Computed tomographic images reflect the biologic behavior of small lung adenocarcinoma: they correlate with cell proliferation, microvascularization, cell adhesion, degradation of extracellular matrix, and K-ras mutation.
We previously reported that the computed tomographic M/L ratio (area of the tumor in the mediastinal computed tomographic image/area of the tumor in the lung computed tomographic image) of small peripheral lung adenocarcinoma is correlated with patient prognosis. Immunostaining for p53, bcl-2, Ki-67, vascular endothelial growth factor, CD34, matrix metalloproteinase 2, matrix metalloproteinase 9, tissue inhibitor of matrix metalloproteinase 2, and mutation of K-ras was assessed in 131 surgically resected, primary peripheral lung adenocarcinomas of 30 mm or less in maximum diameter to clarify the relationship between computed tomographic findings and biologic activities. The numbers of patients with high labeling indexes of Ki-67 and high expression of vascular endothelial growth factor, CD34, matrix metalloproteinase 2, and matrix metalloproteinase 9 in the solid-type group (computed tomographic M/L ratio > or = 50%) were significantly higher than those in the faint density-type group (computed tomographic M/L ratio < 50%; P = .04 for Ki-67, P = .03 for vascular endothelial growth factor, P = .0009 for CD34, P = .001 for matrix metalloproteinase 2, and P = .00001 for matrix metalloproteinase 9). The number of patients with high levels of CD44v6 or tissue inhibitor of matrix metalloproteinase 2 staining in the faint density-type group was significantly higher than that in the solid-type group (P = .02 for CD44v6 and P = .01 for tissue inhibitor of matrix metalloproteinase 2). Independent variables capable of predicting computed tomographic M/L ratio included CD34, matrix metalloproteinase 2, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 2 (P = .0093, P = .0003, P = .0027, and P = .01, respectively; binary logistic regression analysis). Our results suggest that the computed tomographic image of small lung adenocarcinoma is correlated with biologic activities and thus provides possible prognostic information.


Etiology and Outcome of Catheter Ablation in Patients With Onset of Atrial Fibrillation <45 Years of Age.
Etiologic factors and long-term outcomes of catheter ablation of atrial fibrillation (AF) in young patients have not been well characterized. This study aimed to analyze the etiologic factors and outcomes of pulmonary vein isolation (PVI) in patients with young-onset AF (young-AF, defined as having first documented episode <45 years). Consecutive patients with young-AF undergoing PVI (n = 197) in 2 academic centers were enrolled and followed for 36.1 ± 24.5 months. A control group of patients with AF onset ≥45 years (n = 554) was included. The most frequent risk factors in young-AF were intensive exercise (25%), moderate-to-heavy alcohol consumption (23%), and familial AF (22%). Compared with patients with AF onset ≥45-year, patients with young-AF were more often men (82% vs 66%, p <0.001), had more frequently paroxysmal AF (81% vs 60%, p <0.001), had less left atrial dilatation (40.9 ± 6.2 mm vs 44.2 ± 7.2 mm, p <0.001), and had lower 4-year recurrence rate after last PVI procedure (22% vs 45%, p <0.001). In young-AF, structural heart disease (SHD) was the only independent predictor of recurrence. Patients with young-AF selected to undergo cryoballoon (CB) ablation were younger (35.0 ± 7.7 vs 36.6 ± 6.7 years, p = 0.035) and had less persistent AF (6% vs 24%, p = 0.004) and coronary artery disease (2% vs 7%, p = 0.02) compared with radiofrequency ablation. After excluding patients with persistent AF and SHD, there was no difference in single procedural success between radiofrequency or CB PVI (27% vs 17%, p = 0.11). In conclusion, patients with young-AF have diverse etiologies and high single and multiprocedural PVI successes. SHD is the only independent predictor of recurrence. In patients with young-AF, there is a selection bias for CB ablation.


Induction of synapse formation by de novo neurotransmitter synthesis.
A vital question in neuroscience is how neurons align their postsynaptic structures with presynaptic release sites. Although synaptic adhesion proteins are known to contribute in this process, the role of neurotransmitters remains unclear. Here we inquire whether de novo biosynthesis and vesicular release of a noncanonical transmitter can facilitate the assembly of its corresponding postsynapses. We demonstrate that, in both stem cell-derived human neurons as well as in vivo mouse neurons of purely glutamatergic identity, ectopic expression of GABA-synthesis enzymes and vesicular transporters is sufficient to both produce GABA from ambient glutamate and transmit it from presynaptic terminals. This enables efficient accumulation and consistent activation of postsynaptic GABAA receptors, and generates fully functional GABAergic synapses that operate in parallel but independently of their glutamatergic counterparts. These findings suggest that presynaptic release of a neurotransmitter itself can signal the organization of relevant postsynaptic apparatus, which could be directly modified to reprogram the synapse identity of neurons.


The application of a photon-counting camera in sensitive, bioluminescence-enhanced detection systems for nucleic acid hybridization. Ultrasensitive detection systems for protein blotting and DNA hybridization, III.
A relatively simple, bioluminescence-enhanced detection system for nucleic acid hybridization, using alkaline phosphatase as a label, was described recently (Hauber, R. & Geiger, R. (1988) Nucl. Acid Res. 16, 1213). The principle of detection is as follows: Alkaline phosphatase releases D-luciferin (Photinus pyralis) from D-luciferin-O-phosphate. Liberated D-luciferin reacts with luciferase, ATP and oxygen with light emission. Light produced is measured with a very sensitive photon counting camera system (Argus-100), allowing the visualization and localization of the specifically bound alkaline phosphatase on nitrocellulose sheets. Under non-optimized conditions the limit of detection is at present about 30 pg of pBR322. A sulphonylated nucleotide probe was used for hybridization.


Magnetic solid-phase extraction for speciation of mercury based on thiol and thioether-functionalized magnetic covalent organic frameworks nanocomposite synthesized at room temperature.
A simple and practical magnetic solid-phase extraction high-performance liquid chromatography-inductively coupled plasma mass spectrometry (MSPE-HPLC-ICP-MS) method for extraction and determination of trace mercury species, including inorganic mercury (IHg), monomethylmercury (MeHg) and ethylmercury (EtHg), was developed. The MSPE adsorbent, urchin-like thiol and thioether-functionalized magnetic covalent organic frameworks (Fe3O4@COF-S-SH), was synthesized by coating covalent organic frameworks (COFs) on the surface of Fe3O4 nanoparticles at room temperature and then easily grafting 1,2-Ethanedithiol on the COFs. The as-prepared Fe3O4@COF-S-SH has strong adsorption capacity for IHg, MeHg and EtHg, with excellent static adsorption capacity: 571, 559 and 564 mg g-1, respectively. The parameters influencing the extraction and enrichment had been optimized, including pH, adsorption and desorption time, composition and amount of the eluent, co-existing ions and dissolved organic materials etc. Under the optimized condition, the limit of detection (3δ) of the proposed method were 0.96, 0.17 and 0.47 ng L-1 for IHg, MeHg and EtHg, and the developed method has high actual enrichment factors of 370, 395, 365-fold for IHg, MeHg and EtHg based on 200 mL samples, respectively. The high accuracy and reproducibility has been proved by the spiked recoveries (96.0‒108 %) in real water samples and determination of the certified reference material. Both the adsorption and desorption process can be completed within 5 min. The proposed method with simple operation, short pre-concentration time and high sensitivity has been successfully applied to mercury speciation at trace levels in the samples with complicated matrices, including underground water, surface water, sea water and fish samples.


Fully non-homogeneous hidden Markov model double net: a generative model for haplotype reconstruction and block discovery.
In the last decade, haplotype reconstruction in unrelated individuals and haplotype block discovery have riveted the attention of computer scientists due to the involved strong computational aspects. Such tasks are usually addressed separately, but recently, statistical techniques have permitted them to be solved jointly. Following this trend we propose a generative model that permits researchers to solve the two problems jointly. The model inference is based on variational learning, which permits one to estimate quickly the model parameters while remaining robust even to local minima. The model parameters are then used to segment genotypes into blocks by thresholding a quantitative measure of boundary presence. Experiments on real data are presented, and state-of-the-art systems for haplotype reconstruction and strategies for block estimation are considered as comparison. The proposed method can be used for a fast and reliable estimation of haplotype frequencies and the relative block structure. Moreover, the method can be easily used as part of a more complex system. The threshold used for block discovery can be related to the quality-of-fit reached in the model learning, resulting in an unsupervised strategy for block estimation.


Simultaneous recycling of waste solar panels and treatment of persistent organic compounds via supercritical water technology.
The study addresses the application of the supercritical water technology in the simultaneous recycling of obsolete solar panels and treatment of persistent organic compounds. The obsolete solar panels samples were characterized by TEM-EDS, SEM, TG-DTA, XRD, WDXRF, MP-AES and elemental analysis. Initially, the optimized parameters for the degradation of solid organic polymers present in residual solar panels via oxidation in supercritical water were defined by an experimental design. Under optimized conditions, 550 °C, reaction time of 60 min, volumetric flow rate of 10 mL min-1 and hydrogen peroxide as oxidant agent, real laboratory liquid wastewater was used as feed solution to achieve 99.6% of polymers degradation. After the reaction, the solid product free of organic matter was recovered and characterized. On average, a metal recovery efficiency of 76% was observed. Metals such as aluminum, magnesium, copper, and silver, that make up most of the metallic fraction, were identified. Only H2, N2 and CO2 were observed in the gaseous fraction. Then, initial data on the treatment of the liquid decomposition by-products, generated during ScW processing, were reported. A total organic carbon reduction of 99.9% was achieved after the subsequential treatment via supercritical water oxidation using the same experimental apparatus. Finally, insights on the scale-up, energy integration and implementation costs of a ScW solid processing industrial unit were presented using the Aspen Plus V9 software.


