A Systematic Review of Patients' Experiences in Communicating with Primary Care Physicians: Intercultural Encounters and a Balance between Vulnerability and Integrity.
Communication difficulties persist between patients and physicians. In order to improve care, patients' experiences of this communication must be understood. The main objective of this study is to synthesize qualitative studies exploring patients' experiences in communicating with a primary care physician. A secondary objective is to explore specific factors pertaining to ethnic minority or majority patients and their influence on patients' experiences of communication. Pertinent health and social sciences electronic databases were searched systematically (PubMed, Cinahl, PsychNet, and IBSS). Fifty-seven articles were included in the review on the basis of being qualitative studies targeting patients' experiences of communication with a primary care physician. The meta-ethnography method for qualitative studies was used to interpret data and the COREQ checklist was used to evaluate the quality of included studies. Three concepts emerged from analyses: negative experiences, positive experiences, and outcomes of communication. Negative experiences related to being treated with disrespect, experiencing pressure due to time constraints, and feeling helpless due to the dominance of biomedical culture in the medical encounter. Positive experiences are attributed to certain relational skills, technical skills, as well as certain approaches to care privileged by the physician. Outcomes of communication depend on patients' evaluation of the consultation. Four categories of specific factors exerted mainly a negative influence on consultations for ethnic minorities: language barriers, discrimination, differing values, and acculturation. Ethnic majorities also raised specific factors influencing their experience: differing values and discrimination. Findings of this review are limited by the fact that more than half of the studies did not explore cultural aspects relating to this experience. Future research should address these aspects in more detail. In conclusion, all patients seemed to face additional cultural challenges. Findings provide a foundation for the development of tailored interventions to patients' preferences, thus ensuring more satisfactory experiences. Health care providers should be sensitive to specific factors (cultural and micro-cultural) during all medical encounters.


Characterization of benzodiazepinooxazoles: crystal and molecular structure of trans and cis isomers of oxazolam.
The stereochemistry of the trans and cis isomers of 2(S)- and 2(R)-oxazolam is described. A total of four molecular structures of the 11b(R) and 11b(S) diastereomers of 2(S)- and 2(R)-oxazolam have been revealed by X-ray diffraction techniques. 2(S)-Oxazolam crystallizes in space group P2(1)/c, with cell dimensions a = 16.180(2) A, b = 8.791(2) A, c = 13.574(2) A, and beta = 102.07(1) degrees. The molecule in an asymmetric unit exhibited disorder at the 2-carbon (C2) atom, and the structures for trans and cis isomers have been resolved crystallographically. 2(S)-Oxazolam forms polymeric chains with intermediation of ethanol through hydrogen bonding. 2(R)-Oxazolam crystallizes in space group P1, with cell dimensions a = 7.754(1) A, b = 8.654(1) A, c = 15.795(2) A, alpha = 104.09(1) degrees, beta = 91.19(1) degrees, and gamma = 114.00(1) degrees. A similar disorder at the C2 position has been elucidated by a mixture of trans- and cis-2(R)-oxazolams. The two 2(R)-oxazolam molecules form a dimer with a hydrogen bond net. The structural details, focusing on the conformation and molecular complex formation of both oxazolams, have been discussed in connection with the oxazolidine ring stability and the crystal polymorph.


Cajal's contributions to the study of Alzheimer's disease.
Last year 2006, we commemorated two important events in the history of Neuroscience. One hundred years ago, on November 3, Alois Alzheimer (1864-1915) presented the first case of a patient with symptoms of a disease that later would be called Alzheimer's disease. One month later, on December 10, Santiago Ramón y Cajal (1852-1934) and Camilo Golgi (1843-1926) received the Nobel Prize "in recognition of their work on the structure of the Nervous System". These facts seem not to be related, but working in the Museum Cajal we found 37 histological preparations of material from patients suffering from Alzheimer's disease, revealing that Cajal also studied this disease. This paper deals with Cajal's contribution to the study of Alzheimer's disease and it is fully illustrated by original pictures of Cajal's slides preserved in the Cajal Museum, Madrid.


Human Neonatal Thymus Mesenchymal Stem Cells Promote Neovascularization and Cardiac Regeneration.
Newborns with critical congenital heart disease are at significant risk of developing heart failure later in life. Because treatment options for end-stage heart disease in children are limited, regenerative therapies for these patients would be of significant benefit. During neonatal cardiac surgery, a portion of the thymus is removed and discarded. This discarded thymus tissue is a good source of MSCs that we have previously shown to be proangiogenic and to promote cardiac function in an in vitro model of heart tissue. The purpose of this study was to further evaluate the cardiac regenerative and protective properties of neonatal thymus (nt) MSCs. We found that ntMSCs expressed and secreted the proangiogenic and cardiac regenerative morphogen sonic hedgehog (Shh) in vitro more than patient-matched bone-derived MSCs. We also found that organoid culture of ntMSCs stimulated Shh expression. We then determined that ntMSCs were cytoprotective of neonatal rat cardiomyocytes exposed to H2O2. Finally, in a rat left coronary ligation model, we found that scaffoldless cell sheet made of ntMSCs applied to the LV epicardium immediately after left coronary ligation improved LV function, increased vascular density, decreased scar size, and decreased cardiomyocyte death four weeks after infarction. We conclude that ntMSCs have cardiac regenerative properties and warrant further consideration as a cell therapy for congenital heart disease patients with heart failure.


Left Atrial Remodeling Following ST-Segment-Elevation Myocardial Infarction Correlates With Infarct Size and Age Older Than 70 Years.
Background Following myocardial infarction, left ventricular remodeling (LVR) is associated with heart failure and cardiac death. At the same time, left atrial (LA) remodeling (LAR) is an essential part of the outcome of a wide spectrum of cardiac conditions. The authors sought to evaluate the correlates of LAR and its relationships with LVR after myocardial infarction. Methods and Results This is a retrospective analysis of 320 of 443 patients enrolled for study of LVR after ST-elevation myocardial infarction. Left ventricular (LV) volumes, infarct size and LA volume index were assessed by cardiac magnetic resonance imaging during index hospitalization (day 6 [interquartile range, 4-8]) and after a 3-month follow-up. LAR was studied using a linear mixed model for repeated measurements. Overall, there was a decrease in LA volume index between 6 days and 3 months (43.9±10.4 mL versus 42.8±11.1 mL, P=0.003). Patients with changes in LA volume index >8% over time were older, with greater body mass index, lower LV ejection fraction, and larger infarct size. Unadjusted predictors of LAR were age older than 70 years, infarct size, anterior infarction, time to reperfusion, history of hypertension, LV end-diastolic volume, and heart failure at day 6. Independent correlates were age older than 70 years (3.24±1.33, P=0.015) and infarct size (2.16±0.72 per 10% LV, P<0.001). LA remodeling was correlated with LV remodeling (r=0.372, P<0.001), but neither LA nor LV volumes at day 6 were related to LVR or LAR, respectively. Conclusions The authors found LA changes to occur in the months after myocardial infarction, with an overall decrease in LA volumes. While LAR coincided with LVR, the correlates for LAR were age older than 70 years and larger infarct size.


Evaluation of Autism Spectrum Disorder Risk in Infants With Intraventricular Hemorrhage.
Background This study evaluates the long-term risk of autism spectrum disorder (ASD) in infants with intraventricular hemorrhage (IVH) using the Modified Checklist for Autism in Toddlers-Revised with Follow-Up (M-CHAT-R/F) screening tool. Methods This retrospective cohort study compared IVH (exposed) infants across all gestational age groups with no-IVH (non-exposed) infants admitted to level IV neonatal intensive care unit (NICU). The M-CHAT-R/F screening tool was used to assess the ASD risk at 16-30 months of age. Discharge cranial ultrasound (CUS) findings also determined the ASD risk. Descriptive statistics comprised median and interquartile range for skewed continuous data and frequencies and percentages for categorical variables. Comparisons for non-ordinal categorical measures in bivariate analysis were carried out using the χ2 test or Fisher exact test. Results Of the 334 infants, 167 had IVH, and 167 had no IVH. High ASD risk (43% vs. 20%, p = 0.044) and cerebral palsy (19% vs. 5%, p = 0.004) were significantly associated with severe IVH. Infants with CUS findings of periventricular leukomalacia had 3.24 odds of developing high ASD risk (odds ratios/OR: 3.24, 95% confidence interval/CI: 0.73-14.34), and those with hydrocephalus needing ventriculoperitoneal (VP) shunt had 4.75 odds of developing high ASD risk (OR: 4.75, 95% CI: 0.73-30.69). Conclusion Severe IVH, but not mild IVH, increased the risk of ASD and cerebral palsy. This study demonstrates the need for timely screening for ASD in high-risk infants. Prompt detection leads to earlier treatment and better outcomes.


Unusual case of a rectal tumour.
A 48-year-old man presented as an emergency with a 3-week history of rectal bleeding. Examination of his rectum revealed a circumferential tumour, 2 cm from the anal verge. An MRI scan reported a locally infiltrative mid-lower rectal tumour staged as T3d/T4 N2 MX. A colonoscopy revealed appearances of severe proctitis and biopsies did not show any evidence of dysplasia or malignancy. The patient was discussed at the regional colorectal cancer multidisciplinary team meeting with a management plan for neoadjuvant chemoradiotherapy following repeat biopsies, which were again negative for malignancy. He tested positive for the HIV and was referred to genitourinary medicine. A positive Chlamydia trachomatis nucleic acid test from a rectal swab was serovar L2 consistent with a diagnosis of lymphogranuloma venereum. He was treated with doxycycline and subsequent MRI scans showed reduction in tumour size with eventual resolution. This case report highlights the importance of HIV testing in patients with newly diagnosed colorectal tumours.


