The Falconª Eccentric Coronary Balloon Angioplasty Catheter: A Randomized Safety and Efficacy Study.
Percutaneous coronary angioplasty (PTCA) is usually performed using concentric shaped balloon catheters with the guidewire passing through the center of the shaft. The Falconª balloon catheter features a guide wire lumen on the outside of the balloon so that an eccentric balloon catheter profile is obtained concentrating the dilating force on the wire supported side, allowing lower inflation pressures and potentially causing less vessel injury. The aim of this study was to evaluate the safety and efficacy of this new balloon catheter in patients with stable and unstable angina. In 95 prospectively randomized patients, 57 lesions were dilated with a concentric balloon and 51 with the eccentric balloon. Technical success in the two groups was similar (73.3% vs. 74.5% control vs. Falcon respectively). Procedural success was 96.5% vs. 96.1% in the control and Falcon groups respectively. The mean increase in minimum luminal diameter (MLD) was 1.01 +/- 0.41 mm in the control vs 0.85 +/- 0.45 mm in Falcon (p = 0.053). There was an increase in type A dissections in the Falcon group 18 (36.75%) vs. 10 (19.23%) in the control group (p = 0.07) with no difference in stent implantation, myocardial infarction, CABG or death between the two groups. All patients with a technically successful PTCA were followed up. Seventeen (43.6%) in the control and 11 (32.4%) in the Falcon had repeat coronary angiography (p = 0.38), 12 (30.8%) vs. 7 (20.6%) had repeat PTCA (p = 0.37) and time to PTCA was 116 +/- 70 days vs. 154 +/- 103 days respectively (p = 0.36). The Falcon performed technically as well as the concentric balloons. Despite a smaller MLD and increase in Type A dissections there was no associated increase in complications or reintervention for restenosis. Further investigation is required to evaluate the role of this mechanism of dilatation in restenosis.


Connections between Mutually Unbiased Bases and Quantum Random Access Codes.
We present a new quantum communication complexity protocol, the promise-quantum random access code, which allows us to introduce a new measure of unbiasedness for bases of Hilbert spaces. The proposed measure possesses a clear operational meaning and can be used to investigate whether a specific number of mutually unbiased bases exist in a given dimension by employing semidefinite programming techniques.


Myocardial relaxation: effects of preload on the time course of isovolumetric relaxation.
We studied the effect of an isolated increase in preload on isovolumetric relaxation in the intact dog heart and isometric relaxation in isolated cardiac muscle (dog and rat) preparations. In eight anesthetized dogs, 8 to 12 ml of blood was infused into the left ventricle during a single diastole. The exponential time constant (T) of isovolumetric relaxation was measured in single-beat experiments in which the left ventricular systolic pressure increased (112 +/- 2 to 128 +/- 3 mm Hg; p less than .05, n = 62). In a second series of experiments, left ventricular systolic pressure was held constant (109 +/- 2 to 107 +/- 2 mm Hg; p = NS, n = 23) by simultaneous ventricular infusion and aortic unloading. In the first protocol, T increased from 28.0 +/- 0.4 to 30.7 +/- 0.4 msec (p less than .05), whereas in the second protocol (constant systolic pressure) there was no change in T. The time course of isometric relaxation was also studied in six rat left ventricular papillary muscles and four dog right ventricular trabecular muscles. Preload was varied from 30% to 100% of the peak of the isometric length-tension curve in each muscle. Over this wide range of preload, the isometric force decline recordings were superimposable as long as the comparisons were made at equal levels of total load. Thus an isolated increase in preload does not influence the time course of isovolumetric relaxation.


Dorsal laminectomy techniques in the dog.
The effects of various lengths of complete dorsal laminectomy were compared with the effects of Funkquist method B laminectomy on the spinal cord of dogs. Complete dorsal laminectomies were done on L1 (group 1), L1 and L2 (group 2), and L1, L2, and L3 (group 3). Dogs of group 4 had Funkquist method B laminectomies on L1 and L2. Complete dorsal laminectomy on 1 vertebra and Funkquist method B laminectomy on 2 vertebrae did not result in any clinically untoward signs. In conjuction with these results, there was no dorsoventral flattening of the spinal cords and minimal microscopic damage within the spinal cords. If 2 or 3 vertebrae had a complete laminectomy, tonic spasticity of the pelvic limbs developed after surgery. Dorsoventral flattening of the spinal cord and moderate to severe microscopic damage were seen in the spinal cords of these dogs.


Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial.
To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19. A randomized blinded pilot study was carried out with 21 individuals hospitalized with COVID-19 who received 14 sessions of active (a-taVNS) or sham taVNS (s-taVNS). The level of interleukin-6 (IL-6), interleukin-10 (IL-10), cortisol, and C-reactive protein (CRP) in plasma and clinical evolution pre- and post-intervention were evaluated. The memory and attention levels were evaluated 14 days after the end of the treatment. After treatment, significant intragroup differences were found in the CRP (p = 0.01), IL-6 (p = 0.01), and cortisol (p = 0.01) levels; however, in the comparison between the groups, only the CRP level was statistically lower for the a-taVNS (p = 0.04). The impression of improvement in memory and attention was greater in the a-taVNS than in the s-taVNS (p = 0.01, p = 0.04, respectively). There was no difference between the other clinical outcomes. taVNS is a viable and safe intervention in the acute care of patients with COVID-19, which can modulate their inflammatory profile and improve cognitive symptoms. However, improvements in overall clinical outcomes were not detected. Larger sample sizes and longer follow-ups are needed to confirm the anti-inflammatory and clinical effects of taVNS in patients with COVID-19. The Brazilian Registry of Clinical Trials (RBR-399t4g5).


Kinetics and mechanism of bacterial disinfection by chlorine dioxide.
Survival data are presented for a fecal strain of Escherichia coli exposed to three concentrations of chlorine dioxide at four temperatures. Chick's first-order reaction equation is generalized to a pseudo nth-order model. Nonlinear least squares curve-fitting of the survival data to the nth order model was performed on an analogue computer. The data were observed to follow fractional order kinetics with respect to survival concentration, with an apparent activation energy of 12,000 cal/mole. Initial experiments support the thesis that the mechanism of chlorine dioxide kill occurs via disruption of protein synthesis.


Community participation for rural healthcare design: description and critique of a method.
This paper outlines a community participation process that was developed to engage rural community stakeholders in designing new health services. The paper explains what led up to the process and provides critique around applying the process for other health services and in other communities. Internationally, community participation is widely invoked, but it is only broadly explained in the literature, other than reviews of outcomes or descriptions of problems. This paper provides an actual process, derived from iterative research, that others could use, but explains caveats in the method and its application. From developing this method of community participation for service design, we conclude that rather than being a benign and inherently 'good thing', community participation is a process into which health services managers and communities should enter cautiously. Stronger parameters around desirable outcomes and awareness of potential pitfalls in the process are important to address.


T-cell factor 3 regulates embryonic stem cell pluripotency and self-renewal by the transcriptional control of multiple lineage pathways.
The Wnt signaling pathway is necessary both for maintaining undifferentiated stem cells and for directing their differentiation. In mouse embryonic stem cells (ESCs), Wnt signaling preferentially maintains "stemness" under certain permissive conditions. T-cell factor 3 (Tcf3) is a component of the Wnt signaling and a dominant downstream effector in ESCs. Despite the wealth of knowledge regarding the importance of Wnt signaling underlying stem cells functions, the precise mechanistic explanation by which the effects are mediated is unknown. In this study, we identified new regulatory targets of Tcf3 using a whole-genome approach and found that Tcf3 transcriptionally represses many genes important for maintaining pluripotency and self-renewal, as well as those involved in lineage commitment and stem cell differentiation. This effect is in part mediated by the corepressors transducin-like enhancer of split 2 and C-terminal Binding Protein (CtBP). Notably, Tcf3 binds to and represses the Oct4 promoter, and this repressive effect requires both the Groucho and CtBP interacting domains of Tcf3. Interestingly, we find that in mouse preimplantation development embryos, Tcf3 expression is coregulated with Oct4 and Nanog and becomes localized to the inner cell mass of the blastocyst. These data demonstrate an important role for Tcf3 in modulating the appropriate level of gene transcription in ESCs and during embryonic development. Disclosure of potential conflicts of interest is found at the end of this article.


[Clinical value of soluble adhesion molecules in systemic scleroderma].
The aim of the trial was to study clinical significance of estimation of cell adhesion soluble molecules (CASM) in scleroderma systematica (SS). Quantitation of CASM VCAM-1, ICAM-1 and R-selectin was made with enzyme-immunoassay (R&D System kits, USA) in 38 patients with SS (11 with limited SS and 27 with diffuse SS). The levels of VCAM-1, ICAM-1 and R-selectin was elevated in 30 (79%), 17 (45%) and 20 (53%) patients, respectively. Mean values of VCAM-1 and ICAM-1 in patients were significantly higher than in healthy donors. R-selectin was also higher but insignificantly. A mean CASM level and a relative number of patients with elevated count of CASM in patients with diffuse and limited forms of SS did not differ. In 15 patients with active (progressive) course of the disease the level of VCAM-1 was significantly higher than in patients with chronic (non-progressive) course of SS while concentrations of ICAM-1 and R-selectine were almost the same. Thus, SS patients have elevated levels of CASM. CASM VCAM-1 concentration is the most sensitive marker of SS activity compared to other CASM.


