Evaluation of DOI, 8-OH-DPAT, eticlopride and amphetamine on impulsive responding in a reaction time task in rats.
We examined the effects of DOI (2,5-dimethoxy-4-iodoamphetamine), 8-OH-DPAT (8-hydroxy-2-(N,N-dipropylamino)tetralin, eticlopride and amphetamine in a reaction time (RT) task. In this task a trial is initiated after a rat pushes a panel. Rats have to wait (0.5-1.5 s) until a tone is presented before making a response. The number of premature responses, releasing the panel before tone was switched on, was taken as a measure of motor impulsivity. A group of 10 Lewis rats was tested in the RT task after treatment with different doses of drugs which have been shown previously to affect impulsive responding: DOI (0.1, 0.2 mg/kg), 8-OH-DPAT (0.1, 0.3 mg/kg), eticlopride (0.01, 0.03 mg/kg) and D-amphetamine (0.3, 1 mg/kg). A progressive ratio test was used to control for drug effects on food motivation. DOI (0.1 mg/kg) and D-amphetamine (0.3 mg/kg) increased impulsive responding in the RT task. Conversely, 8-OH-DPAT decreased impulsive responding in the RT task. These effects of DOI, D-amphetamine and 8-OH-DPAT on impulsive responding were not associated with changes in food motivation, as assessed by performance in the progressive ratio task. Eticlopride did not affect impulsive responding. The present data suggest that 5-HT2A receptors and dopamine (but not D2 receptors) are associated with motor impulsivity.


Potential pathophysiological role for the vitamin D deficiency in essential hypertension.
Vitamin D deficiency has been indicated as a pandemic emerging public health problem. In addition to the well-known role on calcium-phosphorus homeostasis in the bone, vitamin D-mediated processes have been recently investigated on other diseases, such as infections, cancer and cardiovascular diseases. Recently, both the discovery of paracrine actions of vitamin D (recognized as "local vitamin D system") and the link of vitamin D with renin-angiotensin-aldosterone system and the fibroblast growth factor 23/klotho pathways highlighted its active cardiovascular activity. Focusing on hypertension, this review summarizes the more recent experimental evidence involving the vitamin D system and deficiency in the cardiovascular pathophysiology. In particular, we updated the vascular synthesis/catabolism of vitamin D and its complex interactions between the various endocrine networks involved in the regulation of blood pressure in humans. On the other hand, the conflicting results emerged from the comparison between observational and interventional studies emphasize the fragmentary nature of our knowledge in the field of vitamin D and hypertension, strongly suggesting the need of further researches in this field.


The Physiology of Teaching: Getting the Balance right.
This article was migrated. The article was marked as recommended. Using three human body systems as a metaphor, this paper will discuss how the art of teaching, including the conditions in which students thrive can remedy longstanding curriculum diseases. Based on the concept of a living curriculum, the importance of curiosity, exposing vulnerability, social and collaborative learning, communication and reflective learning processes in transforming teaching and inspiring learning will be explored.


Diuretics or ultrafiltration in the treatment of acute decompensated heart failure: An updated systematic review and meta-analysis.
Hospitalization for decompensated heart failure is a major public health issue. We performed a meta-analysis to summarize and analyze if there is a benefit in using ultrafiltration over diuretics in terms of reducing mortality or hospital readmissions, primarily and identified 10 randomized controlled trials (RCTs) including 941 patients. Compared to diuretics, treatment with ultrafiltration was associated with a significant reduction in heart failure hospitalizations (risk ratio [RR]: 0.72; 95% confidence interval [CI]: 0.55-0.96, p = 0.02) and significant increase in weight and net fluid loss (mean difference [MD]: -1.55, CI: -2.36 to -0.74, p = 0.0002) and (MD: -2.10, CI: -3.32 to -0.89, p = 0.0007), respectively. There was no significant difference among treatments regarding the duration of hospitalization, the increase in serum creatinine levels, and mortality. Among patients with decompensated heart failure, compared to diuretics, ultrafiltration is associated with reduced rehospitalizations and increased weight/net fluid loss.


[Improvement of fecal incontinence with silicone implants in patients with internal anal sphincter injury: First report in North America].
The injection of bulking agents has been described as a useful treatment of urinary and fecal incontinence. Among them, silicone implants have shown benefits in patients with internal anal sphincter (IAS) injury. We describe two patients with a history of hemorrhoidectomy and IAS injuries, which underwent placement of silicone implants. The implants were inserted into the intersphincteric space and the IAS under ultrasound guidance. The Wexner continente score fell from 17 and 19 before treatment, to 6 and 8 at six months follow up, respectively. Patients had no postoperative complications or implants migration. In our patients, injection of silicone implants improved fecal continence score, without postoperative complications or implants migration at six month follow up.


Bisphosphonates in the Management of Breast Cancer.
BACKGROUND: Bone is the most frequent site of metastasis in patients with breast cancer. Bone metastasis, particularly osteolytic bone destruction, is usually associated with significant morbidity and deterioration of quality of life. Bisphosphonates are specific inhibitors of osteoclast activity used in the treatment of hypercalcemia of malignancy and osteolytic bone disease. METHODS: We reviewed pertinent literature on the use of bisphosphonates therapy to treat metastatic breast cancer. RESULTS: The use of bisphosphonates in the management of osteolytic bone metastases results in improved palliation of symptoms. Use of these agents in the adjuvant setting may help to prevent bone metastases. CONCLUSIONS: Bisphosphonates represent an effective palliative treatment when combined with chemotherapy and hormonal therapy for the management of osteolytic bone metastases. Identifying the exact mechanism of action requires further investigation to better define the possibility of a direct antitumor effect. The role of bisphosphonates in the adjuvant setting is still controversial, pending the results of large randomized trials.


Recruiting physicians for office-based research.
Research conducted in community outpatient offices can provide insight into the common experiences of patients and physicians. However, recruiting physicians to participate in office-based research is challenging and few descriptions of methods that have been used to successfully recruit random samples of physicians are available. This article describes recruitment strategies utilized in a project that achieved high rates of participation from community-based primary care physicians and surgeons. Recruitment methods included the use of advisory boards to identify potential barriers to participation, use of respected members of the medical community as recruiters, and obtaining endorsements from physician organizations and prominent members of the medical community. Overall, 81% of physicians contacted from a sample frame agreed to participate in the project. Participating physicians most frequently reported that they participated because the project could provide them with feedback about their interviewing style. The recruitment methods described here can be generalized to other types of investigations.


Atomic Gold Ions Clustered with Noble Gases: Helium, Neon, Argon, Krypton, and Xenon.
High-resolution mass spectra of helium droplets doped with gold and ionized by electrons reveal HenAu+ cluster ions. Additional doping with heavy noble gases results in NenAu+, ArnAu+, KrnAu+, and XenAu+ cluster ions. The high stability predicted for covalently bonded Ar2Au+, Kr2Au+, and Xe2Au+ is reflected in their relatively high abundance. Surprisingly, the abundance of Ne2Au+, which is predicted to have zero covalent bonding character and no enhanced stability, features a local maximum, too. The predicted size and structure of complete solvation shells surrounding ions with essentially nondirectional bonding depends primarily on the ratio σ* of the ion-ligand versus the ligand-ligand distance. For Au+ solvated in helium and neon, the ratio σ* is slightly below 1, favoring icosahedral packing in agreement with a maximum observed in the corresponding abundance distributions at n = 12. HenAu+ appears to adopt two additional solvation shells of Ih symmetry, containing 20 and 12 atoms, respectively. For ArnAu+, with σ* ≈ 0.67, one would expect a solvation shell of octahedral symmetry, in agreement with an enhanced ion abundance at n = 6. Another anomaly in the ion abundance at Ar9Au+ matches a local maximum in its computed dissociation energy.


Evaluating the impact of hepatitis C virus (HCV) on highly active antiretroviral therapy-mediated immune responses in HCV/HIV-coinfected women: role of HCV on expression of primed/memory T cells.
To evaluate the impact of hepatitis C virus (HCV) on the immune system before receipt of highly active antiretroviral therapy (HAART) and on immune recovery after receipt of HAART among human immunodeficiency virus (HIV)/HCV-coinfected women enrolled in the Women's Interagency HIV Study. The study included 294 HIV-infected women who initiated HAART and attended 2 follow-up visits. The women were grouped on the basis of positive HCV antibody and HCV RNA tests. There were 148 women who were HCV antibody negative, 34 who were HCV antibody positive but RNA negative, and 112 who were HCV antibody and RNA positive. Immune recovery was measured by flow-cytometric assessment for markers of activation and maturation on CD4+ and CD8+ T cells. Data analysis used repeated measures of variance.Results. HIV/HCV coinfection is associated with an increased number of CD4+ and CD8+ primed/memory T cells. HIV/HCV coinfection, however, did not affect any further decreases in CD4+ or CD4+ and CD8+ naive/memory T cell counts or enhanced T cell activation. HIV/HCV coinfection also did not affect HAART responses in the CD4+ and CD8+ T cell compartment. HCV does not affect immune responses to HAART in HIV/HCV-coinfected individuals but is associated with an expansion of CD4+ and CD8+ memory T cell subsets. Functional impairment in the CD4+ and CD8+ T cell compartments still needs to be assessed in coinfected patients.


The value of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, red cell distribution width, and their combination in predicting acute pancreatitis severity.
Acute pancreatitis is one of the most common causes of acute abdominal pain requiring hospitalization worldwide. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and red blood cell distribution width (RDW) are novel inflammatory markers that have been investigated in various diseases associated with an inflammatory response, achieving many positive results. Evaluating the NLR, PLR, RDW, and their combination to predict acute pancreatitis severity can help clinicians have an appropriate initial treatment strategy. This prospective cohort study enrolled 131 patients diagnosed with acute pancreatitis at Gia Dinh Hospital, Ho Chi Minh City, between December 2021 and August 2022. Patients with the following features were excluded from our study: age < 18 years old, time from symptom onset to admission of > 72 hours; patients with autoimmune disease, decompensated cirrhosis, active tuberculosis, heart failure (New York Heart Association class 4), end-stage renal failure, pregnancy, active severe acute respiratory syndrome coronavirus 2 infection, and chronic pancreatitis. There were 21 severe acute pancreatitis (SAP) cases (16%). The area under the receiver operating characteristic curve for predicting SAP was 0.82 for NLR, 0.72 for PLR, and 0.73 for RDW. When the cutoffs of 13.5 for NLR, 202.7 for PLR, and 13.1% for the RDW were used, the negative predictive values in predicting SAP were 93.1%, 91.9%, and 98.8%, respectively. This finding demonstrates the value of inflammatory markers in predicting SAP. The combination of these markers did not show an advantage in predicting SAP compared to the single markers. High NLR, PLR, and RDW are associated with SAP. These indices are good indicators for predicting SAP. In our study, the combination of inflammatory markers did not improve SAP prediction compared to the individual markers.


