A rapid and sensitive method for non-isotopic quantitation of HIV-1 RNA using thermophilic SDA and flow cytometry.
Thermophilic strand displacement amplification (tSDA) is an isothermal DNA amplification technique that proceeds at 55-60 degrees C using both a thermostable restriction enzyme and a DNA polymerase. A modification of this system has been developed that allows the simultaneous amplification and detection of a DNA target by the addition of a detector probe to the reaction. This tSDA system has been further modified into a flow cytometry-based, bead capture assay for quantitation of HIV-1 RNA. A biotinylated capture probe and digoxygenin-dUTP have been incorporated into the tSDA reaction. The resulting double labelled amplicons are captured on strepavidin beads, and a fluorescent signal is generated on the beads by staining with fluorescent anti-digoxygenin antibody. The assay has a linear dynamic range of three orders of magnitude with a lower detection limit at 250 HIV-1 RNA molecules.


Direct marketing of pharmaceuticals to consumers.
Revised FDA regulations governing pharmaceutical companies' broadcast advertisements directed to consumers produced substantial increases in direct-to-consumer advertising (DTCA) expenditures. Proponents of DTCA claim it supports patient autonomy in the patient-physician relationship and has motivated some consumers to seek a physician's care for conditions they previously had not discussed with a doctor. However, DTCA's blend of promotion and information has produced more prescription drug awareness than knowledge--it has been largely ineffective in educating patients with medical conditions about the medications for those conditions. The evidence for DTCA's increase in pharmaceutical sales is as impressive as is the lack of evidence concerning its impact on the health of the public. Broadcast advertisements are too brief to include extensive technical information; consequently, the impact of FDA regulations to assure a fair balance of risk and benefit in DTCA is still being assessed.


[A functional MRI study in ADHD children with impulsivity].
Impulsivity is one of the core symptoms of children with attention deficit hyperactivity disorder (ADHD). In order to understand the neuromechanism of the impulsive behaviors in ADHD children, this study investigated the specific functional areas of the brain by functional MRI. The subjects consisted of 10 ADHD children with impulsivity, 7 ADHD children without impulsivity and 9 normal children. A functional MRI examination was performed when the subjects were instructed to finish GO and STOP tasks with the GO-STOP impulsivity paradigm. The MRI data during the two tasks of GO and STOP were averaged and the corresponding activation regions between groups were compared. The data from the GO task revealed that the main activation regions of the normal children included frontal pole (superior frontal gyrus, middle frontal gyrus and medial frontal gyrus); the main activation regions of ADHD children without impulsivity were cerebellum (posterior lobe and anterior lobe bouton) and cingulated gyrus; those of ADHD children with impulsivity were medial globus pallidus and insula. The data from the STOP task showed that the main activation regions of normal children included superior frontal gyrus and middle frontal gyrus; those of ADHD children without impulsivity were middle frontal gyrus and cingulate gyrus; those of ADHD children with impulsivity were uncus and putamen. The activation regions of ADHD children with impulsivity were much fewer than the other two groups. The behavior of impulsivity-control involves a number of specific functional areas in the cerebral cortex. Compared with normal children, ADHD children without impulsivity have weaker brain function and brain activation, and ADHD children with impulsivity demonstrate much fewer brain activation regions, worse brain function and little awareness of the cerebral cortex.


Stratification of 18F-labeled PET imaging agents for the assessment of antiangiogenic therapy responses in tumors.
Successful antiangiogenic therapies have been developed for the treatment of various cancers, but not all patients respond. Therefore, the early determination of therapy efficacy is essential for patient management. This study was done to evaluate the utility of various PET imaging biomarkers for early determination of the response to therapy with the antiangiogenic agent axitinib, a multiple receptor tyrosine kinase inhibitor, in tumors with diverse biologic characteristics. Mice bearing U87-MG and MDA-MB-231 subcutaneous tumors were treated with axitinib (25 mg/kg intraperitoneally daily for 10 d), and tumor volumes were assessed with caliper measurements. The animals were concurrently imaged longitudinally with (18)F-FDG, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT), and 2-(18)F-fluoroethyl-triazolyl conjugated c(RGDyK) peptide ((18)F-FtRGD) to determine the optimal radiopharmaceutical for measuring the early treatment response in the 2 tumor types. Daily administration of axitinib successfully retarded the growth of both U87-MG and MDA-MB-231 subcutaneous tumors, with significant differences in tumor volumes being observed from day 7 after therapy on. (18)F-FDG revealed a treatment efficacy response only at day 10 after treatment in both U87-MG tumor-bearing and MDA-MB-231 tumor-bearing animals. (18)F-FLT afforded earlier detection of the therapy response, revealing a significant difference between drug- and vehicle-treated animals at day 3 for animals bearing U87-MG tumors and at day 7 for animals bearing the more slowly growing MDA-MB-231 tumors. (18)F-FtRGD showed a rapid change in tumor retention that reached significance by day 7 in U87-MG tumor-bearing animals; in contrast, no significant difference in tumor retention was observed in MDA-MB-231 tumor-bearing animals. Longitudinal imaging with different radiopharmaceuticals displays various characteristics in different tumor types, depending on their biologic characteristics. Such studies may provide clinically important information to guide patient management and monitor the response to antiangiogenic therapy with the optimum noninvasive imaging agent in the relevant cancer type.


Body temperature and malaria parasitaemia in rural African children.
Body temperature was measured and the prevalence of malaria parasitaemia was determined in 198 rural school children aged 6-12 years in a hyperendemic area of southwest Nigeria over a 14 week period spanning part of both wet and dry seasons. Body temperature values in apparently healthy children and in children with malaria parasitaemia were similar with group mean of 37.1 to 37.3 degrees C and with little or no variation in these values with season. The proportion of individual measurements with values > 37.5 degrees C in the two groups were respectively 4.3 and 6%. Despite a seasonal variation in parasite rate, with the highest rates in the wet and the lowest rates in the dry season, there was no significant difference in the proportion of subjects with parasite density > 1000/ul between season. There was also no relationship between parasite density and body temperature. In general, children with parasitaemia < 1000/ul were not pyrexial and less than 2% of all episodes of detectable parasitaemia was accompanied by symptoms of acute malaria. These findings suggest that the presence of malaria parasitaemia has little or no effect on body temperature pattern in a group of rural school children in an endemic area.


Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid beta-peptide toxicity: central roles of superoxide production and caspase activation.
Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Overexpression of PS1 mutations in cultured PC12 cells increases their vulnerability to apoptosis-induced trophic factor withdrawal and oxidative insults. We now report that primary hippocampal neurons from PS1 mutant knock-in mice, which express the human PS1M146V mutation at normal levels, exhibit increased vulnerability to amyloid beta-peptide toxicity. The endangering action of mutant PS1 was associated with increased superoxide production, mitochondrial membrane depolarization, and caspase activation. The peroxynitrite-scavenging antioxidant uric acid and the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone protected hippocampal neurons expressing mutant PS1 against cell death induced by amyloid beta-peptide. Increased oxidative stress may contribute to the pathogenic action of PS1 mutations, and antioxidants may counteract the adverse property of such AD-linked mutations.


Very low birthweight: dysregulated gestation versus evolutionary adaptation.
Much medical literature attributes persistently high rates of very low birthweight (VLBW) to "dysregulated" gestation. We offer the alternative view that natural selection conserved well-regulated, though nonconscious, decisional biology that protects the reproductive fitness of women by spontaneously aborting gestations that would otherwise yield frail infants, particularly small males. Modern obstetric practice, however, converts some fraction of these erstwhile spontaneous abortions into live births of very small infants. We further propose that the nonconscious decisional biology of gestation exhibits preferences also seen in consciously made decisions. We hypothesize that the incidence of VLBW among male infants should vary with the population's self-reported intentions to assume financial risk. We apply time-series modeling to monthly birth counts by sex and weight from the Swedish Medical Birth Registry between January 1993 and December 2010. We gauge risk aversion with monthly data from the Micro Index of the Swedish Consumer Tendency Survey (MISCT). Consistent with our argument that nonconscious decisional biology shares risk aversion with conscious decisions, we find that the incidence of VLBW among male infants in Sweden varies with the population's self-reported intentions to assume financial risk. We find increases above expected odds of a very low weight infant among males born 1 month after increases above expected levels of self-reported risk aversion in the Swedish population. We offer this finding as support for the argument that persistently high rates of VLBW arise, at least in part, from a combination of medical interventions and mechanisms conserved by natural selection to protect reproductive fitness.


Polymorphism and optical, magnetic and thermal properties of the either phyllo- or inosilicate-analogous borosulfate Cu[B2(SO4)4].
Two polymorphs of the borosulfate Cu[B2(SO4)4] can be selectively prepared by solvothermal syntheses. The crystal structures of inosilicate-analogous α-Cu[B2(SO4)4] (P1̄, no. 2, a = 5.2636(2), b = 7.1449(2), c = 7.9352(2) Å, α = 73.698(2)°, β = 70.737(2)°, γ = 86.677(2)°, 65 parameters, RBragg = 0.0052) and the new phyllosilicate-analogous polymorph β-Cu[B2(SO4)4] (P21/n, no. 14, a = 7.712(3), b = 8.149(3), c = 9.092(3) Å, β = 111.22(1)°, 3829 independent reflections, 106 parameters, wR2 = 0.054) are discussed. Further, the optical, magnetic and thermal properties of both polymorphs are investigated with focus on the role of the Cu2+ cation and its Jahn-Teller effect. The findings are confirmed by DFT calculations yielding insights in the stability of the synthesised polymorphs as well as a predicted γ-modification. Additionally, the crystal structures of two polymorphs of copper hydrogensulfate Cu(HSO4)2-I (P21/n, no. 14, a = 4.7530(2), b = 8.5325(4), c = 7.3719(3) Å, β = 100.063(1)°, 1063 independent reflections, 55 parameters, wR2 = 0.052) and Cu(HSO4)2-II (P1̄, no. 2, a = 4.79.88(8), b = 7.857(1), c = 8.057(1) Å, α = 77.86(1)°, β = 87.02(1)°, γ = 89.82(1)°, 1044 independent reflections, 109 parameters, wR2 = 0.132) as well as that of Cu[S2O7] (C2/c, no. 15, a = 6.6341(4), b = 8.7302(5), c = 9.0555(8) Å, β = 104.763(3)°, 1117 independent reflections, 48 parameters, wR2 = 0.049) are presented and the cyclosilicate-analogous borosulfate Cu[B(SO4)2(HSO4)] is fully characterised with respect to its optical and thermal properties.