Factors underlying bursting behavior in a network of cultured hippocampal neurons exposed to zero magnesium.
Factors contributing to reduced magnesium-induced neuronal action potential bursting were investigated in primary hippocampal cell culture at high and low culture density. In nominally zero external magnesium medium, pyramidal neurons from high-density cultures produced recurrent spontaneous action potential bursts superimposed on prolonged depolarizations. These bursts were partially attenuated by the NMDA receptor antagonist d-APV. Pharmacological analysis of miniature excitatory postsynaptic currents (EPSCs) revealed 2 components: one sensitive to d-APV and another to the AMPA receptor antagonist DNQX. The components were kinetically distinct. Participation of NMDA receptors in reduced magnesium-induced synaptic events was supported by the localization of the NR1 subunit of the NMDA receptor with the presynaptic vesicular protein synaptophysin. Presynaptically, zero magnesium induced a significant increase in EPSC frequency likely attributable to increased neuronal hyperexcitability induced by reduced membrane surface charge screening. Mean quantal content was significantly increased in zero magnesium. Cells from low-density cultures did not exhibit action potential bursting in zero magnesium but did show increased EPSC frequency. Low-density neurons had less synaptophysin immunofluorescence and fewer active synapses as determined by FM1-43 analysis. These results demonstrate that multiple factors are involved in network bursting. Increased probability of transmitter release presynaptically, enhanced NMDA receptor-mediated excitability postsynaptically, and extent of neuronal interconnectivity contribute to initiation and maintenance of elevated network excitability.


Tunable Bloch Wave Resonances and Bloch Gaps in Uniform Materials with Reconfigurable Boundary Profiles.
We study wave propagation in uniform materials with periodic boundary profiles and introduce for the first time Bloch resonances and Bloch gaps. Bloch resonances are due to transverse phase matching, i.e., the coupling of two transverse standing waves corresponding to different harmonics. These are distinct from well-known Bragg resonances that result from longitudinal phase matching. We show that Bloch gaps can be engineered over the entire first Brillouin zone up to an infinite wavelength, i.e., k_{x}=0, where k_{x} is the wave number in the direction of propagation. This is in contrast to Bragg gaps that open at a fixed wavelength, twice the period of the structure. Bloch resonances and gaps can be tuned by reconfiguring the boundary profile and we derive analytical expressions that predict these phenomena when the amplitude of the profile is small. The theory is fundamental as it broadly applies to wave phenomena that span the quantum to continuum scale with applications that range from condensed matter to acoustics. We validate the theory experimentally for the electromagnetic field at GHz frequencies. We also discuss potential photonic and electronic applications of the theory such as a white-light distributed feedback laser and a two-dimensional electron gas transistor.


Main occluding area in partially edentulous patients: changes before and after implant treatment.
The 'main occluding area', the location where food crushing occurs during the first stroke of mastication, is reported to be an important concept; however, it is currently limited to findings in individuals with normal dentition. The purpose of this study was to assess the changes in the location, area and bite force of the main occluding area before and after implant treatments. We enrolled 50 partially edentulous and 22 normally dentate subjects. To identify the location of the main occluding area, each subject was instructed to freely bite once on a dental stopping using the partially edentulous side or the normally dentate area. The location, occluding contact area and bite force of the main occluding area before and after the implant treatments were analysed. The main occluding area was located at a reproducible location in the partially edentulous and normally dentate subjects. This location was principally the first molar region, and for the partially edentulous patients with missing teeth in the molar regions, it moved from the premolar region to the first molar region after treatment. The occluding contact area and bite force for the main occluding area increased (P < 0·05) after the implant treatment in the partially edentulous patients with missing teeth in the molar regions. These results suggest that the main occluding area can be restored to the first molar region after implant treatment and may be an important factor in the assessment of prosthodontic treatment.


Transcatheter Mitral Valve-in-Valve Implantation With a New Transcatheter Heart Valve for Bioprosthetic Degeneration.
Transcatheter mitral valve-in-valve (TMVIV) procedure with aortic transcatheter heart valves has recently become a less invasive alternative for patients with mitral bioprosthetic dysfunction. This study reports the initial experience of TMVIV implantation using the J-Valve System (JieCheng Medical Technology Corporation Ltd., Suzhou, China). A retrospective observational multicenter study was conducted to evaluate the short-term outcomes of TMVIV. In total, 26 consecutive patients with symptomatic bioprosthetic failure at eight hospitals underwent TMVIV using the J-Valve System between May 2019 and June 2021. Procedural results and clinical outcomes were analyzed using the Mitral Valve Academic Research Consortium criteria. The mean age was 75.3 ± 7.1 years and 69.2% of patients were female. The mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 12.3 ± 8.3%. The technical success rate was 96.2%. Nine of the 26 patients (34.6%) were implanted with a J-Valve of a size equal to the internal diameters of the deteriorated prostheses. At the 30-day and 1-year follow-ups, all-cause mortality was 3.8 and 16.0% and the stroke rates were 0 and 12.0%, respectively. Device-related mortality was 0% and the mean mitral valve gradient was 6.4 ± 2.7 mm Hg. No patient experienced device embolization, left ventricular outflow tract obstruction, or mitral valve reintervention. Postprocedural mitral regurgitation was none or trace in all the patients. All the patients were in the New York Heart Association (NYHA) class ≤ II at the last follow-up. Transcatheter implantation of the J-Valve System in high-risk patients with mitral bioprosthetic dysfunction was found to be a reasonable alternative and associated with good short-term outcomes.


A monoclonal antibody to Ly-6 gene product inhibits generation of functionally active T cells and recognizes single antigenic specificity whose expression is up-regulated in virus-transformed rat fibroblast.
In order to elucidate the relationship between the structure and function of proteins encoded for by the Ly-6 gene complex, a cDNA was constructed for a Ly-6.2 specificity and then monoclonal antibodies (mAb) generated to bacterially synthesized protein. The addition of one of these mAb, designated Pb-19, inhibited the proliferative response of T cells to concanavalin A (Con A) or major histocompatability complex (MHC) alloantigens. Reactivity of Pb-19 to the Ly-6 specificity was blocked by a known anti-Ly-6.A.2 mAb but not by an anti-Ly-6.E.1 mAb. This mAb detected a Ly-6.A.2 specificity (a 33,000 MW antigen) whose expression was increased in a transformed rat fibroblast containing the entire genome of bovine papillomavirus.


Effects of hippotherapy on the thickness of deep abdominal muscles and activity of daily living in children with intellectual disabilities.
[Purpose] The purpose of this study is to investigate the effect of hippotherapy exercise on the thickness of deep abdominal muscles and daily activities of children with intellectual disabilities. [Subjects and Methods] Seven children with intellectual disabilities were treated with hippotherapy for 30 minutes twice a week for 6 weeks. The thickness of deep abdominal muscles and Functional Independence Measure (FIM) of the subjects were measured by ultrasonography before and after the experiment. [Results] There was no significant change in the thickness of the External Oblique and Internal Oblique muscles, but there was a statistically significant change in Transverse Adbominis thickness and FIM score after treatment compared to before treatment. [Conclusion] Hippotherapy exercise has a positive effect on the improvement of Transverse Abdominis (TrA) and activity of daily livings of children with intellectual disabilities.


Effect of oral and intravenous insulin and glutamic acid decarboxylase in NOD mice.
Islet cell antigens have been administered orally and intravenously (I.V.) to NOD mice to assess their abilities to protect from or delay the onset of diabetes, and thereby provide insights that may have therapeutic implications in human trials. Whereas we and others have observed a delay in the onset of diabetes in NOD mice that have been fed with insulin from early life, we report here for the first time that feedings with porcine GAD65 alone (p = 0.226) or in combination with insulin (p = 0.011), have anti-diabetic effects in a prolonged study period (>400 days). While antigen-specific inhibitions of in vitro lymphocytic proliferation responses were seen (p < 0.05), antibody levels were unaffected by oral antigen treatments. IFN-gamma mRNA levels were downregulated in the islet infiltrates following oral antigen treatments while IL-2 and TNF-beta were expressed in all instances. We also observed that I.V. human recombinant GAD65, and porcine GAD given at weaning, delayed diabetes onset (p = 0.004) while similar treatments with a variety of inactive insulin preparations were generally ineffective. These findings thus indicate varying effects of oral and I.V. autoantigen administrations on the development of diabetes in NOD mice, and describe the immunological processes induced by oral autoantigen treatments.


Coronary collateral circulation: its relevance.
The interest in coronary collateral circulation (CCC) as "natural bypasses" is growing, especially in patients in whom the extent of coronary atherosclerosis is too severe to allow for conventional revascularization. The anatomic foundation of CCC has been recognized for long time. Recently, reliable methods have become available for the assessment of the adequacy of collateral flow. However, the debate regarding the importance of CCC in the different clinical settings continues. In this article, we present the recent progress in the understanding of anatomy and physiology of the CCC and focus on the studies addressing their functional significance in acute, subacute, and chronic coronary artery disease. In addition, we provide a focused update on the essential role of collateral circulation in the management of coronary chronic total occlusions.


Purification and characterization of the messenger RNA for the heavy chain of rat immunoglobulin E.
The isolation and translational properties of rat immunoglobulin E (IgE) heavy chain mRNA are described. The mRNA has a sedimentation coefficient of approximately 18S, a chain length of about 2000 nucleotides and directs the synthesis in vitro of a polypeptide of 65000 molecular weight in an mRNA-dependent rabbit reticulocyte lysate. Inclusion of dog pancreatic microsomes in the cell-free translation system resulted in a heavy chain product of about 75000 molecular weight, presumably as a consequence of glycosylation in vitro. This species co-migrated in an SDS polyacrylamide gel with mature IgE heavy chain. Substantial purification of heavy chain mRNA was achieved by denaturing sucrose gradient centrifugation and agarose gel electrophoresis.


