERSPC (0.7140). The inclusion of prostate volume into the risk calculator significantly improved the AUC for cancer detection (AUC = 0.7298; 95% CI, 0.7119 to 0.7478), but not for high-grade cancer (AUC = 0.7256; 95% CI, 0.7017 to 0.7495). The risk calculator also demonstrated an increased net benefit on decision curve analysis. The risk calculator developed has advantages over prior risk stratification of prostate cancer patients before the biopsy. It will reduce the number of men requiring a biopsy and their exposure to its side effects. The interactive tools developed are beneficial to translate the risk calculator into practice and allows for clarity in the clinical recommendations.


The influence of chemotherapy on the management of non-Hodgkin's lymphomata at the Princess Margaret Hospital. A comparison of the results from 1962-64 with 1967-69.
A retrospective study of 460 non-Hodgkin's lymphoma patients seen in 1962-64 (185) and 1967-69 (275) revealed a marked improvement in the survival of patients treated during the later interval. The increased survival was not due to differences in the age or sex distribution of patients, the proportions with systemic symptoms or extranodal presentations. The improvement was due partially to a disproportionate increase in the number of patients with well- and intermediately differentiated nodular lymphocytic lymphomata in 1967-69. When these patients were removed, the proportions of patients with "good" and "poor" pathology were comparable for the two intervals, and a markedly improved survival was still evident for the 1967-69 group. An improvement in the proportion of patients achieving a complete remission occurred only in patients who received some form of chemotherapy. Relapses occurred in 44.6% of patients with Stage I and II disease treated with radiotherapy alone. The results of this study indicate that we must re-evaluate carefully the indications for radiotherapy in the treatment of the non-Hodgkin's lymphomata. The addition of chemotherapy appears to be a promising method for increasing the proportion of patients who will achieve a long complete remission.


Identification and use of the sugarcane bacilliform virus enhancer in transgenic maize.
Transcriptional enhancers are able to increase transcription from heterologous promoters when placed upstream, downstream and in either orientation, relative to the promoter. Transcriptional enhancers have been used to enhance expression of specific promoters in transgenic plants and in activation tagging studies to help elucidate gene function. A transcriptional enhancer from the Sugarcane Bacilliform Virus - Ireng Maleng isolate (SCBV-IM) that can cause increased transcription when integrated into the the genome near maize genes has been identified. In transgenic maize, the SCBV-IM promoter was shown to be comparable in strength to the maize ubiquitin 1 promoter in young leaf and root tissues. The promoter was dissected to identify sequences that confer high activity in transient assays. Enhancer sequences were identified and shown to increase the activity of a heterologous truncated promoter. These enhancer sequences were shown to be more active when arrayed in 4 copy arrays than in 1 or 2 copy arrays. When the enhancer array was transformed into maize plants it caused an increase in accumulation of transcripts of genes near the site of integration in the genome. The SCBV-IM enhancer can activate transcription upstream or downstream of genes and in either orientation. It may be a useful tool to activate enhance from specific promoters or in activation tagging.


Projection neurons in lamina I of rat spinal cord with the neurokinin 1 receptor are selectively innervated by substance p-containing afferents and respond to noxious stimulation.
Lamina I of the spinal cord is densely innervated by nociceptive primary afferents, many of which contain substance P. It contains numerous projection neurons: the majority of these respond to noxious stimuli, however some are activated by cooling. In the rat, approximately 80% of the projection neurons express the neurokinin 1 (NK1) receptor, on which substance P acts, and most cells with this receptor are activated by noxious stimuli. Lamina I neurons can be classified morphologically into pyramidal, multipolar, and fusiform types. It has been reported in the cat that pyramidal neurons are activated only by cooling and that in monkey relatively few pyramidal cells are NK1 receptor-immunoreactive. We have used immunocytochemistry to examine the innervation of lamina I projection neurons in the rat by substance P-containing primary afferents and their responses to a noxious stimulus (subcutaneous formalin injection). NK1 receptor-immunoreactive projection cells received a significantly higher density of contacts from substance P-containing afferents than neurons that lacked the receptor. Most contacts on NK1 receptor-immunoreactive cells were associated with synapses. Formalin injection induced c-Fos in approximately 80% of projection neurons with the NK1 receptor and in 25-45% of those without it. More than 80% of pyramidal neurons expressed the receptor, and for both substance P innervation and c-Fos expression there were no significant differences among different morphological types of NK1 receptor-immunoreactive neuron. We conclude that presence or absence of the NK1 receptor is a better indicator of function than morphology for lamina I projection neurons in the rat.


