Acute dissociation as part of the defense cascade: Associations with behavioral, autonomic, and experiential threat responses in posttraumatic stress disorder.
Dissociative symptoms, such as depersonalization and derealization, are experienced by about half of individuals with posttraumatic stress disorder (PTSD). Theoretical models propose that acute dissociation is accompanied by specific behavioral, physiological, and experiential alterations and contributes to unfavorable PTSD symptom course. Yet, empirical evidence is scarce. Here, we explored associations between dissociative and behavioral, physiological, and experiential threat responses as well as effects of dissociative responding on PTSD symptom course. Individuals with PTSD (N = 71) participated in a preregistered script-driven imagery study including exposure to standardized, detail-enriched trauma, and neutral scripts. Stabilometry, eye-tracking, facial electromyography, autonomic psychophysiology, and self-report data were collected. Moreover, PTSD symptoms were assessed before and 3 months after testing. Analyses did not link acute dissociation to bodily and facial immobility or staring in response to trauma scripts. However, dissociation displayed an inverted U-shaped relationship with heart rate and was linked to higher nonspecific skin conductance fluctuation and higher high-frequency heart rate variability in response to trauma scripts. Moreover, acute dissociation was linked to higher self-reported negative affect responses to trauma scripts and displayed a U-shaped relationship with unfavorable PTSD symptom course. While results did not confirm hypothesized behavioral markers of dissociation, they do support defense-cascade model assumptions of an inverted U-shaped relationship between dissociation and psychophysiological arousal resulting from a progression of parasympathetic versus sympathetic dominance with increasing dissociation. On an experiential level, results did not confirm posttraumatic dissociation-induced emotional numbing, questioning theoretical notions. The observed nonlinear associations may help explain the heterogeneity of prior findings and might inform an updated conceptualization of posttraumatic dissociation. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Pericardial effusion and tamponade in infants with central catheters.
To describe the clinical presentation, cause, and outcome of central venous catheter (CVC)-related pericardial effusions (PCE) in infants. A retrospective case review was conducted of CVC-related PCE at university and private neonatal intensive care units. Data from our cases were combined with published case reports and included clinical presentation and outcome; biochemical evaluation of pericardial fluid; days until diagnosis; cardiothoracic ratios; and CVC characteristics, insertion site, and tip placement site. In our cases, 6 different neonatology groups cared for 14 patients at 6 different hospitals in 2 cities. These data were combined with 47 cases reviewed from the literature. Pericardial fluid was obtained in 54 cases from the combined group and was described qualitatively as consistent with the infusate in 53 of 54 cases (98%). Biochemical analysis was performed in 37 cases, and in 36 of 37 cases (97%), the pericardial fluid was consistent with the infusate. The median gestational age at birth was 30.0 weeks (range: 23.5-42). The median time from CVC insertion to diagnosis was 3.0 days (range: 0.2-37; n = 59). Sudden cardiac collapse was reported in 37 cases (61%), and unexplained cardiorespiratory instability was reported in 22 cases (36%). The CVC tip was last reported within the pericardial reflections on chest radiograph in 56 cases (92%) at the time of PCE diagnosis. The mean cardiothoracic ratio increased 17% (n = 14). No patients died among our cases. Among the reviewed cases, 45% mortality was reported. For the combined group, mortality was 34%. For the combined group, mortality was 8% (3 of 37) in the patients who underwent pericardiocentesis versus 75% (18 of 24) for the patients who did not. In 21 patients, the catheter was withdrawn and remained in use. Survivors and nonsurvivors had comparable gestational age at birth, birth weight, days to PCE diagnosis, and day of life of PCE symptoms/diagnosis. Access site, catheter type, and catheter size were not associated with mortality. An association between larger catheters and shorter time to PCE may be present. Access site and catheter type were not associated with time to PCE. Autopsy specimens reported 6 cases of myocardial necrosis/thrombus formation, 9 cases of perforation without myocardial necrosis/thrombus formation, and 2 cases in which both were reported. The pericardial fluid found in CVC-associated PCE is consistent with the infusate. We speculate that there are several mechanisms, ranging from frank perforation that seals spontaneously to CVC tip adhesion to the myocardium with diffusion into the pericardial space. Routine radiography should be performed, and the CVC tip should be readily identifiable. The CVC tip should remain outside the cardiac silhouette but still within the vena cavae (approximately 1 cm outside the cardiac silhouette in premature infants and 2 cm in term infants). A change in cardiothoracic ratio may be diagnostic of a PCE, and pericardiocentesis is associated with significantly reduced mortality. Increased awareness of this complication may decrease the mortality associated with CVC-related PCE.


A nomenclature for vertebral fossae in sauropods and other saurischian dinosaurs.
The axial skeleton of extinct saurischian dinosaurs (i.e., theropods, sauropodomorphs), like living birds, was pneumatized by epithelial outpocketings of the respiratory system. Pneumatic signatures in the vertebral column of fossil saurischians include complex branching chambers within the bone (internal pneumaticity) and large chambers visible externally that are bounded by neural arch laminae (external pneumaticity). Although general aspects of internal pneumaticity are synapomorphic for saurischian subgroups, the individual internal pneumatic spaces cannot be homologized across species or even along the vertebral column, due to their variability and absence of topographical landmarks. External pneumatic structures, in contrast, are defined by ready topological landmarks (vertebral laminae), but no consistent nomenclatural system exists. This deficiency has fostered confusion and limited their use as character data in phylogenetic analysis. We present a simple system for naming external neural arch fossae that parallels the one developed for the vertebral laminae that bound them. The nomenclatural system identifies fossae by pointing to reference landmarks (e.g., neural spine, centrum, costal articulations, zygapophyses). We standardize the naming process by creating tripartite names from "primary landmarks," which form the zygodiapophyseal table, "secondary landmarks," which orient with respect to that table, and "tertiary landmarks," which further delineate a given fossa. The proposed nomenclatural system for lamina-bounded fossae adds clarity to descriptions of complex vertebrae and allows these structures to be sourced as character data for phylogenetic analyses. These anatomical terms denote potentially homologous pneumatic structures within Saurischia, but they could be applied to any vertebrate with vertebral laminae that enclose spaces, regardless of their developmental origin or phylogenetic distribution.


Properties of a monoclonal antibody directed to the calmodulin-binding domain of rabbit skeletal muscle myosin light chain kinase.
A synthetic peptide representing the calmodulin-binding domain of rabbit skeletal muscle myosin light chain kinase (K-R-R-W-K-K-N-F-I-A-V-S-A-A-N-R-F-K-K-I-S-S-S-G-A-L) was used as an antigen to produce a monoclonal antibody. The antibody (designated MAb RSkCBP1, of the IgM class) reacted with similar affinity (KD approximately 20 nM) by competitive enzyme-linked immunoassay (ELISA) with the antigen peptide and intact rabbit skeletal muscle myosin light chain kinase. MAb RSkCBP1 inhibited rabbit skeletal muscle myosin light chain kinase activity competitively with respect to calmodulin (Ki = 20 nM). The antibody also inhibited myosin light chain kinase activity in extracts of skeletal muscle from several mammalian species (rabbit, sheep, and bovine) and an avian species (chicken). The concentration of MAb RSKCBP1 required for 50% inhibition of enzyme activity was similar for the mammalian species (80 nM) but was significantly higher for the avian species (1.2 microM). A competitive ELISA protocol was used to analyze weak cross-reactivity to other calmodulin-binding peptides and proteins. This assay demonstrated no cross-reactivity with the venom peptides melittin or mastoparan; smooth muscle myosin light chain kinases from hog carotid, bovine trachea, or chicken gizzard; bovine brain calmodulin-dependent calcineurin; or rabbit skeletal muscle troponin I. These data support the contention that the synthetic peptide used as the antigen represents the calmodulin-binding domain of rabbit skeletal muscle myosin light chain kinase and that the calmodulin-binding domains of different calmodulin-regulated proteins may have distinct primary and/or higher order structures.


Parasite control methods used by horse owners: factors predisposing to the development of anthelmintic resistance in nematodes.
One hundred and fifty horse owners, primarily private owners and riding schools, replied to a questionnaire concerning the practices they used to control parasites. Twenty-seven had experienced a parasite problem. Faecal samples from 188 horses selected at random showed that worm control practices were generally successful; however, many owners were not following recommendations for slowing the development of resistant parasites. In 1996, 86 per cent of the owners were using either three or two classes of anthelmintic a year, and they used a median of six doses with a range from one to 11. Approximately half the owners, more commonly owners of up to five horses, picked up their horses' faeces at least once a week, but these owners also used more doses of anthelmintic a year than owners who did not pick up faeces. One-third of the owners manually removed Gasterophilus species eggs from the horses' hairs, but 94 per cent of them also used ivermectin. Many owners treated specifically for Anoplocephala species, cyathostome larvae and Gasterophilus species, and these owners were the most likely to use three classes of anthelmintic a year. One-hundred-and-seven owners replied to a second questionnaire asking for information about the factors that influenced their anthelmintic control practices. Many owners, particularly private owners, were not influenced by the cost of the anthelmintic. For the timing and frequency of treatment, and the choice of drug, owners were most influenced by advertisements, magazine articles and veterinary surgeons. In two magazines aimed at horse owners, the brands of drugs most frequently advertised were the brands most commonly used by the owners, and articles in the magazines recommended the use of three classes of drug per year. These results are discussed in relation to their influence on the development of anthelmintic-resistant nematodes.