Reducing Pediatric Sternal Wound Infections: A Quality Improvement Project.
To evaluate whether a quality improvement intervention reduces sternal wound infection rates in children after cardiac surgery. This is a pre- and postintervention quality improvement study. A 16-bed cardiac ICU in a university-affiliated pediatric tertiary care children's hospital. All patients undergoing cardiac surgery via median sternotomy from January 2010 to December 2014 are included. The sternal wound infection rates for primary closure and delayed sternal closure are reported per 100 sternotomies. The hospital-acquired infection records were used to identify preintervention cases, while postintervention cases were collected prospectively. Implementation of a sternal wound prevention bundle during the preoperative, intraoperative, and postoperative periods for cardiac surgical cases. During the preintervention period, 32 patients (3.8%) developed sternal wound infection, whereas only 19 (2.1%) developed sternal wound infection during the postintervention period (p = 0.04). The rates of sternal wound infection following primary closure were not significantly different pre- and postintervention (2.4% vs 1.6%; p = 0.35). However, patients with delayed sternal closure had significantly lower postintervention infection rates (10.6% vs 3.9%; p = 0.02). Implementation of a sternal wound prevention bundle during the perioperative period was associated with lower sternal wound infection rates in surgeries with delayed sternal closure.


Role of low-latitude forests in modulating forest filter effect on a continental scale: Long-term simulation on PCB-153 in Chinese forests.
Forests are important compartments influencing the environmental fate of persistent organic pollutants (POPs). To illustrate the effect of forests on the regional cycle of POPs, a level IV fugacity fate and transport model coupled with a detailed dynamic-forest module was applied to simulate the long-term variations of PCB-153 in China, where forest coverage accounts for approximately one fifth of land area. In the scenarios with forests, atmospheric outflow from China was 69% of that in the scenario without forests due to the enhanced storage in soil, degradation, and leaching. Previous studies regarded high-latitude areas, such as the polar region and boreal forests, as environments capable of reducing mobility of PCB-153, and they act as sinks of POPs. This modeling result suggests that tropical and subtropical forests may also play a similar role despite high temperatures favoring volatilization. Unlike boreal forest, the low-latitude forests may reduce the overall lifetime of PCB-153 in China due to enhanced degradation in warmer and moist soils of the tropical and subtropical area. Given that approximately half of the global forests are located in tropical and subtropical regions, they can be important environments influencing the global geochemical cycle and distribution of POPs, hence deserving more scientific attention by modeling and empirical studies.


Genetic structure of the Saguenay, 1852-1911: evidence from migration and isonymy matrices.
The Saguenay is a region in northeastern Québec populated in the second half of the 19th century through migration from other parts of Québec. The present-day population of nearly 300,000 is the result of both immigration and high rates of intrinsic growth. This population has been of interest to geneticists because of the high incidence of certain hereditary diseases, notably spastic ataxia, tyrosinemia, agenesis of the corpus callosum, vitamin D-dependent rickets, and myotonic dystrophy. Parent-offspring migration and isonymy matrices were used to estimate random kinship using the Malécot model for six 10-year time periods from 1852-1911. Comparisons between two estimates of kinship--one from parent-offspring migration matrices (phi) and the other from isonymy (R)--and geographic distance were made using both product-moment and Mantel correlation. Comparisons of within- and between-subdivision kinship were made using nonparametric and Mantel correlation. Within-subdivision kinship from the phi matrix was also compared with kinship estimated from marriage dispensations for endogamous marriages. The estimates of random kinship from the parent-offspring matrices showed a good fit with geography. However, isonymy did not correlate well with geographic distance; and phi and R showed no correlation until the last two time periods, and the diagonal of phi did not correlate with the marriage dispensations. Examination of scatterplots of phi vs. R suggests that nonrandom migration during the process of settlement formation is responsible for the lack of correlation. While movement across space seems to be highly dependent on distance, nonrandom selection of migrants means that between-subdivision estimates of kinship based on migration are not congruent with those obtained by other methods. On the whole, genetic differentiation seems to have been low due to the high levels of movement between subdivisions and immigration. The weak dependence of genetic structure on geographic distances in the present population is demonstrated by mapping the geographic distribution of cases of three recessively inherited diseases.


Rapid identification of Aedes albopictus, Aedes scutellaris, and Aedes aegypti life stages using real-time polymerase chain reaction assays.
In 2005, a widespread infestation of Aedes albopictus was discovered in the Torres Strait, the region between northern Australia and New Guinea. To contain this species, an eradication program was implemented in 2006. However, the progress of this program is impeded by the difficulty of morphologically separating Ae. albopictus larvae from the endemic species Aedes scutellaris. In this study, three real-time TaqMan polymerase chain reaction assays that target the ribosomal internal transcribed spacer 1 region were developed to rapidly identify Aedes aegypti, Ae. albopictus, and Ae. scutellaris from northern Australia. Individual eggs, larvae, pupae, and adults, as well as the species composition of mixed pools were accurately identified. The assay method was validated using 703 field-collected specimens from the Torres Strait.


Hydrogen peroxide detection with high specificity in living cells and inflamed tissues.
Hydrogen peroxide (H2O2) detection in biological systems is of significant importance, which act as critical second messenger in fundamental biological processes. Here, we report on a chemoselective fluorescent naphthylimide peroxide probe (NPP) for the H2O2 detection in vitro and in vivo. NPP is a phenylboronic acid-caged chromophore that selectively responds to H2O2 through a self-immolate mechanism. NPP exhibited high sensitivity and selectivity to H2O2 with distinctive fluorescence change due to the excellent two-photon excitation property, which permits the facile detection of inflammation produced H2O2 and offers chance to monitor the inflammatory stages in diseased cells.


Apoptosis: the skin from a new perspective.
In this review we present skin biology from the perspective of apoptosis. We stress that apoptosis acts as an important homeostatic and defence mechanism in the developing and mature epidermis. Programmed cell death functions in establishing the architecture of the human epidermis and its appendages during development by deletion of stage-specific cells and in the adult epidermis by elimination of excess and abnormal cells. Arguments are presented to support the hypothesis that known regulators of keratinocyte growth may act as survival factors which suppress the cell death pathway. Surviving cells continue to divide until they encounter anti-proliferative factors. Then, unless cells are severely injured and die of necrosis, they will terminally differentiate to death or will die by apoptosis. The mechanisms controlling keratinocyte maturation are co-ordinated with cell position within the epidermal strata. Inappropriate regulatory signals or response of a cell inappropriate to its state will activate apoptosis. Parallels between terminally differentiating keratinocytes and apoptotic cells imply that terminal differentiation and apoptosis proceed along the same death pathway. For terminally differentiating cells, however, this pathway is more elaborate because it allows expression of tissue- and differentiation-specific genes. A model is presented that integrates apoptosis and keratinocyte growth and differentiation.


Assessment of deep eutectic solvents toxicity in zebrafish (Danio rerio).
Deep Eutectic Systems (DES) have emerged as a "green alternative" to organic solvents and have been coined as biocompatible and biodegradable. However, the number of studies concerning the real biodegradability and biocompatibility are scarce. Thus, to study the toxicity of certain DES, two different approaches were used: i) zebrafish exposure via water, where the system (DES) was tested at potentially realistic environmental concentrations and ii) via intraperitoneal injection, where the system was tested in different concentrations, relevant to the pharmaceutical industry. These studies were performed using zebrafish, a standardized animal model often used in biomedicine and toxicological assays. The results show low toxicity according to tested concentrations (up to 73.47 μM), when the system CA:T:W, with a 2:1:3 molar ratio, was tested through exposure via water and also in the intraperitoneal injection tests with concentrations up to 6000 μM. The activity of different enzymes involved in antioxidant pathways (glutathione S-transferase, catalase, glutathione peroxidase), the total antioxidant capacity (TAC) and lipoperoxidation (MDA content) were determined suggesting low toxicity of the tested system (DES). The promising results herein presented show that DES present the potential to be used as the new class of green solvents, not only for use in the pharmaceutical industry, but also in cosmetic and chemical engineering processes without causing negative impact on living organisms.


Suppression of Mll1-Complex by Stat3/Cebpβ-Induced miR-21a/21b/181b Maintains the Accumulation, Homeostasis, and Immunosuppressive Function of Polymorphonuclear Myeloid-Derived Suppressor Cells.
Mixed-lineage leukemia 1 (MLL1), which exerts its H3K4 methyltransferase activity by interacting with WDR5, ASH2L, and RBBP5, plays a pivotal role in regulating hematopoietic stem cell homeostasis. Disrupting the integrity of MLL1-complex has been reported to be associated with acute leukemia. However, the exact role of MLL1-complex in myeloid cells is unknown. In this study, microarray analysis revealed that the core components of the Mll1-complex, Wdr5, Ash2l, and Mll1, were concurrently downregulated by tumor-secreted factors as well as GM-CSF + IL-6 during the accumulation and activation of murine myeloid-derived suppressor cells (MDSCs). These changes were further validated by quantitative RT-PCR and Western blotting both in vitro and in vivo. The expression levels of WDR5 and ASH2L were also significantly decreased in bone marrow MDSCs of lung cancer patients compared with that of healthy controls. Functionally, ectopic expression of Wdr5, Ash2l, and Mll1 (C terminus) reversed the accumulation and function of GM-CSF + IL-6-induced as well as tumor-cocultured polymorphonuclear MDSCs (PMN-MDSCs) by promoting them to differentiate into mature neutrophil-like cells. Mechanistically, GM-CSF + IL-6-activated Stat3 and Cebpβ synergistically induced the expression of miR-21a, miR-21b, and miR-181b, and thus inhibited the expression of Wdr5, Ash2l, and Mll1 by targeting to their 3' untranslated regions, respectively. Furthermore, knockdown of these microRNAs also suppressed the expansion and function of GM-CSF + IL-6-induced PMN-MDSCs. Taken together, our findings indicate that the Stat3/Cebpβ-miR-21a/b/181b-Mll1-complex axis may play a critical role in PMN-MDSC expansion, activation, and differentiation, and this axis may provide an effectively immunological therapeutic approach for patients with cancer or other immunological diseases.


