Does morbid obesity influence perioperative outcomes after video-assisted thoracic surgery (VATS) lobectomy for non-small cell lung cancer? Analysis of the Italian VATS group registry.
Obesity in Europe, and worldwide, has been an increasing epidemic during the past decades. Moreover, obesity has important implications regarding technical issues and the risks associated with surgical interventions. Nevertheless, there is a lack of evidence assessing the influence of obesity on video-assisted thoracic surgery (VATS) lobectomy results. Our study aimed to assess the impact of morbid obesity on perioperative clinical and oncological outcomes after VATS lobectomy using a prospectively maintained nationwide registry. The Italian VATS lobectomy Registry was used to collect all consecutive cases from 55 Institutions. Explored outcome parameters were conversion to thoracotomy rates, complication rates, intra-operative blood loss, surgical time, hospital postoperative length of stay, chest tube duration, number of harvested lymph-node, and surgical margin positivity. From 2016 to 2019, a total of 4412 patients were collected. 74 patients present morbid obesity (1.7%). Multivariable-adjusted analysis showed that morbid obesity was associated with a higher rate of complications (32.8% vs 20.3%), but it was not associated with a higher rate of conversion, and surgical margin positivity rates. Moreover, morbid obesity patients benefit from an equivalent surgical time, lymph-node retrieval, intraoperative blood loss, hospital postoperative length of stay, and chest tube duration than non-morbid obese patients. The most frequent postoperative complications in morbidly obese patients were pulmonary-related (35%). Our results showed that VATS lobectomy could be safely and satisfactorily conducted even in morbidly obese patients, without an increase in conversion rate, blood loss, surgical time, hospital postoperative length of stay, and chest tube duration. Moreover, short-term oncological outcomes were preserved.


Six-month follow-up of eosinophil counts in veteran heroin addicts.
Monthly eosinophil counts were taken from 40 patients while they were undergoing narcotic maintenance. The overall results indicate that there was relatively little change in the eosinophil values throughout the six-month period. This hospital found, however, that there was a positive correlation between elevated eosinophil counts and heavy illicit drug use. This seems to indicate a correlation between intravenous drug use and a high eosinophil count.


Utility of postmortem computed tomography in trauma victims.
A possible way to circumvent the continuing decline in the number of autopsies is to perform computed tomography after death. The present study compares the pathologic findings of postmortem CT tomography (PMCT) in trauma fatalities with those disclosed upon conventional forensic autopsy. Within 6 hours of death, the bodies of 25 trauma victims underwent total body CT scanning, all with permission of the relatives, followed by conventional autopsy in 13 cases under court order. The pathologist and roentgenologist were unaware of each other's findings. The pathologic findings of PMCT plus conventional autopsy provided more information than either examination alone. Of the total 127 pathologic findings, 44.9% were diagnosed by both conventional autopsy and PMCT, 29.9% were not revealed by PMCT, whereas conventional autopsy missed 25.2%, and PMCT detected more bone injuries than did autopsy, whereas the latter was superior to PMCT in discovering soft-tissue pathologic states. In all, PMCT revealed 70.5% and autopsy 74.8% of the pathologic states. Although PMCT was not more effective than conventional autopsy in exposing pathologic entities, it increased the yield of findings when combined with conventional autopsy. Where conventional autopsy is unattainable, PMCT may be effective in shedding light on the pathologic state and mechanism of death in trauma fatalities.


Inspiratory and expiratory vital capacity.
Vital capacity (VC) is frequently measured by two different methods (inspiration vs expiration). The difference in results is not readily available in the literature. The VC was measured both ways in 60 subjects, including many with obstructive airway disease. Only a minor difference in mean VC (75 +/- ml SD) was found. The methods are probably interchangeable.


High integrin αVβ6 affinity reached by hybrid domain deletion slows ligand-binding on-rate.
The role of the hybrid domain in integrin affinity regulation is unknown, as is whether the kinetics of ligand binding is modulated by integrin affinity state. Here, we compare cell surface and soluble integrin αVβ6 truncation mutants for ligand-binding affinity, kinetics, and thermodynamics. Removal of the integrin transmembrane/cytoplasmic domains or lower legs has little effect on αVβ6 affinity, in contrast to β1 integrins. In integrin opening, rearrangement at the interface between the βI and hybrid domains is linked to remodeling at the ligand-binding site at the opposite end of the βI domain, which greatly increases in affinity in the open conformation. The larger size of the βI-hybrid interface in the closed state suggests that the hybrid domain stabilizes closing. In agreement, deletion of the hybrid domain raised affinity by 50-fold. Surface plasmon resonance and isothermal titration calorimetry gave similar results and the latter revealed tradeoffs between enthalpy and entropy not apparent from affinity. At extremely high affinity reached in Mn2+ with hybrid domain truncation, αVβ6 on-rate for both pro-TGF-β1 and fibronectin declined. The results suggest that the open conformation of αVβ6 has lower on-rate than the closed conformation, correlate with constriction of the ligand-binding pocket in open αVβ6 structures, and suggest that the extended-closed conformation is kinetically selected for ligand binding. Subsequent transition to the extended-open conformation is stabilized by its much higher affinity for ligand and would also be stabilized by force exerted across ligand-bound integrins by the actin cytoskeleton.


MiR-195 Inhibits Tumor Growth and Metastasis in Papillary Thyroid Carcinoma Cell Lines by Targeting CCND1 and FGF2.
MicroRNA (miRNA) dysregulation was commonly seen in papillary thyroid carcinoma (PTC), and miR-195 was verified to be downregulated in PTC by the large data set analysis from The Cancer Genome Atlas (TCGA). Our study aimed to explore the biological functions and the underlying molecular mechanisms of miR-195 in PTC. The relative expression of miR-195 and its target genes were assessed by quantitative RT-PCR assay in 38 pairs of PTC and the adjacent thyroid tissues. Assays were performed to evaluate the effect of miR-195 on the proliferation, migration, and invasion in PTC cell lines. Moreover, we searched for targets of miR-195 and explored the possible molecular pathway of miR-195 in PTC. We found that miR-195 was downregulated in PTC cell lines and tissues. Overexpression of miR-195 significantly inhibited cell proliferation, migration, and invasion in K1 and BCPAP cell lines. CCND1 and FGF2, which had inverse correlations with miR-195 in clinical specimens, were found to be the direct targets of miR-195. Furthermore, miR-195 might be involved in PTC tumorigenesis by suppressing the Wnt/β-catenin signaling pathway. These results highlight an important role of miR-195 in the initiation and progression of PTC and implicate the potential application of miR-195 in PTC target therapy.


[Swiss warmblood horse with symptoms of hereditary equine regional dermal asthenia without mutation in the cyclophylin B gene (PPIB)].
Hereditary equine dermal asthenia (HERDA) is an autosomal recessive skin disease that affects predominantly Quarter Horses and related breeds. Typical symptoms are easy bruising and hyperextensible skin on the back. The prognosis is guarded, as affected horses cannot be ridden normally and are often euthanised. In the Quarter Horse, HERDA is associated with a mutation in cyclophilin B (PPIB), an enzyme involved in triple helix formation of collagen. Here we describe the case of a Swiss Warmblood filly with symptoms of HERDA without PPIB-mutation and in which we also could exclude Ehlers-Danlos syndrome Type IV, VI, VIIA, VIIB and VIIC (dermatosparaxis type) as etiological diseases.


Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity.
Reactivation of dormant infections causes an immense burden of morbidity and mortality in the world at large. Reactivation can occur as a result of immunosuppression, environmental insult, or aging; however, the cause of reactivation of such infections is often not clear. We have previously shown that persistence of the parasite Leishmania major is controlled by endogenous CD4(+) CD25(+) regulatory T (T reg) cells. In this report, we show that despite efficient parasite clearance at secondary sites of infection, Leishmania superinfection can cause disease reactivation at the primary site. Our results strongly suggest that T reg cells, whose numbers increase in sites of reactivation, are directly responsible for such reactivation. Depletion of CD25(+) cells at the time of secondary challenge prevented disease reactivation at the site of persistent infection while strengthening the expression of immunity at the site of secondary challenge. Finally, transfer of T reg cells purified from infected mice into chronically infected mice was sufficient to trigger disease reactivation and prevent the expression of an effector memory response. Our results demonstrate that after persistence is achieved, an equilibrium between T reg cells and effector lymphocytes, which can be disturbed by superinfection, controls the efficiency of recall immune responses and disease reactivation.


[Detection of fusion genes resulting from chromosome abnormalities in childhood acute lymphoblastic leukemia].
To detect the expression of the fusion genes resulting from chromosome abnormalities in childhood acute lymphoblastic leukemia(ALL) and its conformity to WHO classification. Sixty-two children with ALL were investigated. The expression of fusion genes was determined by multiplex reverse transcription-polymerase chain reaction (RT-PCR), karyotyping (R band) and immunophenotyping (by flow cytometry) were also performed. Of the 62 patients, 23(37.1%) were found to carry 13 different fusion genes. The patients with immunophenotype of Pre-B-ALL were found to carry: TEL/AML1(3 cases); E2A/PBX1, E2A/HLF, TLS/ERG, MLL/AF4, MLL/AF9, MLL/AF10, MLL/AFX-MLL/AF6-MLL/ELL, MLL/AF6-MLL/ELL, dupMLL (one case for each); and HOX11 (6 cases). The patients with immunophenotype of Pre-T-ALL were found to carry: TAL1D (4 cases, one is also found to have HOX11 expression); and HOX11 (2 cases). The multiplex RT-PCR in combination with chromosome analysis revealed genetic abnormalities in 69.4%(43/62) of childhood ALL. Multiplex RT-PCR combined with chromosome analysis and immunophenotyping can provide reliable and helpful information for the diagnosis, therapy evaluation and prognosis prediction in childhood ALL, which may also serve as a basis on which to implement the criteria of WHO classification.


Evaluation of two methods of the jump float serve in volleyball.
A novel jump-focused (JF) technique of the jump float serve was compared with the conventionally used contact-focused (CF) method. Seven elite male (height: 195 ± 6 cm) and two elite female (height: 181 and 182 cm) volleyball players were videoed at 60 Hz performing both techniques. Horizontal and vertical ball contact coordinates, pre- and postcontact ball velocities, and initial projection angles were determined. The JF technique resulted in a significantly higher mean contact height, t(8) = 4.12, p = .006, d = 0.72, initial serve speed, t(8) = 4.71, p = .006, d = 2.03, and significantly flatter initial projection angle, t(8) = 2.53, p = .036, d = 0.63, relative to the CF technique. The precontact vertical ball velocity was also significantly higher, t(8) = 8.04, p = .004, d = 2.86. The higher precontact vertical ball velocity suggests it is more difficult to make accurate contact with the ball during the JF technique. However, this method promotes a more favorable ball trajectory and a greater initial serve speed. When combining the random lateral movement patterns inherent in any float serve, with the reduced flight time associated with the JF technique, a more challenging passing scenario can be presented to the defensive team in comparison with the current CF technique.


