Clinical Approach of High Technology Techniques for Control and Elimination of Endodontic Microbiota.
The main goal in endodontic treatment is to eradicate or at least reduce intraradicular microbial population to levels that are more compatible with periapical lesions healing process. Since endodontic infections are polymicrobial in nature, intraradicular survival of endodontic microbiota and their pathogenic properties are influenced by a combination of their virulence factors. The purpose of this article is to review the endodontic microbiota and their respective virulence attributes, as well as perform a literature review of the effects of disinfection procedures in the treatment of endodontic infections to gain best practices. Conventional technique for root canal preparation includes mechanical debridement and application of antimicrobial irrigants. Recently, laser irradiation has been used to enhance the results of root canal treatment through its thermal effect. To reduce thermal side effects, laser activated irrigation (LAI) and photon induced photoacoustic streaming (PIPS) were introduced. Antimicrobial photodynamic therapy (aPDT) by photochemical reaction uses light at a specific wavelength to activate a nontoxic photosensitizer (PS) in the presence of oxygen to produce cytotoxic products. Different PSs are used in dentistry including methylene blue (MB), toluidine blue O (TBO), indocyanine green (ICG) and curcumin. Among different options, ICG could be the best choice due to its peak absorption at wavelength of 808 nm, which coincides with the commercial diode laser devices. Also, this wavelength has more penetration depth compared to other wavelengths used in aPDT.


Complete nontuberculous mycobacteria whole genomes using an optimized DNA extraction protocol for long-read sequencing.
Nontuberculous mycobacteria (NTM) are a major cause of pulmonary and systemic disease in at-risk populations. Gaps in knowledge about transmission patterns, evolution, and pathogenicity during infection have prompted a recent surge in genomic NTM research. Increased availability and affordability of whole genome sequencing (WGS) techniques provide new opportunities to sequence and construct complete bacterial genomes faster and at a lower cost. However, extracting large quantities of pure genomic DNA is particularly challenging with NTM due to its slow growth and recalcitrant cell wall. Here we report a DNA extraction protocol that is optimized for long-read WGS of NTM, yielding large quantities of highly pure DNA with no additional clean-up steps. Our DNA extraction method was compared to 6 other methods with variations in timing of mechanical disruption and enzymatic digestion of the cell wall, quantity of matrix material, and reagents used in extraction and precipitation. We tested our optimized method on 38 clinical isolates from the M. avium and M. abscessus complexes, which yielded optimal quality and quantity measurements for Oxford Nanopore Technologies sequencing. We also present the efficient completion of circularized M. avium subspecies hominissuis genomes using our extraction technique and the long-read sequencing MinION platform, including the identification of a novel plasmid. Our optimized extraction protocol and assembly pipeline was both sufficient and efficient for genome closure. We expect that our finely-tuned extraction method will prove to be a valuable tool in long-read sequencing and completion of mycobacterial genomes going forward. Utilization of comprehensive, long-read based approaches will advance the understanding evolution and pathogenicity of NTM infections.


Interfacial behavior of N-nitrosodiethylamine/bovine serum albumin complexes at the air-water and the chloroform-water interfaces by axisymmetric drop tensiometry.
Interfacial properties of N-nitrosodiethylamine/bovine serum albumin (NDA/BSA) complexes were investigated at the air-water interface. The interfacial behavior at the chloroform-water interface of the interaction product of phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), dissolved in the chloroform phase, and NDA/BSA complex, in the aqueous phase, were also analyzed by using a drop tensiometer. The secondary structure changes of BSA with different NDA concentrations were monitored by circular dichroism spectroscopy at different pH and the NDA/BSA interaction was probed by fluorescence spectroscopy. Different NDA/BSA mixtures were prepared from 0, 7.5 x 10(-5), 2.2 x 10(-4), 3.7 x 10(-4), 5 x 10(-4), 1.6 x 10(-3), and 3.1 x 10(-3) M NDA solutions in order to afford 0, 300/1, 900/1, 1 500/1, 2 000/1, 6 000/1, and 12 500/1 NDA/BSA molar ratios, respectively, in the aqueous solutions. Increments of BSA alpha-helix contents were obtained up to the 2 000/1 NDA/BSA molar ratio, but at ratios beyond this value, the alpha-helix content practically disappeared. These BSA structure changes produced an increment of the surface pressure at the air-water interface, as the alpha-helix content increased with the concentration of NDA. On the contrary, when alpha-helix content decreased, the surface pressure also appeared lower than the one obtained with pure BSA solutions. The interaction of DPPC with NDA/BSA molecules at the chloroform-water interface produced also a small, but measurable, pressure increment with the addition of NDA molecules. Dynamic light scattering measurements of the molecular sizes of NDA/BSA complex at pH 4.6, 7.1, and 8.4 indicated that the size of extended BSA molecules at pH 4.6 increased in a greater proportion with the increment in NDA concentration than at the other studied pH values. Diffusion coefficients calculated from dynamic surface tension values, using a short-term solution of the general adsorption model of Ward and Tordai, also showed differences with pH and the NDA concentration. Both, the storage and loss dilatational elastic modulus were obtained at the air-water and at the chloroform-water interfaces. The interaction of NDA/BSA with DPPC at the chloroform-water produced a less rigid monolayer than the one obtained with pure DPPC (1 x 10(-5) M), indicating a significant penetration of NDA/BSA molecules at the interface. At short times and pH 4.6, the values of the storage elastic modulus were larger and more sensible to the NDA addition than the ones at pH 7.1 and 8.4, probably due to a gel-like network formation at the air-water interface.


National study for multidisciplinary outpatient oncological rehabilitation: online survey to support revised quality and performance criteria.
More and more people survive cancer, but the disease and its treatment often lead to impairment. Multidisciplinary ambulatory oncological rehabilitation (OR) programs have thus been developed. SW!SS REHA, the organization of major Swiss rehabilitation clinics, has defined ambulatory OR quality criteria for its members (about 50% of the Swiss rehabilitation capacity). However, SW!SS REHA criteria are not fully implemented and/or interpreted differently by different specialties or in different linguistic regions in Switzerland. The aim of our study was to carry out an online survey of existing outpatient programs to define quality criteria for an ideal OR program in Switzerland. A mixed methods approach was used for the survey-qualitative and quantitative. The qualitative part consisted of a guided discussion with OR experts and the quantitative part of an online survey. The quantitative part comprised the development and evaluation of an online questionnaire. It served to record the opinions of OR centers in Switzerland on the desired situation of outpatient rehabilitation. Eighteen OR centers and 71 (49.7% response rate) OR actors participated in the online survey. The survey results indicate that some of the SW!SS REHA quality and performance criteria only partially match with the desired OR criteria for Switzerland. Key disparities occur particularly in the program design and structure and specifically around how many interventions are required to constitute an OR program, the extent of standardization versus individualization of the program, i.e., how many and which modules in a program should be obligatory, and finally the duration and intensity of the program. The online survey did not generate any statistical evidence that OR requirements vary significantly between different linguistic regions and among different specialties. Cancer patients are heterogeneous with respect to cancer type, prognosis, and disability level, such that a standard program cannot be uniformly applied. Therefore, a flexible program is required with few mandatory modules and additional individual modules to achieve the threshold number of modules that would constitute a multidisciplinary OR program. Intensity and frequency of OR needs to consider the health state of the participants. The results indicate a need to modify some of the existing SW!SS REHA criteria to ensure that more patients can gain access and benefit form evidence-based OR interventions. Furthermore, the survey provides important findings so that the existing OR offer can be improved with the goal that OR centers will be able to be quality certified in the future.


Continence care with high QOL(quality of life) for the aged.
At the time to select methods for continence care, doctors should consider not only scien- tific factors but also quality of life. Functions of lower urinary tract are storage and voiding. Urine is waste of human body, so it is essential to void urine perfectly in a view point of to keep homeostasis. All patients who have been using a indwelling urethral catheter for more than a few days have complicated urinary tract infection. A trick of increasing good points of urethral catheter is a use in a limited period. If patients who have lost voiding function can perform clean intermittent self-catheterization, they will be able to enjoy continence without infection.


MicroRNA expression in relation to different dietary habits: a comparison in stool and plasma samples.
MicroRNAs (miRNAs), a class of small non-coding RNAs, are fundamental for the post-transcriptional regulation of gene expression. Altered expression of miRNAs has been detected in cancers, not only in primary tissue but also in easily obtainable specimens like plasma and stools. miRNA expression is known to be modulated by diet (micro and macronutrients, phytochemicals) and possibly by other lifestyle factors; however, such influence has not yet been exhaustively explored in humans. In the present study, we analysed the expression levels of a panel of seven human miRNAs in plasma and stool samples of a group of 24 healthy individuals characterised by different dietary habits (eight vegans, eight vegetarians and eight subjects with omnivorous diet, all groups with similar age and sex distribution). The dual aim of the study was to identify possible differences in miRNA expression due to diet (or other lifestyle factors recorded from questionnaires) and to compare results in both types of specimens. miR-92a was differentially expressed in both plasma and stool samples and with the same trend, among the three groups with different diets (P = 0.0002 and P = 0.02, respectively, with expression levels of vegans>vegetarians>omnivores). miR-92a was also associated with low body mass index (P = 0.04 and P = 0.05, respectively) in both types of specimens, and with several dietary factors. Other analysed miRNAs (miR-16, miR-21, mir-34a and miR-222) were associated with dietary and lifestyle factors, but not consistently in both stool and plasma. Our pilot study provides the first evidence of miRNA modulation by diet and other factors, that can be detected consistently in both plasma and stools samples.