Efficacy and Safety of IV albumin for non-spontaneous bacterial peritonitis infection among patients with cirrhosis: A systematic review and meta-analysis.
Efficacy and Safety of intravenous albumin for non-spontaneous bacterial peritonitis infection among patients with cirrhosis: A systematic review and meta-analysis of randomized controlled trials INTRODUCTION: Bacterial infection is a common cause of acute-on-chronic liver failure (ACLF) and death among cirrhosis. The benefit of intravenous (IV) albumin among cirrhosis with non-SBP infection remains unclear as individual studies are underpowered to detect the survival benefit of IV albumin. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of intravenous albumin for non-SBP infection among cirrhosis patients. We performed a systematic search of electronic databases (Pubmed, MEDLINE and Clinicalkey) up to 1st December 2019. Studies evaluating IV albumin for non-SBP infection were selected. Using random effect model, the pooled odds ratio (OR), 95% confidence interval (95%CI) and heterogeneity were assessed. A total of 3 RCTs (406 subjects) fulfilling the inclusion criteria among 218 citations were identified. There was no significant heterogeneity across included studies. In this meta-analysis, we found that the pooled risk of renal impairment (RI) (OR=0.58, 95%CI: 0.28-1.23, I2=0%), mortality at 30 days (OR=1.61, 95%CI: 0.87-3.00, I2=0%) as well as mortality at 90 days (OR=1.30, 95%CI: 0.81-2.07, I2=0%) were similar between albumin and control group. Pooled event of pulmonary edema occurred more commonly in albumin group (OR 5.17, 95%CI 1.62-16.47, I2=0%). More subjects achieved resolution of ACLF in IV albumin group as compared to control group (OR=0.11, 95%CI: 0.02-0.69, p=0.02). Albumin did not reduce the risk of RI and mortality, yet increases the risk of pulmonary edema. Albumin may promote recovery of ACLF, however, more data is required to validate this benefit.


[Preparation of anti-hNOK antibodies and expression examination of NOK in the lung cancer tissues].
Novel Oncogene with Kinase-domain (NOK) is a novel tumor-related gene, coding receptor like protein with a kinase domain. Overexpression of NOK leads to tumorigenesis and metastasis. To further study NOK function in physiological condition, it is necessary to prepare the anti-NOK antibody. In this report, GST fusion protein was adopted to prepare polyclonal antibodies against hNOK. The result showed that the antibodies we generated is with a very high titriation, and can be used for examination of NOK protein by Westernblot. Furthermore, the antibodies were used for immunohistochemistry in lung cancer tissues, and the results demonstrated high expression of hNOK in the tumor tissues. The antibody of hNOK we generated can serve as a diagnostic method for the lung cancer.


Federal role in dental public health: dental care for special populations.
California is home to more than 70 dental clinics operated or funded by the U.S. government. They operate on annual appropriations from Congress to serve a specific population and regulations that specify the type of dental services provided are usually promulgated at the national level. Dental clinics have the challenge of creating a program that delivers high-quality care within these financial and programmatic constraints. In California, U.S. government appropriations are the main source of funding dental clinics of immigration services, the Veterans Administration, the Bureau of Prisons, the Coast Guard, and American Indian clinics. The evolution and current practices of these five dental public health programs are described.


Health seeking behaviour and delayed management of tuberculosis patients in rural Bangladesh.
Early diagnosis of tuberculosis (TB) and involvement of the public-private partnership are critical to eradicate TB. Patients need to receive proper treatment through the National Tuberculosis Control Programme (NTP). This study describes various predictors for health seeking behaviour of TB patients and health system delay made by the different health care providers. A cross-sectional study was conducted in a public health facility of a rural area in Bangladesh. Newly diagnosed smear positive pulmonary TB (PTB) patients who were ≥ 15 years of age were sequentially enrolled in this study. The socio-demographic characteristics and proportion of health care utilization by the patients, and health system delay made by the health care providers were calculated. Multivariate analysis was conducted to determine the independent association of the risk factors with the time to seek medical care. Two hundred and eighty patients were enrolled in this study. Among them, 73.6% were male and 26.4% were female. A hundred percent of patients primarily sought treatment for their cough, 170 (60.7%) first consulted a non-qualified practitioner while 110 patients (39.3%) first consulted with qualified practitioners about their symptoms. Pharmacy contact was the highest (27.9%) among the non-qualified practitioners, and 58.9% non-qualified practitioners prescribed treatment without any laboratory investigation. The average health system delay was 68.5 days. Multiple logistic regressions revealed a significant difference between uneducated and educated patients (OR 2.33; CI 1.39-3.92), and qualified and non-qualified practitioners (OR 2.34; CI 1.38-3.96) to be independent predictors of health system delay. Compared to men, fewer women sought TB treatment. Uneducated patients and questionably qualified practitioners made for a longer delay in detecting TB. Increasing public health awareness and improving health seeking behavior of females and uneducated patients, and greater participation of the qualified practitioners in the NTP are highly recommended.


A plant wide simulation of polyhydroxyalkanoate production from wastewater and its conversion to methyl crotonate.
This work simulates the production of methyl crotonate from various industrial wastewaters. In the upstream process, wastewater is fermented into volatile fatty acids which are then converted into polyhydroxyalkanoates (PHA) by means of mixed microbial cultures. In the downstream, PHA undergoes a series of thermolysis and esterification reactions to produce methyl crotonate. The origin of the wastewater was found to have a great influence on the composition of the PHA with the effluent of a candy bar factory producing a high polyhydroxybutyrate/polyhydroxyvalerate ratio of 86/14 in favour of methyl crotonate production. It was observed that the use of intracellular polyhydroxybutyrate, instead of purified, significantly lowers the number of separation steps and yet reduces the methyl crotonate recovery by only 20 %. An operating pressure higher than 18 bar led to more transesterification of polyhydroxybutyrate, producing byproducts instead of methyl crotonate. Finally, a 3 h reaction was found sufficient for completion of polyhydroxybutyrate conversion.


The profiles of students with significant cognitive disabilities and complex communication needs.
Understanding the characteristics of students with complex communication needs and significant cognitive disabilities is an important first step toward creating the kinds of supports and services required to help them successfully access the general education curriculum, achieve grade-level standards, and improve overall communication competence. The First Contact Survey was designed to collect important information about students with significant cognitive disabilities who were eligible to take the Dynamic Learning Maps™ (DLM(®)) alternate assessment based on alternate achievement standards. From November 2012-May 2013, the survey was used to gather information regarding more than 44,787 students. At that time, the goal was to use the data to inform the development of the DLM assessment. Although the survey includes a wealth of information regarding this large sample of students, the reanalysis of the data reported in the current study focused on the motor, sensory, language, reading, and writing skills of students with significant cognitive disabilities, based on their speech production abilities. Significant differences were identified across each of the domains between students who do and do not use speech with or without aided augmentative and alternative communication.


Citalopram overdose and severe serotonin syndrome in an intermediate metabolizing patient.
Citalopram is a selective serotonin reuptake inhibitor used for treatment of depression. Metabolism is primarily through CYP3A4 and CYP2C19; activity of the latter can vary depending on genetics. Although rare after single agent exposure, large citalopram ingestions can lead to serotonin syndrome. We report a case of citalopram overdose in an intermediate CYP2C19 metabolizer complicated by severe serotonin syndrome. A 25-year-old female presented after intentional citalopram overdose with seizures, tachycardia, persistent neuromuscular findings, and severe hyperthermia requiring aggressive sedation and cooling. Protracted symptoms required critical care services throughout a 14 day hospital stay despite traditional treatment of serotonin syndrome. Pharmacogenomic studies revealed intermediate CYP2C19 metabolism which reduces citalopram inactivation and may cause increased levels and toxicity. In the majority of serotonin syndrome cases, symptoms resolve rapidly after treatment initiation and discontinuation of the offending agents. Severe cases are typically associated with ingestion of multiple serotonergic agents. Our patient had severe toxicity after single agent ingestion. Pharmacogenetic testing identified abnormal CYP2C19 activity and previous cases have associated enzyme dysfunction and citalopram toxicity. Citalopram overdose may be associated with severe serotonin syndrome and further investigation is warranted to understand the impact of enzyme genotype on toxicity.


The value of serologic markers in indeterminate colitis: a prospective follow-up study.
In the absence of pathognomonic markers for Crohn's disease (CD) and ulcerative colitis (UC), the diagnosis of inflammatory bowel disease depends on a compendium of clinical, radiographic, endoscopic, and histologic criteria that bears imperfect specificity to the individual disorders. In 10% of cases of colitis, no differentiation can be made between CD and UC; these patients are diagnosed with indeterminate colitis (IC). We evaluated the value of anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) to increase diagnostic accuracy in categorizing IC. Since 1996, 97 patients with IC from 3 centers (Leuven, Lille, and Vienna) were enrolled, analyzed for pANCA and ASCA, and followed up prospectively. A definitive diagnosis has been reached for 31 of 97 patients (32%). In these patients, ASCA+/pANCA- correlated with CD in 8 of 10 patients, whereas ASCA-/pANCA+ correlated with UC in 7 of 11 patients. The remaining 4 cases became CD, clinically behaving as UC-like CD. Almost half of the patients (47 of 97 [48.5%]) were negative for ASCA and pANCA, and 40 remain diagnosed with IC to date. Only 7 seronegative cases (14.9%) became CD or UC compared with 48% (24 of 50) of seropositive patients (P < 0.001). Results so far show that ASCA+/pANCA- predicts CD in 80% of patients with IC and ASCA-/pANCA+ predicts UC in 63.6%. Interestingly, 48.5% of patients do not show antibodies against ASCA or pANCA. Most of these patients remain diagnosed with IC during their further clinical course, perhaps reflecting a distinct clinicoserological entity.


[Clinical research and its evaluation].
Biomedical research may be defined as "basic" or "applied." Applied research may be "pre-clinical" or "clinical." The final products of research are publications in peer-review system journals and patents. The measurement of quality in biomedical research is performed by using many parameters, such as impact factor, citations, and number of granted projects. In the United States and some countries in Europe, the evaluation of research in public and private institutions is done by a council of faculty members or by accredited agencies. In Italy, mass media commissions the measurement of quality in biomedical research to non-accredited institutions, as was done recently by Corriere della Sera-Salute.