Single-molecule measurement of protein folding kinetics.
In order to investigate the behavior of single molecules under conditions far from equilibrium, we have coupled a microfabricated laminar-flow mixer to a confocal optical system. This combination enables time-resolved measurement of Förster resonance energy transfer after an abrupt change in solution conditions. Observations of a small protein show the evolution of the intramolecular distance distribution as folding progresses. This technique can expose subpopulations, such as unfolded protein under conditions favoring the native structure, that would be obscured in equilibrium experiments.


Long-Term Outcomes of Pediatric Renovascular Hypertension.
Renovascular hypertension (RVHT) is an important cause of childhood hypertension. This study evaluated the clinical characteristics and outcomes of Korean children with RVHT. Children treated for RVHT between 2000 and 2015 at our center were retrospectively reviewed. Forty-six children were followed for a median of 6.5 (0.66-27.23) years. Forty-five percutaneous transluminal angioplasties (PTAs) were performed in 32 children. At the last visit, clinical benefit was observed in 53.3% of children. Patients with comorbid cerebrovascular disease (CVD) showed less favorable long-term outcomes after PTA (clinical benefit in 41.7% vs. 61.1% in others) and higher restenosis rates (50% vs. 31.6% in others). Surgical procedures (bypass or nephrectomy) were performed in 8 patients. After surgery, blood pressure was normalized in 2 patients, improved in 3 patients, and unchanged in the remaining patients. Between PTA group (n=21) and medication group (n=14), percentage of atrophic kidneys became higher after follow-up period in medication group than in PTA group (60.0% vs. 26.1%, P=0.037). Aggressive treatment of pediatric RVHT yielded fair outcomes in our cohort. CVD comorbidity was associated with relatively poor PTA outcomes. To confirm our findings, larger cohort studies with a longer follow-up period are warranted.


The ABC protein turned chloride channel whose failure causes cystic fibrosis.
CFTR chloride channels are encoded by the gene mutated in patients with cystic fibrosis. These channels belong to the superfamily of ABC transporter ATPases. ATP-driven conformational changes, which in other ABC proteins fuel uphill substrate transport across cellular membranes, in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient. New structural and biochemical information from prokaryotic ABC proteins and functional information from CFTR channels has led to a unifying mechanism explaining those ATP-driven conformational changes.


Thrombotic complications of silicone rubber catheters during autologous marrow and peripheral stem cell transplantation: prospective comparison of Hickman and Groshong catheters.
Thrombosis is common after placement of silicone rubber subclavian vein catheters in patients with malignancy receiving conventional doses of chemotherapy. To determine the incidence of this complication in marrow transplant patients and the effect of different catheter designs on thrombosis rates, patients were randomized to receive either open-ended Hickman catheters or valve-ended Groshong catheters for venous access during the transplantation procedure. A total of 35 catheters were placed, of which 23 were double-lumen (11 Groshong and 12 Hickman) and 12 were single-lumen (six Groshong and six Hickman). Arm venograms were performed on all patients at the time of hematopoietic recovery or occurrence of symptoms of subclavian vein thrombosis. There were 10 cases of total subclavian vein thrombosis (three were symptomatic) and 12 cases of asymptomatic non-occlusive mural thrombi. Only 13 normal veins were found. There was no difference in thrombosis rate between the Hickman and Groshong catheters. Double lumen catheters tended to be more likely to cause total venous occlusion (nine of 23) than single lumen catheters (one of 12) (p = 0.06, Fisher's exact test). We conclude that subclavian vein thrombosis is a common occurrence after placement of silicone rubber catheters for venous access during marrow transplantation. Most cases are asymptomatic. Groshong catheters are just as likely to cause this complication as Hickman catheters.


Acute megakaryoblastic leukaemia with mediastinal tumor.
Acute megakaryoblastic leukemia (AMKL) is a rare myeloproliferative syndrome with a fulminant clinical course characterized by progressive pancytopenia, pallor, weakness and severe hemorrhage. We present a 18-year old male with pancytopenia and massive hemorrhage, lymphadenopathy, organomegaly, and with unusual presentation of retrocardial mediastinal tumor on the right side. The diagnosis of AMKL was established by combining cytological and immunocytochemical analyses of peripheral blood cells (blasts were GPIIIa and GPIb positive); by immunohistochemical analysis of lymph node (dysplastic megakaryocytes were GPIIIa and F VIII positive); in vitro culture studies confirmed enormous growth of CFU-Mk with high proliferative capacity. In spite of therapy, the patient died 3 months after the first signs of the disease.


Evaluation of the role of free hydroxyl radicals in the cytochrome P-450-catalyzed oxidation of benzene and cyclohexanol.
The possible role of free hydroxyl radicals in the oxidation of cyclohexanol to cyclohexanone and of benzene to phenol was examined in a reconstituted system containing rabbit phenobarbital-inducible P-450LM2. From steady state kinetic studies, a KM for cyclohexanol of 8.7 mM and a Vmax of 5.7 nmol of cyclohexanone formed/min/nmol of P-450 were determined. Similarly, a KM for benzene of 105 mM and a Vmax of 22 nmol of phenol formed/min/nmol of P-450 were obtained. With intact microsomes from phenobarbital-treated rabbits, a KM for benzene of 18 mM and a Vmax of 1.7 nmol of phenol formed/min/nmol of P-450 were determined. With the use of substrate concentrations in the range of the respective KM values, superoxide dismutase, desferrioxamine, and dimethyl sulfoxide were found to have no significant effect on the P-450-catalyzed reactions. When the oxidation of benzene or cyclohexanol was examined in a model hydroxyl radical-generating system containing xanthine, xanthine oxidase, and Fe-EDTA, no dependence of the rate of oxidation on the substrate concentrations used was observed. Since the rate of hydroxyl radical generation by the model system was adjusted to be greater than the rate of product formation in the P-450 system, the lack of dependence on substrate concentration suggests that free hydroxyl radicals are not involved in the P-450-catalyzed reactions studied. Taken together, these findings indicate that the free hydroxyl radical-mediated pathway observed by other investigators does not contribute significantly to product formation when these substrates are present at concentrations within the range of their respective KM values.


Family caregiver's burden and the social support for older patients undergoing peritoneal dialysis.
Most elderly people undergoing peritoneal dialysis (PD) treatment have a high incidence of frailty, cognitive impairment and emotional disturbance leading to a significant impact on families. The burden experienced by the family caregivers could affect their physical and emotion health. The objective of this study was to examine the level of burden on family caregivers of elderly adults receiving PD and to identify any contributing factors. This was a cross-sectional study employing convenience sampling. Patient-caregiver dyads were recruited from the outpatient clinic of a university hospital in China in 2019. Caregivers provided information on their perceived burden and health-related quality of life. The elderly patients reported their functional dependence and depressive symptoms in the same interview. Linear regression analyses were used to determine the factors contributing to caregivers' burden. Sixty patient-caregiver dyads were recruited. The patients had a mean age of 70.7 ± 7.4 years. The caregivers reported moderate levels of burden having ZBI score of 30.5 ± 15.9. Multivariate analyses showed that being female, perceiving one's financial status as insufficient, a low level of social support for the caregiver, depressive symptoms in the patients and disability in carrying out the instrumental activities of daily life were statistically significant predictors of caregiver burden (adjusted R2 = 0.46, p < 0.001). Elderly adults receiving PD who experience physical dependence and depressive symptoms are a burden for caregivers. In response to this challenge, interventions designed with the goal of supporting the emotional and mental wellbeing of caregivers are warranted.


Oral Absorption across Organotypic Culture Models of the Human Buccal Epithelium after E-cigarette Aerosol Exposure.
Inhaled aerosols are absorbed across the oral cavity, respiratory tract, and gastrointestinal tract. The absorption across the oral cavity, which is one of the exposure routes, plays an important role in understanding pharmacokinetics and physiological effects. After aerosol exposure from e-cigarettes, tissue viability studies, morphological observation, and chemical analyses at the inner and outer buccal tissues were performed using organotypic 3D in vitro culture models of the buccal epithelium to better understand the deposition and absorption on the inner and outer buccal tissues. The aerosol exposures did not affect the tissue viability and had no change to the tissue morphology and structure. The deposition ratio at the buccal tissue surface is relatively low. This shows that majority of aerosol transfers to the airway tissues. The distribution from the inner tissue to the outer tissue has selectivity among various compounds, depending on the affinity with the liquid crystal structure of phospholipids and glucosylceramide. Although nicotine absorption in the aqueous solution was well known to increase as the unprotonated state of nicotine increased, the nicotine absorption after the aerosol exposure is irrelevant to the protonated-unprotonated state. Furthermore, the results showed that half of nicotine that adhered to the oral cavity transferred to the inner tissue via the oral epithelium and the other half transferred to the gastrointestinal tract accompanying multiple executions of swallowing, while majority of the water-soluble compounds with the hydroxyl group such as propylene glycol and benzoic acid that adhered to the oral cavity were eluted with the saliva and transferred to the gastrointestinal tract by swallowing.


Ceruloplasmin Reduces the Lactoferrin/Oleic Acid Antitumor Complex-Mediated Release of Heme-Containing Proteins from Blood Cells.
Our previous study showed that not only bovine lactoferrin (LF), the protein of milk and neutrophils, but also the human species forms complexes with oleic acid (OA) that inhibit tumor growth. Repeated injections of human LF in complex with OA (LF/8OA) to hepatoma-carrying mice decelerated tumor growth and increased animals' longevity. However, whether the effect of the LF/8OA complex is directed exclusively against malignant cells was not studied. Hence, its effect on normal blood cells was assayed, along with its possible modulation of ceruloplasmin (CP), the preferred partner of LF among plasma proteins. The complex LF/8OA (6 μM) caused hemolysis, unlike LF alone or BSA/8OA (250 μM). The activation of neutrophils with exocytosis of myeloperoxidase (MPO), a potent oxidant, was induced by 1 μM LF/8OA, whereas BSA/8OA had a similar effect at a concentration increased by an order. The egress of heme-containing proteins, i.e., MPO and hemoglobin, from blood cells affected by LF/8OA was followed by a pronounced oxidative/halogenating stress. CP, which is the natural inhibitor of MPO, added at a concentration of 2 mol per 1 mol of LF/8OA abrogated its cytotoxic effect. It seems likely that CP can be used effectively in regulating the LF/8OA complex's antitumor activity.


