Influence of ambient moisture on the compaction behavior of microcrystalline cellulose powder undergoing uni-axial compression and roller-compaction: a comparative study using near-infrared spectroscopy.
This study evaluates the effect of variation in the ambient moisture on the compaction behavior of microcrystalline cellulose (MCC) powder. The study was conducted by comparing the physico-mechanical properties of, and the near infrared (NIR) spectra collected on, compacts prepared by roller compaction with those collected on simulated ribbons, that is, compacts prepared under uni-axial compression. Relative density, moisture content, tensile strength (TS), and Young modulus were used as key sample attributes for comparison. Samples prepared at constant roller compactor settings and feed mass showed constant density and a decrease in TS with increasing moisture content. Compacts prepared under uni-axial compression at constant pressure and compact mass showed the opposite effect, that is, density increased while TS remained almost constant with increasing moisture content. This suggests difference in the influence of moisture on the material under roller compaction, in which the roll gap (i.e., thickness and therefore density) remains almost constant, vs. under uni-axial compression, in which the thickness is free to change in response to the applied pressure. Key sample attributes were also related to the NIR spectra using multivariate data analysis by the partial least squares projection to latent structures (PLS). Good agreement was observed between the measured and the NIR-PLS predicted values for all key attributes for both, the roller compacted samples as well as the simulated ribbons.


The Saccharomyces cerevisiae chromosome III left telomere has a type X, but not a type Y', ARS region.
A yeast Saccharomyces cerevisiae telomeric region was isolated by chromosome walking from HML alpha, the most distal known gene on the chromosome III left (IIIL) end. The terminal heterodisperse 3.3-kilobase (kb) SalI fragment on chromosome IIIL, 8.6 kb distal to HML alpha, was cloned in a circular vector to generate a telomeric probe. Southern hybridization and DNA sequencing analyses indicated that 0.6 kb (+/- 200 base pairs) of 5'-C1-3A-3' simple tandem repeat sequence, adjacent to a 1.2-kb type X ARS region, constitutes the telomere on the chromosome IIIL end, and no type Y' ARS region homologies exist between HML alpha and the IIIL terminus.


Towards normalization selection of Raman data in the context of protein glycation: application of validity indices to PCA processed spectra.
Raman spectroscopy is a candidate technique for diagnosis applications in medicine due to its high molecular specificity. Optimizing the pre-treatment applied for Raman data is important for exploiting Raman signals and ensuring their relevance in medical diagnosis. One of the crucial steps in data pre-processing, normalization, can affect significantly the result interpretation. To select the appropriate normalization method, a strategy based on validity indices (VI) is proposed in this study. VI are based on measuring the quality of data partitioning without involving a full sequence of supervised classification. The approach was tested on Raman data acquired from control and in vitro glycated proteins (albumin and collagen). Protein glycation is a process involved in the molecular ageing of tissues that leads to the formation of products altering the functional and structural properties of proteins. Different methods of normalization were applied on the data sets: integrated intensity of the phenylalanine band, integrated intensity of the amide I band, standard normal variate (SNV), multiplicative signal correction (MSC), and extended multiplicative signal correction (EMSC) that performs simultaneously baseline correction and normalization. Following normalization, principal component analysis (PCA) was applied and VI were calculated from PCA scores resulting from each of the normalization methods mentioned. Based on VI quantitative values, our experiments permit to illustrate the effect of normalization on the data separability of control and glycated samples, and to determine the most appropriate normalization and simultaneously the most discriminant principal components to exploit vibrational information associated with glycation-induced modifications. In parallel, principal component analysis - linear discriminant analysis (PCA-LDA) was carried out for positioning the interest of VI in regard to a common chain of data processing.


Desmopressin for nocturnal enuresis in children.
Enuresis (bedwetting) is a socially disruptive and stressful condition which affects around 15-20% of five year olds, and up to 2% of young adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs to the children can be great. To assess the effects of desmopressin on nocturnal enuresis in children, and to compare desmopressin with other interventions. The following electronic databases were searched: MEDLINE to June 1997; AMED; ASSIA; BIDS; BIOSIS Previews (1985-1996); CINAHL; DHSS Data; EMBASE (1974 to June 1997); PsycLIT and SIGLE. Organisations, manufacturers, researchers and health professionals concerned with enuresis were contacted for information. The reference sections of obtained studies were also checked for further trials. Date of the most recent search: July 1997. All randomised trials of desmopressin for nocturnal enuresis in children were included in the review. Trials were eligible for inclusion if: children were randomised to receive desmopressin compared with placebo, other drugs or other conservative interventions for nocturnal bedwetting; participants with organic causes for their bedwetting were excluded; and baseline assessments of the level of bedwetting were reported. Trials focused solely on daytime wetting were excluded. Two reviewers independently assessed the quality of the eligible trials, and extracted data. Twenty one randomised trials involving 948 children treated with desmopressin, met the inclusion criteria. The quality of many of the trials was poor. Desmopressin was compared with a tricyclic drug in two trials, and with alarms in one. Desmopressin was effective in reducing bedwetting in a variety of doses and forms. Each dose of desmopressin reduced bedwetting by at least one night per week during treatment (eg 20microg: 1.56 fewer wet nights per week, 95% CI -1.94 to -1.19). Participants on desmopressin were 4.6 times more likely to achieve 14 consecutive dry nights (95% CI 1.38 to 15.02) compared with placebo. However, there was no difference after treatment was finished. There was no apparent dose-related effect of desmopressin, but the evidence was limited. Data which compared oral and nasal administration were too few to be conclusive. Desmopressin and imipramine (a tricyclic drug) were equally effective in one small trial. Amitriptyline (another tricyclic) was not consistently better than desmopressin either alone or when used as a supplement. In a single trial, desmopressin was initially superior to using an alarm in reducing the number of wet nights per week: WMD -1.7 (95% CI: -2.96 to -0.45), but this result was not sustained; after three months of treatment, patients using the alarm had 1.4 fewer wet nights per week than with desmopressin: (95% CI: 0.14 to 2.65). Participants receiving the alarm intervention were also nine times less likely to relapse than those given desmopressin: RR 9.2 (95% CI: 1.28 to 65.9). Combining alarm and drug therapy was found to be superior to alarm treatment alone. The addition of desmopressin to an alarm schedule resulted in one less wet night per week: (95% CI: -1.55 to -0.45). Desmopressin rapidly reduced the number of wet nights per week, but there was some evidence that this was not sustained after treatment stopped. Comparison with alternative treatments suggested that desmopressin and tricyclics had similar clinical effects, but that alarms produced more sustained benefits. However, based on the available evidence, these conclusions can only be tentative. There was some evidence of minor side effects of desmopressin in the included trials, such as nasal irritation and nose bleeds. However, the risk of water intoxication associated with over-drinking before bedtime has been reported. Patients and their families need to be warned of potential adverse effects and advise


[Resistance of various herpes simplex virus strains to the action of chemical inhibitors].
The effect of chemical inhibitors on reproduction of 2 laboratory and 3 vaccine strains of herpes simplex virus (HSV), types 1 and 2, was studied. By the time of the study the vaccine strains had undergone from 27 to 69 passages in chick embryo fibroblast cultures. All the vaccine strains (L2, Us, and VN) exhibited 100-1000 fold higher resistance to phosphonoacetic acid than did the laboratory F+ and G strains, and the vaccine L2 strain (HSV-1) was also 1000-fold resistant to 1-beta-D-arabinofuranosine thymine.


Chemical modification of the haem propionate of cytochrome c. A re-evaluation of the reaction of cytochrome c with a water-soluble carbodi-imide.
Horse heart and tuna heart cytochromes c were treated with the water-soluble carbodi-imide 1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide. When the reaction is followed spectroscopically two kinetic phases are apparent. Alteration of the reactivity of the proteins with such ligands as CO, however, occurs in a single phase identical with the faster phase detected spectroscopically. The modified proteins both show spectroscopic and redox properties identical with those described for the tuna heart cytochrome c derivative by Timkovich [Biochem. J. (1980) 185, 47-57]. The use of radiolabelled carbodi-imide identifies two or three sites of reactivity. However, the addition of glycine methyl ester to the reaction mixture leads to the addition of nine glycine moieties in the case of the horse protein and seven in the case of the tuna protein, indicating a larger number of reactive sites than previously reported. A further set of reaction sites was identified by peptide mapping of the modified proteins, and these sites take part in intramolecular reactions leading to internal cross-linking and the formation of an enzymically indigestible 'core particle'. The haem group was identified as a site of reaction with the carbodi-imide, and is as a consequence covalently linked to the peptide by a bond in addition to the thioether bonds normally present. In the light of these findings, the alterations in the properties of the tuna protein, subsequent to reaction with the carbodi-imide, which have been previously explained in structural terms, must be re-evaluated. This study also highlights the importance of internal cross-link formation, which can occur by intramolecular nucleophilic attack, a process that has often been overlooked by investigators employing carbodi-imide modification of carboxylate groups in proteins.


[Ictal semiology of temporal partial complex seizures: usefulness for localizing and lateralizing the origin of the attacks].
To review signs and symptoms associated with temporal complex partial seizures (CPS) and their utility in the localization and lateralization of seizure onset. CPS are particularly resistant to the standard antiepileptic drugs. Since surgical treatment is a therapeutical alternative in patients with intractable seizures, localization and lateralization of seizure origin are the principal aims in the preoperative assessment. Video-EEG monitorization has made possible characterization of ictal behaviour and correlation with cerebral regions generating the epileptic discharge. Therefore, ictal semiology has increased its importance in the localization and lateralization of seizures. The utility of auras, automatisms, motor manifestations, speech disturbances and autonomic features have been reviewed in relation to this approach. Viscerosensorial and experiential auras have been associated with temporal lobe epilepsy. The automatisms are not exclusive of temporal seizures and may be observed in frontal epilepsy and parietal and occipital seizures with spreading to temporal structures. There is not agreement in relation to head turning and version, therefore, this clinical sign should be used in correlation to other clinical manifestations. Distonic posturing, comprehensible ictal speech and postictal dysphasia appear to be the most reliable clinical signs in the lateralisation of temporal lobe seizures.