[Impact of rural land market on farm household's behavior of soil & water conservation and its regional difference: A case study of Xingguo, Shangrao, and Yujiang County in Jiangxi province ecologically vulnerable districts].
The paper analyzed the farm households' decision-making progress of soil & water conservation and its two-stage conceptual model. It also discussed the impacts of rural land market on the farm households' behavior of soil & water conservation. Given that, the article established models for the relations between the land market and soil & water conservation, and the models' parameters were estimated with Heckman's two-stage approach by using the farm household questionnaires in Xingguo, Shangrao and Yujiang counties of Jiangxi province. The paper analyzed the impact o f rural land market on farm household's behavior of soil & water conservation and its regional difference with the result of model estimation. The results show that the perception of soil & water loss and the tax & fee on the farm land have significant influence upon the soil and water conservation from the view of the population; however, because of different social and economic condition, and soil & water loss, there are differences of the influence among the three sample counties. These differences go as follows in detail: In Xingguo County, the rent-in land area and its cost have remarkable effect on the farm households' soil & water conservation behavior; In Yujiang County, the rent-in land area, rent-in cost and rent-out land area remarkably influence the farm households' behavior of soil and water conservation, with the influence of the rent-in land area being greater than Xingguo County; In Shangrao County, only rent-out land area has significant influence on the behaviors of soil & water conservation; In all samples, Xingguo County and Yujiang County samples, the rent-out income has no significant influence on the farm household's decision-making behavior soil and water conservation. Finally, the paper put forward some suggestions on how to bring the soil & water loss under control and use land resource in sustainable ways.


Effect of Clinical Care Pathways on Quality of Life and Physical Function After Fragility Fracture: A Meta-analysis.
To evaluate the effect of clinical care pathways (CCPs) on health-related quality of life (HRQoL) and physical function following fragility fracture and identify the specific characteristics of CCPs that are associated with improved outcomes. Systematic review and meta-analysis. Randomized controlled studies and nonrandomized studies that involved participants aged ≥50 years who sustained a fragility fracture, evaluated the effects of a CCP compared to usual care, and reported outcomes of HRQoL or physical function. We systematically searched Ovid Medline, CINAHL, Embase, and the Cochrane Central Register of Controlled Trials from the earliest records to July 25, 2018. Two reviewers independently extracted study data and assessed methodologic quality. Overall, 22 studies (17 randomized controlled trials, 5 nonrandomized studies) were included, comprising 5842 participants. Twenty-one studies included hip fracture patients, and 1 included wrist fracture patients. Majority of studies (82%) were assessed as high quality. Meta-analyses showed moderate improvements in the CCP group for HRQoL [standardized mean difference (SMD) = 0.24, 95% confidence interval (CI) 0.12, 0.35] and physical function (SMD 0.21, 95% CI 0.10, 0.33) compared with usual care post hip fracture. Inpatient CCPs that extended to the outpatient setting showed greater improvements in HRQoL and physical function compared to CCPs that were only inpatient or outpatient. CCPs that included a care coordinator, geriatric assessment, rehabilitation, prevention of inpatient complications, nutritional advice, or discharge planning also showed greater improvements in outcomes. Treatment with CCPs following fragility fracture showed greater improvements in HRQoL and physical function compared with usual care. Further research is warranted to assess the combination of CCP components that provide the most beneficial results, evaluate the effect of CCPs in patients with nonhip fractures, and determine which patient groups are more likely to benefit from CCPs.


The role of MEG in pre-surgical evaluation of epilepsy: current use and future directions.
Identification of the epileptogenic zone is a critical determinant of seizure control outcomes following surgical resection in medically refractory seizures. There has been increasing recognition of the contributive value of Magnetoencephalography (MEG) studies in the diagnostic evaluation of epilepsy. Biomagnetic signals recorded by MEG studies in combination with source modeling techniques can yield diagnostic information regarding the underlying epileptogenic zone. MEG evaluation is particularly useful in evaluation of non lesional neocortical epilepsy. In these cases, MEG spike sources can guide presurgical and perioperative invasive monitoring. The incorporation of MEG-based diagnostic information into the surgical evaluation and management plan has consistently been shown to be associated with improved seizure control outcomes.


Increased artificial deadspace ventilation is a safe and reliable method for deliberate hypercapnia.
To develop a simple method in an animal model to achieve deliberate hypercapnia, which can be used easily and safely to regulate the pulmonary vascular resistance without changing mean airway pressure and compromising oxygenation. Prospective study, with each animal used as its own control. Minipigs, weighing 11 to 14 kg (n = 7). A quadrilumen thermodilution pulmonary artery catheter was placed in minipigs via the internal jugular vein. Systemic blood pressure was measured with use of a femoral arterial catheter. The animals' lungs were ventilated with an FIO2 of 1.0, and a stable state of eucapnia was achieved and maintained for 30 mins. The artificial deadspace was increased every 30 mins, by connecting 45-mL (3- to 4-mL/kg) corrugated tube segments until a total deadspace volume of 180 mL was added. Hemodynamic performance was evaluated at baseline and after 45 mL (3 to 4 mL/kg), 90 mL (6 to 8 mL/kg), 135 mL (9 to 11 mL/kg), and 180 mL (12 to 15 mL/kg) of added deadspace. Data were indexed to the animal's weight (in kg). Increased artificial deadspace produced a significant (p < .05) increase in PaCO2. These increases in PaCO2 were associated with significant (p < .05) increases of 23%, 32%, 45%, and 46% in the mean pulmonary vascular resistance values, and 6%, 16%, 23%, and 23% in the mean pulmonary arterial pressure, respectively. The systemic pH was decreased from a mean baseline value of 7.45 to 7.39, 7.28, 7.20, and 7.11, respectively. There were no significant changes in PaO2, oxygen consumption, systemic vascular resistance, and cardiac output throughout the experiments. A gradual increase in artificial deadspace ventilation produces a state of deliberate hypercapnia. In our animal model, a moderate increase in artificial deadspace significantly increased the pulmonary vascular resistance but was not associated with detrimental respiratory acidemia. Larger volumes of added artificial deadspace had no detrimental effect on cardiac output, oxygen content, oxygen consumption, and systemic vascular resistance, but were associated with significant respiratory acidemia and therefore should be avoided.


Alignment and fabrication tolerances of planar gratings for board-to-board optical interconnects.
The use of diffraction gratings to trap optical beams in substrates for optical interconnect applications has been proposed by many. We analyze the alignment and fabrication tolerances of such gratings to make them viable for such applications. The use of chirped circular gratings is proposed as a means of compensating for transverse-optical beam misalignments. Fabrication of 1-, 2-, and 4-microm-period gratings on glass substrates through ion-beam milling and their analysis are presented. High diffracted orders were confined to the substrates through total internal reflection.


Use of a Research as Intervention Approach to Explore Telebehavioral Health Services During the COVID-19 Pandemic in Southeastern Idaho.
Since the inception of the COVID-19 pandemic, telebehavioral health services have been a key contributor to continuation of care in rural and underserved areas of southeastern Idaho. Providers of telebehavioral health services faced numerous challenges as they navigated rapidly shifting regulations, variable access to internet and their own personal understandings of practice. This study aimed to characterize provider experiences, generate policy- and practice-level recommendations, and raise awareness among community stakeholders regarding telebehavioral health in southeastern Idaho. Using a newly developed conceptual/analytical framework, a research-as-intervention strategy was employed to conduct and analyze semi-structured interviews, short writings, and photographs from 7 primary care and behavioral health providers in the region. Providers shared examples from practice that addressed technology and training, access-to-care, safety, changing provider roles, payment for services, treatments that are not well suited to telehealth and the nuances of living and working in newly forged spaces of care. Providers found promise in telebehavioral health's utility as a hybrid model of care, but it must be supported by flexible legislation and policy. For example, it would help to make reimbursement expansions permanent and to simplify inter-jurisdictional practice options. Cross-sharing of information between licensing boards could help providers from various disciplines understand the parameters within which their colleagues must work.


Family influences on child nutritional outcomes in Nairobi's informal settlements.
Improving child nutritional status is an important step towards achieving the Sustainable Development Goals 2 and 3 in developing countries. Most child nutrition interventions in these countries remain variably effective because the strategies often target the child's mother/caregiver and give limited attention to other household members. Quantitative studies have identified individual level factors, such as mother and child attributes, influencing child nutritional outcomes. We used a qualitative approach to explore the influence of household members on child feeding, in particular, the roles of grandmothers and fathers, in two Nairobi informal settlements. Using in-depth interviews, we collected data from mothers of under-five children, grandmothers, and fathers from the same households. Our findings illustrate that poverty is a root cause of poor nutrition. We found that mothers are not the sole decision makers within the household regarding the feeding of their children, as grandmothers appear to play key roles. Even in urban informal settlements, three-generation households exist and must be taken into account. Fathers, however, are described as providers of food and are rarely involved in decision making around child feeding. Lastly, we illustrate that promotion of exclusive breastfeeding for 6 months, as recommended by the World Health Organization, is hard to achieve in this community. These findings call for a more holistic and inclusive approach for tackling suboptimal feeding in these communities by addressing poverty, targeting both mothers and grandmothers in child nutrition strategies, and promoting environments that support improved feeding practices such as home-based support for breastfeeding and other baby-friendly initiatives.


Improved method for molecular diagnosis of myotonic dystrophy type 1 (DM1).
Myotonic dystrophy type 1 (DM1) has been identified as the amplification of a polymorphic (CTG)n repeat in the 3' untranslated region of a gene encoding a serine/threonine kinase (DMPK). The length of the CTG repeat correlates with clinical severity and the age at onset of the disease. Thus, the ability to perform quick and accurate molecular genetic diagnoses is of great importance to patients and their families. Polymerase chain reaction (PCR) and Southern blots are essential methods for such diagnoses. All previously published methods are based on Southern blots using radioactive probes. Furthermore, the enzymes used for DNA digestion result in larger fragments, which makes it difficult to accurately determine the insert sizes. In this study, we report an improved method for molecular diagnosis of DM1. This method employs an initial screening with PCR followed by Southern blots using nonradioactive probes and TaqI as the enzyme, and provides a much better resolution of the labeled bands.