Who first created the Chinese term for psychology-Xin Li Xue?
Shu-Chang Yan's (2018) recent article challenged the popular notion that the formal translation of psychology into Chinese-Xin Li Xue ()-was first made by the Japanese scholar Nishi Amane (1829-1897) in 1875 (Nishi, 1875; Zhao, 1983, 1991) when translating Joseph Haven's Mental Philosophy (see Haven, 1869; Howland, 2002; Koizumi, 1971). In the archive of Shanghai News, a popular newspaper in 19th- and 20th-century Shanghai (see Ye, 2017; Zhao & Zhang, 2004), Yan discovered that a Chinese intellectual with the penname of Zhi Quan Ju Shi () had already used Xin Li Xue as the name for psychology or mental philosophy on November 28, 1872- 3 years earlier than Nishi's book Haven's Psychology. The 1872 article was about the author's conversation with a Western missionary on the relation between science and the church in the West and a similar prospect in China- that is, that science was gaining the momentum to push aside religion. In the article, Zhi Quan Ju Shi designated some disciplines, including chemistry, astronomy, and psychology, with the same terms used in modern China. Yan thus argued that before Nishi's translation of psychology was widely accepted in China, Zhi Quan Ju Shi had already coined the same term and published it in mass media. Yan then continued to explore who used the penname of Zhi Quan Ju Shi in Shanghai News. Finally, Yan explained why Zhu's publication of the term did not have as profound an influence as Nishi's book. At the end of the 19th century, with the import of psychological knowledge, some Western missionaries and Chinese intellectuals translated the subject into other terms similar to Xin Li Xue, such as Xin Ling Xue () by C. W. Mateer in 1876 and Yongjing Yan in 1889 and Xin Xue () by Yan Fu in 1886 (see Wang, 2015; Zhao, 1983). They were all products of traditional Chinese culture encountering Western psychology. However, those terms were not widely accepted because the contributors were dictionary editors or newspaper journalists outside psychological institutions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Dual-Energy CT-derived Iodine Maps: Use in Assessing Pleural Carcinomatosis.
Purpose To evaluate the use of spectral CT for differentiation between noncalcified benign pleural lesions and pleural carcinomatosis. Materials and Methods In this retrospective study, patients who underwent contrast agent-enhanced late venous phase spectral CT of the chest between June 1, 2016, and July 1, 2018 with histopathologic and/or imaging confirmation of noncalcified pleural lesions were evaluated. Conventional images, iodine overlay (IO) images, and virtual monoenergetic images at 40 keV (hereafter, VMI40keV) were reconstructed from contrast-enhanced spectral chest CT. Four blinded radiologists determined lesion presence and indicated lesion conspicuity and diagnostic certainty. Hounsfield unit attenuation from conventional images and iodine concentration (IC) (in milligrams per milliliter) from IO images were determined. Area under the receiver operating characteristics curve determined thresholds for quantitative lesion differentiation and cutoff values were validated in an independent data set. Results Eighty-four patients were included (mean age, 66.2 years; 54 men and 30 women; 44 patients with cancer with confirmed pleural carcinomatosis and 40 patients with benign pleural lesions). The area under the receiver operating characteristics curve for IC was greater than that of conventional Hounsfield units (0.96 vs 0.91; P ≤ .05, respectively). The optimal IC threshold was 1.3 mg/mL, with comparable sensitivity and specificity when applied to the test data set. The sensitivities to depict pleural carcinomatosis with spectral reconstructions versus conventional CT were 96% (199 of 208) and 83% (172 of 208), respectively, with specificities of 84% (161 of 192) and 63% (120 of 192), respectively (P ≤ .001 each). Conclusion Compared with conventional images, spectral CT with iodine maps improved both quantitative and qualitative determination of pleural carcinomatosis versus noncalcified benign pleural lesions. © RSNA, 2019 See also the editorial by K. S. Lee and H. Y. Lee .


Neurohumoral contributions to chronic angiotensin-induced hypertension.
A central pressor effect of angiotensin II (ANG II) has been implicated in the pathogenesis of several forms of experimental hypertension. Therefore, the present studies were designed to investigate mechanisms that contribute to hypertension resulting from selective stimulation of brain ANG II receptors by chronic intracerebroventricular (ICV) infusion of ANG II. Specifically, the role of the sympathetic nervous system, the pressor actions of vasopressin, and the direct vasoconstrictor effect of blood-borne ANG II were investigated in rats made hypertensive by 5- to 7-day ICV ANG II infusions (6 micrograms/h). Rats were chronically instrumented with indwelling arterial and venous catheters and a lateral cerebral ventricular cannula. Acute intravenous infusion of the competitive ANG II receptor antagonist [Sar1-Ala8]ANG II during the period of ICV ANG II infusion resulted in a moderate decrease in arterial pressure, indicating that an increase in blood-borne ANG II may account for a small component of the hypertensive response to ICV ANG II. Activation of the sympathetic nervous system appeared to be the major contributor to the elevated arterial pressure, since acute ganglionic blockade and combined alpha- and beta-adrenergic blockade produced greater depressor responses in rats made hypertensive with chronic ICV ANG II infusion than in normotensive rats. Furthermore, peripheral sympathectomy delayed hypertension development. Intravenous administration of a specific antagonist of the vascular vasopressin receptor did not cause a depressor response in rats made hypertensive with chronic ICV ANG II infusions. These studies demonstrate that a major mechanism involved in the pressor response to acute ICV ANG II injections, namely vasopressin release, does not appear to contribute to hypertension produced by chronic ICV infusions of ANG II. Rather, this form of hypertension is characterized predominantly by an increase in sympathetic vasoconstrictor tone and possibly by a mechanism activated by a small increase in circulating levels of ANG II.


Disruption of Dnmt1/PCNA/UHRF1 interactions promotes tumorigenesis from human and mice glial cells.
Global DNA hypomethylation is a hallmark of cancer cells, but its molecular mechanisms have not been elucidated. Here, we show that the disruption of Dnmt1/PCNA/UHRF1 interactions promotes a global DNA hypomethylation in human gliomas. We then demonstrate that the Dnmt1 phosphorylations by Akt and/or PKC abrogate the interactions of Dnmt1 with PCNA and UHRF1 in cellular and acellular studies including mass spectrometric analyses and the use of primary cultured patient-derived glioma. By using methylated DNA immunoprecipitation, methylation and CGH arrays, we show that global DNA hypomethylation is associated with genes hypomethylation, hypomethylation of DNA repeat element and chromosomal instability. Our results reveal that the disruption of Dnmt1/PCNA/UHRF1 interactions acts as an oncogenic event and that one of its signatures (i.e. the low level of mMTase activity) is a molecular biomarker associated with a poor prognosis in GBM patients. We identify the genetic and epigenetic alterations which collectively promote the acquisition of tumor/glioma traits by human astrocytes and glial progenitor cells as that promoting high proliferation and apoptosis evasion.


The Kaplan Fibers of the Iliotibial Band Can Be Identified on Routine Knee Magnetic Resonance Imaging.
The Kaplan fibers (KFs) of the iliotibial band have been suggested to play a role in anterolateral rotational instability of the knee, particularly in the setting of an anterior cruciate ligament (ACL) rupture. Description of the normal magnetic resonance imaging (MRI) anatomy of the KFs may facilitate subsequent investigation into the MRI signs of injury. To assess if the KF complex can be identified on 3-T MRI using standard knee protocols. Cohort study (diagnosis); Level of evidence, 3. 3-T MRI scans of 50 ACL-intact knees were reviewed independently by a musculoskeletal radiologist and 2 orthopaedic surgeons. Identification of the KFs was based on radiological diagnostic criteria developed a priori. Identification of the KFs in the sagittal, coronal, and axial planes was recorded. Interobserver reliability was assessed using the Kappa statistic. Detailed anatomy including distance to the joint line and relationship to adjacent structures was recorded. The mean patient age was 43 years (range, 15-81 years), 58% were male, and 50% were right knees. The KFs were identified by at least 2 reviewers on the sagittal images in 96% of cases, on the axial images in 76% of cases, and on the coronal images in 4% of cases. The mean distance from the KF distal femoral insertion to the lateral joint line was 50.1 mm (SD, 6.6 mm) and the mean distance to the lateral gastrocnemius tendon origin was 10.8 mm (SD, 8.6 mm). The KFs were consistently identified immediately anterior to the superior lateral geniculate artery on sagittal imaging. Interobserver reliability for identification was best in the sagittal plane (Kappa 0.5) and worst in the coronal plane (Kappa 0.1). The KF complex can be identified on routine MRI sequences in the ACL-intact knee; however, there is low to moderate interobserver reliability. Imaging in the sagittal plane had the highest rate of identification and the coronal plane the lowest. There is a consistent relationship between the most distal KF femoral attachment and the lateral joint line, lateral gastrocnemius tendon, and superior lateral geniculate artery.


[Intermittent short QT interval in a patient with sudden cardiac death].
This paper presents a 21 years-old-male without structural heart disease who was reanimated from a sudden cardiac death event. His familial history included two siblings suddenly dead in their first year of life. The patient had 10 episodes of ventricular tachycardia (some of them were registered). Electrocardiographically abnormalities were an intermittent short QT interval (280 ms), short QTc (320 ms) and a short ST segment. QT interval subsequently returned to a normal range (360 ms or more), while occasionally a length of 335 ms was recorded. The electrophysiological study findings (AH and HV intervals, refractory periods) were normal. The patient refused the implantable cardioverter defibrillator and he is receiving oral amiodarone (200 mg/day). The evolution has been satisfactory along four years. Sequential electrocardiograms are very important to identify patients with an intermittent short QT interval. Shortening of the interval J wave-Tpeak is also relevant. Related arrhythmias could be ventricular tachycardia or fibrillation.


BICM-ID scheme for clipped DCO-OFDM in visible light communications.
Visible light communication (VLC) is recommended for indoor transmissions in 5G network, whereby DC-biased optical orthogonal frequency division multiplexing (DCO-OFDM) is adopted to eliminate the inter-symbol interference (ISI) but suffers from considerable performance loss induced by clipping distortion. In this paper, bit-interleaved coded modulation with iterative demapping and decoding (BICM-ID) scheme for clipped DCO-OFDM is investigated to enhance the performance of VLC systems. In order to further mitigate the clipping distortions, a novel soft demapping criterion is proposed, and a simplified demapping algorithm is developed to reduce the complexity of the proposed criterion. Simulation results illustrate that the enhanced demapping algorithm achieves a significant performance gain.