The efficacy and safety of the Chinese herbal medicine Di-Tan decoction for treating Alzheimer's disease: protocol for a randomized controlled trial.
Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is estimated that the global prevalence of dementia will rise from 24.3 million in 2005 to 81.1 million in 2040. AD has a devastating impact on sufferers, caregivers, their communities and the healthcare system in general. "Di-tan decoction" (DTD) is a traditional Chinese medicine (TCM) formula frequently used to treat symptoms that are now defined as AD in clinical treatment. However, the existing evidence for recommending DTD in clinical practice derives from studies that were methodologically flawed. In this study, we aim to determine the efficacy and safety of DTD in AD patients based on a rigidly randomized controlled trial. It will provide critical information on sample size and treatment regimen for conducting a full-scale clinical trial of DTD later. This study will be a double-blind, randomized, placebo-controlled, add-on trial. After a 2-week run-in period, eligible patients with mild to moderate AD will be recruited and given either DTD or placebo twice daily for 24 weeks with follow-up 6 weeks after the last treatment. An increase of four points or greater on the scores of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAD-cog) will be considered as a positive primary outcome. Total scores of the ADAD-cog, the Chinese version of Mini-Mental State Examination (C-MMSE), and the Chinese version of the Disability Assessment for Dementia (C-DAD) score will be used as secondary outcomes. Adverse events will also be reported. This randomized trial will be the first rigorous empirical study on the efficacy of DTD for treating cognitive symptoms in AD patients. Its success will justify and warrant a large-scale clinical trial to further consolidate the evidence for DTD's efficacy in treating AD. Chinese Clinical Trial Registry ( ChiCTR-TRC-12004548 , Date of registration: 22 November 2012).


Reduced effectiveness of long-term interferon-beta treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study.
Multiple sclerosis (MS) patients treated with interferon-beta (IFN-beta) often form anti-IFN-beta antibodies accompanied by a reduction in IFN-beta bioavailability. The clinical effect of these antibodies remains controversial. MS patients in British Columbia, Canada, must be diagnosed and evaluated annually by neurologists in an MS clinic in order to be reimbursed for their IFN-beta prescriptions. We have identified at the UBC MS clinic a cohort of 262 patients, each having been treated with a single IFN-beta preparation more than three years, some for nearly a decade. Of 119 patients treated with Betaseron (IFN-beta1b), 18 (15.1%) were neutralizing antibody positive (NAb+) at the time of the study, whereas of 131 treated with subcutaneous Rebif (IFN-beta1a SC), 16 (12.2%) were NAb+, but none of 12 treated with intramuscular Avonex (IFN-beta1a) had detectable neutralizing antibodies. During the first two years of treatment, the relapse rate was significantly reduced from pre-treatment rates (P<0.001) and appeared to be unaffected by the subsequent NAb status. However, the relapse rates in the NAb+ patients were significantly greater than in the NAb- patients during years 3 (P<0.010) and 4 (P<0.027). Betaseron-treated NAb+ patients tended to have more relapses than NAb- patients during year 3 and this almost reached significance (P=0.056) but their relapse rate did not differ in year 4 and later. In contrast, Rebif-treated NAb+ patients tended to have more relapses in year 3 than Rebif-treated NAb- patients (P=0.074), but in year 4 they clearly (P=0.009) had more relapses than Rebif-treated NAb- patients. There was no convincing effect on progression of disability in any group.


Interaction between a geminivirus replication protein and origin DNA is essential for viral replication.
The geminivirus, tomato golden mosaic virus (TGMV), encodes one protein, AL1, that is absolutely required for viral DNA replication. AL1 interacts with the TGMV DNA genome by binding specifically to the viral origin of replication. We have investigated the nature and significance of AL1/origin interactions in vitro and in vivo by using competitive DNA binding and transient replication assays. Competition assays established that a 13-base pair (bp) element (5'-GGTAGTAAGGTAG) containing two 5-bp direct repeat motifs separated by a 3-bp central core constitutes a high affinity AL1 binding site. DNAs containing intact 3' repeat sequences plus core (TAAGGTAG and ccTAGTAAGGTAG) were stronger competitors for AL1 binding than DNAs containing intact 5' repeat sequences plus core (GGTAGTAA and GGTAGTA-AccTAG), thereby demonstrating that AL1 interacts differently with the repeat motifs. Replication in tobacco protoplasts established that the AL1 binding site is an essential cis-acting element for viral replication. No replication was detected for DNAs containing mutations in either of the repeat motifs of the AL1 recognition sequence when AL1 was provided in trans from a plant gene expression vector. In contrast, a DNA with a mutation in the 5' repeat motif (ccTAGTAAGGTAG) replicated when both AL1 and AL3, a TGMV protein involved in viral DNA accumulation, were provided in trans. No replication was detected for a DNA containing a mutation in the 3' repeat motif (GGTAGTAAccTAG) in the presence of AL1 and AL3. The in vitro and in vivo results suggest that binding of AL1 to the 3' repeat element is an essential step in DNA replication, while binding to the 5' repeat element may serve to enhance viral replication.


Ubc9 negatively regulates BMP-mediated osteoblastic differentiation in cultured cells.
SUMO (small ubiquitin-related modifier) modification (SUMOylation) has been reported to regulate various biological events such as cell-cycle progression, proliferation, and survival. Bone morphogenetic proteins (BMPs) play an important role in osteoblast differentiation and maturation. Although Smad4, which acts as a transcriptional factor in the BMP signaling, is a target of SUMOylation, the involvement of SUMOylation in osteoblast differentiation remains unclear. In this report, we demonstrated spatial expression patterns of SUMO proteins and Ubc9 (ubiquitin conjugating enzyme 9), which is a unique E2-SUMOylation enzyme, in mouse tibia. Furthermore, siRNA knockdown of Ubc9 enhanced osteoblastic differentiation induced by BMP2 in C2C12 mouse myoblasts and ST2 mouse bone-marrow derived stromal cells. Ubc9 knockdown elevated the BMP signaling transduction and reduced the expression of muscle-related genes in cooperation with BMP2. Finally, a luciferase assay using an Id1 (target gene of BMP signaling) reporter revealed that Smad4 mutants prevented from SUMOylation at their Lys158 possessed more potent transcriptional activity than wild-type Smad4. Taken together, these findings suggest that Ubc9 negatively regulates osteoblastic differentiation induced by BMP via, at least in part, SUMOylation of Smad4.


Cross Mapping Between the Priority Nursing Care for Stroke Patients Treated With Thrombolytic Therapy and the Nursing Interventions Classification (NIC).
To verify the correspondence between the priority nursing care for stroke patients treated with thrombolytic therapy and the Nursing Interventions Classification (NIC). A cross-mapping study with a semi-structured interview was conducted with 11 expert nurses who described priority nursing care in clinical practice, and mapped it to the NIC. Eleven nursing care priorities cited by the nurses were mapped to eight NICs, including Thrombolytic Therapy Management (4270). There was correspondence between all priority nursing care interventions for stroke patients treated with thrombolytic therapy and the NIC. The nursing care cited by the nurses was corroborated by the NIC, providing evidence for the clinical practice. Verificar a correspondência entre os cuidados de enfermagem prioritários a pacientes com acidente vascular encefálico tratados com terapia trombolítica e a Classificação das Intervenções de Enfermagem (NIC). MÉTODOS: Estudo de mapeamento cruzado com uma entrevista semi-estruturada aplicada a 11 enfermeiros especialistas que descreveram os cuidados de enfermagem prioritários na prática clínica, e mapeados para a NIC. Onze cuidados de enfermagem prioritários foram citados pelos enfermeiros e mapeados em oito intervenções de enfermagem NIC, incluindo a Thrombolytic Therapy Management (4270). CONCLUSÕES: Houve correspondência entre todos os cuidados de enfermagem prioritários para pacientes com acidente vascular encefálico tratados com a terapia trombolítica e as intervençães de enfermagem NIC. IMPLICAÇÕES PARA A PRÁTICA DE ENFERMAGEM: Os cuidados de enfermagem citados pelos enfermeiros foram corroborados pela NIC, produzindo evidências para a prática clínica.


Law of mass action and saturation in SIR model with application to Coronavirus modelling.
When using SIR and related models, it is common to assume that the infection rate is proportional to the product of susceptible and infected individuals. While this assumption works at the onset of the outbreak, the infection force saturates as the outbreak progresses, even in the absence of any interventions. We use a simple agent-based model to illustrate this saturation effect. Its continuum limit leads a modified SIR model with exponential saturation. The derivation is based on first principles incorporating the spread radius and population density. We use the data for coronavirus outbreak for the period from March to June, to show that using SIR model with saturation is sufficient to capture the disease dynamics for many jurstictions, including the overall world-wide disease curve progression. Our model suggests the R 0 value of above 8 at the onset of infection, but with infection quickly "flattening out", leading to a long-term sustained sub-exponential spread.


Culturally relevant palliative care.
The journey to excellence in palliative care practice is to recognize the three identities of patients, refine skills in assessment to understand these interrelated dimensions of personhood, and hone the practices of caring to deliver truly comprehensive and personalized care. These practices require clinicians to first connect to persons with illness on a human-human level. Being fully present and engaged with patients is critical to practicing high-quality palliative care. Clinicians must encourage and elicit the story of the illness and the life of the person experiencing the illness.


[Magnetic resonance imaging for delineation of prostate in radiotherapy: monocentric experience and review of literature].
To assess the benefits of magnetic resonance imaging (MRI) in the dosimetric treatment planning for prostate radiotherapy. Ten consecutive patients have been enrolled. They were treated for a low risk prostate adenocarcinoma. A rigid superimposition was performed between MRI and scan slides obtained at time of virtual simulation, then prostate volume was delineated by four to five physicians, on TDM slides and on MRI/TDM superimposition. For each treatment plan, we assessed the impact of MRI in terms of planned treatment volume (PTV) position, individual variability of prostate delineation and doses delivered to the critical organs. The prescribed dose was 74 Gy in 37 fractions to the PTV. PTV delineated on TDM (V(TDM)) were 1.15 (SD 3.71) larger than volumes delineated on MRI. Prostate apex was 4.6 mm (SD 2.87) lower on TDM than on MRI. Posterior limit of the prostate was in mean 4 mm more posterior on TDM. The variability between physicians in terms of prostate delineation was lower using MRI. For apex, these variations were 6.8 mm using TDM, versus 3.3 mm using MRI. Mean rectal dose was 8 % lower with MRI, compared to delineation using TDM. Superimposition TDM/MRI improves accuracy, decreases delineation variability, and allows to spare anterior part of the rectum from irradiation. It remains unknown whether this strategy translates into clinical benefit.


