Effects of microRNA-21 targeting PITX2 on proliferation and apoptosis of pituitary tumor cells.
Expression of pituitary homeobox 2 (PITX2) is significantly elevated in pituitary adenoma tissues, which also has lower microRNA (miR)-21 expression, indicating possible tumor-suppression role of miR-21. Bio-informatics analysis revealed targeting onto 3'-UTR of PITX2 by miR-21. This study aims to investigate the role of miR-21/PITX2 expression in proliferation and apoptosis of pituitary adenoma cells and pathogenesis. A total of 48 pituitary adenoma samples were collected in parallel with 12 normal brain tissues and were recruited in this study. Flow cytometry was employed to test Ki-67 expression and apoptosis. Expressions of miR-21 and PITX2 were compared, along with their targeted relationship by dual-luciferase reporter assay. Cultured HP75 cells were transfected with miR-21 mimic and/or si-PITX2. Caspase-3 activity was further quantified, followed by flow cytometry for apoptosis. MiR-21, cleaved caspase-3 and PITX2 expressions were tested. Invasive pituitary adenoma tissues had significantly higher Ki-67 and PITX2, and lower miR-21 expressions or apoptosis than non-invasive tumors. MiR-21 targeted 3'-UTR of PITX2 gene to inhibit its expression. Elevated miR-21 and/or silencing PITX2 significantly depressed PITX2 expression in HP75 cells, potentiating caspase-3 activity, decreasing cell proliferation and facilitating apoptosis. MiR-21 was down-regulated while PITX2 was up-regulated in pituitary adenoma tissues. MiR-21 can inhibit pituitary adenoma cell HP75 proliferation and facilitate apoptosis via inhibiting PITX2 expression.


Interaction of Salmonella enterica serovar Typhi with cultured epithelial cells: roles of surface structures in adhesion and invasion.
In this study we investigate the ability of Salmonella enterica serovar Typhi (S. Typhi) surface structures to influence invasion and adhesion in epithelial cell assay systems. In general, S. Typhi was found to be less adherent, invasive and cytotoxic than S. enterica serovar Typhimurium (S. Typhimurium). Culture conditions had little effect on adhesion of S. Typhi to cultured cells but had a marked influence on invasion. In contrast, bacterial growth conditions did not influence S. Typhi apical invasion of polarized cells. The levels of S. Typhi, but not S. Typhimurium, invasion were increased by application of bacteria to the basolateral surface of polarized cells. Expression of virulence (Vi) capsule by S. Typhi resulted in a modest reduction in adhesion, but profoundly reduced levels of invasion of non-polarized cells. However, Vi capsule expression had no affect on invasion of the apical or basolateral surfaces of polarized cells. Mutation of the staA, tcfA or pilS genes did not affect invasion or adhesion in either the presence or the absence of Vi capsule.


Anxiety sensitivity does not enhance pain signaling at the spinal level.
Anxiety sensitivity (AS) is the fear of anxiety-related sensations and its perceived harmful consequences. AS is associated with enhanced pain and worsened pain outcomes, suggesting it is a contributing factor in acute and chronic pain. However, the mechanisms that mediate the relationship between AS and pain are currently unknown. This study assessed the relationship between AS and 2 measures of spinal nociceptive processes (ie, nociceptive flexion reflex and temporal summation of nociceptive flexion reflex) and measures of subjective pain. This allowed us to determine whether AS engages descending cerebrospinal processes to facilitate pain signaling at spinal levels. AS was assessed in healthy men and women using the Anxiety Sensitivity Index-Revised. Then pain processing was assessed from electric pain threshold, nociceptive flexion reflex threshold, temporal summation of pain, temporal summation of nociceptive flexion reflex, and McGill Pain Questionnaire sensory and affective pain ratings. Associations among variables were assessed using Winsorized correlations (a robust and statistically powerful analytic method). AS was positively associated with sensory pain ratings, affective pain ratings, and temporal summation of pain, but was unrelated to all other outcomes. Given that AS was not significantly associated with measures of spinal nociception, these results suggest that AS may exert its influence on pain processing at the supraspinal, rather than the spinal level.


Asymmetric carbon-carbon coupling of phenols or anilines with aryllead triacetates.
The asymmetric coupling of various phenol or aniline derivatives with bulky aryllead triacetates was thoroughly investigated using optically active amines, including strychnine and brucine. We found that conformationally restricted tertiary amines, as well as lithium aryloxides and molecular sieves, are essential for accelerating the rate of phenol coupling. Consequently, the reaction can be carried out at a low temperature (-40 to -20 degrees C) and gives a high degree of diastereo- and enantioselectivity. In contrast to the effectiveness of lithiation in phenol coupling, magnesation of anilines was a critical technique for aniline coupling with aryllead triacetates. Using these coupling methods, a diverse set of di-, tri, and polyaryl compounds with axial chirality can be easily obtained, and these should be useful for the construction of a variety of aryl-aryl frameworks involved in metal ligands, natural products, and artificial helical polymers.


[The experimental study of biomimetic artificial cartilage fabrication in vitro and ectopic chondrogenesis in vivo].
Tri-dimensional poly (DL-lactic-co-glycolic acid) (PLGA) scaffolds were fabricated using a rapid prototyping (RP) technique and the gene of human bone morphogenetic protein 2 (hBMP-2) was transferred into rabbit bone marrow stromal cells (MSCs) via recombinant adeno-associated virus vectors (rAAV-hBMP-2). Thirty-two PLGA scaffolds, size (4 mm X 4 mm X 4 mm), were coated with collagen type I and equally divided into 2 groups. In group A, each scaffold was loaded with 2 X 10(4) hBMP-2 (+) MSCs to establish a hBMP-2 (+) MSCs/PLGA composite. In group B, each scaffold was loaded with 2 X 10(4) hBMP-2 (-) MSCs to establish a hBMP-2 (-) MSCs/PLGA composite. The composites in both groups were cultured for subcutaneous implantation in nude mice. All animals were killed 30 days after implantation and the differentiation of composites was evaluated. As a result, MSCs infected with rAAV-hBMP-2 efficiently expressed hBMP-2 protein. RP-based PLGA scaffolds had ideal microarchitecture. The diameters of macropore and micropore of the scaffolds were 300 microm and 3-5 microm, respectively. At 3-5 days after culture, a number of seeding cells well grew on the scaffolds of both groups. The composites in group A had chondrogenesis ability in vivo and the expression of collagen type II was positive. In group B, however, only polymers and fiber tissues were predominantly found. The percentage of polymer remnant area was significantly lower in group A than in group B (P<0.01). Our results therefore indicate that RP-based PLGA scaffolds efficiently coated with collagen type I have good biocompatibility with hBMP-2 (+) MSCs and the techniques developed in this study may favor cartilage tissue engineering.


Temporal change in risk of metachronous contralateral renal cell carcinoma: influence of tumor characteristics and demographic factors.
To determine the relative risk (RR) of developing a metachronous contralateral renal tumor after an initial diagnosis of renal cell carcinoma (RCC), with stratification by renal tumor characteristics, demographic factors, and follow-up duration, in order to develop an improved risk-based surveillance strategy. The 1973 to 1997 Surveillance, Epidemiology, and End Results database was used to determine the observed and expected number of metachronous contralateral renal tumors developing after an initial diagnosis of RCC. A total of 43,483 patients had a first diagnosis of RCC. Contralateral RCC developed subsequently in 155 (0.4%) of 40,049 patients with follow-up who had no synchronous diagnosis of RCC, with 10.81 expected cases (RR, 14.3; 95% CI, 12.2 to 16.8). The respective RRs (and 95% CIs) for contralateral RCC for white men and women were 16.0 (11.1 to 22.3) and 13.7 (7.7 to 22.6) at less than 2 years, 8.8 (5.0 to 14.3) and 10.5 (5.0 to 19.3) at 2 to 5 years, 13.5 (8.1 to 21.0) and 5.1 (1.4 to 13.2) at 5 to 10 years, and 13.0 (6.2 to 23.9) and 13.7 (5.0 to 29.9) at > or = 10 years, respectively. The RRs were significantly higher in black compared with white men for the first 5 years, with the RRs (and 95% CIs) in the former group of 95.3 (58.2 to 146.7) at less than 2 years and 41.9 (16.8 to 86.3) at 2 to 5 years. The incidence of metachronous contralateral RCC is stable on long-term follow-up, suggesting that surveillance of the contralateral kidney should remain rigorous on extended follow-up. Black men are at a significantly higher risk of developing contralateral RCC in the first 5 years of follow-up.


Secondary use of the rectus muscle pedicle for TRAM flap volume deficiencies.
The residual subxiphoid rectus muscle pedicle was rotated secondarily to a position underneath the breast mound in 13 patients who had previously undergone transverse rectus abdominis musculocutaneous (TRAM) flap breast reconstruction. The indications for this maneuver were the presence of a subxiphoid muscle bulge and a deficiency of volume or projection of the TRAM flap breast mound. This revisional surgery was performed at least 8 weeks after the TRAM flap, typically at the time of nipple-areolar reconstruction. Minor to moderate volume deficiencies were corrected and aesthetic improvement was substantial. There were no major complications. The danger of vascular compromise to the breast mound itself or to the remobilized muscle appears to be minimal, although the need for caution in the previously irradiated chest wall should be emphasized.


Population exposures to I-131 releases from Hanford Nuclear Reservation and preterm birth, infant mortality, and fetal deaths.
Communities surrounding the Hanford Nuclear Reservation in southeastern Washington were exposed to radionuclides, particularly iodine-131, released during the period 1945 to 1951. This study evaluated whether estimated iodine-131 exposures were risk factors for infant mortality, fetal death, and preterm birth in the years of highest releases, 1945 and 1946. Data on births, fetal deaths, and infant deaths, during the period 1940 to 1950, were abstracted from vital records for an eight county area surrounding the Hanford facility. The analysis included 56,320 births, 1,656 infant deaths, and 806 fetal deaths. The Hanford Environmental Dose Reconstruction project provided iodine-131 dose estimates for the 1,102 grid areas in the study area. The grid areas were collapsed into 4 exposure groups using estimated exposure to iodine-131 during 1945. Each birth and death record was assigned to one of the four grid groups based on mother's residence at the time of birth. Comparisons of preterm birth, infant death, and fetal death rates were made among the grid groupings for the primary exposure period (1945 to 1946) and for other years of the study period (i.e., 1940 to 1944 and 1947 to 1950). In the grid group with the highest estimated iodine-131 exposures, the mother's residence during the latter part of pregnancy was associated with preterm birth (OR = 1.74, 95% CI = 1.09-2.72). An association with infant mortality (OR = 1.26, 95% CI = 0.79-1.97) was suggested. No association was found for fetal deaths. This study found that iodine-131 exposure was associated with increased risk of preterm birth. This finding is biologically plausible because other studies have found that: (1) iodine-131 exposure can cause hypothyroidism, and (2) overt or subclinical hypothyroidism during pregnancy can increase a mother's risk of a preterm delivery.


Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives.
Chronic intake of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing gastrointestinal tumors, in particular colon cancer. Increasing evidence indicates that NSAID exert tumor-suppressive activity on pre-malignant lesions (polyps) in humans and on established experimental tumors in mice. Some of the tumor-suppressive effects of NSAIDs depend on the inhibition of cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins and thromboxane, which is highly expressed in inflammation and cancer. Recent findings indicate that NSAIDs exert their anti-tumor effects by suppressing tumor angiogenesis. The availability of COX-2-specific NSAIDs opens the possibility of using this drug class as anti-angiogenic agents in combination with chemotheapy or radiotherapy for the treatment of human cancer. Here we will briefly review recent advances in the understanding of the mechanism by which NSAIDs suppress tumor angiogenesis and discuss their potential clinical application as anti-cancer agents.


Impairment of thymus-dependent responses by murine dendritic cells infected with foot-and-mouth disease virus.
Foot-and-mouth disease virus (FMDV) is a cytopathic virus that experimentally infects mice, inducing a thymus-independent neutralizing Ab response that rapidly clears the virus. In contrast, vaccination with UV-inactivated virus induces a typical thymus-dependent (TD) response. In this study we show that dendritic cells (DCs) are susceptible to infection with FMDV in vitro, although viral replication is abortive. Infected DCs down-regulate the expression of MHC class II and CD40 molecules and up-regulate the expression of CD11b. In addition, infected DCs exhibit morphological and functional changes toward a macrophage-like phenotype. FMDV-infected DCs fail to stimulate T cell proliferation in vitro and to boost an Ab response in vivo. Moreover, infection of DCs in vitro induces the secretion of IFN-gamma and the suppressive cytokine IL-10 in cocultures of DCs and splenocytes. High quantities of these cytokines are also detected in the spleens of FMDV-infected mice, but not in the spleens of vaccinated mice. The peak secretion of IFN-gamma and IL-10 is concurrent with the suppression of Con A-mediated proliferation of T cells obtained from the spleens of infected mice. Furthermore, the secretion of these cytokines correlates with the suppression of the response to OVA, a typical TD Ag. Thus, infection of DCs with FMDV induces suppression of TD responses without affecting the induction of a protective thymus-independent response. Later, T cell responses are restored, setting the stage for the development of a long-lasting protective immunity.


A one-pot oxidative decarboxylation-Friedel-Crafts reaction of acyclic alpha-amino acid derivatives activated by the combination of iodobenzene diacetate/iodine and iron dust.
An efficient one-pot oxidative decarboxylation-Friedel-Crafts reaction of acyclic alpha-amino acid derivatives with electron-rich aromatic compounds is reported. The reaction is activated by the combination of iodobenzene diacetate, iodine and iron dust, resulting in a mild and simple reaction system. The use of iron avoids the oxidation of aromatic compounds, and in situ generation of Fe(III) salts to promote the Friedel-Crafts reaction avoids the use of the highly hygroscopic FeCl(3).


Postrigor tumble marination strategies for improving color and water-holding capacity in normal and pale broiler breast fillets.
Pale or pale, soft, and exudative-like meat can be caused by a decline in pH early postmortem while carcass temperatures are still high. This decrease in pH leads to protein denaturation, attributing to the pale color and poor water-holding capacity that is characteristic of this lesser quality meat. Marination with NaCl and phosphates has been shown to improve protein functionality, thereby reducing lost meat yield and improving meat quality. However, there are few studies relating marination with phosphates to improvements in pale meat. Therefore, the purpose of this experiment was to determine if meat quality improvements could be obtained in pale meat via marination with various phosphate and NaCl treatments without altering the quality and stability of normal or pale meat. The treatments used in this study were 1) sodium tripolyphosphate, an industry control; 2) a high pH phosphate (11.9); 3) a sodium tripolyphosphate and high pH mixture; 4) an agglomerated phosphate; and 5) a nonagglomerated phosphate. The marinades used in this study increased the pH, decreased the L* values of the pale fillets, and improved water-holding capacity. There were no significant differences in overall flavor preference for any of the 5 phosphate treatments. There was also no difference in oxidation or shelf-life trends in either the pale or normal fillets marinated with each of the 5 treatments. The results of this study were that marination with phosphates can be used to marinate pale meat without altering flavor, increasing the development of oxidation, or reducing shelf life.


Urinary incontinence in adults: nurses' beliefs, education and role in continence promotion. A narrative review.
Urinary incontinence (UI) has a high prevalence worldwide, in both genders; the available data suggest that the number of incontinent people will dramatically increase in the next few years. The costs generated by UI are similar to those induced by HIV and breast cancer. We aimed to investigate nurses' beliefs, knowledge and educational situation in the field of urinary continence. We performed a narrative review of literature, by searching qualitative and qualitative studies (2006-11) in PubMed, CINAHL and the Cochrane Library. Papers investigating pharmacological and/or surgical intervention were excluded. Only studies referred to adults have been taken into consideration. Prevalence ranges from 25 to 45% in women; in men, post-prostatectomy UI occurs in a median of 10-15% of the total cases. Benign prostatic hyperplasia, which affects 50% of men aged 50 to 60, is often associated with urge incontinence. The yearly individual expense for pads in Italy has been estimated to be as high as 913 euros in 2004. People often do not know about the possible solutions to UI; nurses seem to lack education in continence promotion, notwithstanding the proven effectiveness of the conservative interventions they could perform in autonomy. In Italy, few academic programs offer nursing education in this field. Urinary incontinence seems to be an underestimated problem; nurses often lack proper education in continence promotion. Academic, structured courses would be a solution; however, since education itself is not sufficient to really improve clinical practice, organizational support would be required to effectively promote continence in the broadest possible population. This would be a long-term investment for both quality of care and costs. Further studies are needed, regarding conservative management of UI; research could lead to a strong integration between clinical and academic branches of nursing, resulting in good quality evidence for clinical practice.


Harnessing Sun's Energy with Quantum Dots Based Next Generation Solar Cell.
Our energy consumption relies heavily on the three components of fossil fuels (oil, natural gas and coal) and nearly 83% of our current energy is consumed from those sources. The use of fossil fuels, however, has been viewed as a major environmental threat because of their substantial contribution to greenhouse gases which are responsible for increasing the global average temperature. Last four decades, scientists have been searching for alternative sources of energy which need to be environmentally clean, efficient, cost-effective, renewable, and sustainable. One of the promising sustainable sources of energy can be achieved by harnessing sun energy through silicon wafer, organic polymer, inorganic dye, and quantum dots based solar cells. Among them, quantum dots have an exceptional property in that they can excite multiple electrons using only one photon. These dots can easily be synthesized, processed in solution, and incorporated into solar cell application. Interestingly, the quantum dots solar cells can exceed the Shockley-Queisser limit; however, it is a great challenge for other solar cell materials to exceed the limit. Theoretically, the quantum dots solar cell can boost the power conversion efficiency up to 66% and even higher to 80%. Moreover, in changing the size of the quantum dots one can utilize the Sun's broad spectrum of visible and infrared ranges. This review briefly overviews the present performance of different materials-based solar cells including silicon wafer, dye-sensitized, and organic solar cells. In addition, recent advances of the quantum dots based solar cells which utilize cadmium sulfide/selenide, lead sulfide/selenide, and new carbon dots as light harvesting materials has been reviewed. A future outlook is sketched as to how one could improve the efficiency up to 10% from the current highest efficiency of 6.6%.


The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors.
In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization.


Cellular Dynamics of Memory B Cell Populations: IgM+ and IgG+ Memory B Cells Persist Indefinitely as Quiescent Cells.
Despite their critical role in long-term immunity, the life span of individual memory B cells remains poorly defined. Using a tetracycline-regulated pulse-chase system, we measured population turnover rates and individual t1/2 of pre-established Ag-induced Ig class-switched and IgM-positive memory B cells over 402 d. Our results indicate that, once established, both IgG-positive and less frequent IgM-positive memory populations are exceptionally stable, with little evidence of attrition or cellular turnover. Indeed, the vast majority of cells in both pools exhibited t1/2 that appear to exceed the life span of the mouse, contrasting dramatically with mature naive B cells. These results indicate that recall Ab responses are mediated by stable pools of extremely long-lived cells, and suggest that Ag-experienced B cells employ remarkably efficient survival mechanisms.


"As a young girl, I... " the benefits of narrational relationships in the lives of older residents.
1. Using story telling with the older resident provides an opportunity for the nurse to demonstrate caring, and a common reality between them is developed. 2. Story telling by older residents, far from merely "living in the past," can promote their health and well being. 3. In the narrational relationship between nurse and older resident, story telling is encouraged and supported; for the nurse, this means valuing oneself, older adults, and story telling.


Alpha-fetoprotein concanavalin A-binding variants in the diagnosis of neural tube defects and other communicating fetal abnormalities.
We have extended our initial observations (Smith et al., 1979) on th use of determining the alpha-fetoprotein (AFP) concanavalin A-binding variant patterns in amniotic fluid for the detection of certain fetal malformations. We report here our complete series of amniotic fluids between 14 and 36 weeks of gestation from 52 normal pregnancies and 28 abnormal pregnancies including anencephaly, open spina bifida, Turner's syndrome, omphalocele, osteogenesis imperfecta congenita, meningomyelocele, meningocele, spinal cysts, spontaneous abortion and fetal death. The percentage of the total amniotic fluid AFP which was not reactive with concanavalin A was significantly lower in the presence of a communicating fetal abnormality (mean = 4.8%, P less than 0.001), one in which the fetal/amniotic fluid barrier is defective, than in the presence of a normal fetus (mean = 24.7%) (or of a noncommunicating fetal abnormality. We applied the concanavalin A-binding assay to two of the above amniotic fluids from pregnancies in progress and correctly classified the gestations as abnormal. Our results indicate that measurement of the percentage of concanavalin A-non-reactive amniotic fluid AFP is a valuable adjunct in the diagnosis of a communicating fetal abnormality, especially when the elevation of amniotic fluid AFP concentration is equivocal (between 2 and 5 S.D. above the mean), when gestational aging is uncertain or when the total amniotic fluid AFP concentration and ultrasonographic data are inconsistent.