The effect of thyroxine treatment started in the neonatal period on development and growth of two-year-old Down syndrome children: a randomized clinical trial.
Young Down syndrome children appear to have a mild form of congenital hypothyroidism that is rarely detected by neonatal screening and usually left untreated. To investigate the effects of thyroxine treatment on development and growth of young Down syndrome children. Single-center, randomized, double-blind, 24-month trial (enrollment June 1999 to August 2001) with nationwide recruitment, comparing thyroxine administration with placebo in 196 Down syndrome neonates. Neonates were randomly assigned to treatment for 2 yr with either thyroxine (n = 99; initial dose 8 microg/kg) or placebo (n = 97). Daily thyroxine doses were adjusted at regular intervals to maintain plasma TSH in its normal and free T(4) concentrations in its high-normal range. Placebo dose adjustments mirrored those of thyroxine. The primary outcome was mental and motor development at age 24 months, assessed with the Bayley Scales of Infant Development II. At age 24 months, the developmental testing results of 90 thyroxine-, and 91 placebo-treated children were available for analysis. The thyroxine-treated children had a 0.7-month smaller delay in motor developmental age (95% confidence interval, -1.4 to 0), corresponding to a difference of seven motor developmental index points. The mental developmental age delay was also 0.7 month smaller in the thyroxine group (95% confidence interval, -1.5 to 0.2), but lacked statistical significance. Thyroxine-treated children had greater gains in length (1.1 cm; 95% confidence interval, 0.2 to 2.0) and weight (378 g; 95% confidence interval 55 to 701). The data of our study provide evidence to support the hypothesis that thyroxine treatment may improve development and growth of young Down syndrome children. Thyroxine treatment should be considered in Down syndrome neonates to maximize their early development and growth.


Modulation of lymphocyte proliferation induced by gastric MALT lymphoma-associated Helicobacter pylori strains.
Helicobacter pylori infection leads to different chronic diseases, suggesting that this bacterium can evade the host immune defense system. The ability to control lymphocyte proliferation may be a mechanism leading to the development of gastric pathologies. Our aim was to characterize the effects of mucosa-associated lymphoid tissue (MALT) associated H. pylori strains on lymphocyte proliferation. We measured the in vitro proliferation of human lymphocytes originally from blood or tonsil samples in the presence or absence of viable bacteria or lysates. We showed that MALT lymphoma-associated strains are not likely to be directly responsible for anarchical B-cell proliferation in vitro. On the other hand, proliferation of prestimulated T lymphocytes was abolished in vitro by the presence of all H. pylori strains, whether associated with MALT lymphoma or not. Inhibition of T-cell proliferation may be of major importance in the gastric colonization and in the persistence of the infection. Furthermore, this inhibition may favor anarchical B-cell proliferation in vivo and predispose the host to gastric MALT lymphoma, whereas MALT-associated H. pylori strains do not appear to possess a specific capability to directly stimulate B-lymphocyte proliferation.


Uterine fibroid treatment patterns in a population of insured women.
To profile women treated for uterine leiomyomas who are covered by commercial insurance from large, self-insured employers in the United States. Retrospective, observational study. Inpatient, outpatient, and prescription drug experience of women with employer-sponsored insurance in the United States. Data were obtained from the MarketScan insurance databases for 1999 through 2004 and weighted to represent the population of women with employer-sponsored health insurance in the United States. None. The proportion of women with clinically significant leiomyomas was determined in each year, based on inpatient and outpatient medical claims with diagnostic codes indicating leiomyoma. Patient characteristics, comorbidities, prescription drug treatments, and surgical interventions were profiled in 2004. Approximately 1% of women had clinically significant leiomyomas. Comorbid genital or menstrual conditions were common and much more prevalent for women with leiomyomas. Of women with leiomyomas, 18.4% received no surgical or prescription drug treatment, whereas 16.8% received only surgical treatment, 22.4% received only prescription drug treatment, and 42.4% received both. Hysterectomy was the most common surgical treatment. Generalizing from this sample, we estimate that 443,445 women with employer-sponsored insurance in the United States had clinically significant leiomyomas in 2004.


Advances in detection and quantification of methylcytosine and its derivatives.
Methylation of the fifth carbon atom in cytosine is an epigenetic modification of deoxyribonucleic acid that plays important roles in numerous cellular processes and disease pathogenesis. Three additional states of cytosine, that is, 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine, have been identified and associated with the diagnosis and/or prognosis of diseases. However, accurate measurement of those intermediates is a challenge since their global levels are relatively low. A number of innovative methods have been developed to detect and quantify these compounds in biological samples, such as blood, tissue and urine, etc. This review focuses on recent advancement in detection and quantification of four cytosine modifications, based on which, the development, diagnosis, and prognosis of diseases could be monitored through non-invasive procedures.


Anticoagulant Prescribing for Non-Valvular Atrial Fibrillation in the Veterans Health Administration.
Background Direct acting oral anticoagulants (DOACs) theoretically could contribute to addressing underuse of anticoagulation in non-valvular atrial fibrillation (NVAF). Few studies have examined this prospect, however. The potential of DOACs to address underuse of anticoagulation in NVAF could be magnified within a healthcare system that sharply limits patients' exposure to out-of-pocket copayments, such as the Veterans Health Administration (VA). Methods and Results We used a clinical data set of all patients with NVAF treated within VA from 2007 to 2016 (n=987 373). We examined how the proportion of patients receiving any anticoagulation, and which agent was prescribed, changed over time. When first approved for VA use in 2011, DOACs constituted a tiny proportion of all prescriptions for anticoagulants (2%); by 2016, this proportion had increased to 45% of all prescriptions and 67% of new prescriptions. Patient characteristics associated with receiving a DOAC, rather than warfarin, included white race, better kidney function, fewer comorbid conditions overall, and no history of stroke or bleeding. In 2007, before the introduction of DOACs, 56% of VA patients with NVAF were receiving anticoagulation; this dipped to 44% in 2012 just after the introduction of DOACs and had risen back to 51% by 2016. Conclusions These results do not suggest that the availability of DOACs has led to an increased proportion of patients with NVAF receiving anticoagulation, even in the context of a healthcare system that sharply limits patients' exposure to out-of-pocket copayments.


Medical Instrument Detection in 3-Dimensional Ultrasound Data Volumes.
Ultrasound-guided medical interventions are broadly applied in diagnostics and therapy, e.g., regional anesthesia or ablation. A guided intervention using 2-D ultrasound is challenging due to the poor instrument visibility, limited field of view, and the multi-fold coordination of the medical instrument and ultrasound plane. Recent 3-D ultrasound transducers can improve the quality of the image-guided intervention if an automated detection of the needle is used. In this paper, we present a novel method for detecting medical instruments in 3-D ultrasound data that is solely based on image processing techniques and validated on various ex vivo and in vivo data sets. In the proposed procedure, the physician is placing the 3-D transducer at the desired position, and the image processing will automatically detect the best instrument view, so that the physician can entirely focus on the intervention. Our method is based on the classification of instrument voxels using volumetric structure directions and robust approximation of the primary tool axis. A novel normalization method is proposed for the shape and intensity consistency of instruments to improve the detection. Moreover, a novel 3-D Gabor wavelet transformation is introduced and optimally designed for revealing the instrument voxels in the volume, while remaining generic to several medical instruments and transducer types. Experiments on diverse data sets, including in vivo data from patients, show that for a given transducer and an instrument type, high detection accuracies are achieved with position errors smaller than the instrument diameter in the 0.5-1.5-mm range on average.


Silencing of polo-like kinase (Plk) 1 via siRNA causes inhibition of growth and induction of apoptosis in human esophageal cancer cells.
Esophageal cancer ranks among one of the most frequent causes of cancer death in the world. Polo-like kinase 1 (Plk1) is overexpressed in human tumors and has prognostic value in many cancers including esophageal cancer, indicating its potential as a therapeutic target. In this study, we investigated the therapeutic potential of Plk1 in esophageal cancer using the technique of RNA silencing via small interfering RNA (siRNA). Synthetic siRNA duplexes against Plk1 were introduced into 4 esophageal cancer cell lines, which subsequently resulted in a significant inhibition in Plk1 expression in the cells. We found that the targeted depletion of Plk1 caused a dramatic mitotic catastrophe (mitotic cell cycle arrest as well as defects in several mitotic events such as incomplete separation of sister chromatids and failure of cytokinesis) followed by massive apoptotic cell death, and eventually resulted in a significant decrease in growth and viability of all 4 esophageal cancer cell lines studied. In addition, our results also indicated that the mitotic arrest induced by Plk1 depletion is mediated by the inactivation of the cdc2/cyclin B1 complex. Taken together, our study strongly suggests that Plk1 may serve as a potential therapeutic target in human esophageal cancer.


Monitoring methods and dose assessment for internal exposures involving mixed fission and activation products containing actinides.
Internal dose assessment for intakes of radionuclide mixtures is a difficult task. When the radionuclide mixture contains both the easy to detect gamma emitters, e.g., 60Co and 95Zr, and difficult to detect alpha emitters such as 239Pu and 241Am, a single monitoring method, such as in-vivo counting, is inadequate for detection and dose assessment. Recent experience with task related monitoring for such radionuclide mixtures at Ontario Power Generation CANDU nuclear power plants has offered an opportunity to review this topic and suggest a strategy for monitoring that involves a combination of in-vivo and in-vitro methods. Using the radionuclide composition data in a mixture from an actual case as an example, this paper describes a monitoring strategy for mixed fission and activation products, including the advantages and pitfalls of reliance on surrogate radionuclides for signaling the presence of actinides in the mixture. The described monitoring strategy is consistent with the recommendations of ICRP Publication 78, which advocates a "combination of techniques so as to make the best possible evaluation of an unusual situation, for example, a programme of both body activity and excreta measurements." The use of experience and professional judgement for interpreting the combined in-vivo and in-vitro data for interim and ultimate intake and dose assessment is discussed and emphasized.


Evaluation of cytotoxic potential of structurally well-characterized RNA targeted ionic non-steroidal anti-inflammatory (NSAID) Cu(ii) & Zn(ii) DACH-mefenamato drug conjugates against human cancer cell lines.
New RNA targeted ionic [Cu(DACH)2(H2O)2](mef)2, 1 and [Zn(DACH)2(H2O)2](mef)2, 2 drug conjugates were synthesized and characterized by spectroscopic techniques FT-IR, UV-vis, EPR in case of 1 and 1H and 13C NMR in case of 2, ESI-MS, thermogravimetric analysis and single-crystal X-ray structure determination in case of 1. The interaction studies of 1 & 2 with most likely drug targets like ctDNA and tRNA were performed which demonstrated that the complexes 1 and 2 exhibited strong preferential binding to tRNA as compared to ctDNA, K b = 2.52(±0.04) × 105 M-1, 7.85(±0.02) × 104 M-1, respectively. Scanning electron microscopy analyses of complex-ctDNA/tRNA condensates suggested the interaction of complexes with ctDNA/tRNA had occurred, followed by lengthening of DNA double helix and bulge region of tRNA. Cytotoxic activity of 1 and 2 against human cancer cell lines namely; MCF-7 (breast), HeLa (cervical), MIA-PA-CA 2 (pancreatic), A-498 (kidney), Hep-G2 (hepatoma) was evaluated by SRB assay. The obtained results showed that copper complex 1 was an outstanding cytotoxic agent with remarkably good GI50 value (<10 μg ml-1) against the tested cancer cell lines except for MIA-PA-CA 2, while zinc complex 2 revealed moderate cytotoxicity against all the tested cancer cell lines.