Progress in adeno-associated virus type 2 vector production: promises and prospects for clinical use.
Vectors derived from the human parvovirus AAV-2 (adeno-associated virus type 2) are among the most promising gene delivery vehicles currently being developed. These vectors are not only capable of transducing a large variety of human cell types in vitro and in vivo, but in immunocompetent animal models can establish long-term gene expression without being pathogenic to the recipient. However, a limitation of this vector system with respect to its clinical application has long been the laborious work needed to prepare high-titer and pure AAV-2 vector stocks. A number of improvements to the basic manufacturing protocol have recently been reported that now allow the production of AAV-2 vectors of significantly higher quality and quantity. This article considers the most relevant approaches taken so far, which include modifications to the conventional transfection/infection protocol as well as the development of helper virus-free packaging methods and the establishment of vector producer cell lines. The various novel protocols are discussed, including their advantages and drawbacks, with a particular focus being put on their prospects for clinical use. Despite these advancements, the development of an ideal AAV-2 vector production method fully suiting clinical requirements obviously remains a challenging issue.


Evolving ideas of legume evolution and diversity: a taxonomic perspective on the occurrence of nodulation.
Legumes evolved about 60 million years ago (Ma), and nodulation 58 Ma. Nonnodulation remains common in Caesalpinioideae, with smaller numbers in Mimosoideae and Papilionoideae. The first type of infection by bacteria may have been at junctions where lateral roots emerged, followed by formation of infection threads to confine bacteria and convey them to some cells in the developing nodule, where they were generally released into symbiosomes. Infection threads were a prerequisite for root-hair infection, a process better controlled by the host, leading to a higher degree of specificity between symbionts. An alternative process, dating from the same time and persisting in about 25% of legumes, did not involve infection threads, bacteria entering a few host cells, surrounded by an undefined matrix. These cells divided repeatedly to give uniform infected tissue, with bacteria released into symbiosomes. Such legumes may have less stringent control of nodulation processes, and are found mainly in tropical and warm temperate areas. In each type of nodule, meristems may or may not be retained, leading to indeterminate or determinate forms. Nodule morphology and structure are host-determined, but the effectiveness of nitrogen fixation is largely controlled by the bacterial symbionts, which vary greatly in genotypic and phenotypic characters.


Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx.
Vascular pathology is central to malaria pathogenesis and associated with severity of disease. We have previously documented shedding of the cerebral endothelial glycocalyx in experimental malaria and hypothesized that this action is implicated in the pathogenesis of cerebral malaria (CM). Quantification and characterization of the intraluminal vascular glycocalyx are technically challenging. Here, we used ferritin labeling, computerized image analysis, and biochemical characterization by using in vivo biotinylation and pull down. Image analysis divided mice with CM and uncomplicated malaria and uninfected control mice into 3 non-overlapping groups. Biochemical assessment of the luminal surface revealed malaria-induced alterations in all components of the glycocalyx in CM. This loss was mirrored in increases of the same components in peripheral blood samples. Corticosteroid treatment protected against CM, reduced inflammation, and prevented glycocalyx loss. Adjunctive antithrombin-3 also prevented glycocalyx loss and significantly reduced CM-associated mortality, as well as reduced local inflammation and prevented blood-brain barrier leakage. In contrast, inhibition of matrix metalloproteases with batimastat had limited effects on the glycocalyx and disease progression. Thus, glycocalyx loss may be associated with malaria pathogenesis and could be targeted by adjunctive treatment.-Hempel, C., Sporring, J., Kurtzhals, J. A. L. Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx.


Lanthanide Contraction in LnF3 (Ln = Ce-Lu) and Its Chemical and Structural Consequences: Part 2: Specialized Empirical System of R3+ (R = Y, La, and 14 Ln) and F1- Ionic Radii for RF3 Series.
A specialized empirical (Spec-zd Emp) system of ionic radii (SIR) for R = Y3+, La3+, Ln3+, and F1- (R rare earth elements (REE)) was derived from the dependence of lanthanide contraction (LC) on the atomic number (Z) of lanthanides (Ln). LC decreased the radius of the cation with increasing Z. The structures of t-RF3 (LaF3-NdF3, "pseudot-SmF3") of the LaF3 type, 11 β-LnF3 (Ln = Sm-Lu), and β-YF3 of the β-YF3 type were studied. The empirical basis of the shortest (F-F)min and (R-F)min distances was calculated from the structural data for the RF3 complete series. The dependence of (F-F)min on Z reached saturation at Z = 67 (Ho). The base F1- radius r- = 1.2539(16) Å was calculated as the arithmetic mean of five (F-F)min in LnF3 with Ln = Ho-Lu. For the LnF3 series with Ln contributions up to 75 % wt., the dependence of (Ln-F)min on Z reflected the non-uniformity of the 4f orbital filling. SIR was calculated as the difference in the empirical constants of RF3 (ionic radii of (R,Ln)3+ (r+) and F1- (r-)), the change in which was continuous over the series and did not depend on the type of structure: r+ = (ZR-F)min - ½(F-F)min (Z = 57-71). The changes in LC in the LnF3 series were described by a third-degree polynomial. LC reduced r+ by 24% (percentage relative to less) from 1.1671(16) Å (La3+) to 0.9439(17) Å (Lu3+). In the Spec-zd Emp SIR, r+ were constants that did not require corrections for a coordination number (CN). A comparison of r+ in the Spec-zd Emp SIR with other SIRs was performed.


Food chain aspects of chlordane poisoning in birds and bats.
We have observed recurring chlordane poisonings of large numbers of common grackles (Quiscalus quiscula), European starlings (Sturnus vulgaris), and American robins (Turdus migratorius) at suburban roosts in New Jersey during the month of July. This paper describes aspects of the food chain uptake of chlordane that account for the periodicity of these poisonings. Chlordane concentrations ranged from < 0.02 to 20.3 microg/g wet weight in 11 soil samples collected from residential lawns and a golf course near one roost. Of the 10 species of insects and soil invertebrates collected from the area, two scarab beetles, the oriental beetle (Anomala orientalis) and Japanese beetle (Popilla japonica), had the highest concentrations of chlordane-related compounds (15.1 and 5.9 microg/g wet weight, respectively). Concentrations in the other eight species ranged from < 0.04 to 1.3 microg/g. Oriental and Japanese beetles collected from a rural location had concentrations of 0.03 and < 0.02 microg/g, respectively. Emergence of adult beetles peaked in mid- to late July, when bird mortality also peaked. Fecal pellets collected near the roost (n = 24) contained the remains of 1-5 beetles each (mean = 2), and scarab beetles accounted for 40% of the total number of insect parts in the stomach contents of common grackles (n = 8). Unlike soil samples, in which cis- and trans-chlordane predominated, beetles contained large amounts of the more toxic metabolites heptachlor epoxide and oxychlordane. Total chlordane-related compounds ranged from < 0.05 to 18.4 microg/g in Japanese beetles collected from 16 sites in New Jersey and 2 sites in Ohio. The highest concentrations were found in beetles from suburban areas and golf courses. We also analyzed brain tissue from insectivorous bats (15 big brown bats, Eptesicus fuscus, and 5 little brown bats, Myotis lucifugus) that were submitted to the New Jersey Rabies Laboratory in late June/July 1998 and 1999 but found to be rabies-negative. We suggest that high concentrations in three of the bats caused debility or abnormal behavior that may have precipitated submission for rabies testing.


Natural apoptosis in developing mice dopamine midbrain neurons and vermal Purkinje cells.
Natural cell death by apoptosis was studied in two neuronal populations of BALB/c, C57BL/6 and B6CBA-Aw-j/A hybrid stock mice: (I) dopaminergic (DA) neurons in choosing coronal levels throughout the anteroposterior extent of the substantia nigra pars compacta (SNc), and (II) Purkinje cells (PCs) in each vermal lobe of the cerebellar cortex. Mice were collected at postnatal day (P) 2 and P14 for the midbrain study, and at P4 and P7 for the analysis of the cerebellum. No DA cells with morphologic criteria for apoptosis were found. Moreover, when the combination of tyrosine hydroxylase and TUNEL or tyrosine hydroxylase and active caspase-3 immunohistochemistry were performed in the same tissue section, no DA cells TUNEL positives or active caspase-3-stained DA neurons were seen. On the other hand, when PCs were considered, data analysis revealed that more dying PCs were observed at P4 than at P7. Values of neuron death were highest in the central lobe; this was followed by the posterior and anterior lobes and then by the inferior lobe. To determine if apoptotic death of PCs is linked to their time-of-origin profiles, pregnant dams were administered with [3H]TdR on embryonic days 11-12, 12-13, 13-14 and 14-15. When TUNEL and [3H]TdR autoradiography or active caspase-3 immunohistochemistry and [3H]TdR autoradiography were combined in the same tissue section, results reveal that the naturally occurring PC death is not related to its time of origin but, rather, is random across age.


Trends in Incidence of Intracerebral Hemorrhage and Association With Antithrombotic Drug Use in Denmark, 2005-2018.
Spontaneous (nontraumatic) intracerebral hemorrhage (ICH) is the most severe complication of antithrombotic drug use. To estimate the strength of association between use of antithrombotic drugs and risk of ICH and to examine major changes in the incidence of ICH in the general population. This case-control study of patients with a first-ever ICH from January 1, 2005, to December 31, 2018, matched by age, sex, and calendar year with general population controls (1:40 ratio), assessed case and control patients 20 to 99 years of age in population-based nationwide registries in Denmark (population of 5.8 million). Use of low-dose aspirin, clopidogrel, a vitamin K antagonist (VKA), or a direct oral anticoagulant (DOAC). Association of ICH with antithrombotic drug use, annual age- and sex-standardized incidence rate of ICH, and prevalence of treatment with antithrombotic drugs. Conditional logistic regression models estimated adjusted odds ratios (aORs) (95% CIs) for the association of antithrombotic drugs with ICH. Among 16 765 cases with ICH (mean [SD] age, 72.8 [13.1] years; 8761 [52.3%] male), 7473 (44.6%) were exposed to antithrombotic medications at the time of ICH onset. The association with ICH was weakest for current use of low-dose aspirin (cases: 28.7%, controls: 22.6%; aOR, 1.51; 95% CI, 1.44-1.59) and clopidogrel (cases: 6.2%, controls: 3.4%; aOR, 1.65; 95% CI, 1.47-1.84) and strongest with current use of a VKA (cases: 12.0%, controls: 5.0%; aOR, 2.76; 95% CI, 2.58-2.96). The association with ICH was weaker for DOACs (cases: 3.0%, controls: 1.8%; aOR, 1.83; 95% CI, 1.61-2.07) than for VKAs. Compared with 2005, the prevalence of use of oral anticoagulants among general population controls in 2018 was higher (3.8% vs 11.1%), predominantly because of increased use of DOACs (DOACs: 0% vs 7.0%; VKA: 3.8% vs 4.2%). Antiplatelet drugs were used less frequently (24.7% vs 21.4%) because of decreased use of low-dose aspirin (24.3% vs 15.3%), whereas clopidogrel use increased (1.0% vs 6.8%). The age- and sex-standardized incidence rate of ICH decreased from 33 per 100 000 person-years in 2005 to 24 per 100 000 person-years in 2018 (P < .001 for trend). In Denmark from 2005 to 2018, use of antithrombotic drugs, especially VKAs, was associated with ICH. Although use of oral anticoagulation increased substantially during the study period, the incidence rate of ICH decreased.