Visual stimulation by extensive visual media consumption can be beneficial for motor learning.
In this randomized controlled intervention trial, we investigated whether intense visual stimulation through television watching can enhance visual information processing and motor learning performance. 74 healthy young adults were trained in a motor skill with visual information processing demands while being accommodated in a controlled environment for five days. The experimental manipulation (n = 37) consisted of prolonged television watching (i.e., 8 h/day, + 62.5% on average) to induce intense exposure to visual stimulation. The control group (n = 37) did not consume visual media. The groups were compared by motor learning performance throughout the study as well as pre/post visual attention parameters and resting-state network connectivity in functional MRI. We found that the intervention group performed significantly better in the motor learning task (+ 8.21% (95%-CI[12.04, 4.31], t(70) = 4.23, p < 0.001) while showing an increased capacity of visual short-term memory (+ 0.254, t(58) = - 3.19, p = 0.002) and increased connectivity between visual and motor-learning associated resting-state networks. Our findings suggest that the human brain might enter a state of accentuated visuomotor integration to support the implementation of motor learning with visual information processing demands if challenged by ample input of visual stimulation. Further investigation is needed to evaluate the persistence of this effect regarding participants exposed to accustomed amounts of visual media consumption.Clinical Trials Registration: This trial was registered in the German Clinical Trials Register/Deutsches Register klinischer Studien (DRKS): DRKS00019955.


New chemical agents based on adamantane-monoterpene conjugates against orthopoxvirus infections.
Currently, the spectrum of agents against orthopoxviruses, in particular smallpox, is very narrow. Despite the fact that smallpox is well controlled, there is, for many reasons, a real threat of epidemics associated with this or a similar virus. In order to search for new low molecular weight orthopoxvirus inhibitors, a series of amides combining adamantane and monoterpene moieties were synthesized using 1- and 2-adamantanecarboxylic acids as well as myrtenic, citronellic and camphorsulfonic acids as acid components. The produced compounds exhibited high activity against the vaccinia virus (an enveloped virus belonging to the poxvirus family), which was combined with low cytotoxicity. Some compounds had a selectivity index higher than that of the reference drug cidofovir; the highest SI = 1123 was exhibited by 1-adamantanecarboxylic acid amide containing the (-)-10-amino-2-pinene moiety. The produced compounds demonstrated inhibitory activity against other orthopoxviruses: cowpox virus (SI = 30-406) and ectromelia virus (mousepox virus, SI = 39-707).


Leukotrienes and atherosclerosis.
Evidence from experimental and genetic studies suggest the existence of a potential link between the leukotrienes (LT) signalling cascade, and the pathogenesis/progression of atherosclerosis and its serious consequences such as acute myocardial infarction (AMI), stroke, aortic aneurysms, and intimal hyperplasia. LT biosynthetic enzymes are expressed within atherosclerotic lesion, leading to production of cysteinyl-leukotrienes (Cys-LTs) and LTB4 that exert potent pro-inflammatory action through interaction with CysLT and BLT receptor subtypes expressed on inflammatory and structural cells within the vascular wall. Genetic variants in the genes of the 5-LO pathway have been associated with the risk of developing AMI and stroke. As a result, anti-LT have recently received renewed interest for the treatment of atherosclerosis and its ischemic complications. The aim of this short review is to summarize our current understanding of the role of LTs and their receptors in the genesis and progression of atherosclerosis and review the recent developments on the use of antagonists.


Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders.
Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome caused by aberrant telomere biology. The mucocutaneous triad of nail dysplasia, abnormal skin pigmentation and oral leukoplakia is diagnostic, but is not always present; DC can also be diagnosed by the presence of very short leukocyte telomeres. Patients with DC are at high risk of bone marrow failure, pulmonary fibrosis, liver disease, cancer and other medical problems. Germline mutations in one of nine genes associated with telomere maintenance are present in approximately 60% of patients. DC is one among the group of clinically and biologically related telomere biology disorders, including Hoyeraal-Hreidarsson syndrome, Revesz syndrome, Coats plus (also known as cranioretinal microangiopathy with calcifications and cysts) and subsets of aplastic anemia, pulmonary fibrosis, nonalcoholic and noninfectious liver disease and leukemia. The authors review the pathobiology that connects DC and the related telomere biology disorders, methods of diagnosis and management modalities.


How Self-tracking and the Quantified Self Promote Health and Well-being: Systematic Review.
Self-tracking technologies are widely used in people's daily lives and health care. Academic research on self-tracking and the quantified self has also accumulated rapidly in recent years. Surprisingly, there is a paucity of research that reviews, classifies, and synthesizes the state of the art with respect to self-tracking and the quantified self. Our objective was to identify the state of the art of self-tracking and the quantified self in terms of health and well-being. We have undertaken a systematic literature review on self-tracking and the quantified self in promoting health and well-being. After a rigorous literature search, followed by inclusions, exclusions, and the application of article quality assessment protocols, 67 empirical studies qualified for the review. Our results demonstrate that prior research has focused on 3 stakeholders with respect to self-tracking and the quantified self, namely end users, patients and people with illnesses, and health care professionals and caregivers. We used these stakeholder groups to cluster the research themes of the reviewed studies. We identified 11 research themes. There are 6 themes under the end-user cluster: user motivation and goal setting, usage and effects of self-tracking, continuance intention and long-term usage, management of personal data, rejection and discontinuance, and user characteristics. The patient and people with illnesses cluster contains three themes: usage experience of patients and people with illnesses, management of patient-generated data, and advantages and disadvantages in the clinical context. The health care professional and caregiver cluster contains two themes: collaboration among patients, health care professionals, and caregivers, and changes in the roles of patients and professionals. Moreover, we classified the future research suggestions given in the literature into 5 directions in terms of research designs and research topics. Finally, based on our reflections on the observations from the review, we suggest four future research directions: (1) users' cognitions and emotions related to processing and interpreting the information produced by tracking devices and apps; (2) the dark side of self-tracking (eg, its adverse psychosocial consequences); (3) self-tracking as a societal phenomenon; and (4) systemic impacts of self-tracking on health care and the actors involved. This systematic literature review contributes to research and practice by assisting future research activities and providing practitioners with a concise overview of the state of the art of self-tracking and the quantified self.


Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.
TRPV4 ion channels function in epidermal keratinocytes and in innervating sensory neurons; however, the contribution of the channel in either cell to neurosensory function remains to be elucidated. We recently reported TRPV4 as a critical component of the keratinocyte machinery that responds to ultraviolet B (UVB) and functions critically to convert the keratinocyte into a pain-generator cell after excess UVB exposure. One key mechanism in keratinocytes was increased expression and secretion of endothelin-1, which is also a known pruritogen. Here we address the question of whether TRPV4 in skin keratinocytes functions in itch, as a particular form of "forefront" signaling in non-neural cells. Our results support this novel concept based on attenuated scratching behavior in response to histaminergic (histamine, compound 48/80, endothelin-1), not non-histaminergic (chloroquine) pruritogens in Trpv4 keratinocyte-specific and inducible knock-out mice. We demonstrate that keratinocytes rely on TRPV4 for calcium influx in response to histaminergic pruritogens. TRPV4 activation in keratinocytes evokes phosphorylation of mitogen-activated protein kinase, ERK, for histaminergic pruritogens. This finding is relevant because we observed robust anti-pruritic effects with topical applications of selective inhibitors for TRPV4 and also for MEK, the kinase upstream of ERK, suggesting that calcium influx via TRPV4 in keratinocytes leads to ERK-phosphorylation, which in turn rapidly converts the keratinocyte into an organismal itch-generator cell. In support of this concept we found that scratching behavior, evoked by direct intradermal activation of TRPV4, was critically dependent on TRPV4 expression in keratinocytes. Thus, TRPV4 functions as a pruriceptor-TRP in skin keratinocytes in histaminergic itch, a novel basic concept with translational-medical relevance.


High-resolution full-field optical coherence tomography with a Linnik microscope.
We describe an original microscope for high-resolution optical coherence tomography applications. Our system is based on a Linnik interference microscope with high-numerical-aperture objectives. Lock-in detection of the interference signal is achieved in parallel on a CCD by use of a photoelastic birefringence modulator and full-field stroboscopic illumination with an infrared LED. Transverse cross-section (en-face, or XY) images can be obtained in real time with better than 1-microm axial (Z) resolution and 0.5-microm transverse (XY) resolution. A sensitivity of approximately 80 dB is reached at a 1-image/s acquisition rate, which allows tomography in scattering media such as biological tissues.


3D nanostar dimers with a sub-10-nm gap for single-/few-molecule surface-enhanced raman scattering.
Plasmonic nanostar-dimers, decoupled from the substrate, have been fabricated by combining electron-beam lithography and reactive-ion etching techniques. The 3D architecture, the sharp tips of the nanostars and the sub-10 nm gap size promote the formation of giant electric-field in highly localized hot-spots. The single/few molecule detection capability of the 3D nanostar-dimers has been demonstrated by Surface-Enhanced Raman Scattering.


B lymphocytes participate in cross-presentation of antigen following gene gun vaccination.
Although endocytosed proteins are commonly presented via the class II MHC pathway to stimulate CD4(+) T cells, professional APCs can also cross-present Ags, whereby these exogenous peptides can be complexed with class I MHC for cross-priming of CD8(+) T cells. Whereas the ability of dendritic cells (DCs) to cross-present Ags is well documented, it is not known whether other APCs may also play a role, or what is the relative contribution of cross-priming to the induction of acquired immunity after DNA immunization. In this study, we compared immune responses generated after gene gun vaccination of mice with DNA vaccine plasmids driven by the conventional CMV promoter, the DC-specific CD11c promoter, or the keratinocyte-specific K14 promoter. The CD11c promoter achieved equivalent expression in CD11c(+) DCs in draining lymph nodes over time, as did a conventional CMV-driven plasmid. However, immunization with DC-restricted DNA vaccines failed to generate protective humoral or cellular immunity to model Ags influenza hemagglutinin and OVA, despite the ability of CD11c(+) cells isolated from lymph nodes to stimulate proliferation of Ag-specific T cells directly ex vivo. In contrast, keratinocyte-restricted vaccines elicited comparable T and B cell activity as conventional CMV promoter-driven vaccines, indicating that cross-priming plays a major role in the generation of immune responses after gene gun immunization. Furthermore, parallel studies in B cell-deficient mu-MT mice demonstrated that B lymphocytes, in addition to DCs, mediate cross-priming of Ag-specific T cells. Collectively, these data indicate that broad expression of the immunogen is required for optimal induction of protective acquired immunity.