Hypercoagulability biomarkers in Trypanosoma cruzi -infected patients.
There is a current controversy over the hypothesis that a number of thromboembolic events could be related to hypercoagulable state in patients with chronic Chagas disease. This study was designed to determine whether a prothrombotic state existed in chronic Trypanosoma cruzi-infected patients and, if so, to describe its evolution after treatment with Benznidazole. Twenty-five patients with chronic Chagas disease and 18 controls were evaluated. The markers used were prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin, plasminogen, protein C, total protein S, free protein S, factor VIII, D-dimer, activated factor VIIa, tissue-type plasminogen activator inhibitor-1, prothrombin fragment 1+2 (F₁+₂), plasmin-antiplasmin complexes, soluble P-selectin and endogenous thrombin potential (ETP). Despite statistically significant differences between cases and controls in several markers, only ETP (which quantifies the ability of plasma to generate thrombin when activated through tissue factor addition) (p<0.0001) and F₁+₂ (a marker of thrombin generation in vivo) (p<0.0001) showed values outside the normal levels in patients compared with controls. Similar results were obtained in these markers six months after treatment in the cohort of cases (p<0.0008 and p<0.004, respectively). These results may be relevant in clinical practice. Though current treatment for Chagas disease is still controversial, if it were considered as a thromboembolic risk factor the antiparasitic treatment strategy could be reinforced. The results also support further research on haemostasis parameters as candidates for early surrogate biomarkers of cure or progression of Chagas disease.


Actin, a central player in cell shape and movement.
The protein actin forms filaments that provide cells with mechanical support and driving forces for movement. Actin contributes to biological processes such as sensing environmental forces, internalizing membrane vesicles, moving over surfaces, and dividing the cell in two. These cellular activities are complex; they depend on interactions of actin monomers and filaments with numerous other proteins. Here, we present a summary of the key questions in the field and suggest how those questions might be answered. Understanding actin-based biological phenomena will depend on identifying the participating molecules and defining their molecular mechanisms. Comparisons of quantitative measurements of reactions in live cells with computer simulations of mathematical models will also help generate meaningful insights.


Genes contribute to the switching dynamics of bistable perception.
Ordinarily, the visual system provides an unambiguous representation of the world. However, at times alternative plausible interpretations of a given stimulus arise, resulting in a dynamic perceptual alternation of the differing interpretations, commonly referred to as bistable or rivalrous perception. Recent research suggests that common neural mechanisms may be involved in the dynamics of very different types of bistable phenomena. Further, evidence has emerged that genetic factors may be involved in determining the rate of switch for at least one form of bistable perception, known as binocular rivalry. The current study evaluated whether genetic factors contribute to the switching dynamics for distinctly different variants of bistable perception in the same participant sample. Switching rates were recorded for MZ and DZ twin participants in two different bistable perception tasks, binocular rivalry and the Necker Cube. Strong concordance in switching rates across both tasks was evident for MZ but not DZ twins, indicating that genetic factors indeed contribute to the dynamics of multiple forms of bistable perception.


Expanding the scope of strained-alkyne chemistry: a protection-deprotection strategy via the formation of a dicobalt-hexacarbonyl complex.
A protection-deprotection strategy for strained alkynes used for bioorthogonal chemistry is reported. A strained alkyne can be protected with dicobalt-octacarbonyl and we demonstrate for the first time that a strained alkyne can be re-formed and isolated under mild reaction conditions for further bioorthogonal reactivity. The protection-deprotection strategy herein reported will expand the versatility of strained alkynes for the preparation of substrates in chemical biology and materials applications.


Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy.
To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook.


Unveiling the clinical and electrophysiological profile of CMTX6: Insights from two Brazilian families.
X-linked Charcot-Marie-Tooth disease type 6 (CMTX6) is an extremely rare condition associated with mutations in the PDK3 gene. To date, only three families from different countries have been reported (Australia, South Korea, and Germany). In this study, we sought to provide a comprehensive clinical and electrophysiological characterization of two Brazilian families. We conducted comprehensive clinical assessments, extensive electrophysiological evaluations, and performed whole-exome sequencing in the probands to investigate the genetic basis of the disease. Males in the family carrying the Arg162His mutation displayed early-onset motor and/or sensory axonal neuropathy, absence of tendon jerks, pes cavus, and frequently reported pain. Females in the same family exhibited a milder phenotype of the disease with later onset and some remained asymptomatic into their 50s. In the unrelated family with a single affected male, the clinical presentation was characterized by severe progressive sensorimotor polyneuropathy accompanied by neuropathic pain. We report two Brazilian families with CMTX6 including one harboring a previously unpublished variant in the PDK3 gene, which co-segregates with the disease as expected in a X-linked disease. Notably, the clinical presentations across the five families with available descriptions, including our study, share striking similarities. Furthermore, the proximity of the three reported mutations suggests potential functional similarities and common underlying mechanisms. This study contributes to the growing knowledge of CMTX6 and underscores the importance of international collaborations in studying rare genetic disorders.


Entry of Trypanosoma (Schizotrypanum) dionisii to macrophages in vitro and its subsequent fate therein.
Observations by phase contrast, fluorescence and electron microscopy showed that epimastigotes of Trypanosoma (Schizotrypanum) dionisii (grown in vitro) were phagocytosed posterior end first by mouse peritoneal macrophages in vitro. Many were subsequently digested as a result of phagosome-lysosome fusion but others survived by apparently inhibiting this fusion and/or escaping from the phagosome into the host cell's cytoplasm. These survivors replicated as amastigotes. Long trypomastigotes, separated from populations grown in vitro by passage down a column of glass beads (with or without prior exposure to guinea-pig serum), were phagocytosed by either pole and all were subsequently digested.


MAP2 Isoforms in Developing Cat Cerebral Cortex and Corpus Callosum.
The microtubule-associated protein MAP2 was studied in the developing cat visual cortex and corpus callosum. Biochemically, no MAP2a was detectable in either structure during the first postnatal month; adult cortex revealed small amounts of MAP2a. MAP2b was abundant in cortical tissue during the first postnatal month and decreased in concentration towards adulthood; it was barely detectable in corpus callosum at all ages. MAP2c was present in cortex and corpus callosum at birth; in cortex it consisted of three proteins of similar molecular weights between 65 and 70 kD. The two larger, phosphorylated forms disappeared after postnatal day 28, the smaller form after day 39. In corpus callosum, MAP2c changed from a phosphorylated to an unphosphorylated variant during the first postnatal month and then disappeared. Immunocytochemical experiments revealed MAP2 in cell bodies and dendrites of neurons in all cortical layers, from birth onwards. In corpus callosum, in the first month after birth, a little MAP2, possibly MAP2c, was detectable in axons. The present data indicate that MAP2 isoforms differ in their cellular distribution, temporal appearance and structural association, and that their composition undergoes profound changes during the period of axonal stabilization and dendritic maturation.


The use of SCID mice for the growth of retinoblastoma cell lines and for the establishment of xenografts from primary tumours.
We investigated the possibility of growing primary retinoblastoma tumour tissue in SCID mice. In preliminary experiments with the WERI retinoblastoma cell line injected subcutaneously in SCID mice, tumours arose at only 25% of the inoculation sites. After mixing these cells with a reconstituted basement membrane extracellular matrix (Matrigel) prior to inoculation, tumours arose at 100% of inoculated sites. When primary retinoblastoma cells were injected subcutaneously into SCID mice in the presence of Matrigel, tumours arose in 5/8 cases. On average, the latency period was 4 months before the tumours were palpable. Histopathological examination of the tumours showed that they resembled surgically resected human retinoblastomas and one of the tumours formed pseudo-rosettes which is a characteristic of these tumours. Unfortunately, when these xenografted tumours were introduced into tissue culture, it was not possible to establish cell lines directly and the cultures were soon overgrown by mouse cells which could clearly be shown to be infiltrating the tumour. The ability to grow retinoblastoma cell lines and primary tissue subcutaneously in SCID mice offers a convenient model system to study the genetics of tumorigenesis in this tumour type and possibly an opportunity to study the role of chemotherapy in the treatment and progression of the disease.


Adolescent Onset of Maternal Substance Abuse: Descriptive Findings from a Feasibility Trial.
Although maternal substance abuse in child welfare populations is a well-documented occurrence, little is known about the onset of these behaviors or the substance abuse histories of these mothers. Descriptive data from a small feasibility trial of mothers referred for substance abuse and child neglect suggest adolescent onset of hard substance use. Age of onset was associated with family history of use. The majority of mothers reported polysubstance abuse starting at an early age and quickly escalating patterns of behavior including IV drug use. Implications for prevention efforts for children of families identified with substance abuse problems are discussed.


Expression of the EspB protein of enteropathogenic Escherichia coli within HeLa cells affects stress fibers and cellular morphology.
The EspB protein of enteropathogenic Escherichia coli (EPEC) is essential for the signaling events that lead to the accumulation of actin beneath intimately attached bacteria, a process that is known as the attaching and effacing effect. EspB is targeted to the host cell cytoplasm by a type III secretion apparatus. To determine the effect of intracellular EspB on the host cell cytoskeleton, we transfected HeLa cells with a plasmid containing the espB gene under the control of an inducible eukaryotic promoter. A HeLa cell clone that expressed espB mRNA and EspB protein after induction was selected for further study. The expression of EspB in these cells caused a dramatic change in cell morphology and a marked reduction in actin stress fibers. Cells expressing EspB were significantly impaired in their ability to support invasion by EPEC and Salmonella typhimurium. However, the expression of EspB within host cells could not compensate for the lack of EspB expression by an espB mutant strain of EPEC to restore attaching and effacing activity. These studies suggest that EspB is a cytoskeletal toxin that is translocated to the host cell cytoplasm, where it causes a redistribution of actin.


