The association of clinically determined periodontal disease and edentulism with total cancer mortality: The National Health and Nutrition Examination Survey III.
Increasing evidence supports a positive association between periodontal disease and total cancer risk. We evaluated the association of clinically assessed periodontal disease and a consequence, edentulism with total cancer mortality in participants without a prior cancer diagnosis in a U.S. nationally representative population. Included were 6,034 participants aged ≥40 years without a prior cancer diagnosis who participated in the National Health and Nutrition Examination Survey III. Periodontal health was measured by trained dentists. Cancer deaths (n = 702) were ascertained during a median of 21.3 years of follow-up. Cox proportional hazards regression was used to estimate the association of periodontal disease and edentulism with total cancer mortality using no periodontal disease/dentate as the reference and adjusting for potential demographic, lifestyle including smoking and social factor confounders. Fifteen percent had periodontitis and 17% were edentulous. Periodontitis was not statistically significantly associated with risk of total cancer death after multivariable adjustment. Edentulism was associated with an increased risk of cancer mortality (hazard ratio = 1.50, 95% confidence interval = 1.12-2.00) after multivariable adjustment, including in men and women and in each racial/ethnic group studied. The positive association was observed in overweight/obese participants but not participants with normal body mass index, more strongly in prediabetic/diabetic participants than in participants without diabetes and in ever cigarette smokers but not in never cigarette smokers. In this U.S. nationally representative population, those with edentulism, but not periodontal disease, had a higher risk of total cancer death, especially in those with shared risk factors for periodontal disease and cancer.


Comparative bioavailability study of triflusal oral solution vs. triflusal capsules in healthy subjects. A single, randomized, two-way cross-over, open-label phase I study.
Triflusal (CAS 322-79-2) is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), possesses also antiaggregant activity. Recently a new oral 600 mg (10 ml) solution form of triflusal has been developed. The purpose of this clinical trial was to study the relative bioavailability of the new oral solution of triflusal versus the capsules formulation, both administered as a single dose. This was a randomized, two-way, cross-over, open-label, single-site phase I clinical trial, in 24 healthy volunteers who received triflusal as 600 mg oral solution and as two 300 mg capsules in a single administration separated by a washout period of at least 17 days. Blood samples were collected and plasma concentrations of HTB were measured. Pharmacokinetic parameters used for bioequivalence assessment included AUC(0-t), AUC(0-inf) and Cmax. The formulations were considered bioequivalent if the geometric mean ratios of AUC(0-t), AUC(0-inf) and Cmax were within the predetermined equivalence range (80% to 125%). Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiogram (ECG) and laboratory tests. The parameters for bioequivalence, mean [SD] values were as follows: AUC(0-t) (microg x h/ml): 3574.08 [628.17] for triflusal oral solution and 3901.78 [698.43] for triflusal capsules; AUC(0-infinity) (microg x h/ml): 4089.21 [842.54] for triflusal oral solution and 4471.33 [905.93] for triflusal capsules; Cmax, (microg/ml): 91.24 [12.88] for triflusal oral solution and 88.61 [13.46] for triflusal capsules; Cmax/AUC(0-infinity) (h(-1)): 0.03 (0.00) for triflusal oral solution and 0.02 (0.00) for triflusal capsules. The 90% confidence intervals for the ratio experimental/control by analysis of variance after log transformed AUC(0-infinity), AUC(0-t), and Cmax were within 80% to 125%. Similar results were found for the data without log transformation. All adverse events were of mild or moderate intensity and all subjects recovered. Nine and 12 subjects reported at least one adverse event during treatment with triflusal oral solution and with triflusal capsules, respectively. The most frequently reported adverse events were headache and dizziness. It was concluded that the 600-mg solution of triflusal appeared to be bioequivalent to the reference formulation capsules. Both formulations were well tolerated.