Tungsten Oxide-Based Z-Scheme for Visible Light-Driven Hydrogen Production from Water Splitting.
The stoichiometric water splitting using a solar-driven Z-scheme approach is an emerging field of interest to address the increasing renewable energy demand and environmental concerns. So far, the reported Z-scheme must comprise two populations of photocatalysts. In the present work, only tungsten oxides are used to construct a robust Z-scheme system for complete visible-driven water splitting in both neutral and alkaline solutions, where sodium tungsten oxide bronze (Na0.56WO3-x) is used as a H2 evolution photocatalyst and two-dimensional (2D) tungsten trioxide (WO3) nanosheets as an O2 evolution photocatalyst. This system efficiently produces H2 (14 μmol h-1) and O2 (6.9 μmol h-1) at an ideal molar ratio of 2:1 in an aqueous solution driven by light, resulting in a remarkably high apparent quantum yield of 6.06% at 420 nm under neutral conditions. This exceptional selective H2 and O2 production is due to the preferential adsorption of iodide (I-) on Na0.56WO3-x and iodate (IO3-) on WO3, which is evidenced by both experiments and density functional theory calculation. The present liquid Z-scheme in the presence of efficient shuttle molecules promises a separated H2 and O2 evolution by applying a dual-bed particle suspension system, thus a safe photochemical process.


Postictal apnea as an important mechanism for SUDEP: A near-SUDEP with continuous EEG-ECG-EMG recording.
Sudden unexpected death in epilepsy (SUDEP) is one of the most frequent causes of death among patients with epilepsy. Most SUDEP or near-SUDEP are unwitnessed and not observed or recorded during video-EEG recording in epilepsy monitoring units. This report describes a young woman with post ictal apnea and generalized EEG suppression (PGES) after a secondary generalized tonic-clonic seizure (sGTCS). This was accompanied by bradycardia and then ventricular tachycardia (VT). But at the end of VT, the patient's breath recovered without any intervention, such as cardio-respiratory resuscitation. This case report with continuous EEG, EKG, EMG during near SUDEP may provide insights into the mechanism of action.


Effect of selecting a fixed dephosphorylation rate on the estimation of rate constants and rCMRGlu from dynamic [18F] fluorodeoxyglucose/PET data.
Several publications have discussed the estimation and physiologic significance of regional [18F]fluorodeoxyglucose (FDG) rate constants and metabolic rates. Most of these studies analyzed dynamic data collected over 45-60 min; three rate constants (k1-k3) and blood volume (Vb) were estimated and the regional cerebral metabolic rate for glucose (rCMRGlu) was subsequently derived using the measured blood glucose value and a regionally invariant value of the lumped constant (LC). The dephosphorylation rate constant (k4) was either neglected, or a fixed value was used in the estimation procedure to obtain the remaining parameters. To compare the rate constants obtained by different authors using different values of k4 is impossible without knowledge of the effect of selecting different fixed values of k4 (including zero) on the estimated rate constants and rCMRGlu. Based on our analysis of FDG/PET data from nine normal volunteer subjects, we conclude that inclusion of a fixed value for k4, in spite of a scaling effect on the absolute values of model parameters, has no effect on the coefficient of variation (CV) of within- and between-subject parameter estimates and glucose metabolic rates.


Catalytic mechanism of glycosyltransferases: hybrid quantum mechanical/molecular mechanical study of the inverting N-acetylglucosaminyltransferase I.
The Golgi glycosyltransferase, N-acetylglucosaminyltransferase I (GnT-I), catalyzes the transfer of a GlcNAc residue from the donor UDP-GlcNAc to the C2-hydroxyl group of a mannose residue in the trimannosyl core of the Man5GlcNAc2-Asn-X oligosaccharide. The catalytic mechanism of GnT-I was investigated using a hybrid quantum mechanical/molecular mechanical (QM/MM) method with a QM part containing 88 atoms treated with density functional theory (DFT) at the BP/TZP level. The remaining parts of a GnT-I complex, altogether 5633 atoms, were modeled using the AMBER molecular force field. A theoretical model of a Michaelis complex was built using the X-ray structure of GnT-I in complex with the donor having geometrical features consistent with kinetic studies. The QM(DFT)/MM model identified a concerted SN2-type of transition state with D291 as the catalytic base for the reaction in the enzyme active site. The TS model features nearly simultaneous nucleophilic addition and dissociation steps accompanied by the transfer of the nucleophile proton Hb2 to the catalytic base D291. The structure of the TS model is characterized by the Ob2-C1 and C1-O1 bond distances of 1.912 and 2.542 A, respectively. The activation energy for the proposed reaction mechanism was estimated to be approximately 19 kcal mol-1. The calculated alpha-deuterium kinetic isotope effect of 1.060 is consistent with the proposed reaction mechanism. Theoretical results also identified interactions between the Hb6 and beta-phosphate oxygen of the UDP and a low-barrier hydrogen bond between the nucleophile and the catalytic base D291. It is proposed that these interactions contribute to a stabilization of TS. This modeling study provided detailed insight into the mechanism of the GlcNAc transfer catalyzed by GnT-I, which is the first step in the conversion of high mannose oligosaccharides to complex and hybrid N-glycan structures.


Outpatient Deep Brain Stimulation Surgery Is a Safe Alternative to Inpatient Admission.
Deep brain stimulation (DBS) is usually performed as an inpatient procedure. The COVID-19 pandemic effected a practice change at our institution with outpatient DBS performed because of limited inpatient and surgical resources. Although this alleviated use of hospital resources, the comparative safety of outpatient DBS surgery is unclear. To compare the safety and incidence of early postoperative complications in patients undergoing DBS procedures in the outpatient vs inpatient setting. We retrospectively reviewed all outpatient and inpatient DBS procedures performed by a single surgeon between January 2018 and November 2022. The main outcome measures used for comparison between the 2 groups were total complications, length of stay, rate of postoperative infection, postoperative hemorrhage rate, 30-day emergency department (ED) visits and readmissions, and IV antihypertensive requirement. A total of 44 outpatient DBS surgeries were compared with 70 inpatient DBS surgeries. The outpatient DBS cohort had a shorter mean postoperative stay (4.19 vs 39.59 hours, P = .0015), lower total complication rate (2.3% vs 12.8%, P = .1457), and lower wound infection rate (0% vs 2.9%, P = .52) compared with the inpatient cohort, but the difference in complications was not statistically significant. In the 30-day follow-up period, ED visits were similar between the cohorts (6.8% vs 7.1%, P = .735), but no outpatient DBS patient required readmission, whereas all inpatient DBS patients visiting the ED were readmitted ( P = .155). Our study demonstrates that DBS can be safely performed on an outpatient basis with same-day hospital discharge and close continuous monitoring.


Community connection is associated with lower psychological distress for sexual minority women who view community connection positively.
We examined factors associated with sexual minority women's evaluations of belonging to the lesbian, gay, bisexual, transgender and queer (LGBTQ) community in Australia, and assessed whether a positive view of community participation impacted levels of psychological distress. 2424 cisgender sexual minority women participated in a national, online, cross-sectional survey of LGBTIQ adult Australians' health and well-being. Multivariable regression analyses were conducted to investigate sociodemographic factors associated with sexual minority women's belonging to the LGBTQ community, feelings towards community connection, and associations between community connection and recent psychological distress. Most sexual minority women (58.9%) reported feeling that they are part of the LGBTQ community, and a majority of the participants felt positive about being connected to this community (68.5%). Participants who were bisexual, non-university educated, and who resided in an outer-suburban location were least likely to evaluate participation in the LGBTQ community positively. Feeling positive about community connection was associated with lower levels of psychological distress. Feeling a part of LGBTQ community was associated with lower psychological distress, but this link appears contingent upon positive feelings about community participation. Sexual minority women's' relationships to the LGBTQ community are often complex, and community connection and participation in and of itself is not a panacea for the negative outcomes associated with sexual minority stressors.


Absence of transcription of lck (lymphocyte specific protein tyrosine kinase) message in IL-2-independent, HTLV-I-transformed T cell lines.
The expression of lck gene (lymphocyte specific protein tyrosine kinase) in the human system was examined by Northern blot analysis in human T cell leukemia virus type I (HTLV-I)-positive T cell lines, HTLV-I-T cell lines, normal T cell population, and a T cell line infected with human immunodeficiency virus. In the cells of HTLV-I-integrated T cell lines, messages of lck were not detected in IL-2-independent lines, although found profusely in IL-2-dependent ones. The results of nuclear transcription assay indicated that lck expression is shut off at the stage of transcription in those cell lines. RNA products of the viral PX region were not detectable in two out of five HTLV-I+, IL-2-independent lines, suggesting that PX gene products themselves exert no direct effect on the block of lck transcription in the HTLV-I-infected T cells. Other T cell populations and a T cell line infected with human immunodeficiency virus, on the other hand, showed significant levels of lck message. These data presented the possibility that lck gene product may be one of the intervening molecules which transduce the signal from the IL-2R into the cell interior, and play an important role in the pathophysiology of adult T cell leukemia, especially in the transition of these leukemias from the IL-2-dependent stage to IL-2-independent one for their growth.


Doxorubicin and cyclophosphamide, alternated with bleomycin and mitomycin C as a second-line regimen in advanced ovarian carcinoma resistant to cisplatin-based chemotherapy.
Fourteen patients with advanced ovarian carcinoma (FIGO stages III-IV) resistant to cisplatin were submitted to an alternating regimen with doxorubicin (A), cyclophosphamide (C), bleomycin (B) and mitomycin C (M). All patients had measurable disease on entry into the study. No responses were observed while 3 patients, previously showing no change in cisplatin, had disease stabilization lasting 3, 4 and 6 months, respectively. All but 1 patient died with a median survival from the start of ACBM therapy of 7 months (range 6-11). ACBM-induced toxicity was remarkable with 50% grade II-III myelotoxicity which required a dose reduction in 43%, treatment delays in 64% and treatment discontinuation in 14%. All patients suffered from mild to moderate nausea and vomiting while reversible alopecia was seen in 42.8%. The lack of response and the substantial toxicity observed suggest that the ACBM regimen in the doses and schedule employed is not beneficial in ovarian carcinoma resistant to cisplatin.


Anti-HIV active petrosins from the marine sponge Petrosia similis.
A marine sponge Petrosia similis afforded two compounds which belongs to bis-quinolizidine alkaloids namely, petrosin (1) and petrosin-A (2), respectively. Petrosin (1) and petrosin-A (2) showed anti-HIV inhibition with IC(50) values of 41.3 and 52.9 microm respectively. MAGI cell assays indicated that the compounds inhibited early steps of HIV replication. In extracellular HIV-1 Reverse Transcriptase inhibition assay petrosin and petrosin-A inhibited HIV-1 RT at 10.6 and 14.8 microm. This is the first report of petroisns with anti-HIV activity.