Comparative assessment of neuro-cognitive impairments among patients with brain tumor and healthy adults.
Most brain tumor patients encounter cognitive impairments. Coping with such challenges is intolerable for them. This study tries to determine the diagnostic role of cognitive tests, CPT, Stroop and TOL, in assessing neuro-cognitive impairments among patients with brain tumor and healthy participants. A cross-sectional study was done on a sample of 15 to 65 years old of 84 brain tumor patients and 84 healthy Iranians. Participants of both groups were physically and mentally examined and approved by neurosurgeons, neurologists and psychiatrists. By completing the questionnaires, they all entered the study and were referred to the neuroscientist for performing the tests. According to CPT, Stroop and TOL tests, the performance of both groups was significantly regarding about age, sex and education variables (P < 0.05). Brain tumor patients in comparison to healthy participants met more cognitive changes on sustained, selective attention and planning. Therefore, diagnosis and assessment of these cognitive changes before and after the surgery can help rehabilitating patients' brains and improve their lives quality.


Testing for tetrahydrobiopterin responsiveness in patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency.
Pharmacological levels of the phenylalanine hydroxylase enzyme cofactor, tetrahydrobiopterin (BH4), reduce plasma phenylalanine levels in some patients with phenylketonuria (PKU), providing the first pharmacological therapy for PKU. Responsiveness to this therapy must be determined empirically through a BH4 loading test or trial. The authors have analyzed the loading tests currently in use in light of the numerous factors that can influence their results. Sapropterin dihydrochloride is a stable, synthetic form of BH4 approved for treatment of PKU in responsive patients. An expert panel identified evidence from published reports of clinical experience. Reports of research involving at least 25 patients and published in English were considered. In all, 14 studies met both criteria; eight employing the sapropterin dihydrochloride preparation from Schircks Laboratories and six the sapropterin dihydrochloride preparation from Biomarin/Merck Serono. The arbitrary responsiveness definition of a >30% reduction in blood phenylalanine appears to be a good compromise between sensitivity and specificity for the initial screening test. However, individual patient characteristics should be considered when interpreting results, especially in patients with low baseline phenylalanine levels.


Reimagining Children's Rights in the US.
The US faces a pivotal moment of opportunity and risk regarding issues affecting children (aged 0-17 years). Although the US remains the only United Nations member state to not have ratified the Convention on the Rights of the Child (CRC), a child rights framework is essential for child health professionals seeking to advance many issues affecting children in the US. The Reimagining Children's Rights project (2020-2021) conducted an in-depth environmental scan of relevant literature and policy analysis using the Three Horizons design process to assess strategies that could advance the rights and well-being of children in the US. The project was overseen by a steering committee and informed by an advisory committee composed of youth leaders and experts in children's rights, advocacy, health, law, and a range of child-specific issues (eg, youth justice, early childhood development), who provided expert input on strategic considerations for advancing children's rights. Seven findings about advancing children's rights in the US are notable, all reflecting current gaps and opportunities for using a whole-child rights framework in the US, even without formal adoption of the CRC. Actionable strategies, tactics, and tools to leverage sustainable change in the multitude of issue areas can advance the current state of children's rights. High-potential strategies for catalyzing advancement of children's rights include youth activism, innovations in governance and accountability, legislative action, impact litigation, place-based initiatives, education and public awareness, alignment with other children's movements, and research. The child rights framework is unifying and adaptive to future unforeseen challenges. Children's rights provide a powerful, synergistic framework for child health professionals-in partnership with youth and other leaders-to increase equity and protect the rights and well-being of all children in the US.


A case of occipitalization in the human skull.
Occipitalization of the atlas is an osseous anomaly of the craniovertebral junction. The aim of this paper is to present an anatomical variant of the fused atlas with the occipital bone and discuss similar cases described in literature. The skull of an adult male analysed in this study belonged to the cranial collection of the Department of Anatomy of the Jagiellonian University, Medical Collage. A tight bony fusion between the anterior arch of the atlas, the left portion of the posterior arch, the lateral masses of the atlas, and the occipital bone was observed. Hence, the left and right superior articular facets of the atlas were fused with the corresponding occipital condyles. The anteroposterior dimension of both inferior articular facets was the same (20 mm), while the transverse diameter of the right one was considerably smaller (12 mm). The transverse diameter of the left inferior articular facets was 17 mm. The right and the left transverse process of the atlas were normally developed, each of them contained transverse foramen, and they were not fused with the occipital bone. The circumference of the foramen magnum was minimally diminished by the osseous structures of the atlas fused to the occipital bone. The sagittal and transverse diameters of the foramen magnum (38 mm x 34 mm) were within the normal range of variation. However, the asymmetrical anatomy of the inferior articular facets of the atlas give rise to speculation that movement in the atlantoaxial joint was disturbed by assimilation with the occipital bone.


Power and clinical psychology: a model for resolving power-related ethical dilemmas.
This article considers power in clinical psychology. It is argued that power is present at every level of clinical psychologists' practice and can be used positively and negatively. Drawing on organizational, ethical, psychological, and personal influences, a heuristic problem-solving model for the process of understanding and resolving power-related ethical dilemmas is proposed. It is contended that such a model provides a humane and systematic process of understanding and working through power-related ethical dilemmas. It is argued that resolving power-related ethical issues cannot be achieved through the statement of absolute values but rather requires a process of understanding, action, and review. The model is used to draw out implications for promoting ethical practice and preventing the abuse of power in clinical psychology.


Proliferative epithelial disease identified in nipple aspirate fluid and risk of developing breast cancer: a systematic review.
Guideline panels recognize the need to increase the accuracy of identifying women at high risk of developing breast cancer who would benefit from prevention strategies. The characterization of proliferative epithelial disease found in nipple aspirate fluid (PED-NAF) may be a relevant risk factor. To comprehensively review the published literature to characterize and summarize abnormal cytology detected by NAF and the association of PED-NAF with subsequent risk of developing breast cancer. Literature identified by systematic searches in MEDLINE PubMed and the Cochrane Library was screened for articles containing primary data on NAF cytology based on predefined inclusion and exclusion criteria. Study characteristics, cytological group distribution, and incidence of breast cancer. Thirty articles were included after full-text review, of which 16 were analyzed, containing data on 20,808 unique aspirations from over 17,378 subjects. Seven (44%) of the studies used the King cytological classification system. Among aspirations from women free of breast cancer, 51.5% contained fluid, in which over 27.7% had PED on cytology. In the two prospective studies of 7850 cancer-free women, abnormal cytology by NAF carried a 2.1-fold higher risk (95% CI, 1.6-2.6; p < 0.001) of developing breast cancer, compared with women from whom no fluid could be obtained. PED-NAF among women free of breast cancer, compared with no fluid being obtained, has an independent risk of developing breast cancer comparable to the risk of a woman with a positive family history of breast cancer. These findings have implications for augmenting risk prediction and clinical decisions concerning breast cancer surveillance and chemoprevention. As with all reviews, heterogeneity across studies may have influenced the results. The limited literature calls for prospective studies on asymptomatic women with long-term follow-up.


Deoxycholic acid causes DNA damage in colonic cells with subsequent induction of caspases, COX-2 promoter activity and the transcription factors NF-kB and AP-1.
Evidence is accumulating that bile acids induce apoptosis in colonic cells. Therefore, it becomes important to study the underlying molecular mechanisms and the role of this phenomenon in tumor promotion. Minutes after exposure of HCT 116 and HT-29 cells to deoxycholate (DCA), DNA damage, measured using the COMET assay, was evident. Caspase-3 was rapidly activated in HCT 116 cells exposed to DCA, whereas in HT-29 cells, caspase-3 activation was delayed. Using transient transfections with reporter constructs, we showed that the transcription factors activator protein-1 (AP-1) and NF-kB were increased in HCT 116 cells, in a dose-dependent fashion, by DCA COX-2 promoter activity was also induced by DCA and using mutant COX-2 promoter plasmids, we showed that the ability of DCA to induce promoter activity was partly dependent upon a functional NF-kB and C/EBP site, and completely dependent on a functional c-AMP response element site. DNA damage thus appears to be the initiating event in DCA-induced apoptosis. In conclusion, the bile acid, DCA, has a major impact on apoptotic mechanisms in colonic cells and this may be contributing to its effect as a tumor promoter.


A pandemic strain of calicivirus threatens rabbit industries in the Americas.
Rabbit Hemorrhagic Disease (RHD) is a severe acute viral disease specifically affecting the European rabbit Oryctolagus cuniculus. As the European rabbit is the predominant species of domestic rabbit throughout the world, RHD contributes towards significant losses to rabbit farming industries and endangers wild populations of rabbits in Europe and other predatory animals in Europe that depend upon rabbits as a food source. Rabbit Hemorrhagic Disease virus (RHDV) - a Lagovirus belonging to the family Caliciviridae is the etiological agent of RHD. Typically, RHD presents with sudden death in 70% to 95% of infected animals. There have been four separate incursions of RHDV in the USA, the most recent of which occurred in the state of Indiana in June of 2005. Animal inoculation studies confirmed the pathogenicity of the Indiana 2005 isolate, which caused acute death and pathological changes characterized by acute diffuse severe liver necrosis and pulmonary hemorrhages. Complete viral genome sequences of all USA outbreak isolates were determined and comparative genomics revealed that each outbreak was the result of a separate introduction of virus rather than from a single virus lineage. All of the USA isolates clustered with RHDV genomes from China, and phylogenetic analysis of the major capsid protein (VP60) revealed that they were related to a pandemic antigenic variant strain known as RHDVa. Rapid spread of the RHDVa pandemic suggests a selective advantage for this new subtype. Given its rapid spread, pathogenic nature, and potential to further evolve, possibly broadening its host range to include other genera native to the Americas, RHDVa should be regarded as a threat.