Prospective association of common eating disorders and adverse outcomes.
Anorexia nervosa and bulimia nervosa (BN) are rare, but eating disorders not otherwise specified (EDNOS) are relatively common among female participants. Our objective was to evaluate whether BN and subtypes of EDNOS are predictive of developing adverse outcomes. This study comprised a prospective analysis of 8594 female participants from the ongoing Growing Up Today Study. Questionnaires were sent annually from 1996 through 2001, then biennially through 2007 and 2008. Participants who were 9 to 15 years of age in 1996 and completed at least 2 consecutive questionnaires between 1996 and 2008 were included in the analyses. Participants were classified as having BN (≥ weekly binge eating and purging), binge eating disorder (BED; ≥ weekly binge eating, infrequent purging), purging disorder (PD; ≥ weekly purging, infrequent binge eating), other EDNOS (binge eating and/or purging monthly), or nondisordered. BN affected ∼1% of adolescent girls; 2% to 3% had PD and another 2% to 3% had BED. Girls with BED were almost twice as likely as their nondisordered peers to become overweight or obese (odds ratio [OR]: 1.9 [95% confidence interval: 1.0-3.5]) or develop high depressive symptoms (OR: 2.3 [95% confidence interval: 1.0-5.0]). Female participants with PD had a significantly increased risk of starting to use drugs (OR: 1.7) and starting to binge drink frequently (OR: 1.8). PD and BED are common and predict a range of adverse outcomes. Primary care clinicians should be made aware of these disorders, which may be underrepresented in eating disorder clinic samples. Efforts to prevent eating disorders should focus on cases of subthreshold severity.


Short communication: Effects of dietary nitrogen concentration on messenger RNA expression and protein abundance of urea transporter-B and aquaporins in ruminal papillae from lactating Holstein cows.
To test the hypothesis that dietary N concentrations affect gut epithelial urea transport by modifying the expression of urea transporter B (UT-B) and aquaporins (AQP), the mRNA expression and protein abundance of UT-B and AQP3, AQP7, AQP8, and AQP10 were investigated in ruminal papillae from 9 lactating dairy cows. Ruminal papillae were harvested from cows fed low N (12.9% crude protein) and high N (17.1% crude protein) diets in a crossover design with 21-d periods. The mRNA expression was determined by real-time reverse transcription-PCR and protein abundance by immunoblotting. The mRNA expression of UT-B was not affected by dietary treatment, whereas mRNA expression of AQP3, 7, and 10 were greater in the high N compared with the low N fed cows. Using peptide-derived rabbit antibodies to cow AQP3, 7, and 8, immunoblotting revealed bands of approximately 27, 27, and 24 kDa in ruminal papillae, respectively. A peptide-derived chicken antibody to cow UT-B detected a band of approximately 30 to 32 kDa in ruminal papillae. The abundance of UT-B and AQP3 and 7 were not affected by dietary treatment. In contrast, the abundance of AQP8 was greater in high N compared with low N diets. In conclusion, AQP3, 7, and 8 were found to be expressed in bovine rumen papillae. None of the investigated transcripts or proteins correlated to the increased rumen epithelial urea permeability observed with low dietary N concentration.


Robustness and management adaptability in tropical rangelands: a viability-based assessment under the non-equilibrium paradigm.
Rangelands provide the main forage resource for livestock in many parts of the world, but maintaining long-term productivity and providing sufficient income for the rancher remains a challenge. One key issue is to maintain the rangeland in conditions where the rancher has the greatest possibility to adapt his/her management choices to a highly fluctuating and uncertain environment. In this study, we address management robustness and adaptability, which increase the resilience of a rangeland. After reviewing how the concept of resilience evolved in parallel to modelling views on rangelands, we present a dynamic model of rangelands to which we applied the mathematical framework of viability theory to quantify the management adaptability of the system in a stochastic environment. This quantification is based on an index that combines the robustness of the system to rainfall variability and the ability of the rancher to adjust his/her management through time. We evaluated the adaptability for four possible scenarios combining two rainfall regimes (high or low) with two herding strategies (grazers only or mixed herd). Results show that pure grazing is viable only for high-rainfall regimes, and that the use of mixed-feeder herds increases the adaptability of the management. The management is the most adaptive with mixed herds and in rangelands composed of an intermediate density of trees and grasses. In such situations, grass provides high quantities of biomass and woody plants ensure robustness to droughts. Beyond the implications for management, our results illustrate the relevance of viability theory for addressing the issue of robustness and adaptability in non-equilibrium environments.


An iridium(iii)-based irreversible protein-protein interaction inhibitor of BRD4 as a potent anticancer agent.
Bromodomain-containing protein 4 (BRD4) has recently emerged as an attractive epigenetic target for anticancer therapy. In this study, an iridium(iii) complex is reported as the first metal-based, irreversible inhibitor of BRD4. Complex 1a is able to antagonize the BRD4-acetylated histone protein-protein interaction (PPI) in vitro, and to bind BRD4 and down-regulate c-myc oncogenic expression in cellulo. Chromatin immunoprecipitation (ChIP) analysis revealed that 1a could modulate the interaction between BRD4 and chromatin in melanoma cells, particular at the MYC promoter. Finally, the complex showed potent activity against melanoma xenografts in an in vivo mouse model. To our knowledge, this is the first report of a Group 9 metal complex inhibiting the PPI of a member of the bromodomain and extraterminal domain (BET) family. We envision that complex 1a may serve as a useful scaffold for the development of more potent epigenetic agents against cancers such as melanoma.


The endless frontier? The recent increase of R&D productivity in pharmaceuticals.
Studies on the early 2000s documented increasing attrition rates and duration of clinical trials, leading to a representation of a "productivity crisis" in pharmaceutical research and development (R&D). In this paper, we produce a new set of analyses for the last decade and report a recent increase of R&D productivity within the industry. We use an extensive data set on the development history of more than 50,000 projects between 1990 and 2017, which we integrate with data on sales, patents, and anagraphical information on each institution involved. We devise an indicator to quantify the novelty of each project, based on its set of mechanisms of action. First, we investigate how R&D projects are allocated across therapeutic areas and find a polarization towards high uncertainty/high potential reward indications, with a strong focus on oncology. Second, we find that attrition rates have been decreasing at all stages of clinical research in recent years. In parallel, for each phase, we observe a significant reduction of time required to identify projects to be discontinued. Moreover, our analysis shows that more recent successful R&D projects are increasingly based on novel mechanisms of action and target novel indications, which are characterized by relatively small patient populations. Third, we find that the number of R&D projects on advanced therapies is also growing. Finally, we investigate the relative contribution to productivity variations of different types of institutions along the drug development process, with a specific focus on the distinction between the roles of Originators and Developers of R&D projects. We document that in the last decade Originator-Developer collaborations in which biotech companies act as Developers have been growing in importance. Moreover, we show that biotechnology companies have reached levels of productivity in project development that are equivalent to those of large pharmaceutical companies. Our study reports on the state of R&D productivity in the bio-pharmaceutical industry, finding several signals of an improving performance, with R&D projects becoming more targeted and novel in terms of indications and mechanisms of action.


Information density converges in dialogue: Towards an information-theoretic model.
The principle of entropy rate constancy (ERC) states that language users distribute information such that words tend to be equally predictable given previous contexts. We examine the applicability of this principle to spoken dialogue, as previous findings primarily rest on written text. The study takes into account the joint-activity nature of dialogue and the topic shift mechanisms that are different from monologue. It examines how the information contributions from the two dialogue partners interactively evolve as the discourse develops. The increase of local sentence-level information density (predicted by ERC) is shown to apply to dialogue overall. However, when the different roles of interlocutors in introducing new topics are identified, their contribution in information content displays a new converging pattern. We draw explanations to this pattern from multiple perspectives: Casting dialogue as an information exchange system would mean that the pattern is the result of two interlocutors maintaining their own context rather than sharing one. Second, we present some empirical evidence that a model of Interactive Alignment may include information density to explain the effect. Third, we argue that building common ground is a process analogous to information convergence. Thus, we put forward an information-theoretic view of dialogue, under which some existing theories of human dialogue may eventually be unified.


Localization of a short-term memory in Drosophila.
Memories are thought to be due to lasting synaptic modifications in the brain. The search for memory traces has relied predominantly on determining regions that are necessary for the process. However, a more informative approach is to define the smallest sufficient set of brain structures. The rutabaga adenylyl cyclase, an enzyme that is ubiquitously expressed in the Drosophila brain and that mediates synaptic plasticity, is needed exclusively in the Kenyon cells of the mushroom bodies for a component of olfactory short-term memory. This demonstrates that synaptic plasticity in a small brain region can be sufficient for memory formation.


Sexual maturation in female rats: hereditary, developmental and environmental aspects.
Two physiological components of sexual maturation, vaginal opening and first estrus, apparently evolve similarly in Wistar and Sprague-Dawley rats. However, a bimodal distribution in the frequency of the days of vaginal opening is observed within a given strain, which is less related to heredity than to the timing and type of experiment. In addition, when the modulators of sexual maturation are reviewed, it can be observed that sensitivity to external stimuli can vary even within a strain. For a defined set of breeding conditions, one group of rats can be more susceptible to changes in the lighting regimen and not be affected by controlled stressors, while another group responds more to stress and less to light. The reason for susceptibility to one rather than another environmental factor under similar breeding conditions is not understood. In that context, it is difficult to evaluate the role of heredity when we cannot understand the full impact of the environment, not to mention maternal influence in fetal and early life. Using two lines of psychogenetically selected rats, it was possible to show that they had differences in sexual maturation, which strongly suggested a genetic predisposition. Nevertheless, the question arises as to whether the genetic locus directly affects organs implicated in sexual maturation or whether it acts on some unknown factor which only secondarily modifies sexual maturation. In summary, there is more need to understand the role of the environment, including that of the mother early in fetal and neonatal life. It is suggested that the mechanisms underlying organ growth are set for a given species, while developmental and environmental factors fix the timing of vaginal opening and first ovulation. In the rat, there appear to be two times which are preferred for vaginal opening, given the laboratory conditions that have been used in the last 20 or so years: an early period, at 31-35 days, and a late period, at 36-40 days. An explanation for this dichotomy would be that a combination of parameters (not necessarily always the same) is needed for vaginal opening. These parameters oscillate during sexual maturation with different frequencies, which can achieve resonance to lead to vaginal opening and ovulation only during given periods.