Brain-derived neurotrophic factor (BDNF) downregulates mRNA levels of suppressor of cancer cell invasion (SCAI) variants in cortical neurons.
Suppressor of cancer cell invasion (SCAI) acts as a transcriptional repressor of serum response factor (SRF)-mediated gene expression by binding to megakaryoblastic leukemia (MKL)/myocardin-related transcription factor (MRTF), which is an SRF transcriptional coactivator. Growing evidence suggests that SCAI is a negative regulator of neuronal morphology, whereas MKL2/MRTFB is a positive regulator. The mRNA expression of SCAI is downregulated during brain development, suggesting that a reduction in SCAI contributes to the reduced suppression of SRF-mediated gene induction, thus increasing dendritic complexity and developing neuronal circuits. In the present study, we hypothesized that brain-derived neurotrophic factor (BDNF), which is important for neuronal plasticity and development, might alter SCAI mRNA levels. We therefore investigated the effects of BDNF on SCAI mRNA levels in primary cultured cortical neurons. Furthermore, because alternative splicing generates several SCAI variants in the brain, we measured SCAI variant mRNA after BDNF stimulation. Both SCAI variant 1 and total SCAI mRNA expression levels were downregulated by BDNF. Moreover, the extracellular signal-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) pathway was involved in the BDNF-mediated decrease in SCAI mRNA expression. Our findings provide insights into the molecular mechanism underlying a neurotrophic factor switch for the repressive transcriptional complex that includes SCAI.


Nutrition practices and mealtime environments of North Carolina child care centers.
The majority of children in the United States attend out-of-home child care. However, little is known about the nutritional quality of foods served and the mealtime environments. We assessed 96 child care centers over one full day using a researcher-administered structured observation and document review. We focused on eight nutrition domains: (1) fruits and vegetables, (2) whole grains, (3) high-sugar, high-salt, and high-fat foods, (4) beverages, (5) food availability and service, (6) staff behaviors, (7) training and education, and (8) policies. We computed daily means and frequencies for each domain. Seventy-five percent of centers participated in the Child and Adult Care Food Program, indicating they served low-income children. Centers enrolled 66 children on average; 60% were white, 28% were black, 4% were Native American, and 8% identified as mixed race. On the day of observation, seven centers did not serve a fruit and 15 did not serve a vegetable. Eighty centers served a high-sugar or high-salt food and 84 did not serve any whole grains. Five centers did not provide water indoors to children, 22 served juice twice, and 50 served whole milk. Seventeen centers had a vending machine on site visible to parents and children. Overall, children were served excessive juice, high-sugar and high-salt snack foods, and too much whole milk. Centers had room for improvement and could strive to serve more nutritious foods and create healthier mealtime environments for children.


Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide.
Exogenous cholecystokinin selectively antagonizes opiate analgesia, which suggests that endogenous cholecystokinin may act physiologically as an opiate antagonist and may play a role in opiate tolerance. The use of the selective cholecystokinin antagonist proglumide provided a test of these hypotheses in rats that were either inexperienced with or tolerant to opiates. Proglumide potentiated analgesia produced by morphine and endogenous opiates and seemed to reverse tolerance. These results suggest that endogenous cholecystokinin systems oppose the action of opiates.


Prehospital strategies to expedite myocardial salvage.
Recent large-scale clinical investigations have shown the overwhelming importance of early intervention in acute myocardial infarction (AMI), thereby underlining the crucial role of emergency medical technician-paramedics (EMT-Ps) in helping to assess and treat heart attack victims. Some of these studies have included administration of thrombolytic drugs by paramedics. Emergency medical service teams equipped with 12-lead ECGs, diagnostics, checklists, and 2-way communications are becoming the standard in many communities in developed countries and help reduce in-hospital delays in diagnosis. Together with newer diagnostic hardware and software, novel thrombolytics that are rapid and easy to administer will help paramedics overcome current bottlenecks to the expeditious delivery of life-saving care to AMI victims. Public awareness programs as suggested by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines are essential to enlist support for government funding of emergency medical services that can frequently mean the difference between life and death.


Latent profile analysis and principal axis factoring of the DSM-5 dissociative subtype.
A dissociative subtype has been recognized based on the presence of experiences of depersonalization and derealization in relation to DSM-IV posttraumatic stress disorder (PTSD). However, the dissociative subtype has not been assessed in a community sample in relation to the revised DSM-5 PTSD criteria. Moreover, the 20-item PTSD Checklist for DSM-5 (PCL-5) currently does not assess depersonalization and derealization. We therefore evaluated two items for assessing depersonalization and derealization in 557 participants recruited online who endorsed PTSD symptoms of at least moderate severity on the PCL-5. A five-class solution identified two PTSD classes who endorsed dissociative experiences associated with either 1) severe or 2) moderate PTSD symptom severity (D-PTSD classes). Those in the severe dissociative class were particularly likely to endorse histories of childhood physical and sexual abuse. A principal axis factor analysis of the symptom list identified six latent variables: 1) Reexperiencing, 2) Emotional Numbing/Anhedonia, 3) Dissociation, 4) Negative Alterations in Cognition & Mood, 5) Avoidance, and 6) Hyperarousal. The present results further support the presence of a dissociative subtype within the DSM-5 criteria for PTSD.


Studies on somnolence in the daytime caused by drugs used for neuropathic pain.
In the present study, the characteristics of the sleep features of amitriptyline, mexiletine, and N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyradine-1(2H)-carbox-amide (BCTC) were studied. Electrodes were chronically implanted into the frontal cortex and the dorsal neck muscles of rats for electroencephalogram (EEG) and electromyogram (EMG) measurements, respectively. EEG and EMG were recorded with an electroencephalograph, and SleepSign ver. 2.0. was used for sleep-wake state analysis. Recordings were performed from 11:00 to 17:00. Amitriptyline caused significant decreases in sleep latency and total wake time and an increase in total non-rapid eye movement (non-REM) sleep time. Mexiletine caused a significant decrease in sleep latency, but no significant effect was observed in total wake time and total non-REM sleep time. On the other hand, BCTC, which is an antagonist of transient receptor potential vaniloid 1 (TRPV1), showed no significant effect on sleep latency, total wake time, total non-REM sleep time, and total REM sleep time. From these results, it can be concluded that a TRPV1 antagonist may become a useful drug for neuropathic pain without sedative side effects in the daytime, different from amitriptyline and mexiletine.


Optimization of periprosthetic culture for diagnosis of Propionibacterium acnes prosthetic joint infection.
Propionibacterium acnes is increasingly recognized as an important agent of prosthetic joint infection (PJI). However, the optimum culture conditions for recovery of this organism from PJI specimens have not been determined. By applying a prolonged 28-day culture incubation to all periprosthetic specimens received for bacterial culture from 198 revision arthroplasty procedures, we retrospectively determined that a 13-day culture incubation period is necessary for the recovery of P. acnes from patients with PJI. Incubation beyond this period was associated with increasing recovery of nondiagnostic isolates: 21.7% of P. acnes isolates believed to be clinically unimportant were recovered after 13 days of incubation. Importantly, a diagnosis of P. acnes PJI would have been missed in 29.4% of patients had extended culture incubation been applied only to anaerobic culture media. Although specimens from P. acnes PJIs were more commonly associated with the presence of ≥ 2 culture media positive for growth, acute inflammation (≥ 5 neutrophils/high-power field) was observed in only 40% of patients with PJIs that had more than one specimen submitted for bacterial culture. These results support the need for a minimum culture incubation period of 13 days to be applied to both aerobic and anaerobic culture media for all periprosthetic specimens. Optimal recovery of infecting organisms from PJI specimens will be an important component in generating a universal definition for PJI due to indolent agents of infection, such as P. acnes.


Raman spectroscopy in the study of biocompatibility.
This review deals with the application of Raman spectroscopy to the study of the biocompatibility of orthopaedic and ophthalmological materials and includes an introduction, a brief theory on the fundamental concepts of the technique, a description of the method and of the traditional and non-traditional instrumentation and a brief treatment of the surface properties of the different classes of materials. In the orthopaedic field, Raman studies on the structures of glasses, ceramic materials, carbon fibres and polymers before and after implantation are reviewed, particularly as far as structural modifications at the biomaterial-tissues interface are concerned. In the ophthalmological field, the chemical biocompatibility of hydrophobic and hydrophilic polymers for intraocular and intrastromal implants and for soft contact lenses is considered with respect to the presence of monomeric reactive centres in hydrophobic materials and the water amount in hydrophilic ones. The progress of the multichannel Raman technique for 'in-vivo' measurements is also described.


[Effect of preparations melatonin and epitalon on the age-related dynamics of thyrotrophic activity of the hypophysis and thyroid gland function in different light regimes].
The influence of different light regimes (standard lightning--12 hours light/ 12 hours darkness; natural light regime of the North-West of Russia; constant darkness and constant lightning), melatonin and epitalon on the thyrotrophic activity of hypophysis and on the function of thyroid gland was studied. It has been found out that the maximum values of free thyroxin and triiodothyronine in blood were observed in the conditions of constant lightning and the minimal values--in the conditions of light deprivation. In the conditions of natural lightning of Karelia, with orientation on seasonal lightning, the following annual-circadian rhythms were observed: in autumn (period of short lightness duration) the level of free T3 was the lowest; in spring (period of short darkness duration) it was the highest; the inverse relationship was observed by the comparison of free T4 concentration. The lowest values of TSH were observed in old rats kept in constant light and natural light regimes. The concentration of TSH in blood was practically on the same level in the standard regime and in the regime of light deprivation. The age changes of the level of hormones appeared later in rats who received medication, in comparison with the control sets of animals. The use of melatonin and epitalon smoothened the seasonal variations of the level of thyroidal hormones in blood in the lightning conditions of Karelia.


Radical orbital decompression for severe dysthyroid exophthalmos.
A surgical technique is described for radical decompression of the orbit for dysthyroid exophthalmopathy. The operation should be considered in a patient with proptosis greater than 30 mm bilaterally or one with unilateral proptosis of 10 mm or more greater than the opposite eye. Such exophthalmos is frequently associated wih corneal exposure and ulceration, extreme cosmetic disfigurement, and optic neuropathy. The surgical procedure is performed through a 35-mm lateral skin incision and a lateral canthotomy with subconjunctival dissection. All four walls of the orbit are partially removed. This panorbital decompression procedure has been performed on five patients, with reduction of preoperative proptosis by as much as 17 mm. Complications were minimal. A review of the effectiveness of other orbital decompressive procedures is presented. It appears that the four-wall decompressive procedure offers the maximum degree of orbital reduction.