BAsE-Seq: a method for obtaining long viral haplotypes from short sequence reads.
We present a method for obtaining long haplotypes, of over 3 kb in length, using a short-read sequencer, Barcode-directed Assembly for Extra-long Sequences (BAsE-Seq). BAsE-Seq relies on transposing a template-specific barcode onto random segments of the template molecule and assembling the barcoded short reads into complete haplotypes. We applied BAsE-Seq on mixed clones of hepatitis B virus and accurately identified haplotypes occurring at frequencies greater than or equal to 0.4%, with >99.9% specificity. Applying BAsE-Seq to a clinical sample, we obtained over 9,000 viral haplotypes, which provided an unprecedented view of hepatitis B virus population structure during chronic infection. BAsE-Seq is readily applicable for monitoring quasispecies evolution in viral diseases.


Correspondence Analysis to Demonstrate the Relationship Between Musculoskeletal Pain and Body Mass Index.
Background As obese people frequently experience persistent musculoskeletal pain (MSP), understanding the relationship between obesity and pain may help develop therapeutic and preventative approaches to treat discomfort from MSP. MSP can negatively impact such individuals' quality of life and their ability to perform daily tasks. Therefore, more thorough investigations are required to fully understand the connection between obesity and MSP. Aims To assess the relationship between musculoskeletal pain(MSP) and body mass index (BMI) among women in the age group of 25 to 65 years. Methods From July to December 2022, a cross-sectional study among women between the ages of 25 and 65 was carried out near the Rural Health Training Centre (RHTC) of a medical college in the Lucknow District of Uttar Pradesh, India. In total, 443 women took part in the study. BMI was computed, weight and height were recorded, and MSP at any site (i.e., neck, shoulders, upper back, upper arms, lower back, forearms, wrists, hip/buttocks, thighs, knees, lower legs, and ankles) was noted. The data were analyzed through correspondence analysis. Results Of the 443 women that participated in the study, 224 (50.6%) had MSP, and 9.3% and 28.2% were obese or overweight, respectively. Obese and overweight women were found to be at a higher risk of upper and lower back pain. Conclusion In our study, a significant relationship between MSP and BMI was confirmed and visualized by correspondence analysis.


[Therapeutic apheresis: selective methods].
Therapeutic apheresis is a term that describes numerous different procedures that remove pathological substances from the body. They are used in cases when conservative treatment measures fail, and may be useful as an adjuvant method for treatment of different diseases which have a common feature pathogenic protein substance (paraproteins, antibodies...) or pathogenic substance attached to proteins (toxins), that has to be removed from the body. These substances could be removed by nonselective (plasmapheresis and therapeutic plasma exchange), semiselective (cascade apheresis) or selective methods (different adsorption techniques). The best results are achieved by selective methods, while they remove only pathogenic substances (useful substances remain in plasma), do not require replacement fluid, and have significantly less complications. Different methods of therapeutic apheresis achieved good results in treatment of age-related macular degeneration, sudden hearing-loss, dilatative cardiomyopathy, cardiovascular and cerebrovascular diseases, hepatic failure, inflammatory bowel diseases, and different neurologic conditions like Guillain-Barre syndrome, multiple sclerosis and myastenia gravis. They are useful in renal transplantation for cases with positive crossmatch or AB0 blood group incompatibility, as well as for treatment of acute humoral rejection. Methods of therapeutic apheresis are save and efficient when performed by experienced personel, trained to prevent, timely recognize and treate possible complications.


Surface morphology of sound enamel after argon laser irradiation: an in vitro scanning electron microscopic study.
Argon laser irradiation (ALI) at relatively low fluences (energy densities) enhances the caries resistance of sound enamel. The purpose of this SEM study was to compare the effects of argon laser irradiation at relatively low fluences (11.5 Joules/cm2 and 100 Joules/cm2) on enamel surface morphology. Following a fluoride-free prophylaxis, 12 extracted caries-free human molars were sectioned into tooth quarters. Tooth quarters were treated as follows: 1) Mesiobuccal-ALI at 11.5 J/J/cm2 for 10; 2) Distobuccal-Control; 3) Mesiolingual-ALI at 100 J/J/cm2 for 10; and 4) Distolingual-Control. Enamel surface morphology was compared among the two argon laser irradiation groups and matched non-treated control enamel surfaces by SEM. Argon laser treatment resulted in considerable alterations in the surface morphology compared with matched controls. Control enamel surfaces showed relatively smooth contours with occasional termination of enamel prisms at the surface. Both argon laser treatment groups had intact enamel surfaces lacking prism end markings and cratering of the enamel surface. A discontinuous granular surface permeated by numerous microporosities of < 1.0 micron in diameter was created with both argon laser treatment groups. Globular deposits of approximately 0.5 to 2 microns in maximum dimension composed the surface coatings. These deposits were admixed with areas of fine microporosities. Argon laser irradiation at relatively low fluences produces surface coatings which may act as reservoirs for mineral phases during an acidogenic attach of the enamel and may provide a certain degree of protection against a cariogenic challenge.


Characterization of myo-inositol utilization by Corynebacterium glutamicum: the stimulon, identification of transporters, and influence on L-lysine formation.
Although numerous bacteria possess genes annotated iol in their genomes, there have been very few studies on the possibly associated myo-inositol metabolism and its significance for the cell. We found that Corynebacterium glutamicum utilizes myo-inositol as a carbon and energy source, enabling proliferation with a high maximum rate of 0.35 h-1. Whole-genome DNA microarray analysis revealed that 31 genes respond to myo-inositol utilization, with 21 of them being localized in two clusters of >14 kb. A set of genomic mutations and functional studies yielded the result that some genes in the two clusters are redundant, and only cluster I is necessary for catabolizing the polyol. There are three genes which encode carriers belonging to the major facilitator superfamily and which exhibit a >12-fold increased mRNA level on myo-inositol. As revealed by mutant characterizations, one carrier is not involved in myo-inositol uptake whereas the other two are active and can completely replace each other with apparent Kms for myo-inositol as a substrate of 0.20 mM and 0.45 mM, respectively. Interestingly, upon utilization of myo-inositol, the L-lysine yield is 0.10 mol/mol, as opposed to 0.30 mol/mol, with glucose as the substrate. This is probably not only due to myo-inositol metabolism alone since a mixture of 187 mM glucose and 17 mM myo-inositol, where the polyol only contributes 8% of the total carbon, reduced the L-lysine yield by 29%. Moreover, genome comparisons with other bacteria highlight the core genes required for growth on myo-inositol, whose metabolism is still weakly defined.


Role of Intestinal LXRα in Regulating Post-prandial Lipid Excursion and Diet-Induced Hypercholesterolemia and Hepatic Lipid Accumulation.
Post-prandial hyperlipidemia has emerged as a cardiovascular risk factor with limited therapeutic options. The Liver X receptors (Lxrs) are nuclear hormone receptors that regulate cholesterol elimination. Knowledge of their role in regulating the absorption and handling of dietary fats is incomplete. The purpose of this study was to determine the role of intestinal Lxrα in post-prandial intestinal lipid transport. Using Lxrα knockout (nr1h3-/-) and intestine-limited Lxrα over-expressing [Tg(fabp2a:EGFP-nr1h3)] zebrafish strains, we measured post-prandial lipid excursion with live imaging in larvae and physiological methods in adults. We also conducted a long-term high-cholesterol dietary challenge in adults to examine the chronic effect of modulating nr1h3 gene dose on the development of hypercholesterolemia and hepatic lipid accumulation. Over-expression of Lxrα in the intestine delays the transport of ingested lipids in larvae, while deletion of Lxrα increases the rate of lipid transport. Pre-treating wildtype larvae with the liver-sparing Lxr agonist hyodeoxycholic acid also delayed the rate of intestinal lipid transport in larvae. In adult males, deletion of Lxrα accelerates intestinal transport of ingested lipids. Adult females showed higher plasma Lipoprotein lipase (Lpl) activity compared to males, and lower post-gavage blood triacylglycerol (TAG) excursion. Despite the sexually dimorphic effect on acute intestinal lipid handling, Tg(fabp2a:EGFP-nr1h3) adults of both sexes are protected from high cholesterol diet (HCD)-induced hepatic lipid accumulation, while nr1h3-/- mutants are sensitive to the effects of HCD challenge. These data indicate that intestinal Lxr activity dampens the pace of intestinal lipid transport cell-autonomously. Selective activation of intestinal Lxrα holds therapeutic promise.


Clinical effects of continuous theta burst stimulation for generalized anxiety disorder and a mechanism involving α oscillations: a randomized controlled trial.
Continuous theta burst stimulation (cTBS) is a much more rapid protocol than low-frequency repetitive transcranial magnetic stimulation (rTMS), but no clinical trial has yet investigated the efficacy and mechanisms of cTBS for the treatment of generalized anxiety disorder. The purpose of this study was to compare the clinical effects and α oscillations induced by cTBS versus 1 Hz rTMS as predictors of response, and to assess the underlying mechanisms of the therapeutic effects of cTBS in patients with generalized anxiety disorder. We randomly allocated 120 patients with generalized anxiety disorder to receive cTBS (n = 41), 1 Hz rTMS (n = 40) or sham cTBS (n = 39) over the right dorsolateral prefrontal cortex; we also included healthy controls (n = 30) to compare neurophysiological data. We analyzed changes in Hamilton Anxiety Rating Scale scores and α oscillations (frequency and power) at baseline, post-treatment and 1-month follow-up. After 20 sessions of treatment, patients' anxiety had improved and α power had increased in the cTBS and 1 Hz rTMS groups. However, at 1-month follow-up the cTBS group had significantly more responders and remitters, and higher α oscillations than the 1 Hz rTMS group (post hoc analysis: cTBS > rTMS > sham). At baseline, α frequency was inversely correlated with psychological symptom scores on the Hamilton Anxiety Rating Scale (r = -0.613, p < 0.001); post-treatment, this correlation was present only in the cTBS group (r = -0.685, p < 0.001). Electroencephalography data were limited to the α band. Our findings provide evidence for the clinical use of cTBS, a novel brain stimulation protocol. Its therapeutic effects may be the result of increasing α frequency, thereby improving the psychological symptoms of generalized anxiety disorder.


