Dynamic light scattering study of inhibition of nucleation and growth of hydroxyapatite crystals by osteopontin.
We study the effect of isoforms of osteopontin (OPN) on the nucleation and growth of crystals from a supersaturated solution of calcium and phosphate ions. Dynamic light scattering is used to monitor the size of the precipitating particles and to provide information about their concentration. At the ion concentrations studied, immediate precipitation was observed in control experiments with no osteopontin in the solution, and the size of the precipitating particles increased steadily with time. The precipitate was identified as hydroxyapatite by X-ray diffraction. Addition of native osteopontin (nOPN) extracted from rat bone caused a delay in the onset of precipitation and reduced the number of particles that formed, but the few particles that did form grew to a larger size than in the absence of the protein. Recombinant osteopontin (rOPN), which lacks phosphorylation, caused no delay in initial calcium phosphate precipitation but severely slowed crystal growth, suggesting that rOPN inhibits growth but not nucleation. rOPN treated with protein kinase CK2 to phosphorylate the molecule (p-rOPN) produced an effect similar to that of nOPN, but at higher protein concentrations and to a lesser extent. These results suggest that phosphorylations are critical to OPN's ability to inhibit nucleation, whereas the growth of the hydroxyapatite crystals is effectively controlled by the highly acidic OPN polypeptide. This work also demonstrates that dynamic light scattering can be a powerful tool for delineating the mechanism of protein modulation of mineral formation.


Clinicopathological features of childhood nephrotic syndrome in Saudi Arabia.
The clinicopathological features are described in 119 Arab children in Saudi Arabia with the nephrotic syndrome. The clinical and laboratory data are similar to those described in other parts of the world. However, mesangial proliferative glomerulonephritis (MesPGN) was found in 21 of 66 biopsies (31.8%), giving a frequency of 17.6% of all children with the nephrotic syndrome. Minimal-change nephrotic syndrome (MCNS) was diagnosed in 17 biopsies (25.8%) and in 58 patients (48.7%). Onset of the nephrotic syndrome was at less than 1 year of age in 17 patients (14.3%). Seven children had 11 episodes of peritonitis. Seven children had positive hepatitis B surface antigen (HBsAg) in their serum: renal biopsy carried out on four of them showed membranous glomerulonephritis (MGN) in three, and four of the seven patients developed end-stage renal disease (ESRD). There were nine deaths, all in patients with end-stage renal disease: six of the deaths occurred in infants. The pattern of childhood nephrotic syndrome in Saudi Arabia is different from the pattern in tropical countries.


Integrated one-flow synthesis of heterocyclic thioquinazolinones through serial microreactions with two organolithium intermediates.
The synthesis of pharmaceutical compounds via short-lived intermediates in a microreactor is attractive, because of the fast flow and high throughput. Additionally, intermediates can be utilized sequentially to efficiently build up a library in a short time. Here we present an integrated microfluidic synthesis of biologically active thioquinazolinone libraries. Generation of o-lithiophenyl isothiocyanate and subsequent reaction with aryl isocyanate is optimized by controlling the residence time in the microreactor to 16 ms at room temperature. Various S-benzylic thioquinazolinone derivatives are synthesized within 10 s in high yields (75-98%) at room temperature. These three-step reactions involve two organolithium intermediates, an isothiocyanate-functionalized aryllithium intermediate, and a subsequent lithium thiolate intermediate. We also demonstrate the gram-scale synthesis of a multifunctionalized thioquinazolinone in the microfluidic device with a high yield (91%) and productivity (1.25 g in 5 min).


Design of a synchrotron radiation source at Tohoku University.
The construction of a third-generation light source has been proposed at Tohoku University. The emittance is 7.3 nm rad at the nominal beam energy, 1.5 GeV. The circumference is 194 m. The ring consists of 12 double-bend achromatic cells. Ten of 12 dispersion-free long straight sections are 5 m long and will be used for insertion devices and some accelerator components. The remaining two are each 15 m long and reserved for advanced devices, such as a very long undulator or a free-electron laser. A stretcher-booster ring, which is now under commission, will be used as an injector. In total, about 50 beamlines can be constructed and ten of them will be those of insertion devices. The present status of the project is 'waiting for approval'.


Cutting edge: selective requirement for the Wiskott-Aldrich syndrome protein in cytokine, but not chemokine, secretion by CD4+ T cells.
The mechanism of cytokine secretion is not well understood, but cytokines appear to be synthesized and released in a polarized fashion toward an Ag-specific target cell. In this study, we demonstrate that the Wiskott-Aldrich syndrome protein (WASp) is an essential component of the cytokine secretory pathway in CD4(+) T cells. Murine WASp-deficient CD4(+) T cells fail to polarize cytokines toward a target and show an unexpected and striking block in cytokine secretion. In contrast, chemokine secretion and trafficking of plasma membrane proteins, transported via the constitutive secretory pathway, are unaffected by the lack of WASp. These results suggest that CD4(+) T cell cytokines require a specialized, WASp-dependent pathway for cellular traffic and/or vesicle release that is distinct from that required for chemokine release. We propose that the use of different secretory pathways for cytokines and chemokines enables CD4(+) T cell activity to be further fine-tuned to serve specialized effector functions.


Exploration of tricyclic heterocycles as core structures for RIOK2 inhibitors.
Right open reading frame kinase 2 (RIOK2) is an atypical kinase and has been proved to be involved in multiple human cancers including non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), glioblastoma and anemia. Although tremendous efforts have been devoted to the studies of RIOK2, its biological functions remain poorly understood. It is highly important to develop potent and selective RIOK2 inhibitors as potential research tools to elucidate its functions and as drug candidates for further therapies. We have previously identified a highly potent and selective RIOK2 inhibitor (CQ211). To confirm the importance of the "V-shaped" structure of CQ211 for binding with RIOK2, a variety of tricyclic compounds with different core structures instead of the [1,2,3]triazolo[4,5-c]quinolin-4-one core of CQ211 were designed, synthesized, and the binding affinities of these tricyclic heterocycles with RIOK2 were also evaluated.


Inductive temperature measurement: A new sensor improvement for industrial applications.
A remote temperature sensing technique was developed by measuring exponential decay current pulses in a Helmholtz coil. After an initial calibration to extract a mathematical function relating the time constant (τ) to the temperature of the object sensed, the temperature of other similar objects can be estimated with less power, less strict positioning of the object, and more sensitivity than previous techniques, even inside a water-based fluid.


Chloride-sensitive nature of the adrenaline-induced current in guinea-pig cardiac myocytes.
1. Ionic selectivity of an adrenaline-induced current was investigated in single guinea-pig ventricular cells by recording whole-cell currents using the patch clamp technique combined with internal perfusion. Other ionic currents and exchange currents known in ventricular cells were suppressed by appropriate inhibitors and the adrenaline-induced current was defined as a difference between currents obtained in the presence and absence of adrenaline. 2. The adrenaline-induced current was time independent and its I-V relation showed saturation of the inward current in the negative voltage range. 3. The reversal potential was approximately -20 mV with 140 mM-NaCl external solution and Cs(+)-rich internal solution containing 51 mM-Cl-. Replacing Na+ with various monovalent and divalent cations (Li+, K+, Rb+, Cs+, Ca2+, Sr2+ and Ba2+) produced no appreciable change in the reversal potential. 4. Varying the external Cl- concentration ([Cl-]o) in exchange for aspartate or benzenesulphonate greatly changed the reversal potential. The relationship between the reversal potential and log[Cl-]o indicated a slope of 59.5 or 53.6 mV per tenfold change in [Cl-]o in the presence of 51 or 102 mM-Cl- in the internal solution, respectively. 5. Anion substitutions did not appreciably affect the I-V relation before application of adrenaline, suggesting that the cell membrane had a low Cl- conductance in the control state. 6. 4.4'-Dinitrostilbene-2-2'-disulphonic acid (DNDS: 1-10 mM), a specific inhibitor of membrane chloride permeability, depressed the adrenaline-induced current without changing the reversal potential. 7. The results suggest strongly that the adrenaline-induced current is carried mainly by Cl-. However, the development of this current appears to depend also on external cations, since the magnitude of the adrenaline response varied depending on the external cations species, with no response in Tris-HCl or TEA-Cl solution. The external cations may facilitate the adrenaline response with a sequence of efficacy of Na+ greater than K+, Rb+ greater than Cs+, Li+, divalent cations.


Regulation of prolactin gene expression by vasoactive intestinal peptide and dopamine in the turkey: role of Ca signalling.
Our recent work has demonstrated that dopamine, acting through D2 dopamine receptors on pituitary cells, inhibits the stimulatory effects of vasoactive intestinal peptide (VIP) on prolactin release and prolactin gene transcription. It is hypothesised that the stimulatory and inhibitory roles of VIP and dopamine, respectively, on prolactin synthesis and release are mediated by their opposite effects on intracellular Ca2+ concentration ([Ca2+]i) in lactotrophs. The present study aimed: (i) to investigate the effect of VIP and dopamine on [Ca2+]i of cultured turkey anterior pituitary cells and (ii) to examine the role of Ca2+ signalling in mediating the regulatory effects of VIP and dopamine on prolactin mRNA levels and prolactin release. Changes in [Ca2+]i were measured spectrofluorometrically using Fura-2/AM as a fluorescent Ca2+ indicator. Semi-quantitative reverse transcription-polymerase chain reaction and radioimmunoassay were used to determine prolactin mRNA levels and prolactin release, respectively. VIP or the L-type Ca2+ channel activator, Bay K8644 (Bay) increased [Ca2+]i in a concentration- and time-dependent fashion, an effect abolished by preincubating the cells with R(-)-propylnorapomorphine HCl, a D2 dopamine receptor agonist (D2AG) or Verapamil (VR), a specific L-type Ca2+ channel blocker. Similarly, either VR or D2Ag diminished the VIP/Bay stimulatory effect on prolactin expression and release. On the other hand, pretreatment of pituitary cells with thapsigargin (TG) or neomycin (NEO), to deplete the intracellular Ca2+ stores, showed no effect on basal or VIP-stimulated prolactin mRNA levels; although VIP-induced prolactin release was partially inhibited by NEO but not TG. These results suggest that intracellular Ca2+ represents a common signal transduction pathway through which VIP and dopamine can exert antagonistic control on prolactin synthesis and release in avian lactotrophs.


