Regenerative potential of adult O1+ oligodendrocytes.
Remyelination in the adult central nervous system (CNS) is preceded by the generation of new oligodendrocytes (ODCs) but the source of the new ODCs has not been resolved. Adult galactocerebroside positive (O1+)ODCs proliferate when cultured with purified sensory neurons (Wood and Bunge, Nature 320:756-758, 1999), implying that differentiated ODCs could be an important source of new myelinating ODCs. To test this possibility purified O1+ODCs (>96% purity) were plated at low density (20-50 cells/culture) into cultures of purified dorsal root ganglion neurons. Three days after plating, single O1+ODCs were located (209 ODCs/43 cultures) and sequentially observed for 4 weeks. The ODCs began to proliferate by the fifth day after plating and formed large colonies by the third week. Most cells in these colonies were 01- but positive for another ODC antigen, O4. A few O1+, myelin basic protein (MBP)+ODCs, and glial fibrillary acidic protein (GFAP)+cells with astrocytic morphology were observed in some colonies. In similar cultures plated with cell-sorted O1+ODCs (>99.5% purity), ciliary neurotrophic factor (CNTF, 1ng/ml) increased the number and size of colonies, the number of O1+MBP+ODCs (including ODCs producing myelin-like profiles in association with axons) and the number of GFAP+ astrocytes, relative to untreated controls. The results are evidence that CNTF exerts a trophic effect on adult O1+ODCs, and/or their progeny, and that cells generated by division of O1+ODCs can become either new myelin-producing ODC, or astrocytes. This plasticity in regenerative potential of adult O1+ODCs has not been previously demonstrated.


Camera-based Respiratory Imaging for Thoracic Asymmetry in Thoracic Surgery Patients.
The current tool for assessing thoracic asymmetry of thoracic surgery patients is inappropriate for timely or frequent clinical routines due to its dependency on empirical physical examinations or specialized machines. This study investigates the camera-based respiratory imaging for screening thoracic asymmetry, in an intelligent and convenient way. The respiratory heatmaps are generated based on the respiratory magnitudes, phases and angles extracted from the chest video, and bilateral chest region of interest are compared statistically. Due to the variability of chest respiratory direction, spatial enhancement (SDR and SPCA) algorithms are proposed to magnify the respiratory energy. The proposed framework was validated in a clinical trial involving 31 patients, recorded by a smartphone camera. A high correlation was found between the camera measurements and patients' thoracic status in both the visual imaging and quantified indices. The respiratory imaging of camera shows a clear potential for assessing chest abnormalities of thoracic surgery patients.


Non-local correlations via chaotic itinerancy in VCSEL with optical feedback.
Similar to edge-emitting lasers, vertical cavity surface emitting lasers (VCSELs) subjected to optical feedback are known for exhibiting erratic fluctuations of their optical power at slow and fast time scales; these are called low-frequency fluctuations (LFF). Here, we demonstrate both experimentally and numerically that the chaotic itinerancy in phase space associated with LFF has a deep connection with the creation of non-local correlations at multiple time scales between the two linear polarization modes. Our result provides a novel framework to interpret the unknown origin of spectral signatures in the optical power of chaotic lasers with optical feedback, which were observed in the past two decades.


Omalizumab for Management of Refractory Urticaria: Experience of a Tertiary Care Centre in Eastern India.
To study the effects of omalizumab in chronic spontaneous urticaria in Indian patients. The study was conducted in a tertiary care centre and it was retrospective and descriptive in nature. We analysed the data of patients who were administered omalizumab between June 2014 and June 2015 for the management of refractory chronic spontaneous urticaria at our centre. Omalizumab was used in those patients who did not respond to updosing of antihistaminics and cyclosporine. Omalizumab was used in dose of 300 mg per month for 3 doses. Twenty-four patients were administered omalizumab during the study period. Average age of the patients was 36.54 years, female:male ratio was 1.4:1, mean duration of disease was 20.66 months, and autologous serum skin test was positive in 33% of studied individuals. Ninety six percent of cases showed response to treatment in our study. Remission was seen in 25% of patients, 50% showed satisfactory response, and 20.83% showed partial response. Average UAS7 scoring before starting omalizumab in preceding week was 24.4. Average UAS7, 2 weeks after starting omalizumab was 4 in responsive patients. Omalizumab is safe and effective treatment for the management of chronic spontaneous urticaria. It can be used in Indian setting after failure to other third-line therapies such as addition of montelukast and cyclosporine due to high cost of treatment.


Comparison of volumetric breast density estimations from mammography and thorax CT.
Breast density has become an important issue in current breast cancer screening, both as a recognized risk factor for breast cancer and by decreasing screening efficiency by the masking effect. Different qualitative and quantitative methods have been proposed to evaluate area-based breast density and volumetric breast density (VBD). We propose a validation method comparing the computation of VBD obtained from digital mammographic images (VBDMX) with the computation of VBD from thorax CT images (VBDCT). We computed VBDMX by applying a conversion function to the pixel values in the mammographic images, based on models determined from images of breast equivalent material. VBDCT is computed from the average Hounsfield Unit (HU) over the manually delineated breast volume in the CT images. This average HU is then compared to the HU of adipose and fibroglandular tissues from patient images. The VBDMX method was applied to 663 mammographic patient images taken on two Siemens Inspiration (hospL) and one GE Senographe Essential (hospJ). For the comparison study, we collected images from patients who had a thorax CT and a mammography screening exam within the same year. In total, thorax CT images corresponding to 40 breasts (hospL) and 47 breasts (hospJ) were retrieved. Averaged over the 663 mammographic images the median VBDMX was 14.7% . The density distribution and the inverse correlation between VBDMX and breast thickness were found as expected. The average difference between VBDMX and VBDCT is smaller for hospJ (4%) than for hospL (10%). This study shows the possibility to compare VBDMX with the VBD from thorax CT exams, without additional examinations. In spite of the limitations caused by poorly defined breast limits, the calibration of mammographic images to local VBD provides opportunities for further quantitative evaluations.


Description and productivity of emergency medicine researchers receiving K23 or K08 mentored research career development awards.
The primary individual research career development awards for emergency medicine (EM) investigators are the K08 and K23 awards. To the best of the authors' knowledge, postaward productivity of EM K08 and K23 awardees has not been previously described. The objectives were to describe EM researchers who have received K08 or K23 awards and to evaluate their postaward federal funding and publications. This was a cross-sectional study, conducted during January 2012, of clinician-scientists who previously completed EM residency or fellowship programs and have received K08 or K23 awards from the National Institutes of Health (NIH) or Agency for Healthcare Research and Quality (AHRQ) between fiscal years 2000 through 2011. Awardees were identified through the NIH reporting tool (NIH RePORTER). Postaward funding was abstracted, including R01-equivalent funding for K awardees who completed their K training by the end of the 2011 fiscal year. Postaward publications (with journal impact factor) were tabulated for all K awardees using PubMed and Journal Citation Reports. An e-mail survey was also conducted during September and October 2012 to describe the awardee characteristics (demographics and research background) of all EM K awardees using REDCap electronic data captures tools. Simple descriptive statistics are reported. Sixty-three EM awardees were identified; 24 (38%) were K08 awardees, and 39 (62%) were K23 awardees. Of the 38 (60%) awardees who completed their K training, 16 (42%) obtained subsequent federal funding, with six (16%) obtaining R01 funding (median time from end of K award to R01 award was 4.5 years). Overall, EM awardees published a mean (±SD) of 4.0 (±1.3) manuscripts per year (after the start of their K awards); the mean (±SD) impact factor of the journals in which these manuscripts were published was 4.5 (±5.7). Forty-five (71%) of EM K awardees responded to the survey. Respondents had a median age of 36 years (interquartile range [IQR] = 35 to 38 years), and 33 were male (73%). The median time from completion of residency to start of the K award was 6 years (IQR = 4 to 7 years), with 27 (60%) completing a research fellowship prior to the K award. Over 40% of EM K awardees who completed their career development training subsequently obtained federal funding as principal investigator (PI) or co-PI, while approximately one in six obtained R01 equivalent funding. Given the numerous barriers facing emergency care researchers, EM K awardees demonstrate good postaward productivity.


Induction of osteogenic differentiation by hedgehog proteins.
In this study we asked whether members of the hedgehog gene family are involved in osteogenesis. C3H10T1/2 cells and MC3T3-E1 cells expressed the putative hedgehog receptor patched (Ptc) gene. Medium conditioned by chicken embryo fibroblast cultures expressing either Indian hedgehog or Sonic hedgehog stimulated alkaline phosphatase (APase) activity in cultures of the mouse mesenchymal cell line C3H10T1/2 and the osteoblastic cell line MC3T3-E1. These stimulatory effects were synergistically enhanced by bone morphogenetic protein-2 (BMP-2). Treatment with the amino-terminal portion of recombinant Sonic hedgehog proteins (rShh-N) up-regulated the expression of the Ptc gene within 12 h and increased production of APase in C3H10T1/2. rShh-N and BMP-2 also synergistically stimulated APase activity. rShh-N treatment did not affect the expression levels of Bmp-2, -4, -5, -6 and -7 genes. These findings indicate that hedgehog proteins directly act on osteogenic precursor cells and osteoblasts and stimulate osteogenic differentiation of these cells in co-operation with BMPs.


Complementary Approaches to Retinal Health Focusing on Diabetic Retinopathy.
Diabetes mellitus affects carbohydrate homeostasis but also influences fat and protein metabolism. Due to ophthalmic complications, it is a leading cause of blindness worldwide. The molecular pathology reveals that nuclear factor kappa B (NFκB) has a central role in the progression of diabetic retinopathy, sharing this signaling pathway with another major retinal disorder, glaucoma. Therefore, new therapeutic approaches can be elaborated to decelerate the ever-emerging "epidemics" of diabetic retinopathy and glaucoma targeting this critical node. In our review, we emphasize the role of an improvement of lifestyle in its prevention as well as the use of phytomedicals associated with evidence-based protocols. A balanced personalized therapy requires an integrative approach to be more successful for prevention and early treatment.