Cervical and intracranial artery dissections.
This review summarizes recent therapeutic advances in cervical (CeAD) and intracranial artery dissection (IAD) research. Despite unproven benefits, but in the absence of any signal of harm, in patients, with acute ischemic stroke attributable to CeAD, intravenous thrombolysis and, in case of large-vessel occlusion, endovascular revascularization should be considered. Future research will clarify which patients benefit most from either treatment modality. For stroke prevention, the recently published randomized controlled TREAT-CAD study showed that, against the initial hypothesis, aspirin was not shown non-inferior to anticoagulation with vitamin K antagonists (VKAs). With the results of two randomized controlled trials (CADISS and TREAT-CAD) available now, the evidence to consider aspirin as the standard therapy of CeAD is weak. Further analyses might clarify whether the assumption supports, in particular, that patients presenting with cerebral ischemia, clinical or subclinical with magnetic resonance imaging surrogates, might benefit most from VKA treatment. In turn, it remains to be shown, whether in CeAD patients presenting with pure local symptoms and without hemodynamic compromise, antiplatelets are sufficient, and whether a dual antiplatelet therapy during the first weeks of treatment is recommendable. The observation that ischemic strokes occurred (or recurred) very early after CeAD diagnosis, consistently across randomized and observational studies, supports the recommendation to start antithrombotic treatment immediately, whatever antithrombotic agent is chosen in each individual case. The lack of a license for the use in CeAD patients and the paucity of data are still arguments against the use of direct oral anticoagulants in CeAD. Nevertheless, due to their beneficial safety and efficacy profile proven in atrial fibrillation, these agents are a worthwhile treatment option to be tested in further CeAD treatment trials. In IAD, the experience with the use of antithrombotic agents is limited. As the risk of suffering intracranial hemorrhage is higher in IAD than in CeAD, the use of antithrombotic therapy in IAD remains controversial.


Cerebellar remodelling decades after spinal cord insult: neuroplasticity in poliomyelitis survivors.
The cerebellum integrates a multitude of motor and cognitive processes through ample spinal and supratentorial projections. Despite emerging evidence of adaptive neuroplasticity, cerebellar reorganisation in response to severe spinal insult early in life is poorly characterised. The objective of this study is the systematic characterisation of cerebellar integrity metrics in a cohort of adult poliomyelitis survivors as a template condition for longstanding lower motor neuron injury. A total of 143 participants, comprising 43 adult poliomyelitis survivors and 100 age- and sex-matched healthy controls were recruited in a prospective, single-centre neuroimaging study with a uniform structural and diffusion imaging protocol. First, standard voxelwise grey and white matter analyses were performed. Then, the cerebellum was anatomically segmented into lobules, and cortical thickness and grey matter volumes were evaluated in each lobule. The integrity of cerebellar peduncles was also assessed based on their diffusivity profiles. Compared to healthy controls, poliomyelitis survivors exhibited greater cortical thickness in lobules I, II, and III in the right hemisphere and in lobules VIIIA and VIIIB bilaterally. A trend of higher cortical thickness was also detected lobules I, II and III in the left hemisphere. Enhanced cerebellar peduncle organisation was detected, particularly within the middle cerebellar peduncles. Increased cerebellar integrity measures in poliomyelitis survivors are primarily identified in lobules associated with sensorimotor functions. The identified pattern of cerebellar reorganisation may represent compensatory changes in response to severe lower motor neuron injury in childhood and ensuing motor disability.


Innovative pain therapy with a fixed combination of prolonged-release oxycodone/naloxone: a large observational study under conditions of daily practice.
Chronic pain has a marked negative impact on quality of life. Opioid treatment is often effective in controlling this pain, but it has numerous side-effects, particularly affecting bowel function. The objective of the study was to evaluate the efficacy and safety of combined prolonged-release (PR) oxycodone and naloxone for the treatment of chronic pain under conditions of daily practice. This is a multi-center, prospective, non-interventional, observational study. Analgesic efficacy and bowel function were assessed in patients suffering from long-lasting, severe chronic pain of different etiology (cancer and non-cancer) treated with combined PR oxycodone/PR naloxone and observed for 4 weeks. Pain was evaluated using the Brief Pain Inventory (BPI-SF) and constipation symptoms due to opioid treatment using the Bowel Function Index (BFI). Descriptive data are presented based on observed cases, efficacy and tolerability data additionally based on completely documented patients (for each parameter at least more than 2000 patients). This trial was registered with the German Federal Institute for Drugs and Medical Devices (BfArM), study code: OXN9002. A total of 7836 patients were recruited in 6496 centers. Strongest pain was reduced by an average of 2.9 points on an 11-point numeric rating scale (p < 0.001, evaluation populations n = 4271 or 2454, respectively). A progressive rise of patients without pain during the 24 hours prior to each evaluation (first visit, 11.6%; final visit, 33.8%; p < 0.001, evaluation populations n = 4413 or 3014, respectively) was observed. Bowel function improved significantly, indicated by a decrease of the bowel function index from 38.2 +/- 30.9 to 15.1 +/- 18.6 (p < 0.001, evaluation population n = 7640 or 6769, respectively) on a numeric scale of 0-100. Opioid-pretreated patients presented a marked decrease of constipation from 71% at the first visit to 34.1% at the final visit (p < 0.001, evaluation populations n = 5751 or 5123, respectively). Efficacy and tolerability were reported as good or very good by 84% and 87% of patients (evaluation populations n = 7590 and 7577, respectively). There were 4526 adverse events in 1566 patients (20.0%) with 3386 classified as adverse drug reactions; 177 patients (2.3%) suffered serious adverse events which were classified as serious adverse drug reactions in 51 cases. PR oxycodone/PR naloxone achieved good pain control and significantly reduced constipation and associated opioid-induced gastrointestinal symptoms in this observational 4-weeks-trial.


Intraocular lens implantation: report of 100 cases (50 intracapsular vs. 50 extracapsular).
This paper compares the results of 50 intracapsular lens implants with 50 extracapsular lens implants. The intracapsular lens implants were done from 1969 to 1971 and were considered successful in approximately 70% of the cases as compared to the extracapsular lens implants which were done from 1974 to 1975 and were considered successful in 96% of the cases. Extracapsular cataract extraction with lens implantation is a safe procedure. I believe that 80% of all cataract surgery within the next 10 years will be performed with extracapsular extraction and lens implantation.


From green to red: Urban heat stress drives leaf color evolution.
Prevalence of impervious surface and resulting higher temperatures in urban areas, known as urban heat islands, comprises prominent characteristics in global cities. However, it is not known whether and how urban plants adapt to such heat stress. This study focused on Oxalis corniculata, which has intraspecific polymorphism in leaf color (green and red) and examined whether the leaf color variation is associated with urban heat stress. Field observations revealed that green-leaved plants were dominant in green habitats, and red-leaved individuals were dominant in urban habitats, at local (<500 meters), landscape (<50 kilometers), and global scales. Growth and photosynthesis experiments demonstrated that red-leaved individuals performed better under heat stress, while green-leaved individuals performed better under nonstressful conditions. Genome-wide SNP analysis suggests that the red leaf may have evolved multiple times from the ancestral green leaf. Overall, the results suggest that the red leaves of O. corniculata observed in cities worldwide are evidence of plant adaptive evolution due to urban heat islands.


Enhancing effects of the chemical adjuvant levamisole on the DNA vaccine pVIR-P12A-IL18-3C.
DNA-based vaccination is an attractive alternative for overcoming the disadvantages of inactivated virus vaccines; however, DNA vaccines alone often generate only weak immune responses. In this study, the efficacy of LMS as a chemical adjuvant on a DNA vaccine (pVIR-P12A-IL18-3C) encoding the P1-2A and 3C genes of the FMDV and swine IL-18, which provides protection against FMDV challenge, was tested. All test pigs were administered booster vaccinations 28 days after the initial inoculation, and were challenged with 1000 ID50 FMDV O/NY00 20 days after the booster vaccination. Positive and negative control groups were inoculated with inactivated virus vaccine and PBS respectively. The DNA vaccine plus LMS induced greater humoral and cell-mediated responses than the DNA vaccine alone, as evidenced by higher concentrations of neutralizing and specific anti-FMDV antibodies, and by higher concentrations of T-lymphocyte proliferation and IFN-y production, respectively. FMDV challenge revealed that the DNA vaccine plus LMS provided higher protection than the DNA vaccine alone. This study demonstrates that LMS may be useful as an adjuvant for improving the protective efficiency of DNA vaccination against FMDV in pigs.


Neural multi-atlas label fusion: Application to cardiac MR images.
Multi-atlas segmentation approach is one of the most widely-used image segmentation techniques in biomedical applications. There are two major challenges in this category of methods, i.e., atlas selection and label fusion. In this paper, we propose a novel multi-atlas segmentation method that formulates multi-atlas segmentation in a deep learning framework for better solving these challenges. The proposed method, dubbed deep fusion net (DFN), is a deep architecture that integrates a feature extraction subnet and a non-local patch-based label fusion (NL-PLF) subnet in a single network. The network parameters are learned by end-to-end training for automatically learning deep features that enable optimal performance in a NL-PLF framework. The learned deep features are further utilized in defining a similarity measure for atlas selection. By evaluating on two public cardiac MR datasets of SATA-13 and LV-09 for left ventricle segmentation, our approach achieved 0.833 in averaged Dice metric (ADM) on SATA-13 dataset and 0.95 in ADM for epicardium segmentation on LV-09 dataset, comparing favorably with the other automatic left ventricle segmentation methods. We also tested our approach on Cardiac Atlas Project (CAP) testing set of MICCAI 2013 SATA Segmentation Challenge, and our method achieved 0.815 in ADM, ranking highest at the time of writing.


Definition of a population-specific DXA reference standard in Italian women: the Densitometric Italian Normative Study (DINS).
Osteoporosis is currently defined on the basis of the T-score by dual-energy X-ray absorptiometry (DXA). Despite its limitations, this definition is applied worldwide. However, the normal values provided by manufacturers may not be fully representative of specific local populations. So far, there are no normative data in the Italian population using Hologic densitometers. The Densitometric Italian Normative Study (DINS) is an ongoing multi-center study that aims to establish reference values for bone densitometry with dual-energy X-ray absorptiometry (DXA) in the male and female Italian population. In this paper we report the results of the lumbar vertebrae (L2-L4) and proximal femur in 1,622 women aged 20-79 years. Bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry (DXA) on Hologic bone densitometers (Hologic, Waltham, Mass.). Most of the subjects were examined with a QDR 4500. The BMD of the lumbar vertebrae was virtually constant between 20 and 49 years (test for trend: P=0.66); the BMD values between 20-45 in premenopausal women (mean 1.036; SD 0.109 g/cm(2)) were thus defined as the peak bone mass values, significantly lower compared to the Hologic reference curve (mean 1.079, SD 0.11 g/cm(2)). The mean BMD values of the femoral neck were virtually identical to those of the NHANES study in the first 3 decades; after the age of 50 the BMD values were slightly greater than those of the NHANES subject. The subject classification according to the WHO criteria was similar using the DINS and NHANES reference values for the femur; for the spine, the Hologic reference values classified a larger proportion of women as osteoporotic (21 vs. 16%) or osteopenic (42 vs. 38%) compared to DINS.