Carbon monoxide diffusing capacity is a poor predictor of clinically significant bleomycin lung. New Zealand Clinical Oncology Group.
In a retrospective analysis, serial lung function tests from 81 patients receiving bleomycin were studied to determine the accuracy of carbon monoxide diffusing capacity (DLCO) as a predictor of clinically significant bleomycin lung. Six of 81 patients developed clinically significant bleomycin lung, and the DLCO predicted its development in only one patient (sensitivity, one of six patients; 16.7%). Respiratory symptoms and chest x-ray abnormalities were the earliest manifestations in the other five patients. Seventy-five of 81 patients did not develop clinically significant bleomycin lung, and 12 of these had major falls (greater than or equal to 35% pretreatment level) in DLCO (specificity, 63 of 75 patients; 84.0%). In eight patients, bleomycin was continued after a major fall in DLCO, and none developed clinically significant lung toxicity. In this study, the DLCO failed to predict the development of serious bleomycin lung toxicity in all but one case. Furthermore, in some patients, it would appear that bleomycin may be stopped inappropriately after low DLCO measurements. It is important to monitor for respiratory symptoms and chest x-ray abnormalities during bleomycin treatment as these will be the earliest signs of lung toxicity in most cases.


Continuous quality improvement at the frontline: One interdisciplinary clinical team's four-year journey after completing a virtual learning program.
The Veterans Health Administration (VHA) is the largest integrated health system in the U.S. and has identified the learning health system as a strategic priority. Clinicians and staff engaging in active learning through continuous quality improvement (QI) is a key pillar for learning system maturity. An interdisciplinary frontline team at a VHA medical center participated in the Learn. Engage. Act. Process. (LEAP) virtual coaching program to learn how to conduct multidisciplinary team-based QI cycles of change. These clinicians lead and deliver the MOVE! weight management program, an evidence-based comprehensive lifestyle intervention. The team worked to continuously improve patient weight loss by engaging in incremental learning cycles of change. The aim of this study is to tell the story of this team's learning experience and the resulting positive reinforcing loop with patient outcomes. This is a mixed methods case study description of one team that participated in the LEAP Program that provides hands-on QI learning for frontline teams with virtual coaching and a structured curriculum. Autoethnographic qualitative descriptions of team experiences over time illustrate this team's continued engagement in learning loops. Multilevel linear modeling was used to assess patient outcomes before vs after the team's participation in LEAP. The team's participation in LEAP provided a set of fundamental QI skills and established a commitment to continual learning. Incremental improvements led to significant weight loss for patients who participated in MOVE! after the team completed LEAP (mean = 9.80 pounds; SD 10.43) compared to the pre-LEAP time period (mean = -6.83 pounds; SD 9.63). Despite competing priorities and time limitations, this team's experiences provide a positive vision of how team engagement in data-driven continuous learning is feasible at the frontline and can lead to higher job satisfaction and stronger teams. These types of team activities provide much-needed backbone to being a mature learning health system.


Traumatic dural tears: CT diagnosis using metrizamide.
Computed tomography of the spine using intrathecal metrizamide was performed on six patients with spinal trauma. Dural tears with contrast material escaping outside the subarachnoid space were documented in five cases. In one case, the thecal laceration had healed and the contrast material was confined in a post-traumatic meningocele. The characteristics of dural tears are demonstrable by metrizamide computed tomography, either in conjunction with myelography or as a separate procedure. Neurological deficits following spinal trauma may be aggravated by dural tears with entrapment of the spinal nerve roots.


Keratomycosis due to Fusarium oxysporum--a case report.
A 30 year old muslim housewife presented with foreign body sensation to start with and later noticed white patch in the left eye with blurred vision since 3 days. KOH preparation of corneal scrapings revealed fungal elements. Culture isolate is identified as Fusarium oxysporum by standard methods. Fusarium oxysporum causing keratomycosis is reported for its rarity.


Personalized medicine could transform healthcare.
Personalized medicine (PM) is about tailoring a treatment as individualized as the disease. The approach relies on identifying genetic, epigenomic, and clinical information that allows the breakthroughs in our understanding of how a person's unique genomic portfolio makes them vulnerable to certain diseases. PM approach is a complete extension of traditional approach (One-Size-Fits-All) to increasing our ability to predict which medical treatments will be safe and effective for individual patient, and which ones will not be, based on the patient's unique genetic profile. Implementation of PM has the potential to reduce financial and time expenditure, and increase quality of life and life extension of patients. Knowledge of PM facilitates earlier disease detection via enhanced use of existing biomarkers and detection of early genomic and epigenomic events in disease development, particularly carcinogenesis. The PM approach predominantly focuses on preventative medicine and favours taking pro-active actions rather than just reactive. This approach delays or prevents the need to apply more severe treatments which are usually less tolerated and with increased quality of life and financial considerations. Increasing healthcare costs have placed additional pressure on government funded healthcare systems globally, especially regarding end of life care. PM may increase the effectiveness of existing treatments and negate the inherent problems associated with non-PM approaches. PM is a young but rapidly expanding field of healthcare where a physician can select a treatment based on a patient's genetic profile that may not only minimize harmful side effects and guarantee a more successful result, but can be less cost effective compared with a 'trial-and-error' approach to disease treatment. The less efficient non-PM ('trial-and-error') approach, which can lead to drug toxicity, severe side effects, reactive treatment and misdiagnosis continue to contribute to increasing healthcare costs. Increased patient stratification will allow for the enhanced application of PM and pro-active treatment regimens, resulting in reduced costs and quality of life enhancement.


Visualizing sweetness: increasingly diverse applications for fluorescent-tagged glucose bioprobes and their recent structural modifications.
Glucose homeostasis is a fundamental aspect of life and its dysregulation is associated with important diseases, such as cancer and diabetes. Traditionally, glucose radioisotopes have been used to monitor glucose utilization in biological systems. Fluorescent-tagged glucose analogues were initially developed in the 1980s, but it is only in the past decade that their use as a glucose sensor has increased significantly. These analogues were developed for monitoring glucose uptake in blood cells, but their recent applications include tracking glucose uptake by tumor cells and imaging brain cell metabolism. This review outlines the development of fluorescent-tagged glucose analogues, describes their recent structural modifications and discusses their increasingly diverse biological applications.


[Sciatic nerve block by the lateral route at the level of the popliteal fossa with 0.75% ropivacine: advantages of a more proximal approach].
To assess the efficacy of a sciatic nerve block using a lateral approach 11 cm cephalad to the lateral femoral epicondyle for providing surgical anesthesia and postoperative analgesia in scheduled foot surgery (hallux valgus) after a single injection of 30 mL of 0.75% ropivacaine. A block was performed in 30 patients using a point of puncture 11 cm cephalad to the most prominent point of the lateral femoral epicondyle in the groove between the biceps femoris and vastus lateralis muscles. Once the nerve had been located with a stimulator (2 Hz, 0.5 mA), 30 mL of 0.75% ropivacaine was injected. Data recorded were time until block, number of attempts, depth at which the nerve was found, sciatic nerve response obtained, and time until the sensory block was complete. We evaluated quality of anesthesia during surgery, duration of postoperative analgesia, and patient discomfort during performance of the block. Time required to perform the block was 4.3 +/- 1.2 minutes and only one puncture attempt was needed in 27 patients. The nerve was located at 5.5 +/- 0.4 cm, with response located in the common peroneal nerve in 18 patients and in the posterior tibial nerve in 12. The time needed to achieve a full sensory block was 19.3 +/- 5.1 minutes. Twenty-six patients (86%) were very satisfied with the anesthetic quality of the block, 2 were moderately satisfied, and 2 were dissatisfied. Postoperative analgesia lasted 19 +/- 3.4 hours. Four patients reported minimal discomfort during performance of the block. No complications were observed. The sciatic nerve block from a lateral approach 11 cm cephalad to the lateral femoral epidondyle is an appropriate anesthetic technique for foot surgery. It is safe, effective and easy to perform. Infusion of 30 mL of 0.75% ropivacaine provided adequate anesthesia and long-lasting postoperative analgesia for our patients.


Survival and incidence of acute rejection in heart transplant recipients undergoing successful withdrawal from steroid therapy.
Steroid-free immunosuppression is feasible in selected patients after heart transplantation. Survival and incidence of acute rejection are important parameters to evaluate when weighing risks and benefits of steroid withdrawal. One hundred thirty-seven patients were retrospectively reviewed who underwent heart transplant at Emory University between January 1988 and April 1994 and survived >1 year. Standard immunosuppression (cyclosporine, azathioprine and prednisone) without induction therapy was used. Weaning from steroids was attempted in all patients. Scheduled endomyocardial biopsy was used for long-term surveillance screening. Seventy-two patients (52.5%) underwent successful prednisone withdrawal (Group P0) at an average of 13 months after heart transplant, whereas 65 patients (47.5%) did not achieve steroid-free immunosuppression (Group P1). Group P0 had a mean of 1.3 treated rejection episodes (ISHLT Grade > or = 1b) during the first post-transplant year and Group P1 a mean of 2.3 (p <0.0001). In Group P0, 40 patients (55.6%) suffered a subsequent acute rejection with an ISHLT Grade > or = 1b, resulting in treatment. Of these, 15% were ISHLT Grade 1b, 47.5% Grade 2, 35% Grade 3a and 2.5% Grade 3b. The estimated risk of suffering from acute rejection of at least Grade 1b after achieving steroid-free immunosuppression was 50% at 21 months. Estimated survival at 5 years after heart transplant was 92.9% in Group P0 and 72.3% in Group P1 (p <0.01). Cox proportional hazard modeling revealed black recipient race as effect modifier of group status with decreased survival time in both groups. Steroid-free immunosuppression in white heart transplant recipients is associated with improved survival. A low acute rejection score during the first year predicts successful steroid withdrawal. Black recipient race appears to be negatively associated with survival and deserves further detailed study. Long-term surveillance screening using endomyocardial biopsy is recommended.


Mono-allyloxylated Cucurbit[7]uril Acts as an Unconventional Amphiphile To Form Light-Responsive Vesicles.
Serendipitously, mono-allyloxylated cucurbit[7]uril (AO1 CB[7]) was discovered to act as an unconventional amphiphile which self-assembles into light-responsive vesicles (AO1 CB[7]VC) in water. Although the mono-allyloxy group, directly tethered on the periphery of CB[7], is much shorter (C4) than the hydrophobic tails of conventional amphiphiles, it played an important role in vesicle formation. Light-activated transformation of the allyloxy group by conjugation with glutathione was exploited as a remote tool to disrupt the vesicle. The vesicle showed on-demand release of cargo upon irradiation by a laser, after they were internalized into cancer cells. This result demonstrated the potential of AO1 CB[7]VC as a new type of light-responsive intracellular delivery vehicle for the release of therapeutic cargo, within cells, on demand.