Three interfering beams in laser Doppler velocimetry for particle position and microflow velocity profile measurements.
It is proposed to use three interfering and coplanar laser beams to form the probe volume of laser Doppler systems. This allows us to obtain, for each particle crossing this probe volume, a Doppler signal whose frequency amplitude spectrum exhibits two characteristic peaks. Electromagnetic calculations and experimental validations clearly demonstrate that we can estimate simultaneously, from the analysis of these two frequency peaks, the particle position along the optical axis and one velocity component. This technique is expected to have great potentialities for velocity profile measurements in microfluidic or boundary layer flows, as well as for the sizing of spherical particles.


Triplex operation for children with extrahepatic portal hypertension.
How to deal with the vexatious problem of esophageal and gastric varices secondary to extrahepatic portal hypertension has been discussed extensively among pediatric surgeons around the world. The aim of this study is to evaluate the effect of triplex operation (splenopneumopexy, portal azygous devascularization, and ligation of splenic artery) for children with portal hypertension in the author's hospital. From March 1993 to November 1998, 7 children with extrahepatic portal hypertension were admitted to the author's hospital to undergo triplex operation. The diagnoses of these patients were confirmed by gastroscopy, barium meal, and Doppler ultrasonography. The number of white blood cells and platelets and the hepatic function were checked before and after operation. And the free portal pressures (FPP) were checked before and after the ligation of the splenic artery. All patients underwent follow-up for 1 to 7 years (mean, 4.6 years). The episodes of upper gastrointestinal bleeding were recorded. The degree of varices of distal esophagus and proximal stomach were assessed by barium meal and gastroscopy. The diameters of the spleenic and portal vein were obtained by B ultrasonography. The portopulmonary shunt and portal blood flow were evaluated by color Doppler flow image (CDFI). The indices of hemorheology such as hematocrit, viscosity of whole blood and plasma, and the indexes of deformability and aggregability of red blood cells were obtained through viscometer (R-20 Seerle, Beijing, China). There was no operative mortality in this group. Postoperatively, hemorrhage from the esophagus and gastric varices was completely controlled. Although the diameter of spleen reduced progressively, no patient's spleen recovered to normal during the follow-up period. The degree of varices was mitigated, and the FPP was decreased significantly to 34.48 +/- 5.71 cm H(2)O from the preoperative 42.62 +/- 6.72 cm H(2)O (P <.05). The rate of portal flow also was decreased. The direction of portal vein was bidirection (one part was away from the liver and the other was toward the liver). The numbers of white blood cells and platelets were increased. The viscosities of whole blood and hematocrit also were increased after operation. The triplex operation is an effective procedure for the control of hemorrhage from varices in children with extrahepatic portal hypertension.


Recent HIV-1 infection detection: comparison of incidence estimates derived by laboratory assays and repeat testing data.
Advances in laboratory methods capable of detecting recent HIV infection offer the promise of quickly and efficiently measuring HIV incidence in cross-sectional surveys, thereby greatly expanding the capabilities of surveillance programs. We compared HIV-1 incidence estimates derived from 3 different methods: Vironostika-less sensitive, BED capture enzyme immuno assay (BED-CEIA), and repeat testing history. A cross-sectional analysis was performed using HIV testing data from the population of all men who have sex with men presenting for serological HIV voluntary counseling and testing at the largest testing programs in San Francisco from 2000 to 2004 (n = 15,010). Specimens were evaluated for recent HIV-1 infection using Vironostika-LS and BED-CEIA. Concordance between the 2 assays was assessed using the Kappa statistic. The BED-CEIA and Vironostika-LS concurred in 90% of specimen classifications (Kappa = 0.77; "good" strength of agreement). Predictors of recent HIV-1 infection common to both methods were unprotected receptive anal intercourse (P < 0.001), sex with a known HIV-positive partner (P < 0.001), and amphetamine use (P < 0.01). Temporal trends in HIV-1 incidence were also consistent and stable. There was good concordance in the classification of recent HIV-1 infection between BED-CEIA and Vironostika-LS and in the correlates of acquisition of infection. The findings suggest that these incidence assays can be used for the basic epidemiological purposes of measuring HIV-1 incidence, identifying populations at risk for infection, and tracking the leading edge of the epidemic over time.


p14ARF, p15INK4b and p16INK4a methylation status in chronic myelogenous leukemia.
The INK4 family of proteins p15INK4b, p14ARF and p16INK4a function as cell cycle inhibitors where they are involved in the inhibition of G1 phase progression. Methylation of the p15INK4b promoter never seems to occur in solid tumors but is a major gene silencing mechanism in hematological malignancies. p14ARF and p16INK4a promoter methylation often occurs in solid tumors but also in leukemias and lymphomas. In chronic myelogenous leukemia (CML), only a few reports have been published regarding INK4 methylation and the results of the literature are discordant. Thus clearly, more works on large series have to be performed independently.


The Iliotibial Band: A Complex Structure with Versatile Functions.
The development of a pronounced iliotibial band (ITB) is an anatomically distinct evolution of humans. The mechanical behaviour of this "new" structure is still poorly understood and hotly debated in current literature. Iliotibial band syndrome (ITBS) is one of the leading causes of lateral knee pain injuries in runners. We currently lack a comprehensive understanding of the healthy behaviour of the ITB, and this is necessary prior to further investigating the aetiology of pathologies like ITBS. Therefore, the purpose of this narrative review was to collate the anatomical, biomechanical and clinical literature to understand how the mechanical function of the ITB is influenced by anatomical variation, posture and muscle activation. The complexity of understanding the mechanical function of the ITB is due, in part, to the presence of its two in-series muscles: gluteus maximus (GMAX) and tensor fascia latae (TFL). At present, we lack a fundamental understanding of how GMAX and TFL transmit force through the ITB and what mechanical role the ITB plays for movements like walking or running. While there is a range of proposed ITBS treatment strategies, robust evidence for effective treatments is still lacking. Interventions that directly target the running biomechanics suspected to increase either ITB strain or compression of lateral knee structures may have promise, but clinical randomised controlled trials are still required.


16α-Hydroxytrametenolic Acid from Poria cocos Improves Intestinal Barrier Function Through the Glucocorticoid Receptor-Mediated PI3K/Akt/NF-κB Pathway.
This study evaluated the effect of triterpenoids from edible mushroom Poria cocos on intestinal epithelium integrity and revealed the transcriptional regulatory pathways that underpin restorative mechanisms in the gut. Based on computational docking studies, transcriptional activation experiments and glucocorticoid receptor (GR) protein immunofluorescence localization assays in cultured cells, 16α-hydroxytrametenolic acid (HTA) was discovered as a novel GR agonist in this study. HTA ameliorates TNF-α-induced Caco-2 monolayer intestinal epithelial barrier damage and suppressed activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), which attenuated downstream IκB and nuclear factor kappa-B (NF-κB) phosphorylation through GR activation. Moreover, HTA prevented NF-κB translocation into the nucleus and binding to its cis-element and suppressed lipopolysaccharide-induced downstream NO production and pro-inflammatory cytokines at both protein and mRNA expression levels. In conclusion, HTA from P. cocos improves intestinal barrier function through a GR-mediated PI3K/Akt/NF-κB signaling pathway and may be potentially exploited as a supportive dietary therapeutic strategy for restoring gut health.


Solubilization of single-wall carbon nanohorns using a PEG-doxorubicin conjugate.
A procedure for dispersing oxidized single-wall carbon nanohorns (oxSWNHs) in aqueous solution using a polyethylene glycol-doxorubicin (PEG-DXR) conjugate is described. In this procedure, oxSWNHs were first incubated with PEG-DXR in dimethyl sulfoxide (DMSO) or N,N-dimethylformamide (DMF), two organic solvents with relatively high electric dipole moments, after which the solvent was gradually changed to an aqueous one via addition of water until the final concentration of DMSO or DMF reached 10%. The PEG-DXR-oxSWNH complex that was obtained was able to pass through dextran-based chromatographic media (Sephadex G25) equilibrated with water. By contrast, untreated oxSWNHs and DXR-treated or PEG-treated oxSWNHs were unable to penetrate the column, indicating that the PEG-DXR conjugate endowed oxSWNHs with dispersibility in aqueous solution. In gel filtration experiments, the presence of free DXR had an inhibitory effect on the penetrability of PEG-DXR-oxSWNH complexes, which is consistent with the idea that PEG-DXR interacts with the surfaces of oxSWNHs via its DXR moiety. Quantitative analyses showed that the complex contained more than 250 mg of PEG-DXR for each gram of oxSWNHs. The average diameter of the dispersed complex was estimated to be approximately 160 nm using dynamic light scattering analysis. These results suggest that our method has the potential to open the way for the use of oxSWNHs as a clinically practical drug carrier.


On love.
This paper aims to stimulate awareness of the relationship between adult heterosexual love and sexual health. Although rarely discussed in professional circles, adult love is a powerful ideal that strongly influences both individual and relationship psychology. A gap between one's personal ideal of love and the actual experience of it inevitably appears within a long-term relationship. The feelings and behavior that stems from the gap become a crucial management issue for each individual in a relationship. The gap is minimized by an array of defenses and competing life demands, which either enhance or destabilize individual and relationship well-being. Idealization, denial, and rationalization are necessary to preserve the internal sense of loving at all phases of the committed relationship. The limitations of various definitions of sexual health are reviewed. Sixteen suggestions for preserving sexual health in long-term relationships are offered. Most of these involve guidelines for overcoming narcissism. The limitations of modern therapists, even sex therapists, for forthrightly dealing with sexual problems in terms of love are highlighted.


Mesenteric organ production, hepatic metabolism, and renal elimination of norepinephrine and its metabolites in humans.
This study used regional differences in plasma concentrations of norepinephrine and its metabolites to examine how production of the transmitter by sympathetic nerves, in particular, those innervating mesenteric organs, is integrated with metabolism by the liver and elimination by the kidneys. Higher concentrations of norepinephrine, its glycol metabolites 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol and their sulfate conjugates in portal venous than arterial plasma indicate substantial production of norepinephrine by mesenteric organs (15.5 nmol/min). Much lower concentrations of norepinephrine and its glycol metabolites in plasma leaving than entering the liver indicate their efficient hepatic removal (20 nmol/min). Higher concentrations of vanillylmandelic acid in the hepatic outflow than inflow indicate that this metabolic end product is produced largely from the norepinephrine and glycol metabolites removed by the liver. Renal elimination of vanillylmandelic acid (18-20 nmol/min), produced mainly by the liver (17 nmol/min), and of 3-methoxy-4-hydroxyphenylglycol sulfate (7-9 nmol/min), produced largely by mesenteric organs (7 nmol/min), compromised 86-91% of the total renal elimination of norepinephrine metabolites. The results show that mesenteric organs produce about one-half of the norepinephrine formed in the body. The liver removes substantial amounts of circulating norepinephrine and its glycol metabolites and converts these compounds to vanillylmandelic acid, which is then eliminated from the body by the kidneys. The sulfate conjugates are also metabolic end products eliminated by the kidneys. However, these metabolites are produced by extrahepatic tissues, in particular, mesenteric organs, which represent a significant source of sulfate-conjugated norepinephrine and 3,4-dihydroxyphenylglycol, and the main source of sulfate-conjugated 3-methoxy-4-hydroxyphenylglycol.