The prognostic role of gender in survival of adult cancer patients. EUROCARE Working Group.
Many observations indicate that women have a much longer expectancy of life than men. Some population-based studies on cancer patients support the idea of the role of gender in predicting survival. However, the data are somewhat contrasting and inconclusive. The purpose of this paper was to evaluate the prognostic role of gender for cancer patients, making use of the large set of survival data made available by the EUROCARE II project for the period 1985-1989. By applying a multivariate approach the major confounders such as age, geographical area and cancer site were considered in analysing survival data on more than 1 million cancer cases collected by 45 population-based cancer registries in 17 European countries. The results were consistent with the general observation that in the industrialised countries women tend to survive longer than men. The multivariate analysis showed better survival from cancer in women than in men, estimated as an overall 2% lower relative risk of dying. The female advantage was particularly evident in young cases, reduced in patients in middle age groups and in the oldest patients completely reversed so that at this age men had the better prognosis. Longer survival for women was not present immediately after diagnosis, but the major advantage was seen after 3 years of follow-up. The risk of death for women was significantly lower for cancer of the head and neck, oesophagus, stomach, liver and pancreas. For bladder cancer, the risk of death was significantly greater for women. These results can be explained by gender differences in sub-site distributions (head and neck and stomach) and by the differences in the stage at diagnosis (presumably bladder). However, the consistency of the data, evident only when a vast set of data is analysed, suggest that women may be intrinsically more robust than men in coping with cancer.


Brittle type 1 diabetes mellitus.
A small group of patients affected by type 1 diabetes mellitus is characterized by a severe instability of glycemic values with frequent and unpredictable hypoglycemic and/or ketoacidosis episodes which cannot be explained by errors of patients or diabetologists. The quality of life of these patients is dramatically compromised in particular because of the frequency of acute events, hospital recoveries and precocious appearance of chronic complications. This clinical condition has been defined as "brittle diabetes". A precise quantification of these patients is difficult because diagnostic criteria are still not well defined and it is often difficult to verify errors of patients in terms of inappropriate conduct with the pathology. Even more than the other kinds of diabetes, therapy is based on education, glycemic control, intensive therapy and strict interaction between physicians and patients. The introduction of insulin analogous, with either ultra-fast and ultra-slow action and the use of subcutaneous insulin pumps have significantly increased the possibility of treating the most of these cases. However, there is a minority of patients resistant to the therapy. In similar cases, pancreas or islet transplantation represents an effective therapeutic option entailing good expected outcomes. The main limiting factor of beta cell function replacement by transplantation is so far represented by the potentially severe side effects of the immunosuppression therapy necessary to avoid graft rejection and recurrence of autoimmunity.


Comparison of aortic pressures and aortic elastic properties between patients with end-stage renal disease and healthy controls.
Current evidence indicates that vascular calcification plays an essential role in the development of cardiovascular diseases in end-stage renal disease (ESRD) patients. Arterial stiffness is a marker of increased cardiovascular risk in various populations. The aim of this study is to evaluate the elastic properties of ascending aorta in patients with ESRD. This single-center study enrolled 96 patients (45 females, age: 57.2 ± 12.8 years) with ESRD and 96 healthy controls (52 females, age: 55.3 ± 10.1 years). Aortic pressures and aortic elastic parameters including aortic strain, aortic distensibility, aortic stiffness index, and aortic compliance were calculated using accepted formulae. The hemodynamic parameters including aortic pulse pressure, aortic mean pressure, aortic fractional pulse pressure, and aortic pulsatility index were significantly higher in patients with ESRD. Systolic and diastolic aortic diameters were similar between the groups. However, pulsatile aortic diameter change, aortic strain, aortic distensibility, and aortic compliance were significantly lower, whereas aortic stiffness index was significantly higher in ESRD group. The results demonstrated that a significant difference was present in terms of aortic blood pressures between patients with ESRD and controls. In addition, the elastic properties of ascending aorta were decreased in patients with ESRD.


Foraging ecology of African wolves (Canis lupaster) and its implications for the conservation of Ethiopian wolves (Canis simensis).
African wolves (AWs) are sympatric with endangered Ethiopian wolves (EWs) in parts of their range. Scat analyses have suggested a dietary overlap between AWs and EWs, raising the potential for exploitative competition, and a possible conservation threat to EWs. However, in contrast to that of the well-studied EW, the foraging ecology of AWs remains poorly characterized. Accordingly, we studied the foraging ecology of radio-collared AWs (n = 11 individuals) at two localities with varying levels of anthropogenic disturbance in the Ethiopian Highlands, the Guassa-Menz Community Conservation Area (GMCCA) and Borena-Saynt National Park (BSNP), accumulating 845 h of focal observation across 2952 feeding events. We also monitored rodent abundance and rodent trapping activity by local farmers who experience conflict with AWs. The AW diet consisted largely of rodents (22.0%), insects (24.8%), and goats and sheep (24.3%). Of the total rodents captured by farmers using local traps during peak barley production (July to November) in GMCCA, averaging 24.7 ± 8.5 rodents/hectare/day, 81% (N = 3009) were scavenged by AWs. Further, of all the rodents consumed by AWs, most (74%) were carcasses. These results reveal complex interactions between AWs and local farmers, and highlight the scavenging niche occupied by AWs in anthropogenically altered landscapes in contrast to the active hunting exhibited by EWs in more intact habitats. While AWs cause economic damage to local farmers through livestock predation, they appear to play an important role in scavenging pest rodents among farmlands, a pattern of behaviour which likely mitigates direct and indirect competition with EWs. We suggest two routes to promote the coexistence of AWs and EWs in the Ethiopian highlands: local education efforts highlighting the complex role AWs play in highland ecosystems to reduce their persecution, and enforced protection of intact habitats to preserve habitat preferred by EWs.


Establishing Wiring Specificity in Visual System Circuits: From the Retina to the Brain.
The retina is a tremendously complex image processor, containing numerous cell types that form microcircuits encoding different aspects of the visual scene. Each microcircuit exhibits a distinct pattern of synaptic connectivity. The developmental mechanisms responsible for this patterning are just beginning to be revealed. Furthermore, signals processed by different retinal circuits are relayed to specific, often distinct, brain regions. Thus, much work has focused on understanding the mechanisms that wire retinal axonal projections to their appropriate central targets. Here, we highlight recently discovered cellular and molecular mechanisms that together shape stereotypic wiring patterns along the visual pathway, from within the retina to the brain. Although some mechanisms are common across circuits, others play unconventional and circuit-specific roles. Indeed, the highly organized connectivity of the visual system has greatly facilitated the discovery of novel mechanisms that establish precise synaptic connections within the nervous system.


Does self-reported posttraumatic growth reflect genuine positive change?
In this study, we evaluated the validity of self-reported posttraumatic growth (PTG) by assessing the relation between perceived growth and actual growth from pre- to posttrauma. Undergraduate students completed measures tapping typical PTG domains at Time 1 and Time 2 (2 months later). We compared change in those measures with scores on the Posttraumatic Growth Inventory (PTGI; Tedeschi & Calhoun, 1996) for those participants who reported a traumatic event between Time 1 and Time 2 (n= 122). PTGI scores generally were unrelated to actual growth in PTG-related domains. Moreover, perceived growth was associated with increased distress from pre- to posttrauma, whereas actual growth was related to decreased distress, a pattern suggesting that perceived and actual growth reflect different processes. Finally, perceived (but not actual) growth was related to positive reinterpretation coping. Thus, the PTGI, and perhaps other retrospective measures, does not appear to measure actual pre- to posttrauma change.


Contribution of eIF-4E inhibition to the expression and activity of heparanase in human colon adenocarcinoma cell line: LS-174T.
Heparanase degrades heparan sulfate proteoglycans (HSPGs) and is a critical mediator of tumor metastasis and angiogenesis. Recently, it has been cloned as a single gene family and found to be a potential target for antimetastasis drugs. However, the molecular basis for the regulation of heparanase expression is still not quite clear. The aim of this study was to determine whether the expression of eukaryotic initiation factor 4E (eIF-4E) correlated with the heparanase level in tumor cells and to explore the correlation between heparanase expression and metastatic potential of LS-174T cells. A 20-mer antisense s-oligodeoxynucleotide (asODN) targeted against the translation start site of eIF-4E mRNA was introduced into LS-174T cells by lipid-mediated DNA-transfection. eIF-4E protein and mRNA levels were detected by Western blot analysis and RT-PCR, respectively. Heparanase activity was defined as the ability to degrade high molecular weight (40-100 kDa) radiolabeled HS (heparan sulfate) substrate into low molecular weight (5-15 kDa) HS fragments that could be differentiated by gel filtration chromatography. The invasive potential of tumor cell in vitro was observed by using a Matrigel invasion assay system. The 20-mer asODN against eIF-4E specifically and significantly inhibited eIF-4E expression at both transcriptional and translational levels. As a result, the expression and activity of heparanase were effectively retarded and the decreased activity of heparanase resulted in the decreased invasive potential of LS-174T. eIF-4E is involved in the regulation of heparanase production in colon adenocarcinoma cell line LS-174T, and its critical function makes it a particularly interesting target for heparanase regulation. This targeting strategy in antisense chemistry may have practical applications in experimental or clinical anti-metastatic gene therapy of human colorectal carcinoma.