Relational Anatomy of the Mimetic Muscles and Its Implications on Free Functional Muscle Inset in Facial Reanimation.
The human smile is a complex coordinated activity of mimetic muscles predominantly recognizable by a superolateral pull at the commissure and elevation of the upper lip. The aim of this study was to revisit the muscles of facial expression responsible for these motions, evaluate their relational anatomy and orientation, and relate this to optimal positioning of free muscle transfer in smile reanimation. Nineteen hemifaces from fresh cadaveric specimens were dissected. A subsuperficial muscular aponeurotic system skin flap was elevated to expose the zygomaticus major, zygomaticus minor, levator labii superioris, and levator labii superioris alaeque nasi. Muscle location, length, width, angle of pull, and any anatomic variation were noted. All specimens had zygomaticus major, levator labii superioris, and levator labii superioris alaeque nasi muscles present bilaterally. Conversely, the zygomaticus minor was present in only 10 of 19 hemifaces. There was no significant difference in muscle length, width, or line of pull between specimen sides. Of all the assessed muscles, the zygomaticus minor had the most transverse line of pull, at 31.6°; the zygomaticus major was more oblique with a line of pull of 55.5°; and the levator labii superioris and levator labii superioris alaeque nasi were oriented almost vertically with angles of 74.7° and 79.0°, respectively. The mimetic muscle vector is quite vertical in comparison to the angle obtained by traditional dynamic smile reconstruction surgeries. A more vertical vector, especially at the upper lip, should be considered in smile reconstruction.


Discriminating between sick and healthy faces based on early sickness cues: an exploratory analysis of sex differences.
It has been argued that sex and disease-related traits should influence how observers respond to sensory sickness cues. In fact, there is evidence that humans can detect sensory cues related to infection in others, but lack of power from earlier studies prevents any firm conclusion regarding whether perception of sickness cues is associated with sex and disease-related personality traits. Here, we tested whether women (relative to men), individuals with poorer self-reported health, and who are more sensitive to disgust, vulnerable to disease, and concerned about their health, overestimate the presence of, and/or are better at detecting sickness cues. In a large online study, 343 women and 340 men were instructed to identify the sick faces from a series of sick and healthy photographs of volunteers with an induced acute experimental inflammation. Participants also completed several disease-related questionnaires. While both men and women could discriminate between sick and healthy individuals above chance level, exploratory analyses revealed that women outperformed men in accuracy and speed of discrimination. Furthermore, we demonstrated that higher disgust sensitivity to body odors is associated with a more liberal decision criterion for categorizing faces as sick. Our findings give strong support for the human ability to discriminate between sick and healthy individuals based on early facial cues of sickness and suggest that women are significantly, although only slightly, better at this task. If this finding is replicated, future studies should determine whether women's better performance is related to increased avoidance of sick individuals.


Winning the battle, but losing the war: mechanisms and morphology of cancer-therapy-associated cardiovascular toxicity.
In the United States, the lifetime risk of a cancer diagnosis is nearly 40%; in 2016, that represents almost 1.6 million new patients, and despite advances in early diagnosis and treatment, roughly 35% will ultimately die of their malignancy. Fortunately, the number of patients living with a cancer diagnosis also continues to expand, anticipated to be more than 19 million in less than a decade. In calculating the relative risks and benefits of therapy, it is therefore important to consider the morbidity and mortality associated with antitumor therapy itself. Significantly, excluding demise due to the malignancy itself, treatment-induced adverse cardiovascular events are the leading cause of death in cancer patients. Chemotherapy, targeted therapies, immune checkpoint inhibition, and radiation therapy can all adversely impact cardiac function, and their effects can be synergistic. Consequently, it is important that possible side effects of therapy be recognized and effectively controlled. This review highlights the mechanisms and histopathologic findings associated with common forms of potentially cardiotoxic cancer therapy including anthracyclines, tyrosine kinase inhibitors, and most recently immune checkpoint (PD-1) inhibitors. Although for many cases the histologic findings are nonspecific, in the appropriate clinical context, therapeutic cardiotoxicity can be inferred and the treatment approach refined appropriately.


[Evaluation of the vaccination campaign in Cantabria 2 years of epidemiological evolution].
The results of the meningococcal vaccination campaign carried out in Cantabria in February-March 1997 are presented. In the short term, the campaign reduced the rate of incidence in the risk group from 21.33/100,000 in the previous 12 months, to zero in the 12 months following the campaign. In the medium term (2 and a half years later), the rate of incidence was maintained 80% lower in the risk group and 77.3% lower in the population overall. The vaccinal efficacy in the third year following the campaign remained above 91% for all age groups, although some biases commented upon in the study have meant that this efficacy has been underestimated. Also, the vaccinal efficacy is much higher than the percentages of seroprotection measured by the rate of bactericidal antibodies, particularly in the younger age groups. The clinical cases in vaccinated individuals experienced a benign clinical course.


Racial Differences in Geographic Access to Medical Care as Measured by Patient Report and Geographic Information Systems.
Geographic access-the travel burden required to reach medical care-is an important aspect of care. Studies, which typically rely on geographic information system (GIS) calculated travel times, have found some evidence of racial disparities in spatial access to care. However, the validity of these studies depends on the accuracy of travel times by patient race. To determine if there are racial differences when comparing patient-reported and GIS-calculated travel times. Data came from the Philadelphia Area Prostate Cancer Access Study (P Access), a cohort study of men diagnosed with localized prostate cancer. We conducted cross-sectional analysis of 2136 men using multivariable linear mixed-effects models to examine the effect of race on differences in patient-reported and GIS-calculated travel times to urology and radiation oncology cancer providers. Patient-reported travel times were, on an average, longer than GIS-calculated times. For urology practices, median patient-reported travel times were 12.7 minutes longer than GIS-calculated travel times for blacks versus 7.2 minutes longer for whites. After adjusting for potential confounders, including socioeconomic status and car access, the difference was significantly greater for black patients than white patients (2.0 min; 95% confidence interval, 0.58-3.44). GIS-calculated travel time may underestimate access to care, especially for black patients. Future studies that use GIS-calculated travel times to examine racial disparities in spatial access to care might consider including patient-reported travel times and controlling for factors that might affect the accuracy of GIS-calculated travel times.


[Effect of the medium composition on the resting membrane potential in the earthworm longitudinal somatic muscle fibers].
Norepinephrine or increased extracellular K+ hyperpolarize the membrane of the earthworm somatic muscle fibre, whereas removal of Cl- from external solution or a hypotonic solution depolarize the membrane. The dependence of the membrane resting potential on the extracellular K+ is quite characteristic against the background of ouabain action. A preliminary membrane depolarisation by ouabain eliminates the above effects on the membrane resting potential. The data obtained suggest that the ouabain-sensitive active ion pump directly contributes to the membrane resting potential value. This hypothesis is discussed with respect to existence of active Cl- transport combined with Na+, K(+)-pump which presumably takes part in the intracellular osmotic pressure regulation in the earthworm somatic muscle.


Three-party authenticated key agreements for optimal communication.
Authenticated key agreements enable users to determine session keys, and to securely communicate with others over an insecure channel via the session keys. This study investigates the lower bounds on communications for three-party authenticated key agreements and considers whether or not the sub-keys for generating a session key can be revealed in the channel. Since two clients do not share any common secret key, they require the help of the server to authenticate their identities and exchange confidential and authenticated information over insecure networks. However, if the session key security is based on asymmetric cryptosystems, then revealing the sub-keys cannot compromise the session key. The clients can directly exchange the sub-keys and reduce the transmissions. In addition, authenticated key agreements were developed by using the derived results of the lower bounds on communications. Compared with related approaches, the proposed protocols had fewer transmissions and realized the lower bounds on communications.


Effect of captopril on glucose concentration. Possible role of augmented postprandial forearm blood flow.
The goal of this study was to evaluate the effects of captopril on plasma glucose concentration. The daily profiles of the plasma glucose levels were determined in 12 non-insulin-dependent diabetic normotensive subjects, treated with or without captopril at a dose of 25 mg 3 times/day. Forearm blood flow was also measured by strain-gauge plethysmography. Administration of captopril improved the daily profile of the plasma glucose level. Postprandial forearm blood flow was also augmented 2 h after a meal. These results suggest that angiotensin-converting enzyme inhibitors may improve glucose metabolism in diabetic subjects, possibly through enhancement of blood flow to skeletal muscle.


Hemolytic anemia and metastatic carcinoma: case report and literature review.
Hemolytic anemia can complicate the development of a variety of solid tumors and hematologic malignancies. Although patients may have an established diagnosis with documented metastases, microangiopathic hemolytic anemia (MAHA) can be a presenting feature of an occult malignancy. Prompt diagnosis is essential because conditions that mimic the symptoms of MAHA, including thrombotic thrombocytopenic purpura, have different prognoses and therapeutic options. Although the exact pathogenesis is not yet delineated, we present herein a case of cancer-associated MAHA and discuss the known pathways that can contribute to the initiation and propagation of hemolytic anemia in patients with cancer. The patient is a 69-year-old woman with breast carcinoma that had metastasized to her rectum, urinary bladder, and brain. She eventually developed progressive decline in her functional status, with intermittent epistaxis and melena. The results of laboratory studies revealed hemolytic anemia and thrombocytopenia; results of a bone-marrow biopsy confirmed the involvement by metastatic carcinoma. The patient received red blood cell and platelet transfusions and was discharged to hospice care after clinical stabilization. She died soon thereafter.