Change in the locus of dynamic loading axis on the knee joint after high tibial osteotomy.
The purpose of this study was to visualise the locus of the dynamic loading axis on the knee joint, and to evaluate changes in this locus during gait after high tibial osteotomy (HTO) in three patients who underwent HTO for medial compartment osteoarthritis (OA) of a varus knee. The bone structure of the lower limb and the relative position of skin markers were acquired from CT images. Motion capture data was acquired using spherical skin markers. Skeletal model movement during gait was calculated based on the movement of the markers. The locus of the dynamic loading axis on the knee joint was defined as the point on the proximal tibia joint surface that intersected with the loading axis of the lower limb, which passed through the centre of the femoral head and the centroid of multiple points surrounded by the distal tibia joint surface contour. This system was able to visualise the locus of the dynamic loading axis on the knee joint and not only lateral but also anterior-posterior direction movement. After HTO, the locus shifted from a medial and posterior area of the medial joint edge of the knee to a central area of the knee joint surface. This indicates that HTO shifted the dynamic loading axis. Lateral movement of the dynamic loading axis in the early stance phase of gait was reduced within a year after HTO.


55 W kilohertz-linewidth core- and in-band-pumped linearly polarized single-frequency fiber laser at 1950 nm.
Based on core- and in-band-pumped polarization-maintaining ${{\rm Tm}^{3 + }}$Tm3+-doped single-cladding fiber (PM-TSF, the core diameter is 9 µm) by a 1610 nm fiber laser and a distributed Bragg reflector seed laser, a linearly polarized single-frequency fiber laser (LP-SFFL) at 1950 nm with an output power of 55.3 W and a laser linewidth of 6.95 kHz is demonstrated. The output beam qualities of ${M}_x^2$Mx2 and ${ M}_y^2$My2 are measured to be 1.01 and 1.03, respectively. The slope efficiency with respect to the launched pump power is 71.0%, in comparison with a theoretical quantum efficiency of 82.6%. A polarization-extinction ratio of 19 dB and an optical signal-to-noise ratio of 58 dB are obtained from the 1950 nm LP-SFFL. To the best of our knowledge, to date, this is the highest power of 2.0 µm SFFL output directly from a strict single-mode active fiber. Our experiment offers a promising solution to the current limitations of the high-performance fiber lasers at 2.0 µm, which is particularly essential for coherent detection.


Calcium-induced spikes in cultured pigment epithelium of chick retina.
Resting membrane potentials, electrical resistance, and coupling of chick retinal pigment epithelium cells in tissue culture have been measured with micropipette electrodes. Topical application of NaCl, KCl, MgCl2, and CaCl2 produce rapid, reversible changes in the membrane potentials of these cells. CaCl2 uniquely induces a slow hyperpolarizing wave that can lead to barrages of depolarizing action potentials or spikes and a slow, reversible vacuolization of the cells.


Effect of social networks on 10 year survival in very old Australians: the Australian longitudinal study of aging.
To examine if social networks with children, relatives, friends, and confidants predict survival in older Australians over 10 years after controlling for a range of demographic, health, and lifestyle variables. Prospective longitudinal cohort study (the Australian longitudinal study of aging) Adelaide, South Australia. 1477 persons aged 70 years or more living in the community and residential care facilities. After controlling for a range of demographic, health, and lifestyle variables, greater networks with friends were protective against mortality in the 10 year follow up period. The hazard ratio for participants in the highest tertile of friends networks compared with participants in the lowest group was 0.78 (95%CI 0.65 to 0.92). A smaller effect of greater networks with confidants (hazard ratio = 0.84; 95%CI = 0.71 to 0.98) was seen. The effects of social networks with children and relatives were not significant with respect to survival over the following decade. Survival time may be enhanced by strong social networks. Among older Australians, these may be important in lengthening survival.


Effects of Callous-Unemotional Traits on the Association Between Parenting and Child Conduct Problems.
The current study investigated whether and how callous-unemotional traits (CU) moderated the association between specific parenting practices and child conduct problems (CP) with a special consideration of informant patterns. Associations between CU, ODD and CD symptom severity, and the parenting practices of deficient monitoring, positive involvement, and negative/ineffective discipline were examined across parent and teacher reports on 851 elementary-school students. Relative to children with low CU, in children with high CU: (1) positive parenting was associated with lower CD, but increased ODD; (2) negative/ineffective discipline was associated with increased ODD; (3) deficient monitoring was associated with increased CD. Results were not robust across informants. These findings suggest that in the context of CU, the associations between parenting and CP differ based on parenting characteristics, CP dimensions, and informant, and that families may benefit from treatment targeting specific parenting practices based on CP symptom profiles.


Paratracheal air cysts: a common finding on routine CT examinations of the cervical spine and neck that may mimic pneumomediastinum in patients with traumatic injuries.
Collections of extraluminal paratracheal gas may be present on CT images of the neck and cervical spine and the radiologist may question whether this is related to a pathologic process. This study is designed to demonstrate the appearance, clinical presentation, and prevalence of paratracheal air cysts, which, on CT examinations of the neck, can mimic abnormal extraluminal air. From January 1, 2005, through May 22, 2005, a total of 702 CT examinations of the cervical spine or soft tissue of the neck were reviewed. All examinations were at 2- to 5-mm thickness. Sagittal and coronal reconstructions were available for review, if necessary. Paratracheal air cysts were evaluated for size; the presence of visible communication with the trachea; association with pneumothorax, pneumomediastinum, or subcutaneous emphysema; and association with findings of emphysematous changes in the lung apices. Patient demographics of age, sex, and whether the patient had sustained a traumatic injury were also collected. Of the 702 patients evaluated, 26 (3.7%) had paratracheal air cysts, all of which were found on the right, at the level of the thoracic inlet. Ages of the patients ranged from 15 to 74 years. In 9 (34.6%) of the patients, a direct communication with the trachea was seen. Sizes of the paratracheal air cysts ranged from 1 x 2 mm to 10 x 15 mm. No association was found with CT findings of emphysema in the lung apices, abnormal soft tissue air, or trauma. Right paratracheal air cysts are a common CT finding that occur in a predictable location. In the setting of trauma, these characteristic structures can mimic pneumomediastinum and are seen in approximately 3% to 4% of the US population. The cause is unclear but may be either congenital or an acquired phenomenon, given that they are often seen in both children and adults. We found no association with either trauma or the presence of emphysematous changes in the lung apices.


[Repair of finger soft tissue defect with island flap based on vascular chain of cutaneous branch of dorsal metacarpal artery].
To investigate the operative procedure and the clinical results of the island flap based on the vascular chain of the cutaneous branch of dorsal metacarpal artery for repairing finger soft tissue defect. Between January 2008 and March 2012, 28 cases of tissue defect of fingers (32 fingers) were repaired with the island flaps based on the vascular chain of the cutaneous branch of dorsal metacarpal artery. There were 20 males (23 fingers) and 8 females (9 fingers), with an average age of 29.5 years (range, 14-67 years). The injury causes included 14 cases of crush injury, 6 cases of pressing injury, 5 cases of cutting injury, and 3 cases of avulsion injury. The locations included 10 index fingers, 13 long fingers, 6 ring fingers, and 3 little fingers. There were 9 defects of proximal segment, 12 defects of middle segment, and 11 defects of distal segment. The area of defect ranged from 1.0 cm x 0.8 cm to 5.2 cm x 3.5 cm. The disease duration was 1 hour to 15 days. The area of flaps ranged from 1.2 cm x 1.0 cm to 5.5 cm x 3.8 cm. The donors were closed by suture or were repaired with skin graft. Tense blister occurred in 3 cases, which was cured after dressing change; the other flaps survived. Wound obtained primary healing. Twenty-five patients (27 fingers) were followed up 6-25 months (mean, 16.8 months). The flaps had soft texture and satisfactory appearance. Two point discrimination was 6-9 mm (mean, 7.7 mm) at 6 months after operation. The total active movement of fingers was 105-230 degrees (mean, 204.6 degrees). The results were excellent in 17 fingers, good in 8 fingers, and fair in 2 fingers with an excellent and good rate of 92.6%. The island flap based on the vascular chain of the cutaneous branch of dorsal metacarpal artery has the advantages of the deverting point from the dorsal point to the palm, the extended vessel pedicle, and expanded operation indications, so it is not necessary to cut the dorsal metacarpal artery. It can be used to repair finger tissue defect.


Response of cytoplasmic pH to anoxia in plant tissues with altered activities of fermentation enzymes: application of methyl phosphonate as an NMR pH probe.
Acidification of the cytoplasm is a commonly observed response to oxygen deprivation in plant tissues that are intolerant of anoxia. The response was monitored in plant tissues with altered levels of lactate dehydrogenase (LDH) and pyruvate decarboxylase (PDC) with the aim of assessing the contribution of the targeted enzymes to cytoplasmic pH (pH(cyt)) regulation. The pH(cyt) was measured by in vivo (31)P nuclear magnetic resonance (NMR) spectroscopy using methyl phosphonate (MeP) as a pH probe. The potential toxicity of MeP was investigated by analysing its effect on the metabolism of radiolabelled glucose. MeP accumulated to detectable levels in the cytoplasm and vacuole of plant tissues exposed to millimolar concentrations of MeP, and the pH-dependent (31)P NMR signals provided a convenient method for measuring pH(cyt) values in tissues with poorly defined signals from the cytoplasmic inorganic phosphate pool. Pretreatment of potato (Solanum tuberosum) tuber slices with 5 mm MeP for 24 h did not affect the metabolism of [U-(14)C]glucose or the pattern of (14)CO(2) release from specifically labelled [(14)C]-substrates. Time-courses of pH(cyt) measured before, during and after an anoxic episode in potato tuber tissues with reduced activities of LDH, or in tobacco (Nicotiana tabacum) leaves with increased activities of PDC, were indistinguishable from their respective controls. MeP can be used as a low toxicity (31)P NMR probe for measuring intracellular pH values in plant tissues with altered levels of fermentation enzymes. The measurements on transgenic tobacco leaves suggest that the changes in pH(cyt) during an anoxic episode are not dominated by fermentation processes; while the pH changes in the potato tuber tissue with reduced LDH activity show that the affected isozymes do not influence the anoxic pH response.