Prevalence and nature of patient-reported antiseizure medication side effects in a Swedish regional multi-center study.
Side effects is one of the major clinical problems in epilepsy care. We assessed the prevalence of ASM side effects in participants in a large regional multicenter observational study in western Sweden and aimed to identify risk factors and inventory the nature of side effects with different ASM regimes. Cross-sectional analysis of survey answers and clinical characteristics of 406 adult participants recruited to a regional observational study between December 2020 and March 2023. Half of the participants had been seizure free for one year. Second-generation or newer ASMs were the most common. A total of 164 (40 %, 95 %CI: 36-45) patients reported side effects. Patients reporting side effects were younger (median 41 vs 47 years, p = 0.015), had more frequently experienced a seizure in the last year (p = 0.02), and were more often on ASM polytherapy (p < 0.01). ASM polytherapy and age were significant risk factors in regression models, but the explanatory value was low. The most common side effect was tiredness followed by cognitive symptoms. Our findings show that side effects are still common in epilepsy care and suggests that unnecessary polypharmacy should be avoided. Apart from number or ASMs, predicting who will experience side effects is difficult and more research on individual vulnerability is needed.


Visualizing Ultrafast Electron Transfer Processes in Semiconductor-Metal Hybrid Nanoparticles: Toward Excitonic-Plasmonic Light Harvesting.
Recently, it was demonstrated that charge separation in hybrid metal-semiconductor nanoparticles (HNPs) can be obtained following photoexcitation of either the semiconductor or of the localized surface plasmon resonance (LSPR) of the metal. This suggests the intriguing possibility of photocatalytic systems benefiting from both plasmon and exciton excitation, the main challenge being to outcompete other ultrafast relaxation processes. Here we study CdSe-Au HNPs using ultrafast spectroscopy with high temporal resolution. We describe the complete pathways of electron transfer for both semiconductor and LSPR excitation. In the former, we distinguish hot and band gap electron transfer processes in the first few hundred fs. Excitation of the LSPR reveals an ultrafast (<30 fs) electron transfer to CdSe, followed by back-transfer from the semiconductor to the metal within 210 fs. This study establishes the requirements for utilization of the combined excitonic-plasmonic contribution in HNPs for diverse photocatalytic applications.


The neurobiology of oppositional defiant disorder and conduct disorder: altered functioning in three mental domains.
This review discusses neurobiological studies of oppositional defiant disorder and conduct disorder within the conceptual framework of three interrelated mental domains: punishment processing, reward processing, and cognitive control. First, impaired fear conditioning, reduced cortisol reactivity to stress, amygdala hyporeactivity to negative stimuli, and altered serotonin and noradrenaline neurotransmission suggest low punishment sensitivity, which may compromise the ability of children and adolescents to make associations between inappropriate behaviors and forthcoming punishments. Second, sympathetic nervous system hyporeactivity to incentives, low basal heart rate associated with sensation seeking, orbitofrontal cortex hyporeactiviy to reward, and altered dopamine functioning suggest a hyposensitivity to reward. The associated unpleasant emotional state may make children and adolescents prone to sensation-seeking behavior such as rule breaking, delinquency, and substance abuse. Third, impairments in executive functions, especially when motivational factors are involved, as well as structural deficits and impaired functioning of the paralimbic system encompassing the orbitofrontal and cingulate cortex, suggest impaired cognitive control over emotional behavior. In the discussion we argue that more insight into the neurobiology of oppositional defiance disorder and conduct disorder may be obtained by studying these disorders separately and by paying attention to the heterogeneity of symptoms within each disorder.