Co-designing diagnosis: Towards a responsible integration of Machine Learning decision-support systems in medical diagnostics.
This paper aims to show how the focus on eradicating bias from Machine Learning decision-support systems in medical diagnosis diverts attention from the hermeneutic nature of medical decision-making and the productive role of bias. We want to show how an introduction of Machine Learning systems alters the diagnostic process. Reviewing the negative conception of bias and incorporating the mediating role of Machine Learning systems in the medical diagnosis are essential for an encompassing, critical and informed medical decision-making. This paper presents a philosophical analysis, employing the conceptual frameworks of hermeneutics and technological mediation, while drawing on the case of Machine Learning algorithms assisting doctors in diagnosis. This paper unravels the non-neutral role of algorithms in the doctor's decision-making and points to the dialogical nature of interaction not only with the patients but also with the technologies that co-shape the diagnosis. Following the hermeneutical model of medical diagnosis, we review the notion of bias to show how it is an inalienable and productive part of diagnosis. We show how Machine Learning biases join the human ones to actively shape the diagnostic process, simultaneously expanding and narrowing medical attention, highlighting certain aspects, while disclosing others, thus mediating medical perceptions and actions. Based on that, we demonstrate how doctors can take Machine Learning systems on board for an enhanced medical diagnosis, while being aware of their non-neutral role. We show that Machine Learning systems join doctors and patients in co-designing a triad of medical diagnosis. We highlight that it is imperative to examine the hermeneutic role of the Machine Learning systems. Additionally, we suggest including not only the patient, but also colleagues to ensure an encompassing diagnostic process, to respect its inherently hermeneutic nature and to work productively with the existing human and machine biases.


Hikikomori Is Most Associated With Interpersonal Relationships, Followed by Suicide Risks: A Secondary Analysis of a National Cross-Sectional Study.
There have been few population studies of hikikomori (that is, prolonged social withdrawal and isolation), and the basic correlating factors of hikikomori are yet to be identified. Therefore, this study aimed to identify the associated basic characteristics and psychiatric factors of hikikomori. Data were obtained from the Survey of Young People's Attitudes of 5,000 residents (aged 15-39 years) who were randomly selected from 200 urban and suburban municipalities in Japan in February 2010. The chi-square test and multiple logistic regression were used in the analysis. The data contained 3,262 participants (response rate: 65.4%); 47.7% were men (n = 1,555) and 52.3% were women (n = 1,707). Its prevalence was 1.8% (n = 58), and 41% had been in the hikikomori state for more than 3 years. There were fewer hikikomori people in neighborhoods filled with business and service industries. Significantly more men were in the hikikomori group (65.5%) than in the non-hikikomori group (47.3%). The hikikomori group was more likely to drop out of education (p < .001) and to have a psychiatric treatment history compared with non-hikikomori (37.9% vs 5%, p < .001). The multiple logistic regression analyses revealed that interpersonal relationships were significantly associated with hikikomori across three models (Model 1 adjusting for all basic characteristics, OR = 2.30, 95% CI = 1.92-2.76; Model 2 further adjusting for mental health-related factors, OR = 2.1, 95% CI = 1.64-2.68; Model 3 further adjusting for a previous psychiatric treatment history, OR = 1.95, 95% CI = 1.52-2.51). Additionally, the hikikomori group was more likely to have suicide risk factors (Model 1: OR = 1.85, 95% CI = 1.56-2.20; Model 2: OR = 1.33, 95% CI = 1.05-1.67), obsessive-compulsive behaviors (Model 1: OR = 1.57, 95% CI = 1.20-2.05), and addictive behaviors (Model 1: OR = 1.93, 95% CI = 1.37-2.70). This is the first study to show that hikikomori is associated with interpersonal relationships, followed by suicide risks. Hikikomori people are more likely to be male, have a history of dropping out from education, and have a previous psychiatric treatment history.


Visualization and data exploration of chromosome conformation capture data using Voronoi diagrams with v3c-viz.
Chromosome conformation capture (3C) sequencing approaches, like Hi-C or micro-C, allow for an unbiased view of chromatin interactions. Most analysis methods rely on so-called interaction matrices, which are derived from counting read pairs in bins of fixed size. Here, we propose the Voronoi diagram, as implemented in Voronoi for chromosome conformation capture data visualization (v3c-viz) to visualize 3C data. The Voronoi diagram corresponds to an adaptive-binning strategy that adapts to the local densities of points. In this way, visualization of data obtained by moderate sequencing depth pinpoint many, if not most, interesting features such as high frequency contacts. The favorable visualization properties of the Voronoi diagram indicate that the Voronoi diagram as density estimator can be used to identify high frequency contacts at a resolution approaching the typical size of enhancers and promoters. v3c-viz is available at https://github.com/imbbLab/v3c-viz .


Anti-GD(2) with an FC point mutation reduces complement fixation and decreases antibody-induced allodynia.
Monoclonal antibodies against GD(2) ganglioside, such as ch14.18, the human-mouse chimeric antibody, have been shown to be effective for the treatment of neuroblastoma. However, treatment is associated with generalized, relatively opiate-resistant pain. We investigated if a point mutation in ch14.18 antibody (hu14.18K332A) to limit complement-dependent cytotoxicity (CDC) would ameliorate the pain behavior, while preserving antibody-dependent cellular cytotoxicity (ADCC). In vitro, CDC and ADCC were measured using europium-TDA assay. In vivo, allodynia was evaluated by measuring thresholds to von Frey filaments applied to the hindpaws after injection of either ch14.18 or hu14.18K332 into wild type rats or rats with deficient complement factor 6. Other rats were pretreated with complement factor C5a receptor antagonist and tested following ch14.18 injection. The mutation reduces the antibody's ability to activate complement, while maintaining its ADCC capabilities. Injection of hu14.18K322 (1 or 3mg/kg) produced faster resolving allodynia than that engendered by ch14.18 (1mg/kg). Injection of ch14.18 (1mg/kg) into rats with C6 complement deficiency further reduced antibody-induced allodynia, while pre-treatment with complement factor C5a receptor antagonist completely abolished ch14.18-induced allodynia. These findings showed that mutant hu14.18 K322 elicited less allodynia than ch14.18 and that ch14.18-elicited allodynia is due to activation of the complement cascade: in part, to formation of membrane attack complex, but more importantly to release of complement factor C5a. Development of immunotherapeutic agents with decreased complement-dependent lysis while maintaining cellular cytotoxicity may offer treatment options with reduced adverse side effects, thereby allowing dose escalation of therapeutic antibodies.


Lymphocyte suppressive peptides from fibrinogen are derived predominantly from the A alpha chain.
Cellular immune responses can elicit local deposition of fibrin at the site of immunologic reactions, as well as the formation of intravascular fibrin in disseminated reactions. The subsequent physiologic proteolysis of fibrinogen and fibrin by plasmin results in small peptides that suppress lymphocyte functions in vitro and in the immune response in vivo. The intramolecular origin of lymphocyte suppressive activity and the proteolytic events responsible for the release of active peptides have been analyzed. Plasmic peptides from the isolated B beta and gamma constituent chains of fibrinogen did not inhibit mitogen-driven responses of human peripheral blood mononuclear cells. In contrast, plasmic digests of the A alpha chain, but not the intact A alpha chain were suppressive. Advanced plasmic digests of fibrinogen and the A alpha chain were suppressive at similar concentrations, suggesting that biological activity is derived predominantly from the A alpha chain. Limited plasmic digests of fibrinogen were fractionated to yield a heat-precipitable 250,000 dalton fragment X and heat-soluble proteolytic products containing fragments derived from the carboxyl-terminal region of the A alpha chain including a 42,000 dalton major A alpha chain derivative. Neither fragment X nor derivatives produced by its additional plasmic proteolysis were suppressive. In contrast, the heat-soluble fraction from limited plasmic cleavage was suppressive, and this activity was enhanced 10-fold by additional plasmic cleavage of this fraction. The isolated 42,000 dalton A alpha chain fragment was devoid of activity, but plasmic digestion of this derivative generated peptides of less than 8000 daltons that inhibited mitogen-stimulated thymidine uptake by lymphocytes. Two synthetic peptides corresponding to A alpha 220-230 and B beta 43-47, peptides with known vasoactive activities, suppressed lymphocyte thymidine uptake at very high concentrations. Based on their maximal yield from plasmic digests of fibrinogen, these two peptides would account for only 1% of the immunosuppressive activity of fibrinogen derivatives. In summary, the results indicate that the suppressive activity of fibrinogen is predominantly derived from the 42,000 dalton carboxyl terminal region of the A alpha chain of the molecule and is not attributable to the known vasoactive peptides. Initial proteolytic release of this region from the core of fibrinogen does not result in suppressive activity, but additional cleavage releases small peptides with the lymphocyte inhibitory function.


Epidemiological surveillance of respiratory viral infections in SARS-CoV-2-negative samples during COVID-19 pandemic in Iran.
To improve the patient care, public health surveillance, and infection control, it is crucial to identify the presence and frequency of the common respiratory infections in individuals with COVID-19 symptoms but tested negative for SARS-CoV-2. This study aimed to shed light on this during the COVID-19 pandemic in Iran. In this cross-sectional study, a total of 1,002 patients with acute respiratory infection who had negative SARS-CoV-2 test results and referred to Valfajr Health Center, the National Collaborating Laboratory of Influenza and COVID-19 National Reference Laboratory at Pasteur Institute of Iran were recruited between January 2020 and January 2022. Nasopharyngeal and oropharyngeal swab samples were collected to detect 17 common respiratory viruses via TaqMan one-step real-time multiplex PCR. Demographic and clinical data of the participants were obtained from their electronic medical records. In total, 218 samples (21.8%) were tested positive for at least one respiratory virus infection. Most of the common investigated respiratory viruses belonged to the years 2020 and 2022. The number of investigated patients in 2021 was few, which highlights the impact of health measures following the COVID-19 pandemic in Iran. Influenza A was the most common virus (5.8%), while adenovirus had the lowest prevalence (0.1%). Although the rate of respiratory virus infection was higher in men (24%) compared to women (19.3%), this difference was not statistically significant (P = 0.069). The prevalence of respiratory viruses had an inverse association with increasing age, with the highest rate (55.6%) observed in the age group below 2 years and the lowest rate (12.7%) in those above 65 years. Our findings underscore the significance of adopting a comprehensive approach to respiratory infections detection and management. These results can be employed for the development of syndromic surveillance systems and implementation of the effective infection control measures. Furthermore, the results contribute to better understanding of the dynamics of respiratory viruses, both during pandemic periods and in non-pandemic contexts.