[Paragonimosis in the peri-urban zone of Medellín, Antioquia].
Human paragonimosis in Colombia was assumed to be restricted to the sylvatic areas. However, in 2005, crabs infected with Paragonimus were found in Fuente Clara, an urban sector in Medellín. A study was designed to understand the ecoepidemiology of paragonimosis. Programs were initiated to educate the community in the suitable use of wetland ecosystems. Infection rates of Paragonimus in human and wild hosts was documented in the Fuente Clara sector. The presence of larvae and digenic adult worms was detected in mollusks (1,312), crabs (27) and mammals (4). Sputum diagnosis was performed on samples from 18 volunteer individuals. The following determinants of water quality were measured in the stream La Puerta: total fecal/coliform, pH, conductivity and dissolved oxygen were measured. Recreational workshops were conducted with children and teenagers for educational purposes. The percentage of infections found in hosts was as follows: snails, 0.07%; crabs, 55.5%; (wild) mammals, 25%; humans, 0%. During the workshops, children and teenagers identified the Paragonimus hosts and the risk factors for acquiring the disease. The water of the stream was found to be unsuitable for consumption and recreation (the most probable number of total coliforms/100 ml was in a scale of 104). Fuente Clara is the first urban locality in Colombia where a focus of Paragonimus was found. Exposure to and consumption of crabs may constitute a risk for human infection.


A novel method for CT dosimetry with a suspended phantom setup.
This work presents a method for estimating CT dosimetric indices with a prototype designed for suspending the phantom/ion chamber system fixed at the CT isocenter. The purpose of this study was to validate the proposed methodology, which can be used to provide a direct assessment of dosimetric indices in helical scans. The method is based on a reference setup in which the measuring system for CT dosimetry is in a stationary configuration, i.e. not bound to the CT table, and on a mathematical formalism developed for the proposed reference system. The reliability of the method was demonstrated through a set of experimental measurements. Firstly, dosimetric indices were measured with the new method and compared with the indices obtained with the procedure currently used for CT dosimetry (measuring system bound to the CT table). Secondly, dosimetric indices measured with the new method were compared with those displayed on the CT console. There is good agreement between the dosimetric indices obtained with the standard setup and those obtained with the suspended phantom setup, within the expected range of errors. The difference between dosimetric indices estimated with the proposed method and those displayed on the CT console is below 2%. The method enables CT dosimetry to be performed with the dose detector in a stationary longitudinal position thanks to the newly introduced suspended phantom setup. Using this approach, CT dose can be assessed for high pitch helical scans, acquisitions without complete tube rotation and for cases where dynamic collimation is used.


Magnetofection and isolation of DNA using polyethyleneimine functionalized magnetic iron oxide nanoparticles.
This study was carried out to develop a simple and efficient method to isolate DNA directly from biological samples using iron oxide nanoparticles (IONPs) functionalized with polyethyleneimine (PEI). IONPs were synthesized via co-precipitation method followed with direct attachment of branched PEI. Nanoparticles were characterized using STEM, FT-IR spectroscopy and XRD analysis. The binding capacity of synthesized PEI-IONPs for plasmid and genomic DNA was assessed using purified DNA samples. In order to elute bound DNA, elution conditions were optimized, changing pH, salt concentration and temperature. Synthesized PEI-IONPs were subjected to isolation of DNA from bacterial cell culture and from human blood. PCR and magnetofection of the enhanced green fluorescence protein (EGFP) were carried out to verify the downstream applications of isolated DNA. The results indicated that the synthesized nanoparticles were of 5-10 nm. The binding capacity of PEI-IONPs for plasmid DNA and genomic DNA were 5.4 and 8.4 µg mg-1, respectively, which were even higher than the commercially available kits such as Mag-bind, MagJET and Magmax. The optimized condition for plasmid DNA elution was 0.1 M Tris HCl (pH 10.0), 1.5 M NaCl and 5% formamide, maintained at the temperature of 60°C. The optimized condition for genomic DNA elution was 0.1 M Tris HCl (pH 10.0), 1.5 M NaCl and 10% formamide, maintained at 60°C. PCR and magnetofection processes were successful. This study revealed that the magnetic separation of DNA using PEI-IONPs is a simple and efficient method for direct isolation of DNA from biological samples which can be then used in various downstream applications.


Using Panel Data to Understand the Dynamics of Human Behavior in Response to Flooding.
Insights into the dynamics of human behavior in response to flooding are urgently needed for the development of effective integrated flood risk management strategies, and for integrating human behavior in flood risk modeling. However, our understanding of the dynamics of risk perceptions, attitudes, individual recovery processes, as well as adaptive (i.e., risk reducing) intention and behavior are currently limited because of the predominant use of cross-sectional surveys in the flood risk domain. Here, we present the results from one of the first panel surveys in the flood risk domain covering a relatively long period of time (i.e., four years after a damaging event), three survey waves, and a wide range of topics relevant to the role of citizens in integrated flood risk management. The panel data, consisting of 227 individuals affected by the 2013 flood in Germany, were analyzed using repeated-measures ANOVA and latent class growth analysis (LCGA) to utilize the unique temporal dimension of the data set. Results show that attitudes, such as the respondents' perceived responsibility within flood risk management, remain fairly stable over time. Changes are observed partly for risk perceptions and mainly for individual recovery and intentions to undertake risk-reducing measures. LCGA reveal heterogeneous recovery and adaptation trajectories that need to be taken into account in policies supporting individual recovery and stimulating societal preparedness. More panel studies in the flood risk domain are needed to gain better insights into the dynamics of individual recovery, risk-reducing behavior, and associated risk and protective factors.


Dynamical models of tuberculosis and their applications.
The reemergence of tuberculosis (TB) from the 1980s to the early 1990s instigated extensive researches on the mechanisms behind the transmission dynamics of TB epidemics. This article provides a detailed review of the work on the dynamics and control of TB. The earliest mathematical models describing the TB dynamics appeared in the 1960s and focused on the prediction and control strategies using simulation approaches. Most recently developed models not only pay attention to simulations but also take care of dynamical analysis using modern knowledge of dynamical systems. Questions addressed by these models mainly concentrate on TB control strategies, optimal vaccination policies, approaches toward the elimination of TB in the U.S.A., TB co-infection with HIV/AIDS, drug-resistant TB, responses of the immune system, impacts of demography, the role of public transportation systems, and the impact of contact patterns. Model formulations involve a variety of mathematical areas, such as ODEs (Ordinary Differential Equations) (both autonomous and non-autonomous systems), PDEs (Partial Differential Equations), system of difference equations, system of integro-differential equations, Markov chain model, and simulation models.


Training GPs in parent consultation skills. An evaluation of training for the Triple P-Positive Parenting Program.
The Triple P-Positive Parenting Program is a behavioural family intervention program that aims to prevent severe behavioral, emotional and developmental problems in children by enhancing the knowledge, skills, and confidence of parents. This study evaluated the effect of training general practitioners in the use of the primary care version of the TPP on their consultation skills, satisfaction and confidence in conducting consultations with parents. Participants were assigned to an experimental condition that involved a brief behaviorally oriented parent consultation skills training program or to a wait-list comparison group. Thirty-two GPs participated in the training. Fifteen participants attended the first workshop (intervention group) and 17 attended the second (wait-list comparison group). GPs who participated in the training reported greater satisfaction with the outcomes of their parent consultations and showed significantly greater use of targeted parent consultation skills than GPs in the wait-list comparison group. Observations of GP consultation skills during simulated patient interviews with parents showed there was a significant overall improvement in their interactional skills during parent consultations. There was a high level of satisfaction with the quality of training received by the GPs. This was a brief, cost effective program that had significant effects on participating GPs' skills, confidence and satisfaction with child consultations involving behavioral problems. Implications for public health approaches to the prevention of child psychopathology are discussed.


Ciliary Feeding Assisted by Suction From the Muscular Oral Hood of Phoronid Larvae.
Phoronid larvae have an oral hood upstream from a postoral encircling array of ciliated tentacles. Cilia move water over the hood and between the tentacles, from anterior to posterior. When an algal cell or other particle in this current contacts a tentacle, the neighboring part of the hood lifts, and the particle is drawn toward the mouth. The correlation between movements of hood and particles indicates that the particle moves with water entering the enlarged space beneath the hood. Each lift of the hood is preceded by contact between a particle and a tentacle. A hood lift follows contact with a particle anywhere along the length of a tentacle, and clearance rates are thus proportional to the total length of tentacles deployed and the velocity of the current past the tentacles. After being detained at the ciliary bands of tentacles, particles are transported by the hood lift at speeds exceeding measured transport along the frontal ciliated surfaces of other larval forms. Faster transport may aid capture of faster prey. The larva's feeding mechanism is unique to the phylum Phoronida. Larvae of brachiopods, bryozoans, hemichordates, and echinoderms have similar ciliary bands producing feeding currents, but none are known to transport food toward the mouth by suction produced by muscle contractions.


Near-fatal complication of tracheal T-tube use.
Stenosis of the larynx and trachea is an unfortunate sequel to many thermal injuries. Numerous surgical techniques have been developed for correction of such problems, many involving use of a tracheal T-tube. We report a serious complication attributed to the use of such a tube. Factors contributing to this complication are analyzed and methods for avoiding similar near-catastrophes discussed.


Secure State Estimation With Switched Compensation Mechanism Against DoS Attacks.
This article is concerned with the secure state estimation problem for cyber-physical systems under intermittent denial-of-service (DoS) attacks. Based on a switching scheme and the cascade observer technique, a novel resilient state observer with a switched compensation mechanism is designed. Moreover, a quantitative relationship between the resilience against DoS attacks and the design parameters is revealed. Compared with the existing results, where only the boundedness of the estimation error is guaranteed under DoS attacks, the exponential convergence of the estimation error is achieved by employing the proposed observer scheme, such that the estimation performance is improved. More specifically, in the disturbance-free case, it is proven that the state estimation error converges exponentially to 0 despite the existence of DoS attacks. Finally, simulation results are provided to illustrate the effectiveness and merits of the proposed methods.