Zebrafish Model as a Screen to Prevent Cyst Inflation in Autosomal Dominant Polycystic Kidney Disease.
In autosomal dominant polycystic kidney disease (ADPKD), kidney cyst growth requires the recruitment of CFTR (cystic fibrosis transmembrane conductance regulator), the chloride channel that is defective in cystic fibrosis. We have been studying cyst inflation using the zebrafish Kupffer's vesicle (KV) as model system because we previously demonstrated that knocking down polycystin 2 (PC2) induced a CFTR-mediated enlargement of the organ. We have now quantified the PC2 knockdown by showing that it causes a 73% reduction in the number of KV cilia expressing PC2. According to the literature, this is an essential event in kidney cystogenesis in ADPKD mice. Additionally, we demonstrated that the PC2 knockdown leads to a significant accumulation of CFTR-GFP at the apical region of the KV cells. Furthermore, we determined that KV enlargement is rescued by the injection of Xenopus pkd2 mRNA and by 100 µM tolvaptan treatment, the unique and approved pharmacologic approach for ADPKD management. We expected vasopressin V2 receptor antagonist to lower the cAMP levels of KV-lining cells and, thus, to inactivate CFTR. These findings further support the use of the KV as an in vivo model for screening compounds that may prevent cyst enlargement in this ciliopathy, through CFTR inhibition.


Genomic and Immunologic Characterization of INI1-Deficient Pediatric Cancers.
Several aggressive pediatric cancers harbor alterations in SMARCB1, including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors. We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or SMARCB1 genomic alterations on prior somatic sequencing. SMARCB1 two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of SMARCB1 was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a SMARCB1 alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors. A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.


Guidelines for Fabricating Highly Efficient Perovskite Solar Cells with Cu2O as the Hole Transport Material.
Organic hole transport materials (HTMs) have been frequently used to achieve high power conversion efficiencies (PCEs) in regular perovskite solar cells (PSCs). However, organic HTMs or their ingredients are costly and time-consuming to manufacture. Therefore, one of the hottest research topics in this area has been the quest for an efficient and economical inorganic HTM in PSCs. To promote efficient charge extraction and, hence, improve overall efficiency, it is crucial to look into the desirable properties of inorganic HTMs. In this context, a simulation investigation using a solar cell capacitance simulator (SCAPS) was carried out on the performance of regular PSCs using inorganic HTMs. Several inorganic HTMs, such as nickel oxide (NiO), cuprous oxide (Cu2O), copper iodide (CuI), and cuprous thiocyanate (CuSCN), were incorporated in PSCs to explore matching HTMs that could add to the improvement in PCE. The simulation results revealed that Cu2O stood out as the best alternative, with electron affinity, hole mobility, and acceptor density around 3.2 eV, 60 cm2V-1s-1, and 1018 cm-3, respectively. Additionally, the results showed that a back electrode with high work-function was required to establish a reduced barrier Ohmic and Schottky contact, which resulted in efficient charge collection. In the simulation findings, Cu2O-based PSCs with an efficiency of more than 25% under optimal conditions were identified as the best alternative for other counterparts. This research offers guidelines for constructing highly efficient PSCs with inorganic HTMs.


Large particle multiphoton flow cytometry to purify intact embryoid bodies exhibiting enhanced potential for cardiomyocyte differentiation.
Embryoid bodies (EBs) are large (>100 μm) 3D microtissues composed of stem cells, differentiating cells and extracellular matrix (ECM) proteins that roughly recapitulate early embryonic development. EBs are widely used as in vitro model systems to study stem cell differentiation and the complex physical and chemical interactions contributing to tissue development. Though much has been learned about differentiation from EBs, the practical and technical difficulties of effectively probing and properly analyzing these 3D microtissues has limited their utility and further application. We describe advancement of a technology platform developed in our laboratory, multiphoton flow cytometry (MPFC), to detect and sort large numbers of intact EBs based on size and fluorescent reporters. Real-time and simultaneous measurement of size and fluorescence intensity are now possible, through the implementation of image processing algorithms in the MPFC software. We applied this platform to purify populations of EBs generated from murine induced pluripotent stem (miPS) cells exhibiting enhanced potential for cardiomyocyte differentiation either as a consequence of size or expression of NKX2-5, a homeodomain protein indicative of precardiac cells. Large EBs (330-400 μm, diameter) purified soon after EB formation showed significantly higher potential to form cardiomyocytes at later time points than medium or small EBs. In addition, EBs expressing NKX2-5 soon after EB formation were more likely to form beating areas, indicative of cardiomyocyte differentiation, at later time points. Collectively, these studies highlight the ability of the MPFC to purify EBs and similar microtissues based on preferred features exhibited at the time of sorting or on features indicative of future characteristics or functional capacity.