Assessment of the quality of care in Maternity Waiting Homes (MWHs) in Mulanje District, Malawi.
Maternal Mortality Ratio (MMR)in Malawi remains high at 439 deaths per 100,000 live births, primarily due to limited access to skilled birth care. Although Malawi established Maternity Waiting Homes (MWHs) to improve access to skilled labour, the quality of care provided in the homes has received limited assessment. The aim of this study was to assess quality of care in the Maternity Waiting Homes in Mulanje, Malawi. We conducted a descriptive qualitative study in three MWHs in Mulanje district, Malawi, from December 2015 to January 2016. We conducted a non-participatory observation using a checklist, to assess the physical layout of the facilities, six face-to-face in-depth interviews (IDIs)with health providers and four focus group discussions (FGDs) with 27 pregnant women admitted for more than 48 hours in MWHs. We digitally recorded all FGDs and IDIs simultaneously transcribing and translating them verbatim into English. Data were analysed using thematic analysis. There were mixed perceptions towards the quality of care in the MWHs. Factors that were perceived to indicate higher quality included a quiet environment at the MWH and midwifery services. Lack of cooking spaces, lack of 24-hour nursing care, absence of food and recreation services and sleeping on the floor negatively affected perceptions of quality. The study has shown that care provided in MWHs varied across facilities. Perceptions of the quality of care were not uniform and a lack of standards contributed to the differences. Efforts should be made to improve, sustain and standardize care in MWHs in order to improve perceptions of quality of care in MWHs.


Combining glycomimetic and multivalent strategies toward designing potent bacterial lectin inhibitors.
As part of ongoing activities toward the design of potent and selective ligands against galactoside-binding proteins from animal, bacterial, and plant lectins, a systematic investigation involving the synthesis and binding evaluations of a series of original β-C-galactopyranoside mimetics is described. The multivalent presentation of partly optimized candidates on various dendritic scaffolds through Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAc) has also been achieved. Biophysical investigations based on isothermal titration calorimetry (ITC) have indicated a dissociation constant in the low micromolar range for the best optimized monovalent conjugate (K(d)=37 μM). The results thus confirmed that stable C-galactosides could represent efficient synthetic glycomimetics of natural α-linked oligosaccharidic inhibitors of PA-IL lectin (Lec A) from the pathogenic Pseudomonas aeruginosa. Striking enhancements in the avidity of the glycoconjugates were also observed for tri-, hexa-, and nonavalent derivatives, among which the most potent exhibited dissociation constants below 500 nM, corresponding to a 400-fold increase in affinity compared with the β-D-Gal-O-Me used as reference. To deepen our understanding of the binding mode of the best glycomimetics involved in the recognition process, molecular modeling studies, docking calculations, and NMR diffusion measurements have been performed. Although favorable complementary interactions induced by the addition of the hydrophobic aglycon might explain the affinity enhancement, experimental determination of the size and the topology of the multivalent conjugates further supported the formation of aggregative complexes as a major multivalent binding mode. This work represents a systematic and comprehensive study towards a thorough understanding of the protein-carbohydrate interactions involved in Pseudomonas aeruginosa infection, and as such should prove useful for the development of stable and optimized anti-adhesive agents.


Suppression of Unwanted ZZ Interactions in a Hybrid Two-Qubit System.
Mitigating crosstalk errors, whether classical or quantum mechanical, is critically important for achieving high-fidelity entangling gates in multiqubit circuits. For weakly anharmonic superconducting qubits, unwanted ZZ interactions can be suppressed by combining qubits with opposite anharmonicity. We present experimental measurements and theoretical modeling of two-qubit gate error for gates based on the cross resonance interaction between a capacitively shunted flux qubit and a transmon, and demonstrate the elimination of the ZZ interaction.


Effect of heavy chain phosphorylation on the polymerization and structure of Dictyostelium myosin filaments.
In Dictyostelium amebas, myosin appears to be organized into filaments that relocalize during cell division and in response to stimulation by cAMP. To better understand the regulation of myosin assembly, we have studied the polymerization properties of purified Dictyostelium myosin. In 150 mM KCl, the myosin remained in the supernate following centrifugation at 100,000 g. Rotary shadowing showed that this soluble myosin was monomeric and that approximately 80% of the molecules had a single bend 98 nm from the head-tail junction. In very low concentrations of KCl (less than 10 mM) the Dictyostelium myosin was also soluble at 100,000 g. But rather than being monomeric, most of the molecules were associated into dimers or tetramers. At pH 7.5 in 50 mM KCl, dephosphorylated myosin polymerized into filaments whereas myosin phosphorylated to a level of 0.85 mol Pi/mol heavy chain failed to form filaments. The phosphorylated myosin could be induced to form filaments by lowering the pH or by increasing the magnesium concentration to 10 mM. The resulting filaments were bipolar, had blunt ends, and had a uniform length of approximately 0.43 micron. In contrast, filaments formed from fully dephosphorylated myosin were longer, had tapered ends, and aggregated to form very long, threadlike structures. The Dictyostelium myosin had a very low critical concentration for assembly of approximately 5 micrograms/ml, and this value did not appear to be affected by the level of heavy chain phosphorylation. The concentration of polymer at equilibrium, however, was significantly reduced, indicating that heavy chain phosphorylation inhibited the affinity of subunits for each other. Detailed assembly curves revealed that small changes in the concentration of KCl, magnesium, ATP, or H+ strongly influenced the degree of assembly. Thus, changes in both the intracellular milieu and the level of heavy chain phosphorylation may control the location and state of assembly of myosin in response to physiological stimuli.


ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo.
Oxidative stress is pathogenic in neurological diseases, including stroke. The identity of oxidative stress-inducible transcription factors and their role in propagating the death cascade are not well known. In an in vitro model of oxidative stress, the expression of the bZip transcription factor activating transcription factor 4 (ATF4) was induced by glutathione depletion and localized to the promoter of a putative death gene in neurons. Germline deletion of ATF4 resulted in a profound reduction in oxidative stress-induced gene expression and resistance to oxidative death. In neurons, ATF4 modulates an early, upstream event in the death pathway, as resistance to oxidative death by ATF4 deletion was associated with decreased consumption of the antioxidant glutathione. Forced expression of ATF4 was sufficient to promote cell death and loss of glutathione. In ATF4(-/-) neurons, restoration of ATF4 protein expression reinstated sensitivity to oxidative death. In addition, ATF4(-/-) mice experienced significantly smaller infarcts and improved behavioral recovery as compared with wild-type mice subjected to the same reductions in blood flow in a rodent model of ischemic stroke. Collectively, these findings establish ATF4 as a redox-regulated, prodeath transcriptional activator in the nervous system that propagates death responses to oxidative stress in vitro and to stroke in vivo.


Bronchoalveolar lavage cytokines are of minor value to diagnose complications following lung transplantation.
Early diagnosis and treatment of acute cellular rejection (ACR) may improve long-term outcome for lung transplant recipients (LTRs). Cytokines have become valuable diagnostic tools in many medical fields. The role of bronchoalveolar lavage (BAL) cytokines is of unknown value to diagnose ACR and distinguish rejection from infection. We hypothesized that distinct cytokine patterns obtained by surveillance bronchoscopies during the first year after transplantation are associated with ACR and microbiologic findings. We retrospectively analyzed data from 319 patients undergoing lung transplantation at University Hospital Zurich from 1998 to 2016. We compared levels of IL-6, IL-8, IFN-γ and TNF-α in 747 BAL samples with transbronchial biopsies (TBB) and microbiologic results from surveillance bronchoscopies. We aimed to define reference values that would allow distinction between four specific groups "ACR", "infection", "combined ACR and infection" and "no pathologic process". No definitive pattern was identified. Given the overlap between groups, these four cytokines are not suitable diagnostic markers for ACR or infection after lung transplantation.


Evaluation of a clinically intuitive quality assurance method.
There is a pressing need for clinically intuitive quality assurance methods that report metrics of relevance to the likely impact on tumor control of normal tissue injury. This paper presents a preliminary investigation into the accuracy of a novel "transform method" which enables a clinically relevant analysis through dose-volume-histograms (DVHs) and dose overlays on the patient's CT data. The transform method was tested by inducing a series of known mechanical and delivery errors onto simulated 3D dosimetry measurements of six different head-and-neck IMRT treatment plans. Accuracy was then examined through the comparison of the transformed patient dose distributions and the known actual patient dose distributions through dose-volume histograms and normalized dose difference analysis. Through these metrics, the transform method was found to be highly accurate in predicting measured patient dose distributions for these types of errors.


Subcellular localization and properties of rat liver adenosine diphosphatase.
ADPase (adenosine diphosphatase) was assayed in rat liver homogenates with [beta-32P]ADP as substrate. The activity had a pH optimum of 8.0 and was strongly activated by Mg2+. The intracellular localization was determined by analytical subcellular fractionation with single-step sucrose-density-gradient centrifugation. Selective membrane perturbants were used to enhance the resolution of the various organelles. ADPase was localized to the mitochondria. Mitochondria were isolated by differential centrifugation and subfractionated by selective disruption of the inner and outer membranes. The intramitochondrial localization of ADPase was compared with various marker enzymes and was shown to be concentrated in the outer-membrane fractions. The effects of various inhibitors on the ADPase activity were determined and the possibility that the activity could be due to known enzyme systems was considered. It is concluded that ADP degradation is due to a hitherto unrecognized mitochondrial enzyme.


[Role of endogenous compression in the etiopathogenesis of traumatic diseases and complications].
On the basis of roentgen-anatomical examinations on 242 corpses and experiments on 70 dogs it was established that disturbances of blood circulation developed due to the endogenic compression became the leading factor in etiopathogenesis of the diseases and complications of traumas, aggravated the course and often resulted in lethal outcomes.


Helping undergraduates repair faulty mental models in the student laboratory.
Over half of the undergraduate students entering physiology hold a misconception concerning how breathing pattern changes when minute ventilation increases. Repair of this misconception was used as a measure to compare the impact of three student laboratory protocols on learning by 696 undergraduate students at 5 institutions. Students were tested for the presence of the misconception before and after performing a laboratory activity in which they measured the effect of exercise on tidal volume and breathing frequency. The first protocol followed a traditional written "observe and record" ("cookbook") format. In the second treatment group, a written protocol asked students to complete a prediction table before running the experiment ("predictor" protocol). Students in the third treatment group were given the written "predictor" protocol but were also required to verbalize their predictions before running the experiment ("instructor intervention" protocol). In each of the three groups, the number of students whose performance improved on the posttest was greater than the number of students who performed less well on the posttest (P < 0.001). Thus the laboratory protocols helped students correct the misconception. However, the remediation rate for students in the "instructor intervention" group was more than twice that observed for the other treatment groups (P < 0.001). The results indicate that laboratory instruction is more effective when students verbalize predictions from their mental models than when they only "discover" the outcome of the experiment.