The HTLV-1 Rex protein induces nuclear accumulation of unspliced viral RNA by avoiding intron excision and degradation.
The human T-cell leukemia virus (HTLV-1) Rex protein is essential for the cytoplasmic accumulation of incompletely spliced transcripts that code for the viral structural proteins. In this study effects of Rex on the amounts of total, spliced and unspliced RNA from HTLV-1 were determined. In transfected fibroblasts Rex production resulted in reduced amounts of spliced RNA and increased quantities of unspliced RNA in the nucleus. However, the total amount of viral RNA was not affected and the stability of spliced transcripts was not changed, thus indicating that only the rate of splicing was reduced. Rex action also reduced splicing in immortalized human cord blood T-cells. However, the total amount of viral transcripts and the stability of unspliced RNA in these cells were also increased in the presence of Rex. This indicates that Rex also prevents the degradation of unspliced transcripts in T-cells. The changes in the relative amounts of spliced and unspliced RNA induced by Rex were observed not only in the cytoplasm but also in the nucleus. Thus Rex affects the nucleocytoplasmic transport, splicing and stability of HTLV-1 RNA in the nucleus. These observations may suggest that Rex directs the unspliced viral RNA to the cytoplasm via a nuclear compartment that is not accessible to splicing and degradation factors.


Communication during haematological consultations; patients' preferences and professionals' performances.
Many patients with haematological malignancies experience barriers in clinical communication. Reaching effective communication is of great importance as it has been linked to a range of improved patient outcomes such as satisfaction, compliance to treatment, perceived quality of life and physical and mental health. To get a better understanding how communication in haematological consultations can be improved, the current study focussed on patients' preferences and perceived performances regarding the communicative behaviour of their health care professional. Secondly, the mediation of an online communication tool for patients was analysed. Within a controlled pre- post-test design, 78 datasets of clinical consultations could be analysed. Patients considered both affective and instrumental communication aspects important. The affective communication behaviour of the health care professional met the patients' pre-visit preferences well. In the information exchange, more variability and discrepancies were found. Overall, the online intervention did not seem to influence the patients' perceived communication performance of their health care professional much. To further improve the communication during clinical consultations, health care professionals should inquire about patients' expectations, especially during the exchange of information and advices. At the same time, patients should be supported to express their preferences at the start of the consultation. The study was registered in the Netherlands Trial Register, number 3779.


Articular inflammation induced by an enzymatically-inactive Lys49 phospholipase A2: activation of endogenous phospholipases contributes to the pronociceptive effect.
Arthritis is a set of inflammatory conditions that induce aching, stiffness, swelling, pain and may cause functional disability with severe consequences to the patient's lives. These are multi-mediated pathologies that cannot be effectively protected and/or treated. Therefore, the aim of this study was to establish a new model of acute arthritis, using a Lys49-PLA2 (Bothrops asper myotoxin II; MT-II) to induce articular inflammation. The articular inflammation was induced by MT-II (10 μg/joint) injection into the left tibio-tarsal or femoral-tibial-patellar joints. Cellular influx was evaluated counting total and differential cells that migrated to the joint. The plasma extravasation was determined using Evans blue dye. The edematogenic response was evaluated measuring the joint thickness using a caliper. The articular hypernociception was determined by a dorsal flexion of the tibio-tarsal joint using an electronic pressure-meter test. The mediators involved in the articular hypernociception were evaluated using receptor antagonists and enzymatic inhibitors. Plasma extravasation in the knee joints was observed 5 and 15 min after MT-II (10 μg/joint) injection. MT-II also induced a polymorphonuclear cell influx into the femoral-tibial-patellar joints observed 8 h after its injection, a period that coincided with the peak of the hyperalgesic effect. Hyperalgesia was inhibited by the pretreatment of the animals with cyclooxygenase inhibitor indomethacin, with type-2 cyclooxygenase inhibitor celecoxib, with AACOCF3 and PACOCF3, inhibitors of cytosolic and Ca2+-independent PLA2s, respectively, with bradykinin B2 receptor antagonist HOE 140, with antibodies against TNFα, IL-1β, IL-6 and CINC-1 and with selective ET-A (BQ-123) and ET-B (BQ-788) endothelin receptors antagonists. The MT-II-induced hyperalgesia was not altered by the lipoxygenase inhibitor zileuton, by the bradykinin B1 receptor antagonist Lys-(Des-Arg9,Leu8)-bradykinin, by the histamine and serotonin antagonists promethazine and methysergide, respectively, by the nitric oxide inhibitor LNMMA and by the inhibitor of matrix 1-, 2-, 3-, 8- and 9- metalloproteinases GM6001 (Ilomastat). These results demonstrated the multi-mediated characteristic of the articular inflammation induced by MT-II, which demonstrates its relevance as a model for arthritis mechanisms and treatment evaluation.


[The relation of deoxyribonucleic acid contents and nuclear estrogen receptors in breast cancers].
Flow cytometry was applied to the analysis of DNA contents in 59 cases of breast cancer, among which 28 cases were diploidy cancers, and 31 were aneuploid. DNA index of these cases was found to be ranging from 0.45 to 3.35, including S-phase fraction (SPF) from 2.46% to 78.87%, and proliferation index (PI) from 17.06 to 87.04. In 60 cases of breast carcinoma, nuclear estrogen receptors (ERn) were assayed by immunocytochemistry with ER-monoclonal antibody. 29 of them were ERn-, and 31 were ERn+. The DNA contents and ERn levels, both detected in each of 57 cases, were found to be correlated to some extent. In aneuploidy cancer group, there were more ERn- cases than ERn+ cases (P less than 0.05). The mean value of PI was higher in the ERn- group than in the ERn+ group, and the corresponding ERn- cases were more frequent with increase of PI value. Among those cases in which SPF was over 40%, there were more ERn- cases than ERn+ cases. The relations between ERn levels and DNA contents may represent the degree of differentiation of breast cancers and may help to predict prognosis.


[Biochemical changes in cytoplasmic membranes in dog liver during experimental viral hepatitis].
The composition of cytoplasmic membranes isolated from livers of dogs infected with virus of infectious hepatitis of carnivora (IHC) was studied. Inoculation with IHC virus was found not to cause any marked changes in the contents of proteins, lipids and nucleic acids of the membranes under study, but considerable differences in the composition of membrane proteins, lipids and fatty acids of virus-affected cells were demonstrated. The experimental data suggest that the virus infection exerts a considerable effect on the protein-lipid complex of the cytoplasmic membranes of the cell.


Noninvasive imaging tools in dermatology.
The diagnosis of skin disease relies on visual inspection, often followed by biopsy and histopathologic examination, which remains the gold standard in diagnosis. New imaging tools, including dermoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT), can provide noninvasive diagnoses while sparing unnecessary biopsies. We discuss dermoscopy, RCM, and OCT, and compare cost, clinical integration, reimbursement, and accuracy of these imaging modalities.


Back to the roots of a new exon--the molecular archaeology of a SP100 splice variant.
Retropseudogenes are intronless DNA sequences sharing a high degree of homology with the cDNA of their corresponding active genes. They are thought to have originated by reverse transcription of messenger RNA and reintegration of the cDNA into the genome. Usually considered a type of evolutionary waste, they melt into the background of their surrounding DNA by the loss of similarity to the active gene or disappear from the genome by the accumulation of deletions. On the other hand, in this paper we describe the evolutionary recycling of this genomic waste. Recently, a splice variant of the gene encoding the nuclear protein SP100 was identified in which the 3' part of the cDNA is replaced by an alternative exon apparently encoding an HMG1-DNA-binding domain. We were able to show that this HMG box is contributed by a new exon arising from an HMG1 retropseudogene that we have molecularly characterized in detail. In addition to being found in human cells, corresponding fusion transcripts were shown in Pan troglodytes, Gorilla gorilla, and Hylobates lar, but not in Macaca mulatta. Genomic DNA from M. mulatta enabled us to amplify by PCR the 5' part but not the 3' part of the HMG1 retropseudogene. From our data we thus can date the underlying retrotransposition to more than 35 million years ago. Our findings offer a model as to how new exons may evolve during evolution. To our knowledge this is the first example of a retropseudogene becoming part of an active gene in which both parental parts are well characterized and remain in-frame with their cDNA.


[New materials for intraocular lenses].
The first intraocular lens implanted in a human eye 39 years then lenses ago, was made of polymethylmethacrylate (PMMA). Today this material is considered to be the standard, so every new type of material is compared to PMMA and must fulfil the requirements demanded of an intraocular implant today. Therefore, every attempt is made to use PMMA as the main structure while eliminating the disadvantageous characteristics even though they are minimal. Thus, the hydrophobic surface can be made more biocompatible by heparin-surface modification. In recent years, hydroxyethylmethacrylate (HEMA) and silicone have achieved a certain level of clinical importance. Another of the new materials is polycarbonate, which is still in the preclinical phase.