A hypothesis: the protein catabolic rate is dependent upon the type and amount of treatment in dialyzed uremic patients.
Urea kinetic modelling was performed serially, over 24 months, on 55 patients undergoing hemodialysis and eight patients receiving peritoneal dialysis. The data obtained, together with changes in therapy aimed at increasing or decreasing the normalized dose of dialysis [KT/V (urea)], suggested the dependence of dietary protein intake and protein catabolic rate (PCR; g/kg/d) on the KT/V (urea). The studies also indicated that the nature of this relationship may be dependent upon the dialysis treatment used; dialysis by AN69S membrane hemodialyzers required less KT/V (urea) than hemodialysis by cellulosic membranes to obtain a given PCR. This difference may be explained by the beneficial effect of removal of "middle molecular weight" uremic toxins by the AN69S membrane, which has a different solute clearance profile than the cellulosic membrane. The studies also indicated a similar relationship between PCR and KT/V (urea) for peritoneal dialysis. With this form of therapy, however, it is difficult to obtain a PCR greater than 1 g/kg/d without first achieving very high values for KT/V (urea). It is postulated that this is due to an independent adverse effect of peritoneal dialysate in suppressing appetite. The data presented suggest that the conclusions of the National Cooperative Dialysis Study may be reinterpreted by assigning a major role to the nutritional status of patients in morbidity, with satisfactory nutritional status attained only in patients receiving adequate dialysis which, in turn, ensures control of plasma urea levels. Studies to prove this hypothesis are indicated.


Dietary Effects on Stable Carbon Isotope Composition of Fatty Acids in Polar and Neutral Fractions of Intramuscular Fat of Lambs.
In this study we measured δ13C values of the main fatty acids (FA) present in neutral and polar intramuscular lipids of meat samples from 24 lambs, fed with four different diets supplemented with sunflower and linseed oil and the tanniferous shrub Cistus ladanifer L. The objective was to understand if the increase in intramuscular fat observed in lambs fed simultaneously C. ladanifer and oil was explained mostly by incorporation of diet derived FA or by increased de novo FA synthesis. De novo FA synthesis was evaluated by 13C enrichment (‰) of 16:0 in intramuscular lipids compared to bulk diet or compared to dietary 16:0. Oil reduced 13C enrichment of 16:0 in muscle lipid but had no effect when the diet included C. ladanifer (P value <0.01). Thus, dietary C. ladanifer blocked the inhibitory effects of lipid supplementation on de novo FA synthesis.


Differential utilization of long chain fatty acids during triacylglycerol depletion. I. Rat heart after ischemic perfusion.
Rat hearts were perfused with Krebs-Henseleit buffer for 90 min according to the Langendorff procedure. Normoxic perfusion for 90 min resulted in minor changes in fatty acid composition and a decrease in residual heart triacylglycerol to 60% of preperfusion values. When the protocol included 30 min of slow perfusion-induced ischemia, the hearts were observed to be depleted of 89% of their initial triacylglycerol content. The triacylglycerol fatty acid composition (mg %) remained similar after compared to before perfusion except for a 121 mg % increase in stearic acid and a 225 mg % increase in arachidonic acid. The percentage composition of both fatty acids was significantly inversely correlated with the amount of triacylglycerol remaining in the heart after perfusion. Postperfusion, arachidonic acid and stearic acids were present at nearly 1:1 in the residual heart triacylglycerol, suggesting that a common mechanism may be involved in the selective retention of these fatty acids by the heart.


In vitro transcription of viroid RNA into full-length copies by RNA-dependent RNA polymerase from healthy tomato leaf tissue.
RNA-dependent RNA polymerase from healthy tomato plant tissue accepts potato spindle tuber viroid (PSTV) RNA as a template for the in vitro synthesis of full-length RNA copies of the PSTV genome. Viroid transcription requires the presence of Mn2+ and /or Mg2+ ions and is not inhibited by concentrations of 10(-5) M alpha-amanitin. This is the first report of a well-defined product synthesized in vitro by an RNA-dependent RNA polymerase from healthy plants.


Process of drug registration in Israel: the correlation between the number of discussions within the Ministry of Health and postapproval variations by EMA and/or FDA.
US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined. This is an observational retrospective comparative cohort study. Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites. Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45). Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.


Meiotic chromosome pairing and synaptonemal complex transformation in Culex pipiens oocytes.
The synaptonemal complexes of the oocytes of the mosquito Culex pipiens quinquefasciatus have been reconstructed from serial sections. A diffuse structure, probably a chromocenter composed of centromeric heterochromatin, was present during pachytene. As no synaptonemal complexes were visible inside the chromocenter the continuity of the 2 arms of a bivalent was lost. The telomeric ends were clustered on a small area of the nuclear membrane in a bouquet arrangement; they were associated in pairs, and sometimes joined through a special structure. One pair was composed of the 2 telomeres of the shortest bivalent and a ring configuration was thus formed. The other 2 chromosomes may form one or two rings. During a short transitional stage, after the disappearence of the synaptonemal complexes, several thousand annuli, 1200-1500 A in diameter, were present in the nuclei. The annuli disappeared as material originating mainly from the transverse filaments of the synaptonemal complexes formed a "capsule" around the chromosomes during diplotene.


Lung cancer as a second primary.
An unusually high association of other primary cancers (9.7%) was found during the analysis of 403 consecutive cases of carcinoma of the lung diagnosed at DGMC between 1960 and 1975. Incidence by stage included 17.3% for Stage I (75 cases) and 16.9% for Stage II (59 cases). Median survival by stage was not adversely affected by the associated malignancy. Incidence by histologic type was 15.6% for adenocarcinoma (132 cases), 7.7% for epidermoid (130 cases), 1.5% for oat (small cell) (67 cases), 12.5% for large cell (40 cases) and 11.8% for undifferentiated anaplastic type (34 cases). Of 31 cases of Stage I adenocarcinoma, 9 (29%) had second malignancies. Both adenocarcinoma and epidermoid carcinoma exhibited decreasing association of second malignances with increasing stage of lung cancer. The head and neck region was the location of the nonlung malignancy in 22 cases and the GU system in 11 cases. Two cases each of colon carcinoma and basal cell skin carcinoma were found and there was one case each of carcinoma of the pancreas, lymphoma and melanoma. The diagnosis of lung cancer was made first in only 3 instances. The appearance of solitary nodules in patients with known malignancy should receive strong consideration for vigorous diagnostic and therapeutic procedures. Future studies should consider carcinogenic stimuli that may be common etiologic factors in both malignancies.


Cerebral vasoconstriction triggered by sympathomimetic drugs during intra-atrerial chemotherapy.
Reversible cerebral vasoconstriction syndrome is a rare cause of headache and stroke in the pediatric population. Reversible vasoconstriction is reported in a 19-month-old girl with retinoblastoma who underwent selective ophthalmic artery infusion chemotherapy with melphalan. Procedure-related cerebral vasoconstriction was specifically triggered during coadministration of adjunctive medications, which included mydriatic eye drops containing phenylephrine, intranasal oxymetazoline, nebulized albuterol, intravenous hydrocortisone, and intravenous diphenhydramine. The course of cerebral vasospasm, which began with a severe hypertensive surge and resolved spontaneously within hours of blood pressure normalization, was documented by angiography in real time. Subsequent brain magnetic resonance imaging showed no evidence of perfusion abnormality, cerebral infarction, or cerebral hemorrhage, and the patient was discharged home without any neurologic sequelae. In this report, we highlight the potential risk of reversible cerebral vasoconstriction in children administered vasoactive drugs and discuss its relevance during treatment of retinoblastoma by intraarterial chemotherapy.


Vascular plasticity--the role of the angiopoietins in modulating ocular angiogenesis.
Most of the blinding diseases, such as diabetic retinopathy, age-related macular degeneration, neovascular glaucoma or trachoma, are related to an aberrant angiogenic response. Common pathological features are ischaemia and increased vascular permeability, in turn leading to neovascularization or atrophy. Recent effort has led to the identification of several factors, such as the angiopoietin-Tie system, which are operative in the control of vasculogenesis and angiogenesis. The aim of this commentary is to summarize briefly the current knowledge about molecular mechanisms involved in the regulation of vascular integrity with special emphasis on the angiopoietins.


Perspectives on new strategies for the identification and development of insecticide targets.
The discovery and development of new active ingredients to control arthropod populations and circumvent the inevitable evolution of insecticide resistance has been of consistent interest to the field of insecticide science. This interest has resulted in a slow, but steady increase in the diversity of chemical scaffolds and biochemical target sites within the insecticide arsenal over the past 70 years with growth from three biochemical target sites in the 1950s to 22 distinct biochemical targets in 2018. Despite this growth, the number of biochemical target sites for insecticides remains relatively limited when compared to human pharmaceuticals, which has approximately 700 distinct biochemical targets that are targeted by FDA approved drugs. Potential reasons for this large discrepancy between two closely related fields and putative mechanisms to enhance the identification of tractable biochemical targets for insecticides are discussed. Next, this perspective discusses the movement of insecticide science into the "genomic era" and for comparative purposes, I provide a retrospective analysis of the impact the release of the human genome had to human pharmaceutical development. Based on this analysis and because the fields of insecticide science and human pharmaceuticals mirror each other, researchers in the field of insecticide science would do well to heed the lessons learned by the human pharmaceutical industry and to carefully consider the challenges that arise from genomic approaches for chemical development. Lastly, I pose the question if the field of insecticide science would benefit from adapting an industry-academia model through the generation of industry-sponsored centers of excellence. The goal of this article is not to definitively describe strategies to enhance insecticide development, but rather present different thoughts on agrochemical development that will foster discussions among academic, government, and industry scientists to address current and future problems in the field of insecticide science.