Indolent cutaneous T-cell lymphoma presenting as cutaneous lymphocytosis in dogs.
Cutaneous lymphoproliferative diseases encompass a spectrum of lesions, ranging from self-limiting, reactive infiltrates to high-grade lymphomas. In humans, cutaneous lymphocytosis (CL) refers to self-limiting or slowly progressive monomorphic lymphocytic infiltrates of mostly unknown cause. It morphologically mimics cutaneous lymphoma. CL in cats also is a slowly progressive disease. Immunophenotyping and clonality testing of feline CL support an indolent lymphoma for the majority of cases studied. This study reports CL in dogs. Erythematous, scaly and alopecic macules, patches or plaques were present in eight dogs. Breed predilection was not observed; six of eight dogs were females; and ages ranged from 5 to 14 years. Diffuse monomorphic non-epitheliotropic infiltrates of CD3(+) (eight of eight), CD45(-) (four of eight) or CD45(+/-) (four of eight) and CD45RA(-) (seven of eight) T lymphocytes were present in the superficial and mid-dermis. Further immunophenotyping of five cases revealed TCR-gammadelta(+) T cells (one of five) or TCR-alphabeta(+) (four of five) T cells. TCR-alphabeta(+) populations were either CD8(+) (two of four) or CD4(-)CD8(-) (2/4). Clonality testing found clonal (seven of eight) or pseudoclonal (one of eight) rearrangement of the TCR-gamma locus of the lesional T cells. Prednisone, prednisolone and methylprednisolone acetate were the most commonly administered drugs. The lesions remained stable for long periods up to 6 years. Five dogs were euthanized due to progression of the skin lesions (three of five), peripheral lymphadenopathy of unknown origin (one of five) or high-grade lymphoma (one of five). One dog was lost for follow-up and two dogs are still alive (17 and 9 months after diagnosis). Canine CL is best considered an initially indolent lymphoma, with slow progression and a potential for progression to high-grade lymphoma.


Adult-type soft tissue sarcomas in pediatric-age patients: experience at the Istituto Nazionale Tumori in Milan.
Nonrhabdomyosarcoma soft tissue sarcomas are a heterogeneous group of tumors for which optimal treatment remains controversial. We report on a large group of 182 patients younger than 18 years old treated at a single institution over a 25-year period. In this relatively homogeneous subgroup of adult-type histotypes, surgery was the mainstay of treatment; radiotherapy was administered to 73 patients, and chemotherapy was administered to 114 patients (70 received chemotherapy as adjuvant therapy). Overall survival at 5 years was 89% in patients who underwent complete resection at diagnosis, 79% in patients who had marginal resection, 52% in initially unresected patients, and 17% in patients with metastases at onset. Outcome was unsatisfactory in patients with large and high-grade tumors, even after gross resection; adjuvant chemotherapy seemed to improve the results in this group. Initially unresected patients who responded well to chemotherapy and subsequently underwent complete resection had an event-free survival rate of approximately 70%. The rate of response to chemotherapy was 58%. The identification of prognostic variables should enable risk-adapted therapies to be planned. Patients with initially unresectable disease and patients with resected large and high-grade tumors are at high risk of metastases and treatment failure. Although the limits of this retrospective analysis are self-evident, our data would suggest that intensive chemotherapy (with an ifosfamide-doxorubicin regimen) might have a more significant role in these patients than what is generally assumed.


Establishment and interspecific associations in two species of Ichthyocotylurus (Trematoda) parasites in perch (Perca fluviatilis).
Co-infections of multiple parasite species in hosts may lead to interspecific associations and subsequently shape the structure of a parasite community. However, few studies have focused on these associations in highly abundant parasite species or, in particular, investigated how the associations develop with time in hosts exposed to co-infecting parasite species for the first time. We investigated metacercarial establishment and interspecific associations in the trematodes Ichthyocotylurus variegatus and I. pileatus co-infecting three age cohorts of young perch (Perca fluviatilis). We found that the timing of transmission of the two Ichthyocotylurus species was very similar, but they showed differences in metacercarial development essentially so that the metacercariae of I. pileatus became encapsulated faster. Correlations between the abundances of the species were significantly positive after the first summer of host life and also within the main site of infection, the swim bladder. High or low abundances of both parasite species were also more frequent in the same host individuals than expected by chance, independently of host age or size. However, the highest abundances of the species were nevertheless observed in different host individuals and this pattern was consistent in all age cohorts. The results suggest similar temporal patterns of transmission, non-random establishment, and facilitative rather than competitive associations between the parasite species independently of the age of the infracommunities. However, we suggest that spatial differences in exposure are most likely responsible for the segregation of the parasite species observed in the few most heavily infected hosts. Regardless of the underlying mechanism, the result suggests that between-species associations should be interpreted with caution along with detailed examination of the parasite distribution among host individuals.


Highlights on the first line treatment of metastatic pancreatic cancer.
Pancreatic cancer is the fourth leading cause of cancer deaths in men and women. The estimated deaths from pancreatic cancer in 2012 in the United States are 37,390, and the five-year survival for all patients with pancreatic adenocarcinoma is less than 5%. Majority of patients present with incurable metastatic pancreatic cancer. The 2012 American Society of Oncology (ASCO) Annual Meeting offered new insights into metastatic pancreatic cancer and we discuss Abstracts #4018, #4019, #4022, #4042, #4043, #4048, #4050 and comment on them in this paper.


Stakeholder and provider views regarding pericoital contraceptive pills in India and Uganda.
The development of pericoital contraceptive pills is under consideration to address unmet need for family planning, especially among women who have infrequent sexual intercourse. Pericoital pills, an oral contraceptive taken 24 hours before or after intercourse, would be a potentially desirable contraceptive option because it could provide convenience, discretion, and female control over contraceptive use. To gauge receptivity to pericoital contraception, a total of 49 in-depth interviews and 5 focus group discussions were conducted in India and Uganda with family planning providers and stakeholders. In India, the method was seen as filling a demonstrated need, based on perceived widespread and/or repeat use of emergency contraceptives. In Uganda, where emergency contraception has met strong opposition from conservative and religious leaders, respondents were more skeptical about the merits of the product. In both settings, using condoms consistently and taking oral contraceptives daily present challenges for consistent use, thus a new contraceptive method that is easy to use and under female control is likely to be appealing.


A Design and Analytic Strategy for Monitoring Disease Positivity and Biomarker Levels in Accessible Closed Populations.
We advocate and expand upon a previously described monitoring strategy for efficient and robust estimation of disease prevalence and case numbers within closed and enumerated populations such as schools, workplaces, or retirement communities. The proposed design relies largely on voluntary testing, notoriously biased (e.g., in the case of COVID-19) due to non-representative sampling. The approach yields unbiased and comparatively precise estimates with no assumptions about factors underlying selection of individuals for voluntary testing, building on the strength of what can be a small random sampling component. This component enables the use of a recently proposed "anchor stream" estimator, a well-calibrated alternative to classical capture-recapture (CRC) estimators based on two data streams. We show that this estimator is equivalent to a direct standardization based on "capture", i.e., selection (or not) by the voluntary testing program, made possible by means of a key parameter identified by design. This equivalency simultaneously allows for novel two-stream CRC-like estimation of general means (e.g., of continuous variables like antibody levels or biomarkers). For inference, we propose adaptations of Bayesian credible intervals when estimating case counts and bootstrapping when estimating means of continuous variables. We use simulations to demonstrate significant precision benefits relative to random sampling alone.


Long-term seizure outcomes after pediatric temporal lobectomy: does brain MRI lesion matter?
There is emerging data that adults with temporal lobe epilepsy (TLE) without a discrete lesion on brain MRI have surgical outcomes comparable to those with hippocampal sclerosis (HS). However, pediatric TLE is different from its adult counterpart. In this study, the authors investigated if the presence of a potentially epileptogenic lesion on presurgical brain MRI influences the long-term seizure outcomes after pediatric temporal lobectomy. Children who underwent temporal lobectomy between 2007 and 2015 and had at least 1 year of seizure outcomes data were identified. These were classified into lesional and MRI-negative groups based on whether an epilepsy-protocol brain MRI showed a lesion sufficiently specific to guide surgical decisions. These patients were also categorized into pure TLE and temporal plus epilepsies based on the neurophysiological localization of the seizure-onset zone. Seizure outcomes at each follow-up visit were incorporated into a repeated-measures generalized linear mixed model (GLMM) with MRI status as a grouping variable. Clinical variables were incorporated into GLMM as covariates. One hundred nine patients (44 females) were included, aged 5 to 21 years, and were classified as lesional (73%), MRI negative (27%), pure TLE (56%), and temporal plus (44%). After a mean follow-up of 3.2 years (range 1.2-8.8 years), 66% of the patients were seizure free for ≥ 1 year at last follow-up. GLMM analysis revealed that lesional patients were more likely to be seizure free over the long term compared to MRI-negative patients for the overall cohort (OR 2.58, p < 0.0001) and for temporal plus epilepsies (OR 1.85, p = 0.0052). The effect of MRI lesion was not significant for pure TLE (OR 2.64, p = 0.0635). Concordance of ictal electroencephalography (OR 3.46, p < 0.0001), magnetoencephalography (OR 4.26, p < 0.0001), and later age of seizure onset (OR 1.05, p = 0.0091) were associated with a higher likelihood of seizure freedom. The most common histological findings included cortical dysplasia types 1B and 2A, HS (40% with dual pathology), and tuberous sclerosis. A lesion on presurgical brain MRI is an important determinant of long-term seizure freedom after pediatric temporal lobectomy. Pediatric TLE is heterogeneous regarding etiologies and organization of seizure-onset zones with many patients qualifying for temporal plus nosology. The presence of an MRI lesion determined seizure outcomes in patients with temporal plus epilepsies. However, pure TLE had comparable surgical seizure outcomes for lesional and MRI-negative groups.