A stress response pathway involving sirtuins, forkheads and 14-3-3 proteins.
A conserved sir2 deacetylase gene can determine longevity of yeast, flies and worms. Recently we have reported a molecular mechanism of action of the C. elegans homologue sir-2.1. Our study revealed a novel stress-dependent pathway for lifespan determination in which SIR-2.1 binds to 14-3-3 proteins and a forkhead transcription factor DAF-16 to activate transcription of DAF-16 target genes. DAF-16 has long been known as a central protein in the regulation of lifespan that interfaces with multiple pathways. Recent studies by us and other laboratories suggest that DAF-16 requires co-factors for full activity. In this prospective we review recent literature highlighting the role of SIR-2.1, 14-3-3 and other DAF-16 co-factors in DAF-16 activation.


Curcumin Analog Pentagamavunon-1 (PGV-1) Sensitizes Widr Cells to 5-Fluorouracil through Inhibition of NF-κB Activation
Cell cycle regulation and the NF-κB pathway in cancer cells are important in mediating resistance to 5-Fluorouracil (5-FU). Pentagamavunon-1 (PGV-1), a curcumin analog, is known to exhibit stronger growth inhibitory effects than curcumin itself in several cancer cells. In this study, we evaluated the potency of PGV-1 in combination with 5-FU in WiDr colon cancer cells. In MTT assays, PGV-1 did not only exhibit stronger growth inhibitory effects than both 5-FU and curcumin, but also enhanced the cytotoxicity of 5-FU. Flow cytometry demonstrated that single treatments with PGV-1 and 5-FU resulted in different effects on cell cycle profiles. PGV-1 induced G2/M arrest while 5-FU caused S-phase arrest at low concentration (1 μM) and G1-phase arrest at high concentration (100 μM). Interestingly, the combination of 5-FU and PGV-1 enhanced cell accumulation in S-phase. Although a single treatment with either 5-FU or PGV-1 increased cyclin D1 at the protein level, the combination treatment resulted in significant suppression. In addition, PGV-1 inhibited activation of NF-κB and suppressed the expression of cyclooxygenase-2, an NF-κB downstream protein. In conclusion, PGV-1 increased the cytotoxic effect of 5-FU on WiDr cells through inhibition of NF-κB activation.


Improving the Safety of Mesenchymal Stem Cell-Based Ex Vivo Therapy Using Herpes Simplex Virus Thymidine Kinase.
Human mesenchymal stem cells (MSCs) are multipotent stem cells that have been intensively studied as therapeutic tools for a variety of disorders. To enhance the efficacy of MSCs, therapeutic genes are introduced using retroviral and lentiviral vectors. However, serious adverse events (SAEs) such as tumorigenesis can be induced by insertional mutagenesis. We generated lentiviral vectors encoding the wild-type herpes simplex virus thymidine kinase (HSV-TK) gene and a gene containing a point mutation that results in an alanine to histidine substitution at residue 168 (TK(A168H)) and transduced expression in MSCs (MSC-TK and MSC-TK(A168H)). Transduction of lentiviral vectors encoding the TK(A168H) mutant did not alter the proliferation capacity, mesodermal differentiation potential, or surface antigenicity of MSCs. The MSC-TK(A168H) cells were genetically stable, as shown by karyotyping. MSC-TK(A168H) responded to ganciclovir (GCV) with an half maximal inhibitory concentration (IC50) value 10-fold less than that of MSC-TK. Because MSC-TK(A168H) cells were found to be non-tumorigenic, a U87-TK(A168H) subcutaneous tumor was used as a SAE-like condition and we evaluated the effect of valganciclovir (vGCV), an oral prodrug for GCV. U87-TK(A168H) tumors were more efficiently ablated by 200 mg/kg vGCV than U87-TK tumors. These results indicate that MSC-TK(A168H) cells appear to be pre-clinically safe for therapeutic use. We propose that genetic modification with HSV-TK(A168H) makes allogeneic MSC-based ex vivo therapy safer by eliminating transplanted cells during SAEs such as uncontrolled cell proliferation.


Microscopic postmortem changes in adrenal glands of the domestic fowl.
Eighty-four male white leghorn chickens were killed by CO2 gas to determine the type, rate, and sequence of microscopic postmortem changes in the adrenal glands of dry and wet intact carcasses. They were held at 29 or 18 C with 50% relative humidity for different times postmortem. The sequence of microscopic postmortem changes was similar in all chickens except at 18 C, when karyorrhexis of cortical and medullary cells was observed. Cellular changes occurred earlier at 29 C than at 18 C and in dry chickens but not in chickens wet with detergent solution before storage, although slight quantitative and qualitative differences between wet and dry chickens were noted. Medullary cells underwent postmortem changes earlier than cortical cells. Nuclei of medullary cells decreased in size, with chromatin clumping leading to pyknosis, followed by cytoplasmic vacuolation, cellular shrinkage, and finally karyolysis and cell dissociation. Cortical cells had nuclear chromatin marginated, nuclei reduced in size initially, and some nuclear fading, followed by pyknosis and karyolysis. Karyorrhexis was not a prominent feature of cortical and medullary cells, although it occasionally occurred before pyknosis. Cytoplasm of cortical cells remained eosinophilic, granular, and vacuolated, but vacuoles became finer later. Pyknotic medullary cells with vacuolated cytoplasm were observed as early as 3 hr postmortem, regardless of the temperature. Diffuse pyknosis of medullary cells was noted at 18 hr in chickens held at 29 C and at 48 hr in chickens held at 18 C. Marked cortical pyknosis was noted only at 36 hr in wet chickens held at 29 C, when bacterial invasion started. Dry chickens held 36 hr at 29 C had diffuse cellular dissociation, karyolysis and cytoplasmic acidophilia, and marked bacterial invasion. Erythrocytes were pyknotic and had cytoplasmolysis. It was concluded that adrenal glands may still be useful for histopathological examination before 18 hr at 29 C and before 48 hr at 18 C.


A Validated Ultra-Performance Liquid Chromatographic Method for the Simultaneous Determination of Nadifloxacin, Mometasone Furoate and Miconazole Nitrate in Their Combined Dosage Form and Spiked Human Plasma Samples.
Nadifloxacin, mometasone furoate and miconazole nitrate are formulated together as a topical antifungal dosage form. In this work, a reversed-phase ultra-performance liquid chromatographic method coupled with a diode array detector (RP-UPLC-DAD) was developed and validated to determine nadifloxacin, mometasone furoate and miconazole nitrate simultaneously in their bulk powder, in pharmaceutical preparation and in spiked human plasma samples. Separation was achieved on an ACQUITY UPLC C18 column of 2.2 μm particle size (2.1 × 100 mm) via isocratic elution using a mobile phase consisting of methanol, acetonitrile and water with ratio (50:20:30; v/v/v) and 0.1 g ammonium acetate, then pH was adjusted to (7.00) using acetic acid, flow rate 0.6 mL/min, temperature 30°C and UV detection at 220 nm. The method is linear in a range from 5 to 400 μg/mL for both nadifloxacin and miconazole nitrate and from 20 to 500 μg/mL for mometasone furoate. The method was validated according to the ICH guidelines then applied successfully to determine the mentioned drugs in their pharmaceutical preparation and spiked human plasma samples. For plasma samples, the results showed that the method can determine nadifloxacin, mometasone furoate and miconazole nitrate in human plasma samples with high accuracy and precision.


Mechanistic diversity in ATP-binding cassette (ABC) transporters.
ABC transporters catalyze transport reactions, such as the high-affinity uptake of micronutrients into bacteria and the export of cytotoxic compounds from mammalian cells. Crystal structures of ABC domains and full transporters have provided a framework for formulating reaction mechanisms of ATP-driven substrate transport, but recent studies have suggested remarkable mechanistic diversity within this protein family. This review evaluates the differing mechanistic proposals and outlines future directions for the exploration of ABC-transporter-catalyzed reactions.


[Acute pseudo-obstruction of the colon (clinical cases)].
The Authors report 4 cases of Ogilvie's syndrome come to their observation during the last 5 years by the clinical surgery II of the I.R.C.C.S. Polyclinic "San Matteo" of Pavia. Remembering the infrequency of the affection and the controversial etiopathogenesis theories, the Authors study the clinical picture and the diagnostic problems, pointing out how some researches, especially radiological and endoscopical, permit to obtain a therapeutic solution of the syndrome. They underline the colonic perforation risk, certainly overestimated, and they show the therapeutic, medical or surgical, orientations, according to the evolution of the illness, the anatomic situations and the general conditions of the patient.


Impacts of mining activities on water and soil.
Seven coal mines are situated in Wardha River Valley. These mines are located at Wani (Dist. Yavatmal of Maharashtra). Out of these, 5 open cast coal mines are run by Western Coal Field Ltd. India. The present study has been undertaken to assess the impacts of mining activities in the adjacent areas. Total 25 samples of water and 19 samples of soil from Nilapur, Bramhani, Kolera, Gowari, Pimpari and Aheri were analyzed for pH, TDS, hardness, alkalinity, fluoride, chloride, nitrite, nitrate, phosphate, sulfate, cadmium, lead, zinc, copper, nickel, arsenic, manganese, sodium and potassium, and the results were compared with the limits of Indian Standards: 10500.


Let-7b is involved in the inflammation and immune responses associated with Helicobacter pylori infection by targeting Toll-like receptor 4.
Toll-like receptors (TLRs) are important initiators in native immune responses to microbial infections. TLR4 is up-regulated in response to H.pylori infection in gastric epithelial cells. However, the regulatory mechanisms for the expression of TLR4 in H.pylori infection have not been clearly defined. The aims of this study are to present the evidence that microRNA let-7b directly regulates TLR4 expression in human gastric epithelial cells, and subsequently influences the activation of NF-κB and the expression of the downstream genes in H.pylori infection. The expression of let-7b was determined in gastric mucosa specimens and in two gastric epithelial cell lines using quantitative RT-PCR. The expression of TLR4 was determined by immunohistochemistry staining and RT-PCR. The potential target of let-7b was identified by luciferase reporter assay and Western blot. Let-7b mimics and inhibitors were used to examine the effects of let-7b on NF-κB activity. The expression of the downstream genes of NF-κB was also determined in cells infected with H.pylori 26695. Let-7b was significantly decreased in gastric mucosa specimens and in gastric epithelial cell lines (AGS, GES-1) infected with H.pylori 26695 (cagA+). Let-7b was complementary to the 3'-UTR of TLR4 mRNA and regulated TLR4 expression via post-transcriptional suppression in gastric epithelium. Infection of H.pylori induced the expression of TLR4 and activated NF-κB in AGS and GES-1 cells. Overexpression of let-7b by mimics downregulated TLR4, and subsequently attenuated NF-κB, MyD88, NF-κB1/p50, RelA/p65. The expression of IL-8, COX-2 and CyclinD1 was inhibited in H.pylori infected cells with let-7b overexpression. Both TAK-242 (TLR4 inhibitor) and SN50 (NF-κB inhibitor) significantly inhibited the H.pylori induced downregulation of let-7b. Let-7b targets at TLR4 mRNA, and regulates the activation of NF-κB and the expression of the downstream genes related to the inflammation and immune responses in H.pylori infection.