Inhibition of cluster antigen 36 protects against fatty acids-induced lipid accumulation, oxidative stress, and inflammation in bovine hepatocytes.
When ketosis occurs, supraphysiological concentrations of nonesterified fatty acids (NEFA) display lipotoxicity and are closely related to the occurrence of hepatic lipid accumulation, oxidative stress and inflammation, resulting in hepatic damage and exacerbating the progression of ketosis. However, the mechanism of these lipotoxic effects caused by high concentrations of NEFA in ketosis is still unclear. Cluster antigen 36 (CD36), a fatty acid transporter, plays a vital role in the development of hepatic pathological injury in nonruminants. Thus, the aim of this study was to investigate whether CD36 plays a role in NEFA-induced hepatic lipotoxicity in dairy cows with clinical ketosis. Liver tissue and blood samples were collected from healthy (n = 10) and clinically ketotic (n = 10) cows at 3 to 15 d in milk. In addition, hepatocytes isolated from healthy calves were treated with 0, 0.6, 1.2, or 2.4 mM NEFA for 12 h; or infected with CD36 expressing adenovirus or CD36 silencing small interfering RNA for 48 h and then treated with 1.2 mM NEFA for 12 h. Compared with healthy cows, clinically ketotic cows had greater concentrations of serum NEFA and β-hydroxybutyrate (BHB) and activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) but lower serum glucose. Besides, dairy cows with clinical ketosis displayed excessive hepatic lipid accumulation. More importantly, these alterations were accompanied by an increased abundance of hepatic CD36. In the cell culture model, exogenous NEFA (0, 0.6, 1.2, or 2.4 mM) treatment could dose-dependently increase the abundance of CD36. Meanwhile, NEFA (1.2 mM) increased the content of triacylglycerol (TAG), reactive oxygen species (ROS) and malondialdehyde (MDA), and decreased the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). Moreover, NEFA upregulated phosphorylation levels of nuclear factor κB (NF-κB) and the inhibitor of NF-κB (IκB) α, along with the upregulation of protein abundance of NLR family pyrin domain containing 3 (NLRP3) and caspase-1, and mRNA abundance of IL1B, IL6, and tumor necrosis factor α (TNFA). These alterations induced by NEFA in bovine hepatocytes were associated with increased lipid accumulation, oxidative stress and inflammation, which could be further aggravated by CD36 overexpression. Conversely, silencing CD36 attenuated these NEFA-induced detriments. Overall, these data suggest that CD36 may be a potential therapeutic target for NEFA-induced hepatic lipid accumulation, oxidative stress, and inflammation in dairy cows.


Measurement of small molecule binding kinetics on a protein microarray by plasmonic-based electrochemical impedance imaging.
We report on a quantitative study of small molecule binding kinetics on protein microarrays with plasmonic-based electrochemical impedance microscopy (P-EIM). P-EIM measures electrical impedance optically with high spatial resolution by converting a surface charge change to a surface plasmon resonance (SPR) image intensity change, and the signal is not scaled to the mass of the analyte. Using P-EIM, we measured binding kinetics and affinity between small molecule drugs (imatinib and SB202190) and their target proteins (kinases Abl1 and p38-α). The measured affinity values are consistent with reported values measured by an indirect competitive binding assay. We also found that SB202190 has weak bindings to ABL1 with KD > 10 μM, which is not reported in the literature. Furthermore, we found that P-EIM is less prone to nonspecific binding, a long-standing issue in SPR. Our results show that P-EIM is a novel method for high-throughput measurement of small molecule binding kinetics and affinity, which is critical to the understanding of small molecules in biological systems and discovery of small molecule drugs.


Sense of coherence, physical activity and its associations with gender and age among Kosovar adolescents: a cross-sectional study.
The sense of empowerment that comes from good health based on an ability to manage daily challenges is something that needs to be developed and supported from childhood into adulthood. This early empowerment may help to maintain a healthy lifestyle of young people, especially in places which have recently suffered severely from high social tension and stress. This cross-sectional study aimed to investigate the associations of sense of coherence (SOC), physical activity (PA), and the role of gender and age in young adolescents from Kosovo. A total of 1296 adolescents aged 13-16 years from randomly selected schools in the seven major municipalities of Kosovo participated in the study in 2014. SOC was determined with a short version of a SOC-13 questionnaire with its three components: manageability (SOC-Ma), meaningfulness (SOC-Me), and comprehensibility (SOC-Co). The level of PA was determined with a Physical Activity Screening Measure. The associations were examined by a three-way hierarchical regression. The analyses indicated that young Kosovar boys with strong SOC were characterized by a higher level of moderate to vigorous physical activity (MVPA). There was no such effect in girls. Interactional effects were noticed for Kosovar boys for meaningfulness and comprehensibility sub-components of SOC and the level of MVPA. Strong meaningfulness was associated with higher MVPA. For girls, we showed differentiation according to age groups, we noticed that older adolescent girls with strong meaningfulness also had higher MVPA. No significant associations were found in the two other sub-components of SOC. The association between global SOC, gender and age indicated the interactions with the level of MVPA. People with higher SOC are characterized by a higher level of MVPA, but the relation is gender sensitive. This versatility should be taken into account in planning future PA intervention, specifically in societies with high ethnical and religious strains.


Effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children: 3 years of follow-up. Long-term response to nelfinavir in children.
Antiretroviral treatment (ART) in children has special features and consequently, results obtained from clinical trials with antiretroviral drugs in adults may not be representative of children. Nelfinavir (NFV) is an HIV-1 Protease Inhibitor (PI) which has become as one of the first choices of PI for ART in children. We studied during a 3-year follow-up period the effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children. Forty-two vertically HIV-infected children on HAART with NFV were involved in a multicentre prospective study. The children were monitored at least every 3 months with physical examinations, and blood sample collection to measure viral load (VL) and CD4+ cell count. We performed a logistic regression analysis to determinate the odds ratio of baseline characteristics on therapeutic failure. Very important increase in CD4+ was observed and VL decreased quickly and it remained low during the follow-up study. Children with CD4+ <25% at baseline achieved CD4+ >25% at 9 months of follow-up. HIV-infected children who achieved undetectable viral load (uVL) were less than 40% in each visit during follow-up. Nevertheless, HIV-infected children with VL >5000 copies/ml were less than 50% during the follow-up study. Only baseline VL was an important factor to predict VL control during follow-up. Virological failure at defined end-point was confirmed in 30/42 patients. Along the whole of follow-up, 16/42 children stopped HAART with NFV. Baseline characteristics were not associated with therapeutic change. NFV is a safe drug with a good profile and able to achieve an adequate response in children.


Depression and smoking cessation: the role of motivation and self-efficacy.
The aim of this paper is to examine whether depression, assessed using the Beck Depression Inventory, is related to smoking cessation motivation and self-efficacy. In a population sample of 1,547 Finnish men and 1,856 Finnish women, aged between 25-64 years, there were 34% male and 21% female current smokers. The current smokers had higher mean depression scores than former or never smokers. The higher depression scores were related to greater motivation to quit smoking among female smokers [OR = 1.51 (1.15-1.97)]. In addition, higher depression scores were related to lower smoking cessation self-efficacy, especially among male smokers [OR = .63 (.45-.90)]. Depression scores were not related to whether a smoker had had previous cessation attempts. Our results suggest that depression is related to lower smoking cessation self-efficacy while smokers with higher depression scores seem to be more motivated to quit smoking.


LXR, prostate cancer and cholesterol: the Good, the Bad and the Ugly.
Cholesterol is a fundamental molecule for life. Located in the cell membrane, this sterol participates to the cell signaling of growth factors. Inside the cell it can be converted in hormones such as androgens or modulate the immune response. Such important functions could not be solely dependent of external supply by diet hence de novo synthesis could occur from acetate in almost all mammalian cells. If a deficiency in cholesterol sourcing leads to development troubles, overstocking has been associated to various diseases such as atherosclerosis and cancers. Cholesterol homeostasis should thus be tightly regulated at the uptake, de novo synthesis, storage and export processes. Various transcription factors have been described these last years as important to regulate cholesterol levels. Besides, synthetic molecules have been developed for many years to modulate cholesterol synthesis, such as statins. Many articles have associated prostate cancer, whose incidence is constantly increasing, to cholesterol disequilibrium. Targeting cholesterol could thus be a new pharmacological hit to counteract the initiation, development and/or progression of prostate cancer. Among the transcription factors regulating cholesterol homeostasis, the nuclear receptors Liver X Receptors (LXRs) control cholesterol uptake and export. Targeting the LXRs offers a new field of investigation to treat cancer. This review highlights the molecular relationships among LXRs, prostate cancer and cholesterol and why LXRs have good chance to be targeted one day in this tumor. LXRs, prostate cancer and cholesterol, more than a "Ménage à trois", The Good, the Bad and the Ugly.


Hydroxypropyl-guar gellable lubricant eye drops for dry eye treatment.
Dry eye is a medical problem of epidemic proportions, especially among the elderly in developed countries. The treatment of dry eye is still largely inadequate because there is no way of permanently restoring normal tear function and secretion at present. At present, virtually all therapeutic regimens include tear supplements; however, their main drawbacks are the need for frequent instillation, inadequate ocular surface protection and limited mode of action, focusing on rewetting only. A new gellable lubricant eye drop (Systane lubricant eye drops, Alcon) has been designed using the novel concept of a pH-sensitive hydroxypropyl-guar component that prevents surface desiccation, reduces friction and acts as a mucomimetic. The purpose of this review is to consider this topical therapy and its properties. Currently published data on Systane is reviewed, putting an accent on its novel multiple modality of action. By being pH sensitive, Systane adapts its viscosity to the ocular surface pH, which tends to be higher in dry eye. It becomes more viscous when the eye is drier, thus, providing better ocular surface protection. In addition, its characteristics reduce ocular surface friction, which is another factor that exacerbates dry eye symptoms. Data published so far show that it is also well tolerated by the patient, thus, significantly reducing dry eye symptoms and improving the patient's quality of life. By implementing this novel approach, Systane has contributed significantly to dry eye treatment.


Systematic Approach to Developing Splice Modulating Antisense Oligonucleotides.
The process of pre-mRNA splicing is a common and fundamental step in the expression of most human genes. Alternative splicing, whereby different splice motifs and sites are recognised in a developmental and/or tissue-specific manner, contributes to genetic plasticity and diversity of gene expression. Redirecting pre-mRNA processing of various genes has now been validated as a viable clinical therapeutic strategy, providing treatments for Duchenne muscular dystrophy (inducing specific exon skipping) and spinal muscular atrophy (promoting exon retention). We have designed and evaluated over 5000 different antisense oligonucleotides to alter splicing of a variety of pre-mRNAs, from the longest known human pre-mRNA to shorter, exon-dense primary gene transcripts. Here, we present our guidelines for designing, evaluating and optimising splice switching antisense oligomers in vitro. These systematic approaches assess several critical factors such as the selection of target splicing motifs, choice of cells, various delivery reagents and crucial aspects of validating assays for the screening of antisense oligonucleotides composed of 2'-O-methyl modified bases on a phosphorothioate backbone.


