Medical therapy after successful percutaneous coronary revascularization.
Percutaneous coronary revascularization frequently relieves angina in patients with ischemic heart disease and may obviate the need for antianginal medications. To examine the use of antianginal medications after successful percutaneous coronary revascularization. Retrospective cohort study of the Mayo Clinic PTCA [percutaneous transluminal coronary angioplasty] Registry. Tertiary care center. 3831 patients who underwent successful percutaneous coronary revascularization from September 1979 through August 1997 and had not had myocardial infarction within the year before the intervention. Use of antianginal medications (beta-adrenergic blockers, nitrates, and calcium-channel blockers) before the intervention, at hospital discharge, and 6 months after the intervention. 99% of patients reported improvement in their symptoms at hospital discharge. At 6 months, 87% of patients were free of myocardial infarction, coronary bypass surgery, or additional percutaneous intervention. Compared with 66% of patients before the index intervention, only 12% of patients had severe angina at 6 months and 69% were completely free of angina. Nonetheless, at 6 months, 39% of patients were receiving beta-adrenergic blockers (preprocedure proportion, 43%; P < 0.001), 36% were receiving nitrates (preprocedure proportion, 41%; P < 0.001), and 57% were receiving calcium-channel blockers (preprocedure proportion, 50%; P < 0.001). These trends persisted for patients without hypertension and those who had complete revascularization. Successful percutaneous coronary revascularization did not substantially supplant the use of antianginal medications, which were commonly used despite the marked improvement in anginal status. This may reflect reluctance to alter therapy once symptoms of angina subside. Guidelines on continued medical therapy after percutaneous coronary revascularization are needed.


[Determination of left ventricular function parameters and myocardial mass: comparison of MRI and EBT].
Comparative volumetric assessment of the left ventricle by magnetic resonance imaging (MRI) and electron beam tomography (EBT) in patients with ischemic and dilated cardiac disease. Thirty-two patients underwent cine MRI and EBT in the multislice mode. All studies were triggered to the ECG. Left ventricular ejection fraction (EF), end-diastolic (EDV) and end-systolic volume (ESV), and myocardial mass (MM) were determined by 3D-volumetry by MRI and EBT and results were compared. The correlation between MRI and EBT for EF, EDV, ESV, and MM were r = 0.86, r = 0.95, r = 0.95, and r = 0.93, respectively. There is an excellent correlation between MRI and EBT in determining left-ventricular parameters. Both methods are suitable for volumetric assessment of the left ventricle.


Conversations and Reactions Around Severe Hypoglycemia (CRASH) Study: Results From People With Diabetes and Caregivers in the United States.
A survey was conducted in eight countries to examine conversations around, and experiences and treatments during, severe hypoglycemia among people with diabetes and caregivers of people with diabetes. This article reports a subgroup analysis from the United States involving 219 people with diabetes and 210 caregivers. Most respondents (79.7%) did not use professional health care services during their most recent severe hypoglycemic event, and 40.3% did not report the event to their health care providers at a subsequent follow-up visit. Hypoglycemic events left respondents feeling scared (70.9%), unprepared (42.7%), and helpless (46.9%). These clinically important psychosocial impacts on people with diabetes and caregivers underscore the need for conversations about hypoglycemia prevention and management.


Contrasting patterns in the occurrence and biomass centers of gravity among fish and macroinvertebrates in a continental shelf ecosystem.
The distribution of a group of fish and macroinvertebrates (n = 52) resident in the US Northeast Shelf large marine ecosystem were characterized with species distribution models (SDM), which in turn were used to estimate occurrence and biomass center of gravity (COG). The SDMs were fit using random forest machine learning and were informed with a range of physical and biological variables. The estimated probability of occurrence and biomass from the models provided the weightings to determine depth, distance to the coast, and along-shelf distance COG. The COGs of occupancy and biomass habitat tended to be separated by distances averaging 50 km, which approximates half of the minor axis of the subject ecosystem. During the study period (1978-2018), the biomass COG has tended to shift to further offshore positions whereas occupancy habitat has stayed at a regular spacing from the coastline. Both habitat types have shifted their along-shelf distances, indicating a general movement to higher latitude or to the Northeast for this ecosystem. However, biomass tended to occur at lower latitudes in the spring and higher latitude in the fall in a response to seasonal conditions. Distribution of habitat in relation to depth reveals a divergence in response with occupancy habitat shallowing over time and biomass habitat distributing in progressively deeper water. These results suggest that climate forced change in distribution will differentially affect occurrence and biomass of marine taxa, which will likely affect the organization of ecosystems and the manner in which human populations utilize marine resources.


A model of acute infectious neonatal diarrhoea.
Oral inoculation of neonatal MFI mice with enterotoxigenic strains of Escherichia coli that possessed the K99 or F41 antigen or both resulted in severe diarrhoea with high mortality. The diarrhoea was associated with increased fluid in the gut, greatly increased numbers of E. coli in gut homogenates and reduced weight gain compared to control animals. Further studies with strain B44 demonstrated greatly increased numbers of E. coli on the surface of the intestinal mucosa and haemo-concentration. The infection was transmissible between litter-mates. There was no evidence of invasion of the intestinal tissue of infected animals. Gnotobiotic Balb C mice and endotoxin-resistant mice were susceptible to oral inoculation with bovine enterotoxigenic E. coli strains, but neonatal rats were not susceptible to infection with enterotoxigenic E. coli strains B44 or 431. Porcine strains of E. coli that possessed K88 or 987P antigen did not infect neonatal MFI mice but an "atypical" porcine strain (431) which possessed both K99 and F41 antigens caused diarrhoea and a high mortality. The disease in neonatal mice resembled acute diarrhoea caused by these bacteria in other species, particularly the calf, and the model should be of value in assessing the efficacy of therapeutic agents.


Anchoring Polar Organic Molecules in Defective Ammonium Vanadate for High-Performance Flexible Aqueous Zinc-Ion Battery.
Ammonium vanadate (NVO) often has unsatisfactory electrochemical performance due to the irreversible removal of NH4 + during the reaction. Herein, layered DMF-NVO nanoflake arrays (NFAs) grown on highly conductive carbon cloth (CC) are employed as the binder-free cathode (DMF-NVO NFAs/CC), which produces an enlarged interlayer spacing of 12.6 Å (against 9.5 Å for NH4 V4 O10 ) by effective N, N-dimethylformamide (DMF) intercalation. Furthermore, the strong attraction of highly polar carbonyl and ammonium ions in DMF can stabilize the lattice structure, and low-polar alkyl groups can interact with the weak electrostatic generated by Zn2+ , which allows Zn2+ to be freely intercalated. The DMF-NVO NFAs/CC//Zn battery exhibits an impressive high capacity of 536 mAh g-1 at 0.5 A g-1 , excellent rate capability, and cycling performance. The results of density functional theory simulation demonstrate that the intercalation of DMF can significantly reduce the band gap and the diffusion barrier of Zn2+ , and can also accommodate more Zn2+ . The assembled flexible aqueous rechargeable zinc ion batteries (FARZIBs) exhibit outstanding energy density and power density, up to 436 Wh kg-1 at 400 W kg-1 , and still remains 180 Wh kg-1 at 4000 W kg-1 . This work can provide a reference for the design of cathode materials for high-performance FARZIBs.


Adenosine A1-receptor coupling to phosphoinositide metabolism in pregnant guinea pig myometrium.
Adenosine contracts pregnant and nonpregnant guinea pig myometrial smooth muscle (MSM). We have 1) described dissociation of A1-adenosine receptors from adenylate cyclase inhibition in nonpregnant MSM (M. A. Smith, J. L. Silverstein, D. P. Westfall, and I. L. O. Buxton, Cell. Signal. 1: 357-365, 1989); 2) described appearance of such inhibitory coupling in pregnant MSM [W. P. Schiemann, D. P. Westfall, and I. L. O. Buxton, Am. J. Physiol. 261 (Endocrinol. Metab. 24): E141-E150, 1991]; and 3) demonstrated a role for myometrial A1 receptors in the rapid formation of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in nonpregnant MSM and the cyclooxygenase dependence of this effect (W. P. Schiemann, K. O. Doggwiller, and I. L. O. Buxton. J. Pharmacol. Exp. Ther. 258: 429-437, 1991). To further characterize adenosine action in pregnant tissue, we explored A1 coupling to increased phosphoinositide hydrolysis in near-term pregnant MSM. The A1-receptor agonist (+)-N6-(2-phenylisopropyl)adenosine stimulates the rapid dose-dependent formation of Ins(1,4,5)P3 and stimulates rapid degradation of uterine inositol monophosphates (InsP) in a manner paralleling increases in inositol polyphosphates. Both A1-mediated responses were blocked by the A1 antagonist 8-(p-sulfophenyl)theophylline, and, unlike the effect observed in nonpregnant MSM, treatment of pregnant MSM with either meclofenamate or indomethacin failed to block A1-mediated increases in Ins(1,4,5)P3. Pretreatment of MSM with either Li+ or pertussis toxin failed to alter either Ins(1,4,5)P3 formation or InsP degradation. Furthermore, assay of inositol phosphomonoesterase (InsPase) activity in the presence or absence of Li+ confirmed the existence of an MSM Li(+)-insensitive InsPase enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)


Regulation of myofibrillar accumulation in chick muscle cultures: evidence for the involvement of calcium and lysosomes in non-uniform turnover of contractile proteins.
The effect of calcium on myofibrillar turnover in primary chick leg skeletal muscle cultures was examined. Addition of the calcium ionophore A23187 at subcontraction threshold levels (0.38 microM) increased significantly rates of efflux of preloaded 45Ca+2 but had no effect on total protein accumulation. However, A23187 as well as ionomycin caused decreased accumulation of the myofibrillar proteins, myosin heavy chain (MHC), myosin light chain 1f (LC1f), 2f (LC2f), alpha-actin (Ac), and tropomyosin (TM). A23187 increased the degradation rate of LC1f, LC2f, and TM after 24 h. In contrast, the calcium ionophore caused decreased degradation of Ac and troponin-C and had no effect on the degradation of MHC, troponin-T, troponin-I, or alpha, beta-desmin (Dm). In addition, A23187 did not alter degradation of total myotube protein. The ionophore had little or no effect on the synthesis of total myotube proteins, but caused a marked decrease in the synthesis of MHC, LC1f, LC2f, Ac, TM, and Dm after 48 h. The mechanisms involved in calcium-stimulated degradation of the myofibrillar proteins were also investigated. Increased proteolysis appeared to involve a lysosomal pathway, since the effect of the Ca++ ionophore could be blocked by the protease inhibitor leupeptin and the lysosomotropic agents methylamine and chloroquine. The effects of A23187 occur in the presence of serum, a condition in which no lysosomal component of overall protein degradation is detected. The differential effect of A23187 on the degradative rates of the myofibrillar proteins suggests a dynamic structure for the contractile apparatus.