Detection of Candida enolase antibody in patients with candidiasis.
The serodiagnostic value of candida enolase antibody was evaluated in 27 patients with systemic candidiasis. The glycolytic enzyme enolase was prepared from Candida albicans IFM 40009 and used as the antigen for immunoblot assays. IgG class antibody was found in the sera of 17 of 27 patients (62.9%) obtained during the early course of the infection. Serial sampling of sera increased the number of patients with positive Candida enolase antibody, which was detected in 25 of 27 patients (92.5%). None of the patients with localized candidiasis showed a positive IgG titer more than 1:100. The specificity of Candida enolase IgG antibody was 95%. This antibody was observed in various candida species: Candida albicans (6/7, 85.7%); C. parapsilosis (7/9, 77.9%); C. tropicalis (5/5, 100%); C. guilliermondii (4/4, 100%); and C. glabrata (1/3, 33.3%).


Selective Distance-Based K+ Quantification on Paper-Based Microfluidics.
In this study, paper-based microfluidic devices (μPADs) capable of K+ quantification in aqueous samples, as well as in human serum, using both colorimetric and distance-based methods are described. A lipophilic phase containing potassium ionophore I (valinomycin) was utilized to achieve highly selective quantification of K+ in the presence of Na+, Li+, and Mg2+ ions. Successful addition of a suspended lipophilic phase to a wax printed paper-based device is described and offers a solution to current approaches that rely on organic solvents, which damage wax barriers. The approach provides an avenue for future alkali/alkaline quantification utilizing μPADs. Colorimetric spot tests allowed for K+ quantification from 0.1-5.0 mM using only 3.00 μL of sample solution. Selective distance-based quantification required small sample volumes (6.00 μL) and gave responses sensitive enough to distinguish between 1.0 and 2.5 mM of sample K+. μPADs using distance-based methods were also capable of differentiating between 4.3 and 6.9 mM K+ in human serum samples. Distance-based methods required no digital analysis, electronic hardware, or pumps; any steps required for quantification could be carried out using the naked eye.


