Sleep quality in caregivers of patients with Alzheimer's disease and Parkinson's disease and its relationship to quality of life.
Knowledge about sleep complaints of caregivers of patients with Alzheimer's disease (AD) and Parkinson's disease (PD) is limited, and we lack information about the relationship between caregivers' sleep problems and their quality of life (QoL). We evaluated subjective sleep quality and its relationship to QoL in a group of 80 caregivers of patients with AD (ADCG, n = 40) and PD (PDCG, n = 40), and in 150 controls. Information about night-time complaints was collected using the Pittsburgh Sleep Quality Index (PSQI). QoL was measured using the McGill QoL Questionnaire. Eighteen ADCG (45%), 22 PDCG (55%), and 45 (30%) controls reported poor sleep quality. Mean global PSQI score of PDCG (6.25 ± 3.9) was not significantly different from that of ADCG (5.8 ± 3.5; p = 0.67). However, both PDCG and ADCG scored significantly higher than control group (4.3 ± 3.1; p < 0.01). ADCG frequently reported difficulties falling asleep (72.5%) and disturbed sleep (100%). PDCG reported reduced subjective sleep quality (80%) and increased sleep disturbances (100%). Poor sleep quality was associated with depressive symptoms and correlated with QoL in caregivers of both groups, particularly the psychological symptoms domain. Among caregivers of patients with AD and PD, poor sleep quality is frequent and significantly linked to QoL and depressive symptoms. Identifying the nature of sleep disturbances not only in patients but also in their caregivers is important as appropriate treatment may lead to a better management of the needs of families coping with these patients.


The presence of CD25 on bovine WC1+ gammadelta T cells is positively correlated with their production of IL-10 and TGF-beta, but not IFN-gamma.
WC1+ cells in cattle exhibit both regulatory and effector activities. However, it has not been elucidated whether they are so plastic that both activities co-exist in one cell or there are separate subpopulations of effector and regulatory cells. Since the production of IFN-gamma and IL-10 seems to be related to WC1+ cells' effector and regulatory function, respectively, the main aim of this study was to determine whether those cytokines are produced by separate subpopulations of WC1+, or are co-produced by the same cells. Due to increasingly frequent emphasised role of consumption of IL-2 in the mechanism of suppressor action of mouse CD25+CD4+ T regulatory cells, expression of the receptor's alpha chain for interleukin 2 (CD25) on WC1+ lymphocytes has been evaluated. An average of 5.21% of WC1+ cells obtained from PBMCs of 12-month-old heifers show constitutive expression of the CD25 molecule, with CD25(high)WC1+ and CD25(low)WC1+ cells accounting for 1.05% and 4.10% of WC1+ lymphocytes, respectively. For detection of intracellular cytokine production, PBMCs were stimulated with concanavalin A. Both IFN-gamma(-) and IL-10-producing cells within the CD25(-)WC1+ and CD25+WC1+ subpopulations were mainly separate subpopulations. The average percentage of IFN-gamma(+)IL-10(-), IFN-gamma(-)IL-10+ and IFN-gamma(+)IL-10+ cells among CD25(-)WC1+ lymphocytes was 4.03%, 2.67% and 0.51%, respectively. A positive correlation was observed between the presence of the CD25 molecule on WC1+ lymphocytes and production of IL-10 and TGF-beta, because the average percentage of IFN-gamma(-)IL-10+ and IFN-gamma(+)IL-10+ among CD25+WC1+ lymphocytes was 3 and 4.5 times higher as compared to the corresponding cells in the CD25(-)WC1+ subpopulation, whereas the percentage of IFN-gamma(+)IL-10(-) cells in both the subpopulations was not significantly different. The percentage of TGF-beta+ cells within the CD25+WC1+ subpopulation was 2.72 times as high as that of CD25(-)WC1+ lymphocytes. Therefore, with respect to the production of IFN-gamma, IL-10 and TGF-beta, CD25+WC1+ lymphocytes turn out to have a more suppressor profile than CD25(-)WC1+.


[Protective ptosis by botulinum A toxin injection in corneal affectations].
Botulinum toxin A has been introduced as a local injection therapy of different conditions with focal muscular hypercontractions. In the ophthalmologic field the toxin has proven its efficacy in the therapy of blepharospasm and hemifacial spasm. There are only few reports on the use of a botulinum toxin A to induce a protective ptosis in patients with persistent corneal ulcers. 21 patients who failed to respond to conservative therapy of corneal erosions or ulcers of different origin received a botulinum toxin A injection into the levator palpebrae superioris muscle. The ptosis began after a mean of 1.5 days (1-3 days) and was complete after a mean of 5.1 days (3-12 days) after injection. Complete recovery of the levator function could be observed after a mean of 12.4 weeks (4-24 weeks). In 13 patients (61.8%) the botulinum toxin A induced protective ptosis lead to a complete healing of indolent ulcers or erosions, in 4 patients (19%) an additional tarsorrhaphy was necessary. In 3 patients no healing could be observed during follow up, in one patient (with neuroparalytic ulcer) the injection was given prophylactically. The period of healing on average was 3.8 weeks. There was no relationship between the healing rate and the duration of the corneal disease prior to the botulinum toxin injection. The mean healing rate of younger patients was higher (75%) than that of older patients (53.8%) and higher in erosions (70%) than in ulcers (30%). No side effects were observed besides in one patient the undesirable duration of the ptosis of a half year. The induction of a protective ptosis with botulinum toxin A injection is an efficacious treatment alternative in persistent corneal erosions and ulcers before performing a tarsorrhaphy. This method is preferrable especially in patients with lagophthalmos due to facial nerve paresis with potential recovery.


Development of a wireless accelerometer-based Intravaginal device to detect pelvic floor motion for evaluation of pelvic floor dysfunction.
Urinary incontinence (UI) is experienced by an estimated 51% of women in the U.S. and often results from impaired function or weakening of the pelvic floor muscles. Pelvic floor muscle training (PFMT) is a frontline nonsurgical treatment, yet a number of symptomatic individuals cannot accurately perform a pelvic floor muscle contraction with simple verbal or written instruction. Long-term adherence to PFMT regimens is often a barrier to resolution of symptoms. Various biofeedback tools have been utilized to aid correct pelvic floor muscle performance and adherence. One novel device, the leva® Pelvic Digital Health System, utilizes an intravaginal probe embedded with MEMS accelerometer sensors that allow real-time visualization of the shape and motion of the vagina during PFMT. Early positive results with this device prompted design of a wearable version. The purpose of this study was to design a wearable, wireless clinical research device to optimize MEMS accelerometer sensor placement to detect maximal movement during a pelvic floor muscle exercise (PFME) and to test the form factor for retention and user acceptability. The device comprised a ring designed to sit at the fornix with an extension following the length of the vagina. This paper presents design components and results from clinical testing of 10 subjects. It was determined that a ring form factor alone, similar to other vaginal rings (pessaries, estrogen rings) provided less accurate visual information about PFME performance. By contrast, we determined that a ring with an extension allowed for device retention and improved real-time detection of vaginal shape and motion during PFMT.


Lysine-691 of the anion exchanger from human erythrocytes is located on its cytoplasmic surface.
A combination of vectorial modification and site-directed immunochemistry has been used to determine the disposition, with respect to the membrane, of Lys-691 of the anion exchanger from human erythrocytes. Intact erythrocytes and inside-out vesicles were vectorially modified in the same container with pyridoxal phosphate and sodium [3H]borohydride. The modified inside-out vesicles were separated from erythrocytes by differential centrifugation and the vesicles and erythrocyte membranes were treated with alkali and digested with trypsin and thermolysin to liberate the peptides IVSKPER and IVSK¿Nepsilon-[4'-(5'-phospho-[4-3H]pyridoxyl)]¿PER. These peptides, containing the unmodified and modified versions of Lys-691, were retrieved from the digests by site-directed immunochemistry and were identified by HPLC and liquid scintillation spectroscopy. Both the inside-out vesicles and the intact erythrocytes contained the peptide IVSKPER, however, the 3H-label from the phosphopyridoxylated peptide could be detected only in the inside-out vesicles. The incorporation of 3H into Lys-691 of the anion exchanger from inside-out vesicles was at least 30-fold greater than the incorporation into Lys-691 of the anion exchanger from intact erythrocytes. It follows that Lys-691 of the anion exchanger is located on the cytoplasmic surface of the plasma membrane.


Adapting to Adaptations: Behavioural Strategies that are Robust to Mutations and Other Organisational-Transformations.
Genetic mutations, infection by parasites or symbionts, and other events can transform the way that an organism's internal state changes in response to a given environment. We use a minimalistic computational model to support an argument that by behaving "interoceptively," i.e. responding to internal state rather than to the environment, organisms can be robust to these organisational-transformations. We suggest that the robustness of interoceptive behaviour is due, in part, to the asymmetrical relationship between an organism and its environment, where the latter more substantially influences the former than vice versa. This relationship means that interoceptive behaviour can respond to the environment, the internal state and the interaction between the two, while exteroceptive behaviour can only respond to the environment. We discuss the possibilities that (i) interoceptive behaviour may play an important role of facilitating adaptive evolution (especially in the early evolution of primitive life) and (ii) interoceptive mechanisms could prove useful in efforts to create more robust synthetic life-forms.


BDNF Val66Met polymorphism is associated with body mass index in healthy adults.
Although recent studies suggest a possible relationship between the brain-derived neurotrophic factor Val66Met polymorphism and eating disorders, no study has examined the possibility that the Met-Met genotype is associated with a lower body mass index (BMI) in healthy individuals. We examined this possibility in 481 adults (age range 18-82 years) without significant medical or psychiatric history. After adjusting for gender, analysis of covariance showed that persons with the Met-Met genotype had a lower BMI than those with the Val-Met/Val-Val genotypes (22.28 +/-3.77 vs. 24.72+/-4.81). A similar, though nonsignificant, trend emerged when comparing all three genotypes separately. These findings suggest a possible relationship between Val66Met polymorphism and BMI in healthy adults. Further work is needed to clarify possible mechanisms for this relationship.