Scavenging ROS dramatically increase NMDA receptor whole-cell currents in painted turtle cortical neurons.
Oxygen deprivation triggers excitotoxic cell death in mammal neurons through excessive calcium loading via over-activation of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This does not occur in the western painted turtle, which overwinters for months without oxygen. Neurological damage is avoided through anoxia-mediated decreases in NMDA and AMPA receptor currents that are dependent upon a modest rise in intracellular Ca(2+) concentrations ([Ca(2+)]i) originating from mitochondria. Anoxia also blocks mitochondrial reactive oxygen species (ROS) generation, which is another potential signaling mechanism to regulate glutamate receptors. To assess the effects of decreased intracellular [ROS] on NMDA and AMPA receptor currents, we scavenged ROS with N-2-mercaptopropionylglycine (MPG) or N-acetylcysteine (NAC). Unlike anoxia, ROS scavengers increased NMDA receptor whole-cell currents by 100%, while hydrogen peroxide decreased currents. AMPA receptor currents and [Ca(2+)]i concentrations were unaffected by ROS manipulation. Because decreases in [ROS] increased NMDA receptor currents, we next asked whether mitochondrial Ca(2+) release prevents receptor potentiation during anoxia. Normoxic activation of mitochondrial ATP-sensitive potassium (mKATP) channels with diazoxide decreased NMDA receptor currents and was unaffected by subsequent ROS scavenging. Diazoxide application following ROS scavenging did not rescue scavenger-mediated increases in NMDA receptor currents. Fluorescent measurement of [Ca(2+)]i and ROS levels demonstrated that [Ca(2+)]i increases before ROS decreases. We conclude that decreases in ROS concentration are not linked to anoxia-mediated decreases in NMDA/AMPA receptor currents but are rather associated with an increase in NMDA receptor currents that is prevented during anoxia by mitochondrial Ca(2+) release.


[Endoscopic axilla dissection in invasive breast carcinoma. Initial experiences with a new technique].
The presence or absence of involved axillary lymph nodes is the single best predictor of survival of breast cancer, and important treatment decisions are based on it. For staging purpose as well as for local control a level I and II dissection is recommended. In order to lower the morbidity of axillary lymph node dissection less invasive treatment modalities have been evaluated. Beside the sentinel lymph node biopsy another new method is discussed: the endoscopic axillary lymph node dissection. After liposuction of the axillary fat the lymph nodes of level I and II are removed by endoscopy. With this technique enough lymph node can be removed which allows a sufficient staging as well as local control. This technique is not to be recommended for general use unless long term results have proven its value.


An accurate numerical model for calculating the equilibration rate of a hanging-drop experiment.
A numerical model of the equilibration of a hanging-drop experiment has been developed and tested. To obtain accurate calculations with a given precipitant, the vapor pressure of water over water/precipitant solutions must be known for various concentrations of the precipitant. The calculations of the model are in excellent agreement with all available experimental data on hanging-drop equilibration when the necessary vapor pressures are known (ammonium sulfate and sodium chloride). By varying each of the relevant rate constants in the model, the rate-limiting step in the equilibration of a hanging drop is determined. This analysis clearly shows that the rate-limiting step is the diffusion of water vapor from the drop to the reservoir, which agrees with experimental findings. Since the diffusion of water vapor is the rate-limiting step, there is virtually no precipitant concentration gradient in the drop during equilibration. As a result, there is no gravity-induced convection owing to the equilibration. Thus, whereas gravity might have an effect during crystal growth, gravity does not affect the equilibration rate of a hanging-drop experiment to a significant extent, and the diffusion of water vapor will remain the rate-limiting step in the absence of gravity. Finally, the effects of several of the parameters, such as initial drop volume, drop-to-reservoir distance and temperature, are considered quantitatively. The equilibration rate was found to vary nearly linearly with drop volume. The equilibration rate decreases roughly by a factor of three as the temperature decreases from 293 to 276 K. This decrease in the equilibration rate is greater than would be expected when just considering the change in the diffusion coefficient of water vapor in air. This large dependence can, however, be attributed to the change in water-vapor pressure. Most surprisingly, a linear dependence on drop-to-reservoir distance is found, a result that agrees very well with experiment.