Association of maternal polycystic ovary syndrome and diabetes with preterm birth and offspring birth size: a population-based cohort study.
Is the presence of polycystic ovary syndrome (PCOS) associated with more adverse infant outcomes in mothers with different types of diabetes? The presence of PCOS implies higher risks of total (medically indicated and spontaneously combined) and spontaneous preterm birth in mothers with non-insulin-treated type 2 diabetes and gestational diabetes mellitus (GDM), and lower risk of offspring being large for gestational age (LGA) in mothers with insulin-treated diabetes. PCOS is suggested to be an independent risk factor for adverse infant outcomes, and it is highly prevalent in mothers with diabetes. However, the impact of PCOS on the associations of different types of maternal diabetes with preterm birth and offspring birth sizes has not been reported. This is a population-based cohort study including all live births between 1996 and 2014 in Finland. Children with concurrent maternal diagnoses that could cause signs and symptoms similar to PCOS were excluded. A total of 1 097 753 children were included. National registries were linked to identify births with maternal PCOS (n = 24 682), stratified by diabetes types. Logistic regression was used to examine the association of maternal PCOS and comorbid insulin-treated diabetes, non-insulin-treated type 2 diabetes or GDM with offspring LGA and small for gestational age (SGA). Generalized estimating equation was used to assess the risk of preterm birth in relation to maternal PCOS and diabetes. Potential interaction between PCOS and diabetes was evaluated on both additive and multiplicative scales. Using mothers with no PCOS and no diabetes as the reference and adjusting for maternal and birth factors, there were higher risks of total (odds ratio (OR) 2.84, 95% CI 2.21 - 3.66 vs. OR 1.91, 95% CI 1.77 - 2.07, P = 0.01) and spontaneous (OR 4.02, 95% CI 2.94 - 5.50 vs. OR 2.35, 95% CI 2.13 - 2.59, P = 0.001) preterm birth for those with PCOS in mothers with non-insulin-treated type 2 diabetes and higher risks of total (OR 1.42, 95% CI 1.27-1.58 vs. OR 0.89, 95% CI 0.86-0.91, P = 0.0001) and spontaneous (OR 1.80, 95% CI 1.59-2.05 vs. OR 1.01, 95% CI 0.98-1.05, P = 0.0001) preterm birth for those with PCOS in mothers with GDM. Among mothers with type 2 diabetes, further adjusting for maternal BMI eliminated the difference in preterm birth risks between those with and those without PCOS, and adjustment for infertility treatment and pre-eclampsia also reduced the preterm risks associated with PCOS significantly. For mothers with GDM, however, the risks of total and spontaneous preterm birth remained higher for those with PCOS following these aforementioned adjustments or stratified analysis. The risk of offspring being LGA was lower for those with PCOS than those without PCOS among mothers with insulin-treated diabetes (OR 18.90, 95% CI 14.21-25.14 vs. OR 32.04, 95% CI 29.79-34.46, P = 0.0001), showing departure from additivity (relative excess risk due to interaction -11.74, 95% CI -16.17 to -7.31, P < 0.001) and multiplicativity (P < 0.001). PCOS did not alter the risk estimate of preterm birth in mothers with insulin-treated diabetes or offspring LGA and SGA in mothers with type 2 diabetes or GDM. The register-based diagnoses used in this study captured only women with PCOS seeking medical care and having live births. Including female infertility associated with anovulation as PCOS exposure was a risk for misclassification. Sample sizes for pregestational diabetes were small. Insulin purchase during pregnancy in those without a diabetes diagnosis was not accounted for in the analysis. For patients treated with insulin or other medications, we were unable to assess how they complied with such prescriptions. Also, maternal BMI was recorded only once in early pregnancy, thus the potential influence of gestational weight gain on birth outcomes could not be examined. Data on the causes for preterm birth were not available from the registers. The presence of PCOS implied higher risks of total and spontaneous preterm birth in mothers with type 2 diabetes or GDM, and lower risk of offspring being LGA in mothers with insulin-treated diabetes. The higher risks of preterm birth added by PCOS could be explained by prepregnancy BMI or in part by infertility treatment and pre-eclampsia in maternal non-insulin-treated type 2 diabetes, but not in maternal GDM. The differential effects of PCOS on the associations of different types of maternal diabetes with infant outcomes have implications for preventative strategies and clinical counseling for affected pregnancies. This study was supported by Shandong Provincial Natural Science Foundation, China (ZR2020MH064 to X.C.), Shandong Province Medical and Health Technology Development Plan (2018WS338 to X.C.), the joint research funding of Shandong University and Karolinska Institute (SDU-KI-2019-08 to X.C. and C.L.), the Finnish National Institute for Health and Welfare: Drug and pregnancy project (M.G.), the Swedish Research Council (2014-10171 to C.L.), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institute Stockholm County Council (SLL20170292 and SLL20190589 to C.L.), the Swedish Brain Foundation (FO2019-0201 and FO2020-0305 to C.L.). X.C. received grants from the China Scholarship Council at the beginning of the study. The authors have no competing interests to disclose. N/A.


A study of free portal pressure in cynomolgus monkeys with different degrees of liver fibrosis.
The aim of this study was to investigate the patterns of changes in free portal pressure (FPP) in cynomolgus monkeys with different levels of liver fibrosis and to lay a theoretical foundation for the study of FPP in patients with liver fibrosis. Liver fibrosis models were successfully established in 15 of 20 cynomolgus monkeys using carbon tetrachloride, among which 10 monkeys developed severe liver fibrosis (S4; i.e., early cirrhosis). A randomized block design was used to study FPP in the 10 cynomolgus monkeys that developed complete liver fibrosis. The FPP values and the rates of change at different stages of liver fibrosis were analyzed. The normal FPP value of cynomolgus monkeys was 25.56 ± 2.33 mmHg; the FPP value at S1 was 36.05 ± 2.91 mmHg, with an increase of 41.04 ± 3.02%; the value at S2 was 42.79 ± 2.91 mmHg, with an increase of 67.41 ± 2.98%; the value at S3 was 50.27 ± 3.44 mmHg, with an increase of 96.67 ± 5.24%; and the value at S4 was 62.47 ± 3.75 mmHg, with an increase of 144.41 ± 6.34%. FPP and its increase at S4 were significantly higher than the normal value and those at S1, S2, and S3 (P < 0.01). These results showed that FPP increases along with the severity of liver fibrosis. FPP at S4 of severe liver fibrosis were >2-fold higher compared with the normal value.