Quantitative Characterization of a Desalination Membrane Model System by X-ray Photoelectron Spectroscopy.
Aromatic polyamide films form the active layer in reverse osmosis desalination membranes. Despite widespread use of this technology, it suffers from low rejection rates for certain water contaminants and from membrane fouling. Through a better understanding of the fundamental surface chemical processes during reverse osmosis desalination, advances in membrane and material design are expected. The recent invention of a molecular layer-by-layer (mLbL) preparation technique [ Johnson , P. M. ; Molecular Layer-by-Layer Deposition of Highly Crosslinked Polyamide Films . J. Polym. Sci., Part B: Polym. Phys. 2012 , 50 ( 3 ), 168 - 173 ] yields films that are sufficiently smooth to warrant investigation with high-resolution microscopy and spectroscopy methods. We present high-resolution, quantitative X-ray photoelectron spectroscopy (XPS) data on the surface chemistry of ultrathin polyamide films that can serve as a model system for desalination membranes. We show that a quantitative analysis of the XPS spectra gives information about the functional groups of the film as well as other compounds present due to the synthesis under ambient conditions. Unpolymerized functional groups are identified and aid in understanding the degree of cross-linking. Investigation of polymers with synchrotron-based XPS requires taking beam-induced changes into account. We quantify X-ray beam damage and show that beam damage to the polyamide is limited, allowing long-term investigation of thin polyamide films. Characterizing mLbL-grown films via high-resolution XPS is the basis for a better understanding of the chemical interplay of polyamide surface functional groups with the major components of desalination systems.


MEK1-induced physiological hypertrophy inhibits chronic post-myocardial infarction remodeling in mice.
Although activation of MEK-ERK signaling is known to be cardioprotective during acute reperfusion injury, the effect of MEK activation on chronic changes in ventricular structure and function during the more complex process of remodeling after myocardial infarction (MI) with or without reperfusion remains uncertain. Four weeks after permanent coronary ligation, LV fractional shorting, preload recruitable stroke work, and end-systolic elastance were all preserved in transgenic mice with CM-specific upregulation of the MEK1-ERK1/2 signaling pathway (MEK1 Tg) compared to wildtype (WT) controls (5.8% decline vs. 17.3%, P < 0.01; 603 ± 98 mmHg vs. 335 ± 98, P < 0.05; 6.14 ± 0.57 mmHg/µl vs. 3.92 ± 0.60, P < 0.05, respectively). Despite similar initial infarct sizes, post-MI remodeling was significantly reduced in MEK1 Tg, demonstrated by reductions in chronic infarct size (28.5 ± 3.1% vs. 47.8 ± 3.2%), myocardial fibrosis (3.98 ± 0.74% vs. 9.27 ± 1.97%) and apoptosis (0.66 ± 0.11% vs. 1.60 ± 0.34%). Higher phosphorylation (i.e., activation) of pro-survival transcription factor STAT3, higher expression of anti-apoptotic protein Bcl2, and higher phosphorylation (i.e., inactivation) of pro-apoptotic BAD were observed in the post-MI remote myocardium of MEK1 Tg. MMP2 activity was higher in MEK1 Tg, while expression of TIMP3 and MMP9 activity were lower in transgenic mice. Beyond any immediate cardioprotective effect, therapeutic activation of MEK1-ERK1/2 signaling during the chronic post-MI period may preserve LV function by increasing the expression of pro-survival factors and by suppressing factors, such as the balance between matrix modulating proteins, that promote pathological remodeling in the remote myocardium.


Prolongation of renal allograft survival in the rat by pretreatment with donor antigen and cyclosporin A.
Pretreatment of LEW rats with cyclosporin A (10 mg/kg/day orally for 14 days) plus 10(8) DA or (DA X LEW)F1 spleen lymphocytes on two occasions markedly prolonged the survival of subsequent DA renal allografts. The lymphocytotoxic antibody response was suppressed completely and renal biopsies showed a marked mononuclear cell infiltrate, but no other manifestations of rejection. Neither pretreatment with cyclosporin A alone nor pretreatment with splenic lymphocytes alone had any effect on the subsequent immune reaction. The immunosuppressive effect generated was dependent upon the dose of lymphocytes given, because pretreatment with 10(7) cells on two occasions plus cyclosporin A was relatively ineffective at prolonging renal allograft survival. Pretreatment with 10(8) (DA X LEW)F1 spleen cells plus cyclosporin A was also an effective combination, and ruled out the possibility that graft-versus-host (GVH) disease was responsible for the observed immunosuppression. This pretreatment protocol exhibited specificity in terms of rejection of a third-party (PVG) renal allograft, but not in terms of the lymphocytotoxic antibody response to this graft. Chimerism was not detected in long-term surviving animals using a 51Cr release assay. When pretreatment was performed in LEW rats with a DA skin allograft plus cyclosporin A, a subsequent DA renal allograft was rejected normally, in combination with the skin graft. These findings suggest that clonal deletion had not occurred in these pretreatment protocols, but that a shift in immunoregulatory mechanisms was responsible for the long survival. There are possible clinical implications for the use of pretreatment schedules using donor antigen and cyclosporin A.


Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway.
Many lines of evidence suggest that oxidative stress resulting in reactive oxygen species (ROS) generation and inflammation play a pivotal role in the age-associated cognitive decline and neuronal loss in neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases. One cardinal chemical pathology observed in these disorders is the accumulation of iron at sites where the neurons die. The buildup of an iron gradient in conjunction with ROS (superoxide, hydroxyl radical and nitric oxide) are thought to constitute a major trigger in neuronal toxicity and demise in all these diseases. Thus, promising future treatment of neurodegenerative diseases and aging depends on availability of effective brain permeable, iron-chelatable/radical scavenger neuroprotective drugs that would prevent the progression of neurodegeneration. Tea flavonoids (catechins) have been reported to possess potent iron-chelating, radical-scavenging and anti-inflammatory activities and to protect neuronal death in a wide array of cellular and animal models of neurological diseases. Recent studies have indicated that in addition to the known antioxidant activity of catechins, other mechanisms such as modulation of signal transduction pathways, cell survival/death genes and mitochondrial function, contribute significantly to the induction of cell viability. This review will focus on the multifunctional properties of green tea and its major component (-)-epigallocatechin-3-gallate (EGCG) and their ability to induce neuroprotection and neurorescue in vitro and in vivo. In particular, their transitional metal (iron and copper) chelating property and inhibition of oxidative stress.


Impact of Different Selectivity between Soluble and Membrane-bound Forms of Carcinoembryonic Antigen (CEA) on the Target-mediated Disposition of Anti-CEA Monoclonal Antibodies.
Carcinoembryonic antigen (CEA) is a tumor-specific antigen overexpressed in multiple cancers. CEA is expressed as a membrane protein, a part of which is cleaved from the cell membrane and secreted into blood. The soluble form of CEA (sCEA) has been shown to accelerate the clearance of anti-CEA antibody, which limits the antibody distribution in the tumor. To overcome this issue, we developed an anti-CEA monoclonal antibody, 15-1-32, which shows a strong affinity for membrane-bound CEA (mCEA) and relatively weak affinity for sCEA. In this study, we compared the effect of sCEA on the pharmacokinetics of 15-1-32 in mice with that of another anti-CEA monoclonal antibody, labetuzumab, showing less selectivity to mCEA than 15-1-32. As expected, the effect of sCEA on the serum concentration of 15-1-32 was much smaller than that of labetuzumab. The decrease in the area under the curve (AUC) of serum concentration was 22.5% for 15-1-32 when it was coadministered with sCEA, while that of labetuzumab was 79.9%. We also compared the pharmacokinetics of these two antibodies in CEA-positive tumor-bearing mice. The AUCs of 15-1-32 and labetuzumab were decreased in tumor-bearing mice compared with non-tumor-bearing mice to a similar extent (approximately 40% decrease). These results suggested that mCEA also contributes to the clearance of anti-CEA antibodies in CEA-positive tumor-bearing mice. Although the increased selectivity to mCEA minimized the effect of sCEA on the pharmacokinetics of 15-1-32, it may be insufficient to improve the pharmacokinetics in CEA-positive cancer patients. SIGNIFICANCE STATEMENT: Because previous studies reported the rapid clearance of anti-CEA antibodies mediated by soluble CEA, we obtained a monoclonal antibody, 15-1-32, selective to membrane-bound CEA and evaluated the effects of CEA on its pharmacokinetics. Although the effect of soluble CEA on the serum concentration of 15-1-32 was very small, the clearance of 15-1-32 in CEA-positive tumor-bearing mice was still rapid, suggesting membrane-bound CEA also contributes to the clearance of anti-CEA antibodies. These results indicated that increasing selectivity to membrane-bound CEA is not enough to improve the pharmacokinetics of anti-CEA antibody.


[Tracheal reconstruction with preserved tracheal homograft--new aspects].
The treatment of long-segment tracheal stenosis is a biological and surgical problem. The introduction of preserved allografts established new possibilities for functional tracheal reconstruction. Since 1979 preserved allografts were used in 112 patients (including 20 children) with tracheal stenosis. Increasing knowledge in preservation, surgical treatment and pathohistology were put into practice. Implantation of the preserved allografts into the infrahyoid muscles proved to be advantageous. Preservation with the tutoplast method prevented the risk of viral infection, and led to faster and trouble-free post-operative healing. Pathohistological studies let to improve surgical techniques by increasing the knowledge of the nature of tracheal stenosis. Functional tracheal reconstruction for long-segment tracheal stenosis can be achieved by implantation of preserved allografts.