Music and psychophysiological recovery from stress.
This experimental study examined whether listening to self-chosen music after stress exposure improves mood, decreases subjective arousal and rumination, and facilitates cardiovascular recovery. Participants (N = 123) were exposed to a mental arithmetic task with harassment to induce stress. Afterward, participants were randomly assigned to one of four "recovery" conditions where they (1) listened to self-chosen relaxing music, (2) listened to self-chosen happy music, (3) listened to an audio book, or (4) sat in silence. After this 5-minute "recovery manipulation period," participants sat in silence for another 5 minutes. Systolic blood pressure, diastolic blood pressure, and heart rate were continuously measured. The recovery conditions caused differences in positive affect (F(3,119) = 13.13, p < .001) and negative affect (F(3,119) = 2.69, p = .049). As expected, mood improved while listening to either relaxing music or happy music. The conditions showed no differences in subjective arousal (F(3,117) = 2.03, p = .11) and rumination (F(3,119) = 1.10, p = .35). Systolic blood pressure recovery, however, differed between the conditions (linear time trend: F(3,116) = 4.50, p = .005; quadratic time trend: F(3,115) = 5.24, p = .002). Listening to both relaxing and happy music delayed systolic blood pressure recovery when compared with both control conditions. Listening to self-selected music is an effective mood enhancer, but it delays blood pressure recovery.


Di- and tri-oxalkyl derivatives of a boron dipyrromethene (BODIPY) rotor dye in lipid bilayers.
The environment-sensitive fluorescent probes provide excellent tools for studying membranes in their native state. We have modified the BODIPY-based fluorescent molecular rotor by increasing the number of alkyl moieties from one to two or three to achieve a more defined and deeper positioning of the probe in membranes. Detailed characterisation of fluorescence properties and localisation/orientation of probes was performed using a variety of fluorescence techniques and model membranes composed of different lipids. As expected, additional alkyls attached to the fluorophore moiety led to a deeper and more defined localisation of the probe in the lipid bilayer. The results strongly indicate that fluorescence properties of such probes are influenced not only by lipid packing but also by the orientation of the probe in membranes. The orientation of rotors studied herein was significantly altered by changes in the lipid composition of membranes. Our observations demonstrate the limits of BODIPY-based molecular rotors as environmental sensors in cellular membranes with complex lipid composition. The results presented herein also underline the importance of the detailed characterisation of fluorescent membrane dyes and provide a guide for future testing.


Pocket similarity: are alpha carbons enough?
A novel method for measuring protein pocket similarity was devised, using only the alpha carbon positions of the pocket residues. Pockets were compared pairwise using an exhaustive three-dimensional Calpha common subset search, grouping residues by physicochemical properties. At least five Calpha matches were required for each hit, and distances between corresponding points were fit to an Extreme Value Distribution resulting in a probabilistic score or likelihood for any given superposition. A set of 85 structures from 13 diverse protein families was clustered based on binding sites alone, using this score. It was also successfully used to cluster 25 kinases into a number of subfamilies. Using a test kinase query to retrieve other kinase pockets, it was found that a specificity of 99.2% and sensitivity of 97.5% could be achieved using an appropriate cutoff score. The search itself took from 2 to 10 min on a single 3.4 GHz CPU to search the entire Protein Data Bank (133 800 pockets), depending on the number of hits returned.


Time-resolved Photophysical Characterization of Triplet-harvesting Organic Compounds at an Oxygen-free Environment Using an iCCD Camera.
Here, we present a sensible method of the acquisition and analysis of time-resolved photoluminescence using an ultrafast iCCD camera. This system enables the acquisition of photoluminescence spectra covering the time regime from nanoseconds up to 0.1 s. This enables us to follow the changes in the intensity (decay) and emission of the spectra over time. Using this method, it is possible to study diverse photophysical phenomena, such as the emission of phosphorescence, and the contributions of prompt and delayed fluorescence in molecules showing thermally activated delayed fluorescence (TADF). Remarkably, all spectra and decays are obtained in a single experiment. This can be done for solids (thin film, powder, crystal) and liquid samples, where the only limitations are the spectral sensitivity of the camera and the excitation wavelength (532 nm, 355 nm, 337 nm, and 266 nm). This technique is, thus, very important when investigating the excited state dynamics in organic emitters for their application in organic light-emitting diodes and other areas where triplet harvesting is of paramount importance. Since triplet states are strongly quenched by oxygen, emitters with efficient TADF luminescence, or those showing room temperature phosphorescence (RTP), must be correctly prepared in order to remove any dissolved oxygen from solutions and films. Otherwise, no long-lived emission will be observed. The method of degassing solid samples as presented in this work is basic and simple, but the degassing of liquid samples creates additional difficulties and is particularly interesting. A method of minimizing solvent loss and changing the sample concentration, while still enabling to remove oxygen in a very efficient and a repeatable manner, is presented in this work.


Phage liquid crystalline droplets form occlusive sheaths that encapsulate and protect infectious rod-shaped bacteria.
The opportunistic pathogen Pseudomonas aeruginosa is a major cause of antibiotic-tolerant infections in humans. P. aeruginosa evades antibiotics in bacterial biofilms by up-regulating expression of a symbiotic filamentous inoviral prophage, Pf4. We investigated the mechanism of phage-mediated antibiotic tolerance using biochemical reconstitution combined with structural biology and high-resolution cellular imaging. We resolved electron cryomicroscopy atomic structures of Pf4 with and without its linear single-stranded DNA genome, and studied Pf4 assembly into liquid crystalline droplets using optical microscopy and electron cryotomography. By biochemically replicating conditions necessary for antibiotic protection, we found that phage liquid crystalline droplets form phase-separated occlusive compartments around rod-shaped bacteria leading to increased bacterial survival. Encapsulation by these compartments was observed even when inanimate colloidal rods were used to mimic rod-shaped bacteria, suggesting that shape and size complementarity profoundly influences the process. Filamentous inoviruses are pervasive across prokaryotes, and in particular, several Gram-negative bacterial pathogens including Neisseria meningitidis, Vibrio cholerae, and Salmonella enterica harbor these prophages. We propose that biophysical occlusion mediated by secreted filamentous molecules such as Pf4 may be a general strategy of bacterial survival in harsh environments.


Haemagglutination-inhibiting antibody to influenza virus.
The results of the haemagglutination-inhibiting (HI) antibody test for influenza virus antibody in human sera closely match those produced by virus neutralization assays and are predictive of protection. On the basis of the data derived from 12 publications concerning healthy adults, we estimated the median HI titre protecting 50% of the vaccinees against the virus concerned at 28. This finding supports the current policy requiring vaccines to induce serum HI titres of > or = 40 to the vaccine viruses in the majority of the vaccinees. Unfortunately similar studies are scanty for the elderly, the group most at risk of influenza. There still remain many unsolved technical problems with the HI assay and we recommend that these problems be studied and the virus neutralization test as a predictor of resistance to influenza be assessed. Although the studies on this issue often give conflicting results, they generally show that HI antibody responses to influenza vaccination tend to diminish with increasing age, when health is often compromized. Advanced age in itself seems not to be an independent factor in this process. However, even in completely healthy elderly individuals the response to vaccination with an antigenically new virus may be strongly reduced compared with younger vaccinees.


A qualitative study of undergraduate clerkships in the intensive care unit: It's a brand new world.
While ICU clerkships are commonplace in undergraduate medical education, little is known about how students learn there. This study aimed to explore students' perceptions of the ICU as a learning environment, the factors influencing their learning and any perceived differences between learning in the ICU and non-ICU settings. We used interpretivist methodology, a social cognitive theoretical framework and a qualitative descriptive strategy. Ten medical students and four graduate doctors participated in four semi-structured focus group discussions. Data were analyzed by six-step thematic data analysis. Peer debriefing, audit trail and a reflexive diary were used. Social cognitive influences on learning were apparent in the discussions. Numerous differences emerged between ICU and non-ICU clinical clerkships, in particular an unfamiliarity with the environment and the complex illness, and difficulty preparing for the clerkship. A key emergent theme was the concept of three phases of student learning, termed pre-clerkship, early clerkship and learning throughout the clerkship. A social cognitive perspective identified changes in learner agency, self-regulatory activities and reciprocal determinism through these phases. The findings were used to construct a workplace model of undergraduate intensive care learning, providing a chronological perspective on the clerkship experience. The ICU, a rich, social learning environment, is different in many respects to other hospital settings. Students navigate through three phases of an ICU clerkship, each with its own attendant emotional, educational and social challenges and with different dynamics between learner and environment. This chronological perspective may facilitate undergraduate educational design in the ICU.


A novel method for quantitation of AAV genome integrity using duplex digital PCR.
Recombinant adeno-associated virus (rAAV) vectors have become a reliable strategy for delivering gene therapies. As rAAV capsid content is known to be heterogeneous, methods for rAAV characterization are critical for assessing the efficacy and safety of drug products. Multiplex digital PCR (dPCR) has emerged as a popular molecular approach for characterizing capsid content due to its high level of throughput, accuracy, and replicability. Despite growing popularity, tools to accurately analyze multiplexed data are scarce. Here, we introduce a novel statistical model to estimate genome integrity from duplex dPCR assays. This work demonstrates that use of a Poisson-multinomial mixture distribution significantly improves the accuracy and quantifiable range of duplex dPCR assays over currently available models.


Comparison of different extenders with defined protein composition for storage of stallion spermatozoa at 5 degrees C.
To maintain the fertility of stallion spermatozoa during cooled storage, extender media are added to semen. In this study, three semen extenders were compared: EquiPro which contains defined caseinates and whey proteins instead of dried skim milk. The extender is provided in dry form and dissolved in distilled water prior to use. EquiPro TM has the same composition as EquiPro but is provided in a sterilized ready-to-use liquid form. AndroMed-E contains soybean lecithin as protein source. Semen was collected from seven stallions. Ejaculates were divided into three aliquots, diluted with the different extenders and stored at 5 degrees C for 4 days. Total motility, membrane integrity, average path velocity (VAP), curvilinear-velocity (VCL), straight-line velocity (VSL), distance average path (DAP), distance curved line (DCL) and distance straight line (DSL) were determined by computer-assisted analysis. Total motility decreased in all extenders during storage. The parameters VAP, VCL, VSL, DAP, DCL and DSL in semen diluted in EquiPro TM at most times and in semen diluted in AndroMed-E at some times were lower than in semen diluted in EquiPro (p < 0.05). Viability on days 0 and 4 was lowest in semen diluted in AndroMed-E (p < 0.05). Velocity decreased faster when semen had been diluted in the sterilized liquid extender EquiPro TM or in AndroMed-E compared with the dry formula of EquiPro. Therefore the liquid sterilized EquiPro despite no difference in its chemical composition differs from the dry, non-sterilized EquiPro extender. Heat sterilization apparently changes effects of the extender on spermatozoa.