DFT-Based Simulation and Experimental Validation of the Topotactic Transformation of MgAl Layered Double Hydroxides.
The thermal topotactic transformation mechanism of MgAl layered double hydroxides (LDHs) is investigated by a combined theoretical and experimental study. Thermogravimetric differential thermal analysis (TG-DTA) results reveal that the LDH phase undergoes four key endothermic events at 230, 330, 450, and 800 °C. DFT calculations show that the LDH decomposes into CO2 and residual O atoms via a monodentate intermediate at 330 °C. At 450 °C, the metal cations almost maintain their original distribution within the LDH(001) facet during the thermal dehydration process, but migrate substantially along the c-axis direction perpendicular to the (001) facet; this indicates that the metal arrangement/dispersion in the LDH matrix is maintained two-dimensionally. A complete collapse of the layered structure occurs at 800 °C, which results in a totally disordered cation distribution and many holes in the final product. The structures of the simulated intermediates are highly consistent with the observed in situ powder XRD data for the MgAl LDH sample calcined at the corresponding temperatures. Understanding the structural topotactic transformation process of LDHs would provide helpful information for the design and preparation of metal/metal oxides functional materials derived from LDH precursors.


A thieno[3,4-c]pyrrole-4,6-dione-based copolymer for efficient solar cells.
A new low-band-gap thieno[3,4-c]pyrrole-4,6-dione-based copolymer, PBDTTPD, has been designed and synthesized. PBDTTPD is soluble in chloroform or o-dichlorobenzene upon heating and shows a broad absorption in the visible region. The HOMO and LUMO energy levels were estimated to be at -5.56 and -3.75 eV, respectively. These electrochemical measurements fit well with an optical bandgap of 1.8 eV. When blended with PC(71)BM, this polymer demonstrated a power conversion efficiency of 5.5% in a bulk-heterojunction photovoltaic device having an active area of 1.0 cm(2).


Percutaneous catheter biliary decompression.
Percutaneous catheter biliary decompression was performed in 42 patients with obstructive jaundice. Internal drainage was accomplished in 27 patients (64.3%), and external drainage in 15 patients (35.7%). Serum bilirubin levels decreased at a mean rate of 1.4 mg/dl/day. Tissue diagnosis was obtained by percutaneous aspiration biopsy in nine patients (21.4%). Complications occurred in 10 patients (23.8%): septic shock, two; bilious pleural effusion, one; hepatic subcapsular hematoma, one; sepsis, six. There was one death related to the procedure. The catheter management problems encountered included pain, catheter dislodgement or migration, lumen occlusion, and external bile leakage.


Knowledge and attitudes of dentists regarding traumatic dental injuries.
The aim of this study was to evaluate the knowledge levels of dentists regarding the treatment of several dental injuries. Study design: Cross-sectional study. A structured questionnaire was validated and sent electronically to the Professional Dental Schools of each Spanish region and subsequently to the affiliated dentists. The survey collected the dentists' demographic data and asked 11 questions regarding traumatic dental injuries and their potential complications and treatments. The relationships between the demographic data and the correct/incorrect answers regarding dental injuries were estimated by means of Pearson's chi-squared test and post hoc testing. The survey was answered by 1532 dentists. None of the demographic variables was related to better knowledge. However, men, older dentists and more experienced dentists were related to having a self- evaluation of knowledge as comprehensive; 64.1% of the answers given by the respondents were correct. Surprisingly, having more clinical dental experience and a postgraduate degree were not related to better knowledge. The results revealed an uneven knowledge among dentists depending on the type of dental trauma injury. Questions on treatment of avulsion of immature teeth and complicated fractures had a correct answer frequency higher than 70%, while questions regarding intrusion and lateral luxation had a knowledge lower than 60% and less than 30%, respectively. More than 50% of dentists would apply splinting after replantation for more than 14 days. Dentists need to improve their knowledge regarding the treatment of tooth intrusion, lateral luxation and avulsion of mature teeth as well as the use of splinting.


Neostigmine, but not metoclopramide, abolishes ethosuximide-induced functional gastrointestinal disturbances.
Ethosuximide is a drug used for the treatment of absence seizures. Its prolonged application leads to gastrointestinal (GI) disturbances. The purpose of the present study was to determine the severity and nature of the disturbances, as well as the influence exerted upon them by neostigmine methylsulfate and metoclopramide. The drug-induced alterations, occurring in the rat GI tract, were registered by X-ray contrast examination. In vitro experiments were carried out on isolated GI smooth muscle (SM) preparations. The latter revealed that the drug hyperpolarized the SM tissues and inhibited their contractile activity. X-rays of ethosuximide-treated rats showed GI hypotonia, disturbed peristalsis and decreased evacuation activity. The inhibition of the GI functions was associated with hyperpolarization of SM and a reduction in Ca(2+) influx, ensuring spontaneous contractile activity. The application of neostigmine methylsulfate significantly removed ethosuximide-induced functional GI disturbances in rats treated for 15 days with ethosuximide.


Cell fate changes induced by a Distal-less enhancer-trap transgene in the Drosophila antennal imaginal disc.
The imaginal discs of the genetically tractable model organism Drosophila melanogaster have been used to study cell-fate specification and plasticity, including homeotic changes and regeneration-induced transdetermination. The identity of the reprogramming mechanisms that induce plasticity has been of great interest in the field. Here we identify a change from antennal fate to eye fate induced by a Distal-less-GAL4 (DllGAL4) P-element insertion that is a mutant allele of Dll and expresses GAL4 in the antennal imaginal disc. While this fate change is not induced by tissue damage, it appears to be a hybrid of transdetermination and homeosis as the GAL4 expression causes upregulation of Wingless, and the Dll mutation is required for the fate change. Neither GAL4 expression nor a Dll mutation on its own is able to induce antenna-to-eye fate changes. This plasticity appears to be unique to the DllGAL4 line, possibly due to cellular stress induced by the high GAL4 expression combined with the severity of the Dll mutation. Thus, we propose that even in the absence of tissue damage, other forms of cellular stress caused by high GAL4 expression can induce determined cell fates to change, and selector gene mutations can sensitize the tissue to these transformations.


Liver and diabetes. A vicious circle.
The complex and bi-directional relationship linking the liver and diabetes has recently gained intense new interest. This critical review of the published work aims to highlight the most recent basic and clinical data underlying the development of type 2 diabetes, in those with non-alcoholic fatty liver disease. Moreover, the potentially detrimental effects of type 2 diabetes in liver injury are also discussed in each of the two sections of the present paper. Fatty liver and diabetes share insulin resistance as their chief pathogenic determinant. The roles of the hypothalamus, the intestinal microbiome, white adipose tissue and inflammation are discussed in detail. Molecular insights into hepatocyte insulin resistance as the initiator of systemic insulin resistance are also presented with full coverage of the danger of fatty acids. Lipotoxicity, apoptosis, lipoautophagy, endoplasmic reticular stress response and recent developments in genetics are discussed. Closing the circle, special emphasis is given to biochemical pathways and clinical evidence supporting the role of type 2 diabetes as a risk factor for the development of progressive liver disease, including non-alcoholic steatohepatitis, cirrhosis and primary liver cancer. In conclusion, data support non-alcoholic fatty liver disease as a risk factor for the development of type 2 diabetes which is, in turn, a major contributor to progressive liver disease. This pathway leading from fatty liver to type 2 diabetes and back from the latter to the progressive liver disease is a vicious circle.


A modular optically powered floating high voltage generator.
The feasibility of fully floating high voltage (HV) generation was demonstrated producing a prototype of a modular HV system. The primary power source is provided by a high efficiency semiconductor power cell illuminated by a laser system ensuring the floating nature of each module. The HV is then generated by dc-dc conversion and a HV multiplier. The possibility of series connection among modules was verified.


Characterization of Human AB Serum for Mesenchymal Stromal Cell Expansion.
So far, using human blood-derived components appears to be the most efficient and safest approach available for mesenchymal stromal cell (MSC) expansion. In this paper, we report on the characterization of human AB serum (AB HS) produced by using different plasma sources, and its use as an alternative supplement to MSC expansion. Two plasma sources were used for AB HS production: plasma removed from whole blood after 24 h of collection (PC > 24 h) and plasma, cryoprecipitate reduced (PCryoR). The biochemical profile and quality of the produced AB HS batches were analyzed and their ability to support MSC cell growth after different storage times (0, 3, 6, 9 and 12 months) was evaluated. The two plasma sources used showed similar characteristics regarding biochemical constituents and quality parameters and were effective in promoting MSC growth. MSCs cultured in medium supplemented with 10% AB HS presented similar doubling times and cumulative population doublings when compared to the 10% fetal bovine serum(FBS)-supplemented culture while maintaining immunophenotype, functional features, and cytogenetic profile. Overall, the results indicate that AB HS is an efficient FBS substitute and can be used for at least 12 months after production without impairing cell proliferation and quality.


Overexpression of the Arabidopsis thaliana MinE1 bacterial division inhibitor homologue gene alters chloroplast size and morphology in transgenic Arabidopsis and tobacco plants.
Higher-plant chloroplast division requires some of the same genes that are involved in prokaryotic cell division. These include the FtsZ and MinD proteins. Other genes that might be involved in higher-plant chloroplast division have yet to be characterized. The Arabidopsis thaliana (L.) Heynh. MinE ( AtMinE1) gene was identified in the genomic database, isolated by reverse transcription-polymerase chain reaction and constitutively expressed in tobacco ( Nicotiana tabacum L.) and Arabidopsis plants in both the sense and antisense orientation. Confocal and electron-microscopic analysis of the sense-overexpressing AtMinE1 transgenic tobacco and Arabidopsis plants revealed that the chloroplasts were abnormal in size and shape compared to wild-type Arabidopsis and tobacco chloroplasts. Our results, based on the overexpression of the AtMinE1 gene in tobacco and Arabidopsis, confirm that the AtMinE1 gene is involved in plant chloroplast division.