Hybrid Procedure for Neonates With Hypoplastic Left Heart Syndrome at High-Risk for Norwood: Midterm Outcomes.
Hybrid procedure offers patients with severe congenital heart disease an alternative initial procedure to conventional surgical reconstruction. We report the midterm outcomes of a cohort of neonates who had a hybrid procedure for variants of hypoplastic left heart syndrome because they were at high risk for the Norwood procedure. Between December 2005 and January 2013, 41 neonates underwent bilateral pulmonary artery banding followed by ductal stenting by means of a sternotomy at a median age of 6 days (range, 2 to 18 days) and weight of 2.6 kg (range, 1.5 to 3.7 kg). Thirty-five patients had hypoplastic left heart syndrome, and 6 patients had critical aortic stenosis with hypoplastic left ventricle. Primary indications for the hybrid procedure were low birth weight in 17 patients, hypoplastic left ventricle with the possibility of later biventricular repair in 6 patients, intact or near-intact atrial septum in 5 patients, and poor patient condition in 13 patients. Echocardiographic, angiographic, operative, and clinical data were reviewed. Outcomes were summarized with descriptive statistics and risk factors for mortality identified. All but 6 patients had an antenatal diagnosis, and 24 patients were from other congenital cardiac centers. Nine patients had perioperative balloon aortic valvuloplasty, 1 patient had fetal balloon aortic valvuloplasty, and 17 patients had intervention to their atrial septum (41.4%). There were 9 inpatient deaths (21.9%) and 4 interstage deaths (9.8%) after the hybrid procedure. Twenty-eight patients subsequently underwent either the Norwood procedure (11 patients), combined stage I and II (14 patients), or biventricular repair (3 patients). No patient had heart transplantation. Among the patients who had combined stage I and II as a second procedure after the hybrid procedure, there were 2 early deaths, 1 late death before the Fontan, and 1 late death after the Fontan completion after combined stage I and II. All patients who had subsequent Norwood procedure were midterm survivors. Three of the 4 patients who had biventricular repair were midterm survivors. Overall survival was 56.1% at a median follow-up of 32.0 months. By univariate analysis, patient factors, intact or near-intact atrial septum, and aortic atresia were associated with nonsurvival. Hybrid procedure as an alternative to the Norwood procedure offers good midterm survival in patients deemed at high risk for neonatal reconstruction.


Exploring the association between initial serum alcohol concentration and polysubstance use: More than a simple "gateway drug" effect?
Polysubstance abuse (PSA) is a significant problem affecting our society. In addition to negatively affecting the health and well-being of substance users, alcohol and/or drug abuse is also associated with heavy injury burden. The goal of this study was to determine if elevated serum alcohol (EtOH) levels on initial trauma evaluation correlate with the simultaneous presence of other substances of abuse (SOAs). We hypothesized that PSA would be more common among patients who present with EtOH levels in excess of the legal blood alcohol content (BAC) (≥0.10%). An audit of trauma registry records from January 2009 to June 2015 was performed. Abstracted data included patient demographics, BAC measurements, all available formal determinations of urine/serum "drug screening," Glasgow Coma Scale (GCS) assessments, injury mechanism/severity, and 30-day mortality. Stratification of BAC was based on the 0.10% cutoff. Parametric and nonparametric statistical testing was performed, as appropriate, with significance set at α = 0.05. We analyzed 1550 patients (71% males, mean age: 38.7 years) who had both EtOH and SOA screening. Median GCS was 15 (interquartile range [IQR]: 14-15). Median ISS was 9 (IQR: 5-17). Overall 30-day mortality was 4.25%, with no difference between elevated (≥0.10) and normal (<0.10) EtOH groups. For the overall study sample, the median BAC was 0.10% (IQR: 0-0.13). There were 1265 (81.6%) patients with BAC <0.10% and 285 (18.4%) patients with BAC ≥0.10%. The two groups were similar in terms of mechanism of injury (both, ∼95% blunt). Patients with BAC ≥0.10% on initial trauma evaluation were significantly more likely to have the findings consistent with PSA (e.g., EtOH + additional substance) than patients with BAC <0.10% (377/1265 [29.8%] vs. 141/285 [49.5%], respectively, P < 0.001). Among polysubstance users, BAC ≥0.10% was significantly associated with cocaine, marijuana, and opioid use. This study confirms that a significant proportion of trauma patients with admission BAC ≥0.10% present with the evidence of additional substance use. Cocaine and opioids were most strongly associated with acute alcohol intoxication. Our findings support the need for further research in this important area of public health concern. In addition, specific efforts should focus on primary identification, remediation of withdrawal symptoms, prevention of drug-drug interactions, and early PSA intervention.


An immunogenic phenotype in paternal antigen-specific CD8+ T cells at embryo implantation elicits later fetal loss in mice.
Central to pregnancy success is a state of T cell tolerance to paternal antigens, which is initiated at conception. The role and regulation of specific phenotypes of CD8+ T cells in mediating pregnancy tolerance is not clear. This study aimed to investigate the impact on pregnancy outcome of altering the cytokine environment during maternal CD8+ T cell priming in early pregnancy. Transgenic Act-mOVA male mice were mated to C57BL/6 (B6) females to generate fetuses expressing ovalbumin (OVA) as a model paternal antigen. OVA-reactive CD8+ OT-I T cells were activated in vitro with OVA in the presence of either transforming growth factor-β1 (TGFB1) plus interleukin-10 (IL10), or IL2, to mimic normal or dysregulated uterine conditions, respectively, and transferred into pregnant mice on gestational day 3.5. OT-I T cells activated with TGFB1 and IL10, like naive OT-I T cells, did not alter embryo implantation or fetal viability. In contrast, OT-I T cells activated with IL2 caused extensive fetal loss manifesting in mid-gestation. IL2-activated OT-I T cells expressed less FOXP3 and higher interferon-γ (IFNG) than cells activated with TGFB1 and IL10. Fetal loss did not occur in females mated with B6 males, demonstrating the antigen specificity of fetal loss, and was not abrogated by maternal genetic C1q deficiency indicating a mechanism independent of antibody-mediated cytotoxicity. These data indicate that alternative phenotypes generated in maternal CD8+ T cells at the time of priming with paternal antigens can impact pregnancy outcome, such that inappropriate activation of CD8+ T cells before implantation is capable of causing antigen-specific fetal loss later in pregnancy.


Splitting of IVP bovine blastocyst affects morphology and gene expression of resulting demi-embryos during in vitro culture and in vivo elongation.
Embryo splitting might be used to increase offspring yield and for molecular analysis of embryo competence. How splitting affects developmental potential of embryos is unknown. This research aimed to study the effect of bovine blastocyst splitting on morphological and gene expression homogeneity of demi-embryos and on embryo competence during elongation. Grade I bovine blastocyst produced in vitro were split into halves and distributed in nine groups (3 × 3 setting according to age and stage before splitting; age: days 7-9; stage: early, expanded and hatched blastocysts). Homogeneity and survival rate in vitro after splitting (12 h, days 10 and 13) and the effect of splitting on embryo development at elongation after embryo transfer (day 17) were assessed morphologically and by RT-qPCR. The genes analysed were OCT4, SOX2, NANOG, CDX2, TP1, TKDP1, EOMES, and BAX. Approximately 90% of split embryos had a well conserved defined inner cell mass (ICM), 70% of the halves had similar size with no differences in gene expression 12 h after splitting. Split embryos cultured further conserved normal and comparable morphology at day 10 of development; this situation changes at day 13 when embryo morphology and gene expression differed markedly among demi-embryos. Split and non-split blastocysts were transferred to recipient cows and were recovered at day 17. Fifty per cent of non-split embryos were larger than 100 mm (33% for split embryos). OCT4, SOX2, TP1 and EOMES levels were down-regulated in elongated embryos derived from split blastocysts. In conclusion, splitting day-8 blastocysts yields homogenous demi-embryos in terms of developmental capability and gene expression, but the initiation of the filamentous stage seems to be affected by the splitting.


Prevalence of glucose intolerance in young male Ethiopian immigrants.
The prevalence of intolerance to glucose was compared between young immigrant Ethiopian Jews shortly after their arrival to Israel, a similar group of Ethiopians 2-3 years after their arrival to Israel, and young Israeli students. A relatively high prevalence of glucose intolerance was found in both Ethiopian groups, but we could not demonstrate any deterioration in glucose tolerance after 2-3 years of Israeli life-style in the Ethiopian groups. In spite of high blood glucose levels in response to 75 g glucose load, when compared to Israeli students the Ethiopians' fasting insulin levels and insulin response to 75 g of glucose was relatively low, suggesting a higher glucose threshold for insulin secretion. However, in the Ethiopians, impaired glucose tolerance was associated with hyperinsulinemia, suggesting that similar to some other populations glucose intolerance is associated with insulin resistance.


Obesity in patients undergoing dialysis and kidney transplantation.
Obesity poses a major challenge for nephrologists and patients alike, and its prevalence among patients with kidney disease is increasing at least as fast as in the general population. Although the body mass index (BMI) is the most commonly used measurement of excess adiposity, it has important limitations that can be ameliorated by incorporating other markers of body composition. The influence of obesity on outcomes in patients undergoing dialysis and kidney transplantation is of great interest. Although the preponderance of epidemiologic data suggests that, at least in patients undergoing dialysis, obesity has a neutral or protective effect on mortality, although this has not been confirmed in interventional studies needed to establish causality. The effect of obesity on other important outcomes such as quality of life has yet to be determined, and much less information on obesity and outcomes is available in the kidney transplantation population. Similarly, research on the optimal strategies and effects of weight loss in dialysis and kidney transplantation patients is at a nascent stage.