The place of psychodynamic theory in developmental psychopathology.
Psychoanalysis ushered in this century. Will its influence on developmental psychopathology end in the next? The paper explores some critical obstacles in the way of psychodynamic research, including the fragmentation of psychoanalytic theory. the relative independence of theory from its clinical and empirical base, the predominance of inductive scientific logic, the polymorphous use of terms, the privacy of clinical data, the dominance of the reconstructionist stance, and the isolation of psychoanalysis from psychology and neurobiology. Notwithstanding these limitations, core psychoanalytic precepts are not only consistent with some of the most important advances of the last decade but may also be helpful in elaborating these new discoveries in the next century. Psychoanalysis is centered on the notion that complex, conflicting, unconscious representations of mental states constitute a key facet of normal and abnormal development. This notion retains its power, and deserves a prominent position among the major frames of reference to guide developmental science in the next century.


Correlation of cervical lordosis measurement with incidence of motor vehicle accidents.
A retrospective analysis of 500 patient radiographs was conducted to measure the clinical correlation of cervical lordosis measurements and incidence of motor vehicle accident (MVA). Five hundred lateral cervical radiographs were selected at random from the practice of one of the authors (DLM). The C1-7 angle of the cervical curve was then measured by two blinded examiners. Inter-examiner reliability had a confidence interval of 95%. Eighty-two percent of patients who have had a MVA had an abnormal lordosis. The mean lordosis of patients who had been involved in a MVA was 26.1 degrees (SD 11.4), compared with 36.4 (SD 8.4) for those who had not been involved in a MVA. The results suggest a correlation of reduced cervical lordosis measurements following motor vehicle accident (MVA).


Antioxidant and antimicrobial activities of branches extracts of five Juniperus species from Turkey.
Several Juniperus species (Cupressaceae) are utilized in folk medicine in the treatment of infections and skin diseases. This work was designed to evaluate the antioxidant and antimicrobial potential of methanol and water branches extracts of Juniperus species from Turkey: Juniperus communis L. var. communis (Jcc), Juniperus communis L. var. saxatilis Pall. (Jcs), Juniperus drupacea Labill. (Jd), Juniperus oxycedrus L. subsp. oxycedrus (Joo), Juniperus oxycedrus L. subsp. macrocarpa (Sibth. & Sm.) Ball. (Jom). Total phenolics, total flavonoids and condensed tannins were spectrophotometrically determined. The antioxidant properties were examined using different in vitro systems. The toxicity was assayed by Artemia salina lethality test. The antimicrobial potential against bacteria and yeasts was evaluated using minimum inhibitory concentration and minimum bactericidal concentration (MIC/MBC) measurements. The effect on bacteria biofilms was tested by microtiter plate assay. Both in the DPPH (1,1-diphenyl-2-picrylhydrazyl) and TBA (thiobarbituric acid) test Jom resulted the most active (IC(50) = 0.034 ± 0.002 mg/mL and 0.287 ± 0.166 µg/mL). Joo exhibited the highest reducing power (1.78 ± 0.04 ASE/mL) and Fe(2+) chelating activity (IC(50) = 0.537 ± 0.006 mg/mL). A positive correlation between primary antioxidant activity and phenolic content was found. The extracts were potentially non-toxic against Artemia salina. They showed the best antimicrobial (MIC = 4.88-30.10 µg/mL) and anti-biofilm activity (60-84%) against S. aureus. The results give a scientific basis to the traditional utilization of these Juniperus species, also demonstrating their potential as sources of natural antioxidant and antimicrobial compounds.


Otologics Middle Ear Transducer Ossicular Stimulator: performance results with varying degrees of sensorineural hearing loss.
This study was conducted to demonstrate the safety and efficacy of the Otologics Middle Ear Transducer (MET) Ossicular Stimulator and, in particular, to compare the audiologic benefits of this novel form of electromechanical stimulation with those of conventional acoustical amplification. A total of 282 patients were implanted with the device in Europe and the USA. Pure-tone audiometry, speech recognition and subjective assessment of benefit were tested before the surgery and 2, 3, 6 and 12 months afterwards. The US patients were fitted with a digital hearing aid for a minimum of 4 weeks prior to surgery, and the same benefit measures were performed with the digital hearing aid and their "walk-in" hearing aid. Group mean postoperative bone and air conduction thresholds did not change significantly from preoperative levels. Postoperative air conduction thresholds decreased slightly in some individual patients, due to the mass loading effect exerted by the transducer on the ossicles. Sufficient gain was available to reach target prescription levels for moderate to severely impaired hearing individuals. Speech and subjective assessment of patient preference indicated that patients did as well or better with the MET Ossicular Stimulator than with their "walk-in" aid or the standardized digital aid. The capability of the MET Ossicular Stimulator to provide appropriate gain as a function of degree of hearing loss indicates that the device is a viable treatment for moderate to severe sensorineural hearing loss in adults.


Teacher Job Stress and Satisfaction in Urban Schools: Disentangling Individual-, Classroom-, and Organizational-Level Influences.
Schools remain among the most frequent providers of children's mental health services, particularly in low-income urban settings. Several decades of research have focused on training teachers to implement evidence-based interventions for minimizing disruptive behavior. Studies consistently demonstrate robust improvements in student behavior and learning; however, the impact on teachers' work-related stress or satisfaction is not well understood. Six urban, high-poverty elementary schools were randomly assigned to a school mental health services model (Links to Learning; L2L) for referred, disruptive students or to services and professional development as usual (SAU). Teachers (n = 71, K-4 general education teachers) in L2L schools participated in professional development and consultation in two universal and two targeted interventions to reduce disruptive behaviors and promote learning. Teachers (n = 65) in SAU schools participated in professional development as usual. Multiple regression models examined teacher reports of individual-level self-efficacy, classroom-level student functioning, and school-level organizational health as predictors of stress and satisfaction. Findings revealed no significant difference between conditions on teacher work-related stress or satisfaction. Organizational health was the strongest predictor of stress and satisfaction. Training on and implementation of evidence-based classroom interventions did not appear to significantly impact teachers' work-related stress or satisfaction. Instead, findings point to organizational climate and teacher connectedness as potential levers for change, supporting prior work on teacher stress and satisfaction in schools. The significance of targeting organizational factors may be particularly significant in urban school districts.


Elucidating the molecular determinants for binding modes of a third-generation HIV-1 integrase strand transfer inhibitor: Importance of side chain and solvent reorganization.
The first and second-generation clinically used HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) are key components of antiretroviral therapy (ART), which work by blocking the integration step in the HIV-1 replication cycle that is catalyzed by a nucleoprotein assembly called an intasome. However, resistance to even the latest clinically used INSTIs is beginning to emerge. Developmental third-generation INSTIs, based on naphthyridine scaffold, are promising candidates to combat drug-resistant viral variants. Among these novel INSTIs, compound 4f exhibits two distinct conformations when binding to intasomes from HIV-1 and the closely related prototype foamy virus (PFV), despite the high structural similarity of their INSTI binding pockets. The molecular mechanism and the key active site residues responsible for these differing binding modes in closely related intasomes remain elusive. To unravel the molecular determinants governing the two distinct binding modes, we employ a novel molecular dynamics-based free energy approach that utilizes alchemical pathways to overcome the sampling challenges associated with transitioning between two ligand conformations within crowded environments along physical pathways. The calculated conformational free energies successfully recapitulate the experimentally observed binding mode preferences in the two viral intasomes. Analysis of the simulated structures suggests that the observed binding mode preferences are caused by amino acid residue differences in both the front and the central catalytic sub-pocket of the INSTI binding site in HIV-1 and PFV. Additional free energy calculations on mutants of HIV-1 and PFV revealed that while both sub-pockets contribute to the binding mode selection, the central sub-pocket plays a more important role. These results highlight the importance of both side chain and solvent reorganization, as well as the conformational entropy in determining the ligand binding mode and will help inform the development of more effective INSTIs for combatting drug-resistant viral variants.


Targeting the epidermal growth factor receptor (HER) family by T cell receptor gene-modified T lymphocytes.
Human epidermal growth factor receptor 2 (HER2) has been successfully targeted as a breast cancer-associated antigen by various strategies. HER2 is also overexpressed in other solid tumors such as stomach cancer, as well as in hematological malignancies such as acute lymphoblastic leukemia. HER2-targeted therapies are currently under clinical investigation for a panel of malignancies. In this study, we isolated the T cell receptor (TCR) genes of a HER2-reactive allo-human leukocyte antigen-A2-restricted CTL clone and introduced the TCRα- and β-chain genes into the retrovirus vector MP71. Murinization and codon optimization of the HER2-reactive TCR was required for efficient TCR expression in primary human T cells. The tumor recognition efficiency of HER2-TCR gene-modified T cells was similar to the parental CTL clone from which the TCR genes were isolated. The known cross-reactivity of the HER2-reactive TCR with HER3 and HER4 was retained when the TCR was transduced into primary T cells. Our results could contribute to the development of a TCR-based approach for the treatment of HER2-positive breast cancer, as well as of other malignancies expressing HER2, HER3, and/or HER4.