Living with Crohn's disease: an exploratory cross-sectional qualitative study into decision-making and expectations in relation to autologous haematopoietic stem cell treatment (the DECIDES study).
Severe Crohn's disease impacts negatively on individual quality of life, with treatment options limited once conventional therapies have been exhausted. The aim of this study was to explore factors influencing decision-making and expectations of people considering or participating in the Autologous Haematopoietic Stem Cell Treatment trial. An international, cross-sectional qualitative study, involving semistructured face to face interviews across five sites (four UK and one Spain). 38 participants were interviewed (13 men, 25 women; age range 23-67 years; mean age 37 years). The mean age at diagnosis was 20 years. Interviews were audio recorded and transcribed verbatim and transcripts were analysed using a framework approach. Four themes emerged from the analysis: (1) 'making your mind up'-a determination to receive stem cell treatment despite potential risks; (2) communicating and understanding risks and benefits; (3) non-participation-your choice or mine? (4) recovery and reframing of personal expectations. Decision-making and expectations of people with severe Crohn's disease in relation to autologous haematopoietic stem cell treatment is a complex process influenced by participants' histories of battling with their condition, a frequent willingness to consider novel treatment options despite potential risks and, in some cases, a raised level of expectation about the benefits of trial participation. Discussions with patients who are considering novel treatments should take into account potential 'therapeutic misestimation', thereby enhancing shared decision-making, informed consent and the communication with those deemed non-eligible. 2005-003337-40: results.


Evaluation of performances of VERSANT HCV RNA 1.0 assay (kPCR) and Roche COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 at low level viremia.
We assess the concordance between low level HCV values obtained using the VERSANT HCV RNA 1.0 Assay (kPCR) and COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test v2.0. The correlation between the values obtained by the two RT-PCR assays for samples with quantifiable HCV RNA levels revealed that viral load measured by kPCR significantly correlated with that of the CAP/CTM (R=0.644, P<0.0001). The results show a good concordance (n=126/144, 87%); discordant results were mainly observed in the assessment of values below the lower limit of detection of the assays. These variations may have an impact on clinical decisions for patients on HCV triple therapy or interferon- free regimens. It is therefore recommended to monitor individual patients with the same test throughout treatment.


[Theory and surgical technic of capsulorhexis].
Kapsulorhexis is a surgical technique for opening the anterior lens capsule with a circular, smooth-edged and continuous margin. Basically, the technique consists of a precisely controlled continuous capsular tear (rhexis), using only a sharp disposable needle with a bent tip. The method is reproducible, requires minimal instrumentation, is compatible with all current techniques of extracapsular surgery, and can be learned at no risk.


Proposed Performance-Based Metrics for the Future Funding of Graduate Medical Education: Starting the Conversation.
Graduate medical education (GME) in the United States is financed by contributions from both federal and state entities that total over $15 billion annually. Within institutions, these funds are distributed with limited transparency to achieve ill-defined outcomes. To address this, the Institute of Medicine convened a committee on the governance and financing of GME to recommend finance reform that would promote a physician training system that meets society's current and future needs. The resulting report provided several recommendations regarding the oversight and mechanisms of GME funding, including implementation of performance-based GME payments, but did not provide specific details about the content and development of metrics for these payments. To initiate a national conversation about performance-based GME funding, the authors asked: What should GME be held accountable for in exchange for public funding? In answer to this question, the authors propose 17 potential performance-based metrics for GME funding that could inform future funding decisions. Eight of the metrics are described as exemplars to add context and to help readers obtain a deeper understanding of the inherent complexities of performance-based GME funding. The authors also describe considerations and precautions for metric implementation.


The filament sensor for near real-time detection of cytoskeletal fiber structures.
A reliable extraction of filament data from microscopic images is of high interest in the analysis of acto-myosin structures as early morphological markers in mechanically guided differentiation of human mesenchymal stem cells and the understanding of the underlying fiber arrangement processes. In this paper, we propose the filament sensor (FS), a fast and robust processing sequence which detects and records location, orientation, length, and width for each single filament of an image, and thus allows for the above described analysis. The extraction of these features has previously not been possible with existing methods. We evaluate the performance of the proposed FS in terms of accuracy and speed in comparison to three existing methods with respect to their limited output. Further, we provide a benchmark dataset of real cell images along with filaments manually marked by a human expert as well as simulated benchmark images. The FS clearly outperforms existing methods in terms of computational runtime and filament extraction accuracy. The implementation of the FS and the benchmark database are available as open source.


Optimal dose of neuroleptic in acute schizophrenia. A controlled study of the neuroleptic threshold and higher haloperidol dose.
After individual determination of neuroleptic threshold (NT) doses of haloperidol, 106 patients with schizophrenia or schizoaffective disorder (Research Diagnostic Criteria) were treated openly at such doses (mean, 3.7 +/- 2.3 mg/d) for 2 weeks. Ten responding patients were discharged and unavailable for follow-up or refused subsequent randomization, and one non-responding patient refused randomization. The remaining 95 responding or nonresponding patients were then randomly assigned, double-blind, to a dosage of haloperidol two to 10 times higher (mean, 11.6 +/- 4.7 mg/d) or to a continuing NT dosage (mean, 3.4 +/- 2.3 mg/d) for another 2 weeks. Of the 58 patients exposed only to NT dosages of haloperidol, 72% clinically recovered within the 5-week trial. Higher dosages given to 47 patients did not lead to greater improvement in measures of psychosis, but did produce slightly greater declines in measures of hostility. Higher dosages did regularly lead to significant increases in distressing extrapyramidal side effects.


CUTANEOUS SENSITIVITY AFTER PROLONGED VISUAL DEPRIVATION.
Subjects who were placed in darkness for a week but who were otherwise exposed to a normal and varied sensory environment showed an increase in tactual acuity and in sensitivity to heat and pain. This cutaneous supersensitivity was still present several days after the termination of visual deprivation.


Management of the cleft lip nasal deformity.
Management of the cleft lip nasal deformity offers a unique and ongoing challenge in facial plastic surgery. Although there has been no consensus regarding the optimal timing and technique for surgical repair of this deformity, the authors have found a three-tiered approach to be satisfactory. This approach involves a primary rhinoplasty performed at the time of the initial cleft lip repair to address reconstruction of the nasal floor and sill, columellar lengthening, repositioning of the alar base, and repositioning of the skin and mucosa of the lower lateral cartilage. Following alveolar bone grafting, an intermediate rhinoplasty is often performed at 6 to 10 years of age through an open approach to correct the cartilaginous lower nasal deformity. A delayed rhinoplasty is then performed in the later teenage years to correct the bony dorsal deformity and the various causes of nasal obstruction.


Effect of Intravenous Ferric Carboxymaltose on Exercise Capacity After Kidney Transplantation (EFFECT-KTx): rationale and study protocol for a double-blind, randomised, placebo-controlled trial.
Iron deficiency (ID) is common and has been associated with an excess mortality risk in kidney transplant recipients (KTRs). In patients with chronic heart failure and ID, intravenous iron improves exercise capacity and quality of life. Whether these beneficial effects also occur in KTRs is unknown. The main objective of this trial is to address whether intravenous iron improves exercise tolerance in iron-deficient KTRs. The Effect of Ferric Carboxymaltose on Exercise Capacity after Kidney Transplantation study is a multicentre, double-blind, randomised, placebo-controlled clinical trial that will include 158 iron-deficient KTRs. ID is defined as plasma ferritin <100 µg/L or plasma ferritin 100-299 µg/L with transferrin saturation <20%. Patients are randomised to receive 10 mL of ferric carboxymaltose (50 mg Fe3+/mL, intravenously) or placebo (0.9% sodium chloride solution) every 6 weeks, four dosages in total. The primary endpoint is change in exercise capacity, as quantified by the 6 min walk test, between the first study visit and the end of follow-up, 24 weeks later. Secondary endpoints include changes in haemoglobin levels and iron status, quality of life, systolic and diastolic heart function, skeletal muscle strength, bone and mineral parameters, neurocognitive function and safety endpoints. Tertiary (explorative) outcomes are changes in gut microbiota and lymphocyte proliferation and function. The protocol of this study has been approved by the medical ethical committee of the University Medical Centre Groningen (METc 2018/482;) and is being conducted in accordance with the principles of the Declaration of Helsinki, the Standard Protocol Items: Recommendations for Interventional Trials checklist and the Good Clinical Practice guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Study results will be disseminated through publications in peer-reviewed journals and conference presentations. NCT03769441.


The Improving Rural Cancer Outcomes (IRCO) Trial: a factorial cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural patients with cancer in Western Australia: a study protocol.
While overall survival for most common cancers in Australia is improving, the rural-urban differential has been widening, with significant excess deaths due to lung, colorectal, breast and prostate cancer in regional Australia. Internationally a major focus on understanding variations in cancer outcomes has been later presentation to healthcare and later diagnosis. Approaches to reducing time to diagnosis of symptomatic cancer include public symptom awareness campaigns and interventions in primary care to improve early cancer detection. This paper reports the protocol of a factorial cluster-randomised trial of community and general practice (GP) level interventions to reduce the time to diagnosis of cancer in rural Western Australia (WA). The community intervention is a symptom awareness campaign tailored for rural Australians delivered through a community engagement model. The GP intervention includes a resource card with symptom risk assessment charts and local referral pathways implemented through multiple academic detailing visits and case studies. Participants are eligible if recently diagnosed with breast, colorectal, lung or prostate cancer who reside in specific regions of rural WA with a planned sample size of 1350. The primary outcome is the Total Diagnostic Interval, defined as the duration from first symptom (or date of cancer screening test) to cancer diagnosis. Secondary outcomes include cancer stage, healthcare utilisation, disease-free status, survival at 2 and 5 years and cost-effectiveness. Ethics approval has been granted by the University of Western Australia and from all relevant hospital recruitment sites in WA. Results of this trial will be reported in peer-reviewed publications and in conference presentations. Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12610000872033.