Inhibition of antibody responses to phosphocholine by C-reactive protein.
C-reactive protein (CRP) is an acute phase serum protein in man that binds to the cell wall C-polysaccharide (PnC) of Streptococcus pneumoniae via phosphocholine (PC) determinants. We have previously shown that in mice CRP increases splenic clearance of PnC-coated autologous erythrocytes and S. pneumoniae, and increases survival after pneumococcal infection. Because CRP alters clearance of particulate PnC antigens, we tested its effect on immunization with pneumococci. Pretreatment of mice with 50 to 200 micrograms CRP 30 min before immunization with serotype 3 S. pneumoniae resulted in dose-dependent inhibition of the antibody response to PC. Both serum hemagglutinin and splenic PFC against PC were decreased in CRP-treated mice tested from 1 to 10 days after injection of antigen. CRP treatment had no effect on the antibody response to the serotype 3 capsular polysaccharide, another T-independent antigen. To determine whether CRP inhibition was related to altered processing of particulate antigen, mice were immunized with horse red blood cells (HRBC) conjugated with PC or PnC and the PFC responses to PC and HRBC were determined. CRP treatment resulted in specific inhibition of the PFC response to PC in both cases without affecting the response to HRBC. These results indicate that inhibition of the antibody response by CRP is not the result of altered antigen localization and processing, and that CRP may prevent immunization by masking determinants on bacterial or other surfaces.


Photophysical behaviour of an opp-dibenzoporphyrin (2,12-diethyl-3,13-dimethyldibenzo[g,q]porphyrin) in micelles and organic solvents.
Photophysical parameters relevant to photodynamic therapy have been studied for a novel lipophilic opp-dibenzoporphyrin (DBP), 2,12-diethyl-3,13-dimethyldibenzo[g,q]porphyrin, in N,N-dimethylformamide and TX-100 micelles. The structure of DBP is intermediate between a porphyrin and a phthalocyanine and is associated with higher molar extinction coefficients in the red Q-bands than those found in the haematoporphyrin derivative currently used for photodynamic therapy. The ultrafast measurements on DBP in DMF revealed a fast (ps) lifetime for the second excited singlet state. Observed lifetimes of the first excited singlet state were found to be similar in DMF and TX-100 (12.2 and 14.7 ns), but excited triplet lifetimes were different in the two solvents (0.46 and 2.86 micros). The fluorescent quantum yields of DBP in DMF and TX-100 were twice that of free-base tetraphenylporphyrin and the singlet oxygen quantum yield in DMF and TX-100 was high (0.56-0.65). The combination of stable chemical structure, stronger red-absorption, high singlet oxygen quantum yields, and high fluorescent quantum yields suggests that DBP is an potential chromophore for applications in photodynamic therapy.


From the smallest to the largest subcellular plant pathogen: Citrus tristeza virus and its unique p23 protein.
Knowledge on diseases caused by Citrus tristeza virus (CTV) has greatly increased in last decades after their etiology was demonstrated in the past seventies. Professor Ricardo Flores substantially contributed to these advances in topics like: i) improvement of virus purification to obtain biologically active virions, ii) sequencing mild CTV isolates for genetic comparisons with sequences of moderate or severe isolates and genetic engineering, iii) analysis of genetic variation of both CTV genomic RNA ends and features of the highly variable 5' end that allow accommodating this variation within a conserved secondary structure, iv) studies on the structure, subcellular localization and biological functions of the CTV-unique p23 protein, and v) potential use of p23 and other 3'-proximal regions of the CTV genome to develop transgenic citrus resistant to the virus. Here we review his main achievements on these topics and how they contributed to deeper understanding of CTV biology and to new potential measures for disease control.


Two-Part Models and Quantile Regression for the Analysis of Survey Data With a Spike. The Example of Satisfaction With Health Care.
Background: Results of patient satisfaction questionnaires can contain a spike at the value corresponding to a complete satisfaction. A possible interpretation is that there are two types of respondents, those who are willing to provide a negative evaluation to one or more items proposed in the questionnaire and those who will always provide a completely positive evaluation irrespective of the item. The aim of the present study is to compare various statistical approaches to the analysis of such data using data from a rehabilitation patient survey of the German Statutory Pension Insurance Scheme as an example. Method: We used data from 272,806 respondents who participated in the survey from 2008 to 2011. We illustrate four models: linear regression, logistic regression, a two-part model based on the assumption of two underlying populations and quantile regression, which does not require any distributional assumptions. For each model we consider the relationship of the satisfaction score with two covariates. Results: While providing correct estimates of the mean values (marginal effects), the assumptions of the linear model are violated which can lead to false interpretations. A two-part regression which consists of a logistic regression followed by a linear regression conditional on not being fully satisfied is a useful alternative. For research questions focusing on specific parts of the distribution, logistic regression as well as quantile regression are to be considered. Discussion: Data with a spike represents a statistical challenge but a range of modeling approaches is available to provide sound interpretations and correct answers to research questions.


[Determination of deoxynivalenol in grain and its products by solid-phase extraction coupled with high performance liquid chromatography-tandem mass spectrometry].
A method was established for the determination of deoxynivalenol (vomitoxin) in grain and its products based on solid-phase extraction coupled with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The sample was firstly extracted by acetonitrile-water (84:16, v/v). The extract was then cleaned-up by an HLB solid phase extraction cartridge. The separation was carried out on a Phenomenex Kinetex C18 column (100 mm x4. 6 mm, 2.6 microm) with a gradient elution using 0.3% per hundred ammonia solution-acetonitrile as mobile phases. The analysis of deoxynivalenol was performed under electrospray negative ionization mode. The limit of detection (LOD, S/N= 3) and the limit of quantification (LOQ, S/N = 10) were 20 microg/kg and 50 microg/kg, respectively. A good linearity (r > 0.99) was achieved for the target compound over the range of 20-1000 pg/L. The recoveries at the three spiked levels (50, 100, 500 microg/kg) in the blank matrices such as flour, barley, soybean, rice, cornmeal, cassava and wheat, were varied from 75.6% to 111.0% with the relative standard deviations no more than 13. 0%. The method is accurate, efficient, sensitive and practical. The cost of pretreatment is obviously reduced by replacing immunoaffinity columns and Mycosep columns with HLB columns which have the same purification effect.


Human herpesvirus 8 (HHV-8) inhibits monocyte differentiation into dendritic cells and impairs their immunostimulatory activity.
Several viruses interfere with the host immune response by infecting dendritic cells and by altering their functional activity. Here, we report that exposure to Human herpesvirus 8 (HHV-8) of human dendritic cell (DC) monocyte precursors resulted in impaired immature DC (iDC) formation as indicated by a reduced CD1a expression. In accordance, the immunostimulatory ability of such iDC was significantly reduced, as indicated by mixed lymphocyte culture (MLR) assays. The immunostimulatory functions of DCs were similarly inhibited by the UV inactivated viral stocks, suggesting that the virus binding is sufficient to determine the observed effect. Furthermore, HHV8 mediated inhibition of the DC allostimulatory function was present in lipopolysaccharide (LPS) matured DCs. A strong reduction of the expression of the costimulatory molecule CD80 on the surface of the virus-exposed cells was observed as well. Impairment of dendritic cell development and function might represent an important strategy used by HHV-8 to escape from the host defense mechanisms.


Expression levels of eIF4E, VEGF, and cyclin D1, and correlation of eIF4E with VEGF and cyclin D1 in multi-tumor tissue microarray.
The mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E), is a rate-limiting factor of cap-dependent translation initiation. When elevated, eIF4E greatly facilitates translation of a selected spectrum of mRNAs coding for proteins critical to angiogenesis and growth such as vascular endothelial growth factor (VEGF) and cyclin D1. Expression levels of eIF4E, VEGF, and cyclin D1 were examined in multi-tumor tissue microarray by immunohistochemistry and analyzed quantitatively. eIF4E, VEGF and cyclin D1 protein were elevated in tumors of the breast (62, 78, or 40%), colon (72, 77, or 12%), glioblastoma multiforme (48, 68, or 52%), lymphoma (66, 74, or 38%), melanoma (59, 73, or 58%), NSCLC (81, 82, or 29%), ovary (50, 39, or 13%), and prostate (78, 97, or 21%), respectively. eIF4E levels were strongly correlated with VEGF and cyclin D1 in melanoma (Spearman's r=0.97 and 0.77; all P<0.0001); moderately in tumors of the breast (r=0.55 and 0.41; all P<0.0005), colon (0.63 and 0.56; all P<0.0001), lung (0.53 and 0.53; all P<0.005), lymphoma (0.50 and 0.61; all P<0.0005), prostate (0.46 and 0.54; all P<0.005), or ovary (0.56 and 0.46; all P<0.005); and weakly in tumors of glioblastoma multiforme (r=0.20 and 0.31; all P>0.15). The significant association of eIF4E with VEGF and cyclin D1 in multiple tumors supports a role for eIF4E in translational regulation of proteins related to angiogenesis and growth.


Nanoengineered Gallium Ion Incorporated Formulation for Safe and Efficient Reversal of PARP Inhibition and Platinum Resistance in Ovarian Cancer.
Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer (OC). However, the inevitable development of platinum and poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) resistance is associated with poor outcomes, which becomes a major obstacle in the management of this disease. The present study developed "all-in-one" nanoparticles that contained the PARPi olaparib and gallium (Ga) (III) (olaparib-Ga) to effectively reverse PARPi resistance in platinum-resistant A2780-cis and SKOV3-cis OC cells and in SKOV3-cis tumor models. Notably, the olaparib-Ga suppressed SKOV3-cis tumor growth with negligible toxicity. Moreover, the suppression effect was more evident when combining olaparib-Ga with cisplatin or carboplatin, as evaluated in A2780-cis and SKOV3-cis cells. Mechanistically, the combined treatment induced DNA damage, which elicited the activation of ataxia telangiectasia mutated (ATM)/AMT- and Rad3-related (ATR) checkpoint kinase 1 (Chk1)/Chk2 signal transduction pathways. This led to the arrest of cell cycle progression at S and G2/M phases, which eventually resulted in apoptosis and cell death due to unrepairable DNA damage. In addition, effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal models. Altogether, the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells, and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both PARPi and platinum.


Comparative Analysis of Skin Bacterial Diversity and Its Potential Antifungal Function Between Desert and Pine Forest Populations of Boreal Toads Anaxyrus boreas.
The skin microbiome in amphibians has gained a lot of attention as some of its members play a protective role against pathogens such as the fungus Batrachochytrium dendrobatidis (Bd). The composition of skin bacterial communities has been suggested as one of the factors explaining differences in susceptibility to Bd among amphibian species and populations. The boreal toad Anaxyrus boreas is known to be susceptible to Bd, and severe population declines in its southeastern range have been documented. However, throughout A. boreas distribution, populations present differences in susceptibility to Bd infections which may be associated with differences in skin microbial diversity. This study compared the skin bacterial diversity and Bd infection levels of A. boreas in one desert population and one pine forest population from Baja California, Mexico. We found that desert and pine forest toad populations exhibit differences in skin bacterial community structure but show similar Bd infection levels. Using a predictive method, we found that the abundance of bacteria with potential Bd-inhibitory properties differed between uninfected and infected individuals but not between populations. Our data suggest that several bacteria in the skin community may be offering protection from Bd infections in these A. boreas populations. This study provides foundational evidence for future studies seeking to understand the skin-microbial variation among boreal toads' populations and its relation with Bd susceptibility.