Kinect V2 Performance Assessment in Daily-Life Gestures: Cohort Study on Healthy Subjects for a Reference Database for Automated Instrumental Evaluations on Neurological Patients.
The increase of sanitary costs related to poststroke rehabilitation requires new sustainable and cost-effective strategies for promoting autonomous and dehospitalized motor training. In the Riprendo@Home and Future Home for Future Communities research projects, the promising approach of introducing low-cost technologies that promote home rehabilitation is exploited. In order to provide reliable evaluation of patients, a reference database of healthy people's performances is required and should consider variability related to healthy people performances. 78 healthy subjects performed several repetitions of daily-life gestures, the reaching movement (RM) and hand-to-mouth (HtMM) movement with both the dominant and nondominant upper limbs. Movements were recorded with a Kinect V2. A synthetic biomechanical protocol based on kinematical, dynamical, and motor control parameters was used to assess motor performance of the healthy people. The investigation was conducted by clustering participants depending on their limb dominancy (right/left), gender (male/female), and age (young/middle/senior) as sources of variability. Results showed that limb dominancy has minor relevance in affecting RM and HtMM; gender has relevance in affecting the HtMM; age has major effect in affecting RM and HtMM. An investigation of healthy subjects' upper limb performances during daily-life gestures was performed with the Kinect V2 sensor. Findings will be the basis for a database of normative data for neurological patients' motor evaluation.


The extended, transnasal, transsphenoidal approach for anterior skull base meningioma: considerations in patient selection.
In this study, we set out to define our institutional criteria for patient eligibility for transsphenoidal resection of parasellar meningiomas, and to report our experience with extended transnasal approaches for these lesions. We aimed to discuss the important considerations of patient selection and risk stratification to optimize outcomes for patients with these difficult lesions, and also include considerations that should be reviewed during surgical approach selection. Medical records from Brigham and Women's Hospital were retrospectively reviewed for all patients who underwent transsphenoidal surgery for pituitary disease with the senior author from April 2008 to March 2017 (938 procedures). Patients undergoing surgery for anterior skull base meningioma were identified and patient data were collected. Seven patients (four women, three men) underwent transsphenoidal resection (five endoscopic, one microscopic, and one hybrid endoscopic/microscopic) of pathologically-confirmed anterior skull base meningiomas during the study period. Five patients presented with visual field deficits, three presented with headache, two presented with hypopituitarism, and one woman presented with infertility. The median maximum tumor diameter was 1.7 cm (range 1.4-4.2 cm). Six patients underwent subtotal resection, and one underwent gross total resection. The median MIB-1 index was 2.3 (range 1.0-7.6). Complications included two readmissions (one on POD11 for small bowel obstruction, one on POD48 for epistaxis), and the development of new onset thyroid deficiency and transient diabetes insipidus in one patient. Two patients had reoperations by craniotomy for tumor recurrence after 5 and 6 years, respectively. Although more commonly treated transcranially, anterior skull base meningiomas are sometimes amenable to resection transphenoidally. Patient selection is critical, and multiple factors, including tumor size, consistency, and location, patient and surgeon preference, and presenting symptoms each affect the optimum surgical approach. We have developed criteria for patient selection so that transsphenoidal surgery can be used to resect or debulk anterior skull base meningiomas safely and with favorable outcomes.


Increased cytotoxicity of CD4+ invariant NKT cells against CD4+CD25hiCD127lo/- regulatory T cells in allergic asthma.
CD4+CD25(hi)CD127(lo/-) regulatory T cells (Treg) have been implicated in the resolution of asthma-associated inflammation while the opposite role of CD4+ invariant NKT (iNKT) cells has been the subject of recent investigations. Studies here focused on mechanisms of interaction between CD4+ iNKT cells and Treg to further explore their roles in allergic asthma (AA). Flow cytometry analysis revealed a significant increase in the expression of the natural cytotoxicity receptors NKp30 and NKp46 by CD4+ iNKT cells in AA subjects compared to healthy controls (HC) and non-allergic asthmatics (NA). Subsequent intracellular staining showed that CD4+ iNKT cells also expressed higher levels of granzyme B and perforin in AA than HC. In in vitro killing assays, AA CD4+ iNKT cells selectively killed autologous Treg, but not CD4+CD25- T cells, more potently than HC and NA counterparts. This increased cytotoxicity positively correlated with asthma severity and granzyme B/perforin expression of CD4+ iNKT cells. Furthermore, it could be abrogated by either inhibition of the granzyme B-/perforin-dependent cell death pathway or oral corticosteroid administration. Altogether, these findings suggest that increased cytotoxicity of CD4+ iNKT cells against Treg might contribute to dysfunctional cellular interactions in AA.


Conservative management of a three-day-old esophageal perforation with feeding jejunostomy and prokinetic drug.
Spontaneous esophageal perforation is a well-recognized, life-threatening emergency. The spectrum of presentation is a major reason for errors in diagnosis and the failure to institute prompt and imminent management. A case of Boerhaave's syndrome, diagnosed and managed non-operatively in a tertiary center three days after tear, is described. The diagnosis was confirmed with a series of gastrograffin esophagograms which revealed a leak in the lower part of the esophagus, with hydropneumothorax.


Comparison of nuclear DNA yield and STR typing success in Second World War petrous bones and metacarpals III.
DNA yield and STR typing success differ among skeletal element types and within individual bones. Consequently, it is necessary to identify the skeletal elements and their intra-skeletal parts that will most likely yield utilizable and informative endogenous DNA for human identification of skeletal remains. The petrous portion of the temporal bone has been shown to be the most suitable skeletal part for sampling archaeological skeletons, and it has also been used successfully in some forensic cases. When all representative bone types were analyzed for three complete Second World War skeletons, metatarsals and metacarpals yielded more DNA than petrous bones (which generated full profiles even if the DNA yield was lower) and, among almost 200 Second World War metatarsals and metacarpals analyzed, metacarpals III were found to be the highest-yielding bones. To further improve the sampling strategy in DNA analysis of aged skeletal remains, a comparison between 26 petrous bones and 30 metacarpals III from Second World War skeletons was made considering intra-bone DNA yield variability. In metacarpals III only epiphyses were sampled, and in petrous bones only the dense part within the otic capsule was used. To exclude the influence of taphonomic issues as much as possible, petrous bones and metacarpals III from a single Second World War mass grave were examined. The difference between petrous bones and metacarpals III was explored by measuring nuclear DNA yield and success of STR typing. After cleaning the samples, full demineralization extraction was used to decalcify 0.5 g of powdered bone. PowerQuant (Promega) was used to determine DNA content and DNA degradation rates, and STR typing was performed using the PowerPlex ESI 17 Fast System (Promega). Metacarpals III produced the same DNA yields and STR typing success as petrous bones with no intra-individual difference observed in concentration of DNA, degradation rate, percentage of successfully amplified alleles, and intensity of electrophoretic signals. Sampling and processing of metacarpal III epiphyses is consequently recommended for genetic identification of highly degraded skeletal remains in routine forensic casework and in buried non-commingled aged skeletal remains whenever metacarpals III are preserved. Metacarpals III are easy to sample and less prone to contamination with modern DNA because no saw is needed for sampling in comparison to the petrous portion of the temporal bone. The data obtained in this study further improve the sampling strategy for genetic identification of Second World War skeletal remains in Slovenia.


A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro.
An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers) that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2A, UHRF1, CTCF, HOTAIR and ANRIL) were found to have experimental evidence showing that functional perturbations played "driver" roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high-throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints.


Aberrant expression of PROS1 correlates with human papillary thyroid cancer progression.
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). Considering the important association between cellular immunity and PTC progression, it is worth exploring the biological significance of immune-related signaling in PTC. Several bioinformatics tools, such as R software, WEB-based Gene SeT AnaLysis Toolkit (WebGestalt), Database for Annotation, Visualization and Integrated Discovery (DAVID), Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape were used to identify the immune-related hub genes in PTC. Furthermore, in vitro experiments were adopted to identify the proliferation and migration ability of PROS1 knockdown groups and control groups in PTC cells. The differentially expressed genes (DEGs) of five datasets from Gene Expression Omnibus (GEO) contained 154 upregulated genes and 193 downregulated genes, with Protein S (PROS1) being the only immune-related hub gene. Quantitative real-time polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) have been conducted to prove the high expression of PROS1 in PTC. Moreover, PROS1 expression was significantly correlated with lymph nodes classification. Furthermore, knockdown of PROS1 by shRNAs inhibited the cell proliferation and cell migration in PTC cells. The findings unveiled the clinical relevance and significance of PROS1 in PTC and provided potential immune-related biomarkers for PTC development and prognosis.


Cannabinoid 2 (CB2) receptor agonism reduces lithium chloride-induced vomiting in Suncus murinus and nausea-induced conditioned gaping in rats.
We aimed to investigate the potential anti-emetic and anti-nausea properties of targeting the cannabinoid 2 (CB2) receptor. We investigated the effect of the selective CB2 agonist, HU-308, on lithium chloride- (LiCl) induced vomiting in Suncus murinus (S. murinus) and conditioned gaping (nausea-induced behaviour) in rats. Additionally, we determined whether these effects could be prevented by pretreatment with AM630 (a selective CB2 receptor antagonist/inverse agonist). In S. murinus, HU-308 (2.5, 5mg/kg, i.p.) reduced, but did not completely block, LiCl-induced vomiting; an effect that was prevented with AM630. In rats, HU-308 (5mg/kg, i.p.) suppressed, but did not completely block, LiCl-induced conditioned gaping to a flavour; an effect that was prevented by AM630. These findings are the first to demonstrate the ability of a selective CB2 receptor agonist to reduce nausea in animal models, indicating that targeting the CB2 receptor may be an effective strategy, devoid of psychoactive effects, for managing toxin-induced nausea and vomiting.