Mentoring future leaders: The Midwinter SOHN Board Meeting guest attendee program.
Leadership requires vision to fulfill one's mission or purpose. Leadership, in part, is the art of influencing others to achieve goals. Leaders often find creative solutions to achieve their goals and mobilize the resources needed for attainment (McArthur, 2006). The Society of Otorhinolaryngology and Head-Neck Nurses (SOHN) Board of Directors (BOD) and elected officers developed an innovative program to mentor future leaders by awarding two members-at-large the opportunity to attend a national SOHN BOD meeting. The goal of this mentoring program is to provide guidance, encouragement, and support for otorhinolaryngology nurses to assume future leadership roles within the organization (Andresen, 2006; Krouse, 2004). The purpose of this article is to share the author's perspectives after attending a national SOHN BOD meeting as a guest attendee.


Gene-Ontology analysis reveals association of tissue-specific 5' CpG-island genes with development and embryogenesis.
A key open question in the understanding of the biology of DNA methylation relates to the origin and function of CpG islands, stretches of GC-rich and relatively CpG-rich DNA sequence that often colocalize with promoter regions. All housekeeping, but also a substantial minority of tissue-specific genes are associated with the CpG islands. Limited experimental evidence suggests that CpG islands are associated with promoters or replication origins active during early development. Although this hypothesis is attractive for widely expressed genes, which would be expected to be expressed during early development, many tissue-specific genes also contain CpG islands. In this work, we used a genome-wide Gene-Ontology (GO)-based approach to analyze associations between GO terms and the presence of 5' CpG islands in human Reference Sequence (RefSeq) genes. We found that 19 of the 3849 GO terms with at least one annotated human sequence showed a highly significant association with the likelihood of 5' CpG islands being present in genes annotated to that term. In particular, the term 'development' showed a highly significantly increased proportion of 5' CpG island genes. The overrepresentation of 5' CpG island genes was even more significant for tissue-specific RefSeqs annotated to development as well as many of its descendent terms. In addition, the proportion of expressed sequence tags from embryonic libraries amongst tissue-specific genes was twice as high for RefSeqs with 5' CpG islands as for those without CpG islands. These results provide strong support for previous speculations that early embryonic expression is associated with CpG islands.


Solution NMR and computational methods for understanding protein allostery.
Allosterism is an essential biological regulatory mechanism. In enzymes, allosteric regulation results in an activation or inhibition of catalytic turnover. The mechanisms by which this is accomplished are unclear and vary significantly depending on the enzyme. It is commonly the case that a metabolite binds to the enzyme at a site distant from the catalytic site, yet its binding is coupled to and sensed by the active site. This coupling can manifest in changes in structure, dynamics, or both at the active site. These interactions between the allosteric and active site, which are often quite distant from one another, involve numerous atoms as well as complex conformational rearrangements of the protein secondary and tertiary structure. Interrogation of this complex biological phenomenon necessitates multiple experimental approaches. In this article, we outline a combined solution NMR spectroscopic and computational approach using molecular dynamics and network models to uncover mechanistic aspects of allostery in the enzyme imidazole glycerol phosphate synthase.


Phylogenetic relationships of the western North American phoxinins (Actinopterygii: Cyprinidae) as inferred from mitochondrial 12S and 16S ribosomal RNA sequences.
Parsimony analysis of the mitochondrial 12S and 16S rRNA sequences of North American phoxinin taxa indicated the existence of three major clades, the Western Clade, the Creek Chub Clade, and the Open Posterior Myodome Clade. The monophyletic Western Clade identified in this paper contained fewer taxa than that identified by previous authors. This clade contained species restricted to drainages west of the Continental Divide, such as Gila, Acrocheilus, Relictus, Eremichthys, Siphateles, Ptychocheilus, Lavinia, and Orthodon, and the wide-ranging genus Phoxinus found in eastern North America and Eurasia. Within this Western Clade Phoxinus was the basal sister group. Gila was recognized as a monophyletic group exclusive of Siphateles and Snyderichthys, clades traditionally recognized as subgenera of Gila. The genus Gila was most closely related to the genus Acrocheilus and together these formed the sister group to the genus Relictus. These relationships were supported independent of weighting schemes used in analyses. Identification of Phoxinus as the basal sister taxon of the Western clade implies that other major clades of North American Phoxinins likely have Asian or European relatives.


Druggable targets and therapeutic development for COVID-19.
Coronavirus disease (COVID-19), which is caused by SARS-CoV-2, is the biggest challenge to the global public health and economy in recent years. Until now, only limited therapeutic regimens have been available for COVID-19 patients, sparking unprecedented efforts to study coronavirus biology. The genome of SARS-CoV-2 encodes 16 non-structural, four structural, and nine accessory proteins, which mediate the viral life cycle, including viral entry, RNA replication and transcription, virion assembly and release. These processes depend on the interactions between viral polypeptides and host proteins, both of which could be potential therapeutic targets for COVID-19. Here, we will discuss the potential medicinal value of essential proteins of SARS-CoV-2 and key host factors. We summarize the most updated therapeutic interventions for COVID-19 patients, including those approved clinically or in clinical trials.


The normal counterpart of IgD myeloma cells in germinal center displays extensively mutated IgVH gene, Cmu-Cdelta switch, and lambda light chain expression.
Human myeloma are incurable hematologic cancers of immunoglobulin-secreting plasma cells in bone marrow. Although malignant plasma cells can be almost eradicated from the patient's bone marrow by chemotherapy, drug-resistant myeloma precursor cells persist in an apparently cryptic compartment. Controversy exists as to whether myeloma precursor cells are hematopoietic stem cells, pre-B cells, germinal center (GC) B cells, circulating memory cells, or plasma blasts. This situation reflects what has been a general problem in cancer research for years: how to compare a tumor with its normal counterpart. Although several studies have demonstrated somatically mutated immunoglobulin variable region genes in multiple myeloma, it is unclear if myeloma cells are derived from GCs or post-GC memory B cells. Immunoglobulin (Ig)D-secreting myeloma have two unique immunoglobulin features, including a biased lambda light chain expression and a Cmu-Cdelta isotype switch. Using surface markers, we have previously isolated a population of surface IgM-IgD+CD38+ GC B cells that carry the most impressive somatic mutation in their IgV genes. Here we show that this population of GC B cells displays the two molecular features of IgD-secreting myeloma cells: a biased lambda light chain expression and a C&mu-Cdelta isotype switch. The demonstration of these peculiar GC B cells to differentiate into IgD-secreting plasma cells but not memory B cells both in vivo and in vitro suggests that IgD-secreting plasma and myeloma cells are derived from GCs.


Brief Report: Medication Sharing Is Rare Among African HIV-1 Serodiscordant Couples Enrolled in an Efficacy Trial of Oral Pre-exposure Prophylaxis (PrEP) for HIV-1 Prevention.
Sharing of pre-exposure prophylaxis (PrEP) medications is a concern for PrEP implementation. For HIV-1 serodiscordant couples, sharing may undermine the HIV-1 prevention benefit and also cause antiretroviral resistance if taken by HIV-1 infected partners. Within a PrEP efficacy trial among HIV-1 serodiscordant couples, we assessed the occurrence of PrEP sharing by self-report and plasma tenofovir concentrations in HIV-1 infected partners. PrEP sharing was self-reported at <0.01% of visits, and 0%-1.6% of randomly selected and 0% of purposively selected specimens from HIV-1 infected participants had detectable tenofovir concentrations (median: 66.5 ng/mL, range: 1.3-292 ng/mL). PrEP sharing within HIV-1 serodiscordant couples was extremely rare.


Metronomic treatment of advanced non-small-cell lung cancer with daily oral vinorelbine - a Phase I trial.
In a Phase I dose-finding study of metronomic daily oral vinorelbine in advanced non-small-cell lung cancer, a recommended dose was established for this therapeutic approach. In addition, this trial revealed promising efficacy data and an acceptable tolerability profile. The observed vinorelbine blood concentrations suggest continuous anti-angiogenic coverage. We present a Phase I dose-finding study investigating metronomic daily oral vinorelbine (Navelbine® Oral, NVBo) in advanced non-small-cell lung cancer (NSCLC). Patients with stage III/IV NSCLC received daily NVBo at fixed dose levels of 20-50 mg/d for 21 days of each 4-week cycle. Primary end point was the maximum tolerated dose. Secondary end points included tumor response, time to progression (TTP), overall survival (OS) and tolerability. Twenty-seven patients with advanced NSCLC were enrolled. Most of them were extensively pretreated. Daily NVBo was well tolerated up to 30 mg/d. At 40 mg/d, two of five patients experienced dose-limiting toxicities (DLTs). Three of six patients had DLTs at the 50 mg/d level. The recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2, if tolerated. Pharmacokinetic analyses showed continuous blood exposure over 21 days and only marginal accumulation. The tolerability profile was acceptable (all dose levels - all grades: decreased appetite 33%, diarrhea 33%, leukopenia 33%, nausea 30%, vomiting 26%; ≥grade 3: leukopenia 30%, lymphopenia 19%, neutropenia 19%, febrile neutropenia 15%). Disease control rate, OS and TTP signaled a treatment effect. Daily metronomic NVBo therapy in extensively pretreated patients with advanced NSCLC is feasible and safe at the recommended dose of 30 mg/d. Escalation to 40 mg/d in the second cycle is possible. The blood concentrations of vinorelbine after daily metronomic dosing reached lower peaks than intravenous or oral conventional dosing. Blood concentrations were consistent with anti-angiogenic or immune modulating pharmacologic properties of vinorelbine. Further studies are warranted to evaluate the safety and efficacy of this novel approach in specific patient populations.


Bacterial contig map of the 21q11 region associated with Alzheimer's disease and abnormal myelopoiesis in Down syndrome.
We present a high-resolution bacterial contig map of 3.4 Mb of genomic DNA in human chromosome 21q11-q21, encompassing the region of elevated disomic homozygosity in Down Syndrome-associated abnormal myelopoiesis and leukemia, as well as the markers, which has shown a strong association with Alzheimer's Disease that has never been explained. The map contains 89 overlapping PACs, BACs, or cosmids in three contigs (850, 850, and 1500 kb) with two gaps (one of 140-210 kb and the second <5 kb). To date, eight transcribed sequences derived by cDNA selection, exon trapping, and/or global EST sequencing have been positioned onto the map, and the only two genes so far mapped to this cytogenetic region, STCH and RIP140 have been precisely localized. This work converts a further 10% of chromosome 21q into a high-resolution bacterial contig map, which will be the physical basis for the long-range sequencing of this region. The map will also enable positional derivation of new transcribed sequences, as well as new polymorphic probes, that will help in elucidation of the role the genes in this region may play in abnormal myelopoiesis and leukemia associated with trisomy 21 and Alzheimer's Disease.