A Strategy for the Acquisition and Analysis of Image-Based Phenome in Rice during the Whole Growth Period.
As one of the most widely grown crops in the world, rice is not only a staple food but also a source of calorie intake for more than half of the world's population, occupying an important position in China's agricultural production. Thus, determining the inner potential connections between the genetic mechanisms and phenotypes of rice using dynamic analyses with high-throughput, nondestructive, and accurate methods based on high-throughput crop phenotyping facilities associated with rice genetics and breeding research is of vital importance. In this work, we developed a strategy for acquiring and analyzing 58 image-based traits (i-traits) during the whole growth period of rice. Up to 84.8% of the phenotypic variance of the rice yield could be explained by these i-traits. A total of 285 putative quantitative trait loci (QTLs) were detected for the i-traits, and principal components analysis was applied on the basis of the i-traits in the temporal and organ dimensions, in combination with a genome-wide association study that also isolated QTLs. Moreover, the differences among the different population structures and breeding regions of rice with regard to its phenotypic traits demonstrated good environmental adaptability, and the crop growth and development model also showed high inosculation in terms of the breeding-region latitude. In summary, the strategy developed here for the acquisition and analysis of image-based rice phenomes can provide a new approach and a different thinking direction for the extraction and analysis of crop phenotypes across the whole growth period and can thus be useful for future genetic improvements in rice.


Metabolite traits and genetic risk provide complementary information for the prediction of future type 2 diabetes.
A genetic risk score (GRS) comprised of single nucleotide polymorphisms (SNPs) and metabolite biomarkers have each been shown, separately, to predict incident type 2 diabetes. We tested whether genetic and metabolite markers provide complementary information for type 2 diabetes prediction and, together, improve the accuracy of prediction models containing clinical traits. Diabetes risk was modeled with a 62-SNP GRS, nine metabolites, and clinical traits. We fit age- and sex-adjusted logistic regression models to test the association of these sources of information, separately and jointly, with incident type 2 diabetes among 1,622 initially nondiabetic participants from the Framingham Offspring Study. The predictive capacity of each model was assessed by area under the curve (AUC). Two hundred and six new diabetes cases were observed during 13.5 years of follow-up. The AUC was greater for the model containing the GRS and metabolite measurements together versus GRS or metabolites alone (0.820 vs. 0.641, P < 0.0001, or 0.820 vs. 0.803, P = 0.01, respectively). Odds ratios for association of GRS or metabolites with type 2 diabetes were not attenuated in the combined model. The AUC was greater for the model containing the GRS, metabolites, and clinical traits versus clinical traits only (0.880 vs. 0.856, P = 0.002). Metabolite and genetic traits provide complementary information to each other for the prediction of future type 2 diabetes. These novel markers of diabetes risk modestly improve the predictive accuracy of incident type 2 diabetes based only on traditional clinical risk factors.


Cutting Edge: Chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions.
Dual expression of chemokine receptor CCR4 and E-selectin ligand is characteristic of skin-tropic CD4 T cells from blood, lymphoid organs, and the skin itself. A strong and specific correlation exists among CCR4, its ligand CCL17/TARC, and the cutaneous lymphocyte-homing process. Nevertheless, whether CCR4 function is required for skin-specific trafficking remains an open question, which we address in this study. We developed an Ag-specific, TCR-transgenic, murine CD4 T cell adoptive transfer model that induces a mixed Th1 and Th17 cutaneous response. Within the hosts, both CCR4(+/+) and CCR4(-/-) donor CD4 T cells contribute equally well to the circulating E-selectin ligand(+) pool in response to Ag. However, only CCR4(+/+) donor cells accumulate efficiently within the skin. CCR4(-/-) cells home normally to the peritoneum, showing that they do not have a general defect in lymphocyte trafficking. We conclude that under physiological conditions, CCR4 is a nonredundant, necessary component of skin-specific lymphocyte trafficking.


Recall of Philip Morris cigarettes, May 1995-March 1996.
On May 26, 1995, Philip Morris U.S.A. announced a voluntary recall of 36 cigarette product lines (approximately 8 billion cigarettes) because, during production, the company detected unusual tastes and peculiar odors and identified methyl isothiocyanate (MITC) in the cigarette filters. During June 6-8, 1995, public health officials in Minnesota, Oregon, and Texas requested CDC's assistance in investigating consumer health complaints associated with smoking Philip Morris cigarettes near the time of the recall. This report summarizes CDC's ongoing investigation, which suggests that prolonged cigarette smoking caused most of the health complaints; in addition, the investigation has not identified a distinguishing chemical characteristic of the recalled cigarettes.


Genetic Identification of Trichomonas vaginalis by Using the Actin Gene and Molecular Based Methods.
Trichomonas vaginalis is the agent of urogenital tract infection that causes human trichomoniasis with some serious health complications. More understanding about genetic features of the parasite can be helpful in the study of the pathogenesis, drug susceptibility and epidemiology of the infection. For this end, we conducted analysis of the actin gene of T. vaginalis by applying the PCR-SSCP (PCR-Single Stranded Conformational Polymorphism) and nucleotide sequencing method. Fifty T. vaginalis samples were collected from 950 women attending gynecology clinics in two cities of Iran, Hamadan and Tehran, from November 2010 to July 2011. After axenisation of isolates, all samples subjected to PCR-SSCP and nucleotide sequencing. According to the SSCP banding patterns and nucleotide sequencing, seven sequence types were detected among the isolates. Alignment of the nucleotide sequences showed five polymorphic sites in the different strain types. Amino acid substitution was not observed in the nucleotide sequence translation of the all sequences. The actin gene analysis represents genetic diversity of T. vaginalis and it suggests that various strains can be responsible for clinically different trichomoniasis in infected individuals. It is expected that further studies will be conducted to increase our knowledge about relationship between the actin gene polymorphism and different biological behavior of the parasite.


[Cyclic nucleotides and lipids in the realization of the radioprotective effect of ceruloplasmin].
Ceruloplasmin administered 60 min before irradiation diminished cAMP and cGMP levels, which were increased by irradiation at LD50 and LD100, and normalized cAMP/cGMP ratio in the rat liver during the first 24 h following irradiation with a dose of 6.24 Gy. The content of phospholipids increased and that of cholesterol decreased under the effect of ceruloplasmin leading to normalization of the molar cholesterol/phospholipid ratio in the rat liver on the 7th day of radiation sickness (LD50, 6.24 Gy).


A microfluidic chamber for analysis of neuron-to-cell spread and axonal transport of an alpha-herpesvirus.
Alpha-herpesviruses, including herpes simplex virus and pseudorabies virus (PRV), infect the peripheral nervous system (PNS) of their hosts. Here, we describe an in vitro method for studying neuron-to-cell spread of infection as well as viral transport in axons. The method centers on a novel microfluidic chamber system that directs growth of axons into a fluidically isolated environment. The system uses substantially smaller amounts of virus inoculum and media than previous chamber systems and yet offers the flexibility of applying multiple virology and cell biology assays including live-cell optical imaging. Using PRV infection of cultured PNS neurons, we demonstrate that the microfluidic chamber recapitulates all known facets of neuron-to-cell spread demonstrated in animals and other compartmented cell systems.


Current models broadly neglect specific needs of biodiversity conservation in protected areas under climate change.
Protected areas are the most common and important instrument for the conservation of biological diversity and are called for under the United Nations' Convention on Biological Diversity. Growing human population densities, intensified land-use, invasive species and increasing habitat fragmentation threaten ecosystems worldwide and protected areas are often the only refuge for endangered species. Climate change is posing an additional threat that may also impact ecosystems currently under protection. Therefore, it is of crucial importance to include the potential impact of climate change when designing future nature conservation strategies and implementing protected area management. This approach would go beyond reactive crisis management and, by necessity, would include anticipatory risk assessments. One avenue for doing so is being provided by simulation models that take advantage of the increase in computing capacity and performance that has occurred over the last two decades.Here we review the literature to determine the state-of-the-art in modeling terrestrial protected areas under climate change, with the aim of evaluating and detecting trends and gaps in the current approaches being employed, as well as to provide a useful overview and guidelines for future research. Most studies apply statistical, bioclimatic envelope models and focus primarily on plant species as compared to other taxa. Very few studies utilize a mechanistic, process-based approach and none examine biotic interactions like predation and competition. Important factors like land-use, habitat fragmentation, invasion and dispersal are rarely incorporated, restricting the informative value of the resulting predictions considerably. The general impression that emerges is that biodiversity conservation in protected areas could benefit from the application of modern modeling approaches to a greater extent than is currently reflected in the scientific literature. It is particularly true that existing models have been underutilized in testing different management options under climate change. Based on these findings we suggest a strategic framework for more effectively incorporating the impact of climate change in models exploring the effectiveness of protected areas.


Comparison of membrane targeting strategies for the accumulation of the human immunodeficiency virus p24 protein in transgenic tobacco.
Membrane anchorage was tested as a strategy to accumulate recombinant proteins in transgenic plants. Transmembrane domains of different lengths and topology were fused to the cytosolic HIV antigen p24, to promote endoplasmic reticulum (ER) residence or traffic to distal compartments of the secretory pathway in transgenic tobacco. Fusions to a domain of the maize seed storage protein γ-zein were also expressed, as a reference strategy that leads to very high stability via the formation of large polymers in the ER lumen. Although all the membrane anchored constructs were less stable compared to the zein fusions, residence at the ER membrane either as a type I fusion (where the p24 sequence is luminal) or a tail-anchored fusion (where the p24 sequence is cytosolic) resulted in much higher stability than delivery to the plasma membrane or intermediate traffic compartments. Delivery to the tonoplast was never observed. The inclusion of a thrombin cleavage site allowed for the quantitative in vitro recovery of p24 from all constructs. These results point to the ER as suitable compartment for the accumulation of membrane-anchored recombinant proteins in plants.