Degenerate Optical Cavities. III: Effect of Aberrations.
The capability of degenerate optical cavities to transmit faithfully incident optical signals with arbitrary wavefronts is limited primarily by geometrical optics aberrations. This capability is expressed by an acceptance factor which is calculated for various types of cavities lacking first-order degeneracy, or suffering from primary aberrations. It is found that the acceptance factors of spherically symmetric cavities are larger, by orders of magnitude, than the acceptance factors of cavities possessing only rotational symmetry (such as the well-known confocal cavity). The correction of primary aberrations for both types of cavities is discussed. Acceptance factors of the order of 107 with finesses of the order of 100 can be obtained. The mechanical accuracy required is, however, a few orders of magnitude higher than in conventional optical instruments.


Polymorphism of alpha-actinin from human blood platelets. Homodimeric and heterodimeric forms.
In purified solutions of alpha-actinin from human blood platelets, three polypeptides a, b and c, of approximately 100 kDa, were observed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. They were identified as alpha-actinin subunits on the basis of their cross-reactivity with antibodies against skeletal muscle alpha-actinin and their interaction with F-actin. After electrophoresis in the absence of sodium dodecyl sulfate, six forms were observed: aa, ab, bb, ac, bc, cc. The similarity between the one-dimensional peptide maps of a and b and the absence of b in the presence of calcium-dependent protease inhibitors indicated that b is probably derived from the a subunit. The c subunit differs from the a subunit. The results provide evidence that there are actually only two platelet alpha-actinin subunits a and c which give rise to three isoforms: two homodimers aa and cc, and one heterodimer ac.


Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival.
Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukemogenesis, and their presence is associated with poor prognosis in acute myeloid leukemia (AML). To better understand FLT3 signaling in leukemogenesis, we have examined the changes in gene expression induced by FLT3/ITD or constitutively activated wild-type FLT3 expression. Microarrays were used with RNA harvested before and after inhibition of FLT3 signaling. Pim-1 was found to be one of the most significantly down-regulated genes upon FLT3 inhibition. Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. Quantitative polymerase chain reaction (QPCR) confirmed the microarray results and demonstrated approximately 10-fold decreases in Pim-1 expression in response to FLT3 inhibition. Pim-1 protein also decreased rapidly in parallel with decreasing autophosphorylation activity of FLT3. Enforced expression of either the 44-kDa or 33-kDa Pim-1 isotypes resulted in increased resistance to FLT3 inhibition-mediated cytotoxicity and apoptosis. In contrast, expression of a dominant-negative Pim-1 construct accelerated cytotoxicity in response to FLT3 inhibition and inhibited colony growth of FLT3/ITD-transformed BaF3 cells. These findings demonstrate that constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. This up-regulation contributes to the proliferative and antiapoptotic pathways induced by FLT3 signaling.


Depression and associated organic diseases: are there any specific depressive symptoms? Results from the dialogue-2 survey.
The objective of the survey was to compare depressive symptoms in depression with and without a concomitant organic disease. The results based on the HAD and CES-D scales showed that, compared to those with an isolated depression, the patients with an associated chronic organic disease have a higher score on two items on the HAD. Three variables on the CES-D scale also helped to differentiate the two groups of depressed patients. No significant difference was found between the two groups in terms of anxiety or cognitive symptoms, fatigue or feelings of disability. Our results do not indicate any symptom that is specific to a combination of depression and somatic diseases. Guilt and hostility showed a lower level in depression associated with a concomitant somatic disease than in isolated depression.


Structural basis for misfolding in myocilin-associated glaucoma.
Olfactomedin (OLF) domain-containing proteins play roles in fundamental cellular processes and have been implicated in disorders ranging from glaucoma, cancers and inflammatory bowel disorder, to attention deficit disorder and childhood obesity. We solved crystal structures of the OLF domain of myocilin (myoc-OLF), the best studied such domain to date. Mutations in myoc-OLF are causative in the autosomal dominant inherited form of the prevalent ocular disorder glaucoma. The structures reveal a new addition to the small family of five-bladed β-propellers. Propellers are most well known for their ability to act as hubs for protein-protein interactions, a function that seems most likely for myoc-OLF, but they can also act as enzymes. A calcium ion, sodium ion and glycerol molecule were identified within a central hydrophilic cavity that is accessible via movements of surface loop residues. By mapping familial glaucoma-associated lesions onto the myoc-OLF structure, three regions sensitive to aggregation have been identified, with direct applicability to differentiating between neutral and disease-causing non-synonymous mutations documented in the human population worldwide. Evolutionary analysis mapped onto the myoc-OLF structure reveals conserved and divergent regions for possible overlapping and distinctive functional protein-protein or protein-ligand interactions across the broader OLF domain family. While deciphering the specific normal biological functions, ligands and binding partners for OLF domains will likely continue to be a challenging long-term experimental pursuit, atomic detail structural knowledge of myoc-OLF is a valuable guide for understanding the implications of glaucoma-associated mutations and will help focus future studies of this biomedically important domain family.


Let Nature Take Its Course: Cultural Adaptation and Pilot Test of Taoist Cognitive Therapy for Chinese American Immigrants With Generalized Anxiety Disorder.
This report describes initial results from a multi-stage project to manualize and adapt an indigenous therapy, Chinese Taoist Cognitive Psychotherapy (CTCP), for dissemination in the United States context. Study aims were to (a) integrate cultural adaptation and implementation science frameworks to manualize and adapt the original intervention and (b) explore the feasibility, acceptability, and effectiveness of the modified intervention, renamed Taoist Cognitive Therapy (TCT), in a sample of Chinese immigrants with generalized anxiety disorder (GAD). Incorporating bottom-up and top-down adaptation approaches, we involved Chinese American clinician stakeholders and experts in Taoist philosophy, cognitive-behavioral therapy, and GAD to help identify cultural and contextual barriers and solutions to enhance treatment acceptability and implementation. Five treatment-seeking Chinese American immigrants (average age = 43.2 years) with a primary diagnosis of GAD completed 14-16 sessions of TCT. Two participants also had secondary diagnoses of major depressive disorder. Changes on primary measures of worry and anxiety were assessed for statistical and clinical significance using reliable change indices (RCIs; Jacobson and Truax, 1991) and comparisons to normative data. In this sample of patients with limited prior exposure to Taoism, results found evidence of feasibility and acceptability of the modified intervention, with strong endorsement of Taoist principles at termination. Statistically and clinically significant improvements in anxiety, worry, psychological inflexibility, and emotional avoidance were found only for the participants without comorbid depression. Results suggest that Taoist principles of acceptance and flexible adaptation to natural laws may be helpful to Chinese immigrants coping with anxiety. However, additional treatment modifications may be required to address the low self-efficacy and fatalism expressed among those with comorbid depression.


Red blood cell catabolism in lymph nodes of the sheep and rat: quantitation.
Estimates have been made of the number of red blood cells catabolised in the lymph nodes of the sheep and the rat. These estimates were based on observations on the output of bilirubin in intestinal lymph of the sheep and on bilirubin output in thoracic duct lymph of the rat. It was calculated that some 2 to 15 X 10(9) red blood cells were catabolised in a 24 hour period by the lymph nodes of the intestinal region of the sheep, representing approximately 3% of all the red cells destroyed in this period. Similarly, 0.9 to 4.6 X 10(8) red blood cells were estimated to be catabolised every 24 hours in the lymph nodes of those areas drained by the thoracic duct of the rat, representing approximately 6% of all the red cells destroyed in a 24 hour period. Calculations extending these results to include all areas of the body in both species indicated that the lymph nodes may account for some 6-7% of the total number of red blood cells catabolised in the animal.


Visualization of Wound Healing Progression With Near Infrared Spectroscopy: A Retrospective Study.
The aim of this retrospective study is to determine if near infrared spectroscopy (NIRS) can be used to evaluate wounds and adjacent soft tissues to identify patterns involved in tissue oxygenation and wound healing as well as predict which wounds may or may not heal. In this study, 25 patients with either diabetic foot ulcers or venous leg ulcers were examined retrospectively to determine if NIRS could be used to predict which wounds may or may not close. All patients had either diabetic or venous ulcers and were being actively treated in the clinic. Regardless of the treatment rendered, all wounds were tracked with NIRS at regular intervals. Retrospectively, the de-identified images were reviewed to determine any patterns that might exist. Wound bed and periwound oxygenation patterns were observed and classified, including correlation with both the clinical appearance and the NIRS images. Images of wounds that closed and those that did not were compared. Four distinct patterns of tissue oxygenation that appeared to have some value for predicting which wounds would heal, and which would not, were identified among the 25 patients. A mechanism has also been proposed to try to explain the patterns of healing observed; Hyperperfusion, Imbibition, Neovascularization, and Trailing (HINT) describes various aspects of these patterns. As with any imaging technology, both qualitative and quantitative data are used to determine what is happening clinically. This study represents an early attempt to understand the role of NIRS and percent oxygenated hemoglobin in the wound healing process. It also lays the groundwork for identifying patterns associated with wound closure.


The lateral arm/proximal forearm flap.
The classic lateral arm flap is constrained by limited skin availability, thick subcutaneous tissue, a short vascular pedicle, and inconsistent sensory innervation. We report modifications of the lateral arm flap which increase its skin availability, provide thin sensate skin, and extend the overall reach of the flap. The vascular anatomy of the lateral arm/proximal forearm flap was studied in 10 fresh anatomic specimens. The posterior radial collateral artery communicated with a rich vascular plexus that extended well into the proximal forearm. This plexus is also fed by communicating branches from the radial recurrent artery. Fifteen lateral arm/proximal forearm flaps have been utilized for various upper and lower extremity reconstructions and three penile constructions. All flaps survived, and there was primary healing of all wounds. Three are presented which demonstrate the versatility of the lateral arm/proximal forearm flap.