Outcome of laparoscopic ovariohysterectomy or ovariectomy in dogs with von Willebrand disease or factor VII deficiency: 20 cases (2012-2014).
OBJECTIVE To describe surgical techniques and perioperative management of dogs with von Willebrand disease (VWD) or factor VII (FVII) deficiency undergoing laparoscopic ovariohysterectomy or ovariectomy and evaluate outcomes. DESIGN Retrospective case series. ANIMALS 20 client-owned dogs with VWD (n = 16) or FVII deficiency (4). PROCEDURES Dogs with VWD or FVII deficiency that underwent laparoscopic ovariohysterectomy or ovariectomy between 2012 and 2014 were retrospectively identified via a multi-institutional review of medical records. RESULTS Median expression of von Willebrand factor was 19% (interquartile range, 18% to 30%). All 16 dogs with VWD were Doberman Pinschers, and all were pretreated with desmopressin; 4 also received cryoprecipitate. One of 4 dogs with FVII deficiency received plasma preoperatively, and 1 was treated with desmopressin; 2 dogs received no preoperative treatment. Laparoscopic ovariectomy was performed in 9 dogs with VWD and 2 dogs with FVII deficiency, laparoscopic ovariectomy with gastropexy was performed in 6 dogs with VWD and 1 dog with FVII deficiency, and laparoscopic-assisted ovariohysterectomy was performed in 1 dog with VWD and 1 dog with FVII deficiency. Iatrogenic splenic laceration requiring conversion to laparotomy occurred during trocar insertion in 1 dog with VWD. No postoperative complications, including signs of hemorrhage, were reported for any dogs. CONCLUSIONS AND CLINICAL RELEVANCE Laparoscopic ovariohysterectomy or ovariectomy in dogs with VWD or FVII deficiency pretreated with desmopressin, cryoprecipitate, or plasma transfusions were not associated with clinical signs of hemorrhage, suggesting that minimally invasive ovariohysterectomy or ovariectomy may be considered in female dogs affected with these coagulopathies.


Bovine cytomegaloviruses: identification and differential properties.
Biological properties and restriction enzyme patterns of the slowly replicating herpesviruses isolated from cattle affected with different diseases in North America and Europe were analysed. These virus isolates induced identical plaques that developed within 7 to 9 days in bovine foetal spleen cells and within 5 days in actively growing Georgia bovine kidney cells. These virus isolates were found to be antigenically related when tested in the indirect immunofluorescence test, and antigenic relationships with bovine herpesvirus 1 (BHV-1), BHV-2, BHV-3 or BHV-6 were not detected. The genomes of these strains were shown to have virtually identical cleavage sites when treated with restriction enzymes EcoRI, BamHI, SstII, SphI and HindIII. The resulting restriction enzyme patterns differed strikingly from those of BHV-1, BHV-2, BHV-3 and BHV-6. Because the herpesviruses tested become enveloped on the nuclear as well as on endoplasmic membranes, a process through which they induce cytoplasmic vesicles filled with enveloped viral particles, and because of the unique cytoplasmic inclusions that are induced, we classify them tentatively as bovine cytomegaloviruses.


The Relationship of Adolescent Motherhood to the Macronutrient Content of Breast Milk.
Objective: Breast milk is the best nutrient for newborns due to its rich dietary content, immunological factors, ease of accessibility, and affordability. Given the fact that adolescent birth rate in Turkey is high, this study examines the effects of adolescent motherhood with regard to macronutrient contents in breast milk. Study Design: We collected colostrum samples from mothers staying at our hospital. Gestational ages were ≥37 weeks. Demographic characteristics of the patients were registered. The MIRIS (Mid-Infrared Human Milk Analyzer) device was operated to analyze breast milk, adopting a spectroscopy method for measurements. Protein, fat, carbohydrate, and energy levels of the hindmilk samples were measured; thus, study groups were compared. Results: The study included 224 mothers, of whom 49 were adolescents and 125 were adults. Maternal weight and maternal body mass index, weight gain during pregnancy, mode of delivery and gestational age, as well as birth weight and gender of the infants were similar. As breast milk contents were compared, we found out that fat content levels in the colostrum of adolescent mothers were significantly higher, with respect to the other group. Protein and carbohydrate levels were lower in adolescents, even if they were not statistically significant. There was no difference between the groups in terms of energy levels. Conclusion: Adolescent motherhood may have negative influences on infant welfare. However, in terms of breast milk content quality, adult mothers are not superior to adolescents.


Early MR features of hypoxic-ischemic brain injury in neonates with periventricular densities on sonograms.
In the early 1980s, diagnosing periventricular leukomalacia (PVL) in neonates by using cranial sonography was possible for the first time. Our purpose was to investigate the possibility of diagnosing PVL in the acute stage by using MR imaging. We evaluated early MR features of hypoxic-ischemic brain injury in neonates with periventricular densities (flares) on cranial sonograms to determine the added value of MR imaging over sonography alone for early diagnosis of brain damage. In a prospective study, infants who showed flares and/or cysts on sonograms underwent MR imaging during the (sub)acute stage. Fifty infants were classified according to the highest sonographic grade up to the day of MR imaging: 23 infants had sonographic grade 1 (flares < 1 week), 15 had sonographic grade 2 (flares > or = 1 week), four had sonographic grade 3 (small localized cysts), and eight had sonographic grade 4 (extensive periventricular cysts); none had sonographic grade 5 (multicystic leukomalacia) on the day of MR imaging. Overall, the additional information provided by MR imaging (over sonography alone) consisted of the depiction of hemorrhagic lesions in 64% of the infants. Extent and severity of the hemorrhages varied from isolated punctate lesions to extensive hemorrhages throughout the white matter; the latter were followed by cystic degeneration at autopsy in two infants. In nine of the 12 infants with cystic PVL, MR images showed more numerous or more extensive cysts. In addition, in two infants, MR images showed cysts not present on sonograms. In 32% of the infants, MR imaging provided no additional information; in these children, all but one had flares on sonograms whereas MR images showed no abnormalities or a zone of mild periventricular signal change. MR imaging can depict the precise site and extent of hypoxic-ischemic brain injury at an earlier stage and allows a wider differentiation of lesions as compared with sonography alone. Hemorrhagic PVL is considered to be rare, but was present in 64% of our study population.


Universal 2 Wrist Arthroplasty in Rheumatoid Arthritis.
Purpose The aim of this study was to evaluate the mid- to long-term outcomes and complications in patients affected by rheumatic diseases treated with the Universal 2 (U2) total wrist arthroplasty (TWA). Methods We reviewed, in a retrospective, noncontrolled cohort study, 22 patients affected by rheumatoid arthritis (RA), who underwent U2 total wrist replacement between March 2003 and January 2014 for the treatment of 23 rheumatoid wrists with the aim of obtaining the remission of pain and a range of motion (ROM) useful for daily activities, according to the patients' demands, as an alternative to total wrist arthrodesis. The cohort of patients included 20 females and 2 males, with a mean age of 54.9 years. Residual pain, preoperative ROM, postoperative ROM increases, grip strength, radiographic changes, long-term complications, and reasons for revision or failures were evaluated. Results In this study, 22 patients were evaluated at a mean follow-up of 82.3 months (range: 2-12 years). All patients had good or complete pain relief, the mean visual analogue scale pain score was 0.82. The mean grip strength improved and postoperatively was 11 kg (Jamar). The mean total ROM of flexion-extension was 72.3 degrees; radial-ulnar deviation 24.9 degrees. The mean QuickDASH score of 49 and patient rate wrist/hand evaluation of 41.7 a revision surgical procedure in six cases (26%): in two cases, a carpal component revision procedure and in four cases, total implant failures requiring either conversion to a Swanson spacer or wrist joint fusion. Conclusion TWA provides pain relief, preserves motion, and improves function in severe degenerative RA. Our results at a mid- to long-term follow-up with the U2 prosthesis were encouraging and represent, when indicated, a valid alternative to fusion which is less appealing for RA patients. Level of Evidence Level of evidence is therapeutic IV.


In search of an elusive hard threshold: a test of observer's ability to order sub-threshold stimuli.
The contrast transducer function (d' vs. contrast) for sine gratings was claimed to come up from some non-zero contrast value rather than from the origin. This implies that there is a point (a hard threshold) on the grating contrast axis below which observers could not distinguish between presentations containing gratings and those containing a homogeneous field. We studied the ability to order sub-threshold square wave gratings and found, to the contrary, that observers were able to do this no matter how low the contrasts. At the same time, the observers failed to order the sub-threshold gratings when they were of the same contrast. The latter is inconsistent with signal detection theory which predicts that an observer's judgements are based on the same ordered set of sensory states irrespective of whether the stimuli differ or are the same. On the other hand, these data can be reconciled with the notion of a threshold if the latter is thought of as a fuzzy rather than a sharp margin on the contrast axis.


Ethnicity and maternal education as risk indicators for dental caries, and the role of dental behavior.
The aim of this study was to assess differences in dental health between socioeconomic and ethnic groups in a cohort of 5-yr-old children born in 1982 and in a cohort of 11-yr-old children born in 1976. A further aim was to evaluate the putative role of dental behaviors as intervening factors between ethnicity and maternal education on the one hand and caries experience on the other. A secondary analysis was performed on data collected in a study monitoring the oral health of youths covered by public health insurance (Ziekenfonds) in the Netherlands. The results showed both ethnicity and maternal education to be indicators of caries risk in the primary dentition. For caries in the permanent dentition, only maternal education could be identified as a risk indicator. Dental behaviors were related to caries experience as well as to ethnicity and maternal education, though the evidence for the role of these dental behaviors as intervening factors was weak. It is concluded that the validity and reliability of the behavioral measurements might be questionable and that the mechanism underlying the differences in caries experience between the various groups is still little understood.


Glutathione reductase activity, riboflavin status, and disease activity in rheumatoid arthritis.
To measure erythrocyte glutathione reductase (EGR) activity and riboflavin status, and their relations to disease activity, in rheumatoid arthritis patients compared to healthy controls. Patients with rheumatoid arthritis were classified as active if there were features of articular inflammation which required initiation or change of disease modifying therapy, and as inactive if they had little evidence of articular inflammation. EGR was measured in patients and healthy controls by a functional assay with or without the addition of flavin adenine dinucleotide (FAD). The ratio of stimulated EGR (with FAD added) to basal EGR (no added FAD), which measures riboflavin status, is known as the EGR activation coefficient (EGRAC). An EGRAC > or = 1.3 represents biochemical riboflavin deficiency. 91 patients with rheumatoid arthritis, including 57 with active disease, and 220 healthy controls were studied. Both basal and stimulated EGR were significantly higher in patients with rheumatoid arthritis (P = 0.0001) than in controls. Biochemical riboflavin deficiency was identified in 41% controls and 33% patients with active rheumatoid arthritis but was significantly less frequent (9%) in patients with inactive compared to active disease (P = 0.02) or healthy controls (P = 0.0006). Pain score, articular index, C reactive protein, and erythrocyte sedimentation rate were increased in patients with riboflavin deficiency (all P < 0.02). Higher basal and stimulated EGR might be expected in patients with rheumatoid arthritis in response to chronic oxidative stress due to synovial inflammation. The association of riboflavin deficiency with increased disease activity suggests that impaired EGR activity could facilitate continuing inflammation in these patients.