Building a bioinformatics ontology using OIL.
This paper describes the initial stages of building an ontology of bioinformatics and molecular biology. The conceptualization is encoded using the ontology inference layer (OIL), a knowledge representation language that combines the modeling style of frame-based systems with the expressiveness and reasoning power of description logics (DLs). This paper is the second of a pair in this special issue. The first described the core of the OIL language and the need to use ontologies to deliver semantic bioinformatics resources. In this paper, the early stages of building an ontology component of a bioinformatics resource querying application are described. This ontology (TaO) holds the information about molecular biology represented in bioinformatics resources and the bioinformatics tasks performed over these resources. It, therefore, represents the metadata of the resources the application can query. It also manages the terminologies used in constructing the query plans used to retrieve instances from those external resources. The methodology used in this task capitalizes upon features of OIL-The conceptualization afforded by the frame-based view of OIL's syntax; the expressive power and reasoning of the logical formalism; and the ability to encode both handcrafted, hierarchies of concepts, as well as defining concepts in terms of their properties, which can then be used to establish a classification and infer relationships not encoded by the ontologist. This ability forms the basis of the methodology described here: For each portion of the TaO, a basic framework of concepts is asserted by the ontologist. Then, the properties of these concepts are defined by the ontologist and the logic's reasoning power used to reclassify and infer further relationships. This cycle of elaboration and refinement is iterated on each portion of the ontology until a satisfactory ontology has been created.


Bioinspired passive anti-biofouling surfaces preventing biofilm formation.
Biofilm formation enables bacteria to grow under unfavorable conditions, provides them with protection, and increases their resistance to antimicrobial agents. Once a biofilm has formed, it is difficult, and in some systems, impossible to treat. Strategies based on the release of biocidal agents have shown only transient efficiency. Herein, we present a novel bioinspired passive approach to the prevention of surface biofilm attachment by exploiting superhydrophobic surfaces formed via the self-assembly of paraffin or fluorinated wax crystals. Our surfaces show exceptional ability to inhibit biofilm formation of both Gram-positive Bacillus cereus and Gram-negative Pseudomonas aeruginosa over a 7 day period (up to 99.9% inhibition).


Distribution of genes for trimethoprim and gentamicin resistance in bacteria and their plasmids in a general hospital.
The incidence of trimethoprim resistance in enterobacteria causing infection in a London hospital increased from 5.6% in 1970 to 16% in 1979. The proportion of gentamicin-resistant aerobic Gram-negative bacilli had risen to 6.5% by 1979. During a 5-month period in 1977, during which no epidemic was recognized, all isolates resistant to either trimethoprim, gentamicin, tobramycin or amikacin were studied. The proportion of enterobacteria resistant to both trimethoprim and gentamicin (3.8% of the total) was significantly higher than expected assuming no correlation between acquisition of resistance characters. The resistance was transferable in 23% of trimethoprim-resistant and 76% of gentamicin-resistant strains. Trimethoprim resistance was carried by plasmids of seven different incompatibility groups and in at least four instances was part of a transposon. Gentamicin resistance was determined by plasmids of three groups - IncC, IncFII and IncW. Transposition of gentamicin resistance was not shown, though this may have been the means of evolution of the gentamicin R plasmids of InW, which determined aminoglycoside acetyltransferase, AAC(3). Some bacterial strains with their plasmids were endemic. There was evidence for these plasmids (i) acquiring new resistance genes by transposition, (ii) losing resistance genes by deletion and (iii) being transferred between bacterial species in the hospital.


Soluble TNFα Signaling within the Spinal Cord Contributes to the Development of Autonomic Dysreflexia and Ensuing Vascular and Immune Dysfunction after Spinal Cord Injury.
Cardiovascular disease and susceptibility to infection are leading causes of morbidity and mortality for individuals with spinal cord injury (SCI). A major contributor to these is autonomic dysreflexia (AD), an amplified reaction of the autonomic nervous system (hallmarked by severe hypertension) in response to sensory stimuli below the injury. Maladaptive plasticity of the spinal sympathetic reflex circuit below the SCI results in AD intensification over time. Mechanisms underlying this maladaptive plasticity are poorly understood, restricting the identification of treatments. Thus, no preventative treatments are currently available. Neuroinflammation has been implicated in other pathologies associated with hyperexcitable neural circuits. Specifically, the soluble form of TNFα (sTNFα) is known to play a role in neuroplasticity. We hypothesize that persistent expression of sTNFα in spinal cord underlies AD exacerbation. To test this, we intrathecally administered XPro1595, a biologic that renders sTNFα nonfunctional, after complete, high-level SCI in female rats. This dramatically attenuated the intensification of colorectal distension-induced and naturally occurring AD events. This improvement is mediated via decreased sprouting of nociceptive primary afferents and activation of the spinal sympathetic reflex circuit. We also examined peripheral vascular function using ex vivo pressurized arterial preparations and immune function via flow cytometric analysis of splenocytes. Diminishing AD via pharmacological inhibition of sTNFα mitigated ensuing vascular hypersensitivity and immune dysfunction. This is the first demonstration that neuroinflammation-induced sTNFα is critical for altering the spinal sympathetic reflex circuit, elucidating a novel mechanism for AD. Importantly, we identify the first potential pharmacological, prophylactic treatment for this life-threatening syndrome.SIGNIFICANCE STATEMENT Autonomic dysreflexia (AD), a disorder that develops after spinal cord injury (SCI) and is hallmarked by sudden, extreme hypertension, contributes to cardiovascular disease and susceptibility to infection, respectively, two leading causes of mortality and morbidity in SCI patients. We demonstrate that neuroinflammation-induced expression of soluble TNFα plays a critical role in AD, elucidating a novel underlying mechanism. We found that intrathecal administration after SCI of a biologic that inhibits soluble TNFα signaling dramatically attenuates AD and significantly reduces AD-associated peripheral vascular and immune dysfunction. We identified mechanisms behind diminished plasticity of neuronal populations within the spinal sympathetic reflex circuit. This study is the first to pinpoint a potential pharmacological, prophylactic strategy to attenuate AD and ensuing cardiovascular and immune dysfunction.


Urine-based detection of intestinal tight junction loss.
Tight junction breakdown, with loss of the important sealing protein claudin-3, is an early event in the development of intestinal damage. Therefore, noninvasive analysis of intestinal tight junction status could be helpful in early detection of intestinal injury. To investigate the usefulness of urinary claudin-3 as marker for intestinal tight junction loss. A rat hemorrhagic shock model and a human setting of known intestinal damage, that is, patients with relapsed inflammatory bowel disease (IBD), were used to investigate intestinal tight junction status by immunohistochemical staining and urinary claudin-3 levels by western blot. In rats claudin-3 urine levels increased rapidly after histologically proven intestinal tight junction loss, with significantly elevated levels at 90 minutes after shock compared with sham-operated animals [mean+/-SEM: 611+/-101 intensity (INT), n=6 vs. 232+/-30 INT, n=6; P<0.05]. Moreover, in colonic biopsies of patients with IBD relapse claudin-3 staining was reduced compared with biopsies of patients with IBD without signs of disease. Concomitantly, significantly increased claudin-3 urine levels were found in these patients (502+/-67 INT, n=10) compared with patients with IBD in remission (219+/-17 INT, n=10, P<0.001) and healthy volunteers (225+/-38 INT, n=10, P<0.001). Here we show for the first time in both an experimental and clinical setting a strong relation between intestinal tight junction loss and urinary claudin-3 levels. These findings suggest that measurement of urinary claudin-3 can be used as noninvasive marker for intestinal tight junction loss. This offers new opportunities for early diagnosis and follow-up of intestinal injury.


Sleep variability in military-related PTSD: a comparison to primary insomnia and healthy controls.
Sleep disturbances are prevalent in posttraumatic stress disorder (PTSD) and are associated with a number of adverse health consequences. Few studies have used comprehensive assessment methods to characterize sleep in Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OEF/OIF/OND) veterans with PTSD. OEF/OIF/OND veterans with PTSD and sleep disturbance (n = 45) were compared to patients with primary insomnia (n = 25) and healthy control subjects (n = 27). Participants were assessed using questionnaire-based measures as well as daily subjective and objective measures of sleep. The 3 groups were compared with regard to (a) group means, (b) intraindividual (i.e., night-to-night) variability of sleep, and (c) interindividual (i.e., within-group) variability of sleep. In terms of group means, only objective sleep efficiency was significantly worse with PTSD than with primary insomnia (d = 0.54). Those with PTSD differed from those with primary insomnia on measures of intraindividual as well as interindividual variability (d = 0.48-0.73). These results suggested sleep symptoms in OEF/OIF/OND veterans with PTSD are more variable across nights and less consistent across patients relative to sleep symptoms in insomnia patients without PTSD. These findings have implications for research, as well as for personalizing treatment for individuals with PTSD.


Assessing pneumococcal meningitis association with viral respiratory infections and antibiotics: insights from statistical and mathematical models.
Pneumococcus is an important human pathogen, highly antibiotic resistant and a major cause of bacterial meningitis worldwide. Better prevention requires understanding the drivers of pneumococcal infection incidence and antibiotic susceptibility. Although respiratory viruses (including influenza) have been suggested to influence pneumococcal infections, the underlying mechanisms are still unknown, and viruses are rarely considered when studying pneumococcus epidemiology. Here, we propose a novel mathematical model to examine hypothetical relationships between Streptococcus pneumoniae meningitis incidence (SPMI), acute viral respiratory infections (AVRIs) and antibiotic exposure. French time series of SPMI, AVRI and penicillin consumption over 2001-2004 are analysed and used to assess four distinct virus-bacteria interaction submodels, ascribing the interaction on pneumococcus transmissibility and/or pathogenicity. The statistical analysis reveals strong associations between time series: SPMI increases shortly after AVRI incidence and decreases overall as the antibiotic-prescription rate rises. Model simulations require a combined impact of AVRI on both pneumococcal transmissibility (up to 1.3-fold increase at the population level) and pathogenicity (up to threefold increase) to reproduce the data accurately, along with diminished epidemic fitness of resistant pneumococcal strains causing meningitis (0.97 (0.96-0.97)). Overall, our findings suggest that AVRI and antibiotics strongly influence SPMI trends. Consequently, vaccination protecting against respiratory virus could have unexpected benefits to limit invasive pneumococcal infections.