Stakeholders' Perspectives on Postmastectomy Breast Reconstruction: Recognizing Ways to Improve Shared Decision Making.
Postmastectomy breast reconstruction (PMBR) is an elective, preference-sensitive decision made during a stressful, time-pressured period after a cancer diagnosis. Shared decision making (SDM) can improve decision quality about preference-sensitive choices. Stakeholders' perspectives on ways to support PMBR decision-making were explored. Forty semi-structured interviews with stakeholders (20 postmastectomy patients, 10 PMBR surgeons, 10 PMBR nurses) were conducted. Clinicians were recruited from diverse practices across the United States. Patients were recruited using purposive sampling with varying PMBR experiences, including no reconstruction. The interview guide was based on an implementation research framework. Themes were identified using grounded theory approach, based on frequency and emotive force conveyed. Engagement in SDM was variable. Some patients wanted more information about PMBR from clinicians, particularly about risks. Some clinicians acknowledged highlighting benefits and downplaying risks. Many patients felt pressured to make a choice by their clinicians. Clinicians who successfully engaged patients through decisions often used outside resources to supplement conversations. Patient-clinician trust was critical to high-quality decisions, and many patients expressed decision regret when they were not engaged in PMBR discussions. Patients often perceived a race- or age-related bias in clinician information sharing. Interventions to support SDM may enhance decision quality and reduce decision regret about PMBR, ultimately improving patient-centered care for women with breast cancer.


First report of establishment of Trypanosoma evansi infection in pigeon nestlings (Columba livia).
Trypanosomosis (surra) caused by Trypanosoma evansi is quite common among horses where the parasite is endemic. In the present study, T. evansi was isolated from an infected horse and maintained by subinoculation in Swiss albino mice. At the peak of parasitemia (5 x 10(6) parasites per ml of blood), 0.25 ml of the tail blood from infected mice was inoculated intraperitoneally and subcutaneously to 2 groups of adult pigeons and 2 groups of pigeon nestlings. Four days after inoculation, the trypanosomes occurred in the peripheral circulation of pigeon nestlings, but no parasitemia was observed in adult pigeons. The body temperatures of infected nestlings increased to 104 F, whereas uninfected controls remained steady at 102 F; thus, elevated temperatures coincided with parasite presence in the peripheral circulation. A decrease in hemoglobin concentration of blood also was observed in infected nestlings. On microscopic examination, increases in length and breadth of trypomastigotes and vigorous flagellar movement of the parasites were observed. The virulence and pathogenicity of the parasites after adaptation to nestlings remained unchanged for albino mice as proved by the death of all subinoculated mice. Furthermore, polymerase chain reaction studies confirmed that the genomic DNA of trypanosomes in pigeon blood was the same as that of T. evansi. This is the first report of the establishment of T. evansi infection in pigeon nestlings.


In vivo printing of growth factor-eluting adhesive scaffolds improves wound healing.
Acute and chronic wounds affect millions of people around the world, imposing a growing financial burden on patients and hospitals. Despite the application of current wound management strategies, the physiological healing process is disrupted in many cases, resulting in impaired wound healing. Therefore, more efficient and easy-to-use treatment modalities are needed. In this study, we demonstrate the benefit of in vivo printed, growth factor-eluting adhesive scaffolds for the treatment of full-thickness wounds in a porcine model. A custom-made handheld printer is implemented to finely print gelatin-methacryloyl (GelMA) hydrogel containing vascular endothelial growth factor (VEGF) into the wounds. In vitro and in vivo results show that the in situ GelMA crosslinking induces a strong scaffold adhesion and enables printing on curved surfaces of wet tissues, without the need for any sutures. The scaffold is further shown to offer a sustained release of VEGF, enhancing the migration of endothelial cells in vitro. Histological analyses demonstrate that the administration of the VEGF-eluting GelMA scaffolds that remain adherent to the wound bed significantly improves the quality of healing in porcine wounds. The introduced in vivo printing strategy for wound healing applications is translational and convenient to use in any place, such as an operating room, and does not require expensive bioprinters or imaging modalities.


Primary Stability of Short Implants Inserted Using Piezoelectric or Drilling Systems: An In Vitro Comparison.
The primary objective of the present in vitro study was to evaluate the influence of implant site preparation technique (drills vs ultrasonic instrumentation) on the primary stability of short dental implants with two different designs inserted in simulated low-quality cancellous bone. Eighty implant sites were prepared in custom-made solid rigid polyurethane blocks with two different low cancellous bone densities (5 or 15 pounds per cubic foot [PCF]), equally distributed between piezoelectric (Surgysonic Moto, Esacrom, Italy) and conventional drilling techniques. Two short implant systems (Prama and Syra, Sweden & Martina) were tested by inserting 40 fixtures of each system (both 6.0 mm length and 5.0 mm diameter), divided in the four subgroups (drills/5 PCF density; drills/15 PCF density; piezo/5 PCF density; piezo/15 PCF density). Insertion torque (Ncm), implant stability quotient values, removal torque (Ncm), and surgical time were recorded. Data were analyzed by 3-way ANOVA and Scheffé's test (α = 0.05). With slight variations among the considered dependent variables, overall high primary implant stability was observed across all subgroups. Piezoelectric instrumentation allowed for comparable or slightly superior primary stability in comparison with the drilling procedures in both implant systems. The Prama implants group showed the highest mean reverse torque and Syra implants the highest implant stability quotient values. Piezoelectric implant site preparation took prolonged operative time compared to conventional preparation with drills; among the drilling procedures, Syra system required fewer surgical steps and shorter operative time.


Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: a phase II study.
A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen. Our aim was to investigate the efficacy of procarbazine (PCB) combined with high-dose tamoxifen in relation to tumor control, toxicity, and time to progression (TTP). Fifty-three patients were treated with procarbazine in repeated 30-day courses at 100 mg/m2/d plus tamoxifen 100 mg/d, with a 30-day interval between courses. Thirty-four patients had been pretreated with a first-line nitrosourea-based chemotherapy regimen (group A), and 19 patients had also been pretreated with a second-line chemotherapy regimen consisting of carboplatin and teniposide (group B). Twenty-one of the patients had also been procarbazine pretreated, whereas the remaining 32 patients were not procarbazine pretreated. The response was assessed in 51 patients, 28 of whom had glioblastoma multiforme (GBM) and 23 of whom had anaplastic astrocytoma (AA). There were two complete responses (CR) (4%) and 13 partial responses (PR) (25.5%). The overall response rate (CR + PR) was 29.5% (SE, 6.4; 95% confidence interval [CI], 23 to 35.8). Seventeen patients (32%) had stable disease (SE, 6.2; 95% CI, 21 to 33.6). The median TTP was 13 weeks for patients with GBM and 33 weeks for patients with AA (P = .006). The median survival time (MST) was 27 weeks for patients with GBM and 57 weeks for those with AA (P = .006). Combined PCB and tamoxifen as a second-line regimen gave a reasonably high response rate in patients with heavily pretreated high-grade gliomas. However, although it resulted in an improvement in the patients' quality of life and/or performance status, it was not followed by an increased TTP or MST.


Atomically thin NiB6 monolayer: a robust Dirac material.
Two-dimensional (2D) Dirac materials have attracted extensive research interest due to their high carrier mobility and ballistic charge transport, and they hold great promise for next-generation nanoscale devices. Here, we report a computational discovery of a stable 2D Dirac material, an NiB6 monolayer, which is identified by an extensive structure search, and its dynamic and thermal stabilities are confirmed by phonon and ab initio molecular dynamics (AIMD) simulations. This monolayer structure possesses anisotropic elastic properties with a Young's modulus of 189 N m-1, which is higher than that of phosphorene or silicene. Electronic band calculations reveal a double Dirac cone feature near the Fermi level with a high Fermi velocity of 8.5 × 105 m s-1, and the results are robust against external strains. We also propose two possible synthesis approaches based on a stable Ni4B8+ precursor or by embedding Ni atoms into the δ4 boron framework. The present findings offer a strong physics basis for the design and synthesis of a novel 2D Dirac material.


Plethysmograph-Based Self-Assessment Device for Carotid-Femoral Pulse Wave Velocity Measurement: A Pilot Usability Study.
Arterial stiffness, a proxy of vascular aging is an important marker of cardiovascular events and mortality, independent of traditional risk factors. The aortic or carotid-femoral pulse wave velocity (cf-PWV) is the gold standard for determining arterial stiffness. Measuring arterial stiffness can help identify people who are at risk early on. State-of-the-art devices, majorly employing applanation tonometry at the carotid site, demand extensive skill, are costly, and are not intended for out-of-clinic use. However, a device that is suitable for homecare and primary health settings would facilitate primordial care. To address this gap, we have developed a novel easy-to-use, fully automated, and affordable photoplethysmography-based device for measuring cf-PWV. An in-vivo study on 25 subjects was conducted to investigate the device's usability by comparing self and expert-performed measurements, and by quantifying the user experience (score out of 5). A strong correlation (r = 0.88) and a statistically insignificant bias indicated the measurement reproducibility in self-versus expert-performed measurements. An average usability score of 3.98 ± 0.83 given by the participants showed the convenience and ease of use of the device. The results demonstrate the feasibility and reliability of using the device by inexperienced operators, even when newly introduced. Future clinical studies are in progress to assess the device's accuracy in comparison to gold-standard reference equipment.Clinical Relevance-This pilot study revealed the device's potential to offer a user-friendly solution for home care and other non-hospital settings.


Laser Engineered Net Shaping of Nickel-Based Superalloy Inconel 718 Powders onto AISI 4140 Alloy Steel Substrates: Interface Bond and Fracture Failure Mechanism.
As a prospective candidate material for surface coating and repair applications, nickel-based superalloy Inconel 718 (IN718) was deposited on American Iron and Steel Institute (AISI) 4140 alloy steel substrate by laser engineered net shaping (LENS) to investigate the compatibility between two dissimilar materials with a focus on interface bonding and fracture behavior of the hybrid specimens. The results show that the interface between the two dissimilar materials exhibits good metallurgical bonding. Through the tensile test, all the fractures occurred in the as-deposited IN718 section rather than the interface or the substrate, implying that the as-deposited interlayer bond strength is weaker than the interfacial bond strength. From the fractography using scanning electron microscopy (SEM) and energy disperse X-ray spectrometry (EDS), three major factors affecting the tensile fracture failure of the as-deposited part are (i) metallurgical defects such as incompletely melted powder particles, lack-of-fusion porosity, and micropores; (ii) elemental segregation and Laves phase, and (iii) oxide formation. The fracture failure mechanism is a combination of all these factors which are detrimental to the mechanical properties and structural integrity by causing premature fracture failure of the as-deposited IN718.