The dust retention capacities of urban vegetation-a case study of Guangzhou, South China.
Urban vegetation increasingly plays an important role in the improvement of the urban atmospheric environment. This paper deals with the dust retention capacities of four urban tree species (Ficus virens var. sublanceolata, Ficus microcarpa, Bauhinia blakeana, and Mangifera indica Linn) in Guangzhou. The dust-retaining capacities of four tree species are studied under different pollution intensities and for different seasons. Remote sensing imagery was used to estimate the total aboveground urban vegetation biomass in different functional areas of urban Guangzhou, information that was then used to estimate the dust-retaining capacities of the different functional areas and the total removal of airborne particulates in urban Guangzhou by foliage. The results showed that urban vegetation can remove dust from the atmosphere thereby improving air quality. The major findings are that dust retention, or capture, vary between the four species of tree studied; it also varied between season and between types of urban functional area, namely industrial, commercial/road traffic, residential, and clean areas. Dust accumulation over time was also studied and reached a maximum, and saturation, after about 24 days. The overall aboveground biomass of urban vegetation in Guangzhou was estimated to be 52.0 × 10(5) t, its total leaf area 459.01 km(2), and the dust-retaining capacity was calculated at 8012.89 t per year. The present study demonstrated that the foliage of tree species used in urban greening make a substantial contribution to atmospheric dust removal and retention in urban Guangzhou.


Occurrence and removal of drugs and endocrine disruptors in water supply systems in the metropolitan region of Belo Horizonte (Minas Gerais State, Brazil).
This study evaluates both the occurrence and removal of 24 compounds, including drugs and endocrine disruptors, in 8 water treatment plants (WTP) located in the metropolitan region of Belo Horizonte (Minas Gerais State, Brazil). The compounds 4-nonylphenol, 4-octylphenol, 17α-ethinylestradiol, 17β-estradiol, acyclovir, bisphenol A, bezafibrate, caffeine, dexamethasone, diclofenac sodium, diltiazem, estrone, estriol, gemfibrozil, ibuprofen, linezolid, loratadine, losartan, metformin, naproxen, paracetamol, promethazine, propranolol and sulfamethoxazole were monitored at 3 sampling points (raw water, filtered water, treated water) over 10 or 12 collection campaigns for each WTP. The results showed that bisphenol A occurred at higher concentrations during the dry period with a maximum concentration of 3257.1 ng L-1, while the compounds 4-nonylphenol and losartan exhibited higher concentrations in the rainy period with maximum concentrations of 8577.2 ng L-1 and 705.8 ng L-1, respectively. Regarding the removal of compounds in the monitored WTPs, the clarification step demonstrated better removals for 4-nonylphenol, bisphenol-A, paracetamol, and sulfamethoxazole, whereas the disinfection step mainly removed the compounds 4-octylphenol and estrone. Margin of exposure (ME) assessment results indicated that only dexamethasone, ethinyl estradiol, diclofenac, estradiol, and estrone were classified as imminent risk or alert considering the 95th percentile concentration found in the samples of treated water.


Edaravone attenuates lung injury in a hind limb ischemia-reperfusion rat model: A histological, immunohistochemical and biochemical study.
Edaravone is a potent free radical scavenger that has a promising role in combating many acute lung injuries. Ischemia/reperfusion process is a serious condition that may lead to multiple organ dysfunctions. This work was designed to investigate novel mechanisms underlying ischemia/reperfusion-induced lung injury and to evaluate the protective role of edaravone. Thirty adult male rats were divided into three experimental groups; operated with no ischemia (Sham-group), ischemia/reperfusion (I/R) group and edaravone-I/R group. Hind limb ischemia was carried out by clamping the femoral artery. After two hours of ischemia for the hind limb, the rat underwent 24h of reperfusion. Rats in the edaravone-I/R group received edaravone (3mg/kg), 30min before induction of ischemia. At the end of the I/R trial, specimens from the lungs were processed for histological, immunohistochemical, enzyme assay, and RT-qPCR studies. Specimens from I/R group showed focal disruption of the alveolar architecture. Extensive mononuclear cellular infiltration particularly with neutrophils and dilated congested blood capillaries were observed. A significant increase in iNOS, NF-κB, and COX-2 immunoreaction was detected and confirmed by RT-qPCR. Ultrastructural examination showed RBCs and fluid inside alveoli, cellular infiltration, and vacuolations of the inter-alveolar septum. In addition to the presence of extravasated neutrophils and RBCs within the inter-alveolar septum. In contrast, minimal changes were observed in rats which received edaravone before the onset of the ischemia. It could be concluded that edaravone exerted a potent protective effect against lung injury induced by a hind limb I/R in rats through its antioxidant and anti-inflammatory activities.


The MAP3K1/c-JUN signaling axis regulates glioblastoma stem cell invasion and tumor progression.
Glioblastoma (GBM) stem cells (GSCs) are responsible for GBM initiation, progression, infiltration, standard therapy resistance, and recurrence. However, the mechanisms underlying GSC invasion remain incompletely understood. Using public single-cell RNA-Seq data, we identified MAP3K1 as a master regulator of infiltrative GSCs through c-JUN signaling regulation. MAP3K1 knockdown significantly decreased GSC invasion capacity, proliferation, and stemness in vitro. Moreover, in an orthotopic xenograft model, knockdown of MAP3K1 prominently suppressed GSC infiltration along the corpus callosum and tumor progression and prolonged mouse survival. Mechanistically, MAP3K1 regulates GSC invasion through phosphorylation of downstream c-JUN at serine 63 and 73, as confirmed using the CPTAC phosphoproteome dataset. Furthermore, the c-JUN inhibitor JNK-IN-8 significantly decreased GSC invasion, proliferation, and stemness. Taken together, our study demonstrates that MAP3K1 regulates GSC invasion and tumor progression via activation of c-JUN signaling and indicates that the MAP3K1/c-JUN signaling axis is a therapeutic target for infiltrative GBM.


Synthesis, characterization, and in-vitro cytocompatibility of amorphous β-tri-calcium magnesium phosphate ceramics.
Biphasic mixtures of crystalline β-tricalcium magnesium phosphate (β-TCMP) and an amorphous calcium magnesium phosphate have been synthesized and reported to support enhanced hMSC differentiation in comparison to β-tricalcium phosphate (β-TCP) due to the release of increased amounts of bioactive ions. In the current study, completely amorphous β-TCMP has been synthesized which is capable of releasing increased amounts of Mg(2+) and PO4(3-) ions, rather than a biphasic mixture as earlier reported. The amorphous phase formed was observed to crystallize between temperatures of 400-600°C. The scaffolds prepared with amorphous β-TCMP were capable of supporting enhanced hMSC proliferation and differentiation in comparison to commercially available β-TCP. However, a similar gene expression of mature osteoblast markers, OCN and COL-1, in comparison to biphasic β-TCMP was observed. To further study the role of Mg(2+) and PO4(3-) ions in regulating hMSC osteogenic differentiation, the capability of hMSCs to mineralize in growth media supplemented with Mg(2+) and PO4(3-) ions was studied. Interestingly, 5mM PO4(3-) supported mineralization while the addition of 5mM Mg(2+) to 5mM PO4(3-) inhibited mineralization. It was therefore concluded that the release of Ca(2+) ions from β-TCMP scaffolds also plays a role in regulating osteogenic differentiation on these scaffolds and it is noted that further work is required to more accurately determine the exact role of Mg(2+) in regulating hMSC osteogenic differentiation.


The inhibition of the nitric oxide-cGMP-PKG-JNK signaling pathway avoids the development of tolerance to the local antiallodynic effects produced by morphine during neuropathic pain.
Tolerance to the local antiallodynic effects of morphine, DPDPE ([D-Pen(2),D-Pen(5)]-Enkephalin) or JWH-015 ((2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone) after their repeated administration during neuropathic pain was evaluated. The role of the nitric oxide-cGMP-protein kinase G (PKG)-c-Jun N-terminal kinase (JNK) signaling pathway on the peripheral morphine-induced tolerance after the chronic constriction of sciatic nerve in mice was also assessed. The mechanical and thermal antiallodynic effects produced by a high dose of morphine, DPDPE or JWH-015 subplantarly administered daily from days 10 to 20 after nerve injury were estimated with the von Frey filaments and cold plate tests. The antiallodynic effects of the repeated administration of morphine combined with a sub-analgesic dose of a selective inducible nitric oxide synthase (NOS2) (L-N(6)-(1-iminoethyl)-lysine; L-NIL), L-guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ), PKG ((Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs) or JNK (anthra[1,9-cd]pyrazol-6(2H)-one; SP600125) inhibitor from days 10 to 20 after injury were also evaluated. The repeated administration of morphine, but not DPDPE or JWH-015, produced a rapid development of tolerance to its mechanical and thermal antiallodynic effects in sciatic nerve-injured mice. The co-administration of morphine with L-NIL, ODQ, Rp-8-pCPT-cGMPs or SP600125 avoided the development of morphine antiallodynic tolerance after nerve injury. These findings reveal that the repeated local administration of DPDPE or JWH-015 did not induce antinociceptive tolerance after sciatic nerve injury-induced neuropathic pain. Our data also indicate that the peripheral nitric oxide-cGMP-PKG-JNK signaling pathway participates in the development of morphine tolerance after nerve injury and propose the inactivation of this pathway as a promising strategy to avoid morphine tolerance during neuropathic pain.


Evaluation of clinical sensitivity and specificity of hepatitis B virus (HBV), hepatitis C virus, and human immunodeficiency Virus-1 by cobas MPX: Detection of occult HBV infection in an HBV-endemic area.
Transfusion-transmitted infectious diseases remain a major concern for blood safety, particularly with hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Nucleic acid testing (NAT) in donor screening shortens the serologically negative window period and reduces virus transmission. The cobas MPX (Roche Molecular Systems, Inc., Branchburg, New Jersey) is a recently developed multiplex qualitative PCR system that enables the simultaneous detection of HBV, HCV, and HIV with improved sensitivity and throughput using cobas 6800 and 8800 instruments. The aim of this study was to conduct an evaluation of the clinical sensitivity and specificity of cobas MPX detection of HBV, HCV, and HIV in clinical specimens. Among samples referred for HBV, HCV, and HIV-1 quantification at Severance Hospital, Yonsei University College of Medicine, positive samples were selected to evaluate sensitivity. A total of 843 samples was tested using both cobas MPX and COBAS AmpliPrep/COBAS TaqMan Tests for HBV, HCV, and HIV-1 using the cobas 8800 system and a COBAS TaqMan 96 analyzer, respectively. Samples that showed discrepancies were confirmed by nested PCR. The cobas MPX achieved excellent sensitivity and specificity for the detection of HBV, HCV, and HIV-1 in clinical samples. We found that the lower limit of detection (LOD) of blood screening by NAT actually improves clinical sensitivity, and occult HBV infection prevalence among healthy employees of the hospital was rather high.