Applying User-Centered Design to Develop Practical Strategies that Address Overuse in Primary Care.
Engaging patients and frontline clinicians in re-designing clinical care is essential for improving care delivery in a complex clinical environment. This study sought to assess an innovative user-centered design approach to improving clinical care quality, focusing on the use cases of de-intensifying non-beneficial care within the following areas: (1) de-intensifying diabetes treatment in high-risk patients; (2) stopping screening for carotid artery stenosis in asymptomatic patients; and (3) stopping colorectal cancer screening in average-risk, older adults. The user-centered design approach, consisting of patient and patient-clinician charrettes (defined as intensive workshops where key stakeholders collaborate to develop creative solutions to a specific problem) and participant surveys, has been described previously. Following the charrettes, we used inductive coding to identify and categorize themes emerging from the de-intensification ideas prioritized by participants as well as facilitator notes and audio recordings from the charrettes. Thirty-five patients participated in the patient design charrettes, generating 134 unique de-intensification ideas and prioritizing 32, which were then distilled into six patient-generated principles of de-intensification by the study team. These principles provided a starting point for a subsequent patient-clinician charrette. In this follow-up charrette, 9 patients who had participated in an earlier patient design charrette collaborated with 7 clinicians to generate 63 potential de-intensification solutions. Six of these potential solutions were developed into multi-faceted, fully operationalized de-intensification strategies. The de-intensification strategies that patients and clinicians prioritized and operationalized during the co-design charrette process were detailed and multi-faceted. Each component of a strategy had a rationale based on feasibility, practical considerations, and ways of overcoming barriers. The charrette-based process may be a useful way to engage clinicians and patients in developing the complex and multi-faceted strategies needed to improve care delivery.


Anoxic contractions in isolated canine cerebral arteries: contribution of endothelium-derived factors, metabolites of arachidonic acid, and calcium entry.
Experiments were designed to determine the role of the endothelial cells and the metabolism of arachidonic acid in anoxic contractions of isolated canine basilar arteries. Rings, with and without endothelium, of these arteries were suspended for isometric tension recording; anoxia was induced by switching the mixture gassing the organ chamber from 95% O2-5% CO2 to 95% N2-5% CO2. In rings with endothelium, anoxia evoked increases in tension under basal conditions and during contractions to 5-hydroxytryptamine, uridine triphosphate, prostaglandin F2 alpha, and high K+. Under control conditions, these anoxic contractions were not prevented by alpha-adrenergic and serotonergic antagonists, by apyrase, or by inhibitors of cyclooxygenase. Anoxia prevented endothelium-dependent relaxations evoked by vasopressin and thrombin. In rings without endothelium, anoxia caused increases in tension during contractions evoked by various agonists, and in unstimulated preparations after inhibition of cyclooxygenase. Anoxic contractions were abolished by calcium entry blockers. These observations suggest that anoxic contractions of isolated canine basilar artery can be explained by the release of endothelium-derived contracting factor(s) and the accelerated entry of calcium in the smooth muscle cells, which possibly results from a diversion of arachidonic acid from the cyclooxygenase to the lipoxygenase pathway.


Protannotator: a semiautomated pipeline for chromosome-wise functional annotation of the "missing" human proteome.
The chromosome-centric human proteome project (C-HPP) aims to define the complete set of proteins encoded in each human chromosome. The neXtProt database (September 2013) lists 20,128 proteins for the human proteome, of which 3831 human proteins (∼19%) are considered "missing" according to the standard metrics table (released September 27, 2013). In support of the C-HPP initiative, we have extended the annotation strategy developed for human chromosome 7 "missing" proteins into a semiautomated pipeline to functionally annotate the "missing" human proteome. This pipeline integrates a suite of bioinformatics analysis and annotation software tools to identify homologues and map putative functional signatures, gene ontology, and biochemical pathways. From sequential BLAST searches, we have primarily identified homologues from reviewed nonhuman mammalian proteins with protein evidence for 1271 (33.2%) "missing" proteins, followed by 703 (18.4%) homologues from reviewed nonhuman mammalian proteins and subsequently 564 (14.7%) homologues from reviewed human proteins. Functional annotations for 1945 (50.8%) "missing" proteins were also determined. To accelerate the identification of "missing" proteins from proteomics studies, we generated proteotypic peptides in silico. Matching these proteotypic peptides to ENCODE proteogenomic data resulted in proteomic evidence for 107 (2.8%) of the 3831 "missing proteins, while evidence from a recent membrane proteomic study supported the existence for another 15 "missing" proteins. The chromosome-wise functional annotation of all "missing" proteins is freely available to the scientific community through our web server (http://biolinfo.org/protannotator).


Affinity of fentanyl and its derivatives for the σ1-receptor.
Fentanyl and its 11 commercially available derivatives were investigated as to their affinity for the σ1 receptor. The parent compound is a rather poor binder (IC50 = 4973 nM), but its close derivatives (benzylfentanyl or p-fluorofentanyl) have submicromolar affinities. Modelling provides a structural basis for the observed trends in activity.


Salvage external beam radiotherapy for recurrent prostate adenocarcinoma after high-intensity focused ultrasound as primary treatment.
The main objective was to evaluate feasibility, toxicity and biochemical control rates of salvage external beam radiotherapy (EBRT) in recurrent localized prostate cancer after high-intensity focused ultrasound (HIFU) as primary therapy. A total of 24 patients who underwent salvage EBRT after 1 or 2 HIFU sessions and with a minimum post-treatment follow-up of 24 months were retrospectively evaluated. Primary endpoints were toxicity and biochemical disease-free survival (bDFS, defined according to the ASTRO Phoenix definition). Median follow-up was 40.3 months. Gastrointestinal toxicity was low. Acute genitourinary (GU) toxicity grade ≤II rate was 45.8%, with only few patients presenting grade III (8.3%) and grade IV (4.2%) toxicity. Late grade ≥III GU toxicity was registered in 16.7% of patients. The 3-year bDFS rate was 77.8%. Patients achieving a nadir prostate-specific antigen (nPSA) of ≤0.35 ng/ml after EBRT had significantly higher bDFS (3-year bDFS: 87.7 vs. 50%, respectively; p = 0.001). Achieving nPSA ≤0.35 ng/ml was the only factor independently associated to long-term bDFS both on univariate (p = 0.01) and multivariate analysis (HR 7.06, p = 0.039). Salvage EBRT after HIFU failure is feasible and allows to obtain satisfactory biochemical control rates, especially in patients attaining a nPSA ≤0.35 ng/ml after EBRT.


[Contact allergy for perfume ingredients in cosmetics and toilet articles].
Fragrance materials are not only present in products primarily used for their scent such as perfume, eau de toilette, deodorant and aftershave, but also in cosmetics, toiletries, household products and industrial materials. Of the general population, approximately one percent are allergic to fragrance materials, men nearly as frequent as women. Of patients consulting the dermatologist because of dermatitis, 6-11% have a positive patch test to the fragrance mix. Allergic contact dermatitis due to fragrances usually consists of erythema and desquamation, often localized in the neck, behind the ears, in the arm-pits or around the eyes. It can worsen pre-existing dermatoses such as hand eczema, atopic dermatitis, perianal dermatitis or vulvar dermatitis. The diagnosis of contact allergy to fragrances is made by epicutaneous tests with the European standard series (including some markers for fragrance sensitivity: the fragrance mix, balsam of Peru and colophony) and the patient's own contact materials. A positive patch test reaction must be followed by evaluation of its relevance. Advice to the patient is directed towards avoidance of fragranced products, if possible, and explanation of how use tests can identify fragranced products which can be used without ill effects.


Sequences in the terminal protein and reverse transcriptase domains of the hepatitis B virus polymerase contribute to RNA binding and encapsidation.
Hepatitis B virus (HBV) antiviral therapy is plagued by limited efficacy and resistance to most nucleos(t)ide analog drugs. We have proposed that the complex RNA binding mechanism of the HBV reverse transcriptase (P) may be a novel target for antivirals. We previously found that RNA binds to the duck HBV (DHBV) P through interactions with the T3 and RT1 motifs in the viral terminal protein and reverse transcriptase domains, respectively. Here, we extended these studies to HBV P. HBV T3 and RT1 synthetic peptides bound RNA in a similar manner as did analogous DHBV peptides. The HBV T3 motif could partially substitute for DHBV T3 during RNA binding and DNA priming by DHBV P, whereas replacing RT1 supported substantial RNA binding but not priming. Substituting both the HBV T3 and RT1 motifs restored near wild-type levels of RNA binding but supported very little priming. Alanine-scanning mutations to the HBV T3 and RT1 motifs blocked HBV ε RNA binding in vitro and pgRNA encapsidation in cells. These data indicate that both the HBV T3 and RT1 motifs contain sequences essential for HBV ε RNA binding and encapsidation of the RNA pregenome, which is similar to their functions in DHBV. Small molecules that bind to T3 and/or RT1 would therefore inhibit encapsidation of the viral RNA and block genomic replication. Such drugs would target a novel viral function and would be good candidates for use in combination with the nucleoside analogs to improve efficacy of antiviral therapy.