Neurosteroidogenesis: relevance to neurosteroid actions in brain and modulation by psychotropic drugs.
Neurosteroids--i.e., steroid produced in brain ex novo or through metabolism of precursors--affect neuronal and brain functions through genomic and nongenomic mechanisms, depending on their molecular structure. Among neurosteroids, 3alpha-hydroxylated, 5alpha-reduced metabolites of progesterone (3alpha-hydroxy,5alpha-pregnan-20one/3alpha,5alpha-THP) and deoxycorticosterone (3alpha,21-dihydroxy,5alpha-pregnan-20one/3alpha,5alpha-THDOC) are positive allosteric modulators of gamma-aminobutyric acid (GABA) action at GABAA receptors. In rodents, a reduction of their endogenous brain concentrations rapidly lowers the potency of GABA in eliciting GABAA receptor-mediated inhibitory postsynaptic currents. This effect is related to anxiety-like behavior, increased aggression, and a reduced sensitivity to the loss of righting reflex induced by GABAA receptor agonist or positive modulators. Conversely, enhancement of 3alpha,5alpha-THP or 3alpha,5alpha-THDOC brain content results in anxiolysis, sedation/hypnosis, anticonvulsant, and anesthetic action. Different classes of psychotropic drugs--i.e., antidepressants, selected atypical antipsychotics, ethanol, gamma-hydroxybutyric acid--increase neurosteroid concentrations in brain, and these increases may be relevant to their pharmacological actions. Drug-induced increases of neurosteroids in rodent brain are often associated with elevation of their plasma content, such that alterations of plasma steroid concentrations are assumed to reflect parallel changes in brain. Nevertheless, brain neurosteroid concentrations are uneven across various regions, and the dose-dependence of their response to a pharmacological challenge shows brain-regional differences as well. These observations are consistent with the present knowledge on the distribution of steroidogenic enzymes in brain--they show not only a brain region, but also a cell-specific expression that may spatially and temporally determine the local concentrations of specific neurosteroids, either produced ex novo or through metabolism of steroid precursors that reach the brain through blood.


Role of optimal cytoreduction in patients with dysgerminoma.
Dysgerminomas are malignant ovarian germ-cell tumors that typically affect young women. Although these tumors have an excellent response to chemotherapy, surgery is an integral part of primary treatment. To evaluate outcomes of initial cytoreduction in patients diagnosed with dysgerminomas. Patients who underwent primary cytoreductive surgery for ovarian dysgerminoma between January 1985 and December 2013 were identified and included in the study. A comparison was made between patients who underwent optimal versus sub-optimal cytoreduction. Descriptive, comparative statistics and odds ratios were used to establish an association. Survival curves were performed with the Kaplan-Meier method and compared using a log-rank test. A value of p<0.05 was used to establish a statistical difference. A total of 180 patients with a histologically confirmed dysgerminoma were included in the analysis. A subsection of 37 patients in stages III/IV were analyzed. The median age at diagnosis was 21 years (IQR 18-26). Histologically, 166 (92.2%) patients had pure dysgerminomas, whereas the rest had mixed histologies. The median tumor size was 18 (IQR 12-22) cm. In all stages, factors associated with optimal cytoreduction, were higher lactate dehydrogenase levels (OR=1.01; p=0.03), higher CA125 levels (OR=1.01; p=0.04), receiving adjuvant chemotherapy (OR=0.22; p<0.01), or undergoing treatment in a specialized institution (OR=12.68; p<0.01). Patients in stages III/IV, initially managed outside our institution were less likely to be taken for cytoreduction (OR=16.88; p=0.013). Other factors, including age (OR=1.02; p=0.39), pelvic lymph-node positivity (OR=2.24; p=0.36), pregnancy during follow-up (OR=0.91: p=0.80), or recurrence of disease (OR=1.93; p=0.23) were found to be similar in both groups. Overall survival was higher in optimally cytoreducted patients (100% vs 95.7%; p=0.032) including all stages, but not if considering only stages III/IV (100% vs 90%, p=0.186); disease-free survival was the same for both groups regardless of stage (94.3% vs 91.1%; p=0.36). Patients with optimal surgeries were most likely to be treated in referral centers. Initial residual disease did not significantly alter recurrence, progression, disease-free survival, or overall survival.


The subinternship curriculum in internal medicine: a national survey of clerkship directors.
The 4th-year internal medicine subinternship (subI), with its strong emphasis on experience-based learning and increased patient responsibilities, is an important component of undergraduate medical education. Discussions have begun amongst educational leaders on the importance of standardizing curriculum and evaluation tools utilized during the subinternship. The objective of this survey was to describe the current state of educational practices regarding the subI curriculum, use of Clerkship Directors in Internal Medicine (CDIM) curricular guidelines, evaluation methodologies, and subintern call frequency and duty hours. The survey was a part of the CDIM annual survey sent to 109 institutional members in 2005. The subinternship survey included 17 questions that addressed the prevalence of formal curricula in the subinternship, use of CDIM curricular guidelines and resources, and the evaluation tools utilized for assessment of the subinternship. Two questions examined the call frequency and duty hours of the subinterns. Eighty-eight members responded (81%). Of the respondents, 37% have a formal curriculum and 35% used CDIM curricular guidelines for the subinternship. More than half of the respondents agreed that the curricular guide helped organize their subI rotations (53%), and 48% agreed that it enhanced the quality of subI education. A global rating summative evaluation form (56%) was the most commonly used evaluation tool in the subinternship. Objective Structured Clinical Examinations (1%) and Mini-Clinical Evaluation Exercise (mini-CEX)(2%) were much less utilized during the subinternship. The respondents expressed an interest in the development of a standardized exam (47%) and clinical assessment tools such as the mini-CEX (59%). The vast majority of IM subinterns participate in 3 to 9 calls per rotation and spend less than 80 hr in the hospital per week. A formal curriculum is offered in slightly more than one third of subIs. Clerkship directors expressed interest in developing standardized evaluation tools to assess subintern competencies. The majority of IM subinterns spend less than 80 hr in the hospital per week. Further studies are needed to assess barriers to incorporating a formal curriculum and develop standardized tools to assess subintern competencies.


[Disorders of the ventilation-diffusion correlations and of the gas-transport function of the blood in the acute period of burn trauma in children].
External respiration and blood gas composition were examined in 187 children aged 1 to 14 years during the acute period of burn disease (burn shock and toxemia). The patients were divided into three groups with different area of thermal injury to the skin. Group 1 were children with burns of up to 10% of body surface area. The ventilation parameters in this group were changed just negligibly, and the diffusion capacity of the lungs and gas composition of arterial blood were within the normal range of values both during shock and toxemia. In patients with burns involving 11 to 20% of body surface the ventilation parameters were changed appreciably and did not compensate for each other, as was observed in group 1. The diffusion capacity of the lungs and blood gas composition values were moderately decreased. During toxemia the minute-consumption of oxygen was decreased and alveolar oxygen tension remained unchanged. As a result of this, the diffusion capacity of the lungs and blood gas parameters continued to decrease. The most dynamic changes were observed in children with burns involving 21 to 45% of body surface. The ventilation-diffusion disorders and blood gas composition were altered, particularly so during toxemia; the changes consisted in a decrease of the minute ventilation volume and oxygen tension in arterial blood and a moderate increase of alveolar oxygen tension, which led to further decrease of the diffusion capacity of the lungs. In parallel with the disorders in the above parameters, x-ray changes in the lungs were observed, which were characterized by a vascular-interstitial pattern in group 2 and infiltrative changes in group 3. In children with burn wounds of 35 to 45% of body surface these changes presented as the developing lung edema.


Small molecule proprotein convertase inhibitors for inhibition of embryo implantation.
Uterine proprotein convertase (PC) 6 plays a critical role in embryo implantation and is pivotal for pregnancy establishment. Inhibition of PC6 may provide a novel approach for the development of non-hormonal and female-controlled contraceptives. We investigated a class of five synthetic non-peptidic small molecule compounds that were previously reported as potent inhibitors of furin, another PC member. We examined (i) the potency of these compounds in inhibiting PC6 activity in vitro; (ii) their binding modes in the PC6 active site in silico; (iii) their efficacy in inhibiting PC6-dependent cellular processes essential for embryo implantation using human cell-based models. All five compounds showed potent inhibition of PC6 activity in vitro, and in silico docking demonstrated that these inhibitors could adopt a similar binding mode in the PC6 active site. However, when these compounds were tested for their inhibition of decidualization of primary human endometrial stromal cells, a PC6-dependent cellular process critical for embryo implantation, only one (compound 1o) showed potent inhibition. The lack of activity in the cell-based assay may reflect the inability of the compounds to penetrate the cell membrane. Because compound's lipophilicity is linked to cell penetration, a measurement of lipophilicity (logP) was calculated for each compound. Compound 1o is unique as it appears the most lipophilic among the five compounds. Compound 1o also inhibited another crucial PC6-dependent process, the attachment of human trophoblast spheroids to endometrial epithelial cells (a model for human embryo attachment). We thus identified compound 1o as a potent small molecule PC6 inhibitor with pharmaceutical potential to inhibit embryo implantation. Our findings also highlight that human cell-based functional models are vital to complement the biochemical and in silico analyses in the selection of promising drug candidates. Further investigations for compound 1o are warranted in animal models to test its utility as an implantation-inhibiting contraceptive drug.


Effects of cycloartenol on absorption and serum levels of cholesterol in rats.
The possibility that cycloartenol magnifies the hypocholesterolemic effect of beta-sitosterol was studied in two strains of rats fed on cholesterol-enriched (0.5%) diets. Cycloartenol was added to diets containing 1.0% or 0.5% beta-sitosterol at the 0.05% level and to diet free of plant sterol at the 0.5% level. In one experiment, diets included sodium cholate (0.125%). Due to the potent hypocholesterolemic efficacy of beta-sitosterol under the present dietary regimens, no clear additional effect (so-called synergistic effect) of cycloartenol was observed. However, in the experiment using Wistar rats, the decrease in serum apo A-I due to feeding cholesterol was ameliorated more effectively in combination with beta-sitosterol than with beta-sitosterol alone. The hepatic deposition of cholesterol was mitigated by dietary beta-sitosterol, and further, although slightly, by a combination of beta-sitosterol and cycloartenol, except in the experiment with diets containing sodium cholate. Fecal excretion of neutral and acidic steroids was not meaningly magnified by cycloartenol. Cycloartenol itself was not as effective as beta-sitosterol in mitigating lipid disorders due to dietary cholesterol. The rate of appearance of cholesterol in the thoracic duct lymph was not interfered with further by a combination of beta-sitosterol and cycloartenol compared to beta-sitosterol alone. This trimethylsterol was absorbed at a rate approximately 4-fold higher than that of beta-sitosterol, though much lower compared to cholesterol. These results suggest a preference for cycloartenol in cholesterol dynamics. However, cycloartenol seems unlikely to influence cholesterol absorption in the small intestine.