[The role of the neonatal FC receptor in the uncoating of echoviruses and coxsackievirus A9.]
The aim of this study was to determine the role of the human neonatal receptor for the Fc fragment of IgG (hFcRn) as a common uncoating cellular receptor for echoviruses and coxsackievirus A9 during infection of human rhabdomyosarcoma (RD) cells. The protective effect of the human serum albumin, purified from globulins, (HSAGF) and antibodies to hFcRn was studied in RD cells infected with several strains and clones of species B enteroviruses possessing different receptor specificity (echoviruses 3, 9, 11, 30 and coxsackieviruses A9, B4, B5). It was shown that HSA-GF at concentrations of 4% or less protected RD cells from infection with echoviruses 3, 9, 11 and coxsackievirus A9. The antibodies to hFcRn at concentrations of 2.5 ug/mL or less demonstrated the similar spectrum of protective activity in RD cells against infection with echoviruses 3, 9, 11, 30 and coxsackievirus A9. The protective effect of HSA-GF or the antibodies to hFcRn was not observed in RD cells infected with coxsackieviruses B4 and B5 that need coxsackievirus-adenovirus receptor for uncoating. The usage of the previously characterized echovirus 11 clonal variants with different receptor specificity allowed us to define the function of hFcRn as a canyon-binding uncoating receptor in RD cells. The kinetics and magnitude of the observed protective effects correlated with receptor specificity of the enteroviruses used in this work supporting the two-step interaction of DAF-dependent echoviruses with the cellular receptors. In this study, the function of hFcRn was defined in RD cells as a canyon-binding and uncoating receptor for echoviruses and coxsackievirus A9. The two-step interaction of DAF-dependent echoviruses during entry into the cells was confirmed: initially with the binding receptor DAF and subsequently with the uncoating receptor hFcRn.


The bootstrap and identification of prognostic factors via Cox's proportional hazards regression model.
This paper describes the use of the bootstrap, a new computer-based statistical methodology, to help validate a regression model resulting from the fitting of Cox's proportional hazards model to a set of censored survival data. As an example, we define a prognostic model for outcome in childhood acute lymphocytic leukemia with the Cox model and use of a training set of 224 patients. To validate the accuracy of the model, we use a bootstrap resampling technique to mimic the population under study in two stages. First, we select the important prognostic factors via a stepwise regression procedure with 100 bootstrap samples. Secondly we estimate the corresponding regression parameters for these important factors with 400 bootstrap samples. The bootstrap result suggests that the model constructed from the training set is reasonable.


Linking Sustainable Use Policies to Novel Economic Incentives to Stimulate Antibiotic Research and Development.
There is now global recognition that antibiotic resistance is an emerging public health threat. Policy initiatives are underway to provide concrete suggestions for overcoming important obstacles in the fight against antibiotic resistance, like the alarming current paucity of antibacterial innovation. New economic models are needed as incentives for the discovery and development of novel antibacterial therapies especially for infections with too few patients today to justify private sector research and development (R&D) investments. These economic models should focus on rewarding the innovation, not the consumption of the antibiotic since sustainable use policies will reduce selection pressure and slow the emergence of resistance. To effectively stimulate greater innovation, the size of the reward must be commensurate with revenues from other therapeutic areas, estimated at about a billion dollar total pay-out. Otherwise R&D investment will continue to move away from antibiotics to areas where returns are more attractive. A potential sizeable public investment, if implemented, must be protected to ensure that the resulting antibiotics have a lengthy and positive impact on human health. Therefore, public investments in innovation should be bound to sustainable use policies, i.e., policies targeted at a range of actors to ensure the preservation of the novel antibiotics. These policies would be targeted not only at the innovating pharmaceutical companies in exchange for the reward payments, but also at governments in countries which receive the novel antibiotics at reasonable prices due to the reward payment. This article provides some suggestions of sustainable use policies in order to initiate the discussions. These are built on planned policies in the US, EU, WHO and have been expanded to address One Health and environmental aspects to form One World approaches. While further discussion and analyses are needed, it is likely that strong sustainable use policies will help to protect the sizeable public health investments.


UvrA and UvrB suppress illegitimate recombination: synergistic action with RecQ helicase.
Illegitimate recombination is a major cause of genetic instability in prokaryotes as well as in eukaryotes. This recombination usually occurs at a low frequency, but it is greatly enhanced by UV irradiation or other environmental stresses. DNA damages produced by these environmental stresses are thought to induce DNA double-strand breaks, leading to illegitimate recombination. In this paper we show that UV-induced illegitimate recombination is enhanced by mutations of nucleotide excision repair genes, uvrA or uvrB, and partially by uvrC mutation, but not by uvrD mutation. Unexpectedly, the recombination was enhanced by the uvrA uvrB double mutation even without UV irradiation, but the uvrB uvrC double mutation has not shown this effect, suggesting that illegitimate recombination is mostly suppressed by UvrA and UvrB. Moreover, illegitimate recombination was synergistically enhanced by the recQ uvrA double mutation. In addition, overproduction of the UvrA protein suppressed the hyperrecombination phenotype of the recQ or uvrB mutant, but it did not affect the UV-sensitive phenotype of the uvrB mutant. We concluded that the UvrAB complex suppresses illegitimate recombination in a pathway shared with RecQ helicase. In addition, UvrA protein alone can suppress illegitimate recombination in the pathway, in which RecQ helicase and UvrAB complex work. Possible functions of the proteins involved in these pathways are also discussed.


Influence of jet impingement on color Doppler parameters of aortic regurgitation.
In vitro studies have demonstrated that the characteristics of a color Doppler jet are influenced by a number of factors including jet eccentricity and jet impingement. To explore the relationship of a jet impingement and aortic regurgitant color Doppler jet parameters, jet area, width, and length were measured from apical echocardiographic views of 84 patients 4 +/- 11 days prior to catheterization and compared to angiographic grade. An impinging color jet contacted the interventricular septum or mitral valve beneath the aortic valve in the imaging plane and a nonimpinging jet did not contact the septum or mitral valve in the imaging plane. As expected, the percentage of patients with impinging jets increased with aortic regurgitation angiographic grade. Neither left ventricular chamber dimensions nor the presence of an aortic prosthesis significantly influenced the color Doppler variables. For a given angiographic grade of aortic regurgitation, impinging jets were associated with larger color Doppler jet widths (P less than 0.05) and areas (P = 0.001) than nonimpinging jets. The color Doppler area and length increased significantly with angiographic grade for nonimpinging jets (P less than 0.05) but not for impinging jets. Impinging jets are associated with larger color Doppler widths and areas than nonimpinging jets for a given grade of aortic regurgitation, possibly because of the effect of jet deflection toward an adjacent wall. Jet impinging should be considered when using color Doppler techniques to evaluate aortic regurgitation.


Survival analysis of the CEAwatch multicentre clustered randomized trial.
The CEAwatch randomized trial showed that follow-up with intensive carcinoembryonic antigen (CEA) monitoring (CEAwatch protocol) was better than care as usual (CAU) for early postoperative detection of colorectal cancer recurrence. The aim of this study was to calculate overall survival (OS) and disease-specific survival (DSS). For all patients with recurrence, OS and DSS were compared between patients detected by the CEAwatch protocol versus CAU, and by the method of detection of recurrence, using Cox regression models. Some 238 patients with recurrence were analysed (7·5 per cent); a total of 108 recurrences were detected by CEA blood test, 64 (55·2 per cent) within the CEAwatch protocol and 44 (41·9 per cent) in the CAU group (P = 0·007). Only 16 recurrences (13·8 per cent) were detected by patient self-report in the CEAwatch group, compared with 33 (31·4 per cent) in the CAU group. There was no significant improvement in either OS or DSS with the CEAwatch protocol compared with CAU: hazard ratio 0·73 (95 per cent 0·46 to 1·17) and 0·78 (0·48 to 1·28) respectively. There were no differences in survival when recurrence was detected by CT versus CEA measurement, but both of these methods yielded better survival outcomes than detection by patient self-report. There was no direct survival benefit in favour of the intensive programme, but the CEAwatch protocol led to a higher proportion of recurrences being detected by CEA-based blood test and reduced the number detected by patient self-report. This is important because detection of recurrence by blood test was associated with significantly better survival than patient self-report, indirectly supporting use of the CEAwatch protocol.


[Ranking assessment of the General Health Questionnaire using Latent Rank Theory].
The latent rank structure of the General Health Questionnaire (GHQ) was examined and a methodology for "ranking assessment" for use in clinical screening was suggested. Clinical screening is conducted by using dichotomous methods, which is problematic. Recent research has introduced the concept of ranking assessment, which is conducted by dividing clients into ordinal groups according to the Latent Rank Theory (LRT). Participants (N = 949, including 80 neurotic patients) completed the GHQ. They were then divided into four ordinal groups according to LRT. The usual cut-off point of the GHQ (16/17 points) distinguished the third and fourth rank group as the clinical group and the first-rank group as the healthy group. However, the second rank group was classified as neither a healthy or clinical group. These results indicate that the LRT has the potential to facilitate practical and flexible clinical screening.


Narcissism: its structures, systems and affects.
The growth of object relationships may be studied along either the developmental line of the discharge-object or that of the reflexive-object. The former is the well-known line of development from the need-satisfying object to the constant object and is a study of id-ego relationships. The developmental line of the reflexive-object, on the other hand, follows the history of the introjects and is a study of either ego-superego or ego-ego ideal relationships. It is the latter which constitutes the study of narcissism. The development of the ideal ego out of the ego nuclei leads eventually to the child's struggle to maintain a sense of omnipotence and to the narcissistic crisis. Out of this struggle the introjection of the idealized mother occurs which, as the ego ideal, continues the systemic line of development of narcissism. Various narcissistic states and affects such as shame, humiliation, depression, grandiosity, pomposity, arrogance, adoration and enthralment are the result of either hypercathexis of the introjects of the ego ideal (or of persisting remnants of the ideal ego) and the resulting conflict with the ego, or hypocathexis of the introjects and resulting dormancy of the system ego ideal.