Temporal and Force Characteristics of Rapid Single-Finger Tapping in Healthy Older Adults.
The purpose of this study was to examine finger motor function in terms of temporal and force characteristics during rapid single-finger tapping in older adults. Ten older and 10 young males performed maximum frequency tapping by the index, middle, ring, or little finger. Nontapping fingers were maintained in contact with designated keys during tasks. Key-contact force for each of the fingers was monitored using four force transducers. The older subjects had slower tapping rates of all fingers during single-finger tapping than the young subjects. The average forces exerted by the nontapping fingers were larger for the older subjects than for the young subjects during tapping with the ring and little fingers. The ranges of the nontapping finger forces were larger for the older subjects during tapping by the middle, ring, and little fingers than for the young subjects. Thus, the motor abilities of the fingers evaluated by rapid single-finger tapping decline in older adults compared with young adults in terms of both movement speed and finger independence.


Effects of dextranation on the uptake of peptides in micrometastases: studies on binding of EGF in tumor spheroids.
Four different types of radiolabelled dextranated EGF were added to spheroids consisting of the human glioma cells U-343MGaCl2:6. Binding was analysed both in the peripheral well-nourished regions and in the deeper regions containing mainly quiescent cells. The substances had different molecular weights, and they were characterized regarding hydrophilic properties and isoelectric points. Two of the analysed conjugates, 125I-EGF-dextran (CDAP) and 125I-EGF-allyldextran-BSH, gave very low 125I binding in the deeper regions even after 24 h of incubation while better binding in these regions was found for 125I-EGF-dextran-DTPA, 125I-EGF-allyldextran and for the reference substance 125I-EGF. The molecular weight seemed not to be of major importance for the binding properties and there were no clear relationships between binding and the hydrophilic properties or the isoelectric point values. The obtained differences could not be explained by differences in molecular weight or easily measured physicochemical parameters such as hydrophilic properties or isoelectric point values. Thus, other explanations must be found.


Human monocytes express functional receptors for granulocyte colony-stimulating factor that mediate suppression of monokines and interferon-gamma.
In a double-blind, placebo-controlled, randomized study, 10 healthy men received either a single dose of 480 microg granulocyte colony-stimulating factor (G-CSF) or saline. Blood taken from the volunteers was stimulated with 10 microg/mL endotoxin and released cytokines were measured by enzyme-linked immunosorbent assay. Expression of G-CSF receptors on leukocytes was examined by flow cytometry and reverse transcriptase-polymerase chain reaction. Functional activity of these receptors was tested by challenging isolated leukocyte populations to release cytokines with endotoxin in the presence of G-CSF. The G-CSF treatment attenuated the release of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-12, IL-1beta, and interferon (IFN)-gamma in ex vivo lipopolysaccharide (LPS)-stimulated whole blood. In blood from untreated volunteers the presence of G-CSF in vitro also attenuated the LPS-stimulated release of these cytokines. G-CSF in vitro also attenuated TNF-alpha release from elutriation-purified monocytes. In the presence of 10 ng/mL recombinant TNF-alpha, the attenuation of LPS-inducible IFN-gamma release by G-CSF was blunted in whole blood. However, G-CSF had no such effect on IFN-gamma release from isolated lymphocytes stimulated with anti-CD3 or a combination of TNF-alpha and IL-12. G-CSF receptor expression was detected in human neutrophils and monocytes but not in lymphocytes by means of RT-PCR as well as flow cytometry. These results indicate that G-CSF receptors expressed on monocytes are functional in modulating monokine release. We conclude that the attenuation of IFN-gamma release from lymphocytes is not a direct effect of G-CSF on these cells but is rather due to the inhibition of monocytic IL-12 and TNF-alpha release by G-CSF. (Blood. 2000;95:270-276)


Falsely elevated serum tobramycin concentrations in cystic fibrosis patients treated with concurrent intravenous and inhaled tobramycin.
A recently developed tobramycin preparation for inhalation (TOBI(R), Pathogenesis Corp., Seattle, WA) is widely used in CF patients. It is often used in conjunction with intravenous tobramycin. Renal and ototoxicity associated with the use of tobramycin require that serum drug concentrations be monitored during therapy. We report on two patients with falsely elevated, toxic serum tobramycin concentrations while receiving concurrent intravenous and inhaled tobramycin. These cases point out the need for guidelines governing the use and monitoring of simultaneous inhaled and intravenous tobramycin therapy. Pediatr Pulmonol. 2000; 29:43- 45.


Effects of steam and lactic acid treatments on inactivation of Listeria innocua surface-inoculated on chicken skins.
Effectiveness of combined steam (10 and 60 s, 70 degrees C and 98 degrees C) and chemical treatments, using concentrated solutions of lactic acid (1 and 30 min, 5% and 10% lactic acid), on the inactivation of Listeria innocua inoculated on the surface of chicken skins have been studied. Surviving bacteria on the skin were enumerated immediately after treatment, and after 7 days of storage at 4 degrees C. The most effective treatment was the combination of steam of 98 degrees C and 10% lactic acid with its immediate efficacy being mainly attributed to the applied heat treatment. However, after 7-day storage, the treatment's effectiveness was mainly due to the applied acid treatment, which prevented growth of the bacteria that survived the heat treatment. Milder treatments (70 degrees C steam, 5% lactic acid) revealed a genuine synergy between the heat and acid treatments, paving the way for an effective means of reducing bacterial load on the surface of poultry without affecting the product's "raw" appearance.


Criteria from intra-arterial femoral artery pressure measurements combined with reactive hyperaemia to assess the aorto-iliac segment; a prospective study.
Direct femoral artery blood pressure measurements combined with reactive hyperaemia (FAP study) were performed on 50 extremities (45 patients) with multilevel arterial occlusive disease of the lower extremities. In a previous retrospective study we established criteria for detection of significant aorto-iliac occlusive disease. These criteria were used in a prospective way in this study. Twenty-seven extremities were subjected to a proximal and 23 extremities to a distal reconstruction. The half-year postoperative results were evaluated. The criteria used were 86 per cent sensitive, 100 per cent specific and 93 per cent accurate in relation to predicting the postoperative haemodynamic result. The positive predictive value was 100 per cent and the negative predictive value 89 per cent. The criteria are presented and compared with data from the literature. It is concluded that FAP studies are a simple and excellent way to assess the aorto-iliac segment and to predict the outcome of a reconstruction in multilevel arterial occlusive disease.


Association between surgical resident involvement and blood use in noncardiac surgery.
Although there is significant variability in the rate of blood transfusion in surgical patients, the role of surgical skill as a determinant of blood use is unknown. We examined the association between surgery resident participation and intraoperative blood transfusion, and 30-day mortality and complications, among 381,036 patients undergoing noncardiac surgery, adjusting for patient factors and procedure complexity. Compared to attending surgeons working without a resident, cases in which the attendings worked with either Postgraduate Year (PGY) 3 to 4 resident or a PGY5 to 8 resident had a 56% (adjusted odds ratio [AOR], 1.56; 95% confidence interval [CI, 1.48-1.64) or a 78% (AOR, 1.78; 95% CI, 1.70-1.87) higher odds of receiving a blood transfusion, respectively. Involvement of surgical interns or junior residents (PGY1-2), whose role in the operative procedure is assumed to be limited, was associated with a 27% higher odds of receiving a blood transfusion (AOR, 1.27; 95% CI, 1.18-1.37). Overall, resident involvement was not associated with increased risk of 30-day mortality (AOR, 0.97; 95% CI, 0.91-1.04), but was associated with a slightly increased risk of complications (AOR, 1.13; 95% CI, 1.10-1.16). Senior surgery resident participation in noncardiac surgery is associated with between a 56% to 78% higher risk of receiving a blood transfusion intraoperatively compared to attending surgeons working without a resident. Assuming that senior surgical trainees are performing critical parts of the operative procedure and are less skilled than attending surgeons, the findings from this exploratory study suggest that intraoperative blood transfusion may serve as an indirect measure of surgical technical quality.


Computed Tomography is Diagnostic in the Cervical Imaging of Helmeted Football Players With Shoulder Pads.
OBJECTIVE: Prospective, observational case series evaluating the value of cervical spine computed tomography (CT) scans in the initial evaluation of a helmeted football player with suspected cervical spine injury. SUBJECTS: Five asymptomatic male football players, fully equipped and immobilized on a backboard. DESIGN: Multiple 3.0-mm, helically acquired, axially displayed CT images of the cervical spine were obtained from the skull base inferiorly through T1, with images filmed at soft tissue and bone windows. Sagittal and coronal reformatted images were performed. Software was used to minimize metallic artifact. MEASUREMENTS: All series were reviewed by a Board-certified neuroradiologist for image clarity and diagnostic capability. RESULTS: Lateral scout films demonstrated mild segmental degradation, depending on the location of the metallic snaps overlying the spine. Anteroposterior scout films and bone window images were of diagnostic quality. The soft tissue windows showed minimal localized artifact occurring at the same levels as in the lateral scout views. This minimal beam-hardening streak artifact did not affect the diagnostic quality of the soft tissue windows. Reconstructed images were uniformly of clinical diagnostic quality. DISCUSSION: When CT scans were reviewed as a unit, sufficient information was available to allow reliable clinical decisions about the helmeted football player. In light of recent publications demonstrating the difficulty of obtaining adequate radiographs to evaluate cervical spine injury in equipped football players, helmeted athletes may undergo CT scanning without any significant diagnostic limitations.