Neither n-3 Long-Chain PUFA Supplementation of Mothers through Lactation nor of Offspring in a Complementary Food Affects Child Overall or Social-Emotional Development: A 2 × 2 Factorial Randomized Controlled Trial in Rural Ethiopia.
The n-3 (ω-3) long-chain polyunsaturated fatty acid (LC-PUFA) docosahexaenoic acid (DHA) is essential for optimal brain development. There is a lack of evidence on the effect of postnatal n-3 LC-PUFA supplementation on child development in low-income countries. We evaluated the efficacy of fish-oil supplementation through lactation or complementary food supplementation on the development of children aged 6-24 mo in rural Ethiopia. We conducted a double-blind randomized controlled trial of n-3 LC-PUFA supplementation for 12 mo using fish-oil capsules [maternal intervention: 215 mg DHA + 285 mg eicosapentaenoic acid (EPA)] or a fish-oil-enriched complementary food supplement (child intervention: 169 mg DHA + 331 mg EPA). In total, 360 pairs of mothers and infants aged 6-12 mo were randomly assigned to 4 arms: maternal intervention and child control, child intervention and maternal control, maternal and child intervention, and maternal and child control. Primary outcomes were overall developmental performance with the use of a culturally adapted Denver II test that assesses personal-social, language, fine-motor, and gross-motor domains and social-emotional developmental performance using the Ages and Stages Questionnaire: Social Emotional at baseline and at 6 and 12 mo. We used mixed-effects models to estimate intervention effects on developmental performance over time (intervention × time interaction). The evolution in overall and social-emotional developmental performance over time did not differ across study arms (intervention × time: F = 1.09, P = 0.35, and F = 0.61, P = 0.61, respectively). Effects did not change after adjustment for child age, birth order, and nutritional status; maternal age and education; wealth; family size; and breastfeeding frequency. Children's developmental performance significantly decreased during study follow-up (β: -0.03 SDs/mo; 95% CI: -0.04, -0.01 SD/mo; P < 0.01). n-3 LC-PUFA supplementation does not affect overall or social-emotional development of children aged 6-24 mo in a low-income setting. Follow-up of the cohort is recommended to determine whether there are long-term effects of the intervention. This trial was registered at clinicaltrials.gov as NCT01817634.


Single-Stranded DNA-Binding Transcriptional Regulator FUBP1 Is Essential for Fetal and Adult Hematopoietic Stem Cell Self-Renewal.
The ability of hematopoietic stem cells (HSCs) to self-renew is a prerequisite for the establishment of definitive hematopoiesis and life-long blood regeneration. Here, we report the single-stranded DNA-binding transcriptional regulator far upstream element (FUSE)-binding protein 1 (FUBP1) as an essential factor of HSC self-renewal. Functional inactivation of FUBP1 in two different mouse models resulted in embryonic lethal anemia at around E15.5 caused by severely diminished HSCs. Fetal and adult HSCs lacking FUBP1 revealed an HSC-intrinsic defect in their maintenance, expansion, and long-term blood reconstitution, but could differentiate into all hematopoietic lineages. FUBP1-deficient adult HSCs exhibit significant transcriptional changes, including upregulation of the cell-cycle inhibitor p21 and the pro-apoptotic Noxa molecule. These changes caused an increase in generation time and death of HSCs as determined by video-microscopy-based tracking. Our data establish FUBP1 and its recognition of single-stranded genomic DNA as an important element in the transcriptional regulation of HSC self-renewal.


Dynamic interaction between caudate nucleus and hypothalamus.
Continuous low frequency stimulation of the caudate nucleus by constant parameters leads to the appearance of a characteristic "caudate spindle" as well as other "inhibitory" electrophysiological responses (single unit activity intracellular recordings) varying in duration and amplitude in the cerebral cortex. Computerized data processing of the responses (amplitude and duration of individual spindles, numbers of single unit blocking and sizes of EPSP and IPSP) indicated increments and decrements appearing in stable and characteristic sequences. The same low frequency caudate stimulation produces fast bursts in the course of continuous stimulation. The variations and dynamic patterns of inhibitory caudate influences upon the cortex seem to be in equilibrium with the excitatory influences from the hypothalamus representing a unique regulatory system.


Efficacy of intermittent versus daily vitamin D supplementation on improving circulating 25(OH)D concentration: a Bayesian network meta-analysis of randomized controlled trials.
Vitamin D deficiency is a widespread issue globally, resulting in increased use of vitamin D supplements. However, it is unclear whether intermittent (weekly or monthly) vitamin D supplementation is as effective as daily supplementation in improving circulating 25-hydroxyvitamin D [25(OH)D] levels. Three databases including Medline, EMBASE, and the Cochrane Library were systematically searched up to 10 November 2020. The risk of bias was evaluated according to Cochrane Collaboration's tool for rating methodological quality assessment. Direct and indirect comparisons between interventions and controls were performed by a Bayesian network meta-analysis (NMA), where the mean difference (MD) and its 95% confidence interval (CI) were used to indicate the efficacy. This NMA analysis included 116 RCTs with a total of 11,376 participants. Generally, we observed that 25(OH)D concentrations were significantly elevated regardless of vitamin D supplementation frequency. Although the findings of SUCRA indicated that daily vitamin D supplementation had a higher rank value than intermittent supplementation when the supplement dosage was similar, no statistically significant pooled mean differences of 25(OH)D concentration were noted between the daily supplementation group and intermittent supplementation group. Additionally, weekly supplementation with a total of 600,000 IU vitamin D supplementation during 3 months had the best efficacy in elevating 25(OH)D concentration (pooled MD = 63 nmol/L, 95%CI: 49-77). To achieve optimal 25(OH)D concentration (>75 nmol/L), we recommend 60,000 IU vitamin D supplementation monthly (~2,000 IU/day). The efficacy of intermittent vitamin D supplementation was similar to daily supplementation. Coupled with its convenience, the frequency and dosage of intermittent vitamin D supplements were recommended to reach the optimal 25(OH)D level.Systematic review registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=257257, PROSPERO CRD42021257257.


Machine Learning Approach for Pitch Type Classification Based on Pelvis and Trunk Kinematics Captured with Wearable Sensors.
The large stream of data from wearable devices integrated with sports routines has changed the traditional approach to athletes' training and performance monitoring. However, one of the challenges of data-driven training is to provide actionable insights tailored to individual training optimization. In baseball, the pitching mechanics and pitch type play an essential role in pitchers' performance and injury risk management. The optimal manipulation of kinematic and temporal parameters within the kinetic chain can improve the pitcher's chances of success and discourage the batter's anticipation of a particular pitch type. Therefore, the aim of this study was to provide a machine learning approach to pitch type classification based on pelvis and trunk peak angular velocity and their separation time recorded using wearable sensors (PITCHPERFECT). The Naive Bayes algorithm showed the best performance in the binary classification task and so did Random Forest in the multiclass classification task. The accuracy of Fastball classification was 71%, whilst the accuracy of the classification of three different pitch types was 61.3%. The outcomes of this study demonstrated the potential for the utilization of wearables in baseball pitching. The automatic detection of pitch types based on pelvis and trunk kinematics may provide actionable insight into pitching performance during training for pitchers of various levels of play.


Soil type recognition as improved by genetic algorithm-based variable selection using near infrared spectroscopy and partial least squares discriminant analysis.
Soil types have traditionally been determined by soil physical and chemical properties, diagnostic horizons and pedogenic processes based on a given classification system. This is a laborious and time consuming process. Near infrared (NIR) spectroscopy can comprehensively characterize soil properties, and may provide a viable alternative method for soil type recognition. Here, we presented a partial least squares discriminant analysis (PLSDA) method based on the NIR spectra for the accurate recognition of the types of 230 soil samples collected from farmland topsoils (0-10 cm), representing 5 different soil classes (Albic Luvisols, Haplic Luvisols, Chernozems, Eutric Cambisols and Phaeozems) in northeast China. We found that the PLSDA had an internal validation accuracy of 89% and external validation accuracy of 83% on average, while variable selection with the genetic algorithm (GA and GA-PLSDA) improved this to 92% and 93%. Our results indicate that the GA variable selection technique can significantly improve the accuracy rate of soil type recognition using NIR spectroscopy, suggesting that the proposed methodology is a promising alternative for recognizing soil types using NIR spectroscopy.


Horizontal body and trunk center of mass offset and standing balance in scoliotic girls.
In adolescent idiopathic scoliotic girls, postural imbalance is attributed to a sensory rearrangement of the motor system on the representation of the body in space. The objectives of this study were to test if the anteroposterior (AP), mediolateral (ML) and resultant body-head and trunk center of mass (COM) horizontal offsets were similar in able-bodied and scoliotic girls and if these offsets were related to the center of pressure displacements. A total of 21 adolescent idiopathic scoliosis girls and 20 able-bodied girls participated in this study. Their body COM position and that of the head and trunk were estimated according to Damavandi et al. (Med Eng Phys 31:1187-1194, 2009). The COP range and speed in both AP and ML axes were calculated from force plate measurements in quiet standing. The AP offset of the able-bodied group was anterior to the body COM by 11.0 ± 15.9 mm, while that of the scoliotic group was posterior to it by -17.3 ± 11.2 mm. The able-bodied group maintained their head-trunk segment COM more to the right by 14.1 ± 13.1 mm, while that of the scoliotic group was nearly over their body centerline. The scoliotic girls presented higher values for COP range and COP speed than the able-bodied girls. The resultant COM offset was correlated with both the ML COP range and speed only for the scoliotic girls. The small ML COM offset in the scoliotic girls was attributed to a compensatory action of the spinal deformity in the frontal plane resulting in a backward resultant COM offset to regain postural balance concomitant to an increase in the ML neuromuscular demand.