The clinical outcomes of unplanned pregnancy in severely obese women.
The objective of this study was to compare the clinical outcomes of unplanned pregnancies among severely obese women with those of planned pregnancies. This prospective cohort study included severely obese women (Body Mass Index [BMI] ≥ 40.0 kg/m(2)) who delivered a baby weighing ≥ 500 g over 5 years 2009-2013 in a large university hospital. Maternal weight and height were measured and BMI was calculated at the first prenatal visit. Of the 650 women, the mean BMI was 43.8 kg/m(2), mean age was 31.6 years, and 30.0% (n = 195) were nulliparous. Prenatal complications including gestational diabetes mellitus (GDM), hypertensive and thromboembolic disorders occurred in 56.6% (n = 368). Compared with planned pregnancies (58.2%, n = 378), those that were unplanned (41.8%, n = 272) were associated with increased prepregnancy risk factors including essential hypertension (4.0% versus 1.6%, p = 0.03) and depression (6.6% versus 3.2%, p = 0.03). Unplanned pregnancy was associated with a higher macrosomia rate (birthweight > 4.5 kg) compared with planned pregnancies (p = 0.03). This was not explained by a higher GDM rate in unplanned pregnancies. Compared with planned pregnancies, unplanned pregnancies were not associated with increased adverse fetomaternal outcomes. Despite increased prepregnancy risk factors, in severely obese women, unplanned pregnancies were not associated with increased prenatal complications or adverse pregnancy outcomes compared with planned pregnancies.


Multiple calmodulin mRNA species are derived from two distinct genes.
We have observed three calmodulin mRNA species in rat tissues. In order to know from how many expressed genes they are derived, we have investigated the genomic organization of calmodulin genes in the rat genome. From a rat brain cDNA library, we obtained two kinds of cDNAs (pRCM1 and pRCM3) encoding authentic calmodulin. DNA sequence analysis of these cDNA clones revealed substitutions of nucleotides at 73 positions of 450 nucleotides in the coding region, although the amino acid sequences of these calmodulins are exactly the same. DNA sequences in the 5' and 3' noncoding regions are quite different between these two cDNAs. From these results, we conclude that they are derived from two distinct bona fide calmodulin genes, CaMI (pRCM1) and CaMII (pRCM3). Total genomic Southern hybridization suggested four distinct calmodulin-related genes in the rat genome. By cloning and sequencing the calmodulin-related genes from rat genomic libraries, we demonstrated that the other two genes are processed pseudogenes generated from the CaMI (lambda SC9) and CaMII (lambda SC8) genes, respectively, through an mRNA-mediated process of insertions. Northern blotting showed that the CaMI gene is transcribed in liver, muscle, and brain in similar amounts, whereas the CaMII gene is transcribed mainly in brain. S1 nuclease mapping indicated that the CaMI gene produced two mRNA species (1.7 and 4 kilobases), whereas the CaMII gene expressed a single mRNA species (1.4 kilobases).


Developing and validating a model for predicting 7-day mortality of patients admitted from the emergency department: an initial alarm score by a prospective prediction model study.
To set up a prediction model for the 7-day in-hospital mortality of patients admitted from the emergency department (ED) because it is high but no appropriate initial alarm score is available. This is a prospective cohort study for prediction model development. In a tertiary referred hospital in northern Taiwan. ED-admitted medical patients in hospitalist care wards were enrolled during May 2010 to October 2016. Two-thirds of them were randomly assigned to a derivation cohort for development of the model and cross-validation was performed in the validation cohort. 7-day in-hospital mortality. During the study period, 8649 patients were enrolled for analysis. The mean age was 71.05 years, and 51.91% were male. The most common admission diagnoses were pneumonia (36%) and urinary tract infection (20.05%). In the derivation cohort, multivariable Cox proportional hazard regression revealed that a low Barthel Index Score, triage level 1 at the ED, presence of cancer, metastasis and admission diagnoses of pneumonia and sepsis were independently associated with 7 days in-hospital mortality. Based on the probability developed from the multivariable model, the area under the receiver operating characteristic curve in the derivation group was 0.81 (0.79-0.85). The result in the validation cohort was comparable. The prediction score modified by the six independent factors had high sensitivity of 88.03% and a negative predictive value of 99.51% for a cut-off value of 4, whereas the specificity and positive predictive value were 89.61% and 10.55%, respectively, when the cut-off value was a score of 6. The 7-day in-hospital mortality in the hospitalist care ward is 2.8%. The initial alarm score could help clinicians to prioritise or exclude patients who need urgent and intensive care.


Microtubule depolymerization affects endocytosis and exocytosis in the tip and influences endosome movement in tobacco pollen tubes.
Polarized organization of the cytoplasm of growing pollen tubes is maintained by coordinated function of actin filaments (AFs) and microtubules (MTs). AFs convey post-Golgi secretory vesicles to the tip where some fuse with specific domains of the plasma membrane (PM). Secretory activity is balanced by PM retrieval that maintains cell membrane economy and regulates the polarized composition of the PM, by dividing lipids/proteins between the shank and the tip. Although AFs play a key role in PM internalization in the shank, the role of MTs in exo-endocytosis needs to be characterized. The present results show that integrity of the MT cytoskeleton is necessary to control exo-endocytosis events in the tip. MT polymerization plays a role in promoting PM invagination in the apex of tobacco pollen tubes since nocodazole affected PM internalization in the tip and subsequent migration of endocytic vesicles from the apex for degradation. MT depolymerization in the apex and shank was associated with misallocation of a significantly greater amount of internalized PM to the Golgi apparatus and its early recycling to the secretory pathway. Fluorescence Recovery After Photobleaching (FRAP) experiments also showed that MT depolymerization in the tip region influenced the rate of exocytosis in the central domain of the apical PM.


Towards an Informed CNN for Bone SR-microCT Image Classification with an Unsupervised Patched-based Image Clustering.
Bone microscale differences cannot be readily recognizable to humans from Synchrotron Radiation micro-Computed Tomography (SR-microCT) images. Premises are possible with Deep Learning (DL) imaging analysis. Despite this, more attention to high-level features leads models to require help identifying relevant details to support a decision. Within this context, we propose a method for classifying healthy, osteoporotic, and COVID-19 femoral heads SR-microCT images informing a vgg16 about the most subtle microscale differences using unsupervised patched-based clustering. Our strategy allows achieving up to 9.8% accuracy improvement in classifying healthy from osteoporotic images over uninformed methods, while 59.1% of accuracy between osteoporosis and COVID-19.Clinical relevance-We established a starting point for classifying healthy, osteoporotic, and COVID-19 femoral heads from SR-microCTs with human non-discriminative features, with 60.91% accuracy in healthy-osteporotic image classification.


Pectin Nanoparticle-Loaded Soft Coral Nephthea sp. Extract as In Situ Gel Enhances Chronic Wound Healing: In Vitro, In Vivo, and In Silico Studies.
This study shed light for the first time on the in vivo diabetic wound healing potential activity of natural marine soft coral polymeric nanoparticle in situ gel using an excision wound model. A Nephthea sp. methanol-methylene chloride extract loaded with pectin nanoparticles (LPNs) was created. For the preparation of in situ gel, ion-gelation techniques, the entrapment efficiency, the particle size, the polydispersity index, the zeta potential, the in-vitro drug release, and a transmission electron microscope were used and the best formula was selected. Using (UPLC-Q/TOF-MS), 27 secondary metabolites responsible for extract biological activity were identified. Isolation and identification of arachidic acid, oleic acid, nervonic acid, and bis-(2-ethylhexyl)-phthalate (DEHP) of Nephthea sp. was firstly reported here using NMR and mass spectral analyses. Moreover, LPN in situ gel has the best effects on regulating the proinflammatory cytokines (NF-κB, TNF-α, IL-6, and IL-1β) that were detected on days 7 and 15. The results were confirmed with an in vitro enzymatic inhibitory effect of the extract against glycogen synthase kinase (GSK-3) and matrix metalloproteinase-1 (MMP-1), with IC50 values of 0.178 ± 0.009 and 0.258 ± 0.011 µg/mL, respectively. The molecular docking study showed a free binding energy of -9.6 kcal/mol for chabrolosteroid E, with the highest binding affinity for the enzyme (GSK-3), while isogosterone B had -7.8 kcal/mol for the enzyme (MMP-1). A pharmacokinetics study for chabrolohydroxybenzoquinone F and isogosterone B was performed, and it predicted the mode of action of wound healing activity.


Concomitant increases in myonuclear and satellite cell content in female trapezius muscle following strength training.
A skeletal muscle fibre maintains its cytoplasmic volume by means of hundreds of myonuclei distributed along its entire length. Therefore it is hypothesised that changes in fibre size would involve modifications in myonuclear number. In this study, we have examined whether 10 weeks of strength training can induce changes in the number of myonuclei and satellite cells in female trapezius muscles. Biopsies were taken pre- and posttraining from the upper part of the descending trapezius muscle of nine subjects. Muscle samples were analysed for fibre area and myonuclear and satellite cell number using immunohistochemistry. There was a 36% increase in the cross-sectional area of muscle fibres. The hypertrophy of muscle fibres was accompanied by an approximately 70% increase in myonuclear number and a 46% increase in the number of satellite cells. Myonuclei number was positively correlated to satellite cell number indicating that a muscle with an increased concentration of myonuclei will contain a correspondingly higher number of satellite cells. The acquisition of additional myonuclei appears to be required to support the enlargement of multinucleated muscle cells following 10 weeks of strength training. Increased satellite cell content suggests that mitotic divisions of satellite cells produced daughter cells that became satellite cells.


Effect of intravenous immunoglobulin for neonates with severe enteroviral infections with emphasis on the timing of administration.
The benefits of intravenous immunoglobulin (IVIG) therapy for severe neonatal enterovirus infections are still controversial. To evaluate whether timing of IVIG administration might affect clinical outcomes of neonates with severe enteroviral infections. We retrospectively analyzed 67 neonates with culture-confirmed severe enteroviral infection, defined as hepatitis with coagulopathy and thrombocytopenia. Clinical features, outcomes and the usage of IVIG therapy were collected and analyzed. IVIG administered within 3 days of illness onset was classified as early IVIG therapy. Of the 67 cases, 38 (57%) were male, 27 (40%) were premature, 57 (85%) had disease onset within 7 days of life and all but 2 cases were caused by coxsackievirus B group. Ten infants (15%) had clinically evident myocarditis. 41 infants (61%) received IVIG therapy and 29 were early IVIG therapy. Fifteen infants (22%) eventually died, without IVIG therapy for 7 infants. The deceased had a significantly higher peak serum aspartate aminotransferase (AST) level than the survivors (3539 vs. 866 IU/L, p<0.01). The timing of IVIG therapy was highly correlated with the timing of peak AST level in patients with early IVIG therapy. Multiple logistic regression analysis showed that a higher nadir hemoglobin level (adjusted odds ratio 2.8, 95% confidence interval: 1.4-5.4), no concurrent myocarditis (42.6 [3.4-5289]) and early IVIG therapy (14.7 [1.3-163]) were independently associated with a favorable prognosis. In defined severe neonatal enterovirus infections, serum AST level correlated with the disease severity. Early IVIG therapy, if needed, may be beneficial for survival.