Glucose-dependent GPER1 expression modulates tamoxifen-induced IGFBP-1 accumulation.
G protein-coupled estrogen receptor 1 (GPER1) is a seven-transmembrane receptor that mediates rapid cell signaling events stimulated by estrogens. While the role that GPER1 has in the modulation of E2-responsive tissues and cancers is well documented, the molecular mechanisms that regulate GPER1 expression are currently not well defined. The recently identified GPER1-dependent mechanism of tamoxifen action in breast cancer cells underscores the importance of identifying mechanisms that regulate GPER1 expression in this cell type. We hypothesized that GPER1 expression in breast cancer cells is sensitive to [D-glucose] and provide data showing increased GPER1 expression when cells were cultured in low [D-glucose]. To determine if the observed accumulation of GPER1 was AMP-activated protein kinase (AMPK)-dependent, small molecule stimulation or inhibition of AMPK was performed. AMPK inhibition decreased GPER1 accumulation in cells grown in low [D-glucose] while the AMPK-activating compound AICAR increased GPER1 accumulation in cells grown in high [D-glucose] media. Additionally, transfection of cells with a plasmid expressing constitutively active AMPK resulted in increased GPER1 accumulation. To determine if [D-glucose]-dependent GPER1 accumulation altered breast cancer cell response to tamoxifen, cells grown in the presence of decreasing [D-glucose] were co-treated with tamoxifen and IGFBP-1 transcription was measured. The results from these experiments reveal that D-glucose deprivation increased GPER1-mediated and tamoxifen-induced IGFBP-1 transcription suggesting that [D-glucose] may increase breast cancer cell sensitivity to tamoxifen. Taken together, these results identify a previously unknown mechanism that regulates GPER1 expression that modifies one aspect tamoxifen action in breast cancer cells.


Seminal vesicle invasion in prostate cancer: evaluation by using multiparametric endorectal MR imaging.
To retrospectively evaluate the diagnostic performance of multiparametric endorectal magnetic resonance (MR) imaging, including T2-weighted, diffusion-weighted (DW), and dynamic contrast material-enhanced (DCE) MR techniques, for the diagnosis of seminal vesicle invasion (SVI) and to determine the incremental value of DW MR and DCE MR images. This retrospective HIPAA-compliant study was approved by the institutional review board, with a waiver of informed consent. The study included 131 patients (mean age, 68 years; range, 43-75 years) who underwent endorectal MR imaging before radical prostatectomy between January 2007 and April 2010. Two radiologists (A: experienced, B: less experienced) estimated the likelihood of SVI by using a five-point ordinal scale in three image-viewing settings: T2-weighted images alone; T2-weighted and DW MR images; and T2-weighted, DW MR, and DCE MR images. Sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUC) were calculated. Confidence intervals estimated with bootstrapping and the McNemar test or Fisher exact test were used to compare sensitivity, specificity, positive predictive value, and negative predictive value. Of the 131 patients, 23 (17.6%) had SVI identified after surgery. Review of T2-weighted MR images alone resulted in high specificity (93.1% and 93.6%, for radiologists A and B, respectively) and high negative predictive value (94.8% and 94.0%) but moderate sensitivity (59% and 52%) and positive predictive value (52% and 50%). Review of T2-weighted and DW MR images significantly improved specificity (96.6% [P = .02] and 98.3% [P = .003]) and positive predictive value (70% [P < .05] and 79% [P < .05]) without significantly improving AUC. Additional review of DCE MR images did not yield further incremental improvement. Additional review of DW MR images improves specificity and positive predictive value in SVI detection compared with reviewing T2-weighted images alone. Addition of DCE MR images to this combination, however, does not provide incremental value for diagnosis of SVI.


Fluid-Structure Interaction Within Models of Patient-Specific Arteries: Computational Simulations and Experimental Validations.
Cardiovascular disease (CVD) is the leading cause of mortality worldwide and its incidence is rising due to an aging population. The development and progression of CVD is directly linked to adverse vascular hemodynamics and biomechanics, whose in-vivo measurement remains challenging but can be simulated numerically and experimentally. The ability to evaluate these parameters in patient-specific CVD cases is crucial to better predict future disease progression, risk of adverse events, and treatment efficacy. While significant progress has been made toward patient-specific hemodynamic simulations, blood vessels are often assumed to be rigid, which does not consider the compliant mechanical properties of vessels whose malfunction is implicated in disease. In an effort to simulate the biomechanics of flexible vessels, fluid-structure interaction (FSI) simulations have emerged as promising tools for the characterization of hemodynamics within patient-specific cardiovascular anatomies. Since FSI simulations combine the blood's fluid domain with the arterial structural domain, they pose novel challenges for their experimental validation. This paper reviews the scientific work related to FSI simulations for patient-specific arterial geometries and the current standard of FSI model validation including the use of compliant arterial phantoms, which offer novel potential for the experimental validation of FSI results.


[Adult Still's disease with atypical skin manifestations].
Adult Still's disease (ASD) is an uncommon inflammatory disease of unknown etiology. It is characterized by the triad of intermittent high fever, evanescent rash and polyarthralgia or polyarthritis. We present the case of a 29-year-old woman with ASD and persistent erythematous papule on neck and upper part of the trunk. The presence of fixed lesions is not characteristic of ASD, but its appearance during development of the disease suggests that they are a manifestation of it. Recently, other skin manifestations of ASD have been published, but they are not well-known.


Considering the impact drug-like properties have on the chance of success.
Many definitions of 'drug-like' compound properties have been published; based on the analysis of simple molecular properties of successful drugs. These are typically presented as rules that define acceptable boundaries for these properties. When a compound does not 'fit' within these boundaries then its properties differ from those of the majority of drugs, which could indicate a higher risk of poor pharmacokinetics or safety outcomes in vivo. Here, we review the strengths and weaknesses of these rules and note, in particular, that the overly rigid application of strict cut-off points can introduce artificial distinctions between similar compounds, running the risk of missing valuable opportunities. Alternatively, compounds can be ranked according to their similarity to marketed drugs using a continuous measure of drug-likeness. However, being similar to known drugs does not necessarily mean that a compound is more likely to become a drug and we demonstrate how a new approach, employing Bayesian methods, can be used to compare a set of successful drugs with a set of non-drug compounds to identify those properties that give the greatest distinction between the two sets, and hence the greatest increase in the likelihood of a compound becoming a successful drug. This analysis further illustrates that guidelines for drug-likeness might not be generally applicable across all compound and target classes or therapeutic indications. Therefore, it might be more appropriate to consider specific guidelines for drug-likeness that are project specific.


Anatomical Variations of the Intrapetrous Portion of the Facial Nerve.
The intrapetrous facial nerve has the second longest intraosseous course of all cranial nerves, after the mandibular nerve. But it is by far the most complex considering the anatomical structures closely related to it. The auditory and vestibular portions of the inner ear, the dura of the middle fossa and posterior fossa, the sigmoid sinus and jugular bulb, and the internal carotid artery are close enough to merit attention. This article includes an anatomical study on 100 temporal bones with anatomical references as seen from the middle fossa and from the transmastoid approaches that may help identifying the facial nerve and protecting surrounding structures. Anatomical variability was present and noteworthy when considering the venous drainage system through the temporal bone and the mastoid pneumatization. The distance from the geniculate ganglion to the hiatus falopii offered the highest variability with a range of 0 to 7.75 mm and a mean of 3.30 mm. The geniculate ganglion was dehiscent in 20.8% of the specimens and the superior semicircular canal was spontaneously blue-lined in 27% of the cases. Through the transmastoid approach, the highest variability was found regarding the distance between the vertical portion of the facial nerve and the jugular bulb (range from 1.5 to 10.0 mm), the sigmoid sinus (range from 0 to 13.25 mm) and the internal carotid artery (range from 6.0 to 15.0 mm). This study highlights the importance of the relative variability of the facial nerve to other surrounding structures within the petrous portion of the temporal bone. Anat Rec, 302:588-598, 2019. © 2018 Wiley Periodicals, Inc.


The Relationship between Racial Residential Segregation and Black-White Disparities in Fatal Police Shootings at the City Level, 2013-2017.
Although there is a disparity in the rates of fatal police shootings of Black victims compared to White victims throughout the nation, the magnitude of this racial disparity varies widely between cities. Examining the reasons behind this vast variation in the racial disparity in fatal police shootings across different localities could be helpful in identifying the underlying causes of this problem. Therefore, the objective of this study was to assess potential causes of the Black-White racial disparities in police shootings at the city level. Using a cross-sectional design, we examined the relationship between the level of racial residential segregation in a city and the ratio of the rates of fatal police shootings of Black people compared to White people within that city during the period 2013-2017, using data from 69 of the largest cities in the United States. Using linear regression analysis, we modeled the ratio of Black to White fatal police shooting rates as a function of the level of racial segregation in each city as measured by the index of dissimilarity calculated at the Census block level. We controlled for several factors at the city level that might be expected to influence the rate of police shootings by race/ethnicity, including the level of deprivation of the Black population in economic status, the degree of Black representation in the city's police force, the relative size of the police force, crime rates, racial composition of the city, and city population. The level of racial residential segregation was significantly associated with the racial disparity in fatal police shooting rates. For each one standard deviation increase in the index of dissimilarity, the ratio of Black to White fatal police shooting rates increased by 44.4% (95% confidence interval, 17.1%-71.7%). Racial residential segregation is a significant predictor of the magnitude of the Black-White disparity in fatal police shootings at the city level. Efforts to ameliorate the problem of fatal police violence must move beyond the individual level and consider the interaction between law enforcement officers and the neighborhoods that they police.


Naphthalene-Based Polymers as Catalytic Supports for Suzuki Cross-Coupling.
In this work, for the first time, naphthalene (NA)-based polymers were synthesized by one-stage Friedel-Crafts crosslinking. The influence of NA functionalization by -OH, -SO3H, and -NO2 groups on the polymers' porosity and distribution of the catalytically active phase (Pd) was studied. Synthesized catalytic systems containing 1 wt.% of Pd either in the form of Pd(II) species or Pd(0) nanoparticles supported on NA-based polymers were tested in a model reaction of Suzuki cross-coupling between 4-bromoanisole and phenylboronic acid under mild reaction conditions (60 °C, ethanol-water mixture as a solvent). These novel catalysts demonstrated high efficiency with more than 95% of 4-bromoanisole conversion and high selectivity (>97%) for the target 4-methoxybiphenyl.