Impostor phenomenon and mental health: The influence of racial discrimination and gender.
The impostor phenomenon (IP), or feelings of intellectual incompetence, reflects a maladaptive set of cognitions, which pose a significant psychological risk for African American emerging adults. In light of recent evidence suggesting that personal and sociocultural factors may influence the association between IP and psychological adjustment, this study used 2 waves of data to examine the extent to which gender and racial discrimination moderated the association between IP and indices of mental health among 157 African American college students (69% women; mean age = 18.30) attending a predominantly White institution. Analyses revealed that young African American women reporting higher frequencies of racial discrimination and women reporting lower levels of distress resulting from racial discrimination were most vulnerable to negative mental health outcomes, particularly at higher levels of IP. These findings suggest that IP may interact with gender and racial discrimination experiences to influence mental health outcomes. We discuss how these findings can be utilized to inform treatment of African American emerging adults experiencing IP and the importance of considering how gender and discrimination may intersect to exacerbate feelings of intellectual incompetence. (PsycINFO Database Record


The curious death of Constantine Samuel Rafinesque (1783-1840): the case for the maidenhair fern.
Constantine Rafinesque, a French émigré to America in the early 19th century, was a forerunner of Charles Darwin and a zealous field naturalist who identified thousands of new species of plants and animals. His career was controversial in part because of his unfocused ambition to gain scientific recognition. In his later years he published in many areas apart from biology. His polymathic life ended in 1840 with his death (aged 57) from stomach cancer. In 1826 he had developed an illness he thought was consumption and which he believed was cured by a herbal mixture he devised. It may have contained one or more species of ferns related to one now known to induce human gastric carcinoma. Rafinesque's self-medication may have led to his death years later.


LINC00630 promotes cholangiocarcinoma cell proliferation, migration and invasion by mediating the miR-199a/FGF7 axis.
Cholangiocarcinoma (CCA) is a type of cancer with a relatively low morbidity, but poor prognosis. Aberrant long non-coding RNA (lncRNA) expression has been observed in the pathological development of CCA. In the present study, lncRNA long intergenic non-protein coding RNA 630 (LINC00630) was found to be significantly upregulated in CCA tissues and cultured cells. LINC00630 expression was positively associated with histological differentiation, TNM stage and lymph node invasion. Short hairpin RNA (sh)-LINC00630 transfection could effectively decrease CCA cell proliferation, migration and invasion. Further investigations found that LINC00630 could interact with microRNA (miR)-199a, which specifically targeted fibroblast growth factor 7 (FGF7) for degradation. FGF7 overexpression restored the sh-LINC00630 transfection-induced decrease in CCA cell proliferation, migration and invasion. In conclusion, LINC00630 significantly promoted CCA cell proliferation, migration and invasion by upregulating FGF7 through miR-199a sponging.


Partial Purification and Characterization of Uracil-DNA Glycosylase Activity from Chloroplasts of Zea mays Seedlings.
A uracil-DNA glycosylase activity has been purified about 750-fold from the chloroplasts of light-grown Zea mays seedlings. This report represents the first direct demonstration of a DNA-glycosylase repair activity in chloroplasts. The activity, in part, was associated with a chloroplast Triton X-100 sensitive membrane. Its apparent K(m) was 1.0 micromolar for a poly(dA-dT/U) substrate, and its molecular weight, as determined by gel filtration, was 18,000. The enzyme exhibited optimal activity at pH 7.0 with an atypically narrow pH tolerance. Activity was inhibited greater than 60% by 10 millimolar NaCl, 5 millimolar MgCl(2), or 5 millimolar EDTA. Enzyme activity was inhibited 80% by 10 millimolar N-ethylmaleimide, a sulfhydryl group-blocking agent. The activity removed uracil more rapidly from single-stranded DNA than from double-stranded DNA. With this report, uracil-DNA glycosylase activity has now been attributed to all three DNA-containing organelles of eucaryotic cells.


Platelet-associated anti-glycoprotein (GP) IIb-IIIa autoantibodies in chronic immune thrombocytopenic purpura mainly recognize cation-dependent conformations: comparison with the epitopes of serum autoantibodies.
Platelet-associated and serum anti-glycoprotein (GP) IIb-IIIa autoantibodies were investigated in 57 patients with chronic immune thrombocytopenic purpura (ITP). In modified antigen capture ELISA (MACE) using GPIIb-IIIa-specific-, GPIIb-specific-, and GPIIIa-specific-monoclonal antibody (mAb) for antigen capture, platelet-associated anti-GPIIb-IIIa antibodies were detected in 14 out of 37 patients (38%), and these antibodies could be detected with all 3 mAbs used for antigen capture. In the MACE using EDTA-treated platelets at 37 degrees C, the reactivity of platelet-associated anti-GPIIb-IIIa antibodies in 9 out of 10 patients was markedly reduced in both cases of GPIIb-specific- and GPIIIa-specific-mAb used. Immunoprecipitation experiments further confirmed that the EDTA-treatment abrogated the antigenicity of GPIIb-IIIa for platelet-associated antibodies in 2 patients. Serum anti-GPIIb-IIIa autoantibodies were detected in 23 out of 57 patients (40%). However, only 7 out of 23 serum anti-GPIIb-IIIa antibodies could be detected with all 3 mAbs. The MACE using EDTA-treated platelets further showed that the features of serum anti-GPIIb-IIIa antibodies were different from those of platelet-associated antibodies even in the same patient. Our data demonstrate that the platelet-associated anti-GPIIb-IIIa antibodies mainly recognize the cation-dependent antigenic determinants on GPIIb-IIIa and that serum anti-GPIIb-IIIa antibodies may contain some components which differ in specificity from platelet-associated antibodies.


Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients.
The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first- to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10(-5); n = 54, 34%), MRD positive (between <10(-4) and ≥10(-5); n = 20, 12%), and MRD positive (≥10(-4); n = 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P = .007) and overall survival (OS) (HR, 3.1; P = .04), with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10(-4) and ≥10(-5) vs ≥10(-4) (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P = .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P = .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249.


Early breast cancer.
Adoption of urbanised lifestyles together with changes in reproductive behaviour might partly underlie the continued rise in worldwide incidence of breast cancer. Widespread mammographic screening and effective systemic therapies have led to a stage shift at presentation and mortality reductions in the past two decades. Loco-regional control of the disease seems to affect long-term survival, and attention to surgical margins together with improved radiotherapy techniques could further contribute to mortality gains. Developments in oncoplastic surgery and partial-breast reconstruction have improved cosmetic outcomes after breast-conservation surgery. Optimum approaches for delivering chest-wall radiotherapy in the context of immediate breast reconstruction present special challenges. Accurate methods for intraoperative assessment of sentinel lymph nodes remain a clinical priority. Clinical trials are investigating combinatorial therapies that use novel agents targeting growth factor receptors, signal transduction pathways, and tumour angiogenesis. Gene-expression profiling offers the potential to provide accurate prognostic and predictive information, with selection of best possible therapy for individuals and avoidance of overtreatment and undertreatment of patients with conventional chemotherapy. Short-term presurgical studies in the neoadjuvant setting allow monitoring of proliferative indices, and changes in gene-expression patterns can be predictive of response to therapies and long-term outcome.


[Options for the detection and identifications of agents causing viral hemorrhagic fevers].
Viral hemorrhagic fevers (VHFs) belong to the most deadly diseases. Therefore rapid detection and identification of causal agent is very important for epidemiological investigation and countermeasures. The review present all published information about VHF detection and identification, with focus on polymerase chain reaction (PCR) methods. In the first part, basic information about microbiological diagnostic technique is provided. The second part is concerned with detection and identification methods for individual agents causingt VHFs.


Simultaneous phenotypic and genetic characterization of single circulating tumor cells from colon cancer patients.
Since circulating tumor cells (CTCs) have metastatic potential, their genetic and phenotypic characteristics could provide crucial information to establish the most effective therapy. We assessed the clinical utility of a methodology that allows the simultaneous analysis of CTC phenotype and genotype in colon cancer patients and, in addition, whether this methodology could provide complementary information to that obtained by the primary tumor biopsy. Thirty-three non-metastatic (stages 0-III) colon cancer patients and 9 healthy donor samples were evaluated. All peripheral blood samples (10 ml) were analyzed by cytokeratin immunomagnetic enrichment. Eight samples were analyzed by immunocytochemistry and 25 samples were analyzed by FICTION technique for simultaneous cytokeratin expression and chromosome 17 and ERBB2 gene status. A further study was carried out in one patient who showed CTC heterogeneity in chromosomal abnormalities. We analyzed HER2 protein expression on CTCs and FISH and HER2 protein expression in primary tumor of this patient. Our results show that 9.09% of patients had cytokeratin-positive CTCs (CK+/CTCs in peripheral blood). One of the patients showed heterogeneity in chromosomal 17 abnormalities and two different CK expression patterns on CTCs: one CK+/CTCs and one CK-/CTCs. Furthermore, 63.33% of these CTCs overexpressed HER2 protein while the primary tumor of this patient was diploid and did not express HER2 protein. We describe a methodology that allows the simultaneous genetic and phenotypic analysis of CTCs in colon cancer patients, which may provide essential information to select patients who might benefit from specific therapy.


A series of 60 juxtafacet cysts: clinical presentation, the role of spinal instability, and treatment.
Spinal instability may be a cause of juxtafacet cyst formation and the pain and disability that occur after surgical excision of the cyst. To determine the role of instability, a retrospective review of charts identified 60 facet cysts in 56 patients treated over a 6-year period. Three patients developed an asynchronous cyst at the same level but on the opposite side of the previously resected cyst and one patient had a recurrent cyst in the same location. Forty-one cysts were present in patients with radiculopathy and 16 in patients with neurogenic claudication. Two patients presented with myelopathy and one had cauda equina syndrome. Thirty-six of the 60 cysts were located at L4-5, the most mobile segment. Fifteen patients had spondylolisthesis, of whom two experienced worsening spondylolisthesis postoperatively. Seven patients had scoliosis and 20 had systemic arthritis. Fifty-five cysts were resected via mesial facetectomy. Six of the patients undergoing this procedure had transverse process fusions at initial surgery for preoperative instability. Two others required fusion for post-operative instability and increased spondylolisthesis. Follow-up review was available in 95% of patients with an average duration of 12 months. Forty patients had excellent relief of symptoms, 12 had occasional back pain, and one patient did poorly. Flexion/extension views of the spine are recommended both pre- and postoperatively to identify the need for fusion in patients with juxtafacet cysts.