Effect of different surface and heat treatments on the surface roughness, crystallography, and phase composition of high translucency zirconia for monolithic restorations.
High translucency zirconia (HTZ) has gained popularity as an esthetic computer-aided design and computer-aided manufacturing (CAD-CAM) material for monolithic restorations. A detailed comparison between different common surface and heat treatments with a non-treated HTZ control to explain the behavior of the material under stress is lacking. The purpose of this in vitro study was to evaluate the effect of different surface and heat treatments on the surface roughness parameters (SRPs), topography, crystallography, and phase composition of HTZ used for monolithic restorations. Ninety Ø11.9×1.18-mm HTZ disks (Prettau Anterior) were milled, sintered, and distributed into 9 groups (n=10); 8 experimental (coarse diamond grinding GC, fine diamond grinding GF, fine diamond grinding and 3-step polishing kit GF+P1, fine diamond grinding and 3-step polishing kit and diamond paste GF+P1+DP, fine diamond grinding and 2-step polishing kit GF+P2, fine diamond grinding and GF+Gl, fine diamond grinding and 3-step polishing and glazing GF+P1+Gl, airborne-particle abrasion with 50-µm alumina), and a control group (C, as-sintered). SRPs (AveSa, AveSv, AveSz) and 3-dimensional (3D) images were obtained using a noncontact 3D-optic-profilometer. The crystal structure was determined with scanning electron microscopy. Phase composition was analyzed by X-ray diffraction (XRD). Surface roughness parameters data were statistically analyzed by 1-way ANOVA and the Tukey HSD test (α=.05). The applied surface and heat treatment resulted in significantly different SRP mean values (P<.001) with different topographies. GC had the highest AveSa, AveSv, and AveSz mean values (0.95, 8.8, 17.4 µm, respectively) with significant microcracks. GF had significantly lower SRP with finer microcracks. GF+P1 had a significantly smoother surface, but GF+P2 resulted in SRP comparable with the GF group. GF+P1+DP had the smoothest homogenous surface (mean Sa: 0.08 µm). GF+P1 and GF+GL were equally effective, while GF+P1+GL was not superior. Airborne-particle abrasion produced a low Sa mean value (0.11 µm) with relatively high Sv and Sz mean values (5.9, 9.2 µm, respectively) and microcracks. A monoclinic phase was detected in all groups. All experimental groups had broadened XRD-peaks with lower intensity, suggesting the presence of the rhombohedral phase. The different surface and heat treatments altered the HTZ crystals and their surface roughness with distinct topographies. Cubic crystal changes take place under stress as shown by the scanning electron microscope and the XRD diffraction pattern and may transform to the rhombohedral phase.


Effect of different doses of folic acid on serum homocysteine level in patients on hemodialysis.
Hyperhomocysteinemia is common in patients with end-stage renal disease. It is one of the risk factors for cardiovascular disease. We evaluated the effect of different doses of folic acid on serum homocysteine level in patients on hemodialysis. Patients on maintenance hemodialysis were randomized into 4 groups to receive oral folic acid at doses of 2, 5, 10, and 15 mg/d, each for a period of 4 weeks. Serum homocysteine level was measured in all of the patients before and at the end of each week of therapy. Folic acid supplementation was discontinued during a washout period of 1 week between each of the four phases of the trial. Thirty-one hemodialysis patients completed the four phases of treatment with each dose of folic acid (17 women and 14 men). The mean age of patients was 57.6 ± 14.6 years. Serum homocysteine level was reduced significantly compared to its basal level after treatment with folic acid at different doses (P < .001). Different doses of folic acid were not significantly different in lowering serum homocysteine levels. Our study failed to show any difference between high-dose and low-dose folic acid therapy regarding their effect on serum homocysteine level. It seems folic acid, 2 mg/d, is an adequate dose, and there is no need to administer a higher dose of it.


Guest authors or ghost inventors? Inventorship and authorship attribution in academic science.
Authorship and inventorship are the key attribution rights that contribute to a scientist's reputation and professional achievement. This article discusses the concepts of coinventorship and coauthorship in the legal and sociological literature, as well as journals' publication guidelines and technology transfer offices' recommendations. It discusses also the relative importance of social and legal norms in the allocation of scientific credit. This article revises critically the literature on inventorship and authorship in academic science and derives some policy implications on the institutional mechanisms allocating scientific credit. It reports and assesses the recent empirical evidence on the importance of social norms for the attribution of inventorship and authorship in teams of scientists. Finally, it discusses those norms from a social welfare perspective. The social norms that regulate the distribution of authorship and inventorship do not reflect exclusively the relative contribution of each team member but also the members' relative seniority or status. In the case of inventorship, such social norms appear to be as important as the legal norms whose respect is often invoked by technology transfer officers. Authorship and inventorship appear to be obsolete because they do not capture the increasing division of labor and responsibility typical of contemporary scientific research teams. The informative value of both authorship and inventorship attributions may be much more limited than assumed by recent evaluation exercises.


Transdiagnostic Risk and Protective Factors for Psychopathology in Young People: Systematic Review Protocol.
Mental and substance use disorders are among the leading causes of burden of disease worldwide, with risk of onset peaking between the ages of 13 and 24 years. Comorbidity is also common among young people and complicates research, diagnosis and assessment, and clinical decision making. There is increasing support for empirically derived models of psychopathology that overcome issues of comorbidity and provide a transdiagnostic framework for investigating the specificity and generality of risk and protective factors for psychopathology. This systematic review aims to identify transdiagnostic risk and protective factors for psychopathology in young people by synthesizing and evaluating findings from research investigating empirically based models of psychopathology. Searches will be conducted in Medline, EMBASE, and PsycINFO databases. Reference lists of selected articles will also be hand searched for other relevant publications. All studies will be screened against eligibility criteria designed to identify studies that examined empirical models of psychopathology in relation to risk and/or protective factors in young people with a mean age between 10 and 24 years. Study quality will be assessed using the Joanna Briggs Institute Critical Appraisal Checklists for Cohort Studies and Analytical Cross-Sectional Studies. Findings will be summarized in a narrative synthesis, and a meta-analysis will be conducted if sufficient data are available. This review is ongoing. At the time of submission, full-text screening was completed, and hand searching of selected articles was underway. Results are expected to be completed by the end of 2020. This protocol is for a systematic review of evidence for transdiagnostic risk and protective factors associated with empirically based models of psychopathology in young people. To our knowledge, the critical synthesis of this evidence will be the first to date and will provide a better understanding of the factors that contribute to the onset and maintenance of psychopathology in young people. Insights drawn from the review will provide critical new knowledge to improve the targeting of interventions to prevent or reduce mental health problems. This systematic review is registered with PROSPERO (CRD42020161368) and is available via Open Science Framework. DERR1-10.2196/19779.


Comparison between Oligoryzomys nigripes and O. flavescens by RAPD and genetic diversity in O. nigripes (Rodentia, Cricetidae).
The genus of Oligoryzomys includes species of small size, morphologically similar, which may impede taxonomic identification, mainly between O. flavescens (Waterhouse, 1837) and O. nigripes (Olfers, 1818). The main objective of this work was to investigate whether the RAPD markers are capable of genetically differentiating the specimens O. nigripes and O. flavescens, coming from Rio Grande do Sul (RS) and Santa Catarina (SC) states, and also to estimate the genetic variability among populations of O. nigripes, with the Uruguay River as a geographical barrier. For this purpose, samples were collected in fragments of forests situated in the North of RS, at FLONA (Floresta Nacional de Passo Fundo) and in fragments from SC, close to the Uruguay River. The karyotyping of two samples for each species was carried out and compared using the RAPD technique together with non- karyotyped individuals. Samples of O. nigripes presented 2n = 62; NA = 82, with submetacentric arms on the largest chromosomes, while samples of O. flavescens showed 2n = 64; NA = 66, with the largest chromosomes presenting acrocentric morphology, making such a result the main difference between the species. The analysis was able to detect two distinct groups, being the first one with karyotyped O. flavescens and the second with karyotyped O. nigripes. Identification afforded 211 loci, among them 181 (85.78%) polymorphic. The Jaccard similarity coefficient was in the range of 0.45 to 0.87. The UPGMA and Main Coordinate Analysis techniques demonstrated the existence of heterogeneous genetics among populations, but did not separate them completely in terms of geographical standards, and they are not influenced by the Uruguay River, which did not act as an efficient barrier.


IL-1, IL-2 and IFN-gamma production by Theiler's virus-induced encephalomyelitic SJL/J mice.
Interleukins have been postulated to exert an important modulatory and recruiting role in the Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination of the central nervous system (CNS) in SJL/J mice. Using bio- and radioimmunoassays, we have detected and quantified some of the interleukins suspected to play a role in this immune-mediated process. The interleukins 1 and 2 (IL-1, IL-2) and interferon-gamma (IFN-gamma) have been measured in homogenates from the CNS and sera from infected animals, as well as in supernatants from antigen-specific in vitro-stimulated spleen and meningeal cells. IL-1 was detected both in CNS tissue homogenates (approximately 20-40 fmol/ml) and in splenic cultures (200 U/ml). IL-2 was detected only after TMEV-specific antigenic stimulation in spleen cultures (approximately 120 U/ml). In vitro, IL-2 and IL-1 synthesis appear in a dose- and time-dependent manner. IFN-gamma could not be found in any case. The precise nature of IL-1 and IL-2 activity was further assessed by HPLC. The above results strongly indicate the presence of functionally active macrophages in the CNS infiltrates of cells triggering this autoaggressive immune process. In addition, we propose a central role for IL-1 in augmenting the intracerebral immune response leading to the inflammatory demyelination induced by TMEV.


Chronic Sclerosing Osteomyelitis of the Mandible Treated with Hemimandibulectomy and Fibular Free Flap Reconstruction.
Primary chronic osteomyelitis of the mandible is a rare condition that presents with a long-standing chronic facial swelling over the mandible, pain with mastication, and trismus. With no clinically appreciated acute phase, the aetiology often remains unknown. Many patients achieve adequate symptom control with broad-spectrum antibiotics, hyperbaric oxygen therapy and surgical debridement, or decortication of bone sequestration. However, because of the rarity of primary chronic osteomyelitis and the extensive involvement of the mandible that can result, we present a case of a 32-year-old woman with chronic disease of the left mandible requiring a left hemimandibulectomy and fibular free flap reconstruction. Few such cases have been reported in the literature, which require such extensive resection and reconstruction to control long-standing symptoms.