Heroes of the Engram.
In 1904, Richard Semon introduced the term "engram" to describe the neural substrate responsible for (or at least important in) storing and recalling memories (i.e., a memory trace). The recent introduction of a vast array of powerful new tools to probe and manipulate memory function at the cell and neuronal circuit level has spurred an explosion of interest in studying the engram. However, the present "engram renaissance" was not borne in isolation but rather builds on a long tradition of memory research. We believe it is important to acknowledge the debts our current generation of scientists owes to those scientists who have offered key ideas, persevered through failed experiments and made important discoveries before us. Examining the past can also offer a fresh perspective on the present state and future promise of the field. Given the large amount of empirical advances made in recent years, it seems particularly timely to look back and review the scientists who introduced the seminal terminology, concepts, methodological approaches, and initial data pertaining to engrams. Rather than simply list their many accomplishments, here we color in some details of the lives and milestone contributions of our seven personal heroes of the engram (Richard Semon, Karl Lashley, Donald Hebb, Wilder Penfield, Brenda Milner, James McConnell, and Richard Thompson). In reviewing their historic role, we also illustrate how their work remains relevant to today's studies.


Modified convolution method to reconstruct particle hologram with an elliptical Gaussian beam illumination.
Application of the modified convolution method to reconstruct digital inline holography of particle illuminated by an elliptical Gaussian beam is investigated. Based on the analysis on the formation of particle hologram using the Collins formula, the convolution method is modified to compensate the astigmatism by adding two scaling factors. Both simulated and experimental holograms of transparent droplets and opaque particles are used to test the algorithm, and the reconstructed images are compared with that using FRFT reconstruction. Results show that the modified convolution method can accurately reconstruct the particle image. This method has an advantage that the reconstructed images in different depth positions have the same size and resolution with the hologram. This work shows that digital inline holography has great potential in particle diagnostics in curvature containers.


[The effect of excess catecholamines on grooming in rats in postnatal ontogeny].
During the first month of postnatal life, studies have been made of the effect of L-DOPA on grooming in rat puppies. It was found that within the first hour after injection of the drug, its inhibitory effect increases in the course of ontogenetic development. In some of the animals, the increase in grooming was observed, whereas in other ones the effect was absent. Inhibition concerns both the number of grooming outbursts and the duration of rhythmic phase. These changes are associated with the decrease of afferent input to the central nervous system and with inhibition of the activity of pacemakers of rhythmic motor excitation.


Ginsenoside Rb1 inhibits vascular calcification as a selective androgen receptor modulator.
Ginsenoside Rb1 (Rb1), a major component of ginseng, has a steroidal chemical structure, implying that it exerts sex hormone-like actions. Recent studies have been suggested cardioprotective actions of Rb1. However, the actions of Rb1 in vascular calcification, one of the significant pathological features associated with aging and atherosclerosis, have not been examined. In the present study, we examined the effects of Rb1 on vascular calcification, focusing on its androgen-like actions. Using inorganic phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMC), we found that Rb1, like testosterone, significantly inhibited calcium deposition in a concentration-dependent manner. Further, this inhibition of Rb1 was abolished by bicalutamide, an androgen receptor antagonist, but not by MPP or PHTPP, estrogen receptor α or β antagonists. Rb1 significantly inhibited apoptosis, one of the regulatory mechanisms of calcification, and restored growth arrest-specific gene 6 (Gas6) expression that was suppressed by Pi. Moreover, Rb1 transactivated Gas6, and proximal androgen-responsive element (ARE) of the promoter region was found to be crucial for Gas6 transactivation. In contrast, in a human prostate cancer cell line, testosterone-induced ARE activity was abrogated by Rb1. This antagonistic effect was also confirmed by the transrepression and downregulation of prostate-specific antigen in the presence of testosterone and Rb1 together. Thus, these findings provide a novel mechanistic insight into the vasculoprotective actions of Rb1 as a selective androgen receptor modulator, i.e., inhibitory effects on VSMC calcification through androgen receptor-mediated Gas6 transactivation and antagonistic effects in prostate cancer cells.


Xenografting of gonadal tissues into mice as a possible method for conservation and utilization of porcine genetic resources.
In vitro production of embryos, including in vitro maturation, fertilization of oocytes and their subsequent culture to the embryo stage, has become the most popular method of studying gametogenesis and embryogenesis in pigs. As well as their utility for basic studies, these procedures now enable us to generate viable embryos and offspring as a means of conserving genetic resources and rare animal breeds. Recently, more advanced technologies such as xenografting of gonadal (testicular and ovarian) tissues into immunodeficient experimental animals have been developed. In combination with in vitro embryo production techniques, this approach may provide many benefits. We have been carrying out studies to acquire basic information about the application of this method to porcine species, and to improve the existing techniques. Recently, we obtained oocytes from ovarian tissue xenografted and grown in nude mice that had the capacity to be fertilized and the ability to develop into early-stage embryos. We also obtained spermatozoa from the xenografted testicular tissues and injected them intracytoplasmically into in vitro-matured oocytes to produce piglets. Here we discuss the further possibilities of conservation and utilization of porcine gonadal tissue by xenografting into immunodeficient mice.


A turn-on fluorogenic chemosensor for Fe3+ and a Schottky barrier diode with frequency-switching device applications.
A novel highly sensitive and selective fluorescent chemosensor L has been synthesized and characterized by various physicochemical techniques. In 3 : 7 water : MeCN (v/v) at pH 7.2 (10 mM HEPES buffer, μ = 0.05 M LiCl), it selectively recognizes Fe3+ through 1 : 1 complexation resulting in a 106-fold fluorescence enhancement and a binding constant of 8.10 × 104 M-1. The otherwise non-fluorescent spirolactam form of the probe results a dual-channel (absorbance and fluorescence) recognition of Fe3+via CHEF (chelation enhanced fluorescence) through the opening of the spirolactam ring. We have also carried out fluorescence titration and anisotropy (r) studies in pure water in the presence of SDS (sodium dodecyl sulphate). Based on the dependence of FI (fluorescence intensity) and r on [SDS] it was proposed that the probe is trapped between two SDS monolayers which again interact among themselves by ππ stacking. As a result, there is an increase in FI up to [SDS] ∼ 7 mM - a phenomenon reminiscent of aggregation-induced enhancement of emission (AIEE). Beyond this concentration of SDS (7 mM), micelle formation takes place and the ππ stacked polymer now becomes a monomer and is trapped inside the micellar cavity. As a result, there is a decrease in FI at [SDS] > 7 mM. But for anisotropy, it increases with [SDS] beyond 7 mM. Ligand, metal, and SDS interactions are well established through different optical and morphological studies. [L-Fe(NO3)]2+ thin films on FTO (Fluorine-doped Tin Oxide) glass substrates have been designed with the help of the spin-coating deposition technique. The deposited film of thickness 1.6 × 10-5 cm is well characterized by optical band gap calculation with a direct band gap, εg ∼ 1.6 eV. FESEM was also performed for the [L-Fe(NO3)]2+/FTO film. The current-voltage characteristics were measured by the two-probe technique. Light-dependent exciton generation was carried out by taking the top and bottom contacts with graphite paste on FTO and on the [L-Fe(NO3)]2+ films for the measurement of switching behavior. The response ratio curve for the light-induced frequency-switching phenomena has been obtained. The frequency taped here is the oscillation frequency of the photo-generated electron and the hole in an exiton. Thus, the light-induced frequency-switching behavior and Schottky barrier diode characteristics of the material were established.


Glutathione and glutathione-related enzymes in colorectal cancer patients.
In recent years much attention has been focused on the role of glutathione (GSH) and GSH-related enzymes such as glutathione peroxidase (GSH Px), glutathione reductase (GSH Red), and glutathione S-transferase (GST) in the inhibition of free radical-induced carcinogenesis. In this study, erythrocyte GSH levels and activities of GSH Px, GSH Red, and GST were determined in patients with colorectal tumors (n = 20, mean age 54.5 +/- 8.3 yr). Erythrocyte GSH Red and GST activities were significantly higher in patients with colorectal tumors. Erythrocyte GSH levels and GSH Px activities were found to be significantly decreased in the patients. When the patients were classified based on their clinical grading (Dukes classifications), there was no significant difference in studied parameters between Dukes B and Dukes C. Our results suggest that oxidative stress may play an important role in colorectal tumorigenesis and that these events have no effect on the clinical grading of the colorectal tumor.


Conformational dynamics during misincorporation and mismatch extension defined using a DNA polymerase with a fluorescent artificial amino acid.
High-fidelity DNA polymerases select the correct nucleotide over the structurally similar incorrect nucleotides with extremely high specificity while maintaining fast rates of incorporation. Previous analysis revealed the conformational dynamics and complete kinetic pathway governing correct nucleotide incorporation using a high-fidelity DNA polymerase variant containing a fluorescent unnatural amino acid. Here we extend this analysis to investigate the kinetics of nucleotide misincorporation and mismatch extension. We report the specificity constants for all possible misincorporations and characterize the conformational dynamics of the enzyme during misincorporation and mismatch extension. We present free energy profiles based on the kinetic measurements and discuss the effect of different steps on specificity. During mismatch incorporation and subsequent extension with the correct nucleotide, the rates of the conformational change and chemistry are both greatly reduced. The nucleotide dissociation rate, however, increases to exceed the rate of chemistry. To investigate the structural basis for discrimination against mismatched nucleotides, we performed all atom molecular dynamics simulations on complexes with either the correct or mismatched nucleotide bound at the polymerase active site. The simulations suggest that the closed form of the enzyme with a mismatch bound is greatly destabilized due to weaker interactions with active site residues, nonideal base pairing, and a large increase in the distance from the 3'-OH group of the primer strand to the α-phosphate of the incoming nucleotide, explaining the reduced rates of misincorporation. The observed kinetic and structural mechanisms governing nucleotide misincorporation reveal the general principles likely applicable to other high-fidelity DNA polymerases.