Reassessment of the 1997 TNM classification system for renal cell carcinoma.
The 1997 TNM staging classification for renal cell carcinoma (RCC) defined Stage I tumors as organ-confined tumors measuring up to 7 cm in size. The authors evaluated the validity of this cutoff size by assessing the survival of patients with Stage I RCC according to a series of alternative size cutoff values. In addition, the authors determined how these size cutoffs affected the risk of having nonorgan-confined tumors, regional lymph node involvement, and metastatic disease. A database containing the records of 1324 patients with RCC who underwent open radical nephrectomy between 1960 and 1991 was evaluated. Patients with Stage I disease were stratified by size cutoffs ranging from 2.5 to 7.0 cm in 0.5-cm increments. Five-year disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method. The log-rank test was used to compare survival curves. The survival of patients with tumors smaller than a specified size cutoff was compared with the survival of patients with tumors larger than that cutoff and the most discriminating cutoff was identified. The same size cutoffs were used to compare the incidence of local nonorgan-confined, lymph node-positive, and metastatic disease for all patients with tumors 7.0 cm or smaller. Of 544 evaluable patients, 351 patients had tumors 7.0 cm or smaller and 233 of these patients had 1997 Stage I (T1N0M0) disease. When patients with 1997 Stage I tumors were separated using the various size cutoffs, survivals were most different using a 5.0-cm cutoff. The 5-year DSS rates for patients with Stage I tumors 5 cm or smaller versus those with tumors measuring 5.1-7 cm were 94.6% versus 79.2% (P = 0.003). Furthermore, the survival of patients with Stage I RCC lesions measuring 5.1-7.0 cm was the same as for patients with 1997 Stage II (T2N0M0) RCC. The difference in probability of having local nonorgan-confined disease was also greatest with a 5.0 cm cutoff value. Nonorgan- confined disease was reported to be present in 16.2% of the patients with tumors smaller than 5.0 cm compared with 36.8% of the patients with tumors measuring 5.1-7.0 cm in size. The difference in the probabilities of having lymph node-positive or metastatic disease did not change significantly using any of the cutoffs, although the probability of both of these increased with increasing tumor size. Survival and disease recurrence analysis in a large group of patients with RCC who underwent radical nephrectomy showed that the 1997 TNM cutoff of 7.0 cm used to separate Stage I from Stage II disease was too high. A size-related survival difference was found among patients with organ-confined 1997 Stage I disease and a 5.0-cm cutoff best stratified this difference. This finding was in general agreement with the changes made in the 6th edition of the American Joint Committee on Cancer cancer staging manual. Patients with tumors measuring between 5.1 cm and 7.0 cm were found to have the same survival as patients with Stage II disease. Thus, subclassification of T1 into T1a and T1b, as in the 6th edition of the AJCC cancer staging manual, may not be optimal. The 5-cm cutoff also best stratified the risk of developing nonorgan-confined disease. This finding may have an impact on nephron-sparing surgery in selected patients. The findings of the current study, as well as those of others, supported an upper size cutoff of 4-5 cm for patients with Stage I RCC.


Perceived regard, expressive suppression during conflict, and conflict resolution.
The way emotions are expressed during relationship conflict should play an important role in facilitating conflict resolution, but the risk of rejection that conflict poses may promote expressive suppression, which could impede conflict resolution. In the current research, the authors applied a risk regulation perspective to understand when expressive suppression will occur during conflict. They predicted that (a) perceiving lower regard from the partner during conflict would predict greater expressive suppression, and (b) greater expressive suppression would undermine conflict resolution. In Study 1, individuals engaged in a conflict discussion with their romantic partner (N = 180 couples) and then reported the degree to which they felt regarded by their partner and generated a solution to the conflict during the discussion. Independent coders rated how much individuals attempted to suppress their emotional expressions during the conflict. In Study 2, individuals reported on their relationship conflict, perceived regard, expressive suppression, and conflict resolution every day across a 3-week period (N = 73 couples). In both studies, perceiving lower positive regard during conflict was associated with greater expressive suppression. Greater expressive suppression was, in turn, associated with lower conflict resolution. These associations were not due to greater stress/upset or negative emotions, greater withdrawal, greater attachment insecurity, or lower positive regard for the partner. These within-situation associations suggest that expressive suppression may often arise to bypass the risk of rejection that occurs when people feel less positively regarded by their partner, but expressive suppression may also put relationships at further risk by undermining conflict resolution. (PsycINFO Database Record


Androgen responsiveness of the murine beta-glucuronidase gene is associated with nuclease hypersensitivity, protein binding, and haplotype-specific sequence diversity within intron 9.
The tissue specificity and genetic variability of the murine beta-glucuronidase (GUS) response to androgen provide useful markers for identifying elements which underlie this responsiveness. While GUS is expressed constitutively in all examined cell types, kidney epithelial cells uniquely exhibit a manyfold yet slow rise in GUS mRNA and enzyme levels when stimulated by androgens. Three major phenotypes of this androgen response have been described among inbred strains of mice: (i) a strong response in strains of the Gusa haplotype, (ii) a reduced response in strains of the Gusb and Gush haplotypes, and (iii) no response, as observed in Gusor mice. These response variants define a cis-active element(s) which is tightly linked to the GUS structural gene. Nuclease hypersensitivity scans of kidney chromatin within and surrounding the structural gene revealed an androgen-inducible hypersensitive site in intron 9 of the gene in Gusa but not in Gusor mice. When a radiolabeled fragment of Gusa DNA containing this hypersensitive site was incubated with kidney nuclear extracts and then subjected to gel electrophoresis, two shifted bands were observed whose levels were dramatically higher in extracts of androgen-treated than in those of untreated Gusa mice. The shifted bands reflect binding of a kidney-specific factor(s) to a 57-bp region of complex dyad symmetry in Gusa and Gusor mice which is partially deleted in Gusb and Gush mice. This binding site is located approximately 130 bp downstream of a glucocorticoid response element sequence motif which is totally deleted in [Gus]or mice. Taken together, our results suggest that the androgen responsiveness of GUS in murine kidney epithelial cells is controlled by elements within the proximal end of intron 9 of the GUS structural gene.


EGFR Exon 20 Insertion/Duplication Mutations Characterize Fibrous Hamartoma of Infancy.
Fibrous hamartoma of infancy (FHI) is a benign mesenchymal tumor histologically characterized by a mixture of intersecting fascicles of fibroblasts/myofibroblasts in collagenous stroma, nests of primitive oval or stellate cells in basophilic mucoid stroma, and mature adipose tissue. We hypothesized that FHI, because of histologic overlap with mesenchymal overgrowth tumors seen in CLOVES (Congenital Lipomatous Overgrowth with Vascular, Epidermal, Skeletal anomalies) and Proteus syndromes, may harbor mutations in signaling pathways associated with cellular proliferation. Formalin-fixed paraffin-embedded material from a discovery set of 4 cases of FHI was investigated by targeted next-generation sequencing of a panel of cancer-associated genes. The results were confirmed by targeted Sanger sequencing of EGFR exon 20. A validation set of 8 cases of FHI and 10 cases of other pediatric fatty tumors were investigated by targeted Sanger sequencing of EGFR exon 20. All 12 cases of FHI, and none of the 10 control tumors, showed EGFR exon 20 insertion/duplication mutations. This is the first report of molecular aberrations in FHI. The consistent occurrence of EGFR exon 20 insertion/duplication mutations in 100% of cases of FHI studied suggests that they must play a principal role in the pathogenesis of FHI, likely by conferring a potential for growth and local infiltration. Although surgical treatment will remain the mainstay of FHI treatment, tyrosine kinase inhibitors may have an adjunctive role in cases that are difficult to resect.


A single multiplex assay to identify major malaria vectors within the African Anopheles funestus and the Oriental An. minimus groups.
The African Anopheles funestus and the Oriental An. minimus groups are closely related and composed of major malaria vectors in Africa and Southeast Asia, respectively. None of the species of either the An. funestus or the An. minimus group can be identified with absolute certainty using the adult morphology. Polymorphisms present on the internal transcribed spacer 2 (ITS2) of ribosomal DNA allowed the development of 10 primers that combined with an universal forward primer lead to a simple and sensitive multiplex allele-specific polymerase chain reaction (AS-PCR). Moreover, the possible additional amplification of the entire ITS2 allows one to detect other anopheline species in sympatry with members of both groups not included in this assay and serves as a control band. This universal PCR method permits the discrimination of 10 species within the subgenus Cellia, among which figure three major malaria vectors, and constitutes a very efficient and powerful tool to improve our knowledge on these species distribution and biology. Not only restricted to anophelines, this AS-PCR could also be developed and applied to other insect groups.


Lack of efficacy of topical mycophenolic acid in psoriasis vulgaris.
Mycophenolic acid is effective for systemic treatment of psoriasis. However, there is no report about its topical use in this cutaneous disorder so far. We undertook a randomized, placebo-controlled, within subject comparison of mycophenolic acid 1% incorporated in an ointment base and the corresponding vehicle alone (placebo) using the psoriasis plaque test in 7 patients with plaque-type psoriasis over a period of 3 weeks. Scoring of erythema and induration was performed 3 times weekly. After 3 weeks of occlusive treatment there was a reduction of the sum score for erythema and induration in the mycophenolic acid-treated sites of 23% and of 5.7% in the vehicle-treated sites, which was not statistically significant. No adverse advents were noted during the time of study. We conclude that mycophenolic acid is ineffective when applied topically in psoriasis even under occlusion.


Alcohol and mortality in middle-aged men from eastern France.
To evaluate prospectively the effect on mortality of wine drinking in Eastern France, we conducted an analysis on 34,014 consecutive middle-aged men coming for a comprehensive health appraisal between 1978 and 1983. We evaluated education, physical activity, smoking, and drinking habits by a questionnaire. Electrocardiogram, blood pressure, serum total cholesterol, and gamma-glutamyltransferase level were routinely measured. Seventy-seven per cent of the subjects drank wine; there was little difference between social classes in this proportion. We evaluated mortality over 10-15 years of follow-up. We estimated the relative risk (RR) of death by Cox proportional hazard models using nondrinkers as the reference and adjusting for six covariables. For an intake of 22-32 and 33-54 gm of alcohol per day, the RR of all-cause death was 0.70 [95% confidence interval (CI) = 0.59-0.82] and 0.76 (95% CI = 0.66-0.87), respectively. The lower mortality resulted from fewer deaths from cardiovascular disease and cancer. Above 128 gm per day of alcohol consumption, the RR was 1.37 (95% CI = 1.16-1.61). A moderate intake of wine (2-5 glasses per day) was associated with a 24-31% reduction in all-cause mortality, a proportion that was similar for smokers, ex-smokers, and nonsmokers.


Rapid introduction of virtual consultation in a hospital-based Consultant-led Antenatal Clinic to minimise exposure of pregnant women to COVID-19.
The COVID-19 global pandemic dictated rapid change to outpatient services within our London-based maternity hospital. Coupled with long waiting times in the Consultant-led Antenatal clinic, we aimed to reduce hospital footfall and unnecessary contact with a clinically vulnerable patient population by reducing face-to-face consultations. Numerous specialties have already successfully implemented safe and effective teleconferencing, allowing remote review while reducing the risks posed by face-to-face contact. A target to see at least 15% of women remotely was set to reduce footfall in the Consultant-led Antenatal Clinic. We aimed to reduce face-to-face waiting times to a mean of 30 min. In March 2020, clinics were prevetted by the clinic consultant to carefully select appropriate women suitable for video or telephone consultations. Clinic templates were changed, increasing appointment times by 5-25 min each. 'AccuRx' software was tested and used to communicate appointment details and conduct the consultation. In-person waiting times in the clinic and number of virtual consultations over a 3-month period was recorded, along with qualitative feedback from service users and staff through surveys and departmental meetings. Mean waiting times were reduced by 33% from 45-30 min and multiple service-user benefits were noted, including partner involvement, convenience of waiting for appointments at home and removing requirement for childcare. However, limitations of internet connectivity, need for time to prevet clinics and lack of a robust administration system to inform women of their appointment type were highlighted. Further work is required in these areas to ensure sustainability and improvement of this process for the future.