Neuronal release of endogenous dopamine from corpus of guinea pig stomach.
Neuronal release of endogenous dopamine was identified in mucosa-free preparations (muscle layer including intramural plexus) from guinea pig stomach corpus by measuring tissue dopamine content and dopamine release and by immunohistochemical methods using a dopamine antiserum. Dopamine content in mucosa-free preparations of guinea pig gastric corpus was one-tenth of norepinephrine content. Electrical transmural stimulation of mucosa-free preparations of gastric corpus increased the release of endogenous dopamine in a frequency-dependent (3-20 Hz) manner. The stimulated release of dopamine was prevented by either removal of external Ca2+ or treatment with tetrodotoxin. Dopamine-immunopositive nerve fibers surrounding choline acetyltransferase-immunopositive ganglion cells were seen in the myenteric plexus of whole mount preparations of gastric corpus even after bilateral transection of the splanchnic nerve proximal to the junction with the vagal nerve (section of nerves between the celiac ganglion and stomach). Domperidone and sulpiride potentiated the stimulated release of acetylcholine and reversed the dopamine-induced inhibition of acetylcholine release from mucosa-free preparations. These results indicate that dopamine is physiologically released from neurons and from possible dopaminergic nerve terminals and regulates cholinergic neuronal activity in the corpus of guinea pig stomach.


The effect of surface-active solutes on water flow and contaminant transport in variably saturated porous media with capillary fringe effects.
Organic contaminants that decrease the surface tension of water (surfactants) can have an effect on unsaturated flow through porous media due to the dependence of capillary pressure on surface tension. We used an intermediate-scale 2D flow cell (2.44 x 1.53 x 0.108 m) packed with a fine silica sand to investigate surfactant-induced flow perturbations. Surfactant solution (7% 1-butanol and dye tracer) was applied at a constant rate at a point source located on the soil surface above an unconfined synthetic aquifer with ambient groundwater flow and a capillary fringe of approximately 55 cm. A glass plate allowed for visual flow and transport observations. Thirty instrumentation stations consist of time domain reflectometry probes and tensiometers measured in-situ moisture content and pressure head, respectively. As surfactant solution was applied at the point source, a transient flow perturbation associated with the advance of the surfactant solution was observed. Above the top of the capillary fringe the advance of the surfactant solution caused a visible drainage front that radiated from the point source. Upon reaching the capillary fringe, the drainage front caused a localized depression of the capillary fringe below the point source because the air-entry pressure decreased in proportion to the decrease in surface tension caused by the surfactant. Eventually, a new capillary fringe height was established. The height of the depressed capillary fringe was proportional to height of the initial capillary fringe multiplied by the relative surface tension of the surfactant solution. The horizontal transport of surfactant in the depressed capillary fringe, driven primarily by the ambient groundwater flow, caused the propagation of a wedge-shaped drying front in the downgradient direction. Comparison of dye transport during the surfactant experiment to dye transport in an experiment without surfactant indicated that because surfactant-induced drainage decreased the storage capacity of the vadose zone, the dye breakthrough time to the water table was more than twice as fast when the contaminant solution contained surfactant. The extensive propagation of the drying front and the effect of vadose zone drainage on contaminant breakthrough time suggest the importance of considering surface tension effects on unsaturated flow and transport in systems containing surface-active organic contaminants or systems, where surfactants are used for remediation of the vadose zone or unconfined aquifers.


Uses of transcutaneous oxygen monitoring in the management of below-knee amputations and skin envelope injuries (SKI).
Conventional noninvasive hemodynamic techniques may fail to predict reliable healing of skin envelope injuries (SKI) in determining the site and timing of late amputations and the probability of healing of SKI following revascularization of ischemic extremities. This study reports the use of multiple transcutaneous oxygen mapping as performed in a cohort of 12 limbs requiring below-knee amputation (Group I), 21 patients requiring revascularization for SKI with prompt healing (Group II-A) or delayed healing (Group II-B), and 14 patients with nonischemic SKI (Group III) who also experienced healing. PtcO2 values greater or equal to 25 mm Hg were associated with healing of below-knee amputations, while early or late healing complications occurred when amputation flap PtcO2 was less than 25 mm Hg. PtcO2 mapping demonstrated significantly lower (PtcO2 less than 20 mm Hg) values surrounding nonhealing SKI in Group II-B compared to Group II-A and III. These nonhealing SKI appear as "Islands of Ischemia" following revascularization, despite adjacent normal pedal PtcO2 values. These "Islands" tend to occur in diabetic patients with advanced pedal atherosclerosis.


Symmetry-reduced double layer metallic grating structure for dual-wavelength spectral filtering.
In this paper, we propose a metal-dielectric dual-wavelength spectral filtering structure based on symmetry-reduced double layer metallic gratings (SRDMG) coupled to a guided-mode dielectric resonator. The grating symmetry is reduced by alternatively shifting metal nanowires of the top layer metallic grating. Compared to a symmetric double layer metallic grating that usually provides one resonance dip, this SRDMG structure generates two remarkable narrow band transmission dips with a transmission peak in-between at normal incidence. The appearance of the two narrowband resonance dips is attributed to the excitation of different current modes in the metallic grating, leading to different guided mode resonances in the dielectric layer, which is induced by the structural symmetry breaking. Moreover, these two guided modes do not split under oblique incidence and a flat dispersion band over a small angular range can be obtained. The positions of two dips and the frequency gap between them can be controlled by adjusting the thickness of metallic grating without the need to modify the structure period and width, which is an easy method to tune resonance position and bandwidth, and make the fabrication of some filters more convenient. This work can be used to develop subwavelength metallic-grating-based multi-wavelength and narrow-band spectral filters.


Developmental origin of wiring specificity in the olfactory system of Drosophila.
In both insects and mammals, olfactory receptor neurons (ORNs) expressing specific olfactory receptors converge their axons onto specific glomeruli, creating a spatial map in the brain. We have previously shown that second order projection neurons (PNs) in Drosophila are prespecified by lineage and birth order to send their dendrites to one of approximately 50 glomeruli in the antennal lobe. How can a given class of ORN axons match up with a given class of PN dendrites? Here, we examine the cellular and developmental events that lead to this wiring specificity. We find that, before ORN axon arrival, PN dendrites have already created a prototypic map that resembles the adult glomerular map, by virtue of their selective dendritic localization. Positional cues that create this prototypic dendritic map do not appear to be either from the residual larval olfactory system or from glial processes within the antennal lobe. We propose instead that this prototypic map might originate from both patterning information external to the developing antennal lobe and interactions among PN dendrites.


Microtechnique for indirect immunofluorescence.
A microtechnique for staining preparations of cells grown in vitro for indirect immunofluorescence tests is described. Smaller amounts of materials, as well as less handling of cover slips, greatly facilitates the process.


Opportunities from a new disease for an old threat: Extending COVID-19 efforts to address tuberculosis in South Africa.
The COVID-19 pandemic and phased nationwide lockdown have impacted negatively on individuals with tuberculosis (TB) and routine TB services. Through a literature review and the perspective of members of a national TB Think Tank task team, we describe the impact of the pandemic and lockdown on TB patients and services as well as the potential long-term setback to TB control in South Africa (SA). Strategies to mitigate risk and impact are explored, together with opportunities to leverage synergies from both diseases to the benefit of the National TB Programme (NTP). With the emergence of COVID-19, activities to address this new pandemic have been prioritised across all sectors. Within the health system, the health workforce and resources have been redirected away from routine services towards the new disease priority. The social determinants of health have deteriorated during the lockdown, potentially increasing progression to TB disease and impacting negatively on people with TB and their households, resulting in additional barriers to accessing TB care, with early reports of a decline in TB testing rates. Fewer TB diagnoses, less attention to adherence and support during TB treatment, poorer treatment outcomes and consequent increased transmission will increase the TB burden and TB-related mortality. People with TB or a history of TB are likely to be vulnerable to COVID-19. Modifications to current treatment practices are suggested to reduce visits to health facilities and minimise the risks of COVID-19 exposure. The COVID-19 pandemic has the potential to negatively impact on TB control in TB-endemic settings such as SA. However, there are COVID-19-related health systems-strengthening developments that may help the NTP mitigate the impact of the pandemic on TB control. By integrating TB case finding into the advanced screening, testing, tracing and monitoring systems established for COVID-19, TB case finding and linkage to care could increase, with many more TB patients starting treatment. Similarly, integrating knowledge and awareness of TB into the increased healthcare worker and community education on infectious respiratory diseases, behavioural practices around infection prevention and control, and cough etiquette, including destigmatisation of mask use, may contribute to reducing TB transmission. However, these potential gains could be overwhelmed by the impact of increasing poverty and other social determinants of health on the burden of TB.


Intestinal Drug Interactions Mediated by OATPs: A Systematic Review of Preclinical and Clinical Findings.
In recent years, an increasing number of clinical drug-drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion-transporting polypeptides (OATPs); however, only a few of these DDI results were reflected in drug labels. This review aims to provide a thorough analysis of intestinal OATP-mediated pharmacokinetic-based DDIs, using both in vitro and clinical investigations, highlighting the main mechanistic findings and discussing their clinical relevance. On the basis of pharmacogenetic and clinical DDI results, a total of 12 drugs were identified as possible clinical substrates of OATP2B1 and OATP1A2. Among them, 3 drugs, namely atenolol, celiprolol, and fexofenadine, have emerged as the most sensitive substrates to evaluate clinical OATP-mediated intestinal DDIs when interactions with P-glycoprotein by the test compound can be ruled out. With regard to perpetrators, 8 dietary or natural products and 1 investigational drug, ronacaleret (now terminated), showed clinical intestinal inhibition attributable to OATPs, producing ≥20% decreases in area under the plasma concentration-time curve of the co-administered drug. Common juices, such as apple juice, grapefruit juice, and orange juice, are considered potent inhibitors of intestinal OATP2B1 and OATP1A2 (decreasing exposure of the co-administered substrate by ∼85%) and may be adequate prototype inhibitors to investigate intestinal DDIs mediated by OATPs.