Regularized-Ncut: Robust and homogeneous functional parcellation of neonate and adult brain networks.
Brain network parcellation based on resting-state functional MRI (rs-fMRI) is affected by noise, resulting in spurious small patches and decreased functional homogeneity within each network. Obtaining robust and homogeneous parcellation of neonate brain is more difficult, because neonate rs-fMRI is associated with relatively higher level of noise and no prior knowledge from a functional neonate atlas is available as spatial constraints. To meet these challenges, we developed a novel data-driven Regularized Normalized-cut (RNcut) method. RNcut is formulated by adding two regularization terms, a smoothing term using Markov random fields and a small-patch removal term, to conventional normalized-cut (Ncut) method. The RNcut and competing methods were tested with simulated datasets with known ground truth and then applied to both adult and neonate rs-fMRI datasets. Based on the parcellated networks generated by RNcut, intra-network connectivity was quantified. The test results from simulated datasets demonstrated that the RNcut method is more robust (p < 0.01) to noise and can delineate parcellated functional networks with significantly better (p < 0.01) spatial contiguity and significantly higher (p < 0.01) functional homogeneity than competing methods. Application of RNcut to neonate and adult rs-fMRI dataset revealed distinctive functional brain organization of neonate brains from that of adult brains. Collectively, we developed a novel data-driven RNcut method by integrating conventional Ncut with two regularization terms, generating robust and homogeneous functional parcellation without imposing spatial constraints. A broad range of brain network applications and analyses, especially neonate and infant brain parcellation with noisy and large sample of datasets, can potentially benefit from this RNcut method.


Ipilimumab in advanced melanoma: reports of long-lasting responses.
Patients with metastatic melanoma have a poor prognosis; the results of chemotherapy remain unsatisfactory. Ipilimumab, an anticytotoxic T lymphocyte-associated antigen-4 antibody, has shown promising results in several clinical trials. In this report, advanced melanoma patients receiving ipilimumab were scored according to novel immune-related response criteria (irRC) in an attempt to capture additional response patterns and to avoid premature treatment cessation. Thirty-six heavily pretreated metastatic melanoma patients recieved ipilimumab within five international clinical trials at our Institution from May 2006 to August 2008. Disease progression was defined as an increase in tumor burden by at least 25% compared with the nadir, irrespective of any initial increase in baseline lesions or the appearance of new lesions. We report unusually long-lasting responses in patients treated with ipilimumab 10 mg/kg. An overall response was observed in six out of 30 patients (20%), a complete response in three (10%), and disease control in 11 (37%), which seemed to be of a long duration (median of 16 months; complete response 36+, 34+, and 41+ months). All irRC patterns seemed to be strongly associated with an improvement in overall survival. Interestingly, we found a correlation between the presence of a grade 3/4 immune-related adverse event and responses, time to progression, and overall survival. Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, supporting the need for further irRC validation.


Diarrhea induced by infection of Vibrio parahaemolyticus.
Vibrio parahaemolyticus is a human pathogen that naturally inhabits marine and estuarine environments. Infection with V. parahaemolyticus is often associated with the consumption of raw or undercooked seafood, causing gastroenteritis with watery diarrhea. The presence of two type III secretion system (T3SS) proteins, thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH), has been closely associated with the severity of diarrheal illness. TDH and TRH have various biological activities including hemolytic activity, cardiotoxicity, and enterotoxicity. T3SS1 is involved in cytotoxicity to host cells and orchestrates a multifaceted host cell infection by induction of autophagy, cell rounding, and cell lysis. T3SS2 is thought to be related to the enterotoxicity of V. parahaemolyticus. The activities of inducing diarrhea of each of the virulence factors were summarized in this review.


Herniation of the liver: an extremely rare entity.
We hereby present the case of a 75 years old female who was complaining of right upper quadrant abdominal pain. She had a history of cystectomy, cholecystectomy and choledochotomy operations for liver hydatid cyst 5 years ago. In addition, multiple endoscopic retrograde cholangiopancreatography sessions had been performed for recurrent biliary duct stones in the last 4 years. Radiological investigations revealed the presence of cirrhosis and the herniation of the left liver lobe through the abdominal incisional hernia defect. Secondary sclerosing cholangitis as a result of the previous operations was suggested to be the probable etiology for cirrhosis. The cirrhotic patient with an advanced age was found to be high risk for surgery. In addition, her symptoms were minimal. Thus, she was managed conservatively. Herniation of the liver is very rare. It is quite difficult to speculate any predisposing risk factors for liver herniation because of the rarity of this condition.


The oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one reduces hepatic-free iron, lipid peroxidation and fat accumulation in chronically ethanol-fed rats.
The effect of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) on liver nonheme iron, lipid peroxidation and hepatic fat accumulation in the intragastric feeding rat model for alcoholic liver disease was studied. Male Wistar rats (225-250 g) were fed liquid diet and ethanol for 1 month. In control pair-fed animals, ethanol was replaced isocalorically by dextrose. Two additional groups of animals (dextrose and ethanol-fed) received L1 (75 mg/kg/day for 30 days). The blood ethanol level in the ethanol-fed animals was maintained between 150 and 350 mg/dl. For each animal, the levels of hepatic nonheme iron, lipid peroxidation and triglyceride were evaluated. The nonheme iron in alcohol-fed animals was significantly higher (416 +/- 15 nmol/g of liver) than in pair-fed dextrose controls (346 +/- 18.5 nmol/g, P < .05). Animals fed ethanol and L1 had significantly lower nonheme iron (364 +/- 9.3 nmol/g) than rats fed ethanol alone (P < .05). L1 had no effect on nonheme iron levels in dextrose-fed controls. The importance of iron in lipid peroxidation in this model is shown by the positive correlation between the nonheme iron levels and microsomal conjugated dienes (r = 0.67, P < .02) and liver thiobarbituric acid reactive substances (r = 0.62, P < .05). The most significant observations in this study were: 1) the higher hepatic nonheme iron content in ethanol-fed rats compared to pair-fed dextrose controls; 2) lower nonheme iron and liver fat in the ethanol-fed rats treated with L1; and 3) the significant positive correlation between the liver nonheme and lipid peroxidation.


Compressive sensing image sensors-hardware implementation.
The compressive sensing (CS) paradigm uses simultaneous sensing and compression to provide an efficient image acquisition technique. The main advantages of the CS method include high resolution imaging using low resolution sensor arrays and faster image acquisition. Since the imaging philosophy in CS imagers is different from conventional imaging systems, new physical structures have been developed for cameras that use the CS technique. In this paper, a review of different hardware implementations of CS encoding in optical and electrical domains is presented. Considering the recent advances in CMOS (complementary metal-oxide-semiconductor) technologies and the feasibility of performing on-chip signal processing, important practical issues in the implementation of CS in CMOS sensors are emphasized. In addition, the CS coding for video capture is discussed.


Tuning the activity and selectivity of polymerised ionic liquid-stabilised ruthenium nanoparticles through anion exchange reactions.
The development of highly active and selective heterogeneous-based catalysts with tailorable properties is not only a fundamental challenge, but is also crucial in the context of energy savings and sustainable chemistry. Here, we show that ruthenium nanoparticles (RuNPs) stabilised with simple polymerised ionic liquids (PILs) based on N-vinyl imidazolium led to highly active and robust nano-catalysts in hydrogenation reactions, both in water and organic media. Of particular interest, their activity and selectivity could simply be manipulated through counter-anion exchange reactions. Hence, as a proof of concept, the activity of RuNPs could be reversibly turned on and off in the hydrogenation of toluene, while in the case of styrene, the hydrogenation could be selectively switched from ethylbenzene to ethylcyclohexane upon anion metathesis. According to X-ray photoelectron spectroscopy (XPS) and dynamic light scattering (DLS) analyses, these effects could originate not only from the relative hydrophobicity and solvation of the PIL corona but also from the nature and strength of the PIL-Ru interactions.


Multiple Reaction Monitoring for the Quantitation of Serum Protein Glycosylation Profiles: Application to Ovarian Cancer.
Protein glycosylation fingerprints are widely recognized as potential markers for disease states, and indeed differential glycosylation has been identified in multiple types of autoimmune diseases and several types of cancer. However, releasing the glycans leave the glycoproteins unknown; therefore, there exists a need for high-throughput methods that allow quantification of site- and protein-specific glycosylation patterns from complex biological mixtures. In this study, a targeted multiple reaction monitoring (MRM)-based method for the protein- and site-specific quantitation involving serum proteins immunoglobulins A, G and M, alpha-1-antitrypsin, transferrin, alpha-2-macroglobulin, haptoglobin, alpha-1-acid glycoprotein and complement C3 was developed. The method is based on tryptic digestion of serum glycoproteins, followed by immediate reverse phase UPLC-QQQ-MS analysis of glycopeptides. To quantitate protein glycosylation independent of the protein serum concentration, a nonglycosylated peptide was also monitored. Using this strategy, 178 glycopeptides and 18 peptides from serum glycoproteins are analyzed with good repeatability (interday CVs of 3.65-21-92%) in a single 17 min run. To assess the potential of the method, protein glycosylation was analyzed in serum samples from ovarian cancer patients and controls. A training set consisting of 40 cases and 40 controls was analyzed, and differential analyses were performed to identify aberrant glycopeptide levels. All findings were validated in an independent test set (n = 44 cases and n = 44 controls). In addition to the differential glycosylation on the immunoglobulins, which was reported previously, aberrant glycosylation was also observed on each of the glycoproteins, which could be corroborated in the test set. This report shows the development of a method for targeted protein- and site-specific glycosylation analysis and the potential of such methods in biomarker development.


Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer.
Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with 177Lu-PSMA RLT in a mouse model of prostate cancer. Mice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by 68Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) 177Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints. Tumor growth was delayed by ARB while 68Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8- and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT. ARB-mediated increases in PSMA expression in PC xenografts were evident by 68Ga-PSMA11 PET imaging and flow cytometry. 177Lu-PSMA617 effectively decreased C4-2 tumor size. However, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT.