The effect of provider-level ascertainment bias on profiling nursing homes.
Profiling health care providers for the purpose of public reporting and quality improvement has become commonplace. Recently, the Centers for Medicare and Medicaid Services (CMS) began publishing measures of quality for every Medicare/Medicaid-certified nursing home in the country. The facility-specific quality indicators (QIs) reported by CMS are based on quarterly measures from the minimum data set (MDS). However, some QIs from the MDS are potentially subject to ascertainment bias. Ascertainment bias would occur if there was variation in the way items that make up QIs are measured by nurses from each facility. This is potentially a problem for difficult-to-measure items such as pain and pressure ulcers. To assess the impact of ascertainment bias on profiling, we utilize data from a reliability study of nursing homes from six states. We develop methods for profiling providers in situations where the data consist of a response variable for each subject based on assessments from an internal rater, and, for a subset of subjects in each facility, a response variable based on assessments from an independent (external) rater. The internal assessments are potentially subject to provider-level ascertainment bias, whereas the independent assessments are considered the 'gold standard'. Our methods extend popular Bayesian approaches for profiling by using the paired observations from the subset of subjects with error-prone and error-free assessments to adjust for ascertainment bias. We apply the methods to MDS merged with the reliability data, and compare the bias-corrected profiles with those of standard approaches.


Effects of pretreatment protocols on human amniotic fluid protein profiling with SELDI-TOF MS using protein chips and magnetic beads.
There is increasing interest in the use of human amniotic fluid (AF) proteomics with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) for diagnosing pregnancy-associated abnormalities. A critical parameter of diagnostic biomarkers is the accuracy and reproducibility of protein patterns. We evaluated the effects of common pretreatment protocols on protein patterns generated using SELDI mass spectrometry with two different protein capture strategies (including functional protein chips and functionalized magnetic beads prior to MS analysis) in AF. Various extrinsic factors involved in processing and storing amniotic fluid, including matrix composition, sample storage time, temperature and freeze-thaw cycles, were analyzed regarding their impact on AF protein patterns using SELDI mass spectrometry with 2 different protein capture strategies. Three extrinsic factors (sample storage for 3days at either room temperature or 4 degrees C or freeze-thawing the sample 5 times) significantly decreased the number or intensities of protein peaks detected in AF. Matrix dilutions also changed the spectra of AF, with more peaks and higher intensities observed with 50% alpha-cyano-4-hydroxycinnamic acid (CHCA). Moreover, protein chips captured more proteins or peptides than magnetic beads on SELDI-TOF MS profiling of AF. These results suggest that extrinsic factors must be taken into account for valid data interpretation to ensure good reproducibility of AF profiling by SELDI mass spectrometry.


Monitoring DPA release from a single germinating Bacillus subtilis endospore via surface-enhanced Raman scattering microscopy.
A method for monitoring DPA release from a single germinating Bacillus subtilis endospore is reported. High S/N ratio SERS spectra were obtained with excitation power 3 mW at 647.1 nm and 1 min spectral collection times. The method is proof-of-principle for the SERS detection limit at the single spore level. This represents a 100- to 1000-fold improvement over previously reported detection limits for SERS-based measurements of DPA in endospores.


Meeting Ferret Enrichment Needs in Infectious Disease Laboratory Settings.
Environmental enrichment is a necessary component of all research vivarium settings. However, appropriate enrichmentdecisions vary greatly depending on the species involved and the research use of the animals. The increasing use of ferrets inresearch settings-notably for modeling the pathogenicity and transmissibility of viral pathogens that require containmentin ABSL-2 to -4 environments-presents a particular challenge for veterinary and research staff to ensure that enrichmentneeds for these animals are met consistently. Here, we discuss the species-specific enrichment needs of ferrets, enrichmentconsiderations for ferrets housed in research settings, and the challenges and importance of providing appropriate enrichmentduring experimentation, including when ferrets are housed in high-containment facilities. This article is organizedto support the easy availability of information that will facilitate the design and implementation of optimal environmentalenrichment for ferrets used in diverse research efforts in vivarium settings.