Liposomes replace serum for cultivation of fermenting mycoplasmas.
Cholesterol and albumin are limiting factors in the growth of Mycoplasma species. These nutrients are usually supplied in the culture medium by the addition of serum. The growth of M. pneumoniae in a serum-free medium containing an ethanolic cholesterol suspension and albumin was about one-half the level attained in serum-containing medium. M. gallisepticum and M. fermentans were not cultivable in the cholesterol suspension medium even after supplements were included. In another culture medium containing phosphatidylcholine-cholesterol liposomes and albumin as serum replacements, the growth of M. pneumoniae was approximately equal to that in serum-containing medium, and the growth of M. gallisepticum and M. fermentans was significantly greater than that in medium containing serum. M. fermentans produced even higher yields in liposome medium supplemented with arginine. These fermenting mycoplasmas readily adapted to the liposome medium and by the fifth or sixth serial passage produced thick confluent growth on the lower surface of culture bottles. To obtain maximum growth, we serially transferred the mycoplasmas at least 10 times in serum-free medium before quantitations of growth were made. This is the first report of a serum-free mycoplasma medium of high growth-promoting ability.


Classification of bronchial lymphocytes from nonsmokers and smokers.
The population of lymphocytes obtained by endobronchial lavage is significantly different from the distribution of lymphocytes in the peripheral blood. Both B and T lymphocytes are found in fluids lavaged from the normal human lung. Of the lymphocytes that can be classified, the T cell population is larger than the B cell population in both nonsmokers and cigarette smokers, whereas a further increment in T cells is noted in smokers. A third population of unclassified lymphocytes, the "null" cells, also comprise a large portion of the lymphocyte population in both smokers and nonsmokers. Their significance has yet to be determined.


Inhibition of vasopressin action by vanadate in the cortical collecting tubule.
The effect of vanadate, a potent inhibitor of Na-K-ATPase, on the hydroosmotic response to vasopressin (AVP) and transepithelial voltage (Vt) in cortical collecting tubules was examined. At 37 degrees C, exposure of collecting tubules to bath vanadate (10(-4) M) for 30 min inhibited the increase in hydraulic water permeability (Lp) in response to AVP or 8-bromo-cyclic adenosine monophosphate by 68 and 76%, respectively. When vanadate was present only in the lumen no inhibition of the AVP response was observed. Incubation of tubules with ouabain (10(-5) M) for 30 min inhibited the AVP-induced increase in Lp to the same extent as vanadate. At 25 degrees C, vanadate inhibited the increase in Lp by AVP if added before but not after the hormone. Addition of vanadate to the bath caused a rapid decrease in the lumen-negative Vt that is consistent with Na-K-ATPase inhibition. Luminal vanadate also inhibited Vt but the rate of decrease of Vt was much slower than in the presence of bath vanadate. We conclude that vanadate inhibits the development but not the maintenance of the AVP-induced increase in water permeability in the collecting tubule. Since the effect of ouabain was similar to that of vanadate, the results suggest that inhibition of Na-K-ATPase directly or indirectly interferes with the initiation of the AVP-induced increase in luminal membrane water permeability at a site distal to cAMP formation.


Disposition towards critical thinking: a study of Chinese undergraduate nursing students.
The purpose of this study was to explore empirically whether undergraduate nursing students at a selected university in Hong Kong display a disposition towards critical thinking. The California Critical Thinking Dispositions Inventory (CCTDI) was used to measure the key theoretical aspects of the overall dispositional dimension of critical thinking. A cross-sectional descriptive design was used to examine 122 Chinese students who were completing their 1st, 2nd and 3rd year of a university baccalaureate nursing programme. In the majority of sub-scales of CCTDI, students showed a negative disposition towards critical thinking. A one-way ANOVA indicated that year 3 students scored significantly lower than their junior counterparts (P < 0. 001). Pearson product moment correlation coefficient yielded a significant positive relationship between critical thinking dispositions and term grade point average (P < 0.05). Consistent with the findings of western studies, the students scored lowest on the truth-seeking sub-scale and highest on the inquisitiveness. Discussion of the findings with regard to nursing education, curriculum and research is delineated.


ISOLATION AND CHARACTERIZATION OF DEOXYRIBONUCLEIC ACID FROM A STRAIN OF STAPHYLOCOCCUS AUREUS.
Blobel, Hans (University of Wisconsin, Madison). Isolation and characterization of deoxyribonucleic acid from a strain of Staphylococcus aureus. J. Bacteriol. 82:425-429. 1961.-Highly polymerized deoxyribonucleic acid was extracted from washed cells of Staphylococcus aureus with a mixture of equal parts of phenol and 2 m NaCl at pH 7.4. The aqueous phase was treated twice with phenol and the deoxyribonucleic acid precipitated with an equal volume of 2-ethoxyethanol. Residual ribonucleic acid was removed by treatment with ribonuclease and subsequent dialysis. Deoxyribonucleic acid was reprecipitated with 2-ethoxyethanol. The final product contained less than 1% protein. The deoxyribonucleic acid obtained from S. aureus strain S(44) had a (adenosine + thymine)/(guanine + cytosine) base ratio of 1.98. Intrinsic viscosity in 0.15 m NaCl + 0.015 m sodium citrate was approximately 76 dl/g. The sedimentation coefficient, S(20)w, was close to 25 S.


Multiscale Plasma-Catalytic On-Surface Assembly.
Controlled modification of surfaces is one of the key pursuits of the nanoscience and nanotechnology fields, allowing for the fabrication of bespoke materials with targeted functionalities. However, many surface modifications currently require painstakingly precise and/or energy intensive processing to implement, and are thus limited in scope and scale. Here, a concept which can enhance the capacity for control of surfaces is introduced: plasma-assisted nucleation and self-assembly at atomic to nanoscales, scalable at atmospheric pressures.


MR of parenchymal spinal cord signal change as a sign of active advancement in clinically progressive posttraumatic syringomyelia.
Extensive MR signal change in the craniad spinal cord parenchyma was found to be an ancillary sign of disease advancement in three patients with clinically progressive posttraumatic syringomyelia. This craniad margin of parenchymal spinal cord T2 hyperintensity resolved after cystoperitoneal shunt placement. There was a concomittant reduction or disappearance of the cyst in each instance, a halt in the progression of neurologic deficit, and some reversal of signs and symptoms.


Imprinting and Reproductive Health: A Toxicological Perspective.
This overview discusses the role of imprinting in the development of an organism, and how exposure to environmental chemicals during fetal development leads to the physiological and biochemical changes that can have adverse lifelong effects on the health of the offspring. There has been a recent upsurge in the use of chemical products in everyday life. These chemicals include industrial byproducts, pesticides, dietary supplements, and pharmaceutical products. They mimic the natural estrogens and bind to estradiol receptors. Consequently, they reduce the number of receptors available for ligand binding. This leads to a faulty signaling in the neuroendocrine system during the critical developmental process of 'imprinting'. Imprinting causes structural and organizational differentiation in male and female reproductive organs, sexual behavior, bone mineral density, and the metabolism of exogenous and endogenous chemical substances. Several studies conducted on animal models and epidemiological studies provide profound evidence that altered imprinting causes various developmental and reproductive abnormalities and other diseases in humans. Altered metabolism can be measured by various endpoints such as the profile of cytochrome P-450 enzymes (CYP450's), xenobiotic metabolite levels, and DNA adducts. The importance of imprinting in the potentiation or attenuation of toxic chemicals is discussed.


Retinal pigment epithelial tears through the fovea with preservation of good visual acuity.
We describe two patients with spontaneous retinal pigment epithelial tears through the fovea who have maintained at least 20/40 visual acuity for 1 year and 3 years following the rip. Both patients had long-standing serous detachments of the retinal pigment epithelium associated with age-related macular degeneration prior to the development of the tear. Each tear was at least five disc areas in size and centered on the fovea. Foveal fixation was documented despite the presumed absence of pigment epithelium. This observation suggests either that there may be remaining or redundant pigment epithelium or that pigment epithelium directly beneath the central macula is not required for maintenance of 20/40 visual acuity.


Stochastic specification of primordial germ cells from mesoderm precursors in axolotl embryos.
A common feature of development in most vertebrate models is the early segregation of the germ line from the soma. For example, in Xenopus and zebrafish embryos primordial germ cells (PGCs) are specified by germ plasm that is inherited from the egg; in mice, Blimp1 expression in the epiblast mediates the commitment of cells to the germ line. How these disparate mechanisms of PGC specification evolved is unknown. Here, in order to identify the ancestral mechanism of PGC specification in vertebrates, we studied PGC specification in embryos from the axolotl (Mexican salamander), a model for the tetrapod ancestor. In the axolotl, PGCs develop within mesoderm, and classic studies have reported their induction from primitive ectoderm (animal cap). We used an axolotl animal cap system to demonstrate that signalling through FGF and BMP4 induces PGCs. The role of FGF was then confirmed in vivo. We also showed PGC induction by Brachyury, in the presence of BMP4. These conditions induced pluripotent mesodermal precursors that give rise to a variety of somatic cell types, in addition to PGCs. Irreversible restriction of the germ line did not occur until the mid-tailbud stage, days after the somatic germ layers are established. Before this, germline potential was maintained by MAP kinase signalling. We propose that this stochastic mechanism of PGC specification, from mesodermal precursors, is conserved in vertebrates.


Magnetic resonance imaging in multiple sclerosis animal models: A systematic review, meta-analysis, and white paper.
Magnetic resonance imaging (MRI) is the most important paraclinical tool for assessing drug response in multiple sclerosis (MS) clinical trials. As such, MRI has also been widely used in preclinical research to investigate drug efficacy and pathogenic aspects in MS animal models. Keeping track of all published preclinical imaging studies, and possible new therapeutic approaches, has become difficult considering the abundance of studies. Moreover, comparisons between studies are hampered by methodological differences, especially since small differences in an MRI protocol can lead to large differences in tissue contrast. We therefore provide a comprehensive qualitative overview of preclinical MRI studies in the field of neuroinflammatory and demyelinating diseases, aiming to summarize experimental setup, MRI methodology, and risk of bias. We also provide estimates of the effects of tested therapeutic interventions by a meta-analysis. Finally, to improve the standardization of preclinical experiments, we propose guidelines on technical aspects of MRI and reporting that can serve as a framework for future preclinical studies using MRI in MS animal models. By implementing these guidelines, clinical translation of findings will be facilitated, and could possibly reduce experimental animal numbers.