The increasing diversity and complexity of the RNA-binding protein repertoire in plants.
Post-transcriptional regulation has far-reaching implications on the fate of RNAs. It is gaining increasing momentum as a critical component in adjusting global cellular transcript levels during development and in response to environmental stresses. In this process, RNA-binding proteins (RBPs) are indispensable chaperones that naturally bind RNA via one or multiple globular RNA-binding domains (RBDs) changing the function or fate of the bound RNAs. Despite the technical challenges faced in plants in large-scale studies, several hundreds of these RBPs have been discovered and elucidated globally over the past few years. Recent discoveries have more than doubled the number of proteins implicated in RNA interaction, including identification of RBPs lacking classical RBDs. This review will discuss these new emerging classes of RBPs, focusing on the current state of the RBP repertoire in Arabidopsis thaliana, including the diverse functional roles derived from quantitative studies implicating RBPs in abiotic stress responses. Notably, this review highlights that 836 RBPs are enriched as Arabidopsis RBPs while 1865 can be classified as candidate RBPs. The review will also outline outstanding areas within this field that require addressing to advance our understanding and potential biotechnological applications of RBPs.


Functional and structural differences in the hippocampus associated with memory deficits in adult survivors of acute lymphoblastic leukemia.
Radiation and chemotherapy targeted to the central nervous system (CNS) can cause cognitive impairment, including impaired memory. These memory impairments may be referable to damage to hippocampal structures resulting from CNS treatment. In the present study, we explored episodic memory and its neuroimaging correlates in 10 adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy and both systemic and intrathecal chemotherapy and 10 controls matched for age and sex, using a subsequent memory paradigm after episodic encoding of visual scenes. We report behavioral, structural, and functional changes in the brains of the adult survivors. They demonstrated poorer recognition memory, hippocampal atrophy, and altered blood oxygenation level-dependent (BOLD) signal in the hippocampus. Whole brain statistical map analysis revealed increased BOLD signal/activation in several brain regions during unsuccessful encoding in ALL survivors, potentially reflecting ineffective neural recruitment. Individual differences in memory performance in ALL participants were related to magnitude of BOLD response in regions associated with successful encoding. Taken together, these findings describe long term neuroimaging correlates of cognitive dysfunction after childhood exposure to CNS-targeted cancer therapies, suggesting enduring damage to episodic memory systems.


[Cerebelous syndrome by infratentorial brain tuberculornas and mutisystemic tuberculosis in AIDS patient].
We present a clinical case of a patient who consulted for a cerebelous syndrome and diplopia associated to 10 kg weight loss in six months and multiple adenopathies. Cerebral imagenology study evidenced the presence of granulamatous masses at the cerebellum and midbrain level, there were no cerebrospinal fluid abnormalities. Systemic tuberculosis (TB) diagnosis was done based in finding of acid-fast bacilli positive staining in urine and lymph node biopsy. HIV infection was documented by ELISA serology. CD4 cell count was 590 cell/mm3, classifying the case a AIDS Cl stage. TB was treated according to national guidelines leading to good clinical and imagenology evolution. The clinical case scenario of infratentorial tuberculomas without meningitis as a first manifestation of TB and AIDS is unusual, generating our interest in reporting this case.


Repression of TGF-β Signaling in Breast Cancer Cells by miR-302/367 Cluster.
Epigenetic alterations of the malignantly transformed cells have increasingly been regarded as an important event in the carcinogenic development. Induction of some miRNAs such as miR-302/367 cluster has been shown to induce reprogramming of breast cancer cells and exert a tumor suppressive role by induction of mesenchymal to epithelial transition, apoptosis and a lower proliferation rate. Here, we aimed to investigate the impact of miR-302/367 overexpression on transforming growth factor-beta (TGF-β) signaling and how this may contribute to tumor suppressive effects of miR-302/367 cluster. In this experimental study, MDA-MB-231 and SK-BR-3 breast cancer cells were cultured and transfected with miR-302/367 expressing lentivector. The impact of miR-302/367 overexpression on several mediators of TGF-β signaling and cell cycle was assessed by quantitative real-time polymerase chain reaction (qPCR) and flow cytometry. Ectopic expression of miR-302/367 cluster downregulated expression of some downstream elements of TGF-β pathway in MDA-MB-231 and SK-BR-3 breast cancer cell lines. Overexpression of miR-302/367 cluster inhibited proliferation of the breast cancer cells by suppressing the S-phase of cell cycle which was in accordance with inhibition of TGF-β pathway. TGF-β signaling is one of the key pathways in tumor progression and a general suppression of TGF-β mediators by the pleiotropically acting miR-302/367 cluster may be one of the important reasons for its anti-tumor effects in breast cancer cells.


[Modulated electromagnetic field as a factor of selective influence on animal mechanisms of goal-directed behavior].
Proceeding from P.K. Anokhin's theory of the functional systems, the paper considers the action of a modulated electromagnetic field (MEMF) on different stages of the central architectonics of purposeful behaviour of rats: afferent synthesis, decisions making, acceptor of the action results. The action of MEMF was studied in different experimental situations: choice of an alimentary or defensive reaction to one conditioned stimulus in different situations; extinction of conditioned alimentary reactions; elaboration and extinction of alimentary conditioned reactions in animals group contacts; choice of the side of reinforcement in a T-shaped maze, and, lastly, self-stimulation reactions. The experiments have shown that MEMF has a selective effect on the animals' emotional reactions. Greater disturbances are observed in the mechanisms of the animals' appraisal of the action of situational and trigger stimuli or surrounding individuals of their species and, hence, of decisions making and anticipation of future results of the action, the acceptor of the action results.


Breastfeeding and Postpartum Depression: An Overview and Methodological Recommendations for Future Research.
Emerging research suggests that a relationship exists between breastfeeding and postpartum depression; however, the direction and precise nature of this relationship are not yet clear. The purpose of this paper is to provide an overview of the relationship between breastfeeding and postpartum depression as it has been examined in the empirical literature. Also, the potential mechanisms of action that have been implicated in this relationship are also explored. PubMed and PsycINFO were searched using the keywords: breastfeeding with postpartum depression, perinatal depression, postnatal depression. Results of this search showed that researchers have examined this relationship in diverse ways using diverse methodology. In particular, researchers have examined the relationships between postpartum depression and breastfeeding intention, initiation, duration, and dose. Due to a number of methodological differences among past studies we make some recommendations for future research that will better facilitate an integration of findings. Future research should (1) use standardized assessment protocols; (2) confirm diagnosis through established clinical interview when possible; (3) provide a clear operationalized definition for breastfeeding variables; (4) clearly define the postpartum period interval assessed and time frame for onset of symptoms; (5) be prospective or longitudinal in nature; and (6) take into consideration other potential risk factors identified in the empirical literature.


Emergency department patients with psychiatric complaints return at higher rates than controls.
At our 35,000 visit/year emergency department (ED), we studied whether patients presenting to the ED with psychiatric complaints were admitted to the hospital at a higher rate than non-psychiatric patients, and whether these patients had a higher rate of reevaluation in the ED within 30 days following the index visit. We reviewed the electronic records of all ED patients receiving a psychiatric evaluation from January to February 2007 and compared these patients to 300 randomly selected patients presenting during the study period for non-psychiatric complaints. Patients were followed for 30 days, and admission rates and return visits were compared. Two hundred thirty-four patients presented to the ED and were evaluated for psychiatric complaints during the study period. Twenty-four point seven percent of psychiatric patients were admitted upon initial presentation versus 20.7% of non-psychiatric patients (p = 0.258). Twenty-one percent of discharged psychiatric patients returned to the ED within 30 days versus 13.4% of discharged non-psychiatric patients (p=0.041). Patients returning to the ED within 30 days had a 17.1% versus 21.6% admission rate for the psychiatric and non-psychiatric groups, respectively (p=0.485). Patients presenting to this ED with psychiatric complaints were not admitted at a significantly higher rate than non-psychiatric patients. These psychiatric patients did, however, have a significantly higher return rate to the ED when compared to non-psychiatric patients.


[Family life events, maternal mental health status, and the problems of preschool children's behavior--a correlation study].
The purpose of this study was to explore the relationships of family life events and maternal mental health status to mothers' reports of the problems of their preschool children's behavior. Ninety children aged between 2.5 and 4 years old were sampled from 4 private kindergartens in Taipei. There was a positive correlation between family life events and the problems of preschool children's behavior, but "maternal mental health status" was the best predictor for the problems of preschool children's behavior by multiple regression analysis.


The effect of Wolbachia on diapause, fecundity, and clock gene expression in Trichogramma brassicae (Hymenoptera: Trichogrammatidae).
The short day lengths of late summer in moderate regions are used to induce diapause in various insects. Many studies have shown the maternal effect of photoperiod on diapause induction of Trichogramma wasps, but there is no study to show the relationship between photoperiodic regimes and clock genes in these useful biological control agents. Here, we investigated the role of photoperiods on diapause, fecundity, and clock gene expression (clk, cyc, cry2, per, and timeout) in asexual and sexual Trichogramma brassicae as a model insect to find any differences between two strains. Asexual strain was infected by Wolbachia, an endosymbiont bacterium. The diapause percentage was significantly higher under short days (8 h in sexual and 12 h in the asexual T. brassicae), although the diapause percentage of the sexual strain was significantly higher than the asexual one in all the photoperiods. The ANOVA revealed no significant changes between different photoperiods in the clock gene expression in the sexual strain but significant photoperiodic changes in clk, cyc, and timeout in the asexual strain. Our results showed that the mRNA levels of clock genes of asexual T. brassicae were significantly lower than those of sexual strain. The fecundity was significantly higher in the asexual strain. These results suggest that Wolbachia infection makes disturbance on the clock gene expression which consequently reduces the percentage of diapause but increases the fecundity in asexual T. brassicae.