Polydatin attenuates tubulointerstitial fibrosis in diabetic kidney disease by inhibiting YAP expression and nuclear translocation.
The activation of Yes-associated protein (YAP) pathway is mutually causal with the increase of extracellular matrix (ECM) stiffness. Polydatin (PD) has been proved to have anti-fibrosis effect in diabetic kidney disease (DKD), but it is still a mystery whether PD participates in YAP-related mechano-transduction. Therefore, this study intends to solve the following two problems: 1) To construct an in vitro system of polyacrylamide hydrogels (PA gels) based on the true stiffness of kidneys in healthy and DKD rats, and observe the effect of PD on pathological matrix stiffness-induced YAP expression in renal fibroblasts; 2) Compared with verteporfin (VP), a pharmacological inhibitor of YAP, to explore whether the therapeutic effect of PD on DKD in vivo model is related to the regulation of YAP. In this study, the in vitro system of PA gels with 3 kPa, 12 kPa and 30 kPa stiffness was constructed and determined for the first time to simulate the kidney stiffness of healthy rats, rats with DKD for 8 weeks and 16 weeks, respectively. Compared with the PA gels with 3 kPa stiffness, the PA gels with 12 kPa and 30 kPa stiffness significantly increased the expression of YAP, α-smooth muscle actin (α-SMA) and collagen I, and the production of reactive oxygen species (ROS) in renal fibroblasts, and the PA gels with 30 kPa stiffness were the highest. PD significantly inhibited the above-mentioned changes of fibroblasts induced by pathological matrix stiffness, suggesting that the inhibition of PD on fibroblast-to-myofibroblast transformation and ECM production was at least partially associated with regulating YAP-related mechano-transduction pathway. Importantly, the inhibitory effect of PD on YAP expression and nuclear translocation in kidneys of DKD rats is similar to that of VP, but PD is superior to VP in reducing urinary protein, blood glucose, blood urea nitrogen and serum creatinine, as well as decreasing the expression of α-SMA and collagen I, ROS overproduction and renal fibrosis. Our results prove for the first time from the biomechanical point of view that PD is a potential therapeutic strategy for delaying the progression of renal fibrosis by inhibiting YAP expression and nuclear translocation.


Comparing three superovulation protocols in dromedary camels: FSH, eCG-FSH and hMG.
The objective of this study was to compare three superovulation protocols in dromedary camels. Follicular waves of dromedary camel donors (n=6) were synchronized using two GnRH injections. Superovulation was initiated 2 days after the second injection (day 0 of experiment). The experiment was conducted using change over design, where all females received three superovulation treatments one after the other with a resting period of one month in between. Superovulation was carried out for all donors using 390 mg FSH, 1000 IU eCG and 330 mg FSH, or 16.5 ampule hMG (75 i.u. FSH and 75 i.u. LH per ampoule). FSH and hMG were injected twice daily, indecreasing doses, over 5.5 days. Thirty-six h after the last FSH or hMG injection, donors were mated once and received an intravenous injection of the GnRH analogue. The diameter and number of ovarian follicles ≥4 mm on day 4 after superovulation and the total number of corpora lutea and follicles ≥9 mm on day 7.5 after mating were evaluated by ultrasound examinations. No significant differences were found between the total number of corpora lutea among FSH (13.8 ± 2.65), eCG-FSH (15 ± 2.60) and hMG (10.8 ± 2.30) and the number of expanded hatched blastocysts in FSH (5.7 ± 2.32), eCG-FSH (8.8 ± 2.10) and hMG (5.8 ± 2.40) treated donors. This study showed that all three superovulatory protocols could be used successfully and interchangeably in dromedary camels.


Conformations of laulimalide in DMSO-d6.
Laulimalide is one of the newest naturally occurring macrolides known to act as a microtubule stabilizing agent with properties similar to Taxol. It also stands as being one of the most flexible with 18 rotatable bonds. This large number of rotatable bonds allows for approximately 3(18) potential conformers. To examine the conformational energy surface of laulimalide, we have performed an NAMFIS deconvolution analysis for laulimalide in DMSO-d6. The latter has been supplemented with a post-NAMFIS energy analysis at the Becke3LYP/6-31G level that examines the opposing effects of internal hydrogen bonding and syn-pentane interactions. In this way, we have identified 15 laulimalide conformations that can be classified into 5 different families: Supine, Convex, Cobra, Stretch, and Concave motifs.


Circadian variation of secretory IgA in nasal secretions from normal subjects.
In normal subjects the concentration ratio of secretory IgA (sIgA) to total IgA in nasal secretion was measured by means of enzyme-linked immunosorbent assays (ELISA). No marked circadian variation was disclosed in the sIgA/IgA ratio in nasal secretion.


Comparison of marginal adaptation of mineral trioxide aggregate, glass ionomer cement and intermediate restorative material as root-end filling materials, using scanning electron microscope: An in vitro study.
The present study compares the marginal adaption of Mineral Trioxide Aggregate (MTA), Glass Ionomer Cement (GIC) and Intermediate Restorative Material (IRM) as root-end filling materials in extracted human teeth using Scanning Electron Microscope (SEM). Thirty single rooted human teeth were obturated with Gutta-percha after cleaning and shaping. Apical 3 mm of roots were resected and retrofilled with MTA, GIC and IRM. One millimeter transverse section of the retrofilled area was used to study the marginal adaptation of the restorative material with the dentin. Mounted specimens were examined using SEM at approximately 15 Kv and 10(-6) Torr under high vacuum condition. At 2000 X magnification, the gap size at the material-tooth interface was recorded at 2 points in microns. One way ANOVA Analysis of the data from the experimental group was carried out with gap size as the dependent variable, and material as independent variable. The lowest mean value of gap size was recorded in MTA group (0.722 ± 0.438 μm) and the largest mean gap in GIC group (1.778 ± 0.697 μm). MTA showed least gap size when compared to IRM and GIC suggesting a better marginal adaptation.


Abscisic Acid Signaling and Abiotic Stress Tolerance in Plants: A Review on Current Knowledge and Future Prospects.
Abiotic stress is one of the severe stresses of environment that lowers the growth and yield of any crop even on irrigated land throughout the world. A major phytohormone abscisic acid (ABA) plays an essential part in acting toward varied range of stresses like heavy metal stress, drought, thermal or heat stress, high level of salinity, low temperature, and radiation stress. Its role is also elaborated in various developmental processes including seed germination, seed dormancy, and closure of stomata. ABA acts by modifying the expression level of gene and subsequent analysis of cis- and trans-acting regulatory elements of responsive promoters. It also interacts with the signaling molecules of processes involved in stress response and development of seeds. On the whole, the stress to a plant can be susceptible or tolerant by taking into account the coordinated activities of various stress-responsive genes. Numbers of transcription factor are involved in regulating the expression of ABA responsive genes by acting together with their respective cis-acting elements. Hence, for improvement in stress-tolerance capacity of plants, it is necessary to understand the mechanism behind it. On this ground, this article enlightens the importance and role of ABA signaling with regard to various stresses as well as regulation of ABA biosynthetic pathway along with the transcription factors for stress tolerance.


[On the inhibitory effect of chloramphenicol on mitochondrial protein synthesis as a possible cause of its selective toxic side effects (author's transl)].
The inhibition of protein synthesis by tetracycline and chloramphenicol in mitochondria isolated from rat liver or rabbit bone marrow was investigated in vitro. It could be demonstrated that there is but little difference between the inhibitory effect of both substances in regard to mitochondria protein synthesis. Therefore, a selective interference of chloramphenicol with bone marrow mitochondria cannot be concluded. In in vitro tests the concentrations required for inhibiting the mitochondria protein synthesis are comparable to those found in blood levels measured under usual therapeutic conditions. It can be assumed that in the living organism the mitochondria are protected against tetracycline or chloramphenicol interference. This hypothesis is supported by the fact that due to the increase in the substrate concentration (phenylalanine), the expected inhibition of mitochondrial protein synthesis does not occur. There may be an inhibition of influx of the antibiotic by competition with substrate for transport through mitochondrial membrane. The reason for myelotoxicity of chloramphenicol is not an increased sensitivity of mitochondrial ribosomes located in the bone marrow to chloramphenicol. But the existence of special conditions for chloramphenicol influx into mitochondria of bone marrow must be concluded.


Primary salivary clear cell tumors--a diagnostic approach: a clinicopathologic and immunohistochemical study of 20 patients with clear cell carcinoma, clear cell myoepithelial carcinoma, and epithelial-myoepithelial carcinoma.
Primary salivary clear cell tumors comprise an uncommonly encountered subgroup of salivary neoplasia. We hypothesize that clear cell carcinoma does not represent a "monomorphic" variant of epithelial-myoepithelial carcinoma, but is distinct in terms of histogenesis and tumor biology. To compare the clinicopathologic features of 20 cases of salivary primary clear cell tumors, including 12 clear cell carcinomas (CCCs), 7 epithelial-myoepithelial carcinomas (EMECs), and 1 clear cell myoepithelial carcinoma (CCMEC); to investigate their interrelationship with regard to myoepithelial differentiation; and to offer a diagnostic approach for distinguishing between these entities. Retrospective and prospective identification and review of patients diagnosed with primary salivary clear cell neoplasia and review of the English language literature. Three academic tertiary-care hospitals. We identified 12 patients with CCC, 7 with EMEC, and 1 with CCMEC. Patients included 11 men and 9 women, aged 30 to 88 years (median 72.5 years). Immunohistochemical reactivity for S100, muscle-specific actin, and calponin; ultrastructural examination when feasible; review of patient charts; and telephone interviews to establish clinical outcome. Clear cell carcinoma has a predilection for intraoral sites, whereas EMEC has a predilection for the parotid. All 3 of the tumor types studied have a propensity for locoregional recurrence, which can manifest decades after initial surgery. There were no mortalities among patients with CCC, even after pulmonary metastasis in 2 patients, confirming the indolent nature of this group of clear cell tumors. A meta-analysis of reported cases of CCC, EMEC, and CCMEC confirmed that EMEC and CCMEC have a much greater propensity for locoregional recurrence than CCC, despite the predilection of both for a more surgically accessible site (parotid). We found no definitive evidence of myoepithelial differentiation in CCC, indicating that it is probably morphogenetically distinct from EMEC and CCMEC, both tumors with diagnostically requisite myoepithelial differentiation. The initial treatment of choice for CCC, CCMEC, and EMEC is surgical resection with negative margins. Locoregional recurrence should be treated aggressively, as it is still consistent with long disease-free intervals. The lack of myoepithelial differentiation in CCC is consistent with the concept that this tumor is histomorphogenically distinct from EMEC and that it is not merely a monomorphic variant.