Metastatic paraganglioma.
Paragangliomas (PGLs) are chromaffin cell tumors arising from ganglia; when arising in the adrenal gland they are called pheochromocytomas. In recent years the opinion that metastatic disease is rare in PGL had to be revised, particularly in patients presenting with extra-adrenal PGL, with PGLs exceeding 5 cm in diameter, and/or those carrying an SDHB germline mutation. Metastases are expected to be present at the time of diagnosis in more than 10% of these patients. Measurement of plasma and urinary metanephrine levels is well established in diagnosing PGL. Recently, a dopaminergic phenotype (excess dopamine or methoxytyramine) was recognized as a good indicator of metastatic disease. Vast progress in targeted positron emission tomography (PET) imaging (eg, (18)F-FDA, (18)F-FDOPA, (18)F-FDG) now allows for reliable early detection of metastatic disease. However, once metastases are present, treatment options are limited. Survival of patients with metastatic PGL is variable, and frequently short. Here we review recent advances involving findings about the genetic background, the molecular pathogenesis, new diagnostic indicators, pathologic markers, and emerging treatment options for metastatic PGL.


Clinical impact of neoadjuvant treatment in resectable pancreatic cancer: a systematic review and meta-analysis protocol.
Although the only curative strategy for pancreatic cancer is surgical resection, up to 85% of patients relapse after surgery. The efficacy of neoadjuvant treatment in resectable pancreatic cancer (RPC) remains unclear and there is no systematic review focusing fully on this issue. Recently, two prospective trials of neoadjuvant treatment in RPC were terminated early because of slow recruiting and existing randomised controlled trials (RCTs) have too small sample sizes. Therefore, to overcome probable biases, it would be more reasonable to include both RCTs and non-randomised studies (NRSs) with selected criteria. This review aims to investigate the effect of neoadjuvant chemotherapy (CTx) and chemoradiation therapy (CRT) in RPC using RCTs and specific NRSs. This systematic review will include conventional RCTs as group I, and quasi-randomised controlled trials, non-randomised controlled trials and prospective cohort studies as group II. Two groups will be assessed and analysed separately. Comprehensive literature search will use Medline, Embase, Cochrane library and Scopus databases. Additionally, we will search references from relevant studies and abstracts from major conferences. Two authors will independently identify, screen, include studies, extract data and assess the risk of bias. Discrepancies will be resolved by consensus with another author. An independent methodologist will categorise and assess NRSs to minimise heterogeneity. In each study group, meta-analysis will be conducted using a random-effect model and statistical heterogeneity will be evaluated using I(2)-statistics. Publication bias will be visualised with contour-enhanced funnel plots and analysed with Egger's test. In group I, cumulative meta-analysis will be considered because the CTx regimen and CRT protocol have changed. The quality of evidence will be summarised using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. This review does not use primary data, and formal ethical approval is not required. Findings will be disseminated through peer-reviewed journals and committee conferences. CRD42015023820.


Using L-systems for modeling source-sink interactions, architecture and physiology of growing trees: the L-PEACH model.
Functional-structural plant models simulate the development of plant structure, taking into account plant physiology and environmental factors. The L-PEACH model is based on the development of peach trees. It demonstrates the usefulness of L-systems in constructing functional-structural models. L-PEACH uses L-systems both to simulate the development of tree structure and to solve differential equations for carbohydrate flow and allocation. New L-system-based algorithms are devised for simulating the behavior of dynamically changing structures made of hundreds of interacting, time-varying, nonlinear components. L-PEACH incorporates a carbon-allocation model driven by source-sink interactions between tree components. Storage and mobilization of carbohydrates during the annual life cycle of a tree are taken into account. Carbohydrate production in the leaves is simulated based on the availability of water and light. Apices, internodes, leaves and fruit grow according to the resulting local carbohydrate supply. L-PEACH outputs an animated three-dimensional visual representation of the growing tree and user-specified statistics that characterize selected stages of plant development. The model is applied to simulate a tree's response to fruit thinning and changes in water stress. L-PEACH may be used to assist in horticultural decision-making processes after being calibrated to specific trees.


Cerebellar Golgi cells in the rat: receptive fields and timing of responses to facial stimulation.
Golgi cells are the only elements within the cerebellar cortex that inhibit granule cells. Despite their unique position there is little information on how Golgi cells respond to afferent input. We studied responses of Golgi cells to mechanical stimulation of the face, in Crus I-II of ketamine-xylazine anaesthetized rats. In 41 rats, 87 putative Golgi cells were identified, based on spike characteristics and on location of electrolytic lesions in the granular layer. They displayed a slow firing rhythm at rest (8.4 spikes/s). Most Golgi cells (84%) showed excitatory responses to tactile input. Their receptive fields (RFs) included, in 78%, the entire ipsilateral infraorbital nerve territory, and extended, in 14%, to other trigeminal nerve branches and, in 48%, to the contralateral face. Excitatory responses consisted of multiple, precisely timed (+/- 1 ms) spikes. Most peristimulus time histograms (PSTHs) (69%) showed an early (5-10 ms) and a late (13-26 ms) excitatory component, with each component consisting of a single PSTH peak. In some PSTHs the early component was a double peak (< 4 ms interval). In others, only one, early or late, PSTH peak was observed. The excitatory components were followed by a silent period (28-69 ms latency), the duration of which (13-200 ms) varied with response amplitude. In single cells, response profiles changed with stimulus location. In simultaneously recorded cells, evoked profiles differed for identical stimuli. Differences in RF size between early 'double' and 'single' peaks suggested that they resulted from direct mossy fibre and parallel fibre input, respectively. Late PSTH peaks were assumed to reflect corticopontine activation.


MIR137 Regulates Starvation-Induced Autophagy by Targeting ATG7.
Autophagy is a cellular catabolic mechanism in response to stress conditions and has been implicated in the progression and chemoresistance of various cancers. Human microR-137 (MIR137) is involved in neuronal maturation and neurogenesis, while little is known about its role in cancer. In this study, we showed that starvation increased the formation of autophagic marker microtubule-associated protein 1 light chain 3 (LC3) without significant change of MIR137 level in U87 cells. In addition, overexpression of MIR137 decreased LC3 expression and inhibited the degradation of the autophagy receptor sequestosome 1(SQSTM1/p62), while the MIR137 antagomirs showed the opposite effect on these autophagic markers. Moreover, MIR137 overexpression decreased, while its antagomirs increased the expression of autophagy-related 7(ATG7) mRNA and protein. MIR137-mediated inhibition of autophagy was prevented by ATG7. Finally, MIR137 promoted the sensitivity of U87 cells to adriamycin, an anticancer drug. Taken together, our study demonstrated that MIR137 attenuated starvation-induced autophagy by regulating the expression of ATG7.


Supracervical hysterectomy in patients with advanced epithelial ovarian cancer.
To assess whether supracervical hysterectomy (SCH) is a reasonable alternative to total abdominal hysterectomy in patients with advanced ovarian cancer. We reviewed the records of patients with advanced ovarian cancer who underwent a SCH at one institution between 1993 and 2004 and a similar cohort who underwent total abdominal hysterectomy (TAH) at the same institution during the same period. Patients without complete surgical staging done at the institution were excluded. Independent-sample t tests, Fisher exact test, and log rank tests were used for statistical analysis. The study included 47 patients who underwent SCH (mean age, 59.6 years) and 190 who underwent TAH. There were no significant differences between the two groups in age (P=.51), preoperative CA 125 level (P=.55), or receipt of taxane-based and platinum-based chemotherapy (P=.84). Although limited by sample size, there were no significant differences between the two groups in rates of intraoperative complications (4 of 47 in the SCH group, or 8.5%, compared with 7 of 190 in the TAH group, or 3.7%; P=.24), vaginal or cervical recurrence (5 of 47 in the SCH group, or 10.6%, compared with 22 of 190 in the TAH group, or 11.6%; P=1.00), or in progression-free survival (SCH of 1.01 years compared with TAH of 1.19 years; P=.64) or overall survival (SCH of 3.28 years compared with TAH of 3.36 years; P=.12). Supracervical hysterectomy may be a reasonable alternative to TAH in patients with advanced ovarian cancer. II.


Risk of harm among gamblers in the general population as a function of level of participation in gambling activities.
To examine the relationship between gambling behaviours and risk of gambling-related harm in a nationally representative population sample. Risk curves of gambling frequency and expenditure (total amount and percentage of income) were plotted against harm from gambling. Data derived from 19, 012 individuals participating in the Canadian Community Health Survey-Mental Health and Well-being cycle, a comprehensive interview-based survey conducted by Statistics Canada in 2002. Gambling behaviours and related harms were assessed with the Canadian Problem Gambling Index. Risk curves indicated the chances of experiencing gambling-related harm increased steadily the more often one gambles and the more money one invests in gambling. Receiver operating characteristic analysis identified the optimal limits for low-risk participation as gambling no more than two to three times per month, spending no more than 501-1,000 CAN dollars per year on gambling and investing no more than 1% of gross family income on gambling activities. Logistic regression modelling confirmed a significant increase in the risk of gambling-related harm (odds ratios ranging from 2.0 to 7.7) when these limits were exceeded. Risk curves are a promising methodology for examining the relationship between gambling participation and risk of harm. The development of low-risk gambling limits based on risk curve analysis appears to be feasible.