Are early and current erectile problems associated with anxiety and depression in young men? A retrospective self-report study.
Erectile dysfunction (ED) has been extensively studied in the past few decades, and significant advances have been made in understanding its etiology. Most cases of this type of dysfunction have an organic etiology, and ED occurs primarily in older men. However, relatively little is known about erectile problems in young men or about the interconnection between psychiatric symptoms and ED etiology. In this study, the authors investigated ED symptoms in a large, population-based sample of 18-48-year-old men. Participants reported ED symptoms from their first intercourse experience as well as those occurring at present. The authors assessed the association between reported ED symptoms during early partnered sexual experiences and present ED symptoms. Furthermore, the authors investigated associations between age, symptoms of anxiety and depression, and erectile problems. Results indicated that age was a significant predictor of ED problems already in young age groups. ED problems were prevalent to a much higher extent during early sexual intercourse experiences and appeared to pass with time for most men. Anxiety and depression were significant predictors of present erectile problems. Implications of the results and potential limitations were discussed.


Latent viral infection of cells in tissue culture. I. Studies on latent infection of chick embryo tissues with psittacosis virus.
Chick embryo tissues maintained for from 11 to 28 days in Hank's balanced salt solution lost their capacity to support the multiplication of psittacosis virus. The virus however infected such cells, as active multiplication of the virus occurred on the addition of beef embryo extract to this nutritionally poor medium at any period up to 28 days of cultivation in balanced salt solution. The virus remained in a state of latency for as long as 15 days in these starved cells in a non-infectious phase. These results obtained in this in vitro model system for the investigation of latent infections of cells with psittacosis virus suggest that cell nutrition as well as an alteration in the immunological defenses of the host may prove to be an important factor in the activation of latent viral infections.


Endothelium and acute coronary syndromes.
The vascular endothelium is a dynamic endocrine organ that regulates contractile, secretory, and mitogenic activities in the vessel wall and hemostatic processes within the vascular lumen. Risk factors for atherosclerosis such as cigarette smoking, hypertension, and increased serum lipid concentrations impair endothelial function and lead to the development of atherosclerotic vessels, which cause acute coronary syndromes. Atherosclerotic vessels progress from scattered foam cells to complex lesions with a lipid core and fibrous cap. Factors that weaken and cause the rupture of the fibrous cap will expose circulating blood products to the procoagulant materials in the lipid core. Thrombosis and subsequent remodeling of the unstable plaque may be catastrophic or clinically silent depending on the degree of vascular occlusion and availability of collateral blood flow. Evidence is presented that supports the view that endothelial dysfunction is an early marker of atherosclerosis and an important contributor to the atherogenic process.


Shoulder posterior internal impingement in the overhead athlete.
Posterior internal impingement (PII) of the glenohumeral joint is a common cause of shoulder complex pain in the overhead athlete. This impingement is very different from standard outlet impingement seen in shoulder patients. Internal impingement is characterized by posterior shoulder pain when the athlete places the humerus in extreme external rotation and abduction as in the cocking phase of pitching or throwing. Impingement in this position occurs between the supraspinatus and or infraspinatus and the glenoid rim. Understanding regarding this pathology continues to evolve. Definitive understanding of precipitating factors, causes, presentation and methods of treatment have yet to be determined. A high index of suspicion should be used when attempting to make this diagnosis. This current concepts review presents the current thinking regarding pathophysiology, evaluation, and treatment of this condition. 5.


An evaluation of a handheld indirect calorimeter against a standard calorimeter in obese and nonobese adults.
Handheld indirect calorimetry has the potential to allow simple and inexpensive measurement of resting metabolic rate in spontaneously breathing people. However, validation work on these devices is contradictory. The purpose of the current study was to determine the bias and level of agreement of oxygen consumption and resting metabolic rate as measured by a handheld indirect calorimeter against a standard open-circuit indirect calorimetry cart. One hundred community-living, spontaneously breathing, ambulatory nonobese and obese adults were studied in single sessions by a single investigator. Sequential measurements were undertaken using the handheld indirect calorimeter and the standard metabolic cart. Measurement sequence was varied randomly. The mean value for oxygen consumption and metabolic rate of the 2 devices was not significantly different. However, agreement between the 2 devices was only 43% in nonobese and obese participants, and there was proportional and fixed bias, with the handheld calorimeter tending to produce a higher value for oxygen consumption and resting metabolic rate. Limits of agreement for resting metabolic rate between the 2 calorimeters were -240 to +300 kcal/d. Measurements of resting metabolic rate by the handheld indirect calorimeter tested in this study are not equivalent to measurements by standard indirect calorimetry.


[Urethral replacement in women. Experimental works and clinical application].
Numerous operations have been previously described in view of replacing the urethra, but attempts to provide continence have rarely been satisfactorily achieved. Urethral replacement using ileum with an ileal intussuspected valve for continence has be39 successfully performed in ten dogs. This report details the experimental model with the results obtained in the long range. It is followed by the evaluation, surgical technique and postoperative results of the clinical application of this surgical alternative in three patients.


Predictive Factors for Rebleeding after Negative Capsule Endoscopy among Patients with Overt Obscure Gastrointestinal Bleeding.
Although capsule endoscopy (CE) is useful to evaluate obscure gastrointestinal bleeding (OGIB), CE does not always identify the responsible lesions in patients with overt OGIB. To identify factors predictive of rebleeding after negative CE in patients with overt OGIB. We retrospectively analyzed the clinical data of 221 patients who underwent CE for overt OGIB. Among 120 patients with negative CE findings, clinical course of 112 patients after CE was followed-up. Clinical factors associated with rebleeding after negative CE and lesions responsible for rebleeding were investigated. Rebleeding was identified in 37 patients (33.0%) during follow-up after negative CE, and 36 patients (32.1%) developed rebleeding within 24 months after negative CE. Multivariate analyses showed that ongoing overt OGIB (OR 2.67; 95% CI 1.07-5.80; p = 0.036) and severe anemia at the initial CE examination (OR 2.54; 95% CI 1.33-4.96; p = 0.005) were independent factors -associated with rebleeding. Rebleeding source was detected in 13 patients. Rebleeding is not a rare condition among patients with overt OGIB after negative CE. Patients with ongoing overt OGIB or severe anemia at the initial CE examination seem to have a higher risk of rebleeding.


Improvement of multiple sclerosis-associated tremor as a treatment effect of natalizumab.
Tremor is among the most physically disabling symptoms associated with MS. The effect of MS disease modifying therapies (DMTs) on the severity of MS tremor is unclear. To compare the change over time in scores reflecting tremor severity between subjects treated with natalizumab and other disease modifying drugs. Questionnaires were sent to North American Research Committee on MS registrants reporting mild or greater tremor on semiannual updates. Respondents on natalizumab and other MS therapies completed a survey which included tremor-specific scales to indicate tremor severity both currently and when the current therapy was initiated. Differences between natalizumab and non-natalizumab groups were compared using ANOVA. Surveys were returned by 567 registrants, including 202 taking natalizumab. Subjects on natalizumab were more likely to report tremor improvement (29.6%) than those never (15.2%) or previously (14.8%, p=0.0002) on natalizumab. Over a mean recall period of 6.2+4.6 years, the Tremor Related Activities of Daily Living score worsened by 1.8 points among natalizumab-treated subjects, 3.3 points among those previously on natalizumab, and 5.3 points among those who never took natalizumab (p=0.009). Respondents taking natalizumab were more likely to experience tremor improvement than those taking other MS disease modifying therapies.


Effective enzymatic debridement of burn wounds depends on the denaturation status of collagen.
The treatment of burn wounds by enzymatic debridement using bromelain has shown promising results in our burn center. However, inadequate debridement occurred in a few cases in which the etiology of the burn was attributed to relatively low temperature burns. We hypothesized that bromelain is ineffective in burns in which collagen denaturation, which occurs approximately at 65°C, has not taken place. Our objective was to assess whether there is a relationship between the denaturation of collagen and the ability of bromelain to debride acute scald burn wounds of different temperatures. Ex vivo human skin from four different donors was cut into 1x1 cm samples, and scald burns were produced by immersion in water at temperatures of 40°C, 50°C, 60°C, 70°C, and 100°C for 20 minutes. Denaturation of collagen was assessed with histology, using hematoxylin and eosin (H&E) staining and a fluorescently labeled collagen hybridizing peptide (CHP), and with second harmonic generation (SHG) microscopy. Burned samples and one control sample (room temperature) were weighed before and after application of enzymatic debridement to assess the efficacy of enzymatic debridement. After enzymatic debridement, a weight reduction of 80% was seen in the samples heated to 70°C and 100°C, whereas the other samples showed a reduction of 20%. Unfolding of collagen, loss of basket-weave arrangement, and necrosis was seen in samples heated to 60°C or higher. Evident CHP fluorescence, indicative of collagen denaturation, was seen in samples of 60°C, 70°C and 100°C. SHG intensity, signifying intact collagen, was significantly lower in the 70°C and 100°C group (P <.05) compared to the lower temperatures. In conclusion, denaturation of collagen in skin samples occurred between 60°C and 70°C and strongly correlated with the efficacy of enzymatic debridement. Therefore, enzymatic debridement with the use of bromelain is ineffective in scald burns lower than 60°C.


Assessing the accuracy of predictive models with interval-censored data.
We develop methods for assessing the predictive accuracy of a given event time model when the validation sample is comprised of case $K$ interval-censored data. An imputation-based, an inverse probability weighted (IPW), and an augmented inverse probability weighted (AIPW) estimator are developed and evaluated for the mean prediction error and the area under the receiver operating characteristic curve when the goal is to predict event status at a landmark time. The weights used for the IPW and AIPW estimators are obtained by fitting a multistate model which jointly considers the event process, the recurrent assessment process, and loss to follow-up. We empirically investigate the performance of the proposed methods and illustrate their application in the context of a motivating rheumatology study in which human leukocyte antigen markers are used to predict disease progression status in patients with psoriatic arthritis.