Surgical treatment results of intestinal and diffuse type gastric cancer. Implications for a differentiated therapeutic approach?
To study the outcome of patients who were surgically treated for primary gastric cancer with specific attention to differences in treatment results for intestinal and diffuse type tumours. All patients who underwent a potentially curative gastric resection between 1995 and 2011 in our institute were included. Patient, tumour and treatment characteristics were obtained retrospectively. Binary logistic and Cox regression models were used for multivariate analysis. A consecutive series of 132 patients was included. Median follow-up was 53 months. There were no significant differences between patients with intestinal (N = 62) versus diffuse type (N = 70) gastric cancer with regard to the proportion of patients who underwent (neo)adjuvant treatment. Postoperative mortality was 2%. Pathological T- and N-stage were significantly more advanced for patients with diffuse type tumours. There was a significant difference in the percentage of microscopically irradical resections (2% versus 24%, p < 0.001) and median overall survival (129 versus 17 months, p < 0.001) between patients with intestinal type tumours and those with diffuse type tumours. On multivariate analysis, diffuse type histology was the only factor significantly associated with an R1 resection. In a multivariate Cox regression model, diffuse type histology was a significant adverse prognostic factor for overall survival. Striking differences were found between patients with diffuse type tumours and those with intestinal type tumours. These differences call for a differentiated approach in the potentially curative treatment of these two tumour types.


Prognostic and predictive biomarkers of abdominal aortic aneurysm growth rate.
To test the utility of clinical and circulating biomarkers to predict abdominal aortic aneurysm (AAA) growth rate and response to doxycycline therapy. Plasma samples were obtained in the Pharmaceutical Aneurysm Stabilization Trial that tested the effect of doxycycline (n = 44) vs. placebo (n = 49) in patients with a 35-50 mm AAA. Approximately 200 biomarkers were evaluated in a candidate approach that included markers of matrix turnover and cathepsin S activity and a broad-based approach of predominantly inflammation-related and clinical biomarkers. In a recursive partitioning based analysis, total cholesterol, baseline AAA size, and apolipoprotein B were prognostic of AAA growth in the placebo group whereas elastin and biglycan degradation products were predictive of AAA growth with doxycycline treatment. Univariate analysis of these biomarkers showed that baseline total cholesterol (r = 0.38, unadjusted P = 0.011), apolipoprotein B (r = 0.41, unadjusted P = 0.005), and baseline AAA size (r = 0.35, unadjusted P = 0.013) correlated with AAA growth in the placebo but not the doxycycline group. Elastin fragments were associated with 18 month AAA growth (r = 0.33, unadjusted P = 0.031) in the doxycycline group. Limitations of this study include small sample size, a retrospective growth analysis, and translatability of the method used to measure the analytes. This study implies that total cholesterol, baseline AAA size, and apolipoprotein B are predictors of AAA growth. Levels of elastin and biglycan fragments are predictive of doxycycline effects on AAA growth and provide a clue towards this unexpected negative effect.


Patterns of carbon storage in relation to shade tolerance in southern South American species.
Carbon (C) allocation to storage in woody tissues at the expense of growth is thought to promote shade tolerance, yet few studies on the subject examined C storage during maximum growth and considered stand influences. I asked how C storage in different plant tissues relates to shade tolerance in temperate forests with contrasting climates and physiognomies, and whether relationships vary during the growing season. In the late spring and late summer, I harvested seedlings of eight species with contrasting light requirements from the understory of a cold rainforest and a Mediterranean forest in Chile. Nonstructural carbohydrate (NSC) concentrations and pools (i.e., biomass x NSC concentration) were determined in leaves, aboveground wood, and roots. The effects of shade tolerance and sampling date on the NSCs were analyzed for each forest and tissue with linear mixed-effects models. In both forests, concentrations of NSC and soluble sugars in woody tissues, as well as fractions of NSC in these tissues, were lower in shade tolerant than in shade intolerant species. For root NSC concentrations, these trends depended on the sampling date: in the late spring the concentrations were similar in shade tolerant and intolerant species, while in the late summer they were lower in shade tolerant species. Shade tolerance is not linked to C storage in the two studied forests, suggesting that allocation to growth or defenses could be more advantageous for low light persistence. Alternatively, high levels of C storage could be also selected in shade intolerant species to face herbivory or drought.


Integrative-interpersonal dynamic therapy for poststroke depression (INID): study protocol of a randomised controlled pilot trial.
Depression is the most frequent psychiatric disorder following stroke, affecting about one-third of stroke survivors. Patients experience poorer recovery, lower quality of life and higher mortality compared with stroke survivors without depression. Despite these well-known malign consequences, poststroke depression (PSD) is regarded underdiagnosed and undertreated. Evidence of beneficial effects of psychotherapy to treat PSD remains scarce and inconclusive and is limited by heterogeneity in design, content and timing of the intervention. This pilot study aims to assess the feasibility of a newly developed integrative-interpersonal dynamic PSD intervention in an outpatient setting and provide a first estimation of the potential effect size as basis for the sample size estimation for a subsequent definite trial. Patients will be recruited from two German stroke units. After discharge from inpatient rehabilitation, depressed stroke survivors will be randomised to short-term psychotherapy (12 weeks, ≤16 sessions) or enhanced treatment as usual. The manualised psychotherapy integrates key features of the Unified Psychodynamic and Cognitive-Behavioural Unified Protocol for emotional disorders and was adapted for PSD. Primary endpoints are recruitment feasibility and treatment acceptability, defined as a recruitment rate of ≥20% for eligible patients consenting to randomisation and ≥70% completion-rate of patients participating in the treatment condition. A preliminary estimation of the treatment effect based on the mean difference in Patient Health Questionnaire-9 (PHQ-9) scores between intervention and control group six months poststroke is calculated. Secondary endpoints include changes in depression (PHQ-9/Hamilton Depression Scale) and anxiety (Generalised Anxiety Disorder 7) of all participants across all follow-ups during the first year poststroke. The INID pilot study received full ethical approval (S-321/2019; 2022-2286_1). Trial results will be published in a peer-reviewed journal in the first half of 2025. One-year follow-ups are planned to be carried out until summer 2025. DRKS00030378.


Risk factors for the development of extended-spectrum beta-lactamase-producing bacteria in nonhospitalized patients.
Although the risk factors for acquiring infection by extended-spectrum beta-lactamase (ESBL)-producing bacteria have been investigated in hospitalized patients, such risk factors have not been defined in the community setting. In this study, clinical data from a total of 311 nonhospitalized patients with community-acquired urinary tract infection (128 with ESBL-positive strains and 183 with ESBL-negative strains) were obtained. According to a multivariate analysis, the following were identified as independent risk factors: previous hospitalization in the past 3 months (OR=8.95, 95%CI, 3.77-21.25), antibiotic treatment in the past 3 months (OR=3.23, 95%CI, 1.76-5.91), age over 60 years (OR=2.65, 95%CI, 1.45-4.83), diabetes (OR=2.57, 95%CI, 1.20-5.51), male gender (OR=2.47, 95%CI, 1.22-5.01), Klebsiella pneumoniae infection (OR=2.31, 95%CI, 1.17-4.54), previous use of third-generation cephalosporins (P=0.014, OR=15.8, 95%CI, 1.7-143), previous use of second-generation cephalosporins (P<0.0001, OR=10.1, 95%CI, 4.2-24), previous use of quinolones (P=0.001, OR=4.1, 95%CI, 1.8-9.0), and previous use of penicillin (P=0.003, OR=4.0, 95%CI, 1.6-9.0).


Aplastic anemia associated with submassive hepatic necrosis. Report of four cases.
Four cases of fatal aplastic anemia were associated with submassive hepatic necrosis. The subjects were males, ranging in age from 20 to 33 years. Pathogenesis remained obscure.


Synthesis of novel lipidated iridoid glycosides as vaccine adjuvants: 6-O-palmitoyl Agnuside elicit strong Th1 and Th2 response to ovalbumin in mice.
Novel lipidated analogs of iridoids viz., Agnuside and Negundoside with different chain length were synthesized and tested for immune adjuvant activity in the presence of weak antigen ovalbumin. Based on in vitro assay, 6-O-palmitoyl Agnuside (AG-3) was further taken up for detailed in vivo activity and found to significantly enhance the production of anti OVA IgG titer, neutralizing antibody (IgG1 and IgG2a) titer as well as soluble mediators of a Th1 (IL-2, IFN-γ)/Th2 response (IL-4) and proliferation of T lymphocyte subsets (CD4/CD8) and co stimulatory molecules CD80/CD86. Furthermore, the SAR studies revealed that presence of acyl group at aglycon moiety of these iridoid glycosides is crucial for immune adjuvant activity.


Comparison of fludarabine-melphalan and fludarabine-treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party.
In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m2 (FluMel) and fludarabine/treosulfan 42 g/m2 (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.


The central nervous system in canine giant axonal neuropathy.
The pathology of the central nervous system (CNS) in a dog with giant axonal neuropathy (GAN) is presented. Swollen axons containing excessive and disorganised neurofilaments were present in the spinal cord, mainly at the distal portions of long tracts. The fasiculus gracilis and dorsal spinocerebellar tracts were affected only in the rostral cervical cord while the lateral cortico spinal tract was principally involved in the lower thoracic and lumbar cord. Occasional swellings were also found in the central dorsal columns of the rostral lumbar segments and in the dorsal and intermediate grey matter. The nuclei gracilis and cuneatus, restiform body and ventral spinocerebellar tracts were all involved in the brain stem. Spheroids were seen in the white matter of the rostral cerebellar vermis and in the granule cell layer. The brachium of the superior colliculus contained swollen axons and the cortex was diffusely involved with spheroids. The distribution was of a distal axonopathy and the cortical changes provided an explanation for the abnormal EEG and mental retardation found in some human patients.