Population dynamics of Anopheles culicifacies and malaria in the tribal area of central India.
A longitudinal study (1993-94) on malaria was conducted in Dungaria, a typical forest fringe tribal village in Mandla district of central India (Madhya Pradesh). Our initial objective was to obtain in-depth baseline data on malaria transmission in the tribal village to elucidate the factors responsible for persistent malaria in the area and thereby to help in formulating an improved malaria control program. Anopheles culicifacies Giles was the predominant vector of malaria, although Anopheles fluviatilis James were recorded in small numbers. The transmission season was from May to November. Analysis of the malaria cases revealed hyperendemic malaria, with Plasmodium falciparum the predominant species. The prevalence of Plasmodium vivax was mainly in the summer and that of P. falciparum in autumn. The study suggested that a number of factors were responsible for the continuation of malaria transmission in the village.


Towards a patient journey perspective on causes of unplanned readmissions using a classification framework: results of a systematic review with narrative synthesis.
Several literature reviews have been published focusing on the prevalence and/or preventability of hospital readmissions. To our knowledge, none focused on the different causes which have been used to evaluate the preventability of readmissions. Insight into the range of causes is crucial to understand the complex nature of readmissions. We conducted a systematic review to: (1) evaluate the range of causes of unplanned readmissions in a patient journey, and (2) present a cause classification framework that can support future readmission studies. A literature search was conducted in PUBMED and EMBASE using "readmission" and "avoidability" or "preventability" as key terms. Studies that specified causes of unplanned readmissions were included. The causes were classified into eight preliminary root causes: Technical, Organization (integrated care), Organization (hospital department level), Human (care provider), Human (informal caregiver), Patient (self-management), Patient (disease), and Other. The root causes were based on expert opinions and the root cause analysis tool of PRISMA (Prevention and Recovery Information System for Monitoring and Analysis). The range of different causes were analyzed using Microsoft Excel. Forty-five studies that reported 381 causes of readmissions were included. All studies reported causes related to organization of care at the hospital department level. These causes were often reported as preventable. Twenty-two studies included causes related to patient's self-management and 19 studies reported causes related to patient's disease. Studies differed in which causes were seen as preventable or unpreventable. None reported causes related to technical failures and causes due to integrated care issues were reported in 18 studies. This review showed that causes for readmissions were mainly evaluated from a hospital perspective. However, causes beyond the scope of the hospital can also play a major role in unplanned readmissions. Opinions regarding preventability seem to depend on contextual factors of the readmission. This study presents a cause classification framework that could help future readmission studies to gain insight into a broad range of causes for readmissions in a patient journey.


The Capacity to Mourn: Thoughts for a Developmental Line.
The purpose of this article is to examine the developmental transformative milestones and cognitive achievements that mediate the mourning process. Selected literature review and theoretical considerations to formulate hypotheses referencing mourning. We identify three predominant venues through which we experience losses: (1) The child moving from dependence to independence with the shedding of infantile ties. (2) The uncertainties of the life cycle with the inevitable and fateful losses of family members and loved ones; and (3) the passage of time with diminishing options and inevitable decline. Mourning requires consideration of the role of object constancy, the capacity for ambivalence, the successful negotiation of the normative adolescent mourning process, critical cognitive achievements including the acceptance of transience and chance happenings, and identification and the stabilization of the inner relationship with the mental representation of the lost object. Our life experiences require that we develop strategies for dealing with the various losses associated with our journey through the life cycle. The complex process of mourning and the ability to mourn evolves along a developmental line. There are certain developmental transformative milestones and cognitive achievements which if achieved facilitate mourning and which if not achieved may impede the process of mourning.


Cognitive improvement following endovascular embolization in patients with intracranial dural arteriovenous fistula: The Neuropsychology in dural ArterIal Fistula (NAIF) Study.
Cognitive improvement after endovascular embolization of an intracranial dural arteriovenous fistula (dAVF) remains unexplored. We aim to investigate cognitive changes following endovascular embolization of dAVFs. Neuropsychology in dural ArterIal Fistula (NAIF) was a prospective multicentric study including patients with an angiographic diagnosis of dAVF who underwent endovascular embolization over the course of 4 years. A complete neuropsychological evaluation comprising five cognitive domains (attention and executive functions, memory, language, praxis, gnosis) was performed at baseline and 3 months follow-up. Mean Z scores for cognitive tests were compared pre- and post-treatment using paired sample t-tests, where higher Z scores indicate better cognition. Effect sizes were computed as Cohen's d. A total of 32 patients (mean age 61.1±15.4 years, 10 (31.3%) females) were included. Patients exhibited improved performance in attention and executive functions: executive functions-attention (+0.282, P=0.009, d=0.29), executive functions-fluencies (+0.283, P=0.029, d=0.4), and executive functions-processing speed (+0.471, P=0.039, d=0.41). There was an increase in memory: verbal learning and verbal delayed recall scores (+0.513, P<0.001, d=0.55, and +0.385, P=0.001, d=0.41, respectively), while verbal recognition parameters (+0.839, P=0.086, d=0.37) and visual memory (delayed recall) (+0.430, P=0.060, d=0.35) displayed trends toward improved performance. Regarding language, there was significant overall improvement (+0.300, P=0.014, d=0.24), but neither praxis nor gnosis changed significantly. These cognitive outcomes were independent of the severity (measured as Cognard classification), and no patient experienced cognitive worsening. This study suggests that endovascular embolization confers cognitive benefits on dAVF patients undergoing endovascular embolization and may be beneficial even for patients with a low risk of hemorrhage.


Identification of iNOS inhibitors using InteraX.
Inducible nitric oxide synthase (iNOS) is active as a homodimer. A cell-based assay suitable for high-throughput screening (HTS) was generated to identify inhibitors of iNOS dimerization using the InteraX enzyme complementation technology of Applied Biosystems. The cells contain 2 chimeric proteins of complementing deletion mutants of beta-galactosidase, each fused to the oxygenase domain of human iNOS. The assay was characterized using known iNOS dimerization inhibitors, which gave a decrease in beta-galactosidase activity. Surprisingly, the assay was also able to identify compounds that have the same profile as known inhibitors of fully formed dimeric iNOS by causing an increase in beta-galactosidase activity. The iNOS InteraX assay was used to screen approximately 800,000 compounds in a 384-well format. After hit confirmation, 3359 compounds were taken forward for full IC50 determination in InteraX and cytotoxicity assays. Of these compounds 40.5% were confirmed as greater than 10-fold more active in InteraX compared to a cytotoxicity assay and were classified as potential iNOS dimerization inhibitors as they did not inhibit beta-galactosidase alone. In the same primary screen, 901 compounds gave a significant increase in beta-galactosidase activity. Many of these were known inhibitors of iNOS. After IC50 determination in InteraX and cytotoxicity assays, 182 novel compounds remained as potential arginine-competitive inhibitors of dimeric iNOS.


Screening for gestational diabetes mellitus based on different risk profiles and settings for improving maternal and infant health.
Gestational diabetes mellitus (GDM) is a form of diabetes that occurs in pregnancy. Although GDM usually resolves following birth, it is associated with significant morbidities for mothers and their infants in the short and long term. There is strong evidence to support treatment for GDM. However, there is uncertainty as to whether or not screening all pregnant women for GDM will improve maternal and infant health and if so, the most appropriate setting for screening. This review updates a Cochrane Review, first published in 2010, and subsequently updated in 2014. To assess the effects of screening for gestational diabetes mellitus based on different risk profiles and settings on maternal and infant outcomes. We searched Cochrane Pregnancy and Childbirth's Trials Register (31 January 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (14 June 2017), and reference lists of retrieved studies. We included randomised and quasi-randomised trials evaluating the effects of different protocols, guidelines or programmes for screening for GDM based on different risk profiles and settings, compared with the absence of screening, or compared with other protocols, guidelines or programmes for screening. We planned to include trials published as abstracts only and cluster-randomised trials, but we did not identify any. Cross-over trials are not eligible for inclusion in this review. Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of the included trials. We resolved disagreements through discussion or through consulting a third reviewer. We included two trials that randomised 4523 women and their infants. Both trials were conducted in Ireland. One trial (which quasi-randomised 3742 women, and analysed 3152 women) compared universal screening versus risk factor-based screening, and one trial (which randomised 781 women, and analysed 690 women) compared primary care screening versus secondary care screening. We were not able to perform meta-analyses due to the different interventions and comparisons assessed.Overall, there was moderate to high risk of bias due to one trial being quasi-randomised, inadequate blinding, and incomplete outcome data in both trials. We used GRADEpro GDT software to assess the quality of the evidence for selected outcomes for the mother and her child. Evidence was downgraded for study design limitations and imprecision of effect estimates. Universal screening versus risk-factor screening (one trial) MotherMore women were diagnosed with GDM in the universal screening group than in the risk-factor screening group (risk ratio (RR) 1.85, 95% confidence interval (CI) 1.12 to 3.04; participants = 3152; low-quality evidence). There were no data reported under this comparison for other maternal outcomes including hypertensive disorders of pregnancy, caesarean birth, perineal trauma, gestational weight gain, postnatal depression, and type 2 diabetes. ChildNeonatal outcomes: large-for-gestational age, perinatal mortality, mortality or morbidity composite, hypoglycaemia; and childhood/adulthood outcomes: adiposity, type 2 diabetes, and neurosensory disability, were not reported under this comparison. Primary care screening versus secondary care screening (one trial) MotherThere was no clear difference between the primary care and secondary care screening groups for GDM (RR 0.91, 95% CI 0.50 to 1.66; participants = 690; low-quality evidence), hypertension (RR 1.41, 95% CI 0.77 to 2.59; participants = 690; low-quality evidence), pre-eclampsia (RR 0.80, 95% CI 0.36 to 1.78; participants = 690;low-quality evidence), or caesarean section birth (RR 1.00, 95% CI 0.80 to 1.27; participants = 690; low-quality evidence). There were no data reported for perineal trauma, gestational weight gain, postnatal depression, or type 2 diabetes. ChildThere was no clear difference between the primary care and secondary care screening groups for large-for-gestational age (RR 1.37, 95% CI 0.96 to 1.96; participants = 690; low-quality evidence), neonatal complications: composite outcome, including: hypoglycaemia, respiratory distress, need for phototherapy, birth trauma, shoulder dystocia, five minute Apgar less than seven at one or five minutes, prematurity (RR 0.99, 95% CI 0.57 to 1.71; participants = 690; low-quality evidence), or neonatal hypoglycaemia (RR 1.10, 95% CI 0.28 to 4.38; participants = 690; very low-quality evidence). There was one perinatal death in the primary care screening group and two in the secondary care screening group (RR 1.10, 95% CI 0.10 to 12.12; participants = 690; very low-quality evidence). There were no data for neurosensory disability, or childhood/adulthood adiposity or type 2 diabetes. There are insufficient randomised controlled trial data evaluating the effects of screening for GDM based on different risk profiles and settings on maternal and infant outcomes. Low-quality evidence suggests universal screening compared with risk factor-based screening leads to more women being diagnosed with GDM. Low to very low-quality evidence suggests no clear differences between primary care and secondary care screening, for outcomes: GDM, hypertension, pre-eclampsia, caesarean birth, large-for-gestational age, neonatal complications composite, and hypoglycaemia.Further, high-quality randomised controlled trials are needed to assess the value of screening for GDM, which may compare different protocols, guidelines or programmes for screening (based on different risk profiles and settings), with the absence of screening, or with other protocols, guidelines or programmes. There is a need for future trials to be sufficiently powered to detect important differences in short- and long-term maternal and infant outcomes, such as those important outcomes pre-specified in this review. As only a proportion of women will be diagnosed with GDM in these trials, large sample sizes may be required.