[The role of medical autopsies as a quality control of patients management in internal medicine units].
The number of medical autopsies has declined in recent decades due to the development of imaging techniques and some risks linked to autopsies. However, the contribution of autopsy is diagnostically significant, even better than new technologies currently available. It is thus a good indicator of quality, but also a training tool, and has a significant impact in the grieving process. At the CHUV, under the leadership of Pathology Department, institutional projects have been implemented in order to increase the number of autopsies, including a pre- and post-graduate training and systematic request for autopsy, with significant gain for clinicians and pathologists, but also for families who get systematic and customized return results.


Effect of mechanical ventilation with end-inspiratory pause on blood-gas exchange.
The effects of end-inspiratory pause (EIP) on gas exchange were measured in 10 adult patients with acute respiratory insufficiency while maintained on mechanical ventilation. Four inspiratory patterns were studied with a constant tidal volume (10 to 15 ml/kg body weight), respiratory rate (9 to 12 breaths/min), FIO2 (0.5) and end-expiratory pressure. Inspiratory flow rate (V insp) and EIP time were varied to produce a control pattern (V insp = 60 L/min, EIP = 0), 2 EIP patterns of 0.6 and 1.2 seconds with a similar V insp and a "slow" flow pattern (V insp = 30 L/min) without EIP. The control pattern was applied before and after each study period. Arterial oxygenation was unchanged with both EIP and "slow" flow patterns when compared to control. Dead-space ventilation (VD/VT) and Paco2 were significantly decreased (p less than 0.01) as EIP was increased from 0 to 1.2 seconds, but remained unchanged with slow inspiratory flow. Thus, EIP improved the efficiency of ventilation with no apparent improvement in oxygenation in patients with acute respiratory insufficiency.


Comparative growth and development of spiders reared on live and dead prey.
Scavenging (feeding on dead prey) has been demonstrated across a number of spider families, yet the implications of feeding on dead prey for the growth and development of individuals and population is unknown. In this study we compare the growth, development, and predatory activity of two species of spiders that were fed on live and dead prey. Pardosa astrigera (Lycosidae) and Hylyphantes graminicola (Lyniphiidae) were fed live or dead fruit flies, Drosophila melanogaster. The survival of P. astrigera and H. graminicola was not affected by prey type. The duration of late instars of P. astrigera fed dead prey were longer and mature spiders had less protein content than those fed live prey, whereas there were no differences in the rate of H. graminicola development, but the mass of mature spiders fed dead prey was greater than those fed live prey. Predation rates by P. astrigera did not differ between the two prey types, but H. graminicola had a higher rate of predation on dead than alive prey, presumably because the dead flies were easier to catch and handle. Overall, the growth, development and reproduction of H. graminicola reared with dead flies was better than those reared on live flies, yet for the larger P. astrigera, dead prey may suit smaller instars but mature spiders may be best maintained with live prey. We have clearly demonstrated that dead prey may be suitable for rearing spiders, although the success of the spiders fed such prey appears size- and species specific.


[Effect of ultraviolet-filtering contact lens on rabbit eyes after exposure to ultraviolet light].
We evaluated the protective effect of a newly designed soft contact lens (SCL) on rabbit eyes. This SCL absorbs the ultraviolet B light of wavelengths between 280 nm and 320 nm. Three weeks after resecting the nictitating membrane, the rabbit corneas were covered either by the new SCL or a conventional SCL. The eyes were exposed to ultraviolet light from two 15 W lamps placed 20 cm anteriorly for 3 hours. Another three hours after the exposure, the cornea was examined first with a slitlamp biomicroscope after staining with fluorescein and then by histopathological means after enucleation. Six eyes wearing the new SCL showed moderate superficial punctate keratopathy. Six eyes wearing conventional SCL showed severe superficial keratopathy or corneal erosion. These findings were in good agreement with the histopathological findings. The new ultraviolet-filtering SCL was thus effective in protecting the rabbit cornea under our experimental conditions.


Tumoral Calcinosis as an Initial Complaint of Juvenile-Onset Amyopathic Dermatomyositis.
Calcinosis is rarely observed in juvenile-onset amyopathic dermatomyositis in contrast to juvenile-onset dermatomyositis. A 6-year-old female presented with several 0.5 to 2 cm-sized painless grouped masses on both knees for 3 years. The patient also presented with multiple erythematous scaly patches and plaques on both elbows, knuckles, buttock, ankles and cheeks. Her mother had similar skin lesions which were erythematous scaly patches on the knuckles and elbows, since her childhood. When skin biopsy was performed from a left knee nodule, liquid chalky discharge was observed. The biopsy results were consistent with calcinosis cutis. Other biopsies from erythematous patch of the patient and erythematous patch of her mother showed vacuolization of basal cell layer with inflammatory cell infiltrations. Laboratory findings showed normal range of serum phosphorus (4.5 mg/dl), calcium (9.3 mg/dl), 1,25-dihydroxy-vitamin D (10.8 ng/ml) and parathyroid hormone levels (11 pg/ml). Both patient and her mother had no history of muscle weakness and showed normal levels of muscle-specific enzyme. Both patients were diagnosed with juvenile-onset amyopathic dermatomyositis based on histopathology and cutaneous manifestations with no evidence of muscle weakness and no serum muscle enzyme abnormalities. Tumoral calcium deposits observed in daughter was diagnosed as dystrophic calcinosis which can be rarely seen in juvenile-onset amyopathic dermatomyositis. The patient is being treated with oral acetazolamide (40 mg/kg/d) for calcinosis.


[Management of children and adolescents with diabetes mellitus: personal experience].
The increasing prevalence of type 2 diabetes in the USA has closely paralleled the increase in childhood obesity noted there, but now across the Western world and therefore in Belgium. (Pre)type 2 diabetes is preceded by insulin resistance which must be diagnosed and treated. In Belgium, type 1 diabetes is the predominant (97%) form of diabetes in young people (< 2,000 cases under the age of 18 years). Type 1 diabetes is an auto-immune disease which is more aggressive in younger children. At onset, the key-symptoms are : polyuria, polydipsia, weight loss, asthenia. Diagnosis is confirmed with 2 strips measuring glycaemia and glycosuria. Treatment and diabetes education for self-management should be initiated immediately in paediatric clinics of diabetology with a specialised multidisciplinary team. Thanks to the Belgian Social medicine, medical consultations and material necessary for treatment are nearly without cost. The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications by maintaining blood glucose concentrations close to the normal range and an HbA1c level under 7%. The number of daily insulin injections, 2 or > or = 4, by itself does not necessarily give better results, but the 4-injection regimen allows greater freedom, taking into account that the proper insulin adjustment is difficult before adolescence. Successful glycaemic control in young patients depends mainly on the quality and intensity of diabetes education. Any dogmatism must be avoided. Dietary recommendations issued over the last few years are the same for diabetic and non-diabetic individuals in order to avoid degenerative diseases. In the twice-daily injection regimen, the allocation of carbohydrates throughout the day is essential. Due to their pharmakokinetic characteristics, rapid-acting and long-acting insulin analogues have specific indications in both the twice-daily injection regimen and the basal-bolus insulin therapy. They improve quality of life, without necessarily reducing HbA1c.


Indole Alkaloids from Hunteria zeylanica.
Six new bisindole alkaloids, hunterizeylines A-F (1-6), three new monomers, hunterizeylines G-I (7-9), and 13 known alkaloids were isolated from an aqueous MeOH extract of the twigs and leaves of Hunteria zeylanica. Hunterizeyline H, geissoschizol, and dihydrocorynantheol displayed weak insecticidal activity against the aphid Rhodobium porosum, with IC50 values of 168.2, 360.5, and 290.6 μM, respectively.


Early detection of breast cancer by leukocyte adherence inhibition assay.
The hematocytometer leukocyte adherence inhibition technique was used to study cell-mediated immune activity against breast carcinoma. In a group of 83 patients with untreated breast cancer in stage I, 74% showed a positive response, among 47 patients in stage II, 64% responded, while only 51% of the 37 patients in stages III and IV responded. Of 86 control persons, only two women showed a positive response. In a group of 296 women with benign breast disease, 21% showed a positive reaction against breast carcinoma antigen. The percentage of positive responses was higher than the average among women with risk factors such as: mother or sister with breast cancer, previous removal of benign breast lumps, microcalcifications, and increased intraductal epithelial proliferation found in the biopsies. Women with benign breast disease having two or more of the above risk factors were assigned to the high risk group. Of 49 women in this group, 47% had reactive leukocytes. Ninety-two women had only one risk factor, and 27% of those showed a positive reaction. Of the 155 women with none of the risk factors, only 10% had a positive reaction. The results suggest that leukocyte adherence inhibition test may be used to identify groups of women with an increased possibility of developing breast cancer.


Regulation of cytotoxic T lymphocyte-mediated graft rejection following bone marrow transplantation.
Cytotoxic T lymphocytes have been implicated as the effector cell mediating graft rejection following human allogeneic bone marrow transplantation. We have studied a BMT patient who rejected haploidentical T cell-depleted marrow. In vitro studies demonstrated that the circulating lymphocytes were CD3+ and CD8+, of recipient origin, and exhibited selective cytotoxicity against donor-specific class I major histocompatibility complex antigens. Cytotoxicity was inhibited by monoclonal antibodies directed against CD3, CD8, CD2, and lymphocyte function-associated antigen-1 on the T cell, and against MHC class I proteins on the target cell. Furthermore, these circulating cells inhibited the in vitro growth and differentiation of enriched donor bone marrow progenitor cells, an inhibition that was partially reversed by anti-CD3 MAb. Donor-specific recipient-derived CTL may mediate resistance to engraftment, and CTL activity may be inhibited by a number of MAb. The implications of these findings for host preparation and treatment are discussed.