Experimental and theoretical study of skylight polarization transmitted through Snell's window of a flat water surface.
The celestial polarization pattern may be scrambled by refraction at the air-water interface. This polarization pattern was examined in shallow waters with a submersible polarimeter, and it was calculated by using land measurements ('semiempirical predictions') and models of the skylight polarization. Semiempirically predicted and measured e-vector orientations were significantly similar. Conversely, predicted percent polarization was correlated but lower than measurements. Percent polarization depended on wavelength, where at high sun altitudes maximal percent polarization generally appeared in the UV and red spectral regions. The wavelength dependency of polarization may lead to differential spectral sensitivity in polarization-sensitive animals according to time and type of activity.


Shuffling of pig interleukin-2 gene and its enhancing of immunity in mice to Pasteurella multocida vaccine.
In order to explore the safe and effective adjuvant for promotion of immunity of animals against infection, the experiment was carried out to shuffle Tibet pig IL-2 cDNA with other IL-2 cDNA from human, yak and mouse, and the effect of shuffled IL-2 (IL-2S) gene in vivo was investigated on immunity of mice to Pasteurella multocida. The IL-2S protein was found to remarkably promote the proliferation of pig lymphoblasts than the native pig IL-2 protein. Then the IL-2S gene was cloned into VR1020 eukaryotic plasmid (VRIL2S) and enwrapped with chitosan nanoparticles (CNP-VRIL2S). Twenty-one day old female Kunming mice were muscularly inoculated respectively with the CNP-VRIL2, CNP-VRIL2S and CNP-VR1020 along with Pasteurella multocida vaccine, and orally challenged with virulent Pasteurella multocida on 28 days post-vaccination. The blood was weekly collected to detect the change of IgG, IgA, IgM, specific antibody, IL-2, IL-4 and IL-6 by ELISA. The immunoglobulins, specific antibody and interleukins significantly increased in CNP-VRIL2S group compared with the control mice after vaccination and challenge, and 9 of 10 immunized mice survived challenge, while the all control mice manifested severe symptoms and lesions, and finally died of infection. These indicated that VRIL2S entrapped with CNP is a novel safe and effective adjuvant to boost the specific immunity and resistance of animal against infectious pathogen, which could facilitate the development of highly promising powerful adjuvant.


Resumption of Sexual Intercourse Among Postnatal Women Enrolled on Lifelong Antiretroviral Therapy in Uganda.
The postnatal period is critical to the delivery of interventions aimed at improving maternal health outcomes. This study examined the timing to resumption of sexual intercourse and associated factors among postnatal women living with HIV (WLWH) in Uganda. A sample of 385 women was drawn from a larger prospective cohort study conducted between 2013 and 2015. We used survival analysis to estimate the postpartum time periods during which women had a higher risk of sexual intercourse resumption within 6 months after childbirth. Cox proportional hazards regression was used to examine associated factors with sexual intercourse resumption. The cumulative probability of sexual intercourse resumption was lowest (6.2%) in the sub-acute postpartum period (1-45 days since delivery) and highest (88.2%) in the delayed postpartum period (151-183 days since delivery). Having a live-term baby (adjusted HR 0.52, 95% CI 0.31-0.85, p = 0.01) and an advanced education (adjusted HR 0.63, 95% CI 0.40-0.98, p = 0.04) were associated with a lower risk of sexual intercourse resumption. Desire for another child (adjusted HR 1.36, 95% CI 1.08-1.73, p = 0.01), having a sexual partner (adjusted HR 5.97, 95% CI 3.10-11.47, p < 0.001) and contraceptive use (adjusted HR 2.21, 95% CI 1.65-2.95, p < 0.001) were associated with a greater risk of sexual intercourse resumption. However, only 1 in 4 women who resumed sexual intercourse by the 90th day after childbirth, reported currently using contraception. HIV programs should focus on supporting postnatal women to align the timing of sexual intercourse resumption with their return to contraceptive use. Interventions aimed at improving contraceptive uptake among postnatal WLWH should target the delayed postpartum period.


The suppressive effect on CD4 T cell alloresponse against endothelial HLA-DR via PD-L1 induced by anti-A/B ligation.
While donor-specific human leukocyte antigen (HLA) antibodies are a frequent cause for chronic antibody-mediated rejection in organ transplantation, this is not the case for antibodies targeting blood group antigens, as ABO-incompatible (ABO-I) organ transplantation has been associated with a favorable graft outcome. Here, we explored the role of CD4 T cell-mediated alloresponses against endothelial HLA-D-related (DR) in the presence of anti-HLA class I or anti-A/B antibodies. CD4 T cells, notably CD45RA-memory CD4 T cells, undergo extensive proliferation in response to endothelial HLA-DR. The CD4 T cell proliferative response was enhanced in the presence of anti-HLA class I, but attenuated in the presence of anti-A/B antibodies. Microarray analysis and molecular profiling demonstrated that the expression of CD274 programmed cell death ligand 1 (PD-L1) increased in response to anti-A/B ligation-mediated extracellular signal-regulated kinase (ERK) inactivation in endothelial cells that were detected even in the presence of interferon-γ stimulation. Anti-PD-1 antibody enhanced CD4 T cell proliferation, and blocked the suppressive effect of the anti-A/B antibodies. Educated CD25+ CD127- regulatory T cells (edu.Tregs ) were more effective at preventing CD4 T cell alloresponses to endothelial cells compared with naive Treg ; anti-A/B antibodies were not involved in the Treg -mediated events. Finally, amplified expression of transcript encoding PD-L1 was observed in biopsy samples from ABO-I renal transplants when compared with those from ABO-identical/compatible transplants. Taken together, our findings identified a possible factor that might prevent graft rejection and thus contribute to a favorable outcome in ABO-I renal transplantation.


Including parents in inclusive practice: Supporting students with disabilities in higher education.
While a number of research studies have endeavoured to understand students with disabilities' experience in higher education and have recommended ways to effectively support student success, the role of parental support has been neglected. Many studies have been hampered by a limited understanding of students with disabilities and have, in particular, underestimated students' 'access to economic, social and cultural forms of capital' that caring parents provide. This article seeks to explore students with disabilities' experiences of parental support in the South African higher education context. The research question guiding this article is: What forms of economic, social and cultural capital do parents and extended families provide to students with disabilities to enable them to succeed in higher education? In-depth semi-structured individual and focus group interviews were conducted with 17 students with disabilities at two universities of technology. The interview transcripts were thematically analysed with a view to understanding Pierre Bourdieu's forms of capital that parents provided. The study found that while parents are not always able to provide material support, they offered rich and varied forms of social and cultural capital that enabled students with disabilities' academic success. Given that parental support plays an important role in the success of students with disabilities, and this role changes as these students become more independent, this study recommends the need for universities to also pay more attention to involving parents in the education of the former. It is hoped that putting in place appropriate forms of parental involvement can create a conducive environment for universities to provide inclusive education holistically.


MALAT-1 interacts with hnRNP C in cell cycle regulation.
As a conserved non-coding RNA gene, transcripts of MALAT-1 localize predominately in the nucleus. However in G2/M cell cycle phase, MALAT-1 transcripts were surprisingly found to translocate from the nucleus into the cytoplasm. Investigation also found that in this process MALAT-1 interacts with an abundant nuclear factor, hnRNP C protein. Using a loss-of-function assay, we found that down-regulation of MALAT-1 expression compromised the cytoplasmic translocation of hnRNP C in the G2/M phase and resulted in G2/M arrest. In addition to characterize the physiological interaction between MALAT-1 and hnRNP C, our study also highlights the role of MALAT-1 in cell cycle regulation.


New insight into the correlations between land use and water quality in a coastal watershed of China: Does point source pollution weaken it?
Uncovering the associations between land use and river water quality is useful for managing land-based pollution in the catchment-coast continuum. However, it is not clear how land use affects water quality in the context of simultaneous point source (PS) pollution. In this study, we develop a self-organizing map (SOM)-based approach to explore the relationship between land use and water quality in the Minjiang River Watershed, Southeast China. Water samples from 139 headwater sub-watersheds were associated with six land use categories, namely, Woodland, Agriculture, Orchard, Built-up, Unused land and Water. Sampling sites are delineated into six clusters based on six water quality parameters: ammonium-N, nitrate-N, total nitrogen, soluble reactive phosphate, total phosphate and potassium permanganate index. Local relationships between land use and water quality among four clusters that have sufficient sample sizes are further identified. There is no significant land use-water quality correlation in one of the four clusters (including 37 sub-watersheds). And the greater the PS pollution is, the less significant the land use-water quality correlations are in clusters. The results demonstrate how PS pollution weakens the land use-water quality correlation. Our method can help to determine whether non-point source or PS pollution exerts greater influence on the quality of the water coming from watershed.


The case for flexibility in online science courses: Strategies and caveats.
The COVID-19 pandemic created an unpredictable and stressful situation for both students and instructors. With current instruction largely occurring in an online environment, we propose that increased flexibility in course structure will best support student learning. Flexible course structure offers a trauma-aware approach to teaching, is in line with the Universal Design for Learning, and increases student motivation and meaningful learning. It can also provide more authentic experiences akin to science-based careers. We provide several specific suggestions for incorporating flexibility in one's class, as well as outline considerations and caveats. Our hope is that flexibility necessitated by the COVID-19 pandemic will continue to inspire change in future course design and educational paradigms.


Pubic Candida Folliculitis, A Case Report in a Patient With Recurrent Vaginal Candidiasis.
Folliculitis is a skin infection and inflammation that develops in the hair follicles. While most cases of folliculitis are caused by bacterial infections, here is a case of folliculitis caused by the Candida fungi in an immunocompetent host. A 23-year-old non-diabetic immunocompetent female with recurrent vaginal candidiasis developed clusters of erythematous, pruritic papules in the pubic area. Upon evaluation, the clusters were determined to be folliculitis. Risk factors for folliculitis included shaving of the pubic area, hot tub use, and wearing of tight, restrictive clothing. Cultures and skin samples of the folliculitis demonstrated Candida albicans. The patient was subsequently and successfully treated with clotrimazole solution and cream. There was no recurrence of the folliculitis upon her 3-month follow-up appointment. Candida folliculitis is a rare condition in non-diabetic patients. The patient's history, risk factors and immune status assessment, and physical examination with proper diagnostic testing, are crucial steps in attaining the correct diagnosis.