Preschoolers' use of form class cues to learn descriptive proper names.
This study examined 3- and 4-year-old preschoolers' ability to learn proper names containing familiar descriptions. Children saw a novel creature with a familiar property (it was red) and heard either an adjective ("This is a red one") or a descriptive proper name ("This is Mr. Red"). The creature was then transformed, losing the property (e.g., it became green). Children had to extend the word to either the transformed original creature or a new creature bearing the original property (another red creature). Children, especially 4-year-olds, extended the adjective to the new creature but were significantly more likely to extend the proper name to the original creature. Lexical form class cues provided potent information about word meaning, directing preschoolers to reinterpret familiar descriptive terms (adjectives) as homophonic terms designating unique individuals (proper names).


Seizures Prior to Radiotherapy of Gliomas: Prevalence, Risk Factors and Survival Prognosis.
Seizures represent a common manifestation of gliomas. This study evaluated the prevalence of pre-radiotherapy seizures, potential risk factors and associations with survival. Eight factors were analyzed in 222 patients for associations with seizures including number, size and location of glioma, World Health Organization (WHO) grade, performance score, gender, age and upfront resection. These factors plus pre-radiotherapy symptoms and seizures were assessed for survival. Prevalence of pre-radiotherapy seizures was 29.3%. A significant correlation was found for grade II (p=0.002), trends for age ≤59 years (p=0.123) and lack of upfront resection (p=0.113). Unifocal gliomas (p<0.001), grade II (p=0.045) and upfront resection (p<0.001) showed significant associations with survival (univariate analyses). A trend was found for seizures (p=0.075) and age ≤59 years (p=0.091). In the multivariate analysis, grade II (p=0.002) and upfront resection (p=0.004) maintained significance; unifocal gliomas showed a trend (p=0.062). Pre-radiotherapy seizures appeared to be correlated with WHO grade, age and lack of upfront resection, and with better survival.


Role of CD26/dipeptidyl peptidase IV in human immunodeficiency virus type 1 infection and apoptosis.
To examine the role of CD26/dipeptidyl peptidase IV (DPPIV; EC 22.214.171.124) in infection by human immunodeficiency virus type 1 (HIV-1), we utilized CD26 cDNA-transfected Jurkat T-cell lines. Both CD26- parental Jurkat cells and mutant CD26+ (DPPIV-) transfected Jurkat cells were readily infected with HIV-1, whereas wild-type CD26+ (DPPIV+) transfected Jurkat cells were more resistant to HIV-1 infection. Our results suggest that CD26 is not essential for HIV-1 infectivity as suggested by others but that DPPIV enzyme activity may decrease the efficiency of HIV-1 infection. Of great interest, we found that mutant CD26+ (DPPIV-) transfectants and CD26- parental Jurkat cells strongly expressed CD95 (Fas/Apo-1) and were more sensitive than wild-type CD26+ (DPPIV+) transfectants to the induction of apoptosis by anti-CD95 monoclonal antibody. These results suggest that CD26 may play a role in HIV-1-associated loss of -CD4+ cells through the process of programmed cell death.


Sublabial-endonasal approach to the sella turcica.
In this paper the authors describe the sublabial-endonasal-transsphenoidal approach to the sella turcica, a modification that combines elements of the sublabial-submucosal-transseptal approach and the endonasal approach. It provides a midline, or near midline, trajectory, wide exposure of the sella, and secure speculum placement on the osseous edge of the pyriform aperture, while avoiding dissection of the nasal mucosa, and it can be used for microscopic and endoscopic surgery.


The role of proteases in the pathogenesis of osteoarthritis.
It is proposed that the cartilage contains enzymes which are responsible for the degradation of the principle components of the matrix, the proteoglycan and collagen. Measurement of acid, lysosomal bound proteases, or neutral proteases shows increases in proportion to the severity of the disease. Collagenase activity also increases in human osteoarthritic cartilage in the same manner. In an experimental model of osteoarthritis, induced by mechanical factors, enzymatic activity also increased. By inhibiting the enzyme activity with chelators, the arthritic process could be slowed.


Structural Dynamics of Short Ligands on the Surface of ZnSe Semiconductor Nanocrystals.
ZnSe semiconductor nanocrystals (NCs) with a size comparable to their Bohr radius are synthesized, and the native capping agents with long hydrocarbon tails are replaced with short thiocyanate (SCN) ligands through a ligand exchange method. The structural dynamics of SCN ligands on the surface of ZnSe NCs in solution is investigated by ultrafast infrared spectroscopy. Vibrational population relaxation of SCN ligands is accelerated due to the specific interaction with the positively charged sites on the surface of NCs. The orientational anisotropy of the bound SCN ligands decayed at a rate much faster than that in the control solution containing Zn2+ cations. From the wobbling-in-the-cone model analysis, we found that the SCN ligand undergoes wobbling orientational diffusion with a relatively large cone semiangle on the surface of ZnSe NCs, and the overall orientational diffusion of bound SCN is found to be strongly dependent on the size of ZnSe NCs.


Overall Survival Differences in Young Black Colorectal Cancer Patients: a Report from the National Cancer Database.
Objectives: Black patients have the highest overall incidence rate of early onset colorectal cancer, with many of these patients presenting with more aggressive disease at diagnosis, ultimately leading to decreased overall survival. We aimed to (1) evaluate how race and age affected overall survival in colorectal cancer patients, and (2) determine the different demographic and clinical covariables that may influence survival in younger individuals. Methods: The 2017 National Cancer Database (NCDB) was used to identify all patients that had colorectal cancer between 2004-2017. These patients were then divided into groups according to age (<45 and ≥45 years old) and race (white and black). Overall survival (OS) between white and black groups according to age was compared. Initial testing of survivor functions between groups revealed violations of the proportional hazards assumption. Accordingly, we used parametric maximum likelihood analyses fitting the survivor functions to Weibull distributions. Logistic regression analysis was used to determine univariate and multivariate relationships between the covariates and race for younger subjects. Propensity score matching analysis was also used to control for differences in the demographic or clinical variables between the young black versus white subgroups. Results: Out of 1.4 million potential cases initially identified, 207,823 unique cases were deemed eligible for evaluation based on study criteria. Black patients in the study population were more likely to be female, have medical comorbidities, and come from areas with lower average income and baseline education. OS was lower in older patients of both race categories when compared to the younger cohorts. Among patients older than 45 years, there were no significant differences in proportional hazard of death between black and white patients. However, among those younger than 45 years, younger black patients had significantly increased hazard of death. Regarding disease burden at diagnosis, pathologic characteristics and overall risk of death, there were no significant differences between black and white patients. Conclusions: Overall survival in young black patients with colorectal cancer is significantly reduced when compared to young white patients, even when controlling for demographic and pathologic factors. This suggests that the outcome disparities between black and white patients are complex, and the underlying factors are not well understood.


Identification of transglutaminase reactive residues in human osteopontin and their role in polymerization.
Osteopontin (OPN) is a highly posttranslationally modified protein present in several tissues where it is implicated in numerous physiological processes. OPN primarily exerts its functions through interaction with integrins via the Arg-Gly-Asp and Ser-Val-Val-Tyr-Gly-Leu-Arg sequences located in the N-terminal part of the protein. OPN can be polymerized by the cross-linking enzyme transglutaminase 2 (TG2), and polymerization has been shown to enhance the biological activity of OPN. However, little is known about the reactivity and location of the glutamine and lysine residues involved in the TG2-mediated modification of OPN. Here we show that TG2 catalyses the incorporation of 5-(Biotinamido)pentylamine at glutamines in both the N- and C-terminal parts of OPN, whereas TG2 primarily incorporated the glutamine-donor peptide biotinyl-TVQQEL-OH into the C-terminal part of OPN. By mass spectrometric analyses we identified Gln34, Gln42, Gln193 and Gln248 as the major TG2 reactive glutamines in OPN. The distribution of reactive Gln and Lys residues in OPN proved to be important, as the full-length protein but not the physiologically highly active integrin-binding N-terminal part of OPN were able to polymerize in a TG2-mediated reaction. Collectively, these data provide important new molecular knowledge about the mechanism of OPN polymerization.


Phaeochromocytoma in Nepal--a single centre experience.
Phaeochromocytomas are rare tumors of chromaffin cells of neural crest that classically present with symptoms of catecholamine excess such as palpitations, headache and sweating. They are diagnosed by measuring plasma or urinary levels of catecholamines or their metabolites. Anatomic localization is done by computed tomographic scan or magnetic resonance imaging, or meta-iodobenzyl guanidine scan in certain cases. Adequate preoperative catecholamine blockade prevents perioperative hemodynamic instability. To study the clinical spectrum and management of phaeochromocytomas in a tertiary care centre, Tribhuvan University Teaching Hospital, in Nepal. Retrospective review of case records of histologically proven cases of phaeochromocytomas from 2008 -2011 was done, and data collected on clinical spectrum, diagnostic modalities, perioperative management and follow-up. Twelve cases of phaeochromocytomas were operated. The mean age was 36.41+/-14.07 years. There were 2 bilateral phaeochromocytomas and 1 extraadrenal paraganglioma. Apart from the common symptoms of catecholamine excess, patients had atypical presentations like psychiatric manifestations and blurred vision. A combination of urinary Vanillyl Mandelic Acid and computed tomographic scan was used for diagnosis, and open surgery was done in all cases. Pre-operative blood pressure control was achieved by prazocin or calcium channel blockers. Ten patients had intraoperative surge in blood pressure. There were no major morbidity or mortality. Three patients had high blood pressure postoperatively, but were effectively managed with antihypertensives. Phaeochromocytomas can have variable presentation. Good preoperative preparation and perioperative management can result in an excellent outcome.