Substance use and mental health predictors of patterns of non-partner youth violence among high-risk urban youth.
This study examined the association between baseline substance use and mental health, and non-partner violence trajectories among youth presenting to an urban emergency department who screened positive for drug use. Non-partner violence is physically violent victimization or aggression involving someone other than a dating partner. Group-based trajectory modeling was used to identify longitudinal trajectories of non-partner violence in N = 599 youth (14-24 years old) at baseline, 6, 12, 18 and 24 month follow-ups. Multinomial logistic regression analyses were used to examine associations between baseline substance use and mental health conditions (i.e., anxiety, depression, and post-traumatic stress disorder [PTSD]), and non-partner violence trajectories. Six trajectory groups were identified for non-partner violence. Binge drinking and cannabis, illicit drug, nonmedical prescription stimulant, and polysubstance use in the 30 days leading up to their initial ED visit were associated with the likelihood of medium to high non-partner violence group membership during the two years following their ED visit. Post-traumatic stress disorder (PTSD) and depression/anxiety at baseline were also associated with greater risk of belonging to medium to high non-partner violence trajectory groups. Our findings highlight distinct trajectories of violent behavior, with roughly 60 % of young adults belonging to one of the non-partner violence groups. Although general trajectory trends were of decreasing violent behavior, the constellation of baseline risk factors differentially predicted group membership. These findings indicate that violence does not operate in a vacuum; interventions to reduce violence should also address previous trauma, substance use, and mental health issues.


Cerebral Palsy: A Lifelong Challenge Asks for Early Intervention.
One of the oldest and probably well-known examples of cerebral palsy is the mummy of the Pharaoh Siptah about 1196-1190 B.C., and a letter from Hippocrates (460-390 B.C.). Cerebral palsy (CP) is one of the most common congenital or acquired neurological impairments in paediatric patients, and refers to a group of children with motor disability and related functional defects. The visible core of CP is characterized by abnormal coordination of movements and/or muscle tone which manifest very early in the development. Resulting from pre- or perinatal brain damage CP is not a progressive condition per se. However, without systematic medical and physiotherapeutic support the dystonia leads to muscle contractions and to deterioration of the handicap. Here we review the three general spastic manifestations of CP hemiplegia, diplegia and tetraplegia, describe the diagnostic procedures and delineate a time schedule for an early intervention.


High frequency of TTK mutations in microsatellite-unstable colorectal cancer and evaluation of their effect on spindle assembly checkpoint.
Frameshift mutations frequently accumulate in microsatellite-unstable colorectal cancers (MSI CRCs) typically leading to downregulation of the target genes due to nonsense-mediated messenger RNA decay. However, frameshift mutations that occur in the 3' end of the coding regions can escape decay, which has largely been ignored in previous works. In this study, we characterized nonsense-mediated decay-escaping frameshift mutations in MSI CRC in an unbiased, genome wide manner. Combining bioinformatic search with expression profiling, we identified genes that were predicted to escape decay after a deletion in a microsatellite repeat. These repeats, located in 258 genes, were initially sequenced in 30 MSI CRC samples. The mitotic checkpoint kinase TTK was found to harbor decay-escaping heterozygous mutations in exon 22 in 59% (105/179) of MSI CRCs, which is notably more than previously reported. Additional novel deletions were found in exon 5, raising the mutation frequency to 66%. The exon 22 of TTK contains an A(9)-G(4)-A(7) locus, in which the most common mutation was a mononucleotide deletion in the A(9) (c.2560delA). When compared with identical non-coding repeats, TTK was found to be mutated significantly more often than expected without selective advantage. Since TTK inhibition is known to induce override of the mitotic spindle assembly checkpoint (SAC), we challenged mutated cancer cells with the microtubule-stabilizing drug paclitaxel. No evidence of checkpoint weakening was observed. As a conclusion, heterozygous TTK mutations occur at a high frequency in MSI CRCs. Unexpectedly, the plausible selective advantage in tumourigenesis does not appear to be related to SAC.


Interhemispheric differences in extrastriate areas during visuo-spatial selective attention.
Functional asymmetries between hemispheres have been reported in relation to spatial and temporal information processing. Here we used functional magnetic resonance imaging to investigate the influence of task on activity in extrastriate areas during selective spatial attention. During bilateral visual stimulation, subjects attended either the left or the right hemifield. Within the attended side, the task was either to discriminate the orientation of the stimuli or to judge their temporal characteristics. The bilateral stimulation caused symmetric activation of the left and right occipitotemporal junction. Within these regions we investigated the modulatory effects attention and the effect of task upon these. A region of interest approach was used to compare activity in the two hemispheres. The signal at occipitotemporal junction was analyzed in a 2 x 2 x 2 factorial design, with attended side, type of task, and hemisphere as factors. We found that, in both hemispheres, activity was higher when attention was directed to the contralateral hemifield compared with the ipsilateral hemifield. However, the size of these contralateral attentional modulations was dependent on the task. In the left occipitotemporal junction, contralateral modulations were stronger during the temporal task, while in the right occipitotemporal junction contralateral modulations were stronger during orientation discrimination. Overall, this pattern of activity lead to a significant three-way interaction between attended side, type of task, and hemisphere. We conclude that task characteristics influence brain activity associated with spatial selective attention. Our results support the hypothesis that temporal and orientation processing are preferentially associated with the left and right hemisphere, respectively.


[Large false aortic aneurysm after 30 years of a coarctation repair].
We report a case of a large false aortic aneurysm that had developed in a 43-year-old man who had had coarctation repair 30 years previously. The coarctation repair had been done by inserting an end-to-end Dacron tubular graft which was sutured with silk. The re-operation was successfully performed under deep hypothermic arrest and it was noted that there was complete separation of the graft from both ends and no sutures were visualised. The deep hypothermic technique has considerably improved the ease and safety of this operation. We attribute this complication to the reabsorption of the silk sutures. Patients after coarctectomy with graft material should have regular chest X-rays for life in order to detect false aneurysms.


Adult human cytokeratin 19-positive cells reexpress insulin promoter factor 1 in vitro: further evidence for pluripotent pancreatic stem cells in humans.
Human pancreatic cells with a typical ductal phenotype and potential to proliferate can be obtained in vitro, but the differentiation capacity of these putative human pancreatic stem cells remains to be documented. We investigated the protein and mRNA expression of insulin promoter factor 1 (IPF-1) (or pancreas/duodenal homeobox 1), a transcription factor critical for pancreatic development and endocrine cell neogenesis, in human pancreatic ductal cells derived from cultured exocrine tissue. In vitro, exocrine cells rapidly adhered (within 12 h) and were de-/transdifferentiated to ductal cells after 3 days with a dramatic loss of amylase protein (n = 4, 92 +/- 3.3%, P < 0.05 vs. day 1) and a simultaneous increase of ductal cytokeratin 19 protein (n = 4, 3.4-fold on day 3 and 7-fold on day 9, P < 0.05 vs. day 1). IPF-1 protein and mRNA levels were low to undetectable in exocrine preparations before culture. After 2 days of culture, a 3.2-fold increase in IPF-1 protein was observed, corresponding to the characteristic 46-kDa protein in Western blots. Reverse transcriptase-polymerase chain reaction confirmed a 10.5-fold increase in IPF-1 mRNA levels after 3 days of culture (n = 5, P < 0.001 vs. day 1). Double immunocytochemistry showed direct evidence that IPF-1 appeared during culture in these exocrine-derived ductal cells (cytokeratin 7-positive) and was not merely in contaminating endocrine cells (chromogranin A-positive). In conclusion, we describe herein the first converging evidence on both the molecular and protein level that human cells with a typical ductal phenotype derived ex vivo from pancreatic exocrine tissue (obtained from healthy donors) can reexpress IPF-1 in culture, suggesting their pancreatic precursor/stem cell potential.


The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas.
Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC.


Epigenetic aging in older people living with HIV in Eswatini: a pilot study of HIV and lifestyle factors and epigenetic aging.
People living with HIV (PLHIV) on effective antiretroviral therapy (ART) are living near-normal lives. Although they are less susceptible to AIDS-related complications, they remain highly vulnerable to non-communicable diseases (NCD). In this exploratory study of older PLHIV (OPLHIV) in Eswatini, we investigated whether biological aging (i.e., the difference between epigenetic age and chronological age, termed 'epigenetic age acceleration [EAA]') was associated with HIV-related parameters, and whether lifestyle factors modified these relationships. We calculated EAA focusing on the second-generation epigenetic clocks, PhenoAge and GrimAge, and a pace of aging biomarker (DunedinPACE) among 44 OPLHIV in Eswatini. Among participants, the PhenoAge clock showed older epigenetic age (68 years old [63, 77]) but a younger GrimAge epigenetic age (median=56 years old [interquartile range=50, 61]) compared to the chronological age (59 years old [54, 66]). Participants diagnosed with HIV at an older age showed slower DunedinPACE (β-coefficient [95% Confidence Interval]; -0.02 [-0.04, -0.01], p=0.002) and longer duration since HIV diagnosis was associated with faster DunedinPACE (0.02 [0.01, 0.04], p=0.002). The average daily dietary intake of fruits and vegetables was associated with faster DunedinPACE (0.12 [0.03, 0.22], p=0.01) and modified the relationship between HIV status variables (number of years living with HIV since diagnosis, age at HIV diagnosis, CD4+ T cell counts) and PhenoAge EAA, and DunedinPACE. Biological age is accelerated in OPLHIV in Eswatini, with those living with HIV for a longer duration at risk for faster biological aging. Lifestyle factors, especially healthier diets, may attenuate biological aging in OPLHIV. To our knowledge, this is the first study to assess biological aging in Eswatini and one of the few in sub-Saharan Africa.