Proximal femoral replacements with megaprostheses.
The exact role of proximal femoral replacement (megaprosthesis) in revision hip surgery is unclear. During the past decade remarkable advances in the field of revision hip reconstruction have been made including the availability of allograft cancellous and cortical bone. With the increased use of cortical strut grafts to augment host bone, the indications for the use of megaprostheses have narrowed. Currently, we reserve the use of megaprostheses for elderly or sedentary patients with massive proximal femoral bone loss that cannot be reconstructed by other reconstructive procedures. This may include failed total hip arthroplasty (THA), nonunion of the proximal femur with multiple failed attempts at osteosynthesis, and hip salvage after a failed resection arthroplasty.


Effective connectivity gateways to the Theory of Mind network in processing communicative intention.
An Intention Processing Network (IPN), involving the medial prefrontal cortex, precuneus, bilateral posterior superior temporal sulcus, and temporoparietal junctions, plays a fundamental role in comprehending intentions underlying action goals. In a previous fMRI study, we showed that, depending on the linguistic or extralinguistic (gestural) modality used to convey the intention, the IPN is complemented by activation of additional brain areas, reflecting distinct modality-specific input gateways to the IPN. These areas involve, for the linguistic modality, the left inferior frontal gyrus (LIFG), and for the extralinguistic modality, the right inferior frontal gyrus (RIFG). Here, we tested the modality-specific gateway hypothesis, by using DCM to measure inter-regional functional integration dynamics between the IPN and LIFG/RIFG gateways. We found strong evidence of a well-defined effective connectivity architecture mediating the functional integration between the IPN and the inferior frontal cortices. The connectivity dynamics indicate a modality-specific propagation of stimulus information from LIFG to IPN for the linguistic modality, and from RIFG to IPN for the extralinguistic modality. Thus, we suggest a functional model in which the modality-specific gateways mediate the structural and semantic decoding of the stimuli, and allow for the modality-specific communicative information to be integrated in Theory of Mind inferences elaborated through the IPN.


The risk of seizure recurrence following a first unprovoked seizure: a quantitative review.
Knowledge of the recurrence risk following a first unprovoked seizure and the predictors of that risk are necessary for rational treatment decisions. Published estimates of recurrence risk range from 23% to 71%. In a meta-analysis of 16 reports, three methodologic factors explained much of the reported variation: (1) study inclusion criteria, ie, whether patients were enrolled at the time of their first seizure or if patients with prior seizures were included; (2) retrospective versus prospective ascertainment of patients; (3) the interval between the first seizure and the time at which risk was assessed. The average recurrence risk across the 16 studies was 51%. The risk was 40% and 52% in prospective and retrospective studies that employed first-seizure methods and 67% in non-first seizure studies. At or near 2 years following the first seizure, the recurrence risk was 36% and 47% in prospective and retrospective first-seizure studies. The distribution of prognostic factors was also important. Seizure etiology and the EEG were the strongest predictors of recurrence distinguishing between patient subgroups, with recurrence risks as low as 24% and as high as 65%. Partial seizures were associated with an increased recurrence risk, but not consistently. There is considerable agreement among studies concerning the recurrence risk following a first seizure, and much of the discrepancies among studies can be explained by differences in study methods and distributions of important prognostic factors.


Stimuli-Actuated Turn-On Theranostic Nanoplatforms for Imaging-Guided Antibacterial Treatment.
Antibacterial theranostic nanoplatforms, which integrate diagnostic and therapeutic properties, exhibit gigantic application prospects in precision medicine. However, traditional theranostic nanoplatforms usually present an always-on signal output, which leads to poor specificity or selectivity in the treatment of bacterial infections. To address this challenge, stimuli-actuated turn-on nanoplatforms are developed for simultaneous activation of diagnostic signals (e.g., fluorescent, photoacoustic, magnetic signals) and initiation of antibacterial treatment. Specifically, by combining the infection microenvironment-responsive activation of visual signals and antibacterial activity, these theranostic nanoplatforms exert both higher accurate diagnosis rates and more effective treatment effects. In this review, the imaging and treatment strategies that are commonly used in the clinic are first briefly introduced. Next, the recent progress of stimuli-actuated turn-on theranostic nanoplatforms for treating bacterial infectious diseases is summarized in detail. Finally, current bottlenecks and future opportunities of antibacterial theranostic nanoplatforms are also outlined and discussed.


A randomized, controlled trial of a multifaceted intervention including alcohol-based hand sanitizer and hand-hygiene education to reduce illness transmission in the home.
Good hand hygiene may reduce the spread of infections in families with children who are in out-of-home child care. Alcohol-based hand sanitizers rapidly kill viruses that are commonly associated with respiratory and gastrointestinal (GI) infections. The objective of this study was to determine whether a multifactorial campaign centered on increasing alcohol-based hand sanitizer use and hand-hygiene education reduces illness transmission in the home. A cluster randomized, controlled trial was conducted of homes of 292 families with children who were enrolled in out-of-home child care in 26 child care centers. Eligible families had > or =1 child who was 6 months to 5 years of age and in child care for > or =10 hours/week. Intervention families received a supply of hand sanitizer and biweekly hand-hygiene educational materials for 5 months; control families received only materials promoting good nutrition. Primary caregivers were phoned biweekly and reported respiratory and GI illnesses in family members. Respiratory and GI-illness-transmission rates (measured as secondary illnesses per susceptible person-month) were compared between groups, adjusting for demographic variables, hand-hygiene practices, and previous experience using hand sanitizers. Baseline demographics were similar in the 2 groups. A total of 1802 respiratory illnesses occurred during the study; 443 (25%) were secondary illnesses. A total of 252 GI illnesses occurred during the study; 28 (11%) were secondary illnesses. The secondary GI-illness rate was significantly lower in intervention families compared with control families (incidence rate ratio [IRR]: 0.41; 95% confidence interval [CI]: 0.19-0.90). The overall rate of secondary respiratory illness was not significantly different between groups (IRR: 0.97; 95% CI: 0.72-1.30). However, families with higher sanitizer usage had a marginally lower secondary respiratory illness rate than those with less usage (IRR: 0.81; 95% CI: 0.65-1.09). A multifactorial intervention emphasizing alcohol-based hand sanitizer use in the home reduced transmission of GI illnesses within families with children in child care. Hand sanitizers and multifaceted educational messages may have a role in improving hand-hygiene practices within the home setting.


Evaluation of angiographic computed tomography in the follow-up after endovascular treatment of cerebral aneurysms--a comparative study with DSA and TOF-MRA.
Following coil embolization of intracranial aneurysms, many centers perform at least one digital subtraction angiography (DSA) continuing with time-of-flight magnetic resonance angiography (TOF-MRA). Angiographic computed tomography (ACT) provides high-resolution data from a rotational acquisition of a c-arm-mounted flat panel detector. This study evaluates possible advantages of applying ACT in aneurysm follow-up. In 22 patients DSA examinations with a rotational acquisition were performed. Rotational data were processed into an isotropic high-resolution volume. TOF-MRA was performed the day before DSA. Three experienced neuroradiologists performed a rating of the occlusion rate and a subjective method comparison. Weighted kappa statistics were calculated to assess the level of interobserver agreement. Compared to DSA, the diagnostic value of ACT as well as of TOF-MRA was rated to be inferior, although the sensitivity of detecting residual necks was higher with both techniques. Compared to TOF-MRA, ACT achieves favorable ratings only in aneurysms after stent-remodeling. Interobserver agreement was high for all techniques. Ratings of the occlusion rate correlated highly between all observers (r>0.85, p<0.001, respectively). In selected patients ACT can add valuable diagnostic information to DSA. TOF-MRA remains a highly sensitive method for aneurysm follow-up.


The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models.
Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents.