Home-based palliative care for adult cancer patients in Ibadan-a three year review.
Home-based palliative care is a recognised model of health service provision globally, but is just emerging in Nigeria. The aim of this study isto review the spectrum of adult cancer patients involved in home-based palliative care, the services provided, outcome and benefits. Records of all adult cancer patients seen on home-based palliative care between March 2009 and January 2013 by the hospice and palliative care unit, University College Hospital (UCH), Ibadan were reviewed. Their biographical data, days on programme, diagnosis, stage of disease, major complaint, pain score, other symptoms, services offered, number of home visits, follow-up, and outcomes were extracted, reviewed, and analysed. The data were analysed using SPSS version 16.0. Sixty patients were enrolled during the study period: there were 20 (33.3%) males and 40 (66.7%) females out of a total of 787 patients. All of them reside within catchment area of the hospice. Breast and prostate cancer constitute 21.7% each, gastrointestinal 16.7%, liver 11.7%, and cervical cancer 10.0%. Homes were visited 1-23 times per person. Days on programme ranged from 9-1207 days (average: 286 days). Pain was reported by 52 (86.7%) with scores of 7 to10 in 26 (50.0%). Only eight (13.3%) were pain-free. Services offered included pain and other symptom control, counselling and training for carers at home, provision of funds and comfort packs, bereavement services. The cost of services was heavily subsidised by the Centre for Palliative Care, Nigeria (CPCN), a non-governmental organisation and UCH. Although all patients are now deceased, the compassionate care received at a subsidised cost was highly valued, as shown from the appreciative comments of relations and carers. Home-based palliative care provided at low cost was beneficial to patients and their families. More can be achieved through the training of more health professionals, increased funding, and increased public awareness of the services.


Mapping the N-Terminal Hexokinase-I Binding Site onto Voltage-Dependent Anion Channel-1 To Block Peripheral Nerve Demyelination.
The voltage-dependent anion channel (VDAC), the most abundant protein on the outer mitochondrial membrane, is implicated in ATP, ion and metabolite exchange with cell compartments. In particular, the VDAC participates in cytoplasmic and mitochondrial Ca2+ homeostasis. Notably, the Ca2+ efflux out of Schwann cell mitochondria is involved in peripheral nerve demyelination that underlies most peripheral neuropathies. Hexokinase (HK) isoforms I and II, the main ligands of the VDAC, possess a hydrophobic N-terminal structured in α-helix (NHKI) that is necessary for the binding to the VDAC. To gain further insight into the molecular basis of HK binding to the VDAC, we developed and optimized peptides based on the NHKI sequence. These modifications lead to an increase of the peptide hydrophobicity and helical content that enhanced their ability to prevent peripheral nerve demyelination. Our results provide new insights into the molecular basis of VDAC/HK interaction that could lead to the development of therapeutic compounds for demyelinating peripheral neuropathies.


Hospital Readmissions by Variation in Engagement in the Health Care Hotspotting Trial: A Secondary Analysis of a Randomized Clinical Trial.
Variability in intervention participation within care management programs can complicate standard analysis strategies. To evaluate whether care management was associated with reduced hospital readmissions among individuals with higher participation probabilities. A total of 800 hospitalized patients aged 18 years and older were randomized as part of the Health Care Hotspotting randomized clinical trial, which was conducted in Camden, New Jersey, from June 2014 to September 2017. Data were collected through October 2018. In this new analysis performed between April 6, 2022, and April 23, 2023, the distillation method was applied to account for variable intervention participation. A gradient-boosting machine learning model produced predicted probabilities of engaged participation using baseline covariates only. Predicted probabilities were used to trim both intervention and control populations in an equivalent manner, and intervention effects were reevaluated within study population subsets that were increasingly concentrated with patients having higher participation probabilities. Patients had 2 or more hospitalizations in the 6-month preenrollment period and documented evidence of chronic illness and social complexity. Multidisciplinary teams provided services to patients in the intervention arm for a mean 120 days after hospital discharge. Patients in the control group received usual postdischarge care. Hospital readmission rates and counts 30, 90, and 180 days postdischarge. Of 800 eligible patients, 782 had complete discharge information and were included in this analysis (mean [SD] age, 56.6 [12.7] years; 395 [50.5%] female). In the intent-to-treat analysis, the unadjusted 180-day readmission rate for treatment and control groups was 60.1% vs 61.7% (adjusted odds ratio, 0.95; 95% CI, 0.71-1.28; P = .73) and the mean (SD) number of 180-day readmissions was 1.45 (1.89) vs 1.48 (1.94) (adjusted incidence rate ratio, 0.99, 95% CI, 0.88-1.12; P = .86). Among the population with the highest participation probabilities, the mean (SD) 180-day readmission count was 1.22 (1.74) vs 1.57 (1.74) and the incidence rate ratio attained statistical significance (adjusted incidence rate ratio, 0.74; 95% CI, 0.56-0.99; P = .045). Adjusted odds ratios and adjusted incidence rate ratios for 30- and 90-day outcomes reached statistical significance after population distillation. This secondary analysis of a randomized clinical trial found that care management was associated with reduced readmissions among patients with higher participation probabilities, suggesting that program operation could be improved by addressing barriers to participation and refining inclusion criteria to identify patients most likely to benefit. ClinicalTrials.gov Identifier: NCT02090426.


Petrographic and spectroscopic characterization of phosphate-stabilized mine tailings from Leadville, Colorado.
The use of soluble PO4(3-) and lime as a heavy metal chemical stabilization agent was evaluated for mine tailings from Leadville, Colorado. The tailings are from piles associated with the Wolftone and Maid of Erin mines; ore material that was originally mined around 1900, reprocessed in the 1940s, and now requires stabilization. The dominant minerals in the tailings are galena (PbS), cerrusite (PbCO3), pyromorphite (Pb5(PO4)3Cl), plumbojarosite (Pb0.5Fe3(SO4)2(OH)6), and chalcophanites ((Pb,Fe,Zn,Mn)Mn2O5 x 2H2O). The tailings were treated with soluble PO4(3-) and lime to convert soluble heavy metals (principally Pb, Zn, Cu, Cd) into insoluble metal phosphate precipitates. The treatment process caused bulk mineralogical transformations as well as the formation of a reaction rind around the particles dominated by Ca and P. Within the mineral grains, Fe-Pb phosphosulfates, Fe-Pb sulfates (plumbojarosite), and galena convert to Fe-Ca-Pb hydroxides. The Mn-Pb hydroxides and Mn-(+/-Fe)-Pb hydroxides (chalcophanites) undergo chemical alteration throughout the grains during treatment. Bulk and surface spectroscopies showed that the insoluble reaction products in the rind are tertiary metal phosphate (e.g. (Cu,Ca2)(PO4)2) and apatite (e.g. Pb5(PO4)3Cl) family minerals. pH-dependent leaching (pH 4,6,8) showed that the treatment was able to reduce equilibrium concentrations by factors of 3 to 150 for many metals; particularly Pb2+, Zn2+, Cd2+, and Cu2+. Geochemical thermodynamic equilibrium modeling showed that apatite family and tertiary metal phosphate phases act as controlling solids for the equilibrium concentrations of Ca2+, PO4(3-) Pb2+, Zn2+, Cd2+, and Cu2+ in the leachates during pH-dependent leaching. Both end members and ideal solid solutions were seen to be controlling solids.


Quantification of turbulence and velocity in stenotic flow using spiral three-dimensional phase-contrast MRI.
Evaluate spiral three-dimensional (3D) phase contrast MRI for the assessment of turbulence and velocity in stenotic flow. A-stack-of-spirals 3D phase contrast MRI sequence was evaluated in vitro against a conventional Cartesian sequence. Measurements were made in a flow phantom with a 75% stenosis. Both spiral and Cartesian imaging were performed using different scan orientations and flow rates. Volume flow rate, maximum velocity and turbulent kinetic energy (TKE) were computed for both methods. Moreover, the estimated TKE was compared with computational fluid dynamics (CFD) data. There was good agreement between the turbulent kinetic energy from the spiral, Cartesian and CFD data. Flow rate and maximum velocity from the spiral data agreed well with Cartesian data. As expected, the short echo time of the spiral sequence resulted in less prominent displacement artifacts compared with the Cartesian sequence. However, both spiral and Cartesian flow rate estimates were sensitive to displacement when the flow was oblique to the encoding directions. Spiral 3D phase contrast MRI appears favorable for the assessment of stenotic flow. The spiral sequence was more than three times faster and less sensitive to displacement artifacts when compared with a conventional Cartesian sequence.


Percutaneous Image-guided Core Needle Biopsy for Upper Tract Urothelial Carcinoma.
To better understand the safety and diagnostic yield of percutaneous core-needle biopsy (PCNB) for upper tract urothelial carcinoma (UTUC). Of 444 patients undergoing radical nephroureterectomy (RNU) for UTUC between 2009 and 2017 at our institution, 42 who had PCNB prior to RNU were identified for analysis. Endpoints included safety, diagnostic yield, and concordance with RNU pathology. PCNB specimens were deemed histologically concordant with RNU specimens for cases when cytologic evaluation of biopsy specimen and corresponding pathologic evaluation of RNU specimen both made a histologic diagnosis of urothelial carcinoma. Median tumor size was 3.8 cm (1.2-10.2 cm). All lesions arose from the pelvicalyceal system. CT-guidance was utilized in 52% (n = 22), and ultrasound-guidance in 48% (n = 20). Relative to RNU pathology, 95% of PCNBs demonstrated histologic concordance. Histologic grade was provided in 69% (n = 29) of PCNBs, with a 90% (n = 26) concordance with surgical pathology. Grades 1-2 and 3 complications occurred in 14.3% (n = 6) and 2.4% (n = 1), respectively. At a median follow-up of 28.2 months (range, 1.2-97.1 months) after biopsy, no cases of radiographic tract seeding were identified. In our cohort of 42 patients undergoing RNU for UTUC, PCNB appeared a safe diagnostic tool with high histologic yield and grade concordance. With greater than 2 years of follow-up, no cases of tract seeding were identified.


Hospitalizations and costs associated with hepatitis C and advanced liver disease continue to increase.
Disease burden models have predicted worsening morbidity of liver disease caused by hepatitis C in the United States. The aim of this study was to determine the trend in hospitalizations caused by hepatitis C and advanced liver disease. We analyzed data for the period 2004-11 from the Nationwide Inpatient Sample, the largest nationwide all-payer hospital inpatient care database. Hospitalization rates for hepatitis C per 100,000 people increased significantly from 4.76 in 2004-05 to 13.81 in 2010-11-an increase of 190 percent. Hospitalization rates for advanced liver disease also increased, particularly for hepatorenal syndrome (93 percent) and portal hypertension (62 percent). Hepatitis C was the principal diagnosis for 64,867 hospitalizations in 2010-11, resulting in a total charge of $3.5 billion. We found nationwide trends in increasing morbidity and medical costs for advanced liver disease associated with hepatitis C. Our findings suggest that hepatitis C is a public health problem and has been growing in magnitude in recent years. Stakeholders and policy makers should implement both recommended screenings for people born in the period 1945-65 and more effective treatment for hepatitis C, which have the potential to reverse the rising morbidity and costs of hepatitis C.