Cochlear Implant Access in Six Developed Countries.
Access to cochlear implantation varies greatly around the world. It is affected by factors that are specific to each country's health care system, by awareness, and by societal attitudes regarding deafness. Cochlear implant clinicians and researchers from six countries explored and discussed these variations and their likely causes: Robert Briggs from Australia; Wolfe-Dieter Baumgartner from Austria; Thomas Lenarz from Germany; Eva Koltharp from Sweden; Christopher Raine from the United Kingdom, and Craig Buchman, Donna Sorkin, and Christine Yoshinago from the United States. Utilization rates are quite different for the pediatric and adult demographics in all six countries. Pediatric utilization ranges in the six countries (all in the developed world) ranged from a low of 50% in the United States to a high of 97% in Australia. Adult utilization is less than 10% everywhere in the world. Pediatric access to care was excellent for children with the exception of Germany and the United States where there is an inadequate referral system. Adult utilization was low everywhere because of the lack of screening for adults and the fact that primary care physicians and even audiologists are unfamiliar with CI candidacy criteria and outcomes, and hence typically do not make patient referrals.


Glasgow prognostic score as a prognostic factor in metastatic castration-resistant prostate cancer treated with docetaxel-based chemotherapy.
The modified Glasgow Prognostic Score (mGPS), derived from C-reactive protein (CRP) and albumin levels, and the neutrophil-lymphocyte ratio (NLR) have demonstrated prognostic significance in a number of malignancies. Baseline mGPS and NLR were calculated in a prospective cohort of chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) (AT-101-CS-205 trial) who received docetaxel and prednisone ± AT101. Cox proportional hazards regression models estimated their effects on overall survival (OS). Of 220 eligible patients, mGPS and neutrophil and lymphocyte counts were available for 184, 193, and 112 patients, respectively. Albumin (hazard ratio [HR], 0.28; 95% confidence interval [CI]: 0.14-0.56; P < .001) and CRP (HR, 1.22; 95% CI, 1.00-1.48; P = .048) were independently prognostic for OS. An association between mGPS and OS was found (HR, 1.87; 95% CI, 1.35-2.59; P < .001; median survival, 23.5 months at mGPS 0 vs. 9.8 months at mGPS 2). mGPS was significant after controlling for 3 previously published nomograms or NLR (P ≤ .001). NLR was not prognostic for OS (HR, 0.98; P = .91), and no association between mGPS and toxicity was noted. Our results demonstrate the prognostic role of the mGPS in mCRPC over variables previously identified. mGPS is inexpensive, easily measured, and could be incorporated into routine clinical testing if our results are confirmed in a subsequent validation study. The utility of the NLR in mCRPC remains uncertain despite evidence in other malignancies.


Altered Resting State Functional Connectivity and Its Correlation with Cognitive Functions at Ultra High Risk for Psychosis.
The aim of this study is to identify robust resting state-functional connectivity (rs-FC) alterations and their correlations with the neuropsychological characteristics of Ultra-High Risk (UHR) for psychosis subjects compared to healthy controls (HCs). Twenty individuals with UHR and sixteen HCs underwent resting-state functional magnetic resonance imaging (rs-fMRI) and a cognitive battery evaluating attention, episodic memory and executive functions. Compared to HCs, UHR individuals showed working memory and set-shifting impairments. In functional connectivity (FC) analyses, the Default Mode Network (DMN) of the UHR subjects displayed increased FC with the visual areas and decreased FC with the Dorsal Attention Network (DAN). Additionally, the salience network (SN) of the UHR subjects displayed increased connectivity with wide posterior cortical areas in the temporal, parietal and occipital lobes, corresponding to posterior nodes of the SN itself, the Somato-Motor Network (SMN) and the DAN. The SN connectivity with the left SMN and DAN was positively correlated with the Trail Making Test - B scores of the UHR subjects. These findings show that the SN and DMN, which mostly show abnormal connectivity patterns in psychosis, are also affected in UHR subjects, while the SN plays a more central role with its hyperconnectivity to the DAN and SMN.


Influence of various concentrations of terpene-4-ol enhancer and carbopol-934 mucoadhesive upon the in vitro ocular transport and the in vivo intraocular pressure lowering effects of dorzolamide ophthalmic formulations using albino rabbits.
The objectives of the current study are (i) to maximize the ocular bioavailability of dorzolamide hydrochloride (DZD) through; (a) enhancement of the DZD corneal transport using various concentrations of selected natural terpene-4-ol enhancers, (b) increasing the contact time of the drug with the absorbing tissues of the eye using selected carbopol-934 (C-934) as mucoadhesive to reduce the extensive pre-corneal loss of the installed dose due to the physiologically normal fast tear-washout, and (ii) to assess the in vivo intraocular pressure (IOP) lowering effects of the gel test formulations using normotensive New Zealand albino rabbits. In this study, DZD was formulated as 2% formulations ophthalmic gels containing different concentrations of C-934 as mucoadhesive, as well as, with various concentrations of terpene-4-ol as a natural corneal penetration enhancers. The transport of DZD from the gel formulations was quantitatively determined using in vitro diffusion experiments. The permeability parameters of DZD were calculated employing the most appropriate mathematical equations. Further, the in vivo IOP lowering effects of the test formulations were also assessed using the TONO-PEN(R)XL applanation tonometer in normotensive New Zealand albino rabbits. The overall results revealed that there is a direct correlation between both the in vitro permeability parameters and the contact period with the ocular tissues and the in vivo DeltaIOP. In such case, the in vitro permeability parameters of DZD could be used as a determinant for the in vivo IOP measurements. The magnitude of the DZD-IOP lowering effects as well as the durations of actions for the test formulations has been found to be greatly dependent upon (a) the concentration of the terpene-4-ol corneal penetration enhancer and (b) the duration of contact period with the ocular tissues, which was found to be a single-valued function of the C-943 mucoadhesive concentration.


Ten recommendations to improve pharmacy practice in low and middle-income countries (LMICs).
Medicines are important health interventions and their appropriate use could improve health outcomes. Throughout the globe, pharmacists play a very important role to improve the use of medicines. Though high-income countries are debating on futuristic approaches, independent prescribing of pharmacists, clinical skills, and to expand pharmacy services; a large majority of low and middle-income countries still lag behind to strengthen pharmacy practice. This paper presents a key set of recommendations that can improve pharmacy practice in low and middle-income countries (LMICs). The ten recommendations include (1) Mandatory presence of graduate-level pharmacists at community pharmacies (2) Clear demarcation of the roles and responsibilities of different categories of pharmacists (3) Effective categorization and implementation of medicines into (a) prescription medicines (b) pharmacists only medicines (c) over the counter medicines (4) Enforcement of laws and regulations for the sale of medicines (5) Prohibiting doctors from dispensing medicines (the dispensing separation between pharmacists and doctors). (6) Involving pharmacies and pharmacists in Universal Health Coverage Schemes to improve the affordability of medicines (7) Strengthening national medicines regulatory authorities to improve the quality, safety, and effectiveness of medicines (8) Training of pharmacists in clinical skills, vaccination, and minor ailment schemes (9) Promoting independent medicines information for consumers and healthcare professionals by developing national medicines information strategy (10) Mandatory Continuing Professional Development (CPD) programs for the Pharmacists.


Detection of cytomegalovirus infections in specimens other than urine by the shell vial assay and conventional tube cell cultures.
Blood, bronchoscopy-lavage, biopsy (lung, liver, kidney), sputum, and other (cecum, bone) specimens were inoculated into shell vials and conventional cell tube cultures seeded with MRC-5 cells over a 23-month period. Of 1,472 specimens, 182 (12.4%) yielded cytomegalovirus (CMV)-positive results from 81 patients. Significantly more CMV-positive specimens were detected in shell vials (n = 154; 84.6%) than in conventional tube cell cultures (n = 126; 69.2%) (P less than 0.01). We found that 98 (53.8%) of the total 182 and 41 (42.7%) of the 96 blood specimens positive for CMV were detected by both the shell vial assay and conventional tube cell cultures. However, 56 (30.7%) of the total 182 and 31 (32.3%) of the 96 blood specimens positive for CMV were obtained exclusively in shell vials after detection with monoclonal antibody. Alternatively, 28 (15.4%) of the total 182 and 24 (25%) of the 96 blood specimens positive for the virus were isolated only in conventional tube cell cultures. Thus, although the shell vial assay was more sensitive and rapid than the conventional tube cell culture method, both systems must be used, especially for blood specimens, for the laboratory diagnosis of CMV infections.


Limitations of magnetic resonance imaging and magnetic resonance angiography in the diagnosis of intracranial aneurysms.
Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) are being used with increasing frequency for the diagnosis of intracranial aneurysms. Although the literature suggests that MRI and MRA are accurate, we have observed that both are associated with a high likelihood of false-positive results in the diagnosis of aneurysms. We prospectively evaluated and compared the accuracy of MRI/MRA versus digital subtraction angiography (DSA) for the diagnosis of intracranial aneurysms. Over the course of 2 years, 133 patients diagnosed with one or more unruptured intracranial aneurysms by MRI/MRA were prospectively evaluated in an outpatient setting. The patients were advised to undergo cerebral four-vessel DSA, and the results from DSA were compared with MRI/MRA findings. In 59% of cases, the DSA and MRI/MRA findings were markedly different. Specifically, in 38% of MRI/MRA-positive cases, DSA findings were completely normal, showing no aneurysms. In an additional 21% of cases, although DSA confirmed the presence of an aneurysm, it differed substantially from MRI/MRA findings in terms of aneurysm location, number of aneurysms, or aneurysm type. In general, the false-positive aneurysms by MRI/MRA were smaller than 5 mm and were most commonly identified in the anterior communicating artery region. MRI/MRA studies are often inaccurate in the diagnosis of intracranial aneurysms and should not be used as the sole diagnostic studies for intracranial aneurysms. Other radiographic modalities should be further investigated as alternatives to MRI/MRA for the diagnosis of intracranial aneurysms.