Cysteinyl leukotriene-1 receptor activation in a human bronchial epithelial cell line leads to signal transducer and activator of transcription 1-mediated eosinophil adhesion.
We studied the effect of leukotriene D(4) (LTD(4)) on a human bronchial epithelial cell line (16HBE) overexpressing the cysteinyl leukotriene (CysLT) (1) receptor (HBECysLT(1)R), looking at the associated signal transduction mechanisms as well as at effects on inflammatory cell adhesion. The results obtained showed that LTD(4) increases the phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 and of the signal transducer and activator of transcription 1 (STAT-1) in serine 727 (STAT-1Ser727), resulting in increased eosinophil adhesion to HBECysLT(1)R, associated with enhanced surface expression of intercellular adhesion molecule (ICAM) 1. Pretreatment with a CysLT(1)R-selective antagonist or with a selective inhibitor of protein kinase C (PKC) or with a selective inhibitor of the mitogen-activated protein kinase kinase (MEK) successfully suppressed both LTD(4)-induced STAT-1Ser727 phosphorylation and the associated increase in eosinophil adhesion. The use of the MEK inhibitor and of the selective CysLT(1)R antagonist in electrophoretic mobility shift assay experiments showed that LTD(4) promotes the nuclear translocation of STAT-1 through the activation of ERK1/2 pathway. The key role of STAT-1 in leukotriene D(4) transduction signaling was confirmed by RNA interference experiments, where silencing of STAT-1 expression abolished the effect of leukotriene D(4) on eosinophil adhesion. In conclusion, for the first time, we provide evidence of the involvement of STAT-1 in the signal transduction mechanism of the CysLT(1) receptor; phosphorylation of STAT-1, through PKC and ERK1/2 activation, causes enhanced ICAM-1 surface expression and eosinophil adhesion. Effective CysLT(1)R antagonism may therefore contribute to the control of the chronic inflammatory condition that characterizes human airways in asthma.


AN IMPROVED METHOD FOR THE SIMPLE AND ACCURATE COLORIMETRIC DETERMINATION OF UREA WITH EHRLICH'S REAGENT.
An improved method for the colorimetric determination of urea is described. The method is simple, requiring a deproteinized filtrate obtained after treatment of a small quantity of whole oxalated blood, serum, plasma or urine with 12.5% trichloracetic acid containing 50 g. activated carbon. The addition of Ehrlich's reagent to this filtrate results in the immediate production of a stable yellow colour. The determination is accurate, very sensitive and rapid, taking place in only 10 minutes.


Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid.
Conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in > 95% de. Amination of the lithium (E)-enolates of tert-butyl (3S,alphaR)-3-N-benzyl-N-alpha-methylbenzylamino-3-phenylpropanoate or tert-butyl (3S,alphaS)-3-N-benzyl-N-alpha-methylbenzylaminobutanoate with trisyl azide gives the (2R,3R,alphaR)- and (2S,3S,alphaS )-anti-2-azido-3-amino esters in good yields and in 85% de and > 95% de respectively. Alternatively, tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate may be converted selectively to tert-butyl anti-(2S,3S,alphaS)-2-azido-3-N-benzyl-N-alpha-methylbenzylaminobutanoate by aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S,3S,alphaS)-2-azido-3-aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S,3S)-diaminobutanoic acid in 98%, de and 98% ee. The asymmetric synthesis of the diastereomeric syn-(2R,3S)-diaminobutanoic acid (98% de and 98% ee) was accomplished via functional group manipulation of tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate in a protocol involving azide inversion of tert-butyl (2S,3S)-2-mesyloxy-3-N-Boc-butanoate and subsequent deprotection.