A calorimetric and spectroscopic comparison of the effects of cholesterol and its immediate biosynthetic precursors 7-dehydrocholesterol and desmosterol on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine bilayer membranes.
We performed differential scanning calorimetric (DSC) and Fourier transform infrared (FTIR) spectroscopic studies of the effects of cholesterol (CHOL), 7-dehydrocholeterol (7DHC) and desmosterol (DES) on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine (DPPC) bilayer membranes. 7DHC and DES are the immediate biosynthetic precursors of CHOL in the Kandutch-Russell and Bloch pathways and 7DHC and DES differ in structure from CHOL only by the presence of an additional double bond at C7 of ring B or C24 of the alkyl side chain, respectively. Our DSC results indicate that the incorporation of all three sterols produces comparable decreases in the temperature of the pretransition of DPPC, but CHOL decreases its cooperativity and enthalpy more strongly than 7DHC and especially DES. These findings indicate that all three sterols decrease the thermal stability of gel phase DPPC bilayers but that 7DHC and especially DES are less miscible in them. However, the incorporation of CHOL and DES produce comparable increases in the temperature of the broad component of the main phase transition of DPPC while 7DHC decreases it, but again CHOL produces greater decreases in its cooperativity and enthalpy then 7DHC and especially DES. These results indicate that CHOL and DES stabilize the sterol-rich domains of fluid DPPC bilayers, but that 7DHC and especially DES are less miscible in them. Our FTIR spectroscopic results indicate that CHOL increases the rotational conformational order of fluid DPPC bilayers to a somewhat and markedly greater degree than DES and 7DHC, respectively, consistent with our DSC findings. Our spectroscopic results also indicate that although all three sterols produce comparable degrees of H-bonding (hydration) of the DPPC ester carbonyl groups in fluid bilayers, CHOL is again found to be fully soluble in gel state DPPC bilayers at low temperatures, whereas 7DHC and especially DES are not. In general, we find that 7DHC and DES incorporation produce considerably different effects on DPPC bilayer membranes. In particular, the presence of an additional double bond at C7 or C24 produces a marked reduction in the ability of 7DHC to order fluid DPPC bilayers and in the miscibility of DES in such bilayers, respectively. These different effects may be the biophysical basis for the reduction of these double bonds in the last steps of CHOL biosynthesis, and for the deleterious biological effects of the accumulation of these sterols in vivo.


Evaluation of epidemiology and immunogenetics of IDDM in Spanish- and Portuguese-heritage registries. A key to understanding the etiology of IDDM? Diabetes Epidemiology Research International Group.
There appears to be extraordinary international variation in the incidence of insulin-dependent diabetes mellitus (IDDM), the reasons for which are not known. By evaluating the incidence of IDDM in Spanish- and Portuguese-heritage populations, important insight into reasons for the major worldwide differences in IDDM risk may be gained. The limited data that are available for Hispanic populations suggest that there is at least a 10-fold difference in risk between individuals of Hispanic ancestry in Colorado and Mexicans in Mexico City. Standard methods for assessing IDDM incidence are needed to further elucidate the patterns of risk among populations of iberian heritage. Therefore, we propose that comparable IDDM registries be established in the Spanish- and Portuguese-speaking world. Once registries are established, further investigation of the characteristics of IDDM among various populations (including seasonal distributions, sex differences, age at onset, and changing trends over time) may help explain the large international incidence differences among not only Spanish- and Portuguese-heritage populations but also among all children.


Assessing impacts of future climate change on extreme fire weather and pyro-regions in Iberian Peninsula.
Weather conditions play an important role in wildfire activity. In many regions, future climate could lead to different fire weather, with impacts on the ignition, behaviour, and suppression of wildfires, which may, therefore, force new fire regimes. This study aimed to assess the evolution of fire weather indices and the Number of Extreme Days (NED) in the context of climate change. We estimated the impact of these changes on monthly Normalized Burnt Area (NBA) and in the spatial distribution of Pyro-Regions (PR), using a recently identified relationship between NED and NBA intra-annual patterns. The components of the Canadian Forest Fire Weather Index System (CFFWIS) in the Iberian Peninsula were analysed for present-day conditions and future climate scenarios, using daily data from ERA-Interim (1980-2014) and an ensemble of simulations from 11 EURO-CORDEX high spatial resolution models, for two future periods (2041-2070 and 2071-2100) and scenarios (RCP4.5 and RCP8.5). Results suggest a significant increase in future fire weather risk, especially in late spring and early autumn, and also in southern and eastern Iberian Peninsula. NED is expected to strongly increase in summer months in the four PRs, but also to decrease in March and April in the northwestern and southwestern PR. This could change the spatial distribution of PRs, with a general northwards movement: the northern PR is expected to disappear except north of the Cantabrian Mountains, being replaced by the northwestern PR; the southwestern PR is expected to grow and occupy part of the area currently in the northwestern PR; and a new PR could appear in parts of the current eastern PR. These PR changes follow the projected modifications in the major climate regions. Results suggest different fire regimes in the future, with higher fire weather risk, and a longer and harsher fire season.


Using the RE-AIM framework to evaluate the implementation and effectiveness of a WHO HEARTS-based intervention to integrate the management of hypertension into HIV care in Uganda: a process evaluation.
World Health Organization (WHO) HEARTS packages are increasingly used to control hypertension. However, their feasibility in persons living with HIV (PLHIV) is unknown. We studied the effectiveness and implementation of a WHO HEARTS intervention to integrate the management of hypertension into HIV care. This was a mixed methods study at Uganda's largest HIV clinic. Components of the adapted WHO HEARTS intervention were lifestyle counseling, free hypertension medications, hypertension treatment protocol, task shifting, and monitoring tools. We determined the effectiveness of the intervention among PLHIV by comparing hypertension and HIV outcomes at baseline and 21 months. The RE-AIM framework was used to evaluate the implementation outcomes of the intervention at 21 months. We conducted four focus group discussions with PLHIV (n = 42), in-depth interviews with PLHIV (n = 9), healthcare providers (n = 15), and Ministry of Health (MoH) policymakers (n = 2). Reach: Among the 15,953 adult PLHIV in the clinic, of whom 3892 (24%) had been diagnosed with hypertension, 1133(29%) initiated integrated hypertension-HIV treatment compared to 39 (1%) at baseline. Among the enrolled patients, the mean age was 51.5 ± 9.7 years and 679 (62.6%) were female. Among the treated patients, hypertension control improved from 9 to 72% (p < 0.001), mean systolic blood pressure (BP) from 153.2 ± 21.4 to 129.2 ± 15.2 mmHg (p < 0.001), and mean diastolic BP from 98.5 ± 13.5 to 85.1 ± 9.7 mmHg (p < 0.001). Overall, 1087 (95.9%) of patients were retained by month 21. HIV viral suppression remained high, 99.3 to 99.5% (p = 0.694). Patients who received integrated hypertension-HIV care felt healthy and saved more money. Adoption: All 48 (100%) healthcare providers in the clinic were trained and adopted the intervention. Training healthcare providers on WHO HEARTS, task shifting, and synchronizing clinic appointments for hypertension and HIV promoted adoption. WHO HEARTS intervention was feasible and implemented with fidelity. Maintenance: Leveraging HIV program resources and adopting WHO HEARTS protocols into national guidelines will promote sustainability. The WHO HEARTS intervention promoted the integration of hypertension management into HIV care in the real-world setting. It was acceptable, feasible, and effective in controlling hypertension and maintaining optimal viral suppression among PLHIV. Integrating this intervention into national guidelines will promote sustainability.


Ni electrodes with 3D-ordered surface structures for boosting bubble releasing toward high current density alkaline water splitting.
The performance of alkaline water electrolysis (AWE) at high current densities is limited by gas bubble generation on the surface of electrodes, which covers active sites and blocks mass transfer, resulting in lower AWE efficiency. Here, we utilize electro-etching to construct Ni electrodes with hydrophilic and aerophobic surfaces to improve the efficiency of AWE. Ni atoms on the Ni surface can be exfoliated orderly along the crystal planes by electro-etching, forming micro-nano-scale rough surfaces with multiple crystal planes exposed. The 3D-ordered surface structures increase the exposure of active sites and promote the removal of bubbles on the surface of the electrode during the AWE process. In addition, experimental results from high-speed camera reveal that rapidly released bubbles can improve the local circulation of electrolyte. Lastly, the accelerated durability test based on practical working condition demonstrates that the 3D-ordered surface structures are robust and durable during the AWE process.


Obesity should not influence the management of appendicitis.
Obesity implies an adverse effect on outcome after appendectomy. This study aimed to determine whether obese patients with appendicitis should be managed differently than nonobese patients. After appendectomy, all patients were enrolled in a prospective clinical pathway and followed from initial presentation to full outpatient recovery. In 1 year, 272 adults underwent appendectomy, 55 (22%) of whom were obese. The obese patients were slightly older (35 vs 33 years; p < 0.001). The time to diagnosis (8.5 vs 8.6 h), and the need for computed tomography (CT) scanning (40% vs 49%) was similar in both populations. The obese patients had similar rates of perforation (35% vs 35%) and laparoscopy (47% vs 41%). The median hospital length of stay (LOS) (2 days) and complications, including wound complications (9.1% vs 10.9%) and intraabdominal abscesses (3.6% vs 3.1%), were similar. Subgroup analysis showed a longer LOS for the obese patients with perforation than for the nonobese patients (6 vs 5.5 days; p = 0.036). Obese patients had no greater delay in diagnosis, had no greater need for CT scan, gained no additional benefit from laparoscopy, and did not incur significantly worse outcomes after appendectomy except for an increased LOS among those with perforation.


Psychosis as the initial manifestation of adult-onset Niemann-Pick disease type C.
Niemann-Pick disease type C (NPC) is a neurometabolic genetic disorder that is distinguished from Niemann-Pick disease by its later onset, more insidious progression, variable visceromegaly, and abnormalities of intracellular cholesterol metabolism. We describe a patient who presented with an 8-year history of psychosis requiring chronic neuroleptic therapy for a presumed diagnosis of schizophrenia. He was subsequently diagnosed with NPC as the emerging features of dementia, ataxia, dysarthria, and vertical supranuclear ophthalmoplegia were recognized. The characteristic features of adult-onset NPC and the obstacles to early diagnosis are reviewed.