Extralobar pulmonary sequestration with hemothorax secondary to pulmonary infarction.
Pulmonary sequestration is an uncommon condition that accounts for 0.5-6% of all pulmonary malformations and is typically diagnosed in childhood. Of the two forms of pulmonary sequestration, intralobar and extralobar, the latter is less frequently encountered. The current report describes the case of a 32-year-old female patient with chest and abdominal pain. Imaging (chest X-rays and CT scans of the chest) revealed consolidation and pleural effusion. The initial thoracocentesis revealed hemothorax. Subsequent diagnostic video-assisted thoracoscopy revealed extralobar pulmonary sequestration. Consequently, the therapeutic decision was to make the conversion to thoracotomy in order to resect the lesion and safely ligate the intercostal vascular pedicle.


Fast-track program for liver resection--factors prolonging length of stay.
Fast-track programs involving multi-modal measures to enhance recovery after surgery, reduce morbidity and decrease hospital length of stay (LOS) are used for different major surgical procedures. For liver resections, factors influencing LOS within a fast-track program have been studied only to a limited extent, which was the aim of the present study. The present study comprises the first 64 patients included in a fast-track program for liver resections introduced in March 2012. Patient outcomes were compared to a historical cohort of patients (n=62) operated in 2009. Factors prolonging LOS was analyzed by uni- and multivariate analysis. Median LOS was 6 days (range 3-42 days) within the fast-track program as compared with 8 days (range 5-47 days) in the historical cohort (P=0.004). On multivariate analysis, factors increasing LOS in the fast-track group were found to be the presence of complication (P=0.018), extent of resection (major as compared to minor) (P=0.001) and inability to drink > 1250 ml on the day after surgery (P=0.002). Patients who can only drink limited amounts of fluid the day after liver resection represent a subset of patients that should be given special attention within a fast-track program.


Regulation of the circadian clock in the Aplysia eye: mimicry of neural action by serotonin.
In Aplysia, activity of efferent fibers in the optic nerve can influence the circadian clock in the eye. In addition, serotonin (5-HT) is present in the eye and influences the function of the clock. Accordingly, we hypothesized that 5-HT is the transmitter of the optic efferents, and tested the prediction that exogenous 5-HT would mimic the action of the optic efferents on the clock. We also tested the prediction that the action of the efferents would be prevented by blocking synaptic secretions with high Mg2+, low Ca2+ (HMLC). Activity of the optic efferents enhances clock resetting in response to the onset of darkness. We used this neural enhancement as a measure of neural action on the eye clock. We found that HMLC blocked neural enhancement. Serotonin enhanced resetting to the same extent as efferent activity. Enhancement by 5-HT did not summate with neural enhancement. High concentrations of 5-HT ([5-HT] greater than or equal to 6 X 10(-4) did not cause enhancement. High concentrations of 5-HT also blocked neural enhancement. Enhancement by 5-HT depended on the phase of drug application, much as neural enhancement depends on the phase of neural activity. Enhancement by 5-HT depended on day length in a manner similar to the enhancement by neural activity. HMLC did not block the facilitatory action of 5-HT. Several other transmitters that may be active in the eye did not enhance resetting.(ABSTRACT TRUNCATED AT 250 WORDS)


Target lymphoid cells for the cytotoxic factor produced in the spleen of dengue virus-infected mice.
In previous studies we have observed the production of a cytotoxic factor by the T-lymphocytes in the spleen of dengue type-2 virus- (DV) infected mice which killed normal mouse spleen cells in vitro. In the present study types of spleen cells affected in vitro by the cytotoxic factor (CF) have been investigated. It was observed that it kills of the macrophages, one-third of T-lymphocytes and a few of the granulocytes, normoblasts and megakaryocytes. It had no effect on B-lymphocytes. The proportion of killed cells could not be significantly enhanced by retreatment of cells by additional CF. The cytotoxic activity of CF is not affected by adsorption with susceptible or non-susceptible cells. CF also kills lymphoid cells of animals of other species, viz. albino rats, rabbits, guinea pigs but had no effect on those of rooster. It had no effect on various cell cultures.


Remote ischemic preconditioning improves the cognitive function of elderly patients following colon surgery: A randomized clinical trial.
Cognitive function impairment is one of the most common complications in elderly patients after surgery, and an ideal nonpharmacological therapy has not yet been identified. Thus, we hypothesized that remote ischemic preconditioning could improve cognitive functions in elderly patients after surgery and investigated the mechanism underlying this effect. Ninety patients classified as American Society of Anaesthesiologists (ASA) physical status of 2 or 3 and aged 65 to 75 years who were scheduled for elective colon surgery under general anesthesia were randomly allocated to either a remote ischemic preconditioning group (Group R, n = 45) or a control group (Group C, n = 45). Remote ischemic preconditioning was performed by applying a static pressure of 200 mm Hg with a blood pressure cuff wrapped around the right upper limb for 3 ischemia cycles of 5 minutes each. The Montreal Cognitive Assessment (MoCA) scores between the 2 groups were not significantly different on the day before surgery or the seventh day after surgery, but the scores on the first day after surgery (26.87 ± 0.84 vs 25.96 ± 0.85, P < .001) and third day after surgery (27.49 ± 0.66 vs 27.02 ± 0.92, P = .009) were significantly higher for Group R than those for Group C. Moreover, remote ischemic preconditioning markedly decreased the serum concentrations of the interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and S100B proteins compared with the control group (P < .001). Remote ischemic preconditioning improves postoperative cognitive function in elderly patients following colon surgery. The cognitive protective effects of remote ischemic preconditioning are partially related to the inhibition of inflammation.


Iodination increases the activity of verapamil derivatives in reversing PGP multidrug resistance.
Iodinated derivatives of verapamil were synthesized and tested as P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) reversal agents. The ability of these compounds to revert MDR was evaluated on daunorubicin-resistant K562 cells, by measuring the intracellular accumulation of rhodamine 123, a fluorescent probe of Pgp transport activity. One of the investigated compounds (16c) was found to be a more potent MDR reversal agent than verapamil and cyclosporin A, used as reference molecules. Further in vitro studies showed that compound 16c restored daunorubicin activity and, when used alone, did not induce cell death, cell cycle perturbation and modification of calcium channel activity in comparison with verapamil.


"Phantom smokers": Young cigarillo users who do not identify as smokers.
Many young consumers of non-cigarette tobacco products, such as cigarillos, do not identify as smokers. These "phantom smokers" tend to underestimate risks to health and feel little urgency to quit. This study examines the prevalence and characteristics of phantom smoker status among young cigarillo users. An online survey was conducted among 14-28 year olds who smoke at least 2 cigarillos per week. Phantom smoker status was determined by a negative response to "Do you consider yourself a smoker?" Other variables included smoking frequency, group smoking and sharing, and confidence in ability to quit. Associations between smoker identity and these variables were tested using chi square, independent samples t-tests and multivariable logistic regression. Of 1089 respondents, 242 (22%) were identified as phantom smokers. Phantoms smoked half as many cigarillos per week as identified smokers (M = 4.75, SD = 5.11 vs. M = 11.33, SD = 0.88, p < .001) and phantoms were more likely to smoke only when sharing (39.7% vs 21.8%, p < .001). While 59.5% of identified smokers also smoked cigarettes, only 33.5% of phantoms did so (p < .001). Most phantom smokers (83.8%) were unconcerned about addiction. Phantoms also expressed greater confidence in their ability to quit (M = 4.40, SD = 0.98) than did identified smokers (M = 3.72, SD = 1.25, p < .001). Despite regular cigarillo use, over 20% of respondents did not identify as smokers. Cigarillo smoking, along with non-daily and shared use, should be routinely assessed among youth. Phantom smokers' lack of concern about addiction and high confidence in their ability to quit may render conventional messages about smoking risk ineffective.


Analysis of the genes encoding the antigen 85 complex and MPT51 from Mycobacterium avium.
The components of the fibronectin-binding antigen 85 complex (85A, 85B, and 85C) and the related protein MPB/MPT51 are major secreted proteins in Mycobacterium tuberculosis and Mycobacterium bovis BCG. The fbpA, fbpC, and mpt51 genes encoding 85A, 85C, and MPT51, respectively, were isolated from Mycobacterium avium and sequenced in this study. The structures of these genes, and that of the fbpB gene encoding the 85B protein, were conserved in these three species. The secreted amounts of 85A, 85B, 85C, and MPB/MPT51 were compared for M. tuberculosis, BCG, and M. avium. These four proteins were found in large amounts in the culture filtrates from M. tuberculosis and BCG. In contrast, in the culture filtrate from M. avium, 85B and MPT51 were abundant whereas 85A and 85C were hardly found, in spite of the presence of the encoding genes. The difference in the secretion amounts might be regulated at the transcription level. These facts might reflect host immunopathogenesis, the protective immunities against infections, and the drug susceptibilities of these organisms.


Genetic markers for analysing symbiotic relationships and lateral gene transfer in Neotropical bradyrhizobia.
Assays with seven sets of lineage-specific polymerase chain reaction (PCR) primers in the ribosomal RNA region were performed on 96 isolates of the Bradyrhizobium sp. nodule bacteria from Barro Colorado Island, Panama. The isolates were derived from 10 legume host species in six genera (Centrosema, Desmodium, Dioclea, Inga, Machaerium and Vigna). The PCR assays differentiated 13 composite genotypes, and sequencing of a 5' 23S rRNA region indicated that all but one had a unique sequence. The most common genotype (seen in 44% of the isolates) was associated with all six legume host genera, and had a marker profile and 5' 23S rRNA sequence identical to a Bradyrhizobium lineage associated with several other legume genera in Panama and Costa Rica. Another 46% of the isolates had genotypes found to be associated with two to three legume genera. Bradyrhizobium strains with low host specificity thus appear to be prevalent in this tropical forest. Based on 16S rRNA and 5' 23S rRNA markers, most of the isolates had clear affinities to either B. japonicum or B. elkanii. However, one strain (Cp5-3) with a B. elkanii-type 16S rRNA marker had a 5' 23S rRNA region resembling B. japonicum. A partition homogeneity test indicated that relationships of strain Cp5-3 were significantly discordant for 16S rRNA vs. 23S rRNA sequences, and a runs test detected significant mosaic structure across the rRNA region. Lateral gene transfer events have therefore played a role in the evolution of symbiotic bacteria in this environment.