Evaluation of the effect of transcranial direct current stimulation on language impairments in the behavioural variant of frontotemporal dementia.
The behavioural variant of frontotemporal dementia is a neurodegenerative disease characterized by bilateral atrophy of the prefrontal cortex, gradual deterioration of behavioural and executive capacities, a breakdown of language initiation and impaired search mechanisms in the lexicon. To date, only a few studies have analysed the modulation of language deficits in the behavioural variant of frontotemporal dementia patients with transcranial direct current stimulation, yet with inconsistent results. Our goal was to assess the impact on language performance of a single session of transcranial direct current stimulation on patients with the behavioural variant of frontotemporal dementia. Using a sham-controlled double-blind crossover design in a cohort of behavioural frontotemporal dementia patients (n = 12), we explored the impact on language performance of a single transcranial direct current stimulation session delivering anodal or cathodal transcranial direct current stimulation, over the left and right dorsolateral prefrontal cortex, compared with sham stimulation. A Letter fluency and a Picture naming task were performed prior and following transcranial direct current stimulation, to assess modulatory effects on language. Behavioural frontotemporal dementia patients were impaired in all evaluation tasks at baseline compared with healthy controls. Computational finite element method (FEM) models of cortical field distribution corroborated expected impacts of left-anodal and right-cathodal transcranial direct current stimulation over the dorsolateral prefrontal cortex and showed lower radial field strength in case of atrophy. However, none of the two tasks showed statistically significant evidence of language improvement caused by active transcranial direct current stimulation compared with sham. Our findings do not argue in favour of pre-therapeutic effects and suggest that stimulation strategies evaluating the modulatory role of transcranial direct current stimulation in the behavioural variant of frontotemporal dementia must carefully weigh the influence of symptom severity and cortical atrophy affecting prefrontal regions to ensure clinical success.


Mushrooms and poisoning.
The mushrooms are probably one of the oldest consumption of mankind having mythological and spiritual significance apart from being a great delicacy. Its poisoning is a common yet poorly recognised. There are more than 2000 varieties which are edible, and nearly 80 varieties are non-edible (or poisonous) type. Not only they resemble some of the edible types, they even grow long with them. Most of the toxic events go unnoticed, yet, sometimes it may be life threatening as some mushrooms are one of the most toxic fungi known to manking. Awareness is pobably the only prevention.


Interactions of 1 alpha,25-dihydroxyvitamin D3 with IL-12 and IL-4 on cytokine expression of human T lymphocytes.
1 alpha,25-Dihydroxyvitamin D3 (1 alpha,25[OH](2)D(3)) exerts its effects on the immune system, particularly through suppression of T helper/cytotoxic cell 1 (T(H)/T(C)1)-mediated reactions, although direct actions of 1 alpha,25(OH)(2)D(3) on human T lymphocytes have not yet been studied in detail. We evaluated the effect of 1 alpha,25(OH)(2)D(3) on basal and cytokine-driven T-cell functions at the single-cell level. We used 4-color flow cytometry for simultaneous detection of intracellular cytokines in CD4(+) and CD8(+) human PBMCs that had been cultured in the presence of 1 alpha,25(OH)(2)D(3) singly or in combination with either IL-12 or IL-4. According to the exploratory nature of these investigations, the Bonferroni correction was not applied for data analysis and presentation. 1 alpha,25(OH)(2)D(3) had little effect on T(H)/T(C)1 cytokines but significantly inhibited IL-12-induced IFN-gamma production. Constitutive synthesis of T(H)/T(C)2-related cytokines was also only modestly affected by 1 alpha,25(OH)(2)D(3) alone. When T(H)/T(C)2 differentiation was induced by IL-4, 1 alpha,25(OH)(2)D(3) significantly expanded the percentages of IL-4(+) and IL-13(+) cells. However, the predominant effect of 1 alpha,25(OH)(2)D(3) on T lymphocytes, particularly in the presence of IL-4, was the induction of separate CD4(+) and CD8(+) subpopulations with almost exclusive expression of IL-6. This might be an important facet of the immunomodulatory action of 1 alpha,25(OH)(2)D(3) because IL-6 might act in parallel with 1 alpha,25(OH)(2)D(3) in modulation of T(H)/T(C) effector cell functions. Our data imply that the specific actions of 1 alpha,25(OH)(2)D(3) on cytokine-stimulated T-cell functions could play a role in the prevention of T(H)/T(C)1-related autoimmune diseases but also predispose toward T(H)/T(C)2-mediated allergic reactions.


Occupational health in industrializing countries.
In this introductory chapter, the editor of this issue of Occupational Medicine: State of the Art Reviews briefly examines some of the market, social, governmental, and other forces affecting occupational health in industrializing countries. Evidence of progress is emphasized, and suggestions for better collaboration are provided.


Ascertainment bias causes false signal of anticipation in genetic prion disease.
Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G > A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.


Intracavitary bleomycin for the control of malignant effusions.
The results of treatment with intracavitary bleomycin are reported in twenty patients with a malignant pleural effusion and five patients with malignant ascites. The control rate was 17/20 (85%) patients with malignant pleural effusions and 3/5 (60%) patients with malignant ascites. Toxicities were minimal with fever being the most common side effect in four patients (16%. Bleomycin is an effective and nontoxic sclerosing agent.


Rio Doce Acoustic Surveys of Fish Biomass and Aquatic Habitat.
Following the failure of the Fundão mine tailings dam in Brazil, approximately 32 million cubic meters of Fe ore tailings were released into the downstream riverine system. The postevent monitoring surveys implemented the use of noninvasive acoustic methods to improve the understanding of the fish biomass distribution patterns and aquatic habitat condition of the impacted reaches of the Rio Gualaxo do Norte, Rio do Carmo, and Rio Doce. The primary focus of the program was to collect hydroacoustic measurements of fish biomass, which was accompanied by sonar imaging of aquatic habitats using high-resolution side scan and downward imaging sonar at each site visited. The biannual surveys began in April 2017 and were fundamentally a multiple control-impact design because before data (prior to the dam failure event) were not available. Up to 22 sites were visited for each survey, including reservoir and river sites. Results indicate similar levels of instream habitat between control and impact river and reservoir sites. Average volumetric biomass was not significantly different between impact sites and their corresponding controls in the August 2018 survey (latest to date). Preliminary temporal analysis of the biomass data set collected indicates that either stable or increasing levels of biomass are detected at tailings impacted sites within the Rio Doce. Integr Environ Assess Manag 2020;16:615-621. © 2020 Hydrobiology QLD Pty Ltd. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).


Isoproterenol, endotoxin shock, and the generalized shwartzman reaction.
Adult hybrid albino rabbits were divided into seven groups. Three groups were given two respective intravenous doses of 10 mug, 25 mug, or 100 mug of endotoxin at an interval of 24 hours. Three other groups were given endotoxin as above, and, in addition, were given 0.5 mg of isoproterenol hydrochloride (Isuprel) by subcutaneous injections at eight-hour intervals beginning at the time of the first injection of endotoxin. A single group was given isoproterenol only. The animals were observed for clinical signs of shock beginning at the time of the first injection of endotoxin. The mortality during the course of the experiment was noted. At the time of death, the animals were studied grossly, and sections were taken for light microscopy. Results showed no meaningful enhancement of endotoxin toxicity as manifested by shock, generalized Shwartzman reaction, or mortality.


An application of the moiré method to three-dimensional measurements of the occlusal aspects of molars.
Moiré photographs of the occlusal surface of human molars were made by means of a specially designed apparatus for moiré contourography. Since molars show contour lines with equal intervals, three-dimensional measurement of the complicated relief of the occlusal surface is possible. The positioning of molar teeth for making the photographs and the technique of the moiré photography for small objects were presented. The three-dimensional measuring method of the molar surface and its use for anthropological purpose were discussed.


Laparoscopic adrenalectomy for isolated adrenal metastasis.
Laparoscopic adrenalectomy is accepted by many as the standard of care for the majority of adrenal masses less than 8 cm. The question exists whether laparoscopic removal of metastatic lesions to the adrenal is more difficult than laparoscopic removal of primary adrenal lesions. We performed a retrospective analysis of all laparoscopic adrenalectomies performed at a single institution from 1998 to 2001, comparing laparoscopic adrenalectomies for primary lesions of the adrenal gland versus isolated metastatic lesions to the adrenal gland. Fourteen laparoscopic adrenalectomies were attempted, 10 for primary disease and 4 for metastatic disease. All 10 laparoscopic procedures were completed successfully for primary disease (average operative time=218 minutes, average tumor size=4 cm, median hospital stay=2 days). Only one of the 4 laparoscopic adrenalectomies for metastatic disease was completed successfully (average operative time=332 minutes, average tumor size=7.3 cm, median hospital stay=2 days). No major complications occurred in either group. We feel laparoscopic adrenalectomy is the preferred approach for primary adrenal masses less than 8 cm. Based on our experience and a review of the literature, isolated metastatic lesions to the adrenal gland appear less amenable to laparoscopic removal than do primary lesions of the same size.


The impact of smoking on wound healing: the role of the nurse.
Smoking is known to have a deleterious effect on health in general and on wound healing in particular. Poor oxygenation and the impact of the impurities contained in cigarette smoke interfere with wound healing. It is the role of the nurse when caring for a person with a wound to treat them in a holistic manner, which includes encouraging and supporting patients who smoke to stop doing so. This paper looks at the evidence surrounding disrupted wound healing in patients who smoke and identifies why nurses should help them quit. It also identifies some of the strategies nurses might employ to aid smoking cessation.


Incidence and prevalence of motor neuron disease in two Danish counties.
A total of 186 cases of motor neuron disease (MND) was identified in two Danish counties during the period 1974-1986. The average annual incidence rate was 1.4/100,000 population, and the male:female ratio of incidence rates was 1.5. Mean age at diagnosis was 64.3 +/- 10.0 years. The incidence rates increased significantly with advancing age and reached a maximum at age 60-79 years, followed by a nonsignificant decrease. The average point prevalence was 3.1/100,000 population. Bulbar symptoms were part of the initial symptoms in 65% of cases, and patients with bulbar onset were older than patients with spinal onset. Age- and sex-specific incidence rates indicated a marked male preponderance amongst the youngest patients, in contrast to a female preponderance in patients above 60 years with bulbar onset of MND. Familial MND accounted for 2.7% of cases.


Effect of fibrin on osteogenic differentiation and VEGF expression of bone marrow stromal cells in mineralised scaffolds: a three-dimensional analysis.
The aim of the present study was to test the hypothesis that a fibrin matrix enhances the osteogenic differentiation and expression of vascular endothelial growth factor (VEGF) by human bone marrow stromal cells (hBMSCs) seeded into mineralised scaffolds. Porous calcium carbonate scaffolds were droplet seeded with hBMSCs using a matrix containing 3 % fibrinogen and cultured for 3 weeks. Seeded scaffolds without the fibrin matrix served as controls. The scaffolds were evaluated, using undecalcified thick sections, for fluorescence staining for nuclei, osteocalcin (OC) and VEGF. The sections were systematically scanned using optical sectioning and three dimensional distributions of cells and positive staining indicating expression of OC and VEGF were reconstructed from the z-stacks. The fibrin matrix maintained a significantly higher level of cell numbers after 2 d and 1 week and delayed the onset of osteogenic differentiation while sustaining a significantly higher level of OC and VEGF expression after 2 and 3 weeks, starting from the periphery of the scaffolds. There was a decrease in cell density from the periphery to the centre of the scaffolds in both groups The percentage of cells expressing OC and VEGF was significantly different between the centre and the periphery of the scaffolds in the fibrin(+) group but not in the controls. It is concluded that the fibrin matrix used appears to be a useful adjunct for supporting and sustaining osteogenic and angiogenic activity of hBMSCs in tissue engineered constructs. This could help to improve their performance in a clinical setting.