A comparison of hydrogen ion concentration and pH genetic predictions and fixed effect estimations when assessing pork quality.
An evaluation of ultimate pH (pH) and hydrogen ion concentration (H+) was conducted to determine if the mathematical conversion of H+ to pH could affect 1. fixed and random effect inferences and 2. prediction of genetic merit of animals when either pH or H+ is used as an indicator in the assessment of pork quality. Data from 4,262 purebred animals and 577 sires having complete three-generation pedigrees from the 1991 to 2001 National Barrow Show Progeny Tests were utilized in this study. Existing loin muscle pH data were converted to their original H+. Numerical changes in values occurred across all fixed effects and in the case of breed and test, changes in differences among subclasses occurred. These changes may result in differing inferences that can be made depending on whether pH or H+ is used as the dependent variable. Heritability estimates for pH and H+ were 0.52 +/- 0.074 and 0.62 +/- 0.078, respectively. The Pearson correlation between pH and H+ breeding values was -0.92. Spearman Rank correlation of -0.91 between pH and H+ breeding values was calculated and indicates that sires do not rank the same when ordered by breeding values for each trait. When pH is the selection objective, the selection differential reduction in H+ from these data ranges from 3.8 to 9.1%. Additionally, only 77.7% of the estimated genetic progress per generation in H+ is realized when selection (5% selected) is based on pH. The genetic correlation between pH and H+ was -0.96. Changes in the absolute values of the genetic correlations between various pork quality indicator traits and pH or H+ concentration were 0.04 or less. Differences in pH and H+ results could impact decisions made by swine breeders and meat processors who are concerned about pork quality. This, combined with the greater heritability and biochemical reality for H+, indicates that H+ rather than pH is the more appropriate trait breeders and processors should focus on when attempting to improve pork quality.


Spondylolysis and spondylolisthesis in children and adolescents: II. Surgical management.
Surgical management is indicated for children and adolescents with spondylolysis and low-grade spondylolisthesis (< or =50% slip) who fail to respond to nonsurgical measures. In situ posterolateral L5 to S1 fusion is the best option for those with a low-grade slip secondary to L5 pars defects or dysplastic spondylolisthesis at the lumbosacral junction. Pars repair is reserved for patients with symptomatic spondylolysis and low-grade, mobile spondylolisthesis with pars defects cephalad to L5 and for those with multiple-level defects. Screw repair of the pars defect, wiring transverse process to spinous process, and pedicle screw-laminar hook fixation are surgical options. The ideal surgical management of high-grade spondylolisthesis (>50% slip) is controversial. Spinal fusion has been indicated for children and adolescents with high-grade spondylolisthesis regardless of symptoms. In situ L4 to S1 fusion with cast immobilization is safe and effective for alleviating back pain and neurologic symptoms. Instrumented reduction and fusion techniques permit improved correction of sagittal spinal imbalance and more rapid rehabilitation but are associated with a higher risk of iatrogenic nerve root injuries than in situ techniques. Wide decompression of nerve roots combined with instrumented partial reduction may diminish the risk of neurologic complications. Pseudarthrosis and neurologic injury presenting as L5 radiculopathy and sacral root dysfunction are the most common complications associated with surgical management of high-grade spondylolisthesis.


A digital self-care intervention for Ugandan patients with heart failure and their clinicians: User-centred design and usability study.
The prevalence of heart failure (HF) is increasing in Uganda. Ugandan patients with HF report receiving limited information about their illness and associated self-care behaviours. Interventions targeted at improving HF self-care have been shown to improve patient quality of life and reduce hospitalizations in high-income countries. However, such interventions remain underutilized in resource-limited settings like Uganda. This study aimed to develop a digital health intervention that enables improved self-care amongst HF patients in Uganda. We implemented a user-centred design (UCD) process to develop a self-care intervention entitled Medly Uganda. The ideation phase comprised a scoping review and preliminary data collection amongst HF patients and clinicians in Uganda. An iterative design process was then used to advance an initial prototype into a functional digital health intervention. The evaluation phase involved usability testing of the intervention amongst Ugandan patients with HF and their clinicians. Medly Uganda is a digital health intervention that allows patients to report daily HF symptoms, receive tailored treatment advice and connect with a clinician when showing signs of decompensation. The system harnesses Unstructured Supplementary Service Data (USSD) technology that is already widely used in Uganda for mobile phone-based financial transactions. Usability testing showed Medly Uganda to be both acceptable and feasible amongst clinicians, patients and caregivers. Medly Uganda is a functional digital health intervention with demonstrated acceptability and feasibility in enabling Ugandan HF patients to better care for themselves. We are hopeful that the system will improve self-care efficacy amongst HF patients in Uganda.


Unfolded protein response activation in cataracts.
To analyze the expression of 78 kDa glucose-regulated protein (GRP78) and activating transcription factor 6 (ATF6), 2 factors in the unfolded protein response (UPR), in age-related and diabetes-associated cataract. Universidad Autónoma de Aguascalientes, Aguascalientes, México. Experimental study. The qualitative and quantitative expression of GRP78 and ATF6 were measured in surgical samples from 11 senile cataracts, 9 diabetic-associated cataracts, and 3 normal lenses. Both proteins were detected by immunofluorescence and immunogold-conjugated antibodies. Quantitative morphometry was used to analyze the differences in GRP78 and ATF6 between samples. The Mann-Whitney test was used for statistical analysis. Scanning electron microscopy showed the characteristic organization of fibers in normal lenses with regular alignment and interdigitation between them. On the other hand, lenses from eyes with senile or diabetic cataract showed the same pattern of misalignment and disorganization of the fibers. Both proteins were detected through immunofluorescence in senile and diabetic cataracts, but not in normal lenses. Immunogold-conjugated antibodies and transmission electron microscopy showed that GRP78 and ATF6 grains were 30% higher and 35% higher, respectively, in diabetic cataracts than in senile cataracts (P<.05). These data show for the first time in humans that GRP78 and ATF6 are present in lens fibers of senile cataracts and diabetic cataracts, establishing that the UPR may be important in the process of cataractogenesis. No author has a financial or proprietary interest in any material or method mentioned.


Oncological outcomes of minimally invasive partial versus minimally invasive radical nephrectomy for cT1-2/N0/M0 clear cell renal cell carcinoma: a propensity score-matched analysis.
To compare the oncologic outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) for cT1-2/N0 renal tumors and pathologically confirmed pT1-pT3a-pNx clear cell (cc)-renal cell carcinoma (RCC). Few studies compared the oncologic outcomes of PN and RN for renal tumors >7 cm. A prospective "renal cancer" database was queried for cT<3-cN0-cM0 and pT1a-pT3a-pNx cc-RCC. Out of 1650 cases treated between 2001 and 2013, 921 were cc-RCC and 666 met inclusion criteria, 232 of which treated with minimally invasive RN and 434 with MIPN. A 1:1 propensity score-matched (PSM) analysis was employed to minimize the selection bias of non-random assignment of patients to PN as opposed to RN. Kaplan-Meier method was used to compare the oncologic outcomes of the PSM cohorts. Survival rates were computed at 2, 5, and 10 years after surgery, and the log-rank test was applied to assess statistical significance between the two PSM groups. RN tumors were significantly larger (p < 0.001), with higher pT stages (p < 0.001), higher Fuhrman grades (p = 0.002) and a more frequent sarcomatoid differentiation (p = 0.04). After applying the PSM analysis, the two cohorts of 155 RN and 155 PN cases did not differ for all clinical and pathologic covariates (all p ≥ 0.32). PN and RN cohorts displayed comparable 5-year metastasis-free survival (88.9 vs 89.9 %, p = 0.811), local recurrence-free survival (94.2 vs 95.9 %, p = 0.283), overall survival (94.5 vs 96.8 %, p = 0.419) and cancer-specific survival (96 vs 98.6 %, p = 0.907) rates. PN and RN for patients with cc-RCC larger than 7 cm provided equivalent oncologic outcomes. Safety and reproducibility of our findings should be further investigated in larger multicentric cohorts.


Triptan-induced contractile (5-HT1B receptor) responses in human cerebral and coronary arteries: relationship to clinical effect.
Triptans are agonists at 5-HT1B and 5-HT1D (where 5-HT is 5-hydroxytryptamine; serotonin) receptors and cause vasoconstriction of isolated blood vessels. The aim of the present study was to determine vasoconstrictor potency (EC50) of triptans in human coronary and cerebral arteries and to examine whether there was any relationship with the maximal plasma concentrations (Cmax; nM) of the drugs achieved following oral administration of clinically relevant doses to man using values reported in the literature. We also examined the expression of 5-HT1B receptors in atherosclerotic and normal coronary arteries. The vasocontractile responses to sumatriptan, rizatriptan or eletriptan were characterized by in vitro pharmacology. The ratio of Cmax/EC50 was calculated. 5-HT1B and 5-HT1D receptors were visualized by immunohistochemical techniques in coronary arteries. Sumatriptan, rizatriptan and eletriptan were powerful vasoconstrictors in cerebral artery. The rank order of agonist potency was eletriptan=rizatriptan=sumatriptan. In the coronary artery, the triptans were weaker vasoconstrictors. The rank order of potency was similar. In cerebral artery the ratio of Cmax/EC50 was not significantly different from unity, indicating a relationship between these two parameters. In general for the coronary artery, the ratios were significantly less than unity, indicating no direct relationship. Immunohistochemistry showed expression of 5-HT1B receptors in the medial layer, but did not reveal any obvious difference in 5-HT1B receptor expression between normal and atherosclerotic coronary arteries. The results support the notion that triptans are selective vasoconstrictors of cerebral arteries over coronary arteries and that there is a relationship between vasoconstrictor potency in cerebral arteries and clinically relevant plasma levels.