Sunitinib Efficacy in Patients with Advanced pNET in Clinical Practice.
Sunitinib treatment leads to improvement in progression-free survival in patients with advanced pancreatic neuroendocrine tumours (pNETs). However, limited data exist regarding the effectiveness, safety and tolerability in clinical practice. We present the results of the first detailed pNET cohort analysis since sunitinib was approved. Patients with advanced, differentiated pNET treated with sunitinib were retrospectively analysed. All patients had progressive disease before start of sunitinib treatment. Twenty-one patients, with a median age of 64 years (range 28-78), were included in this study. Nineteen patients could be analysed for treatment effectiveness. Twelve (57%) patients exhibited either a partial response (1 patient) or stable disease (11 patients) according to the RECIST criteria. The median progression-free survival was 7.0 months (95% CI 3.0-12.0); the probability of being event-free at 6 months was 52.6% (95% CI 28.4-72.1). Potential influencing factors as Ki-67 index, age or duration of disease did not show significant correlations with the response to sunitinib therapy. Considering the differences in patients' characteristics, sunitinib in daily practice showed effectiveness parameters similar to the phase III trial.


A pathway for disulfide bond formation in vivo.
Protein disulfide bond formation in Escherichia coli requires the periplasmic protein DsbA. We describe here mutations in the gene for a second protein, DsbB, which is also necessary for disulfide bond formation. Evidence suggests that DsbB may act by reoxidizing DsbA, thereby regenerating its ability to donate its disulfide bond to target proteins. We propose that DsbB, an integral membrane protein, may be involved in transducing redox potential across the cytoplasmic membrane.


Ebola virus triggers receptor tyrosine kinase-dependent signaling to promote the delivery of viral particles to entry-conducive intracellular compartments.
Filoviruses, such as the Ebola virus (EBOV) and Marburg virus (MARV), are causative agents of sporadic outbreaks of hemorrhagic fevers in humans. To infect cells, filoviruses are internalized via macropinocytosis and traffic through the endosomal pathway where host cathepsin-dependent cleavage of the viral glycoproteins occurs. Subsequently, the cleaved viral glycoprotein interacts with the late endosome/lysosome resident host protein, Niemann-Pick C1 (NPC1). This interaction is hypothesized to trigger viral and host membrane fusion, which results in the delivery of the viral genome into the cytoplasm and subsequent initiation of replication. Some studies suggest that EBOV viral particles activate signaling cascades and host-trafficking factors to promote their localization with host factors that are essential for entry. However, the mechanism through which these activating signals are initiated remains unknown. By screening a kinase inhibitor library, we found that receptor tyrosine kinase inhibitors potently block EBOV and MARV GP-dependent viral entry. Inhibitors of epidermal growth factor receptor (EGFR), tyrosine protein kinase Met (c-Met), and the insulin receptor (InsR)/insulin like growth factor 1 receptor (IGF1R) blocked filoviral GP-mediated entry and prevented growth of replicative EBOV in Vero cells. Furthermore, inhibitors of c-Met and InsR/IGF1R also blocked viral entry in macrophages, the primary targets of EBOV infection. Interestingly, while the c-Met and InsR/IGF1R inhibitors interfered with EBOV trafficking to NPC1, virus delivery to the receptor was not impaired in the presence of the EGFR inhibitor. Instead, we observed that the NPC1 positive compartments were phenotypically altered and rendered incompetent to permit viral entry. Despite their different mechanisms of action, all three RTK inhibitors tested inhibited virus-induced Akt activation, providing a possible explanation for how EBOV may activate signaling pathways during entry. In sum, these studies strongly suggest that receptor tyrosine kinases initiate signaling cascades essential for efficient post-internalization entry steps.


Flavanol-Rich Cacao Mucilage Juice Enhances Recovery of Power but Not Strength from Intensive Exercise in Healthy, Young Men.
(1) Background: Mucilage within cacao pods contains high levels of polyphenols. We investigated whether consumption of cacao juice enhances the recovery of muscle function following intensive knee extension exercise. (2) Methods: Ten recreationally active males completed two trials of 10 sets of 10 single leg knee extensions at ~80% one repetition maximum. Participants consumed each supplement (ZumoCacao® juice, CJ or a dextrose drink, PL) for 7 days prior to and 48 h post exercise. Knee extension maximum voluntary contraction (MVC) and a counter movement jump (CMJ) were performed at baseline, immediately, 24 h, and 48 h post-exercise. Venous blood samples were collected at each time point and analyzed for indices of inflammation, oxidative damage, and muscle damage. (3) Results: CMJ height recovered faster with CJ at 24 h and 48 h post-exercise (p < 0.05), but there was no effect of CJ on recovery of MVC (both p > 0.05). There was also no effect of the trial on any blood markers (all p > 0.05). (4) Conclusions: Supplementation with CJ for 7 days prior to and 2 days after intensive knee extensor exercise improved functional recovery as shown by an improved recovery of CMJ up to 48 h post-exercise. However, the precise mechanism of action is unclear and requires further investigation.


The criminal transmission of HIV: issues with condom use and viral load.
This article considers two issues in relation to the criminal transmission of HIV. Currently, the use of condoms, and a defendant's viral load, has not been an issue that has been raised in the courts. The article considers how the defence, prosecution and judge may deal with such evidential issues. It will discuss how an expert opinion may be utilised or discredited by counsel for the defendant and counsel for the prosecution. The article will consider how the defence can demonstrate that the defendant was not reckless and how the prosecution can establish that the defendant was actually reckless. It will also assess how the judge, in trial, may address condom use and the level of the defendant's viral load when directing the jury. Finally, it is argued that it is in the public interest to allow condom use and viral loads to be used to negate recklessness.


Prevalence of household falls in long-lived adults and association with extrinsic factors.
to identify the prevalence of falls among older adults and the extrinsic factors associated with them. population-based cross-sectional study with 350 older adults. A household survey was conducted using a questionnaire addressing socio-demographic, clinical, and environmental characteristics. Data were analyzed using Stata Software V.10. Pearson's chi-square test and logistic regression analysis were used with stepwise criteria for selection of variables in the model, with measures of effect expressed in Prevalence Ratio. For input into the multiple model, the variables with p ≤ 0.20 were considered. All ethical care regarding research on human beings has been observed and respected. the prevalence of falls was 46.9%. The extrinsic factors associated with falls were: stairs, uneven floor and pets in the main entrance, lack of anti-slip loose throw rugs and slippery floor in the kitchen, lack of anti-slip loose throw rugs and objects on the floor in the room, lack of grab bars in the shower, lack of grab bars in the toilet and switch away from the bathroom door (p <0.05). falls are frequent in long-lived adults. The identification of the extrinsic factors associated with the occurrence of this event can help in its prevention.


State anxiety, psychological stress and positive well-being responses to yoga and aerobic exercise in people with schizophrenia: a pilot study.
Worsening of schizophrenia symptoms is related to stress and anxiety. People with schizophrenia often experience difficulties in coping with stress and possess a limited repertoire of coping strategies. A randomised comparative trial was undertaken in patients with schizophrenia to evaluate changes in state anxiety, psychological stress and subjective well-being after single sessions of yoga and aerobic exercise compared with a control condition. Forty participants performed a single 30-min yoga session, 20-min of aerobic exercise on a bicycle ergometre at self-selected intensity and a 20-min no exercise control condition in random order. After single sessions of yoga and aerobic exercise individuals with schizophrenia or schizoaffective disorder showed significantly decreased state anxiety (p < 0.0001), decreased psychological stress (p < 0.0001) and increased subjective well-being (p < 0.0001) compared to a no exercise control condition. Effect sizes ranged from 0.82 for psychological stress after aerobic exercise to 1.01 for state anxiety after yoga. The magnitude of the changes did not differ significantly between yoga and aerobic exercise. People with schizophrenia and physiotherapists can choose either yoga or aerobic exercise in reducing acute stress and anxiety taking into account the personal preference of each individual.


Lispro insulin treatment in comparison with regular human insulin in type 2 diabetic patients living in nursing homes.
Lispro insulin has been demonstrated to be effective in reducing post-prandial blood glucose levels. Thirty Type 2 diabetic subjects (18 women and 12 men) living in nursing homes, aged 77 +/- 3 yr, mean systolic pressure 147 +/- 6 and diastolic 82 +/- 4 mmHg, body mass index 27.5 +/- 2 kg/m2, known diabetes duration 10.1+/- 0.7 yr, mean HbA1c 8.5 +/- 0.8%, fasting C-peptide 1.3 +/- 0.5 ng/ml, treated with intensive (4 insulin injections per day) therapy, mean insulin need 45 +/- 7 IU per day, with 2.0 +/- 0.6 hypoglycaemic (blood glucose level below 60 mg/dl) and 13 +/- 4 hyperglycaemic episodes (blood glucose level over 250 mg/dl) per wk, were studied. Their own informed consent or that provided by a family member was obtained before these patients took part in a therapy protocol divided into 3 four-mo periods; in the 1st and 3rd period regular insulin (75% of the total dose) was administered 30 min before each meal, in the second lispro insulin was administered immediately at the end of each meal, according to the carbohydrate quantity ingested with the meal. During the lispro treatment period there was a significant decrease of the mean daily blood glucose 166 +/- 12 regular vs 143 +/- 9 lispro; p<0.01, HbA1c 8.5 +/- 0.6 regular vs 7.6 +/- 0.5 % lispro; p<0.01, triglycerides 261 +/- 40 regular vs 218 +/- 20 mg/dl lispro; p<0.01, hypoglycaemic 2.1 +/- 0.2 regular vs 1.6 +/- 0.3 lispro; p<0.01 and hyperglicaemic 12 +/- 1 regular vs 8 +/- 0.3 lispro; p<0.01 episodes per wk. No statistical difference was recorded between the 1st and the 3rd treatment period. The lispro treatment produced a better metabolic control (mean blood glucose, HbA1c, triglycerides), better lifestyle (less hypo- and hyperglycaemic episodes), better nurse management (no waiting time before, but a more accurate calculation of the right dose administered immediately at the end of each meal). Lispro insulin seems to be a good therapeutic choice not only in Type 1, but also in the large population of elderly Type 2 diabetic patients.