Heart Failure Increases the Risk of Adverse Renal Outcomes in Patients With Normal Kidney Function.
Heart failure (HF) is associated with poor cardiac outcomes and mortality. It is not known whether HF leads to poor renal outcomes in patients with normal kidney function. We hypothesized that HF is associated with worse long-term renal outcomes. Among 3 570 865 US veterans with estimated glomerular filtration rate (eGFR) ≥60 mL min-1 1.73 m-2 during October 1, 2004 to September 30, 2006, we identified 156 743 with an International Classification of Diseases, Ninth Revision, diagnosis of HF. We examined the association of HF with incident chronic kidney disease (CKD), the composite of incident CKD or mortality, and rapid rate of eGFR decline (slopes steeper than -5 mL min-1 1.73 m-2 y-1) using Cox proportional hazard analyses and logistic regression. Adjustments were made for various confounders. The mean±standard deviation baseline age and eGFR of HF patients were 68±11 years and 78±14 mL min-1 1.73 m-2 and in patients without HF were 59±14 years and 84±16 mL min-1 1.73 m-2, respectively. HF patients had higher prevalence of hypertension, diabetes mellitus, cardiac, peripheral vascular and chronic lung diseases, stroke, and dementia. Incidence of CKD was 69.0/1000 patient-years in HF patients versus 14.5/1000 patient-years in patients without HF, and 22% of patients with HF had rapid decline in eGFR compared with 8.5% in patients without HF. HF patients had a 2.12-, 2.06-, and 2.13-fold higher multivariable-adjusted risk of incident CKD, composite of CKD or mortality, and rapid eGFR decline, respectively. HF is associated with significantly higher risk of incident CKD, incident CKD or mortality, and rapid eGFR decline. Early diagnosis and management of HF could help reduce the risk of long-term renal complications.


Successful salvage using combined radiation and ABMT for patients with recurrent CNS NGGCT following failed initial transplant.
Intracranial germ cell tumours (GCTs) are a rare and diverse group of tumours. Histology determines the type of treatment, natural history and prognosis. Germinoma GCTs account for the majority and are very radiosensitive. Conversely, non-germinoma GCTs (NGGCTs) are heterogeneous, relatively radioresistant and have a high risk of relapse despite multimodality therapy. Treatment of recurrence in these patients remains a therapeutic challenge. In this report we review the current literature for treatment of recurrent NGGCTs and present a case of recurrent NGGCT who relapsed despite autologous stem cell transplant (ASCT). The patient was successfully cured using multimodality therapy, consisting of repeat ASCT, intensity modulated radiation therapy and stereotactic radiosurgery.


Improvements in three-dimensional back contour after spinal fusion for idiopathic scoliosis.
Quantec raster stereography has been recognized as an accurate and reliable tool for evaluating back contour and posterior truncal rotation in patients with scoliosis. In this prospective study, 35 patients with adolescent idiopathic scoliosis underwent both spinal radiography and Quantec three-dimensional evaluation of their idiopathic scoliosis before and after surgical intervention, consisting of anterior and/or posterior spinal fusion, with or without thoracoplasty. Comparison of established key parameters showed significant improvement in thoracic and thoracolumbar Cobb angle, as well as Quantec Q-angle. Thoracic rotation, Suzuki rib hump sum, and posterior trunk asymmetry also improved due to spinal fusion.


Serial Lactic Dehydrogenase Activity in Plasma of Mice with Growing or Regressing Tumors.
Close correlation has been observed between the serially tested plasma level of a glycolytic enzyme, lactic dehydrogenase, and the growth of several transplanted mouse tumors. The character of the lactic dehydrogenase curve determined by serial blood sampling of the animals during the development of such tumors is found to consist of five separate phases. The first three appear before any visible evidence of tumor growth. Inhibition or regression of tested tumors, induced by therapeutic compounds, was accurately reflected in a corresponding reduction of lactic dehydrogenase activity in the peripheral plasma of the host.


A muscle growth-promoting treatment based on the attenuation of activin/myostatin signalling results in long-term testicular abnormalities.
Activin/myostatin signalling acts to induce skeletal muscle atrophy in adult mammals by inhibiting protein synthesis as well as promoting protein and organelle turnover. Numerous strategies have been successfully developed to attenuate the signalling properties of these molecules, which result in augmenting muscle growth. However, these molecules, in particular activin, play major roles in tissue homeostasis in numerous organs of the mammalian body. We have recently shown that although the attenuation of activin/myostatin results in robust muscle growth, it also has a detrimental impact on the testis. Here, we aimed to discover the long-term consequences of a brief period of exposure to muscle growth-promoting molecules in the testis. We demonstrate that muscle hypertrophy promoted by a soluble activin type IIB ligand trap (sActRIIB) is a short-lived phenomenon. In stark contrast, short-term treatment with sActRIIB results in immediate impact on the testis, which persists after the sessions of the intervention. Gene array analysis identified an expansion in aberrant gene expression over time in the testis, initiated by a brief exposure to muscle growth-promoting molecules. The impact on the testis results in decreased organ size as well as quantitative and qualitative impact on sperm. Finally, we have used a drug-repurposing strategy to exploit the gene expression data to identify a compound - N6-methyladenosine - that may protect the testis from the impact of the muscle growth-promoting regime. This work indicates the potential long-term harmful effects of strategies aimed at promoting muscle growth by attenuating activin/myostatin signalling. Furthermore, we have identified a molecule that could, in the future, be used to overcome the detrimental impact of sActRIIB treatment on the testis.


Differential effects of acute stress on spatial learning and memory in the open-field tower maze across the female estrous cycle.
The purpose of the present investigation was to test how acute stress and levels of circulating estrogens together influence acquisition and retention of spatial learning, as well as explorative behaviors in female rats. We used the hippocampus-dependent Open-field Tower Maze (OFTM) task to assess acquisition followed by a retention test (reacquisition) that was given 48 h later. Immediately prior to acquisition, experimental rats were exposed to an acute restraint stress and were trained under bright lights. Female rats' estrous cycles were tracked throughout training and testing. Exposure to stress did not affect learning when levels of estrogens were low (i.e., during estrus and metestrus). However, acute stress exposure significantly lowered spatial acquisition of the female rats in the phases with rising levels of estrogens (i.e., during diestrus and proestrus). Furthermore, this stress-induced diminishment during acquisition was evident at the beginning of the retention without any presentation of stress. The present findings provide insight about the interactive relationship between stress and sex hormones on cognitive functions.


Early-adult development in the medical student.
This report focuses on young-adult development as it pertains to medical students. After a brief review of Erikson's developmental tasks, this article examines medical school stresses and pressures that impede attainment of these tasks. Medical school itself is also viewed within an Eriksonian framework, with each year presenting a series of developmental tasks that the student must overcome. The unique stresses of women medical students are also examined. Suggestions for prevention and intervention are proffered.


Dynamic vs static ABCG2 inhibitors to sensitize drug resistant cancer cells.
Human ABCG2, a member of the ATP-binding cassette transporter superfamily, plays a key role in multidrug resistance and protecting cancer stem cells. ABCG2-knockout had no apparent adverse effect on the development, biochemistry, and life of mice. Thus, ABCG2 is an interesting and promising target for development of chemo-sensitizing agents for better treatment of drug resistant cancers and for eliminating cancer stem cells. Previously, we reported a novel two mode-acting ABCG2 inhibitor, PZ-39, that induces ABCG2 degradation in addition to inhibiting its activity. In this manuscript, we report our recent progresses in identifying two different groups of ABCG2 inhibitors with one inhibiting only ABCG2 function (static) and the other induces ABCG2 degradation in lysosome in addition to inhibiting its function (dynamic). Thus, the inhibitor-induced ABCG2 degradation may be more common than we previously anticipated and further investigation of the dynamic inhibitors that induce ABCG2 degradation may provide a more effective way of sensitizing ABCG2-mediated MDR in cancer chemotherapy.


The Impact of COVID-19-based Suspension of Surgeries on Plastic Surgery Practices: A Survey of ACAPS Members.
The coronavirus disease 2019 (COVID-19) pandemic led to a drastic decline in the number of elective surgeries performed in the United States. Many national societies and local governments provided recommendations for surgeons to initially suspend and progressively resume elective surgery. The authors used a survey to the American Council of Academic Plastic Surgeons (ACAPS) to assess the effect on plastic surgeons. An electronic survey questionnaire was distributed to 532 members of ACAPS. Data on individual and plastic surgery practice demographics, COVID-19 prevention measures, and procedures or services that were being performed or delayed were collected and analyzed. An estimated 161 members (30.2%) completed the survey. Changes in hospital policy were cited as the most common reason (89%) for determining which procedures were currently offered. Results vary by specialty. Notably, <10% of respondents who normally offered aesthetic procedures currently offered any procedures during the survey. Subspecialty-specific results and prevention measures when seeing clinic patients are further summarized and discussed. Plastic surgeons have seen a drastic decrease in the variety of procedures and services they are allowed to offer during the COVID-19 pandemic. To help plan a return to normalcy, surgeons should create and implement plans to protect patients and staff from coronavirus transmission, assure financial solvency, and consider the effects of delayed surgeries on both the physical and mental health of their patients. In doing so, surgeons and their patients will be better prepared in the event of a resurgence of the virus.


[Microsurgical operations on the nerves].
Employment of microsurgical methods in operations on nerves seems to be essential and inevitable, but it is delayed due to defects in the appropriate apparatus. Microphotography of cross sections of the nerve is absolutely necessary for the well-grounded prognosis and estimation of the results of treatment. The degree of freshening of nerve endings gained during surgery is mostly conditioned by the gravity and extent of intratruncal changes in the nerve. A precise passing of sutures through the epineurium and the corresponding juxtaposition of bundles, especially in joining fine nerves, is most reliably provided by operations with the use of an operative microscope.


Somatotopic mapping of the primary motor cortex in humans: activation studies with cerebral blood flow and positron emission tomography.
1. The somatotopic representation of the human primary motor cortex was examined noninvasively with estimates of cerebral blood flow (CBF) obtained with positron emission tomography. Twelve normal subjects performed a motor tracking task with the arm, first finger, tongue, and great toe commensurate with the bolus injection of radioactive H215O. Images of the relative percent increase of blood flow, compared with control studies, demonstrated reproducible foci of CBF increases in the motor cortex in every subject. Each motor task could be localized to a predictable site on a coronal section containing the precentral gyrus. 2. In reproducibility experiments of repeated measures, it was determined that two foci of activation in the primary motor cortex could be discriminated with a 95% confidence if they were separated by 5.4 mm. 3. In five subjects with matched magnetic resonance imaging studies, the sites of activation were variable with respect to surface anatomy and could be found at the depth of sulci or the surface of gyri. The findings were similar to previously reported electrophysiological studies using direct cortical stimulation. 4. The method may be applied to the in vivo functional mapping of the primary motor cortex in patients with cerebral disorders.