The Hibernator Microbiome: Host-Bacterial Interactions in an Extreme Nutritional Symbiosis.
Animals that undergo seasonal cycles of feeding and fasting have adaptations that maintain integrity of organ systems when dietary nutrients are lacking. Food deprivation also challenges the gut microbiota, which relies heavily on host diet for metabolic substrates and the gastrointestinal tract, which is influenced by enteral nutrients and microbial activity. Winter fasting in hibernators shifts the microbiota to favor taxa with the capacity to degrade and utilize host-derived substrates and disfavor taxa that prefer complex plant polysaccharides. Microbiome alterations may contribute to hibernation-induced changes in the intestinal immune system, epithelial barrier function, and other host features that are affected by microbial short-chain fatty acids and other metabolites. Understanding mechanisms by which the hibernator host and its gut symbionts adapt to the altered nutritional landscape during winter fasting may provide insights into protective mechanisms that are compromised when nonhibernating species, such as humans, undergo long periods of enteral nutrient deprivation.


Chemical performance of multi-environment trials in lens (Lens culinaris M.).
Genotype-environment (GE) interaction has been a major effect to determine stable lens (Lens culinaris (Medik.) Merr.) cultivars for chemical composition in Turkey. Utilization of the lines depends on their agronomic traits and stability of the chemical composition in diverse environments. The objectives of this study were: (i) to evaluate the influence of year and location on the chemical composition of lens genotypes; and (ii) to determine which cultivar is the most stable. Genotypes were evaluated over 3 years (2005, 2006 and 2007) at four locations in Turkey. Effects of year had the largest impact on all protein contents. GE interaction was analyzed by using linear regression techniques. Stability was estimated using the Eberhart and Russell method. 'Kişlik Kirmizi51' was the most stable cultivar for grain yield. The highest protein was obtained from 'Kişlik Kirmizi51' (4.6%) across environments. According to stability analysis, 'Firat 87' had the most stable chemical composition. This genotype had a regression coefficient (b(i) = 1) around unity, and deviations from regression values (delta(ij) = 0) around zero. Chemical composition was affected by year in this study. Temperature might have an effect on protein, oil, carbohydrate, fibre and ash. Firat 87 could be recommended for favourable environments.


Toxicological features of maleilated polyflavonoids from Pinus radiata (D. Don.) as potential functional additives for biomaterials design.
Polyflavonoids from Pinus radiata (D. Don.) are an abundant natural oligomers highly desirable as renewable chemicals. However, structural modification of polyflavonoids is a viable strategy in order to use such polyphenols as macrobuilding-blocks for biomaterial design. Polyflavonoids were esterified with three five-member cyclic anhydrides (maleic, itaconic, and citraconic) at 20 °C during 24 h in order to diversify physicochemical-, and biological-properties for agricultural, and food-packaging applications. In addition, the influence of the chemical modification, as well as the chemical structure of the grafting on toxicological features was evaluated. Structural features of derivatives were analyzed by spectroscopy (FT-IR and 1H-NMR), and the degree of substitution was calculated. Toxicological profile was assessed by using three target species in a wide range of concentration (0.01-100 mgL-1). Effect of polyflavonoids on the growth rate (Selenastrum capricornutum), mortality (Daphnia magna), and germination and radicle length (Lactuca sativa) was determined. Chemical modification affects the toxicological profile on the derivatives in a high extent. Results described remarkable differences in function of the target specie. The bioassays indicate differences of the polyflavonoids toxicological profile associated to the chemical structure of the grafting. Results allowed conclude that polyflavonoids from pine bark show slight toxic properties.


Partial purification and kinetics of oestriol 16 alpha-glucuronyltransferase from the cytosol fraction of human liver.
An enzyme that conjugates the 16alpha-hydroxyl group of oestriol with glucuronic acid was found in the cytosol fraction of human liver. The enzymic activity could not be sedimented when the cytosol fraction was centrifuged at 158000g(av.) for 120min. The oestriol 16alpha-glucuronyltransferase was purified 100-fold by 0-30% saturation of the cytosol fraction with ammonium sulphate followed by filtration of the precipitate through Sephadex G-200. The activity was eluted at the void volume. The product of the reaction, oestriol 16alpha-monoglucuronide, was identified by paper chromatography and by crystallization of radioactive product to constant specific radioactivity. The optimum temperature was 37 degrees C, and the activation energy was calculated to be 11.1kcal/mol. The apparent Michaelis-Menten constants for oestriol and UDP-glucuronic acid were 13.3 and 100mum respectively. Cu(2+), Zn(2+) and Hg(2+) inhibited, whereas Mg(2+), Mn(2+) and Fe(2+) stimulated the enzyme. Substrate-specificity studies indicated that the amount of oestradiol-17beta, oestradiol-17alpha and oestrone conjugated was not more than about 5% of that found for oestriol. Oestriol 16alpha-monoglucuronide, a product of the reaction, did not inhibit the 16alpha-oestriol glucuronyltransferase; in contrast, UDP, another product of the reaction, inhibited the enzyme competitively with respect to UDP-glucuronic acid as the substrate, and non-competitively with respect to oestriol as the substrate. ATP and UDP-N-acetylglucosamine did not affect the oestriol 16alpha-glucuronyltransferase. 17-Epioestriol acted as a competitive inhibitor and 16-epioestriol as a non-competitive inhibitor of the glucuronidation of oestriol. 5alpha-Pregnane-3alpha,20alpha-diol also inhibited the enzyme non-competitively. It is most likely that the oestriol 16alpha-glucuronyltransferase described here is bound to the membranes of the endoplasmic reticulum.


UGT1A1 Gene Polymorphisms in Patients with Small Cell Lung Cancer Treated with Irinotecan-Platinum Doublet Chemotherapy and Their Association with Gastrointestinal Toxicity and Overall Survival.
Irinotecan (CPT11) is an important drug for small cell lung cancer (SCLC) chemotherapy (CTx). UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms can influence CPT11-related toxicity. This study aimed to assess prevalence of UGT1A1 polymorphisms and their association with clinical outcomes in patients with SCLC on CPT11-CTx. An observational cohort of treatment-naïve patients with SCLC was given CPT11-platinum doublet at a referral center in North India over 3 years. Clinical outcomes assessed were hematological and gastrointestinal toxicity (Common Terminology Criteria for Adverse Events, version 3.0), response rates (RECIST), and overall survival (OS). Peripheral blood was drawn from all enrolled patients just prior to CPT11-CTx initiation, and genomic DNA was isolated. Genotyping was done by polymerase chain reaction (PCR)-restriction fragment length polymorphism for UGT1A1*7, UGT1A1*6, and UGT1A1*27 and by PCR-DNA sequencing for UGT1A1*28. Patients were classified as homozygous wild-type (WT/WT), heterozygous mutant (WT/M), or homozygous mutant (M/M) for each polymorphism assessed. Of 140 patients enrolled, no mutant alleles were found for UGT1A1*27 or UGT1A1*7. Frequency of UGT1A1*6 polymorphisms (n = 111) was 89.2% for WT/WT, 8.1% for WT/M, and 2.7% for M/M. For UGT1A1*28 (n = 102), this was 41.2% for WT/WT, 43.1% for WT/M, and 15.7% for M/M. UGT1A1*6 WT/WT patients tolerated >95% predicted CPT11 dose more frequently (59.6% vs. 25.0% in WT/M-M/M combined group; p = .026). The UGT1A1*6 WT/M-M/M group also experienced severe (grade ≥3) diarrhea (41.7% vs. 17.2% in WT/WT; p = .044) and mucositis (41.7% vs. 8.1% in WT/WT; p = .005) more frequently. On multivariate logistic regression analysis, UGT1A1*6 WT/M-M/M status was the only variable associated with occurrence of both mucositis (odds ratio [OR], 10.4) and severe diarrhea (OR, 4.8). UGT1A1*28 WT/M-M/M patients had better OS (320 days [95% confidence interval, 203-437] vs. 216 days [95% confidence interval, 140-292] in WT/WT group; p = .047). On multivariate Cox proportional hazards analysis, UGT1A1*28 WT/M-M/M status was independently associated with better OS (hazard ratio, 0.35), whereas lack of objective radiological response, moderate/heavy smoking, and increasing age were associated with worse OS. UGT1A1*6 and UGT1A1*28 polymorphisms were associated with increased gastrointestinal toxicity and improved OS, respectively, in North Indian patients with SCLC receiving CPT11-CTx. UGT1A1 gene polymorphisms are known to influence irinotecan-related toxicity. In this prospective cohort study of patients with small cell lung cancer receiving first-line irinotecan-platinum chemotherapy, the prevalence of UGT1A1*6 polymorphisms was found to be 10.8% UGT1A1*6 and 58.8% UGT1A1*28 homo/heterozygous mutant, respectively. UGT1A1*6 homo/heterozygous mutant status was associated with severe diarrhea and mucositis. UGT1A1*28 homo/heterozygous mutant status was independently associated with improved overall survival.


Floral Scent Chemistry of Luculia yunnanensis (Rubiaceae), a Species Endemic to China with Sweetly Fragrant Flowers.
Luculia plants are famed ornamentals with sweetly fragrant flowers. Luculia yunnanensis Hu is an endemic plant from Yunnan Province, China. Headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) was used to identify the volatile organic compounds (VOCs) of the different flower development stages of L. yunnanensis for the evaluation of floral volatile polymorphism. The results showed that a total of 40 compounds were identified at four different stages. The main aroma-active compounds were 3-carene, α-cubebene, α-copaene, δ-cadinene, and isoledene. Floral scent emission had the tendency to ascend first and descend in succession, reaching its peak level at the initial-flowering stage. The richest diversity of floral volatiles was detected at the full-flowering stage. Principal component analysis (PCA) indicated that the composition and its relative content of floral scent differed at the whole flower development stage. In comparison with the other two species of Luculia (L. pinceana and L. gratissima), the composition and its relative content of floral scent were also different among the tree species.