Detection of carbamazepine-induced changes in valproic acid relative clearance in man by simple pharmacokinetic screening.
Selecting the optimum dose of valproic acid is difficult because the pharmacokinetics are complicated by inter-patient variability and by effects arising as a result of co-administration with other antiepileptic drugs. The multiple peak approach has been used to evaluate the effect of age, total body weight, dose, gender and comedication (carbamazepine-induced change) on population estimates of valproic acid relative clearance. Routine clinical pharmacokinetic data (n = 479) were collected from 207 epilepsy patients on combination therapy. The data were analysed by a simple steady-state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic analysis that enables pooling of data. NONMEM estimates suggested that the rate of valproic acid clearance in patients receiving concomitant administration of valproic acid and carbamazepine decreased non-linearly with increasing total body weight in the maturation process, and increased non-linearly with increasing valproic acid dose. The clearance in females was 5.7% less than in males. NONMEM estimates also suggested that the rate of valproic acid clearance increased non-linearly with increasing carbamazepine dose. Concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs resulted in an increase in valproic acid clearance of 10%. The final regression model of valproic acid relative clearance was CL = 6.06TBW-0.168 x DOSE0.414 x CBZDOSE0.093 x 0.943GEN x 1.10CO, where CL is the clearance (mL kg-1 h-1), TBW is the total body weight (kg), DOSE is the dose of valproic acid, CBZDOSE is the dose of carbamazepine, GEN = 0 for males and 1 for females and CO = 0 for concomitant administration of valproic acid and carbamazepine and 1 for concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs. This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent to which patient characteristics influence drug pharmacokinetics.


Significant linkage to chromosome 22q for exploratory eye movement dysfunction in schizophrenia.
A genome-wide scan for a locus responsible for exploratory eye movement (EEM), which is quantitative and can be disturbed in association with schizophrenia, was performed. A 10-cM resolution genome-wide linkage analysis of the EEM disturbance with 358 highly polymorphic microsatellite markers in 38 nuclear families with 122 members (38 probands, 47 sibs, and 37 parents) including 58 sib-pairs yielded the suggestive linkage to the GCT10C10 marker on chromosome 22q11.2 (LOD = 2.48). Dense mapping with additional markers around the GCT10C10 marker yielded evidence for significant linkage between EEM disturbance and markers D22S429 and D22S310 on chromosome 22q12.1 (LOD score of 4.63) with suggestive evidence for the chromosome region 22q11.2-q12.1. Our findings suggest that a relatively small number of loci may control the schizophrenia-related quantitative EEM trait. We believe that identifying gene(s) on chromosome 22q associated with the EEM phenotype may forward our understanding of the etiology of schizophrenia.


Including gene networks to predict calving difficulty in Holstein, Brown Swiss and Jersey cattle.
Calving difficulty or dystocia has a great economic impact in the US dairy industry. Reported risk factors associated with calving difficulty are feto-pelvic disproportion, gestation length and conformation. Different dairy cattle breeds have different incidence of calving difficulty, with Holstein having the highest dystocia rates and Jersey the lowest. Genomic selection becomes important especially for complex traits with low heritability, where the accuracy of conventional selection is lower. However, for complex traits where a large number of genes influence the phenotype, genome-wide association studies showed limitations. Biological networks could overcome some of these limitations and better capture the genetic architecture of complex traits. In this paper, we characterize Holstein, Brown Swiss and Jersey breed-specific dystocia networks and employ them in genomic predictions. Marker association analysis identified single nucleotide polymorphisms explaining the largest average proportion of genetic variance on BTA18 in Holstein, BTA25 in Brown Swiss, and BTA15 in Jersey. Gene networks derived from the genome-wide association included 1272 genes in Holstein, 1454 genes in Brown Swiss, and 1455 genes in Jersey. Furthermore, 256 genes in Holstein network, 275 genes in the Brown Swiss network, and 253 genes in the Jersey network were within previously reported dystocia quantitative trait loci. The across-breed network included 80 genes, with 9 genes being within previously reported dystocia quantitative trait loci. The gene-gene interactions in this network differed in the different breeds. Gene ontology enrichment analysis of genes in the networks showed Regulation of ARF GTPase was very significant (FDR ≤ 0.0098) on Holstein. Neuron morphogenesis and differentiation was the term most enriched (FDR ≤ 0.0539) on the across-breed network. Genomic prediction models enriched with network-derived relationship matrices did not outperform regular GBLUP models. Regions identified in the genome were in the proximity of previously described quantitative trait loci that would most likely affect calving difficulty by altering the feto-pelvic proportion. Inclusion of identified networks did not increase prediction accuracy. The approach used in this paper could be extended to any instance with asymmetric distribution of phenotypes, for example, resistance to disease data.


Magnetic alignment in grazing and resting cattle and deer.
We demonstrate by means of simple, noninvasive methods (analysis of satellite images, field observations, and measuring "deer beds" in snow) that domestic cattle (n = 8,510 in 308 pastures) across the globe, and grazing and resting red and roe deer (n = 2,974 at 241 localities), align their body axes in roughly a north-south direction. Direct observations of roe deer revealed that animals orient their heads northward when grazing or resting. Amazingly, this ubiquitous phenomenon does not seem to have been noticed by herdsmen, ranchers, or hunters. Because wind and light conditions could be excluded as a common denominator determining the body axis orientation, magnetic alignment is the most parsimonious explanation. To test the hypothesis that cattle orient their body axes along the field lines of the Earth's magnetic field, we analyzed the body orientation of cattle from localities with high magnetic declination. Here, magnetic north was a better predictor than geographic north. This study reveals the magnetic alignment in large mammals based on statistically sufficient sample sizes. Our findings open horizons for the study of magnetoreception in general and are of potential significance for applied ethology (husbandry, animal welfare). They challenge neuroscientists and biophysics to explain the proximate mechanisms.


The contribution of culture to Korean American women's cervical cancer screening behavior: the critical role of prevention orientation.
Despite the proven benefits of Pap testing, Korean American women have one of the lowest cervical cancer screening rates in the United States. This study examined how cultural factors are associated with Pap test utilization among Korean American women participants. Quota sampling was used to recruit 202 Korean American women participants residing in New York City. Hierarchical logistic regression was used to assess the association of cultural variables with Pap test receipt. Overall, participants in our study reported significantly lower Pap test utilization; only 58% reported lifetime receipt of this screening test. Logistic regression analysis revealed one of the cultural variables--prevention orientation--was the strongest correlate of recent Pap test use. Older age and married status were also found to be significant predictors of Pap test use. Findings suggest cultural factors should be considered in interventions promoting cervical cancer screening among Korean American women. Furthermore, younger Korean American women and those not living with a spouse/partner should be targeted in cervical cancer screening efforts.


The effect of human amniotic epithelial cells on urethral stricture fibroblasts.
Urethral stricture disease (USD) is effectively managed by buccal mucosa (BM) urethroplasty. Lack of adequate healthy BM has led to the use of autologous tissue-engineered BM grafts. Such grafts are costly, not easily scalable and recurrence of the stricture is still a problem. Hence, there is a requirement for cost-effective, scalable cells with innate antifibrotic properties which seem to be fulfilled by human amniotic epithelial cells (HAMECs). The effect of HAMECs on USD is unknown. To study the effect of HAMECs-CM on human urethral stricture fibroblast (USF) cells by using in-vitro migration assay and molecular techniques. USF cells were derived from six patients undergoing urethroplasty. HAMECs were derived from one placenta after delivery. The effect of HAMECs-CM on USF cell migration was observed using a standard in vitro scratch assay over a period of 3 days. The effect of HAMECs-CM on the expression levels of markers alpha-smooth muscle actin (α-SMA) and tissue inhibitor of metalloproteinases (TIMP-1) in USF cells was also examined. The HAMECs-CM suppressed the migration of USF cells in in vitro scratch assay. The HAMECs-CM consistently downregulated α-SMA, but not TIMP-1. HAMECs have shown antifibrotic activity on USF cells in this in vitro study. HAMECs could serve as an alternative cell source for tissue-engineered urethroplasty.


Kdm6a deficiency restricted to mouse hematopoietic cells causes an age- and sex-dependent myelodysplastic syndrome-like phenotype.
Kdm6a/Utx, a gene on the X chromosome, encodes a histone H3K27me3 demethylase that has an orthologue on the Y chromosome (Uty) (Zheng et al. 2018). We previously identified inactivating mutations of Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2-15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis.


Self-adjuvanting lipopeptide vaccines.
Despite the important role of adjuvants for vaccine development, relatively few adjuvants have been successfully incorporated into vaccines intended for human administration. This is in part due to the high toxicity associated with many experimental adjuvants. This lack of choice effectively hinders the ability to produce vaccines against many diseases, or to improve current vaccine formulations. The conjugation of immunostimulatory lipids to peptide antigens, to produce self-adjuvanting lipopeptide vaccines, has been tested in human clinical trials. These systems appear to have a number of advantages over more traditional adjuvants (e.g. alum salts) including the capacity for these vaccines to be administered via mucosal routes (e.g. orally or nasally) instead of by injection, elicitation of antigen-specific cytotoxic T-lymphocytes and mucosal immunity, as well as little-to-no observed toxicity. Several lipopeptide vaccine systems have been described in the literature, ranging from the conjugation of single fatty acid chains, to the conjugation of more complex lipids and glycolipids onto peptide antigens. The following review provides an overview of the most studied lipopeptide vaccine systems grouped into the following categories: 1) bacterial lipopeptides, including tri-palmitoyl-S-glyceryl cysteine (Pam3Cys) and di-palmitoyl-S--glyceryl cysteine (Pam2Cys); 2) the lipid-core peptide (LCP) and multiple antigen lipophilic adjuvant carrier (MALAC) systems; 3) single-chain palmitoylated peptides; and 4) glycolipids (e.g. monophosphoryl lipid A). The review also discusses the potential mechanisms of action for lipopeptide and glycolipopeptide vaccines, as well as structure activity relationships, and provides examples of studies utilising each system.