Headform and N95 filtering facepiece respirator interaction: contact pressure simulation and validation.
This article presents a computational and experimental study of contact pressure between six N95 filtering facepiece respirators (FFRs) and five newly developed digital headforms (small, medium, large, long/narrow, and short/wide). Contact interaction is simulated using the finite element method and validated by experiments using a pressure mapping system. The headform model has multiple layers: a skin layer, muscle layer, fatty tissue layer, and bone layer. Each headform is divided into five parts (two parts for the cheeks, one part for the upper forehead, one part for the chin, and one part for the back side of the head). Each respirator model comprises multiple layers and two straps. The simulation process has two stages for each respirator/headform combination. The first stage is to wrap the straps around the back of the headform and pull the respirator away from the face. The second stage is to release the respirator so that the respirator moves toward the face. Strap forces and contact interactions are generated between the respirators and the headforms. Meanwhile, a real-time surface pressure mapping system is used to record the pressures at six key locations to validate the computational results. There is a strong correlation between computational and experimental results (R(2) = 0.88). By comparing the pressure values from simulations and experiments, we have validated the simulation models.


Health Insurance and Mental Health Care Utilization Among Adults Who Identify as Transgender and Gender Diverse.
Transgender people are less likely to have health insurance, which has been associated with reduced utilization of health care. In the current study, the authors sought to assess the role of health insurance in mental health care utilization among transgender individuals. A total of 4,334 adults who self-identified as transgender or gender diverse (neither male nor female) participated in the 2017 Trans Lifeline Mental Health Survey, which included self-report measures of current insurance type and lifetime history of having seen a therapist or psychiatric provider. Logistic regression analyses assessed the association of insurance status with lifetime utilization of a mental health therapist or psychiatric provider. Although only 8% of the sample were uninsured, these individuals were significantly less likely to have seen a therapist or psychiatric provider in their lifetime compared with those with health insurance, even after the analyses were adjusted for sociodemographic factors. Conversely, those with insurance through the military or the Veterans Health Administration were more than twice as likely as those with employer-provided insurance to have seen a therapist or psychiatric provider. There were no significant differences in mental health care utilization between those with employer-provided insurance versus public or privately purchased insurance. Rates of being uninsured were lower than in earlier assessments of transgender adults and adults who identify as gender diverse. However, type of health insurance also appeared to be a notable structural factor contributing to disparities in mental health care utilization among transgender individuals.


Dry coating, a novel coating technology for solid pharmaceutical dosage forms.
Dry coating is a coating technology for solid pharmaceutical dosage forms derived from powder coating of metals. In this technology, powdered coating materials are directly coated onto solid dosage forms without using any solvent, and then heated and cured to form a coat. As a result, this technology can overcome such disadvantages caused by solvents in conventional liquid coating as serious air pollution, high time- and energy-consumption and expensive operation cost encountered by liquid coating. Several dry coating technologies, including plasticizer-dry-coating, electrostatic-dry-coating, heat-dry-coating and plasticizer-electrostatic-heat-dry-coating have been developed and extensively reported. This mini-review summarized the fundamental principles and coating processes of various dry coating technologies, and thoroughly analyzed their advantages and disadvantages as well as commercialization potentials.


Treatment of small and medium congenital nevi with the Q-switched ruby laser.
The Q-switched ruby laser has been used successfully to treat a variety of benign pigmented lesions. In this study, congenital nevi (diameter, < or = 5 cm) in 18 prepubertal children were treated with the Q-switched ruby laser. Photographic evaluation revealed an average of 57% clearance of pigmentation in all treated nevi by the fourth treatment session and an average maximum clearance of 76% after approximately eight sessions. Greater than 90% clearance of pigment was attained in five patients. Partial repigmentation was seen in all patients who were followed up after discontinuation of therapy. Findings from histopathologic studies, obtained from one patient, revealed reduction of nevus cells in papillary dermis and upper reticular dermis that correlated with clinical lightening. There was no such reduction in the lower reticular dermis. side effects were limited to transient erythema and hypopigmentation. The Q-switched ruby laser effectively lightens and may clear pigmentation and eliminate superficial nevus cells from small and medium congenital nevi safely without scarring. However, these results are not permanent. The Q-switched ruby laser may be a viable alternative for providing cosmetic improvement for unresectable lesions, but it should not be considered definitive treatment. Additional studies are needed to address the long-term results of this therapy.


How do immune response genes work?
Ir genes could operate either by controlling T-cell receptor repertoires, or by controlling antigen presentation to T cells. The idea thatIr genes are a germline set ofV genes for T-cell receptors for foreign antigens can be excluded. Models involving indirect control of the T-cell receptor repertoire during somatic generation of diversity are still possible, though evidence fromH-2 mutations suggests that the probability of their being correct is low. The idea thatIr genes control cell-surfaceMHC antigens that must associate closely with foreign antigens in the surface of antigen-presenting cells to cause T-cell activation is compatible with most, if not all of the available data.


Indirect effect of 7-valent pneumococcal conjugate vaccine on pneumococcal colonization among unvaccinated household members.
Since the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, rates of invasive pneumococcal disease have decreased in both vaccinated and unvaccinated age groups. Reduction of invasive pneumococcal disease in unvaccinated groups has been attributed to reduced transmission of vaccine-type pneumococci in the community. Understanding the impact of PCV7 on carriage among vaccinated and unvaccinated community members is critical to interpreting, predicting, and understanding the impact of PCV7 on disease. A group-randomized, phase III efficacy trial of PCV7 was conducted among southwestern American Indian communities. Meningococcal conjugate vaccine against serogroup C was used as the control. After the trial was unblinded, we conducted a carriage study of participating communities to evaluate the impact of PCV7 on colonization among trial participants and their unvaccinated household members. Adults and unvaccinated children aged <5 years living in households with a PCV7 vaccinee were less likely to be colonized with vaccine-type pneumococci (odds ratio [OR] for adults, 0.57; 95% confidence interval [CI], 0.33-0.99; OR for children, 0.57; 95% CI, 0.26-0.98) than were those living in a household with a control vaccinee. There was no difference for children aged 5-17 years. Decreases in vaccine-type carriage were offset by increases in carriage of nonvaccine types. Among adults living with a trial participant colonized with vaccine-type pneumococcus, those in the households randomized to receive PCV7 were less likely to be colonized with the same serotype than were those in the households randomized to receive the control vaccine (OR, 0.34; 95% CI, 0.11-0.99). Vaccine-type pneumococcal carriage was lower among adults and unvaccinated children living with a PCV7 vaccinee. This is attributable to reduced exposure and reduced transmission when exposure occurs.


Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide.
Synthetic oligodeoxynucleotides (ODN) expressing "CpG motifs" show promise as immune adjuvants, antiallergens, anticancer, and immunoprotective agents. Two structurally distinct classes of CpG ODN have been identified that stimulate human PBMC. This work establishes that both types of ODN bind to and are internalized by the same individual B cells, NK cells, and monocytes. However, the intracellular localization of "D" and "K" ODN differs, as does their functional activity: "K" type ODN trigger monocytes and B cells to proliferate and secrete IL-6 and IgM, whereas "D" type ODN induce NK cells to produce IFN-gamma and monocytes to differentiate into CD83(+)/CD86(+) dendritic cells. In monocytes, these two types of ODN (which differ in backbone composition and CpG motif) cross-inhibit one another's activity. Thus, different types of CpG ODN have distinct and in some cases incompatible effects on the same cells, a finding with important implications for the therapeutic use of these agents.


The social gradient in oral health: Is there a role for dental anxiety?
To evaluate the contribution of dental anxiety to social gradients in different oral health outcomes and whether social gradients in oral health persist once dental anxiety is removed from the population examined. Data from 9035 British adults were analysed. Participants' socioeconomic position (SEP) was measured through education and household income. Dental anxiety was measured with the Modified Dental Anxiety Scale. Poor subjective oral health, oral impacts on quality of life and edentulism among all adults and the number of teeth, the number of decayed, missing and filled surfaces (DMFS) and sextants with pocketing among dentate adults were the oral health outcomes. The contribution of dental anxiety to absolute and relative social inequalities in each oral health outcome (measured with the Slope and Relative Index of Inequality [SII and RII], respectively) was estimated from regression models without and with adjustment for dental anxiety and quantified with the percentage attenuation. Interactions between each SEP indicator and dental anxiety were used to test what would happen if dental anxiety were removed from the whole population. The largest contribution of dental anxiety to explaining oral health inequalities was found for education gradients in perceived outcomes (11%-13%), but dental anxiety explained <4% of social gradients in edentulism. Among dentate adults, dental anxiety accounted for <5% and <7% of education and income gradients, respectively. Only four of the 24 interactions tested were statistically significant. Hence, the education- and income-based SII and RII for oral impacts were nonsignificant among anxiety-free adults but were significant at higher levels of dental anxiety. Little support was found for the role of dental anxiety in explaining social inequalities in various perceived and clinical oral health measures. Oral health inequalities were found among both nondentally anxious and anxious participants.