Enhancing Extinction Learning in Posttraumatic Stress Disorder With Brief Daily Imaginal Exposure and Methylene Blue: A Randomized Controlled Trial.
The memory-enhancing drug methylene blue (MB) administered after extinction training improves fear extinction retention in rats and humans with claustrophobia. Robust findings from animal research, in combination with established safety and data showing MB-enhanced extinction in humans, provide a foundation to extend this work to extinction-based therapies for posttraumatic stress disorder (PTSD) such as prolonged exposure (PE). Patients with chronic PTSD (DSM-IV-TR; N = 42) were randomly assigned to imaginal exposure plus MB (IE + MB), imaginal exposure plus placebo (IE + PBO), or waitlist (WL/standard PE) from September 2011 to April 2013. Following 5 daily, 50-minute imaginal exposure sessions, 260 mg of MB or PBO was administered. Waitlist controls received PE following 1-month follow-up. Patients were assessed using the independent evaluator-rated PTSD Symptom Scale-Interview version (primary outcome), patient-rated PTSD, trauma-related psychopathology, and functioning through 3-month follow-up. Both IE + MB and IE + PBO showed strong clinical gains that did not differ from standard PE at 3-month follow-up. MB-augmented exposure specifically enhanced independent evaluator-rated treatment response (number needed to treat = 7.5) and quality of life compared to placebo (effect size d = 0.58). Rate of change for IE + MB showed a delayed initial response followed by accelerated recovery, which differed from the linear pattern seen in IE + PBO. MB effects were facilitated by better working memory but not by changes in beliefs. The findings provide preliminary efficacy for a brief IE treatment for PTSD and point to the potential utility of MB for enhancing outcome. Brief interventions and better tailoring of MB augmentation strategies, adjusting for observed patterns, may have the potential to reduce dropout, accelerate change, and improve outcomes. ClinicalTrials.gov identifier: NCT01188694.


SpaceANOVA: Spatial co-occurrence analysis of cell types in multiplex imaging data using point process and functional ANOVA.
Multiplex imaging platforms have enabled the identification of the spatial organization of different types of cells in complex tissue or tumor microenvironment (TME). Exploring the potential variations in the spatial co-occurrence or co-localization of different cell types across distinct tissue or disease classes can provide significant pathological insights, paving the way for intervention strategies. However, the existing methods in this context either rely on stringent statistical assumptions or suffer from a lack of generalizability. We present a highly powerful method to study differential spatial co-occurrence of cell types across multiple tissue or disease groups, based on the theories of the Poisson point process (PPP) and functional analysis of variance (FANOVA). Notably, the method accommodates multiple images per subject and addresses the problem of missing tissue regions, commonly encountered in such a context due to the complex nature of the data-collection procedure. We demonstrate the superior statistical power and robustness of the method in comparison to existing approaches through realistic simulation studies. Furthermore, we apply the method to three real datasets on different diseases collected using different imaging platforms. In particular, one of these datasets reveals novel insights into the spatial characteristics of various types of precursor lesions associated with colorectal cancer. The associated R package can be found here, https://github.com/sealx017/SpaceANOVA.


Determination of Domoic Acid in Plankton Net Samples from Golden Horn Estuary, Turkey, Using HPLC with Fluorescence Detection.
This study focused on the fluctuations of domoic acid (DA) levels in plankton net samples collected from the Golden Horn Estuary (GHE), Turkey, between August 2011 and July 2012. DA concentrations were determined by high-performance liquid chromatography (HPLC), using a fluorenylmethoxycarbonyl (FMOC) derivatization technique. Monthly and biweekly data were evaluated with environmental variables, and their influence on DA production is discussed. DA levels in plankton net samples varied between 0.36 and 94.34 µg L- 1. DA levels showed remarkable seasonal variation and they were generally higher in May, 2012, but no DA was detected between February and April, 2012. DA production was mostly controlled by temperature, with nitrate and silicate limitations being secondary factors that influenced DA concentrations.


[Diagnosis and treatment of lymphatic malformations].
More than seventy percent of lymphatic malformations (LMs) occur in head and neck region. The management of head and neck LMs is challenging,especially for diffuse and infiltrative cases.It can cause deformity and death in severe patients. Surgical resection is the main method to treat LMs in the past and sclerotherapy has also greatly improved the treatment out come of LMs over the past 20 years. However, it is still hardly to achieve satisfactory prognosis for the patients with extensively infiltrative lesions, regardless of surgical resection or sclerotherapy. In the past five years, some scholars have made a preliminary exploration of new treatment methods, such as oral medicine, to diversify the treatment options of head and neck LMs. This article will review the general situation, biological properties, clinical characteristics, diagnostic methods, and current treatment strategies for LMs as well as trends in management of LMs.


Evolution of Alternative Splicing in Eudicots.
Alternative pre-mRNA splicing (AS) is prevalent in plants and is involved in many interactions between plants and environmental stresses. However, the patterns and underlying mechanisms of AS evolution in plants remain unclear. By analyzing the transcriptomes of four eudicot species, we revealed that the divergence of AS is largely due to the gains and losses of AS events among orthologous genes. Furthermore, based on a subset of AS, in which AS can be directly associated with specific transcripts, we found that AS that generates transcripts containing premature termination codons (PTC), are likely more conserved than those that generate non-PTC containing transcripts. This suggests that AS coupled with nonsense-mediated decay (NMD) might play an important role in affecting mRNA levels post-transcriptionally. To understand the mechanisms underlying the divergence of AS, we analyzed the key determinants of AS using a machine learning approach. We found that the presence/absence of alternative splice site (SS) within the junction, the distance between the authentic SS and the nearest alternative SS, the size of exon-exon junctions were the major determinants for both alternative 5' donor site and 3' acceptor site among the studied species, suggesting a relatively conserved AS mechanism. The comparative analysis further demonstrated that variations of the identified AS determinants significantly contributed to the AS divergence among closely related species in both Solanaceae and Brassicaceae taxa. Together, these results provide detailed insights into the evolution of AS in plants.


Insight into Radical Initiation, Solvent Effects, and Biphenyl Production in Iron-Bisphosphine Cross-Couplings.
Iron-bisphosphines have attracted broad interest as highly effective and versatile catalytic systems for two- and three-component cross-coupling strategies. While recent mechanistic studies have defined the role of organoiron(II)-bisphosphine species as key intermediates for selective cross-coupled product formation in these systems, mechanistic features that are essential for catalytic performance remain undefined. Specifically, key questions include the following: what is the generality of iron(II) intermediates for radical initiation in cross-couplings? What factors control reactivity toward homocoupled biaryl side-products in these systems? Finally, what are the solvent effects in these reactions that enable high catalytic performance? Herein, we address these key questions by examining the mechanism of enantioselective coupling between α-chloro- and α-bromoalkanoates and aryl Grignard reagents catalyzed by chiral bisphosphine-iron complexes. By employing freeze-trapped 57Fe Mössbauer and EPR studies combined with inorganic synthesis, X-ray crystallography, reactivity studies, and quantum mechanical calculations, we define the key in situ iron speciation as well as their catalytic roles. In contrast to iron-SciOPP aryl-alkyl couplings, where monophenylated species were found to be the predominant reactive intermediate or prior proposals of reduced iron species to initiate catalysis, the enantioselective system utilizes an iron(II)-(R,R)-BenzP* bisphenylated intermediate to initiate the catalytic cycle. A profound consequence of this radical initiation process is that halogen abstraction and subsequent reductive elimination result in considerable amounts of biphenyl side products, limiting the efficiency of this method. Overall, this study offers key insights into the broader role of iron(II)-bisphosphine species for radical initiation, factors contributing to biphenyl side product generation, and protocol effects (solvent, Grignard reagent addition rate) that are critical to minimizing biphenyl generation to obtain more selective cross-coupling methods.


Characterization of pregnancy-associated plasma protein-A: comparison with alpha 2-macroglobulin.
Pregnancy-associated plasma protein-A (PAPP-A), like alpha 2-macroglobulin (alpha 2M), is a large protein with homotetrameric molecular conformation. Each monomer has Mr 205 kDa. Total carbohydrate content of PAPP-A (19.4%) exceeded that of alpha 2M (8.6%). In addition to glucose (9.4%), fucose (3.1%), mannose (2.3%) and galactose (0.8%), PAPP-A contained glucuronic acid (3.8%). The amino acid composition of PAPP-A differed most significantly from alpha 2M, in the content of glutamate, glycine and lysine. Although the peptide core of both proteins were of similar size, the difference in size, of native molecules was due to the carbohydrate moiety. Whereas alpha 2M monomer was autolytically cleaved into two smaller non-identical subunits (Mr 128 and 65 kDa), no such breakdown products were observed with PAPP-A. Unlike alpha 2M, PAPP-A is not a broad spectrum protease inhibitor. Both proteins inhibited human granulocyte elastase (HGE) in a dose dependent relationship, with PAPP-A (Ki 0.2 x 10(-6) M) being a more potent inhibitor than alpha 2M (Ki 1.02 x 10(-6) M). Since PAPP-A lacked internal thiolester groups, the mechanism of HGE inhibition was unlikely to be entrapment, as defined for alpha 2M. Inhibition kinetics of HGE for PAPP-A (noncompetitive inhibitor) and alpha 2M (uncompetitive inhibitor) were distinct. Thus, these findings do not support the tenet of a common ancestral protein for PAPP-A and alpha 2M.


Stochastic model of ultrafine particle deposition and clearance in the human respiratory tract.
Deposition and clearance of insoluble ultrafine particles, ranging from 1 to 100 nm, were simulated by stochastic models using Monte Carlo methods. Brownian motion is the dominant mode of deposition in human airways. The additional effects of convective diffusion in bifurcations and axial diffusion (convective mixing) primarily affect particle transport and deposition of particles in the 1-10 nm range. Regarding total deposition, the effects of both convective mechanisms are practically compensated by the concomitant effect of molecular radial diffusion (Brownian motion). During the first hours following inhalation, 1 nm particles are predicted to be cleared much faster than particles in the size range from 10 to 100 nm, with a retained fraction of about 80% after 24 h. For 1-10 nm particles, extracellular transfer to blood is the most likely mode of clearance, while uptake and subsequent accumulation in epithelial cells are assumed to be the preferential mechanisms for 10-100 nm particles.