Epidemiologic patterns of diarrheal disease in Argentina: estimation of rotavirus disease burden.
Information on the burden of diarrheal diseases and rotavirus diarrheal diseases would help define strategies for management and prevention and clarify the potential benefits of candidate vaccines. This report of our study of the epidemiology of rotavirus diseases in Argentina analyzes the burden of rotavirus diarrhea, based on those studies and national statistics of diarrhea-associated medical visits, hospital discharges and deaths. Information of diarrhea-associated medical visits, hospital discharges and deaths were provided by the Argentine Health Ministry. Estimation of rotavirus disease burden was performed using the percentage of rotavirus identification from previous reports. The incidence of diarrhea-associated medical visits (1999) was 14 times greater for ages 0 to 4 years than for ages of > or =5 years. Diarrhea-associated hospital discharges (0 to 4 years of age) decreased between 1981 and 1995 from 1.3 per 100 to 0.9 per 100 person-years) and diarrheal deaths (<2 years of age) decreased by a factor of 4 between 1985 and 1999 (64.7 per 100 000 to 16.1 per 100 000 person-years). Frequency of diarrheal deaths, hospital discharges and medical visits were highest in some of the northern Argentine provinces (26.2, 14.7 and 5.9 times greater, respectively, than in the lower risk areas of the country). We estimated that 1 in 2 children born in 1995 visited a public hospital, 1 in 12 required hospitalization, 1 in 1599 died of diarrheal diseases before their fifth year of life; 1 in 6, 1 in 35 and 1 in 4169 of those, respectively, died as a result of rotavirus diarrhea before their third year of life. The number of preventable diarrhea-associated and rotavirus-associated hospitalizations and deaths in Argentina is significant. The lack of rotavirus diagnostic capability in Argentine hospitals has resulted in underestimation of the disease burden of this virus. A rotavirus vaccine would have the potential to avoid thousands of hospitalizations and dozens of deaths, especially in the poor high risk Argentine provinces.


Telemedicine in obstetrics.
Telemedicine lends itself to several obstetric applications and is of growing interest in developed and developing nations worldwide. In this article we review current trends and applications within obstetrics practice. We searched electronic databases, March 2010 to September 2012, for telemedicine use studies related to obstetrics. Thirty-four of 101 identified studies are the main focus of review. Other relevant studies published before March 2010 are included. Telemedicine plays an important role as an adjunct to delivery of health care to remote patients with inadequate medical access in this era of limited resources and emphasis on efficient use of those available resources.


Role of urinary NGAL and KIM-1 as biomarkers of early kidney injury in obese prepubertal children.
Objectives Childhood obesity is an important cause of end-stage renal disease. To date, available markers do not characterize kidney changes, especially in the early stages. kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are already detected before the onset of proteinuria or alterations of glomerular filtration rate and thus might represent biomarkers that directly reflect kidney injury. Methods We characterize kidney injury in a group of 40 obese-prepubertal children compared to 29-healthy age- and gender matched-peers. Anthropometric measurements and body composition were determined. Fasting blood samples were collected for measurement of insulin, glucose, lipid profile, transaminases, cystatin C and creatinine. Urine samples were collected to assess urinary NGAL, KIM-1 and urinary isoprostanes. Kidney length was measured with ultrasound evaluation. Differences between the two groups were evaluated by Mann-Whitney U test, and Spearman correlation analysis was used to explore relationship between variables. Results Triglycerides, alanine transaminase (ALT), glucose, insulin, homeostasis model assessment insulin resistance, triglycerides/high-density lipoprotein (HDL)-cholesterol ratio and cystatin C values were significantly higher in obese children than normal weight peers. Creatinine values were normal and similar between the two groups, while isoprostanes were higher in obese. Obese children had larger kidney sizes, indicating organ hypertrophy. NGAL and KIM-1 were increased in obese children compared to controls. A significant association between NGAL and KIM-1 with adiposity indices, insulin status and markers of oxidative stress postulated a possible effect of obesity in inducing kidney abnormalities. KIM-1 and NGAL are directly related respectively to cystatin C and isoprostanes, supporting the ability of these biomarkers in reflecting early kidney damages in obese subjects. Conclusions These findings suggest that obese subjects exhibit a certain degree of renal damage before kidney function loss.


Technique for bonding gold and silver metals on sapphire.
A technique is described for bonding gold and silver metals onto sapphire. This technique has been successfully used in ac calorimetry for heat capacity of films.


[The analytical approach in using the results of the 1985 population and housing census].
"The possibilities offered by the analytical approach for the use of...statistical information in general and especially...[the] volume and variety [of] information provided by the 1985 [Bulgarian] population and housing census and the concomitant sociological sample surveys are discussed." (SUMMARY IN ENG AND RUS)


Fetus in fetu associated with an undescended testis.
Fetus in fetu is an extremely uncommon cause of an abdominal mass in the neonate; fewer than 30 generally accepted cases are recorded in the literature. We report a case of intraabdominal fetus in fetu, with a unique location within an undescended left testicle. Chromosomal studies of cells from the fetus in fetu and the surviving infant revealed identical 46,XY karyotypes.


TRPM7 is not associated with amyotrophic lateral sclerosis-parkinsonism dementia complex in the Kii peninsula of Japan.
Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS/PDC) is a distinct neurodegenerative disorder characterized by ALS pathology with neurofibrillary tangles (NFTs) in the spinal cord and brain. Recent clinical studies have revealed a high incidence and a high familial occurrence of ALS/PDC in both Guam and the Kii peninsula of Japan, suggesting a strong genetic predisposition to this disorder. The T1482I variant (rs8042919) of TRPM7 gene which is suggested to play roles in regulating the cellular homeostasis of Ca(2+), Mg(2+), and trace metals, has recently been reported to be associated with Guamanian patients with ALS/PDC. To investigate whether TRPM7 is associated with Kii ALS/PDC, we conducted parametric linkage analyses of the TRPM7 locus in a large extended family with ALS/PDC. Linkage analysis did not reveal any evidence supporting the linkage to the TRPM7 locus. Resequencing of the entire coding region of TRPM7 did not reveal any pathogenic mutations in an affected individual in this family. The allele frequencies of the T1482I in affected individuals in this family or in those from other families are not significantly different from those in regional controls or those in HapMap-JPT samples. These results indicate that TRPM7 is not associated with ALS/PDC in the Kii peninsula of Japan.


Identification of a neuronal cell surface molecule, plexin, in mice.
We searched for mouse homologues of the cell adhesion protein plexin which was originally found in Xenopus, and obtained a cDNA encoding a plexin-like protein. We referred to this protein as mouse plexin 1. The overall amino acid identity between mouse plexin 1 and Xenopus plexin was 84%. As in the Xenopus plexin, the extracellular segment of mouse plexin 1 protein possessed three cysteine-rich domains which showed significant homology with the cysteine-rich domain of the c-Met proto-oncogene protein product (c-Met protein) and Met-like receptor protein tyrosine kinases. Northern blot analysis indicated that mouse plexin 1 was predominantly expressed in the brain.


Lymphocyte cell membrane handling of sodium and blood pressure control during salt restriction in normotensive subjects.
Intralymphocytic sodium and potassium concentrations, 22Na efflux rate constants (EFRC) and blood pressures (BPs) were studied in nine normotensive young males without a history of essential hypertension before, during and after 5 weeks of severe sodium depletion. Diastolic and median BPs decreased significantly as estimated by both ambulatory and home readings. A slight decrease in intralymphocytic potassium content and a significant increase in sodium content was found. Measurements of 22Na-EFRC were reduced by 15% in the ouabain-sensitive component of the sodium pump, while the absolute sodium efflux stayed constant during sodium depletion. These results are evidence of a primary inhibition of the sodium pump during salt restriction in normotensives.


Extraoral or intraoral approach in the oblique sliding osteotomy of the mandibular rami? Clinical experience and results.
The clinical results of oblique sliding (subcondylar) osteotomy of the mandibular rami performed by the extraoral or intraoral approach were compared. The patient material comprised 40 patients with mandibular prognathism. Twenty patients were operated upon using the extraoral approach and 20 patients were operated on using the intraoral approach. All patients had intermaxillary fixation for 7 weeks. The patients in both groups were followed up for 18 months. The experience of the operations was that the intraoral approach gave a shorter operation time than the extraoral approach. The extraoral approach, however, gave better visibility in the operation field and greater possibilities of manipulating the proximal fragment into an optimal position. In the follow-up evaluation, there were no significant differences between the two surgical techniques with regard to dental relapse, post-operative occlusion and mandibular function.


Maternal practices that influence Hispanic infants' health and cognitive growth.
Infants born to immigrant mothers, including Hispanic mothers, display birth weight and mortality advantages, compared with other disadvantaged groups. We examined prenatal biological factors and maternal practices that account for this advantage. Then we estimated the extent to which healthy birth outcomes, along with maternal and family factors, contribute to the health and cognitive functioning of Hispanic infants. A representative US sample of 8114 newborns, including 1450 newborns of Hispanic mothers, was drawn randomly in 2001. We compared the mean attributes of infants in subgroups that vary in maternal practices, family attributes, and acculturation levels. We accounted for variations in newborns' gestational age and size for gestational age and their health status and cognitive functioning at 9 months of age. Mexican-heritage and less-acculturated mothers were no more likely than white mothers to bear premature or small-for-gestational age infants, despite large social class disparities, which was explained in part by Hispanic women's low level of prenatal tobacco use. Parenting practices and lower class status of Hispanic mothers then began to slow infants' cognitive development, compared with white infants, because of weaker maternal education and cognitive facilitation during interaction tasks and larger family size. These findings extend earlier research, detailing healthy births among most immigrant Hispanic women. Robust birth outcomes contribute to the early health and cognitive growth of Hispanic infants, but risk factors linked to maternal and home practices overtake these early protective factors by late infancy. Robust births and early health indicators displayed by Hispanic infants should not distract pediatricians from attending to uneven cognitive growth.