Anti‑lung cancer effect of glucosamine by suppressing the phosphorylation of FOXO.
Lung cancer is the most common cause of cancer‑associated mortality worldwide, and glucosamine has the potential to exhibit antitumor activity. To reveal its anti‑lung cancer mechanism, the present study investigated the effect of glucosamine on the transcriptional activity of forkhead box O (FOXO)1 and FOXO3, and associated signal transduction pathways in A549 cells. An MTT assay was performed to investigate cell viability and immunoblotting was performed to detect protein levels of FOXO1/3, phosphorylated (p)‑FOXO1/3, AKT, p‑AKT, extracellular signal‑regulated kinase (ERK) and p‑ERK, and the levels of β‑O‑linked N‑acetylglucosamine (O‑GlcNAc)‑modified FOXO1 protein. Immunoprecipitation was performed to purify O‑GlcNAc‑modified protein prior to immunoblotting. Glucosamine inhibited FOXO1‑ and FOXO3‑specific amino acid phosphorylation, which was correlated with its translocation from the nucleus to cytoplasm, indicating a possible anti‑lung cancer mechanism of glucosamine. The present study also examined the phosphoinositide 3‑kinase (PI3K)/AKT and mitogen‑activated protein kinase (MAPK)/ERK pathways, which induce FOXO1‑ and FOXO3‑specific site phosphorylation. The data showed that glucosamine suppressed the translocation of FOXO from the cytoplasm to the nucleus via glucosamine‑induced O‑GlcNAc modification. These observations suggested that glucosamine modulated A549 cell proliferation, possibly via O‑GlcNAc modification‑induced downregulation of the PI3K/AKT and MAPK/ERK pathways and their downstream signaling molecules, FOXO1 and FOXO3.


Patients with Fabry Disease after Enzyme Replacement Therapy Dose Reduction and Switch-2-Year Follow-Up.
Because of the shortage of agalsidase-β supply between 2009 and 2012, patients with Fabry disease either were treated with reduced doses or were switched to agalsidase-α. In this observational study, we assessed end organ damage and clinical symptoms with special focus on renal outcome after 2 years of dose-reduction and/or switch to agalsidase-α. A total of 89 adult patients with Fabry disease who had received agalsidase-β (1.0 mg/kg body wt) for >1 year were nonrandomly assigned to continue this treatment regimen (regular-dose group, n=24), to receive a reduced dose of 0.3-0.5 mg/kg and a subsequent switch to 0.2 mg/kg agalsidase-α (dose-reduction-switch group, n=28), or to directly switch to 0.2 mg/kg agalsidase-α (switch group, n=37) and were followed-up for 2 years. We assessed clinical events (death, myocardial infarction, severe arrhythmia, stroke, progression to ESRD), changes in cardiac and renal function, Fabry-related symptoms (pain, hypohidrosis, diarrhea), and disease severity scores. Determination of renal function by creatinine and cystatin C-based eGFR revealed decreasing eGFRs in the dose-reduction-switch group and the switch group. The Mainz Severity Score Index increased significantly in these two groups (P=0.02 and P<0.001, respectively), and higher frequencies of gastrointestinal pain occurred during follow-up. In conclusion, after 2 years of observation, all groups showed a stable clinical disease course with respect to serious clinical events. However, patients under agalsidase-β dose-reduction and switch or a direct switch to agalsidase-α showed a decline of renal function independent of the eGFR formula used.


Injection time-dependent effect of adult human bone marrow stromal cell transplantation in a rat model of severe traumatic brain injury.
The object of this study is to evaluate the effects of injecting adult human bone marrow stromal cells (hBMSCs) into rats with severe traumatic brain injury in acute phase and to determine more optimal injection timing between day 1 and day 2 postinjury. The lateral fluid percussion injury model was used. Adult hBMSCs were transplanted into hemisphere to injury sites in the corpus callosum ipsilateral on day 1 (n = 12) or day 7 (n = 8) after injury. A control group (n = 7) underwent only a sham operation without stem cell transplantation. Rats in all groups were analyzed by magnetic resonance spectroscopy (MRS), and by using behavioral, rotarod, and Barnes maze tests on day 1, 7, 14, and 42. Another nine randomly designated rats were sacrificed for immunohistochemical staining. Behavioral test scores increased significantly at all time-points after TBI in the day 7-injected group, compared to the others (p=0.008). GFAP staining was lower on day 42 in day 7-injected rats than in those injected on day 1. But no significant inter- or intra-group differences were observed for other tests. The injection of hBMSCs was found to have limited therapeutic potential with respect to neuroprotection after traumatic brain injury. However, because injection on day 7 after TBI produced greater functional improvements in neurobehavioral tests and more effectively suppressed astroglial activation than an injection on post-injury day 1, we cautiously recommend the injection time of day 7 post injury in hBMSCs transplantation in severe TBI, rather than day 1 post injury but further studies on developing hBMSC-based new therapeutic approaches should be warranted for improving neuroprotection in severe TBI.


Return of visual function after bilateral visual loss following flow diversion embolization of a giant ophthalmic aneurysm due to both reduction in mass effect and reduction in aneurysm pulsation.
Large and giant paraclinoid aneurysms are challenging to treat by either surgical or endovascular means. Visual dysfunction secondary to optic nerve compression and its relationship with aneurysm size, pulsation and thrombosis is poorly understood. We present a patient with a giant paraclinoid aneurysm resulting in bilateral visual loss that worsened following placement of a Pipeline Embolization Device and adjunctive coiling. Visual worsening occurred in conjunction with aneurysm thrombosis, increase in maximal aneurysm diameter and new adjacent edema. Her visual function spontaneously improved in a delayed fashion to better than pre-procedure, in conjunction with reduced aneurysmal mass effect, size and pulsation artifact on MRI. This report documents detailed ophthalmologic and MRI evidence for the role of thrombosis, aneurysm mass effect and aneurysm pulsation as causative etiologies for both cranial nerve dysfunction and delayed resolution following flow diversion treatment of large cerebral aneurysms.


Comparison of simulated quenching algorithms for design of diffractive optical elements.
We compare the performance of very fast simulated quenching; generalized simulated quenching, which unifies classical Boltzmann simulated quenching and Cauchy fast simulated quenching; and variable step size simulated quenching. The comparison is carried out by applying these algorithms to the design of diffractive optical elements for beam shaping of monochromatic, spatially incoherent light to a tightly focused image spot, whose central lobe should be smaller than the geometrical-optics limit. For generalized simulated quenching we choose values of visiting and acceptance shape parameters recommended by other investigators and use both a one-dimensional and a multidimensional Tsallis random number generator. We find that, under our test conditions, variable step size simulated quenching, which generates each parameter's new states based on the acceptance ratio instead of a certain theoretical probability distribution, produces the best results. Finally, we demonstrate experimentally a tightly focused image spot, with a central lobe 0.22-0.68 times the geometrical-optics limit and a relative sidelobe intensity 55%-60% that of the central maximum intensity.


Normal mode analysis as a method to derive protein dynamics information from the Protein Data Bank.
Normal mode analysis (NMA) can facilitate quick and systematic investigation of protein dynamics using data from the Protein Data Bank (PDB). We developed an elastic network model-based NMA program using dihedral angles as independent variables. Compared to the NMA programs that use Cartesian coordinates as independent variables, key attributes of the proposed program are as follows: (1) chain connectivity related to the folding pattern of a polypeptide chain is naturally embedded in the model; (2) the full-atom system is acceptable, and owing to a considerably smaller number of independent variables, the PDB data can be used without further manipulation; (3) the number of variables can be easily reduced by some of the rotatable dihedral angles; (4) the PDB data for any molecule besides proteins can be considered without coarse-graining; and (5) individual motions of constituent subunits and ligand molecules can be easily decomposed into external and internal motions to examine their mutual and intrinsic motions. Its performance is illustrated with an example of a DNA-binding allosteric protein, a catabolite activator protein. In particular, the focus is on the conformational change upon cAMP and DNA binding, and on the communication between their binding sites remotely located from each other. In this illustration, NMA creates a vivid picture of the protein dynamics at various levels of the structures, i.e., atoms, residues, secondary structures, domains, subunits, and the complete system, including DNA and cAMP. Comparative studies of the specific protein in different states, e.g., apo- and holo-conformations, and free and complexed configurations, provide useful information for studying structurally and functionally important aspects of the protein.


Acquired haemophilia A and Kaposi's sarcoma in an HIV-negative, HHV-8-positive patient: a discussion of mechanism and aetiology.
Acquired haemophilia A (AHA) is a rare bleeding disorder caused by an imbalance in the immune system leading to the production of factor VIII antibodies. In half of the cases, the underlying cause is not known. We report on a patient with AHA and Kaposi's sarcoma (KS), which is caused by the human herpes virus 8 (HHV-8). The patient presented with appendicitis and developed several severe post-operative haemorrhages. He spent 3 months in intensive care due to long and difficult infections. While recuperating on the ward, the patient developed KS in the lower extremities. He had a positive HHV-8 infection. Due to its latency and replication in the lymphoid system, HHV-8 is an ideal candidate for causing an imbalance in the immune system in susceptible patients. Our conclusion is that AHA was caused or prompted by the HHV-8 infection. Since HHV-8 viral infection is often subclinical, viral testing might be an important tool in acquired haemophilia diagnostics even when viral symptoms are absent.


Chemical synthesis of a biologically active gene for human immune interferon-gamma. Prospect for site-specific mutagenesis and structure-function studies.
A 453-base pair DNA duplex consisting of a gene coding for human interferon-gamma and initiation and termination signals plus appropriate restriction enzyme sites for plasmid insertion has been totally synthesized. The synthesis involved preparation of 66 oligodeoxynucleotides by a modified, solid phase phosphite procedure and enzymatic ligation of the oligonucleotides. The gene, when inserted into a previously constructed expression vector, was expressed in Escherichia coli, demonstrating functional activity for the synthetic gene. Several strategically located restriction cleavage sites have been introduced into the sequence. This provides a convenient system for site-specific mutagenesis for structure-function studies.