Permanent and temporary pacemaker implantation after orthotopic heart transplantation.
To determine the indication for and incidence and evolution of temporary and permanent pacemaker implantation in cardiac transplant recipients. A retrospective review of 114 patients who underwent orthotopic heart transplantation InCor (Heart Institute USP BR) between March 1985 and May 1993. We studied the incidence of and indication for temporary pacing, the relationship between pacing and rejection, the need for permanent pacing and the clinical follow-up. Fourteen of 114 (12%) heart transplant recipients required temporary pacing and 4 of 114 (3.5%) patients required permanent pacing. The indication for temporary pacing was sinus node dysfunction in 11 patients (78.5%) and atrioventricular (AV) block in 3 patients (21.4%). The indication for permanent pacemaker implantation was sinus node dysfunction in 3 patients (75%) and atrioventricular (AV) block in 1 patient (25%). We observed rejection in 3 patients (21.4%) who required temporary pacing and in 2 patients (50%) who required permanent pacing. The previous use of amiodarone was observed in 10 patients (71.4%) with temporary pacing. Seven of the 14 patients (50%) died during follow-up. Sinus node dysfunction was the principal indication for temporary and permanent pacemaker implantation in cardiac transplant recipients. The need for pacing was related to worse prognosis after cardiac transplantation.


Personal development plans (in primary dental care)--getting started.
This article reviews how to develop a personal development plan, its benefits and how it may relate to the GDC's proposed revalidation scheme. Revalidation is an essential part of reassuring the public that the profession delivers care to appropriate standards in safe work environments. A personal development plan is a key element in improving performance and quality of care.


Applying ideation-to-action theories to predict suicidal behavior among adolescents.
Although many risk factors for adolescent suicidal behavior have been identified, less is known about distinct risk factors associated with the progression from suicide ideation to attempts. Based on theories grounded in the ideation-to-action framework, we used structural equation modeling to examine risk and protective factors associated with the escalation from suicide ideation to attempts in adolescents. In this cross-sectional study, data from the 2013 and 2015 Hawaii High School Youth Risk Behavior Surveys (N = 8,113) were analyzed. The sample was 54.0% female and racially/ethnically diverse. Risk factors included depression, victimization, self-harm, violent behavior, disinhibition, and hard substance use, and protective factors included adult support, sports participation, academic achievement and school safety. One in 6 adolescents (16.4%) reported suicide ideation, and nearly 1 in 10 (9.8%) adolescents had made a suicide attempt. Overall, disinhibition predicted the escalation to attempts among adolescents with suicide ideation, and higher academic performance was associated with lower suicide attempt risk. Depression and victimization were associated with suicide ideation. This study examined data from the Youth Risk Behavior Survey, and other known risk factors such as anxiety and family history of suicide were not available in these data. Findings provide guidance for targets for clinical interventions focused on suicide prevention. Programs that incorporate behavioral disinhibition may have the greatest potential for reducing suicide attempt risk in adolescents with suicidal thoughts.


Evaluation of a real-time polymerase chain reaction method for the quantification of CYP1B1 gene expression in MCF-7 human breast carcinoma cells.
Cytochrome P450 1B1 (CYP1B1) catalyzes the bioactivation of numerous procarcinogens and it is expressed in tumor cells, including human breast cancer cells. To study CYP1B1 gene expression, it is important to have an accurate, precise, reproducible, specific, and quantitative method. MCF-7 human breast carcinoma cells were treated with beta-naphthoflavone (BNF; 50 microM), emodin (0.1-3 microM), trans-resveratrol (2.5-20 microM), or 0.1% dimethylsulfoxide (DMSO; vehicle control). Total cellular RNA was isolated and reverse transcribed. cDNA samples were quantified by a fluorescence assay and a constant amount (1 ng) was amplified in a real-time DNA thermal cycler (LightCycler). Melting curve analysis and agarose gel electrophoresis of the amplicons resulted in a single peak and a single band, respectively. The identity of the amplicon was confirmed to be CYP1B1 by sequencing analysis. The standard curve for the real-time PCR amplification of CYP1B1 cDNA was log-linear for at least four orders of magnitude. The limit of quantitation (LOQ) of the assay was 100 copies. At the LOQ, the assay had an accuracy of 8% and a precision of 10%. The intraday (n=4) variability (expressed as percent coefficient of variation) was 9% for a sample with low CYP1B1 mRNA expression (cells treated with 0.1% DMSO; i.e., Sample A) and 3% for a sample with elevated CYP1B1 mRNA expression (cells treated with BNF; i.e., Sample B). The interday (n=4) variability was 16% for Sample A and 15% for Sample B. Emodin increased CYP1B1 mRNA expression in cultured MCF-7 cells (maximal effect of ninefold induction achieved at 1 microM), whereas trans-resveratrol suppressed it (IC(50)=6.6+/-1.0 microM, mean+/-S.E.M., n=3). An accurate, precise, reproducible, and specific method is described for the real-time PCR quantification of CYP1B1 gene expression in MCF-7 human breast carcinoma cells.


The role of mitochondrial matrix enzymes in the metabolism and toxicity of cysteine conjugates.
The submitochondrial localization and identity of enzymes which metabolize cysteine conjugates were investigated. Glutamine transaminase K was purified from rat kidney mitochondrial soluble fraction and was shown to be a cysteine conjugate beta-lyase. The purified mitochondrial enzyme is similar to the cytosolic glutamine transaminase K whose beta-lyase activity with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is regulated by concurrent transamination (Stevens, J. L., Robbins, J. D., and Byrd, R. A. (1986) J. Biol. Chem. 261, 15529-15537). However, beta-lyase activity in whole mitochondria is largely independent of regulation by cosubstrates for transamination suggesting that factors present in mitochondria are able to support the beta-lyase activity in the absence of added alpha-keto acid. Fractionation of mitochondria results in a loss of the independent beta-lyase activity. However, the majority of the beta-lyase activity can be recovered in the matrix if it is stimulated by the addition of alpha-keto-gamma-methiolbutyrate. The data suggest that the regulation of beta-elimination by the competing transamination pathway is different for each substrate and that multiple beta-lyases may exist in rat kidney. S-(2-Benzothiazolyl)-L-cysteine (BTC) is a poor substrate for purified glutamine transaminase K from mitochondria and cytosol, but BTC is as active as DCVC in crude mitochondrial matrix suggesting that other enzymes may be present. In contrast to DCVC, with BTC as substrate, the beta-lyase activity of the purified enzyme and enzyme(s) in the mitochondrial matrix is largely alpha-keto acid-independent. The existence of multiple enzymes is also supported by the observation that alpha-keto acids which are not substrates for purified glutamine transaminase K from mitochondria and cytosol do stimulate beta-lyase activity in the mitochondrial matrix fraction. Mitoplasts were found to be sensitive to DCVC toxicity consistent with the matrix localization of beta-lyase activity. The possible role in cysteine conjugate toxicity of matrix enzyme regulation by alpha-keto acids is discussed.


[Mutation analysis of presenilin 1 gene in a Chinese family affected with early-onset familial Alzheimer's disease].
To explore the clinical phenotype and genotype in a Chinese family affected with early-onset familial Alzheimer's disease (EOFAD). Potential mutation of beta-amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene and apolipoprotein E (APOE) gene was detected with polymerase chain reaction (PCR) and direct sequencing. Homozygous APOE ε 2 allele and no gene mutation of APP gene were detected in the proband (III1). A 488A>G mutation (His163Arg) of the PSEN1 gene was found in the proband and other 4 family members (IV1, IV12, IV21, V2). A mutation (c.488A>G, p.His163Arg) of PSEN1 gene was found in a Chinese family affected with EOFAD.


Exploring How the Terms "Black" and "African American" May Shape Health Communication Research.
Several distinct terms are used to identify descendants of the African diaspora (DADs) as fellow members of a racialized population. However, "Black" and "African American" are the two labels most commonly used. Given the recent calls for examining institutionalized racism in the United States, health scholars must contemplate the problems that may arise when these two terms are used interchangeably, namely the extent to which mislabeling may reify already significant health disparities. This essay examines the histories and meanings of "Black" and "African American" as identity labels and explores their importance in relationship to the effective recruitment of DADs to health research and clinical trials. In this paper, we employ the communication theory of identity and critical race theory as lenses to call attention to the discursive challenges associated with recruitment of DADs in health research. We also encourage health communication scholars to explore and extend the scope of this research. We do this by first describing the unintended consequences in health research through disregard of DADs' chosen identity labels. We then use the various terms to describe DADs to illuminate existing tensions between "Black" and "African American." We describe how each moniker is used and perceived, broadly and in health contexts. Finally, we call for more research into the effects of mislabeling and propose a plan for researchers' next steps.


Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero.
Plasma amino acid concentrations were determined in 28 pregnant women and their infants at term. Samples were obtained from 17 appropriate for gestational age and eight small for gestational age infants at cesarean section, while three small for gestational age fetuses were studied in utero by transabdominal cord sampling by means of ultrasonic guidance. Small for gestational age fetuses have significantly lower concentrations of alpha-aminonitrogen, compared with those of appropriate for gestational age fetuses, in both the umbilical artery and vein. Most of the difference is accounted for by the branched chain amino acids valine, leucine, and isoleucine. In contrast, hydroxyproline concentration is significantly higher in both the umbilical artery and vein of small for gestational age fetuses. The sum of the branched chain amino acid concentrations in the umbilical vein is directly related to maternal arterial values in both appropriate for gestational age and small for gestational age fetuses. Maternal arterial concentrations were slightly lower in small for gestational age fetuses and the regression analysis of umbilical venous versus maternal arterial branched chain amino acid concentrations was significantly different for small for gestational age and appropriate for gestational age infants. Umbilical venoarterial concentration differences in normal fetuses are significantly positive for most essential amino acids and for total alpha-aminonitrogen. In contrast, these differences were significant only for four essential amino acids in small for gestational age infants, while the total alpha-aminonitrogen venoarterial difference was not significant. The data obtained by transabdominal cord sampling from relatively undisturbed fetuses were in agreement with the data obtained at cesarean section; this information suggests that these differences between small for gestational age and appropriate for gestational age infants reflected steady-state conditions.