Rat cytomegalovirus: studies on the viral genome and the proteins of virions and nucleocapsids.
The nucleocapsids (N-capsids) isolated from the nuclei of rat cytomegalovirus (RCMV)-infected rat embryo fibroblasts (REF) are composed of three major proteins: 142 X 10(3) (142K), 40K and 32K mol. wt. Nucleocapsids isolated from the cytoplasmic fraction (C-capsids) are composed of proteins found in N-capsids and five major and seven minor new protein species. Most of the proteins present in C-capsids are found in the extracellular enveloped virions, although the ratios vary. Proteins that are abundantly present, particularly in virions (mol. wt. 125K, 116K, 87K, 79K, 71K, 68K, 62K, 50K, 43K and 28K), are probably the major constituents of the viral envelope. The DNA recovered from extracellular virions was purified to homogeneity and by equilibrium centrifugation in CsCl one density class of 1.716 (+/- 0.001) g/ml was found. Contour length measurements showed one size class of a linear double-stranded DNA corresponding to an average mol. wt. of 144(+/-9) X 10(6) which is in good agreement with data obtained by restriction endonuclease analysis (REA), which yielded mol. wt. values of 132(+/-9) X 10(6) (HindIII), 138(+/-2) X 10(6) (EcoRI) and 137 X 10(6) (BglII). The REA patterns also revealed the presence of 0.25 M and 0.5 M fragments, which might indicate, in analogy with other cytomegalo- and herpesviruses, the existence of four different configurations of the RCMV genome. The infectivity of RCMV DNA was determined in subconfluent REF monolayers. A cytopathic effect characteristic of RCMV was observed 6 days post-transfection and up to 60 plaques/microgram DNA were obtained. Using DNA-DNA filter hybridization the degree of homology between the genomes of RCMV and murine or human CMV was examined. Under stringent conditions (50% formamide) values of 12(+/-2)% and 3(+/-1)% were found whereas under non-stringent conditions (20% formamide) values of 21(+/-2)% and 6 (+/-1)% were obtained, respectively.


The role of Chlamydia trachomatis in epididymitis.
Microbiological studies have identified an infective micro-organism in 28 of 54 patients (52%) with epididymitis. Chlamydia trachomatis was the commonest infection isolated, occurring in 15 patients. An additional 17 patients (31%) who were culture negative had serological evidence which suggested recent chlamydial infection. Most patients with chlamydia were under 26 years of age, in contrast to patients over 35 years, in whom coliform infections predominated. Of the 12 consorts of patients with chlamydial epididymitis who were screened, nine were also positive for this micro-organism. These findings have important implications in the management of epididymitis, especially in young men.


Variation in RAD51 details a hub of functions: opportunities to advance cancer diagnosis and therapy.
Loss of genome stability is one of the hallmarks of the enabling characteristics of cancer development. Homologous recombination is a DNA repair process that often breaks down as a prelude to developing cancer. Conversely, homologous recombination can be the Achilles' heel in common anti-cancer therapies, which are effective by inducing irreparable DNA damage. Here, we review recent structural and functional studies of RAD51, the protein that catalyzes the defining step of homologous recombination: homology recognition and DNA strand exchange. Specific mutations can be linked to structural changes and known essential functions. Additional RAD51 interactions and functions may be revealed. The identification of viable mutations in this essential protein may help define the range of activity and interactions needed. All of this information provides opportunities to fine-tune existing therapies based on homologous recombination status, guide diagnosis, and hopefully develop new clinical tools.


CD8+ T cell-induced expression of tissue inhibitor of metalloproteinses-1 exacerbated osteoarthritis.
Despites the fact that T cells are involved in the pathogenesis of osteoarthritis (OA) little is known about the roles of CD8+ T cells in this disease. We investigated the effects of CD8+ T cells and the expression of tissue inhibitor of metalloproteinases 1 (TIMP-1) on joint pathology. Using anterior cruciate ligament-transection (ACLT), OA was induced in mice. The knee joints were histologically assessed for manifestations of OA. The CD8+ T cells from splenocytes and synovium were flow-cytometrically and immunochemically evaluated, respectively. Local expression of TIMP-1, matrix metalloproteinase (MMP)-13, and VEGF were examined. Cartilage degeneration was slower in CD8+ T cell knockout mice than in control mice. CD8+ T cells were activated once OA was initiated and expanded during OA progression. More CD8+ T cells from splenocytes expressed TIMP-1 in ACLT-group mice than in Sham-group mice. The number of TIMP-1-expressing CD8+ T cells in OA mice correlated with the disease severity. TIMP-1 expression in cartilage was co-localized with that of MMP-13 and VEGF. TIMP-1 protein was detected in synovium in which angiogenesis occurred. During the pathogenesis of OA, the expression of TIMP-1, VEGF and MMP-13 accompanying with CD8+ T cells activation were increased. Furthermore, inhibiting the expression of TIMP-1 in joints could retard the progression of OA.


The weight of US residence among immigrants: a systematic review.
As the number of immigrants in the USA continues to rise, it becomes increasingly important to understand how their health differs from native-born individuals. Obesity is a public health concern and a component of health that may differ and change in important ways in immigrants. This research synthesizes the current literature on the relationship between immigrant duration of residence in the USA and body weight. Five databases from the health and social sciences were searched for all pertinent publications. Fifteen articles met inclusion criteria, 14 of which reported a significant, positive relationship between body mass index and duration of residence in the USA (all P-values <0.10). Two studies reported a threshold effect of weight gain after 10 years of US residence, and another study reported that body mass index peaks after 21 years of duration for men and after 15 years for women. The results of this review suggest that weight gain prevention programmes would be beneficial for many immigrants within the first decade of residence in the USA. Prevention efforts may be more successful if nativity and acculturation are considered in addition to race/ethnicity. Future research is needed to identify the specific mechanisms through which living in the USA may adversely affect health outcomes.


The Parallel Pandemic: A Systematic Review on the Effects of the COVID-19 Pandemic on OCD among Children and Adolescents.
The COVID-19 pandemic and the accompanying social changes severely impacted mental health globally. Children and adolescents may have been vulnerable to adverse mental health outcomes, especially obsessive-compulsive disorder (OCD), due to their underdeveloped resilience and coping skills stemming from their progressing physical and psychological development. Few studies have explored the parallels between the pandemic and OCD trends in this population. This systematic review aims to identify the impacts of COVID-19 on OCD among children and adolescents. Using the PRISMA guidelines, a systematic search of eight databases for studies that assessed OCD outcomes independently or as part of other psychiatric diagnoses during the COVID-19 pandemic was conducted. The search was limited to studies on humans and those written in English and published between January 2020 and May 2023. We identified 788 articles, out of which 71 were selected for a full-text review. Twenty-two papers were synthesized from 10 countries for the final analysis. We found that 77% of our studies suggested that the COVID-19 pandemic had a negative impact on OCD among children and adolescents. We also found a complex interplay of individual, household, and socio-structural factors associated with the aggravation of OCD. Conversely, a few studies revealed that the pandemic strengthened relationships and resilience. The findings of this study emphasize the need for mental health screening and support for this population, especially during pandemic periods.


Comparison between short-term food restriction and exercise on whole body glucose disposal in high-fat rats.
High-fat diets induce whole-body insulin resistance. The aim of this study was to compare effect of two interventions: 3-day food restriction (66% of ad libitum fed) and 3-day exercise training (voluntary running wheels), on decreased insulin-mediated whole body glucose uptake in high-fat fed rats (5 mo old) using the hyperinsulinemic euglycemic clamp procedure. The control group was maintained on rat chow alone. After high-fat feeding for 2 wk, insulin-stimulated whole body glucose utilization was significantly decreased by 26%. The exercise training was more effective than food restriction in lowering plasma concentrations of insulin and triacylglycerol and tissue concentrations of triacylglycerol in soleus muscles. Diminished whole-body glucose uptake resulting from high-fat feeding was reversed completely by exercise training, but only partially by food restriction. The time course of starvation on insulin-stimulated glucose uptake was also observed in high-fat fed rats. Although the extension of starvation time to 48 h resulted in decreased plasma glucose, insulin and triacylglycerol concentrations, whole body glucose uptake did not increase further. These findings suggest that short-term exercise has a higher restorative effect on insulin sensitivity in high-fat fed rats than food restriction, in spite of the same loss in body weight, presumably due in part to improved local lipid availability.


Anti-Biofilm Effect of Bacteriophages and Antibiotics against Uropathogenic Escherichia coli.
Escherichia coli is a common cause of biofilm-associated urinary tract infections. Bacteria inside the biofilm are more resistant to antibiotics. Six E. coli strains isolated from patients with urinary tract infections were screened for biofilm-forming capability and antimicrobial susceptibility. Two of the most significant biofilm-producing strains were selected for minimal inhibitory concentration and minimal biofilm eradication concentration in vitro testing using amoxicillin-clavulanic acid, ciprofloxacin, and three commercial bacteriophage cocktails (Pyobacteriophag, Ses, and Intesti). In case of a low phage effect, an adaptation procedure was performed. Although the biofilms formed by strain 021UR were resistant to amoxicillin-clavulanic acid and ciprofloxacin, the three phage cocktails were able to reduce biofilm formation. In contrast, phages did not affect the 01206UR strain against planktonic and biofilm-forming cells. After Pyobacteriophag adaptation, the effect improved, and, regardless of the concentration, the adapted phage cocktail could destroy both planktonic cells and the biofilm of strain 01206UR. Bacteriophages capable of killing bacteria in biofilms can be used as an alternative to antibiotics. However, each case should be considered individually due to the lack of clinical trials for phage therapy. Antimicrobial and phage susceptibility should be determined in biofilm models before treatment to achieve the desired anti-biofilm effect.