Scope for regulation of cigarette smoke toxicity according to brand differences in published toxicant emissions.
To explore the scope for regulating to reduce the toxicity of manufactured cigarettes sold in New Zealand (NZ), based on published toxicant emissions by brand. Internet searches of published cigarette smoke emissions of 13 toxicants chosen on risk assessment principles, for 20 British Columbian, 15 Australian brands, and one NZ brand, Holiday Extra-mild (HEM), tested by Health Canada intensive smoke machine method at Labstat Inc, Kitchener, Ontario, as a ratio of toxicant to nicotine yield. We estimated relative overall smoke toxicity per disease group and per brand, after adjusting for the published cigarette-attributed mortality fractions for cancer, cardiovascular, and respiratory disease. After allowing for nicotine yield, filter ventilation, and compensatory over-smoking, there were significant differences between brands, with the NZ brand estimated to be the most toxic. Low-yield cigarettes (<0.9 mg nicotine ISO) were estimated to be on average 19% more potent overall than medium-yield cigarettes (p<0.01). Of toxicants identified and measurable in smoke; 1,3-butadiene accounted for 45% of cancer potency; hydrogen cyanide for 89% of cardiovascular; and acrolein for 97% of respiratory potency--these three toxicants accounting for 65% of identified brand potency. Individual toxicant emissions varied across brands by a factor of 1.5 for carbon monoxide, to 32 for lead. Compared with HEM, one Canadian brand, 'Export A full flavor', carried a 37% lower cancer risk. This lower risk was largely due to differences in nicotine yield, lowering the toxicant/nicotine ratio. Cigarettes, unregulated, are unduly dangerous. Though many smoke toxicants cannot yet be quantified, risk assessment based on current data suggests that regulation could partly reduce identifiable cancer risk, and possibly eliminate the excess cardiovascular and respiratory toxicity of HEM, when compared with regular Canadian brands. The first goal should be to reduce emissions of the leading three toxicants, in addition to more effective charcoal filters. Tobacco smoke, unlike unburnt or non-smoking tobacco, contains toxic gases and trillions of reactive oxygen species molecules per puff, and will remain inherently harmful. Regulation could usefully part-reduce smoke toxicity exposure for continuing smokers, while not relenting on efforts to assist smokers and society to be quit of smoking.


Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection.
The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the predominant histologic pattern-lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)-present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT). Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis. A total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01). The new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes.


Galanin pathogenic mutations in temporal lobe epilepsy.
Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment.


Arabidopsis KCBP interacts with AIR9 but stays in the cortical division zone throughout mitosis via its MyTH4-FERM domain.
The preprophase band of microtubules performs the crucial function of marking the plane of cell division. Although the preprophase band depolymerises at the onset of mitosis, the division plane is 'memorized' by a cortical division zone to which the phragmoplast is attracted during cytokinesis. Proteins have been discovered that are part of the molecular memory but little is known about how they contribute to phragmoplast guidance. Previously, we found that the microtubule-associated protein AIR9 is found in the cortical division zone at preprophase and returns during cell plate insertion but is absent from the cortex during the intervening mitosis. To identify new components of the preprophase memory, we searched for proteins that interact with AIR9. We detected the kinesin-like calmodulin-binding protein, KCBP, which can be visualized at the predicted cortical site throughout division. A truncation study of KCBP indicates that its MyTH4-FERM domain is required for linking the motor domain to the cortex. These results suggest a mechanism by which minus-end-directed KCBP helps guide the centrifugally expanding phragmoplast to the cortical division site.


Decreased expression of CCNG2 is significantly linked to the malignant transformation of gastric carcinoma.
This study aimed to analyze the expression, clinical significance of cyclin G2 (CCNG2) in gastric carcinoma, and the biological effect in its cell line by CCNG2 overexpression. Immunohistochemistry and western blot were used to analyze CCNG2 protein expression in 87 cases of gastric cancer and normal tissues to study on the relationship between CCNG2 expression and clinical factors. CCNG2 lentiviral vector was transfected into gastric SGC-7901 cell line. RT-PCR and western blot were used to detect the mRNA level and protein of CCNG2. MTT assay and cell cycle were also conducted as to the influence of the upregulated expression of CCNG2 that might be found on SGC-7901 cell biological effect. Immunohistochemically, the level of CCNG2 protein expression was found to be significantly lower in gastric cancer tissue than in normal tissues (P < 0.05). Western blot shows that the relative amount of CCNG2 protein in gastric cancer tissue was found to be significantly lower than in normal tissues (P < 0.05). The level of CCNG2 protein expression was correlated with T stages, lymph node metastasis, clinical stage, and histological grade (P < 0.05). Loss of CCNG2 expression correlated significantly with poor overall survival time by Kaplan-Meier analysis (P < 0.05). The result of biological function showed that SGC-7901 cell-transfected CCNG2 had a lower survival fraction, higher percentage of the G0/G1 phases, and lower CDK2 protein expression compared with SGC-7901 cell untransfected CCNG2 (P < 0.05). CCNG2 expression decreased in gastric cancer and correlated significantly T stages, lymph node metastasis, clinical stage, histological grade, and poor overall survival, suggesting that CCNG2 may play important roles as a negative regulator to gastric cancer cell by promoting degradation of CDK2.


Argyrophilic nucleolar organizer regions in Helicobacter pylori-associated gastric lesions.
Three hundred and fifty biopsies from patients undergoing upper gastrointestinal endoscopy were studied for histopathological changes, H. pylori infection and argyrophilic nucleolar organizer region (AgNOR) counts. Histopathological examination revealed normal gastric mucosa in 10 (2.85%), gastritis in 254 (72.56%), intestinal metaplasia in 12 (4.0%), dysplasia in 13 (3.7%) and adenocarcinoma in 61 (17.4%). The mean (SD) AgNOR count was 1.66 (0.20) in normal, 2.43 (0.64) in gastritis, 3.09 (0.52) in intestinal metaplasia, 4.17 (0.31) in dysplasia, and 6.57 (0.98) in carcinoma. A statistically significant difference was observed between the AgNOR count of normal gastric mucosa and gastritis (p<0.001), gastritis and dysplasia (p<0.001), and dysplasia and adenocarcinoma (p<0.001). A statistically significant increase in mean AgNOR count was found with increase in H. pylori density in gastric biopsies (p<0.001) with gastritis. No significant difference was observed between mean AgNOR count of intestinal and diffuse type carcinomas. The AgNOR count in gastric biopsies with adenocarcinoma and H. pylori infection was 7.03 (0.85) as compared to 6.89 (0.73) in gastric biopsies with evidence of adenocarcinoma but without H. pylori infection. The difference was not statistically significant. The findings support the role of H. pylori as a promoting agent in gastric carcinogenesis by stimulating gastric epithelial cell proliferation at the stage of chronic inflammation, thereby making the cells more susceptible to endogenous or exogenous carcinogenic agents.


Structure of the adult central complex in Drosophila: organization of distinct neuronal subsets.
The central complex (CX) is a defined set of neuropils located on the midline of the protocerebrum in several arthropods and has been implicated in a number of behaviors. To investigate the function of the CX further it is imperative to know the neuroarchitecture of this structure and to ensure all known neuron types conform to a common nomenclature system. Several types of CX neuron have been identified but it is not known if these exist singly or as components of isomorphic sets. We used an enhancer trap approach to study the adult structure, connectivity, and polarity of CX neurons in Drosophila. We observed several isomorphic sets of small-field neurons including pontine and fb-eb neurons, and also isomorphic sets of large-field neurons including R neurons and F neurons. We found that several types of large-field F neurons existed in isomorphic sets of approximately eight (four per hemisphere) and found evidence for small-field neuron types existing as isomorphic sets of 16. Small-field neurons were observed in clearly organized layers. This study provides a novel insight into CX structure and connectivity and provides a set of characterized enhancer trap lines that will be valuable for future study.


Rheumatoid arthritis in a north american native population: longitudinal followup and comparison with a white population.
To describe differences in phenotype and outcomes in North American Native (NAN) patients with rheumatoid arthritis (RA) followed prospectively and compared to white patients with RA. Patients from a single academic center were followed over 20 years using a custom database. Data included diagnoses, year of disease onset, ethnicity, modified Health Assessment Questionnaire (mHAQ) score, patient and physician global scores, tender and swollen joint counts, treatment, serology, and erythrocyte sedimentation rate (ESR). Records of all white (n = 1315) and NAN (n = 481) patients with RA were abstracted. Cumulative treatment data and clinical measures were compared. Disease duration was longer in white patients compared to NAN patients (16 +/- 11 vs 14 +/- 10 years, respectively; p = 0.03). Onset age was 34 years for NAN patients and 43 years for white patients (p < 0.001). NAN patients were more frequently positive for rheumatoid factor (89% vs 74%; p < 0.001) and antinuclear antibody (57% vs 21%; p < 0.001). Although mean tender joint counts and swollen joint counts were similar, NAN patients had higher Lansbury scores (weighted joint count; 66.5 vs 49.7; p < 0.001), mHAQ scores (1.1 vs 0.9; p = 0.001), and ESR (31 vs 25 mm/h; p < 0.012). NAN patients had more frequent knee (53% vs 34%; p < 0.001) and elbow (62% vs 48%; p = 0.007) involvement. Compared to white patients, NAN patients took a higher lifetime number of disease-modifying antirheumatic drugs (3.2 +/- 1.9 vs 2.2 +/- 1.7; p < 0.001), had more combination therapy (38% vs 29%; p = 0.002), and had more frequent prednisone use (55% vs 39%; p < 0.001). Compared to white patients, NAN patients with RA develop disease earlier, are more frequently seropositive, have greater large joint involvement, and greater disease burden, although treatment is more aggressive. These differences are present early and persist throughout the disease course.


Initial pioneer venus magnetic field results: dayside observations.
Initial observations by the Pioneer Venus mangnetometer in the sunlit ionosphere reveal a dynamic ionosphere, very responsive to external solar-wind conditions. The localtions of the bow shock and ionosphere are variable. The strength of the magnetic field just olutside the ionopause is in approximate pressure balance with the thermal plasma of the ionosphere and changes markedly from day, to day in response to changes in solar wind pressure. The field strength in the ionosphere is also variable from day to day. The field is often weak, at most a few gammas, but reaching many tens of gammas for periods of the order of seconds. These field enchantments are interpreted as due to the passage of spacecraft through flux ropes consisting of bundles of twisted field lines surrounded by the ionospheric plasma. The helicity of the flux varies through the flux tube, with lows pitch angles on the inside and very lage angles in the low-field outer edges of the ropes. These ropes may have external or internal sources. Consistent with previous results, the average position of the bow shock is much closer to the planet than would be expected if the solar wnd were completely deflected by the planet. In total, these observations indicate that the solar wind plays a significant role in the physics of the Venus ionosphere.