Optimization of the reconstruction parameters in [123I]FP-CIT SPECT.
The aim of this work was to obtain a set of parameters to be applied in [123I]FP-CIT SPECT reconstruction in order to minimize the error between standardized and true values of the specific uptake ratio (SUR) in dopaminergic neurotransmission SPECT studies. To this end, Monte Carlo simulation was used to generate a database of 1380 projection data-sets from 23 subjects, including normal cases and a variety of pathologies. Studies were reconstructed using filtered back projection (FBP) with attenuation correction and ordered subset expectation maximization (OSEM) with correction for different degradations (attenuation, scatter and PSF). Reconstruction parameters to be optimized were the cut-off frequency of a 2D Butterworth pre-filter in FBP, and the number of iterations and the full width at Half maximum of a 3D Gaussian post-filter in OSEM. Reconstructed images were quantified using regions of interest (ROIs) derived from Magnetic Resonance scans and from the Automated Anatomical Labeling map. Results were standardized by applying a simple linear regression line obtained from the entire patient dataset. Our findings show that we can obtain a set of optimal parameters for each reconstruction strategy. The accuracy of the standardized SUR increases when the reconstruction method includes more corrections. The use of generic ROIs instead of subject-specific ROIs adds significant inaccuracies. Thus, after reconstruction with OSEM and correction for all degradations, subject-specific ROIs led to errors between standardized and true SUR values in the range [-0.5, +0.5] in 87% and 92% of the cases for caudate and putamen, respectively. These percentages dropped to 75% and 88% when the generic ROIs were used.


Development of multistage magnetic deposition microscopy.
Magnetic deposition microscropy (MDM) combines magnetic deposition and optical analysis of magnetically tagged cells into a single platform. Our multistage MDM uses enclosed microfabricated channels and a magnet assembly comprising four zones in series. The enclosed channels alleviate the problem plaguing previous versions of MDM: scouring of the cell deposition layer by the air-liquid interface as the channel is drained. The four-zone magnet assembly was designed to maximize capture efficiency, and experiments yielded total capture efficiencies of >99% of fluorescent- and magnetically-labeled Jurkat cells at reasonable throughputs (10(3) cells/min). A digital image processing protocol was developed to measure the average pixel intensities of the deposited cells in different zones, indicative of the marker expression. Preliminary findings indicate that the multistage MDM may be suitable for depositing cells and particles in successive zones according to their magnetic properties (e.g., magnetic susceptibilities or magnetophoretic mobilities). The overall goal is to allow the screening of multiple disease conditions in a single platform.


[Hemodynamic effect of captopril in children with dilated cardiomyopathy].
Hemodynamic effects of captopril were prospectively studied in 12 children suffering from dilative cardiomyopathy. Before the administration of the drug all patients were put on a stable medication of diuretics and/or glycosides. A median daily dose of 1.83 mg captopril/kg body weight was given in 3 or 4 single doses depending on age. Median body weight of the children was 18.6 kg (range 2.7-42.2) and the median age was 5.8 years (range 0.2-15). Left ventricular volume was determined in systole and diastole using 2-D echo, and the stroke volume als well as the ejection fraction were calculated. Cardiac index (CI) and systemic resistance (Rs) were measured by Doppler echo. Blood pressure and heart rate were recorded at each echo registration. ESVI (-32%), EDVI (-21%) and SVI (-7%) were significantly (p less than 0.05) reduced by short-term captopril treatment. This effect was maintained under long-term therapy. EF, CI, Rs, blood pressure and heart rate showed only minor changes under captopril. Adverse effects were recorded only in one child. They disappeared after dose reduction.


[Efficacy and safety of pemetrexed or gemcitabine combined with carboplatin as the first-line therapy in elderly patients with advanced non-small cell lung cancer].
To observe the clinical efficacy and safety of pemetrexed or gemcitabine combined with carboplatin as the first-line therapy in elderly patients with advanced non-small cell lung cancer (NSCLC). Seventy patients aged 70 years or over with stage IIIb-IV NSCLC were equally and randomly divided into pemetrexed plus cisplatin group (PC) and gemcitabine plus carboplatin group (GC). Patients in the PC group received pemetrexed (PEM) 500 mg/m(2) on day 1, and carboplatin (CBP) AUC5 on day 1 for 21-day cycle. Patients in the GC group received gemcitabine 1000 mg/m(2) on days 1 and 8, CBP AUC5 on day 1 for a 21-day cycle. In the PC and GC groups, CR 0 and 0, PR 10 and 8, response rates 28.6% and 22.9% were observed, respectively. There was no statistically significant difference between the two groups (χ(2) = 0.299, P = 0.584). The 1-year and 2-year survival rates of the PC and GC groups were 48.6% vs. 45.7% and 11.4% vs. 11.4%, respectively, with a median survival of 11.00 and 10.00 months, without a statistically significant difference between the two groups (χ(2) = 0.01, P = 0.919). Regarding toxicities, the incidences of neutropenia/thrombocytopenia, nausea and vomiting (grade III ∼ IV) in the GC group were significantly higher than those in the PC group (P < 0.05). According to the observer scale of lung cancer symptoms, the post-treatment scores improved in both the two groups, and with no significant difference between them (P > 0.05). PC and GC show similar efficacy for elderly NSCLC patients, however, the toxicities in PC patients are lower than those in GC patients. Thus, pemetrexed combined with carboplatin is an effective chemotherapeutic regimen for advanced NSCLC in elderly patients.


Growth of microbial populations in nonminimal media: some considerations for modeling.
Ramkrishna and his co-workers have developed so-called cybernetic models which purport to describe, among other things, how microorganisms make choices when presented with two or more functionally equivalent, or substitutable, nutrients that are sources of carbon and available energy. In general, however, organisms are presented with choices not just between nutrients that are substitutable for one another, but also between sets of nutrients some of which are by no means substitutable for one another. It is postulated herein that the main ideas of cybernetic modeling apply to these more general choices as they seem to apply to the choices considered by Ramkrishna and his co-workers. Some consequences of the postulate are worked out for steady-state growth situations where two, or in one case three, nutrients limit or potentially limit growth rate. If predicted phenomena are observed experimentally so as to verify the postulate, a significantly improved basis for understanding growth of microorganisms in practical fermentation media as well as in natural situations will be provided by this application of cybernetic modeling ideas.


Body surface maps in 2 cases of atrial flutter.
Body surface maps during one cycle of atrial flutter were recorded in 2 cases. The sequences of movements of the maximum and the minimum were compared to those of the sinus P waves. The maps of normal sinus P waves usually show that a maximum first appears at the anterior chest near the sternum and moves to the left side of the thorax in the later half of the P wave. The maps of atrial flutter in Case 1 showed that a maximum first appeared on the upper right back and then moved to the right side of the anterior chest. The maps of Case 2 showed that a maximum first appeared on the upper right back and then moved down the right side of the posterior thorax. There were no movements of the maxima in either case from the right side of the chest to the left as seen in the sinus P waves.


Colossal magnetoresistance is a Griffiths singularity.
It is now widely accepted that the magnetic transition in doped manganites that show large magnetoresistance is a type of percolation effect. This paper demonstrates that the transition should be viewed in the context of the Griffiths phase that arises when disorder suppresses a magnetic transition. This approach explains unusual aspects of susceptibility and heat capacity data from a single crystal of La0.7Ca0.3MnO3.


Videoconferencing psychotherapy: a systematic review.
Individuals with mental health problems may face barriers to accessing effective psychotherapies. Videoconferencing technology, which allows audio and video information to be shared concurrently across geographical distances, offers an alternative that may improve access. We conducted a systematic literature review of the use of videoconferencing psychotherapy (VCP), designed to address 10 specific questions, including therapeutic types/formats that have been implemented, the populations with which VCP is being used, the number and types of publications related to VCP, and available satisfaction, feasibility, and outcome data related to VCP. After electronic searches and reviews of reference lists, 821 potential articles were identified, and 65 were selected for inclusion. The results indicate that VCP is feasible, has been used in a variety of therapeutic formats and with diverse populations, is generally associated with good user satisfaction, and is found to have similar clinical outcomes to traditional face-to-face psychotherapy. Although the number of articles being published on VCP has increased in recent years, there remains a need for additional large-scale clinical trials to further assess the efficacy and effectiveness of VCP.


Study of microstructure and fracture properties of blunt notched and sharp cracked high density polyethylene specimens.
This paper examines the effect of a broad range of crosshead speed (0.05 to 100 mm/min) and a small range of temperature (25 °C and 45 °C) on the failure behaviour of high density polyethylene (HDPE) specimens containing a) standard size blunt notch and b) standard size blunt notch plus small sharp crack - all tested in air. It was observed that the yield stress properties showed linear increase with the natural logarithm of strain rate. The stress intensity factors under blunt notch and sharp crack conditions also increased linearly with natural logarithm of the crosshead speed. The results indicate that in the practical temperature range of 25 °C and 45 °C under normal atmosphere and increasing strain rates, HDPE specimens with both blunt notches and sharp cracks possess superior fracture properties. SEM microstructure studies of fracture surfaces showed craze initiation mechanisms at lower strain rate, whilst at higher strain rates there is evidence of dimple patterns absorbing the strain energy and creating plastic deformation. The stress intensity factor and the yield strength were higher at 25 °C compared to those at 45 °C.


LBC petition fails to prompt law change.
A petition signed by more than 116,000 people has failed to convince the government that a new law is needed to deal specifically with assaults on NHS staff.


PARGT: a software tool for predicting antimicrobial resistance in bacteria.
With the ever-increasing availability of whole-genome sequences, machine-learning approaches can be used as an alternative to traditional alignment-based methods for identifying new antimicrobial-resistance genes. Such approaches are especially helpful when pathogens cannot be cultured in the lab. In previous work, we proposed a game-theory-based feature evaluation algorithm. When using the protein characteristics identified by this algorithm, called 'features' in machine learning, our model accurately identified antimicrobial resistance (AMR) genes in Gram-negative bacteria. Here we extend our study to Gram-positive bacteria showing that coupling game-theory-identified features with machine learning achieved classification accuracies between 87% and 90% for genes encoding resistance to the antibiotics bacitracin and vancomycin. Importantly, we present a standalone software tool that implements the game-theory algorithm and machine-learning model used in these studies.