Dynamic nuclear pore complexes: life on the edge.
The exchange of molecules between the nucleus and cytoplasm is mediated through nuclear pore complexes (NPCs) embedded in the nuclear envelope. Altering the interactions between transport receptors and their cargo has been shown to be a major regulatory mechanism to control traffic through NPCs. New evidence now suggests that NPC proteins play active roles in translocation, and that transport is also controlled by dynamic changes in NPC composition and architecture. This view of ever-changing NPCs necessitates the re-evaluation of current models of nuclear transport and how this process is regulated.


Folding and stability of trp aporepressor from Escherichia coli.
Equilibrium and kinetic studies of the urea-induced unfolding of trp aporepressor from Escherichia coli were performed to probe the folding mechanism of this intertwined, dimeric protein. The equilibrium unfolding transitions at pH 7.6 and 25 degrees C monitored by difference absorbance, fluorescence, and circular dichroism spectroscopy are coincident within experimental error. All three transitions are well described by a two-state model involving the native dimer and the unfolded monomer; the free energy of folding in the absence of denaturant and under standard-state conditions is estimated to be 23.3 +/- 0.9 kcal/mol of dimer. The midpoint of the equilibrium unfolding transition increases with increasing protein concentration in the manner expected from the law of mass action for the two-state model. We find no evidence for stable folding intermediates. Kinetic studies reveal that unfolding is governed by a single first-order reaction whose relaxation time decreases exponentially with increasing urea concentration and also decreases with increasing protein concentration in the transition zone. Refolding involves at least three phases that depend on both the protein concentration and the final urea concentration in a complex manner. The relaxation time of the slowest of these refolding phases is identical with that for the single phase in unfolding in the transition zone, consistent with the results expected for a reaction that is kinetically reversible. The two faster refolding phases are presumed to arise from slow isomerization reactions in the unfolded form and reflect parallel folding channels.


Bioinformatics: indispensable, yet hidden in plain sight?
Bioinformatics has multitudinous identities, organisational alignments and disciplinary links. This variety allows bioinformaticians and bioinformatic work to contribute to much (if not most) of life science research in profound ways. The multitude of bioinformatic work also translates into a multitude of credit-distribution arrangements, apparently dismissing that work. We report on the epistemic and social arrangements that characterise the relationship between bioinformatics and life science. We describe, in sociological terms, the character, power and future of bioinformatic work. The character of bioinformatic work is such that its cultural, institutional and technical structures allow for it to be black-boxed easily. The result is that bioinformatic expertise and contributions travel easily and quickly, yet remain largely uncredited. The power of bioinformatic work is shaped by its dependency on life science work, which combined with the black-boxed character of bioinformatic expertise further contributes to situating bioinformatics on the periphery of the life sciences. Finally, the imagined futures of bioinformatic work suggest that bioinformatics will become ever more indispensable without necessarily becoming more visible, forcing bioinformaticians into difficult professional and career choices. Bioinformatic expertise and labour is epistemically central but often institutionally peripheral. In part, this is a result of the ways in which the character, power distribution and potential futures of bioinformatics are constituted. However, alternative paths can be imagined.


Radioprotection against biological effects of internal radionuclides in vivo by S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET).
Radionuclides employed in diagnostic and therapeutic nuclear medicine impart radiation energy to tissue over an extended period of time, which depends on the physical half-life and the biological properties of the radiochemical employed. It is therefore important to examine the capacity of chemical radioprotectors to mitigate damage caused by chronic irradiation by incorporated radionuclides. Spermatogenesis in mouse testis is used as the experimental model, and spermatogonial cell survival as measured by testicular spermhead count is the biological end point. The capacity of S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET) to mitigate radiation damage caused by chronic irradiation by the radiochemicals 125IUdR, H125IPDM and 210Po-citrate, is investigated. The radioprotection provided by AET is substantial and similar for both of the radioiodinated compounds with dose modification factors (DMF) of 4.0 +/- 1.2 for 125IUdR and 3.4 +/- 0.4 for H125IPDM. In contrast, the damage caused by 210Po alpha particles is protected against to a lesser degree (DMF = 2.4 +/- 0.5). The present radioprotection data for AET, in conjunction with our earlier findings for the chemical protectors cysteamine and vitamin C in the same experimental model, suggest that such compounds may be clinically useful as mitigating agents against biological damage caused by incorporated radionuclides. The observed DMFs for AET also support our earlier premise that the mechanism by which DNA-incorporated Auger emitters impart biological damage is primarily radical mediated, and hence indirect in nature.


Anti-obesity effects of Diospyros lotus leaf extract in mice with high-fat diet-induced obesity.
Diospyros (D.) lotus has been demonstrated to have antioxidant and anti‑inflammatory properties. The purpose of the present study was to evaluate the effect of D. lotus leaf water extract (DLE) on high‑fat diet (HFD)‑induced obesity in C57BL/6 mice. The present study first investigated the effect of DLE on the lipid accumulation and triglyceride (TG) contents in 3T3‑L1 cells, and the results revealed that treatment with DLE suppressed the lipid accumulation and TG level. Subsequently, the anti‑obesity effects of DLE were investigated in vivo. Oral administration of DLE reduced the body weight gain, food efficiency ratio, and liver and visceral fat weight in mice fed with a HFD. DLE administration in these mice also reduced TG, total cholesterol, low‑density lipoprotein cholesterol, glucose, insulin and leptin levels, as well as the atherogenic index. Furthermore, DLE administration decreased hepatic steatosis, as well as serum aspartate transaminase, alanine transaminase and alkaline phosphatase levels in mice fed with HFD. It was further observed that treatment of the HFD‑fed mice with DLE prevented lipid peroxidation, while it recovered glutathione depletion and the activities of superoxide dismutase, catalase and glutathione peroxidase. In conclusion, the current study suggests that the anti‑obesity effect of DLE may provide positive insights as a potential functional food ingredient for the prevention of obesity.


Feeding Behaviour and Lifestyle of Children and Adolescents One Year after Lockdown by the COVID-19 Pandemic in Chile.
Lockdown caused by the COVID-19 pandemic may have influenced feeding behaviour and lifestyle in children and adolescents. The purpose of this study was to analyse feeding behaviour and lifestyle in children and adolescents one year after lockdown by the COVID-19 pandemic in Chile. In this cross-sectional study an online survey was implemented in 1083 parents and caregivers regarding their children's feeding behaviour and lifestyle and sociodemographic background. The results showed that "eat breakfast daily" (89.2%), "not overnight food intake" (69.9%) and "not fast-food intake" (66.0%) were the most frequent reported feeding behaviours, particularly in pre-school children. Respondents declaring healthy feeding behaviours and lifestyle were 23.4 and 23.7%, respectively, with no significant differences by sex. In pre-school children, families with three or fewer members and parents or caregivers with an undergraduate or postgraduate degree reported a significantly better feeding behaviour and lifestyle compared to families with more than three members and parents or caregivers without an undergraduate or postgraduate degree. In conclusion, the pandemic lockdown had a negative impact in lifestyle in children and particularly in adolescents. Healthier feeding behaviour was associated with fewer family members and parents or caregivers with at least an undergraduate degree.


Association between Advanced Glycation End-Products and Sarcopenia in Patients with Chronic Kidney Disease.
In patients with chronic kidney disease (CKD), there is an overproduction and accumulation of advanced glycation end-products (AGEs). Since AGEs may have detrimental effects on muscular trophism and performance, we evaluated whether they may contribute to the onset of sarcopenia in CKD patients. We enrolled 117 patients. The AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer and soluble receptor for AGE (sRAGE) isoforms by ELISA. As for the sarcopenia definition, we used the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. The average age was 80 ± 11 years, 70% were males, and the mean eGFR was 25 + 11 mL/min/1.73 m2. Sarcopenia was diagnosed in 26 patients (with a prevalence of 22%). The sarcopenic patients had higher levels of circulating AGEs (3405 ± 951 vs. 2912 ± 722 A.U., p = 0.005). AGEs were higher in subjects with a lower midarm muscle circumference (MAMC) (3322 ± 919 vs. 2883 ± 700 A.U., respectively; p = 0.005) and were directly correlated with the gait test time (r = 0.180, p = 0.049). The total sRAGE and its different isoforms (esRAGE and cRAGE) did not differ in patients with or without sarcopenia. In older CKD patients, AGEs, but not sRAGE, are associated with the presence of sarcopenia. Therefore, AGEs may contribute to the complex pathophysiology leading to the development of sarcopenia in CKD patients.


Mineral Surface-Templated Self-Assembling Systems: Case Studies from Nanoscience and Surface Science towards Origins of Life Research.
An increasing body of evidence relates the wide range of benefits mineral surfaces offer for the development of early living systems, including adsorption of small molecules from the aqueous phase, formation of monomeric subunits and their subsequent polymerization, and supramolecular assembly of biopolymers and other biomolecules. Each of these processes was likely a necessary stage in the emergence of life on Earth. Here, we compile evidence that templating and enhancement of prebiotically-relevant self-assembling systems by mineral surfaces offers a route to increased structural, functional, and/or chemical complexity. This increase in complexity could have been achieved by early living systems before the advent of evolvable systems and would not have required the generally energetically unfavorable formation of covalent bonds such as phosphodiester or peptide bonds. In this review we will focus on various case studies of prebiotically-relevant mineral-templated self-assembling systems, including supramolecular assemblies of peptides and nucleic acids, from nanoscience and surface science. These fields contain valuable information that is not yet fully being utilized by the origins of life and astrobiology research communities. Some of the self-assemblies that we present can promote the formation of new mineral surfaces, similar to biomineralization, which can then catalyze more essential prebiotic reactions; this could have resulted in a symbiotic feedback loop by which geology and primitive pre-living systems were closely linked to one another even before life's origin. We hope that the ideas presented herein will seed some interesting discussions and new collaborations between nanoscience/surface science researchers and origins of life/astrobiology researchers.