Effect of angiosonography to monitor response during imatinib treatment in patients with metastatic gastrointestinal stromal tumors.
Gastrointestinal stromal tumor (GIST) metastases are typically intra-abdominal and hypervascular. We assessed the effect of angiosonography with a second-generation contrast agent to monitor response during imatinib treatment in patients with metastatic KIT+ GIST. Ten consecutive patients with known advanced KIT+ GIST were investigated with angiosonography and computerized tomography (CT). We also monitored the serum levels of the major angiogenic growth factor, vascular endothelial growth factor. Angiosonography showed a reduction in tumor vascularization of liver metastases during imatinib treatment in all cases. We observed a reduction in tumor vascularization before a reduction in tumor size. The tumor perfusion appeared reduced in the central part of the liver metastases. With a median follow-up of 18 months (range 3-33), a reduction in tumor vascularization was initially observed in all patients, but progressive disease was documented in four patients following imatinib treatment. CT documented tumor response according to standardized criteria in six patients, stable disease in four, and progressive disease according to angiosonography. The reduction of tumor perfusion at angiosonography correlated with the pseudocystic appearance at CT. The "nodule(s) within a mass" pattern of recurrence occurred in two patients with no difference observed between angiosonography and CT. Early decreasing serum vascular endothelial growth factor levels were observed in the two cases with higher pretreatment levels. Imatinib could induce antiangiogenic and/or antivascular effects in GIST, and this effect could be easily monitored with angiosonography. Angiosonography might be a useful complement for monitoring the therapeutic effect of imatinib in these patients.


Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women.
Lower-than-commonly-prescribed doses of conjugated equine estrogens (CEEs) with medroxyprogesterone acetate (MPA) improve vasomotor symptoms and vaginal atrophy, provide acceptable bleeding and lipid profiles, and afford endometrial protection. This lower-dose therapy's protection against loss of bone mineral density (BMD) associated with menopause has not been thoroughly investigated. To determine the effects of lower doses of CEEs only or CEEs-MPA on spine and hip BMD, total body bone mineral content (BMC), and biochemical markers of bone turnover in postmenopausal women. Two-year randomized, double-blind, placebo-controlled substudy of the Women's Health, Osteoporosis, Progestin, Estrogen trial, conducted at 19 US centers between August 1995 and October 2000. Eight hundred twenty-two healthy postmenopausal women aged 40 to 65 years who were within 4 years of their last menstrual period. Patients were randomly assigned to receive CEEs, 0.625; CEEs, 0.625 and MPA, 2.5; CEEs, 0.45; CEEs, 0.45 and MPA, 2.5; CEEs, 0.45 and MPA, 1.5; CEEs, 0.3; CEEs 0.3 and MPA, 1.5 (all doses in mg/d); or placebo for 2 years. All participants also received elemental calcium at 600 mg/d. Changes from baseline in spine and total hip BMD, total body BMC, and biochemical markers of bone turnover (serum osteocalcin and urinary cross-linked N-telopeptides of type I collagen), assessed at 6-month intervals and compared among treatment groups with a modified intention-to-treat approach. At 24 months, women assigned to all of the active treatment groups had significant gains from baseline (P<.001) in spine and hip BMD and total body BMC (except total body BMC in the group receiving CEEs, 0.3 mg/d). These changes were significantly different from those in the placebo group, in which losses of bone mass in spine and total body were evident over the course of the study (P<.001). The loss in hip BMD from baseline in the placebo group was significant at 18 (P =.02) but not at 24 months (P =.06). Osteocalcin and N-telopeptides of type I collagen were significantly reduced from baseline (P<.001) for all active treatment groups at all time points; no changes were found for the placebo group. For women treated with CEEs alone, the gains in spine BMD for the group taking CEEs, 0.625 mg/d, were significantly higher than those of the group taking CEEs, 0.3 mg/d (P =.02), but not the group treated with CEEs, 0.45 mg/d (P =.48). Doses of CEEs or CEEs-MPA lower than 0.625 mg/d effectively increase BMD and BMC in early postmenopausal women.


Gait disorders and balance disturbances in Parkinson's disease: clinical update and pathophysiology.
Gait disorders and balance impairments are one of the most incapacitating symptoms of Parkinson's disease. Here, we discuss the latest findings regarding epidemiology, assessment, pathophysiology and treatment of gait and balance impairments in Parkinson's disease. Recent studies have confirmed the high rate and high risk of falls of patients with Parkinson's disease. Therefore, it is crucial to detect patients who are at risk of falling and how to prevent falls. Several studies have shown that multiple balance tests improve the prediction of falls in Parkinson's disease. Difficulty turning may be caused by axial rigidity, affected interlimb coordination and asymmetries. Turning difficulties are easily assessed by timed performance and the number of steps during a turn. Impaired sensorimotor integration, inability of switching between sensory modalities and lack of compensatory stepping may all contribute to the high incidence of falls in patients with Parkinson's disease. Similarly, various studies highlighted that pharmacotherapy, neurosurgery and physiotherapy may adversely affect balance and gait in Parkinson's disease. Insights into the pathophysiology of Parkinson's disease continue to grow. At the same time, it is becoming clear that some patients may in fact deteriorate with treatment. Future research should focus on the development and evaluation of multifactorial fall prevention strategies.


A compartmental approach to the radiographic evaluation of soft-tissue calcifications.
Musculoskeletal radiology, like most areas of diagnostic radiology, has seen a dramatic increase in the use of cross-sectional imaging techniques over the last decade. However, conventional radiography remains a vital role in the evaluation of disease involving the spine and extremities. Given its widespread availability and low cost, radiography should be the initial examination obtained when imaging is clinically indicated. Therefore it is essential that the practicing radiologists be able to maximize the diagnostic value of this common study to aid the clinicians with a focused differential diagnosis, if not a definitive diagnosis. While much emphasis has been placed on radiographic interpretation of osseous lesions, similar diagnostic yield can be often obtained about calcified or ossified soft-tissue lesions. Detailed evaluation of the distribution and morphology of the soft-tissue calcifications, combined with a thorough knowledge of the entities that may occur at the site of the noted abnormality, provides significant interpretive value to provide a definitive diagnosis or accurately recommend the next most effective management step. We provide a compartmental-based approach to the interpretation of soft-tissue calcifications.


Effects of hypothermia on short latency somatosensory evoked potentials in humans.
Short latency somatosensory evoked potentials (SSEPs) elicited by median nerve stimulation were monitored in 14 adult patients undergoing cardiac surgery under cardiopulmonary bypass and induced hypothermia. SSEPs were recorded at 1-2 degrees C steps as the body temperature was lowered from 37 degrees C to 20 degrees C to determine temperature-dependent changes. Hypothermia produced increased latencies of the peaks of N10, P14 and N19 components, the prolongation was more severe for the later components so that N10-P14 and P14-N19 interpeak latencies were also prolonged. The temperature-latency relationship had a linear correlation. The magnitude of latency prolongation (msec) with 1 degree C decline in temperature was 0.61, 1.15, 1.56 for N10, P14 and N19 components, respectively, and 0.39 and 0.68 for interpeak latencies N10-P14 and P14-N19, respectively. The rise time and duration of the 3 SSEP components increased progressively with cooling. Cortically generated component, N19, was consistently recordable at a temperature above 26 degrees C, usually disappearing between 20 degrees C and 25 degrees C. On the other hand, more peripherally generated components, N10 and P14, were more resistant to the effect of hypothermia; P14 was always elicitable at 21 degrees C or above, whereas N10 persisted even below 20 degrees C. The amplitude of SSEP components had a poor correlation with temperature; there was a slight tendency for N10 and P14 to increase and for N19 to decrease with declining temperature. Because incidental hypothermia is common in comatose and anesthetized patients, temperature-related changes must be taken into consideration during SSEP monitoring under these circumstances.


Induction of Diabetes Abolishes the Antithrombotic Effect of Clopidogrel in Apolipoprotein E-Deficient Mice.
Patients with acute coronary syndrome with diabetes mellitus (DM) exhibit an impaired platelet inhibitory response to clopidogrel which is only partially understood. DM was induced by the administration of streptozotocin (STZ) to 9-week-old mice. The antithrombotic effects of clopidogrel (10 mg/kg/d, orally × 5 days) were determined using a FeCl 3 -induced thrombosis model employing wild-type (WT), apolipoprotein E (apoE)-deficient, and diabetic apoE-deficient mice at 21 weeks. Antiplatelet effects were determined using flow cytometry. The antithrombotic effects of clopidogrel were similar in WT and apoE-deficient mice but were attenuated in diabetic apoE-deficient mice with the percent inhibition of thrombus area (µm 2 ) by clopidogrel being 85.5% (WT mice), 75.0% (apoE-deficient mice), and 1.9% (diabetic apoE-deficient mice). The time to first occlusion and lumen stenosis also reflected a significant loss of the antithrombotic effects of clopidogrel in diabetic apoE-deficient mice. Ex vivo platelet activation, which was assessed using ADP-induced expression of activated glycoprotein IIb/IIIa, was completely inhibited by clopidogrel in these three groups of mice. In contrast, the effect of clopidogrel on the ex vivo expression of platelet P-selectin induced by protease-activated receptor 4-activating peptide was diminished in diabetic apoE-deficient mice compared with that in WT and apoE-deficient mice. These data suggest that diabetic apoE-deficient mice may serve as a useful model to better understand the impaired responses to clopidogrel in patients with DM, which may partially reflect a reduction of the effect of clopidogrel on thrombin-induced platelet activation.


Gd-Dots with Strong Ligand-Water Interaction for Ultrasensitive Magnetic Resonance Renography.
Magnetic resonance imaging contrast agents with both significantly enhanced relaxivity and minimal safety risk are of great importance for sensitive clinical diagnosis, but have rarely been reported. Herein, we present a simple strategy to improve relaxivity by introducing surface ligands with strong interaction to water molecules. As a proof of concept, NaGdF4 nanoparticles (NPs) capped by poly(acrylic acid) (PAA) show superior relaxivity to those capped by polyethylenimine and polyethylene glycol, which is attributed to the strong hydrogen-bond capacity of PAA to water molecules as revealed by theoretical calculation. Furthermore, benefiting from PAA and ultrasmall particle size, Gd-dots, namely PAA-capped GdOF NPs (2.1 ± 0.2 nm), are developed as a high-performance contrast agent, with a remarkable ionic relaxivity of ∼75 mM-1 s-1 in albumin solution at 0.5 T. These Gd-dots also exhibit efficient renal clearance with <3% of injected amount left 12 h post-injection. Ultrasensitive MR renography achieved with Gd-dots strongly suggests their great potential for practical applications.