Provider time and costs to vaccinate adult patients: Impact of time counseling without vaccination.
Amid provider reports of financial barriers as an impediment to adult immunization, this study explores the time and costs of vaccination in adult provider practices. Both a Vaccination Time-Motion Study and Vaccine Practice Management Survey were conducted (March - October 2017) in a convenience sample of 19 family medicine (FM), internal medicine (IM), and obstetrician-gynecology (OBGYN) practices, in nine states. Practices were directly observed during a one week period; estimates were collected of time spent on activities that could not be directly observed. Cost estimates were calculated by converting staff time for performed activities. In the time-motion study, FM and IM practices spent similar time conducting vaccination activities (median = 5 min per vaccination), while OBGYN practices spent more time (median = 29 min per vaccination). Combining results from the time-motion study and the practice management survey, the median costs of vaccination remained similar for FM practices and IM practices at $7 and $8 per vaccination, respectively, but was substantially higher for OBGYN practices at $43 per vaccination. Factors that contributed to higher costs among OBGYN practices were the increased time to counsel patients, administer vaccines, and to plan and manage vaccine supplies. In addition, 68% of OBGYN patients who were offered and counseled to receive vaccines declined to receive them. Counseling patients who ultimately do not go on to receive a vaccine may be an important cost factor. Lower costs of vaccination services may be achieved by increasing efficiencies in workflow or the volume of vaccinations.


Screening for Down syndrome pregnancy using beta-core fragment: prospective study.
Two recent publications by Cuckle et al., and one each by Canick et al. and Kellner et al., describe the use of urine beta-core fragment measurements as a screening test for Down syndrome pregnancies. Median levels of over 5.4 MOM were reported for cases of Down syndrome, with an over 72 per cent detection rate for a 5 per cent false-positive rate. Urine beta-core fragment was suggested as a superior screening test for Down syndrome pregnancies. These four studies were retrospectives, with samples from affected cases collected at different sites from those from normal cases. In the present study, prospective data were collected for 726 pregnancies over a 9-month period at a single medical centre. Fresh samples were assayed continuously, without knowledge of the karyotype. Urinary beta-core fragment levels in 709 unaffected samples continually declined from 12 to 24 weeks of pregnancy. A logarithmic fit was optimal for the median curve. The log standard deviation of unaffected samples was 0.368. All 13 Down syndrome cases had levels exceeding 1.0 MOM, with a median value of 4.1 MOM. Eight of 13 Down syndrome cases (62 per cent) had levels exceeding the 95th centile. Results have not been adjusted for maternal age, which may improve the detection rate. The results reported here, while less impressive than those reported previously, confirm the usefulness of urine beta-core fragment as a screening test for Down syndrome. Because of the prospective nature of this study, the 62 per cent sensitivity suggested here might be more representative of the true performance of urinary beta-core fragment in clinical practice than the higher rates observed in previous studies. Results for this single urine test are similar to those for triple screen and other serum combination tests. Single analyte urine beta-core fragment tests, or beta-core fragment combination protocols, may eventually replace serum analytes in screening for Down syndrome pregnancies.


Comply with regulations or risk paying hefty fines: ten tips for choosing call recording to help ensure compliance.
Medical practices are paying hundreds of thousands of dollars in fines for not complying with various governmental regulations, including a variety of HIPAA rules and credit card compliance. One solution to help reduce this risk and avoid fines is to use call recording to help ensure compliance. This article provides readers with key considerations for choosing and implementing a call recording solution for their medical practices to ensure that it will be compliant with key regulations. These tips include being able to customize call recording policies and procedures for their unique needs; providing secure, private storage; allowing easy access for authorized users; secure sharing of call recordings; regulatory compliance training; disaster recovery; and maintaining an audit-ready and compliant-evident state at all times.


Pre-colonial culture, post-colonial economic success? The Tswana and the African economic miracle.
Cultural explanations of economic phenomena have recently enjoyed a renaissance among economists. This article provides further evidence for the salience of culture through an in-depth case study of one of the fastest-growing economies in the world during the last 50 years-Botswana. The unique culture that developed among the Tswana before and during the early days of colonialism, which shared many features with those of western nation-states, appears to have contributed significantly to the factors widely seen as determinants of Botswana's post-colonial economic success: state legitimacy, good governance and democracy, commercial traditions, well-established property rights, and inter-ethnic unity. Neighbouring Southern African cultures typically did not exhibit these traits.


Prevalence and pattern of the elongated styloid process among geriatric patients in Saudi Arabia.
The objectives of this study were to assess the elongation of the styloid process on digital panoramic radiographs and to evaluate the prevalence of the elongation according to age, sex and types. Digital panoramic radiographs of 198 geriatric edentulous patients were analyzed. The radiographic length of the styloid process was measured on both sides using the measurement toolbars on the accompanying analysis software. For statistical analysis, Student's t-test, chi-square test and analysis of variance test were used. The elongated styloid process was seen in 87 of the 198 patients. It was observed that as age increased, elongation of the styloid process increased with a male predominance. Type I elongation was more common than other types of elongation. Bilateral elongation was most commonly found than unilateral elongation, and both types of elongation were frequently seen in males compared with females. The prevalence of the elongated styloid process in the present study was higher in comparison to the other reports from edentulous patients.


Label-free detection of hypoxia-induced extracellular vesicle secretion from MCF-7 cells.
Nanoscale extracellular vesicles (EVs) including exosomes (50-150 nm membrane particles) have emerged as promising cancer biomarkers due to the carried genetic information about the parental cells. However the sensitive detection of these vesicles remains a challenge. Here we present a label-free electrochemical sensor to measure the EVs secretion levels of hypoxic and normoxic MCF-7 cells. The sensor design includes two consecutive steps; i) Au electrode surface functionalization for anti-CD81 Antibody and ii) EVs capture. The label-free detection of EVs was done via Differential Pulse Voltammetry (DPV) and Electrochemical Impedance Spectroscopy (EIS). The working linear range for the sensor was 102-109 EVs/ml with an LOD 77 EVs/mL and 379 EVs/ml for EIS and DPV based detection. A blood-abundant protein, RhD was used for the selectivity test. In order to assess the performance of the biosensor, the level of EVs secretion by the human breast cancer MCF-7 cell line was compared with enzyme-linked immunosorbent assays (ELISA) and Nanoparticle Tracking Analysis (NTA). Designed label-free electrochemical sensors utilized for quantification of EVs secretion enhancement due to CoCl2-induced hypoxia and 1.23 fold increase with respect to normoxic conditions was found.


Resting electrical network activity in traps of the aquatic carnivorous plants of the genera Aldrovanda and Utricularia.
In this study the MEA (multielectrode array) system was used to record electrical responses of intact and halved traps, and other trap-free tissues of two aquatic carnivorous plants, Aldrovanda vesiculosa and Utricularia reflexa. They exhibit rapid trap movements and their traps contain numerous glands. Spontaneous generation of spikes with quite uniform shape, propagating across the recording area, has been observed for all types of sample. In the analysis of the electrical network, higher richer synchronous activity was observed relative to other plant species and organs previously described in the literature: indeed, the time intervals between the synchronized clusters (the inter-spike intervals) create organized patterns and the propagation times vary non-linearly with the distance due to this synchronization. Interestingly, more complex electrical activity was found in traps than in trap-free organs, supporting the hypothesis that the nature of the electrical activity may reflect the anatomical and functional complexity of different organs. Finally, the electrical activity of functionally different traps of Aldrovanda (snapping traps) and Utricularia (suction traps) was compared and some differences in the features of signal propagation were found. According to these results, a possible use of the MEA system for the study of different trap closure mechanisms is proposed.


Energy transfer as parametric excitation: an examination of nonlinearity in enzymatic reaction, nerve conduction, muscle contraction, electron tunneling, and electron transfer.
Chemical parametric excitation is presented as the fundamental mechanism of energy transfer. Together with the Franck-Condon principle, it provides a mechanically sound explanation for enzymatic reaction, nerve excitation, muscle contraction, and electron transfer at a basic level. Intermediate between macroscopic models of membrane asymmetry and molecular models, the new model rests on a systematic approach, proposed here, to organizational aspects of the energy transfer processes. In support, a derivation is given of the chemical analog of the Manley-Rowe power conservation relations for parametrically excited electrical networks. This extension to chemical systems indicates for the first time an explanation of power flow directionality and delegates a pumping role to the enzyme. The generalized Manley-Rowe relations are suggested to be a universal law of nature. In such case, nonlinearity could be attributable to the coupling of three systems by these generalized Manley-Rowe conditions relating flows/reactions/oscillations--even though separately each system might be described by linear (Onsager) relations.


Flavoprotein hydroxylase PgaE catalyzes two consecutive oxygen-dependent tailoring reactions in angucycline biosynthesis.
A simplified model system composed of a NADPH-dependent flavoprotein hydroxylase PgaE and a short-chain alcohol dehydrogenase/reductase (SDR) CabV was used to dissect a multistep angucycline modification redox cascade into several subreactions in vitro. We demonstrate that the two enzymes are sufficient for the conversion of angucycline substrate 2,3-dehydro-UWM6 to gaudimycin C. The flavoenzyme PgaE is shown to be responsible for two consecutive NADPH- and O(2)-dependent reactions, consistent with the enzyme-catalyzed incorporation of oxygen atoms at C-12 and C-12b in gaudimycin C. The two reactions do not significantly overlap, and the second catalytic cycle is initiated only after the original substrate 2,3-dehydro-UWM6 is nearly depleted. This allowed us to isolate the product of the first reaction at limiting NADPH concentrations and allowed the study of the qualitative and kinetic properties of the separated reactions. Dissection of the reaction cascade also allowed us to establish that the SDR reductase CabV catalyzes the final biosynthetic step, which is closely coupled to the second PgaE reaction. In the absence of CabV, the complete PgaE reaction leads invariably to product degradation, whereas in its presence, the reaction yields the final product, gaudimycin C. The result implies that the C-6 ketoreduction step catalyzed by CabV is required for stabilization of a reactive intermediate. The close relationship between PgaE and CabV would explain previous in vivo observations: why the absence of a reductase gene may result in the lack of C-12b-oxygenated species and, vice versa, why all C-12b-oxygenated angucyclines appear to have undergone reduction at position C-6.