Scalp Microinfusion: A Novel Drug Delivery Technique for Hair Loss Treatment.
Scalp microinfusion is a promising novel drug delivery technique for hair loss treatment. We discuss the MMP® technique and review its possible use in alopecias. MMP® technique provides a small amount of drugs delivered homogeneously into the skin combined with micro-needling and can, therefore, provide optimal delivery. However, literature on this technique is limited to a few case reports despite its wide use in some countries. Further studies are needed to standardize protocols.


Optimal design and mathematical model applied to establish bioassay programs.
Bioassays can be used to estimate the initial intake I for the case of an acute intake exposure for an individual worker. To evaluate the effective dose, apart from I, we need to know other parameters such as activity median aerodynamic diameter (AMAD) or the fraction absorption ( f(1)) in the blood from the GI tract, but in an accident situation these parameters are often unknown. The bioassay measurement values can be used to estimate by fitting the parameters unknown. In this paper, optimal designs for the estimation of the unknown parameters are developed. The efficiency of the design will depend on the number of samples and the measurement accuracy. The method described applies D-optimality that maximises the determinant of the Fisher information matrix to find the best moments where the bioassay measurements should be taken. It requires obtaining the analytical solution of the biokinetic model as a function of the parameters to be fitted. The method has been implemented in a computer program.


[Postnatal cell proliferation in the rat cerebrum: immunohistochemical study with bromodeoxyuridine (BrdU)].
The postnatal cell proliferation in the rat cerebrum was studied immunohistochemically using a monoclonal antibody to bromodeoxyuridine (BrdU). Since BrdU, a halogenated analogue of thymidine, is incorporated into nuclear DNA during duplication, S-phase cells can be detected by demonstrating intranuclear BrdU. 200 mg/kg of BrdU was administered to normal Wistar rats intraperitoneally on the day of birth or intravenously 1, 2, 3, 5, 8 or 24 weeks after birth. Thirty minutes later, the brain was fixed by perfusion with ethanol, and the paraffin-embedded sections were processed for the avidin biotin peroxidase-complex method. BrdU-positive nuclei were counted among 500 to 10,000 cells in several regions of the brain to obtain the BrdU-labeling index (the number of BrdU-positive cells per 100 cells scored, LI, %). The present study demonstrated that (1) proliferating cells in the gray matter (cerebral cortex and caudate-putamen) are only few at birth (LI = 0.54-0.78%), which further decrease during the following few weeks, and disappear by adulthood, (2) in the white matter (corpus callosum), cell proliferation is relatively active within 1 week after birth (LI = 5.6-6.3%), but becomes inactive thereafter, (3) the proliferative activity of the cells in the subependymal layer of the lateral ventricle is very high at birth (LI = 15.5%), which somewhat decreases during the following few weeks, but still remains high in adulthood (LI = 7.5%). This kind of continued cell proliferation in the brain after birth seems important in the postnatal development of the normal cerebral structure, and in several pathologic processes such as tissue repair and the development of brain neoplasm.


Identification of key genes and specific pathways potentially involved in androgen-independent, mitoxantrone-resistant prostate cancer.
Resistance to mitoxantrone (MTX), an anthracenedione antineoplastic agent used in advanced and metastatic androgen-refractory prostate cancer (PCa), seriously limits therapeutic success. Xenografts from two human PCa cell lines (VCaP and CWR22) were established in male severe combined immunodeficiency mice, and MTX was administered, with or without concurrent castration, three times a week until tumors relapsed. Microarray technology was used to screen for differentially expressed genes (DEGs) in androgen-independent, MTX-resistant PCa xenografts. Gene expression profiles of MTX-treatment xenografts and their respective parental cell lines were performed using an Agilent whole human genome oligonucleotide microarray and analyzed using Ingenuity Pathway Analysis software. A total of 636 genes were differentially expressed (fold change ≥1.5; P<0.05) in MTX-resistant castration-resistant prostate cancer (CRPC) xenografts. Of these, 18 were selected to be validated and showed that most of these genes exhibited a transcriptional profile similar to that seen in the microarray (Pearson's r=0.87). Western blotting conducted with a subset of genes deregulated in MTX-resistant CRPC tumors was shown through network analysis to be involved in androgen synthesis, drug efflux, ATP synthesis, and vascularization. The present data provide insight into the genetic alterations underlying MTX resistance in androgen-independent PCa and highlight potential targets to improve therapeutic outcomes.