Gestational impaired glucose tolerance (GIGT)-induced suppression of fetal thyroid secretion: effect on fetal outcome.
Gestational impaired glucose tolerance (GIGT) is a milder form of gestational diabetes mellitus (GDM), which is often poorly managed. Although, GDM is known to be associated with increased incidence of thyroid dysfunction, no study has been done to study the effect of GIGT on thyroid status and its effect on fetal outcome. Here, we carried out a study to assess thyroid function and glycemic status in both maternal and cord blood of the subjects with GIGT, and to find their association with the fetal outcome. Women who came to the hospital for safe confinement during 37-40th weeks of gestation were recruited in the study. Based on the 2 hours post prandial blood glucose levels with 75 grams OGTT, done at 24-28 weeks of gestation, all the subjects were stratified into two groups: (1) Cases or GIGT group - women with blood glucose levels between 120 and 140 mg/dl and (2) Controls - women with blood glucose levels of less than 120 mg/dl. Three milliliters of venous blood was collected from mothers and 3 ml of cord blood was collected during delivery. New-borns were assessed for birth weight, head circumference, abdominal circumference, thigh circumference, and crown-heel length. Glycated hemoglobin was carried out using immunoturbidimetry (DiaSys Diagnostic Systems GmbH, Holzheim, Germany) and fructosamine was estimated using dye binding method (Biosystems, Spain). Estimation of total T3 (TT3), free T3 (FT3), total T4 (TT4), free T4 (FT4), and TSH was done by chemiluminescence in Siemens Advia Centaur CP using competitive immunoassay. Although within the normal reference range, GIGT mothers had higher concentration of free and total T4 than controls. Cord fructosamine levels were significantly higher in babies of GIGT mothers than controls, indicating the reflection of maternal hyperglycemia. There was a positive correlation between the maternal glycated hemoglobin and cord blood fructosamine in the GIGT group. Statistically significant lower levels of total T3 and T4 with high TSH levels were found in babies with GIGT mothers, indicating the suppressive effect of maternal hyperglycemia on fetal thyroid function. Birth weight, head circumference, and thigh circumference were significantly higher in babies born to mothers with GIGT, which may be a combined effect of maternal hyperglycemia and fetal thyroid suppression. Maternal hyperglycemia, even in milder form of GIGT may cause suppression of fetal thyroid function. Both these factors may predispose to change in fetal anthropometry, leading to a large baby. Therefore, it is recommended to evaluate maternal and cord thyroid function for timely management strategies.


Aer on the inside looking out: paradigm for a PAS-HAMP role in sensing oxygen, redox and energy.
Aer, the Escherichia coli aerotaxis (oxygen-sensing) receptor, is representative of a small class of receptors that face the cytoplasm in bacteria. Instead of sensing oxygen directly, Aer detects redox changes in the electron transport system or cytoplasm when the bacteria enter or leave a hypoxic microniche. As a result, Aer sensing also enables bacteria to avoid environments where carbon deficiency, unfavourable reduction potential or other insults would limit energy production. An FAD-binding PAS domain is the sensor for Aer and a HAMP domain interacts with the PAS domain to form an input-output module for signal transduction. By analogy to the first solution structure of an isolated HAMP domain from Archaeoglobus, Aer HAMP is proposed to fold into a four-helix bundle that rotates between a signal-on and signal-off conformation. Aer is the first protein in which a PAS-HAMP input-output module has been investigated. The structure and signal transduction mechanism of Aer is providing important insights into signalling by PAS and HAMP domains.


Reduced model of plasma evolution in hydrogen discharge capillary plasmas.
A model describing the evolution of the average plasma temperature inside a discharge capillary device including Ohmic heating, heat loss to the capillary wall, and ionization and recombination effects is developed. Key to this approach is an analytic quasistatic description of the radial temperature variation which, under local thermal equilibrium conditions, allows the radial behavior of both the plasma temperature and the electron density to be specified directly from the average temperature evolution. In this way, the standard set of coupled partial differential equations for magnetohydrodynamic (MHD) simulations is replaced by a single ordinary differential equation, with a corresponding gain in simplicity and computational efficiency. The on-axis plasma temperature and electron density calculations are benchmarked against existing one-dimensional MHD simulations for hydrogen plasmas under a range of discharge conditions and initial gas pressures, and good agreement is demonstrated. The success of this simple model indicates that it can serve as a quick and easy tool for evaluating the plasma conditions in discharge capillary devices, particularly for computationally expensive applications such as simulating long-term plasma evolution, performing detailed input parameter scans, or for optimization using machine-learning techniques.


Estradiol stabilizes the 105-kDa phospho-form of the adhesion docking protein NEDD9 and suppresses NEDD9-dependent cell spreading in breast cancer cells.
Recent data suggest that the adhesion docking protein NEDD9/HEF1/Cas-L is a critical regulator of adhesion-dependent signalling pathways during mammary tumour development. Multiple phosphorylation modifications of NEDD9 regulate interaction with downstream protein partners, thus the regulation of NEDD9 phospho-forms is an important point of control for NEDD9 function. As estradiol (E2) plays a central role in the development and progression of breast cancer, we have investigated NEDD9 phospho-form regulation in MCF-7 estrogen receptor (ER)-positive breast cancer cells in response to estrogen. We find that levels of the 105-kDa NEDD9 phospho-form are significantly increased after 3days of estrogen exposure, and this is suppressed by the anti-estrogen tamoxifen. Analysis of protein decay kinetics following treatment with the protein synthesis inhibitor cycloheximide indicates that increased 105-kDa levels are due to a slower rate of protein decay. Moreover, exogenous expression of NEDD9 failed to induce spreading in the presence of E2, and this was reversed by tamoxifen treatment. Finally, we show that the 105-kDa NEDD9 phospho-form appears to predominate in ER-positive versus ER-negative breast cancer cell lines. Taken together, our results suggest that estradiol may suppress phospho-form-specific functions of NEDD9.


Rate constants for the gas-phase reactions of a series of alkylnaphthalenes with the OH radical.
Naphthalene and its C1- and C2-alkyl derivatives are semivolatile polycyclic aromatic hydrocarbons expected to be in the gas phase in ambient atmospheres and subject to degradation by gas-phase reactions with the hydroxyl (OH) radical. Using a relative rate method, rate constants for the gas-phase reactions of OH radicals with a series of alkylnaphthalenes have been measured at 298 +/- 2 K and at atmospheric pressure of air. The compounds studied include naphthalene, 1- and 2-methylnaphthalene (1-, 2-MN), 1- and 2-ethylnaphthalene (1-, 2-EN), and the 10 dimethylnaphthalene isomers (1,2-; 1,3-; 1,4-; 1,5-; 1,6-; 1,7-; 1,8-; 2,3-; 2,6-; and 2,7-DMN). Using 1,2,3-and 1,3,5-trimethylbenzene as reference compounds, the rate constant obtained for the OH radical reaction of naphthalene was (2.39 +/- 0.09) x 10(-11) cm3 molecule(-1) s(-1). Relative to naphthalene, the rate constants measured for the alkylnaphthalenes were (in units of 10(-11) cm3 molecule(-1) s(-1), where the errors given are two standard deviations and include the above uncertainty in the naphthalene rate constant) 1-MN, 4.09 +/- 0.20; 2-MN, 4.86 +/- 0.25; 1-EN, 3.64 +/- 0.41; 2-EN, 4.02 +/- 0.55; 1,2-DMN, 5.96 +/- 0.55; 1,3-DMN, 7.49 +/- 0.39; 1,4-DMN, 5.79 +/- 0.36; 1,5-DMN, 6.01 +/- 0.35; 1,6-DMN, 6.34 +/- 0.36; 1,7-DMN, 6.79 +/- 0.45; 1,8-DMN, 6.27 +/- 0.43; 2,3-DMN, 6.15 +/- 0.47; 2,6-DMN, 6.65 +/- 0.35; 2,7-DMN, 6.87 +/- 0.43. These data show that, under atmospheric conditions, the DMN isomers react most rapidly with the OH radical with calculated lifetimes of 1.9-2.4 h, followed by the MNs and ENs with lifetimes of 2.9-3.8 h and naphthalene with a lifetime of 5.8 h. These differences in reactivity were confirmed by the nighttime/daytime concentration ratios of the alkylnaphthalenes measured in ambient Riverside, CA, samples.


Histologic assessment of low-voltage electrical burns: experimental study with pigskin.
The authors have carried out an experimental protocol on pigs, producing identical electrical burns to examine clinically and histologically the evolution of these burns with time. A clinical lesion in the form of a rosette was observed. It was composed of three zones: a central zone of carbonization, a pale ischemic intermediate zone, and an erythematous peripheral zone. Microscopic observation showed vascular thrombosis in the intermediate and peripheral zones in addition to necrosis of the central zone. These vascular lesions can be classified in three stages, I, II and III, according to the degree of vascular damage. The evolution of the lesions was stabilized at 72 hours after burn injury. These observations are important in determining the surgical treatment, particularly debridement, on postburn day 3, when the prognosis of the intermediate and peripheral zones must be taken into account.


Pedometer assessed physical activity in urban pubertal children: first report from India.
Inadequate physical activity is a risk factor for several lifestyle diseases. In the current study we have tried to evaluate the physical activity levels in urban Indian pubertal children as well as investigate the relationship between step counts and body composition. A total of 1032 children aged 12 to 15 years wore pedometers for 2 weekdays and 2 weekend days, the final cohort included 910 subjects with 467 boys and 443 girls. Mean weekday steps were 11,062 ± 4741 for boys and 9619 ± 4144 for girls; weekend steps were 10,842 ± 5034 for boys and 9146 ± 5159 for girls, which were both significantly different. The weekend steps were consistently lower in both genders. Analysis of children not meeting a cut-off of 10,000 steps indicated that 45% of the boys aged 12; 54% aged 13; 43% to 48% aged 14 and 50% in the aged 15 did not meet the cut-off. In girls higher levels of inactivity were seen with 58% to 65% aged 12; 69% to 73% aged 13; 49% to 58% aged 14 and 50% to 100% in age-group 15 did not meet the cut-off on weekdays and weekends respectively. The high level of physical inactivity in the representative urban Indian children is a cause of grave concern and necessitates urgent intervention strategies to be formulated.