A controlled release form of madopar in parkinsonian patients with advanced disease and marked fluctuations in motor performance.
Flucuations in motor performance is a major problem in long-term levodopa treatment of Parkinsonian patients. A slow release preparation of levodopa with benserazide, Madopar HBS, has been developed in an attempt to decrease this problem. Eleven of 22 Parkinsonian patients with advanced disease and marked fluctuations experienced long-lasting benefit with reduction of their fluctuations in motor performance on treatment with Madopar HBS; 11 dropped out within the first 5 months of the trial. This was probably due to lack of experience with the effect of this new slow-release formulation. Nine patients (82%) required an additional dose of standard Madopar, especially in the morning. Significant improvements were found for akinetic phenomenon and dystonic cramps, and with the global evaluation of motor fluctuations. The occurrence of peak dose dyskinesia remained unchanged. No abnormalities in laboratory values were found.


M2 and M3 muscarinic receptors are involved in enteric nerve-mediated contraction of the mouse ileum: Findings obtained with muscarinic-receptor knockout mouse.
The involvement of muscarinic receptors in neurogenic responses of the ileum was studied in wild-type and muscarinic-receptor (M-receptor) knockout (KO) mice. Electrical field stimulation to the wild-type mouse ileum induced a biphasic response, a phasic and sustained contraction that was abolished by tetrodotoxin. The sustained contraction was prolonged for an extended period after the termination of electrical field stimulation. The phasic contraction was completely inhibited by atropine. In contrast, the sustained contraction was enhanced by atropine. Ileal strips prepared from M2-receptor KO mice exhibited a phasic contraction similar to that seen in wild-type mice and a sustained contraction that was larger than that in wild-type mice. In M3-receptor KO mice, the phasic contraction was smaller than that observed in wild-type mice. Acetylcholine exogenously administrated induced concentration-dependent contractions in strips isolated from wild-type, M2- and M3-receptor KO mice. However, contractions in M3-receptor KO mice shifted to the right. The sustained contraction was inhibited by capsaicin and neurokinin NK2 receptor antagonist, suggesting that it is mediated by substance P (SP). SP-induced contraction of M2-receptor KO mice did not differ from that of wild-type mice. SP immunoreactivity was located in enteric neurons, colocalized with M2 receptor immunoreactivity. These results suggest that atropine-sensitive phasic contraction is mainly mediated via the M3 receptor, and SP-mediated sustained contraction is negatively regulated by the M2 receptor at a presynaptic level.


Preparation of single smooth muscle cells from guinea pig taenia coli by combinations of purified collagenase and papain.
Procedures for isolation of single smooth muscle cells from taenia coli of guinea pigs have been developed. The preparation was performed with a combination of highly purified collagenase prepared by Amano Pharmaceutical Co. (Japan) and papain obtained from Sigma Chemical Co. (Type III). This combination resulted in very high yield of the single cells (39.2 +/- 4.5 X 10(3) cells/mg tissue wet wt) and less cell debris. In the ordinary procedure, commercially available collagenase preparations contaminated with various peptidases have been used. With these enzyme preparations, however, the yield of single cells was dependent on the batch of the preparations, and a large amount of cell debris was contaminated. Combination of the highly purified collagenase and papain resulted in higher yields constantly. Cells, isolated with these enzymes in a medium consisting of 140 mM KCl, 1.0 mM MgCl2, 4.2 mM Hepes, and 5.6 mM glucose (pH 7.4), were spindle shaped. The length of the cells was 185.9 +/- 5.2 micron (n = 90) and the diameter was approximately 12.6 micron. The diameter was not dependent on the cell length. More than 80% of the single cells were viable when examined by trypan blue exclusion technique. Under the depolarized condition, cells remained viable longer because of lower energy consumption, and these cells were contracted by Ca dose dependently. The dose-response relationship was similar to that obtained with intact tissue. Because the cells are constantly available with higher yield, the preparation might be applicable for biochemical research such as ion flux. Details of cell properties under the physiological conditions are under investigation.


Competence, risk, and resilience in military families: conceptual commentary.
This commentary highlights conceptual themes in the opening section of this special issue on military families in relation to a new synthesis of developmental systems theory that emerged from developmental, ecological, and family systems theory, as well as developmental psychopathology and risk/resilience frameworks. Articles in this special issue draw on these concepts to characterize and guide the burgeoning research on military families. This perspective emphasizes that multiple dynamic systems interact across levels to shape individual development, as well as the function of families and military units. Developmental timing is important for understanding how challenges of military life may impact individuals and families. Cascade effects are noted, where stress experienced by one family or service member can influence the function of other individuals or larger systems. Capacity for resilience is distributed across systems, including families and cultures, as well as resources or supports provided by military organizations to foster adaptive responses or recovery. These systems include schools and educational programs that play key roles in fostering and supporting resilience for children. Overall, developmental system concepts have considerable utility for guiding research with military families, particularly in regard to promoting resilience. Moreover, lessons learned from military families and programs may have much broader implications for many other nonmilitary children, families, and organizations that share similar goals and challenges.


Dynamic acousto-elastic testing of concrete with a coda-wave probe: comparison with standard linear and nonlinear ultrasonic techniques.
The use of nonlinear acoustic techniques in solids consists in measuring wave distortion arising from compliant features such as cracks, soft intergrain bonds and dislocations. As such, they provide very powerful nondestructive tools to monitor the onset of damage within materials. In particular, a recent technique called dynamic acousto-elasticity testing (DAET) gives unprecedented details on the nonlinear elastic response of materials (classical and non-classical nonlinear features including hysteresis, transient elastic softening and slow relaxation). Here, we provide a comprehensive set of linear and nonlinear acoustic responses on two prismatic concrete specimens; one intact and one pre-compressed to about 70% of its ultimate strength. The two linear techniques used are Ultrasonic Pulse Velocity (UPV) and Resonance Ultrasound Spectroscopy (RUS), while the nonlinear ones include DAET (fast and slow dynamics) as well as Nonlinear Resonance Ultrasound Spectroscopy (NRUS). In addition, the DAET results correspond to a configuration where the (incoherent) coda portion of the ultrasonic record is used to probe the samples, as opposed to a (coherent) first arrival wave in standard DAET tests. We find that the two visually identical specimens are indistinguishable based on parameters measured by linear techniques (UPV and RUS). On the contrary, the extracted nonlinear parameters from NRUS and DAET are consistent and orders of magnitude greater for the damaged specimen than those for the intact one. This compiled set of linear and nonlinear ultrasonic testing data including the most advanced technique (DAET) provides a benchmark comparison for their use in the field of material characterization.


Zone-specific computer-aided diagnosis system aimed at characterizing ISUP ≥ 2 prostate cancers on multiparametric magnetic resonance images: evaluation in a cohort of patients on active surveillance.
To assess a region-of-interest-based computer-assisted diagnosis system (CAD) in characterizing aggressive prostate cancer on magnetic resonance imaging (MRI) from patients under active surveillance (AS). A prospective biopsy database was retrospectively searched for patients under AS who underwent MRI and subsequent biopsy at our institution. MRI lesions targeted at baseline biopsy were retrospectively delineated to calculate the CAD score that was compared to the Prostate Imaging-Reporting and Data System (PI-RADS) version 2 score assigned at baseline biopsy. 186 patients were selected. At baseline biopsy, 51 and 15 patients had International Society of Urological Pathology (ISUP) grade ≥ 2 and ≥ 3 cancer respectively. The CAD score had significantly higher specificity for ISUP ≥ 2 cancers (60% [95% confidence interval (CI): 51-68]) than the PI-RADS score (≥ 3 dichotomization: 24% [CI: 17-33], p = 0.0003; ≥ 4 dichotomization: 32% [CI: 24-40], p = 0.0003). It had significantly lower sensitivity than the PI-RADS ≥ 3 dichotomization (85% [CI: 74-92] versus 98% [CI: 91-100], p = 0.015) but not than the PI-RADS ≥ 4 dichotomization (94% [CI:85-98], p = 0.104). Combining CAD findings and PSA density could have avoided 47/184 (26%) baseline biopsies, while missing 3/51 (6%) ISUP 2 and no ISUP ≥ 3 cancers. Patients with baseline negative CAD findings and PSAd < 0.15 ng/mL2 who stayed on AS after baseline biopsy had a 9% (4/44) risk of being diagnosed with ISUP ≥ 2 cancer during a median follow-up of 41 months, as opposed to 24% (18/74) for the others. The CAD could help define AS patients with low risk of aggressive cancer at baseline assessment and during subsequent follow-up.


Changes in abduction and rotation range of motion in response to simulated dorsal and ventral translational mobilization of the glenohumeral joint.
Translational mobilization techniques are frequently used by physical therapists as an intervention for patients with limited ranges of motion (ROMs). However, concrete experimental support for such practice is lacking. The purpose of the study was to evaluate the effect of simulated dorsal and ventral translational mobilization (DTM and VTM) of the glenohumeral joint on abduction and rotational ROMs. Fourteen fresh frozen shoulder specimens from 5 men and 3 women (mean age=77.3 years, SD=10.1, range=62-91) were used for this study. Each specimen underwent 5 repetitions of DTM and VTM in the plane of scapula simulated by a material testing system (MTS) in the resting position (40 of abduction in neutral rotation) and at the end range of abduction with 100 N of force. Abduction and rotation were assessed as the main outcome measures before and after each mobilization procedure performed and monitored by the MTS (abduction, 4 N m) and by a servomotor attached to the piston of the actuator of the MTS (medial and lateral rotation, 2 N m). There were increases in abduction ROM for both DTM (mean=2.10 , SD=1.76 ) and VTM (mean=2.06 , SD=1.96 ) at the end-range position. No changes were found in the resting position following the same procedure. Small increases were also found in lateral rotation ROM after VTM in the resting position (mean=0.90 , SD=0.92 , t=3.65, P=.003) and in medial rotation ROM after DTM (mean=0.97 , SD=1.45 , t=2.51, P=.026) at the end range of abduction. The results indicate that both DTM and VTM procedures applied at the end range of abduction improved glenohumeral abduction range of motion. Whether these changes would result in improved function could not be determined because of the use of a cadaver model.