Thoracic radiotherapy plus Durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy - employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy: study protocol of the TRADE-hypo trial.
Non-small cell lung cancer is the most common cause of cancer death worldwide, highlighting the need for novel therapeutic concepts. In particular, there is still a lack of treatment strategies for the group of elderly and frail patients, who are frequently not capable of receiving standard therapy regimens. Despite comprising the majority of lung cancer patients, this group is underrepresented in clinical trials. This applies also to elderly and frail patients suffering from unresectable stage III NSCLC, who are unfit for chemotherapy, and, therefore, cannot receive the standard therapy comprising of radiochemotherapy and the recently approved subsequent durvalumab consolidation therapy. These patients often receive radiotherapy only, which raises the concern of undertreatment. The TRADE-hypo trial aims at optimizing treatment of this patient group by combining radiotherapy with concomitant durvalumab administration, thereby employing the immune-promoting effects of radiotherapy, and determining safety, feasibility, and efficacy of this treatment. In this prospective phase II clinical trial, durvalumab therapy will be combined with either conventionally fractionated (CON-group) or hypofractionated (HYPO-group) thoracic radiotherapy. A safety stop-and-go lead-in phase will assess safety of hypofractionated radiotherapy with respect to severe pneumonitis in small patient cohorts before opening full enrollment. Tumor tissue, blood and stool samples will be collected before and during the study period to investigate the immunological mechanisms responsible for checkpoint inhibitor efficacy and immune-promoting effects of radiotherapy. Preclinical data suggests that irradiation-induced immunogenicity can be further increased if applied in a hypofractionated setting, potentially boosting the expected synergistic effect with immune checkpoint inhibition in restoring the immune anti-tumor response. If proven safe and efficient, a hypofractionated radiation schedule can provide a considerably more practicable option for the patient. Taking into consideration the intend to develop a combination treatment strategy that can be made available to patients soon after proving to be efficient and the potentially elevated toxicity of a hypofractionated radiotherapy approach, this trial was designed as a two-trials-in-one design. An accompanying translational research program is planned striving to gain insights into the tumor-host biology and to identify suitable biomarkers to predict therapy response. Clinicaltrials.gov , NCT04351256 . Registered 17 April 2020, Eudra-CT, 2019-002192-33 . Registered 24 October 2019.


Functional Polyimide/Polyhedral Oligomeric Silsesquioxane Nanocomposites.
The preparation of hybrid nanocomposite materials derived from polyhedral oligomeric silsesquioxane (POSS) nanoparticles and polyimide (PI) has recently attracted much attention from both academia and industry, because such materials can display low water absorption, high thermal stability, good mechanical characteristics, low dielectric constant, flame retardance, chemical resistance, thermo-redox stability, surface hydrophobicity, and excellent electrical properties. Herein, we discussed the various methods that have been used to insert POSS nanoparticles into PI matrices, through covalent chemical bonding and physical blending, as well as the influence of the POSS units on the physical properties of the PIs.


A Virus-Spike Tumor-Activatable Pyroptotic Agent.
Invoking the occurrence of pyroptosis is an emerging strategy for the treatment of cancer. However, the practical applications of pyroptosis for cancer therapy are currently hindered due to the lack of tumor-specific and efficient pyroptotic agents in vivo. Herein, a virus-spike tumor-activatable pyroptotic agent (VTPA) for cancer-specific therapy is reported. The VTPA is composed of an organosilica coated iron oxide nanoparticle core and spiky manganese dioxide protrusions, which can readily accumulate in tumor after systemic administration, facilitate the tumor intracellular lysosomal rupture, and be degraded by tumor over-expressed intracellular glutathione (GSH) to release Mn ions and iron oxide nanoparticles (IONPs) for the synergetic activation of nucleotide binding oligomerization domain-like receptors protein 3 (NLRP3) inflammasomes. Consequently, the activation of NLRP3 inflammasomes and the release of lactate dehydrogenase of tumor cells are observed after the treatment of VTPA, resulting in a specific pyroptotic cell death. To our best knowledge, the structure-dependent and tumor intracellular GSH activatable pyroptotic agents represent the first demonstration of cancer-specific pyroptosis in vivo, providing a novel paradigm for the development of next-generation cancer-specific pyroptotic nanomedicine.


Syntheses, luminescence behavior, and assembly reaction of tetraalkynylplatinate(II) complexes: crystal structures of [Pt((t)Bu(3)trpy)(Ctbd1;CC(5)H(4)N)Pt((t)Bu(3)trpy)](PF(6))(3) and [Pt(2)Ag(4)(Ctbd1;CCtbd1;CC(6)H(4)CH(3)-4)(8)(THF)(4)].
A series of tetraalkynylplatinate(II) complexes, (NBu(4))(2)[Pt(Ctbd1;CR)(4)] (R = C(6)H(4)N-4, C(6)H(4)N-3, and C(6)H(3)N(2)-5), and the diynyl analogues, (NBu(4))(2)[Pt(Ctbd1;CCtbd1;CR)(4)] (R = C(6)H(5) and C(6)H(4)CH(3)-4), have been synthesized. These complexes displayed intense photoluminescence, which was assigned as metal-to-ligand charge transfer (MLCT) transitions. Reaction of (Bu(4)N)(2)[Pt(Ctbd1;CC(5)H(4)N-4)(4)] with 4 equiv of [Pt((t)Bu(3)trpy)(MeCN)](OTf)(2) in methanol did not yield the expected pentanuclear platinum product, [Pt(Ctbd1;CC(5)H(4)N)(4)[Pt((t)Bu(3)trpy)](4)](OTf)(6), but instead afforded a strongly luminescent 4-ethynylpyridine-bridged dinuclear complex, [Pt((t)Bu(3)trpy)(Ctbd1;CC(5)H(4)N)Pt((t)Bu(3)trpy)](PF(6))(3,) which has been structurally characterized. The emission origin is assigned as derived from states of predominantly (3)MLCT [d(pi)(Pt) --> pi((t)Bu(3)trpy)] character, probably mixed with some intraligand (3)IL [pi --> pi(Ctbd1;C)], and ligand-to-ligand charge transfer (3)LLCT [pi(Ctbd1;C) --> pi((t)()Bu(3)trpy)] character. On the other hand, reaction of (Bu(4)N)(2)[Pt(Ctbd1;CCtbd1;CC(6)H(4)CH(3)-4)(4)] with [Ag(MeCN)(4)][BF(4)] gave a mixed-metal aggregate, [Pt(2)Ag(4)(Ctbd1;CCtbd1;CC(6)H(4)CH(3)-4)(8)(THF)(4)]. The crystal structure of [Pt(2)Ag(4)(Ctbd1;CCtbd1;CC(6)H(4)CH(3)-4)(8)(THF)(4)] has also been determined. A comparison study of the spectroscopic properties of the hexanuclear platinum-silver complex with its precursor complex has been made and their spectroscopic origins were suggested.


Attenuation Effect of Salvianolic Acid B on Testicular Ischemia-Reperfusion Injury in Rats.
During testicular ischemia-reperfusion, overproduction of reactive oxygen species is associated with testicular injury. We injected hydrogen peroxide (a representative of reactive oxygen species) into normal testis via the testicular artery. The experiment demonstrates that reactive oxygen species can cause spermatogenic injury. Salvianolic acid B, the most abundant bioactive component in Salvia miltiorrhiza Bunge, has been reported to possess a potent antioxidant activity. This study was conducted to evaluate the effect of salvianolic acid B on testicular ischemia-reperfusion injury in a rat testicular torsion-detorsion model. Rats were randomly separated into three groups, including 20 rats in each group: control group with sham operation, testicular ischemia-reperfusion group, and testicular ischemia-reperfusion + salvianolic acid B-treated group. In the testicular ischemia-reperfusion group, left testicular torsion of 720° for 2 hours was induced, and then testicular detorsion was carried out. Rats in the salvianolic acid B-treated group additionally had salvianolic acid B administered intravenously at detorsion. At 4 hours after detorsion, testes of 10 rats from each group were collected to analyze the protein expression of xanthine oxidase which catalyzes generation of reactive oxygen species and malondialdehyde concentration (an indirect indicator of reactive oxygen species). At 3 months after detorsion, testes of the remaining 10 rats from each group were collected to analyze spermatogenesis. Compared with the control group, xanthine oxidase protein expression and malondialdehyde concentration in ipsilateral testes of testicular ischemia-reperfusion group increased significantly, while spermatogenesis decreased significantly. In the salvianolic acid B-treated group, xanthine oxidase protein expression and malondialdehyde concentration in ipsilateral testes decreased significantly, while spermatogenesis increased significantly, compared with the testicular ischemia-reperfusion group. These results suggest that salvianolic acid B can attenuate testicular torsion/detorsion-induced ischemia/reperfusion injury by downregulating the xanthine oxidase protein expression to inhibit reactive oxygen species formation.


Male Breast Cancer: 13-Year Single Institution Experience.
Due to the low incidence of male breast cancer (BC), there are few studies evaluating outcomes. We evaluated the clinicopathologic features and outcomes of male BC. Male patients with BC from January 2006 to December 2018 were identified. Of 49 patients, mean age was 64 (range 33-94) years. Of the 27 (55.1%) patients who had genetic testing, 9 (33.3%) had a Breast Cancer gene (BRCA) 1 or 2 mutation. The majority of patients had a mastectomy (n = 43/49, 87.8%) and had invasive ductal carcinoma (n = 47/49, 95.9%). 20 patients (n = 20/43, 46.5%) had positive lymph nodes. 41 (n = 41/47, 87.2%) patients had estrogen receptor positive disease. The majority of patients were pathologic stage 2 (n = 21/46, 45.7%), followed by stage 1 (n = 15/46, 32.6%), stage 3 (n = 6/46, 13.0%), and stage 4 (n = 4/46, 8.7%). Eight patients had the 21-gene recurrence score performed. Of patients with stage 1-3 BC, 10 (n = 10/43, 23.3%) patients had recurrence. With median follow-up of 4.1 (range .6-10.6) years, 5-year overall survival was 82.9% and 5-year disease-free survival was 65.9%. In conclusion, our cohort of patients with male BC had a high incidence of BRCA mutations and most commonly had high-grade estrogen positive stage 2 tumors. Breast conserving surgery was utilized in 4% of patients and genomic testing utilized in 55% of patients.


Approaches to immunotherapy of cancer: characterization of lymphokines as second signals for cytotoxic T-cell generation.
Lymphokines, the soluble molecules produced by cells of the immune system, regulate cell-cell interactions and, consequently, the functional status of the immune system. Altering immunoregulatory pathways with lymphokines in vivo may provide a mechanism for controlling a variety of immunologic disorders. Although normally produced in vivo in very small quantities, the widespread availability of recombinant lymphokines has made it possible to study the molecular signals involved in production of lymphocyte effectors with activity against tumor. For example, interleukin-2-based cancer immunotherapy programs have, in certain clinical situations, suggested that immunologic intervention can influence the regression of metastatic cancer. Ultimately the successful application of these biologic agents requires an understanding of the interaction between the immune system and tumor on a molecular level. To induce a given biologic effect, it is necessary both to classify the required lymphokines and to identify the relevant effector cell populations. This review will examine the progress made in identifying the requirements for lymphokine-induced cytotoxic T-lymphocyte function.