Expression profiles of long noncoding RNAs in lung adenocarcinoma.
This study aimed to analyze expression profiles of long noncoding RNAs (lncRNAs) in lung adenocarcinoma. lncRNA microarray technology was employed to detect lncRNA profiles of 3 pairs of lung adenocarcinoma tissues and adjacent tissues. We found 134 upregulated lncRNAs and 460 downregulated lncRNAs in lung adenocarcinoma tissues compared to adjacent tissues. Among them, LINC00152, LINC00691, and LINC00578 showed the most significant changes of upregulation, while LINC00668, LINC00710, and LINC00607 showed the most significant changes of downregulation. Fluorescent quantitative polymerase chain reaction (PCR) analysis of tissue samples from an additional 90 patients with lung adenocarcinoma showed significantly increased levels of LINC00152, LINC00691, and LINC00578 and decreased levels of LINC00668, LINC00710, and LINC00607 in lung adenocarcinoma tissues. In addition, LINC00578 was closely associated with the existence of metastasis of lung adenocarcinoma, but the other 5 lncRNAs showed no significant correlation with clinicopathologic characteristics such as age, gender, tumor stage, and the existence of metastasis. Further follow-up study showed that LINC00578 expression was closely associated with the survival of patients with lung adenocarcinoma. We revealed the expression profiles of lncRNAs in lung adenocarcinoma and identified LINC00578 as a promising biomarker and therapeutic target for lung adenocarcinoma.


Genetic characterization of highly fluoroquinolone-resistant clinical Escherichia coli strains from China: role of acrR mutations.
The genetic basis for fluoroquinolone resistance was examined in 30 high-level fluoroquinolone-resistant Escherichia coli clinical isolates from Beijing, China. Each strain also demonstrated resistance to a variety of other antibiotics. PCR sequence analysis of the quinolone resistance-determining region of the topoisomerase genes (gyrA/B, parC) revealed three to five mutations known to be associated with fluoroquinolone resistance. Western blot analysis failed to demonstrate overexpression of MarA, and Northern blot analysis did not detect overexpression of soxS RNA in any of the clinical strains. The AcrA protein of the AcrAB multidrug efflux pump was overexpressed in 19 of 30 strains of E. coli tested, and all 19 strains were tolerant to organic solvents. PCR amplification of the complete acrR (regulator/repressor) gene of eight isolates revealed amino acid changes in four isolates, a 9-bp deletion in another, and a 22-bp duplication in a sixth strain. Complementation with a plasmid-borne wild-type acrR gene reduced the level of AcrA in the mutants and partially restored antibiotic susceptibility 1.5- to 6-fold. This study shows that mutations in acrR are an additional genetic basis for fluoroquinolone resistance.


Effects of the serotonin transporter (5-HTTLPR) and α2A-adrenoceptor (C-1291G) genotypes on substance use in children and adolescents: a longitudinal study.
Twin studies suggest that substance use initiation in children and adolescents is determined primarily by environmental influences, whereas the establishment of use patterns is strongly controlled by genetic factors. The present study analysed the effects of the serotonin transporter promoter polymorphism [5-HT transporter gene-linked polymorphic region (5-HTTLPR)] and the α(2A)-adrenoceptor C-1291G genotype (ADRA2A C-1291G) as well as their interaction effects on alcohol, tobacco and drug use from preadolescence to the late adolescence. Initial sample of 9-year-old children of Estonian Children Personality Behaviour and Health Study (n = 583) was recalled at ages 15 and 18. Participants reported in all waves how frequently they smoked and used alcohol and illicit drugs. 5-HTTLPR had age-dependent effects on alcohol, tobacco and drug use: substance use did not differ by genotype at age 9, but at age 15, the participants with the short (s)/s genotype had higher tobacco use, and at age 18, they were more active alcohol, drug and tobacco users. Effects of ADRA2A C-1291G on drug use were dependent on gender, age and 5-HTTLPR. Males (age 18) with ADRA2A CG genotype, when compared to other participants, tended to have higher drug use especially when they had s/s genotype of 5-HTTLPR. Our results reveal that expression of genetic vulnerability for substance use in children and adolescents may depend on age, gender, interaction of genes, and type of substance.


Rational design of new agrochemical fungicides using substructural descriptors.
The increasing resistance of several phytopathogenic fungal species to existing agrochemical fungicides has alarmed the worldwide scientific community. In an attempt to overcome this problem, a discriminant model based on substructural descriptors was developed from a heterogeneous database of compounds for the design of, search for and prediction of agrochemical fungicides. The discriminant model classifies correctly 81.95% of the fungicides and 81.54% of the inactive compounds in the training series, with an accuracy of 81.72%. In the prediction series, the percentage of correct classification was 80.59 and 85.56% for fungicides and inactive compounds respectively, with an accuracy of 83.44%. Some fragments were extracted and their contributions were calculated. From the fragments that were determined to make positive contributions to the fungicidal activity, new molecules such as pyrrole derivatives were designed and the probabilities of their being fungicides were calculated. These molecules were correctly classified as potential fungicides. The discriminant model based on substructural descriptors provides a promising methodology for the development of molecular patterns to be used in the design of, search for and prediction of agrochemical fungicides of wide spectrum. This constitutes an alternative for the discovery of compounds that are able to decrease crop losses caused by phytopathogenic fungal species.


Phimosis. Preputial plasty using transversal widening on the dorsal side with EMLA local anesthetic cream.
In the United States, the treatment of choice for the correction of phimosis is circumcision, whereas in European countries, the condition is usually treated by preputial plasty using Duhamel's method or modified versions. We report our experience in correcting phimosis by preputial plasty using transversal widening on the dorsal side with EMLA local anesthetic cream. Twenty-six patients with phimosis were operated on by preputial plasty, under local anesthesia with EMLA cream. A transversal incision is made on the dorsal side of the ring of prepuce, like 3 contiguous Ts, the middle one inverted with the long arm on the preputial mucosa side. The 2 small mucocutaneous flaps of the prepuce are separated and then sutured with interrupted stitches, thus transforming the incisions from T to V. No postoperative complications were observed. At 1-year follow-up, the cosmetic and functional results were satisfactory. The technique of preputial plasty that the authors present enlarges the stenotic ring of prepuce by a transversal widening on the dorsal side. The ring of prepuce obtained is wide and symmetrical on its dorsal and ventral sides and therefore cosmetically and functionally satisfactory. It is a good alternative to the more radical circumcision technique.


Chronic treatment in vivo with dimethylthiourea, a hydroxyl radical scavenger, prevents diabetes-induced endothelial dysfunction.
Oxidative stress is believed to play a role in diabetes-induced vascular complications. In this study, we tested whether chronic treatment with a known hydroxyl radical scavenger, dimethylthiourea (DMTU), could prevent endothelial dysfunction in diabetes. Lewis strain rats were made diabetic by an intravenous injection of streptozotocin. A subgroup of diabetic animals received daily intraperitoneal injections of 50 mg/kg DMTU beginning at 72 h after streptozotocin and throughout 8 weeks of diabetes. Diabetes caused an increase in aortic catalase activity (an index of compensatory in vivo oxidative stress) that was not prevented by long-term DMTU treatment. Long-term treatment of diabetic animals with DMTU did not alter serum insulin levels, blood glucose concentrations, or total glycosylated hemoglobin. Descending thoracic aortas were isolated, sectioned into rings and suspended in isolated tissue baths, and contracted with a submaximal concentration of norepinephrine. Relaxation to the endothelium-dependent vasodilator, acetylcholine, was impaired in diabetic aortas, whereas relaxation to A23187 and nitroglycerin was unaltered. DMTU treatment prevented the diabetes-induced impairment in endothelium-dependent relaxation to acetylcholine but had no effect on relaxations induced by either A23187 or nitroglycerin. These data suggest that chronic exposure to increased levels of hydroxyl radicals in vivo likely play a significant role in the origin of diabetes-associated endothelial dysfunction.


Age differences in affective and cardiovascular responses to a negative social interaction: the role of goals, appraisals, and emotion regulation.
Older adults often report less affective reactivity to interpersonal tensions than younger individuals, but few studies have directly investigated mechanisms explaining this effect. The current study examined whether older adults' differential endorsement of goals, appraisals, and emotion regulation strategies (i.e., conflict avoidance/de-escalation, self-distraction) during a controlled negative social interaction may explain age differences in affective and cardiovascular responses to the conflict discussion. Participants (N = 159; 80 younger adults, 79 older adults) discussed hypothetical dilemmas with disagreeable confederates. Throughout the laboratory session, participants' subjective emotional experience, blood pressure, and pulse rate were assessed. Older adults generally exhibited less reactivity (negative affect reactivity, diastolic blood pressure reactivity, and pulse rate reactivity) to the task and more pronounced positive and negative affect recovery following the task than did younger adults. Older adults appraised the task as more enjoyable and the confederate as more likeable and more strongly endorsed goals to perform well on the task, which mediated age differences in negative affect reactivity, pulse rate reactivity, and positive affect recovery (i.e., increases in posttask positive affect), respectively. In addition, younger adults showed increased negative affect reactivity with greater use of self-distraction, whereas older adults did not. Together, findings suggest that older adults respond less negatively to unpleasant social interactions than younger adults, and these responses are explained in part by older adults' pursuit of different motivational goals, less threatening appraisals of the social interaction, and more effective use of self-distraction, compared with younger adults.