Enabling a multidisciplinary approach to the study of ageing and Alzheimer's disease: an update from the Australian Imaging Biomarkers and Lifestyle (AIBL) study.
The Australian Imaging Biomarkers and Lifestyle (AIBL) study is a longitudinal study of 1,112 volunteers from healthy, mild cognitive impairment (MCI) and Alzheimer's disease (AD) populations who are assessed at 18-month intervals in order to enable prospective research into ageing and AD. Using a multidisciplinary battery, AIBL assessments comprise the extensive study of clinical factors and cognitive function, collection of blood and cerebrospinal fluid (CSF) samples for biomarker discovery, structural and β-amyloid (Aβ) neuroimaging, and obtaining information on diet and physical activity patterns of the cohort. Now in its seventh year, AIBL is part of a substantial international effort to prospectively study the relationships between clinical characteristics and putative AD biomarkers in groups who carry different risk factors for AD. The identification of biomarkers would provide a window of opportunity to assess AD risk in individuals prior to the onset of advanced clinical symptoms, in addition to facilitating testing of therapeutic and lifestyle interventions likely to emerge within the next decade that prevent or delay symptom emergence in those at high risk for developing AD. In this paper, we present key findings from the AIBL study and discuss how they contribute to our understanding of AD pathogenesis and diagnosis.


Cyclic AMP regulates somatostatin mRNA accumulation in primary diencephalic cultures and in transfected fibroblast cells.
Although the factors controlling the secretion of the neuropeptide somatostatin have been extensively studied, little is known about the mechanisms that control somatostatin biosynthesis. Somatostatin secretion is regulated by numerous agents that increase intracellular levels of cAMP. We sought to determine whether cAMP also regulates somatostatin mRNA accumulation. We found that forskolin elicited an increase in somatostatin secretion and mRNA levels in primary cultures of rat diencephalic cells. Another secretagogue, KCl, was as effective as forskolin in causing somatostatin secretion but had no effect on mRNA accumulation. Somatostatin expression in fibroblast cells transfected with the somatostatin gene was also regulated by forskolin. These results demonstrate that somatostatin mRNA accumulation can be regulated through a cAMP-dependent pathway, that this pathway is operative in heterologous cells transfected with the somatostatin gene, and that stimulation of somatostatin secretion and mRNA accumulation can be uncoupled from one another.


Alloimmune response results in expansion of autoreactive donor CD4+ T cells in transplants that can mediate chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) is considered an autoimmune-like disease mediated by donor CD4(+) T cells, but the origin of the autoreactive T cells is still controversial. In this article, we report that the transplantation of DBA/2 donor spleen cells into thymectomized MHC-matched allogeneic BALB/c recipients induced autoimmune-like cGVHD, although not in control syngeneic DBA/2 recipients. The donor-type CD4(+) T cells from the former but not the latter recipients induced autoimmune-like manifestations in secondary allogeneic BALB/c as well as syngeneic DBA/2 recipients. Transfer of donor-type CD4(+) T cells from secondary DBA/2 recipients with disease into syngeneic donor-type or allogeneic host-type tertiary recipients propagated autoimmune-like manifestations in both. Furthermore, TCR spectratyping revealed that the clonal expansion of the autoreactive CD4(+) T cells in cGVHD recipients was initiated by an alloimmune response. Finally, hybridoma CD4(+) T clones derived from DBA/2 recipients with disease proliferated similarly in response to stimulation by syngeneic donor-type or allogeneic host-type dendritic cells. These results demonstrate that the autoimmune-like manifestations in cGVHD can be mediated by a population of donor CD4(+) T cells in transplants that simultaneously recognize Ags presented by both donor and host APCs.


Regulation of Epha4 expression in paraxial and lateral plate mesoderm by ectoderm-derived signals.
Somitogenesis in all vertebrates involves a mesenchymal to epithelial transition of segmental plate cells. Such a transition involves cells altering their morphology and their adhesive properties. The Eph family of receptor tyrosine kinases has been postulated to regulate cytoskeletal organization. In this study, we show that a receptor belonging to this family, EphA4, is expressed in the segmental plate in a region where cells are undergoing changes in cell shape as a prelude to epithelialization. We have identified the ectoderm covering the somites and the midline ectoderm as sources of signals capable of inducing EphA4. Loss of EphA4 results in cells of irregular morphology and somites fail to form. We also show that when somites fail to develop, expression of EphA4 in the lateral plate is also lost. We suggest that signaling occurs between the somites and the lateral plate mesoderm and provide evidence that retinoic acid is involved in this communication.


Attitude and preferences of nigerian antenatal women to social support during labour.
SummaryThis was a hospital-based cross-sectional study of 224 randomly selected antenatal women receiving care at the University College Hospital, Ibadan, Nigeria. The study aimed to seek the attitude and preferences of respondents about social support during childbirth and also identify variables that may influence their decisions. Seventy-five per cent of respondents desired companionship in labour. Approximately 86% preferred their husband as companion while 7% and 5% wanted their mother and siblings as support person respectively. Reasons for their desire for social support were emotional (80.2%), spiritual (17.9%), errands (8.6%) and physical activity (6.8%). Socio-demographic variables found to be statistically significant on logistic regression analysis for the desire of a companion in labour were nulliparity (OR 3.57, 95% CI 1.49-8.52), professionals (OR 3.11, 95% CI 1.22-7.94) and women of other ethnic groups besides Yoruba (OR 2.90, 95% CI 1.02-8.26), which is the predominant ethnic group in the study area. Only those with post-secondary education were found to want their husbands as doula (OR 2.96, 95% CI 1.08-8.11). More than half of the respondents wanted information about labour prior to their experience. It is important that Nigerian women are allowed the benefit of social support during childbirth, particularly as there is a lack of one-to-one nursing care and other critical services, including epidural analgesia in labour, at many of the health care facilities in Nigeria. Men could play a pivotal role in the process of introducing support in labour so as to improve the outcome for both the mother and her newborn.


Defective-interfering particles of Semliki Forest virus: intracellular events during interference.
Purified defective-interfering (DI) particles of Semliki Forest virus are unable to carry out any of the steps in virus multiplication except uncoating. Cells co-infected with DI particles and standard virus contain several virus-specified RNA species (DI particle-specific species) absent from cells infected with standard virus alone. Moreover, synthesis of all the virus-specified components distinctive of standard virus-infected cells is reduced. The DI particle-specific RNA species comprise two poly A-containing single-stranded RNAs (DIss1 and DIss2), identical to those found in purified DI particles, two double-stranded RNA'S (RFs) and a new size class of replicative intermediate (RI). Hybridization experiments showed that the nucleotide sequences of DIss1 and DIss2 (i) are present in the 42S genome of standard virus but absent from the 26S RNA- the RNA from standard virus-infected cells which encodes the structural proteins of the virion (Clegg & Kennedy, 1975 a) and (ii) are complementary to the negative strands of the DI paritcle-specific RFs and RI. Oligonucleotide fingerprinting revealed extensive nucleotide sequence homology between DIssI and DIss2. Analysis of the mRNA complement of standard virus-infected, co-infected and uninfected cells strongly indicated that neither DIss1 nor DIss2 can serve as a functional messenger RNA. From these studies we propose a mechanism for the multiplication of and interference by DI particles of Semliki Forest virus.


Synthesis, Characterization, and Single-Crystal X-ray Structures of Refractory Metal Compounds as Precursors for the Single-Source Chemical Vapor Deposition of Metal Nitrides.
The chemical vapor deposition of refractory metal nitrides requires volatile precursors and has previously been achieved by using metal complexes containing a variety of imide ligands. Recently, the 1,4-di-tert-butyl-1,3-diazabutadiene (DAD) adduct of bis(tert-butylimide)dichloridemolybdenum(VI) was shown to be an excellent precursor for the single-source CVD of Mo2N thin films. Leveraging the success of this work, we prepared chromium and tungsten compounds with the same framework. Additionally, the framework has been modified slightly to allow the isolation of mono(tert-butylimide)trichloride complexes of vanadium, niobium, tantalum, and molybdenum(V) to extend the search for new vapor-phase precursors. These compounds were all fully characterized using the standard methods of multinuclear magnetic resonance spectroscopy, combustion analysis, and single-crystal X-ray diffraction. Their thermal properties were determined by using thermogravimetric analysis and differential scanning colorimetry to assess their utility as vapor-phase precursors. Finally, preliminary deposition studies were carried out to investigate their potential as single-source CVD precursors.


The Role of Power in Health Care Conflict: Recommendations for Shifting Toward Constructive Approaches.
The combination of power and conflict is frequently reported to have a detrimental impact on communication and on patient care, and it is avoided and perceived negatively by health care professionals. In view of recent recommendations to explicitly address power and conflict in health professions education, adopting more constructive approaches toward power and conflict may be helpful. This study examined the role of power in conflicts between health care professionals in different cultural contexts to make recommendations for promoting more constructive approaches. The authors used social bases of power (positional, expert, informational, reward, coercive, referent) identified in the literature to examine the role of power in conflicts between health care professionals in different cultural settings. They drew upon semistructured interviews conducted from 2013 to 2016 with 249 health care professionals working at health centers in the United States, Switzerland, and Hungary, in which participants shared stories of conflict they had experienced with coworkers. The authors used a directed approach to content analysis to analyze the data. The social bases of power tended to be comparable across sites and included positional, expert, and coercive power. The rigid hierarchies that divide health care professionals, their professions, and their specialties contributed to negative experiences in conflicts. In addition, the presence of an audience, such as supervisors, coworkers, patients, and patients' families, prevented health care professionals from addressing conflicts when they occurred, resulting in conflict escalation. These findings suggest that fostering more positive approaches toward power and conflict could be achieved by using social bases of power such as referent power and by addressing conflicts in a more private, backstage, manner.