Disability, rehabilitation and after-care of stroke patients after discharge from hospital, Singapore 1983-84.
135 new onset stroke patients admitted over a nine-month period to a medical unit in Singapore were studied with emphasis on their rehabilitation and community care after discharge. Follow-up visits were made to 79 survivors at third month after onset. 16.7% of the patients made apparently complete recoveries, 20.3% remained slightly disabled, 21.5% moderately disabled, and the remaining 41.8% severely disabled. Sixty-five patients were staying in private households at third month follow-up. The main care-givers were usually female relatives. These informal carers assisted a large proportion of patients in various activities of living: 62.0% in dressing, 54.4% in walking and toileting, 30.4% in feeding, and 22.8% in turning in bed. The study establishes the need to develop and strengthen supportive services to enable disabled stroke patients to be cared for in their own homes. These include the home nursing service, elderly day care service, home help service, and meals-on-wheel service.


The Study on the Influence of Green Inclusive Leadership on Employee Green Behaviour.
As a result of the implementation of the "double carbon" strategy, the issue of how to encourage green behaviour has become a prominent one in society. According to the cognitive-affective processing system theory, this study constructs two paths through which green inclusive leadership influences employee green behaviours: the cognitive pathway mediated by pro-environmental goals clarity and the affective way mediated by green organization identification. Data analysis of 372 employees in chemical enterprises reveals that first, employees' perception of green inclusive leadership positively affects employee green behaviour; second, green inclusive leadership enhances employee awareness of environmental goals and green organization identification so that employees are more likely to behave environmentally; furthermore, green HRM practices positively moderate the relationship between green inclusive leadership and pro-environmental goals clarity, as well as positively moderate the relationship between green inclusive leadership and green organization identification. This study aims to provide theoretical and practical insight into how to promote the green development of organizations from the perspective of leadership style to facilitate green development.


Response to comment on "Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation".
According to the literature review, CO2 insufflation on parasitic myoma implantation is not well studied, and we concur that our study is related to "Morcellation-induced parasitic myomas." We did not compare CO2 insufflation to non-insufflation in our study. The reason is the efficacy of gasless laparoscopic myomectomy and morcellation is not well established and this modality is seldom performed. Moreover, the effects of pneumoperitoneum on mesothelial cells and the role of the entire peritoneal cavity as a cofactor in adhesion formation have become well established, the role of CO2 insufflation in the establishment of parasitic myomas has not yet been studied. As such, more in-depth and well-designed studies for the role of CO2 insufflation are needed.


Synthesis of carbonylated heteroaromatic compounds via visible-light-driven intramolecular decarboxylative cyclization of o-alkynylated carboxylic acids.
An efficient strategy for the easy access to carbonylated heteroaromatic compounds has been developed via a visible-light-promoted intramolecular decarboxylative cyclization reaction of o-alkynylated carboxylic acids. This method is characterized by its benign conditions and the tolerance to a wide range of functionalities.


Higher proportion of agricultural land use around the residence is associated with higher urinary concentrations of AMPA, a glyphosate metabolite.
Pesticides, including herbicides, are widely used for agricultural and sanitary reasons and concerns have been raised about their various health effects. Little research has been done into the extent to which agricultural land use in the residential surroundings contributes to (internal) exposure of pesticides. We investigated the associations between the proportion of agricultural land use around the residence and the exposure to pesticides in adolescents in Flanders (Belgium). We included 424 adolescents participating in the fourth Flemish Environment and Health Study (FLEHS IV) between 2016 and 2020. The residential address of all participants was geocoded and the proportion of agricultural land use around the residence was estimated in several buffers (300 m, 500 m, 1000 m and 2000 m). The concentrations of the following biomarkers of pesticides were measured in urine and adjusted for the specific gravity: glyphosate and its metabolite, aminomethyl-phosphonic acid (AMPA); 3-phenoxybenzoic acid (3-PBA); 3,5,6-trichloro-2-pyridinol (TCPy) and 2,4-dichlophenoxy-acetic acid (2,4-D). We categorized the pesticide biomarkers in three categories according to the exposure levels and used ordinal logistic regression models adjusted for sex, season and household education to estimate the odds ratio for an increase in an interquartile range (IQR) of proportion of agricultural land use. We also used binary logistic regression models in which the category of highest exposure was compared to the category of lowest exposure. In addition, we explored potential effect modification by sex and season. We found a significant association between the proportion of agricultural land use in a buffer of 2000 m around the residence and the levels of urinary AMPA divided into three categories (OR = 1.35 for an IQR increase in the proportion of agricultural land use around residence; 95% CI: 1.00-1.83). This association was less pronounced and not statistically significant for the other studied pesticides (OR ranging between 0.95 and 1.16). Stratified analysis showed the strongest association of the proportion of agricultural land use within 2000 m buffers for AMPA among boys (OR = 1.89; 95% CI: 1.19-3.04). Results using smaller buffers were comparable, but did not reach statistical significance. Our findings suggest that a higher proportion of agricultural land use around the residence might increase exposure to AMPA.


Effects of HIV-related stigma among an early sample of patients receiving antiretroviral therapy in Botswana.
Botswana, with its estimated HIV prevalence of 37%, instituted a policy of universal access to antiretroviral therapy (ART) in 2002. Initial enrolment lagged behind expectations, with a shortfall in voluntary testing that observers have attributed to HIV-related stigma - although there are no published data on stigma among HIV-positive individuals in Botswana. We interviewed 112 patients receiving ART in 2000, finding evidence of pervasive stigma in patterns of disclosure, social sequelae, and delays in HIV testing. Ninety-four percent of patients reported keeping their HIV status secret from their community, while 69% withheld this information even from their family. Twenty-seven percent of patients said that they feared loss of employment as a result of their HIV status. Forty percent of patients reported that they delayed getting tested for HIV; of these, 51% cited fear of a positive test result as the primary reason for delay in seeking treatment, which was often due to HIV-related stigma. These findings suggest that success of large-scale national ART programmes will require initiatives targeting stigma and its social, economic and political correlates.


Immunologic relationship between breast carcinoma and benign breast disease as detected by the leukocyte migration inhibition assay.
Patients with benign diseases of the breast reacted in a migration inhibition assay with extracts of breast cancer and benign breast lesions and a human breast cancer-derived cell line, MCF-7. The incidence of reactivity of the patients with benign breast diseases against these antigens was similar to that of breast cancer patients. In addition, patients with breast cancer reacted to some extracts of benign breast lesions. The reactivity occurred in patients with several different histopathologic types of breast lesions, but was not found in women with no detectable pathologic lesions.


Lessons Learned Using Real-World Data to Emulate Randomized Trials: A Case Study of Treatment Effectiveness for Newly Diagnosed Immune Thrombocytopenia.
Regulatory agencies are increasingly considering real-world evidence (RWE) to support label expansions of approved medicines. We conducted a comparative effectiveness study to emulate a proposed randomized trial of romiplostim vs. standard-of-care (SOC) therapy among patients with recently diagnosed (≤12 months) immune thrombocytopenia (ITP), that could support expansion of the romiplostim label. We discuss challenges that we encountered and solutions that were developed to address those challenges. Study size was a primary concern, particularly for romiplostim initiators, given the rarity of ITP and the stringent trial eligibility criteria. For this reason, we leveraged multiple data sources (Nordic Country Patient Registry for Romiplostim; chart review study of romiplostim initiators in Europe; Flatiron Health EMR linked with MarketScan claims). Additionally, unlike the strictly controlled clinical trial setting, platelet counts were not measured at regular intervals in the observational data sources, and therefore the end point of durable platelet response often used in trials could not be reliably measured. Instead, the median platelet count was chosen as the primary end point. Ultimately, while we observed a slightly higher median platelet count in the romiplostim group vs. SOC, precision was limited because of small study size (median difference was 11 × 109 /L (95% CI: -59, 81)). We underscore the importance of conducting comprehensive feasibility assessments to identify fit-for-purpose data sources with sufficient sample size, data elements, and follow-up. Beyond technical challenges, we also discuss approaches to increase the credibility of RWE, including systematic incorporation of clinical expertise into study design decisions, and separation between decision makers and the data.


Peptide Metal-Organic Frameworks for Enantioselective Separation of Chiral Drugs.
We report the use of a chiral Cu(II) 3D metal-organic framework (MOF) based on the tripeptide Gly-l-His-Gly (GHG) for the enantioselective separation of metamphetamine and ephedrine. Monte Carlo simulations suggest that chiral recognition is linked to preferential binding of one of the enantiomers as a result of either stronger or additional H-bonds with the framework that lead to energetically more stable diastereomeric adducts. Solid-phase extraction of a racemic mixture by using Cu(GHG) as the extractive phase permits isolating >50% of the (+)-ephedrine enantiomer as target compound in only 4 min. To our knowledge, this represents the first example of a MOF capable of separating chiral polar drugs.


Dimensions of delusional experience scale: a psychometric evaluation of a german version.
Delusional experience is a fundamental symptom of psychotic illness. Over recent years, a multidimensional perspective has become increasingly important regarding this phenomenon. Several instruments to measure different dimensions of delusions have been constructed. The aims of this study were to examine the reliability and validity of a German version of the Dimensions of Delusional Experience Scale (DDE). Two hundred inpatients with a schizophrenic spectrum disorder or an affective disorder with delusions were examined with the DDE, the Positive and Negative Syndrome Scale (PANSS) and other rating scales for delusional experiences. The scale was found to have good reliability and excellent inter-rater reliability. The 2 factors, delusional involvement and delusional construct, found by Kendler et al. [Am J Psychiatry 1983;140:466-469] could be replicated. The convergent and differential validity of the scale was supported. Besides the content-related aspect 'bizarreness', the DDE mainly assesses cognitive aspects, emotional and behavioral aspects are not incorporated. The results support the value of a multidimensional perspective of delusional experiences. The German version of the DDE is a reliable and valid assessment tool for different dimensions of delusions, and an economical instrument for research and clinical practice. Further research is needed to reveal the dimensional structure underlying delusional experience.


A Low-Valent Iron Imido Heterocubane Cluster: Reversible Electron Transfer and Catalysis of Selective C-C Couplings.
Enzymes and cofactors with iron-sulfur heterocubane core structures, [Fe4 S4 ], are often found in nature as electron transfer reagents in fundamental catalytic transformations. An artificial heterocubane with a [Fe4 N4 ] core is reported that can reversibly store up to four electrons at very negative potentials. The neutral [Fe4 N4 ] and the singly reduced low-valent [Fe4 N4 ](-) heterocubanes were isolated and fully characterized. The low-valent species bears one unpaired electron, which is localized predominantly at one iron center in the electronic ground state but fluctuates with increasing temperatures. The electrons stored or released by the [Fe4 N4 ]/[Fe4 N4 ](-) redox couple can be used in reductive or oxidative CC couplings and even allow catalytic one-pot reactions, which show a remarkably enhanced selectivity in the presence of the [Fe4 N4 ] heterocubanes.