Unravelling post-ICU mortality: predictors and causes of death.
To study the characteristics of patients dying in the ICU, dying after ICU treatment during the same hospitalization period in general wards and post-ICU hospital survivors. In addition, causes of death and post-ICU mortality (PICUM) predictors were addressed. The present study is a retrospective single centre cohort study in a mixed medical-surgical 12-bed ICU. Patients were divided into three groups: ICU deaths, post-ICU deaths and hospital survivors. Causes of death were determined by an independent review panel of three intensive care physicians. Daly's mortality prediction model was applied in retrospect to evaluate risk of PICUM. Other predictors were also tested for predictive value. In total, 405 patients were included: 146 ICU deaths, 92 post-ICU deaths and 167 survivors (random computerized sample from 680 survivors). ICU mortality was 16.3% and PICUM 10.3%. Sepsis was the most common cause of death in both ICU deaths (48.3%) and post-ICU deaths (30.1%). Multivariate analysis identified age, comorbidities, length of stay in ICU, Acute Physiology and Chronic Health Evaluation II score and a do-not-resuscitate code as independent predictors of PICUM. Based on Daly's mortality prediction model, 63% of patients were discharged with a high risk of PICUM. Of these, 51% actually died. Specificity was low. Causes of deaths were equally distributed among study groups, except for sepsis. Sepsis was more frequently encountered among ICU deaths. Five PICUM predictors were found: age, Acute Physiology and Chronic Health Evaluation II score, length of ICU stay, do-not-resuscitate code and comorbidities. A do-not-resuscitate code during the first 24 h after admission was the most important predictor of PICUM. Prospective research is warranted to evaluate the applicability of PICUM prediction models in individual ICU patients.


Adenocarcinoma arising from an enteric cyst of the posterior mediastinum.
Mediastinal enteric cysts are rare congenital thoracic cysts. The majority of mediastinal enteric cysts occur in infants, while they are rare in adults. Although most of these cysts are benign, surgical resection is sometimes performed, and malignant changes found in enteric cysts are rare. A 52-year-old man was incidentally discovered to have a posterior mediastinal mass and we excised the mass thoracoscopically. Histopathological findings showed an enteric cyst with adenocarcinoma. Comparing the pathological and magnetic resonance imaging (MRI) findings, MRI would help to detect malignant changes in such cysts. Although malignant changes found in mediastinal enteric cysts are extremely rare, clinicians should always keep in mind that those cysts have malignant potential and careful evaluation of MRI would be a clue for surgical indication.


Continuous micellar electrokinetic focusing of neutral species driven by ion concentration polarization.
Ion concentration polarization (ICP) has been broadly applied to accomplish electrokinetic focusing of charged species. However, ICP-based extraction and enrichment of uncharged (neutral) compounds, important for pharmaceutical, biological, and environmental applications, has not yet been reported. Here, we report the ICP-based continuous extraction of two neutral compounds from aqueous solution, by their partition into an ionic micellar phase. Our initial results show that the efficiency of the extraction increases with the concentration of the surfactant comprising the micellar phase, reaching 98 ± 2%, and drops precipitously when the concentration of the target compound exceeds the capacity of the micelles. As a key feature relevant to the practical application of this method, we show that focusing occurs even an order of magnitude below the critical micelle concentration through the local enrichment and assembly of surfactants into micelles, thus minimizing their consumption. To underscore the relevance of this approach to water purification, this method is applied to the extraction of pyrene, a model for polyaromatic hydrocarbons. This approach provides access to a broad range of strategies for selective separation that have been developed in micellar electrokinetic chromatography.


A vision-based masking model for spread-spectrum image watermarking.
We present a perceptual model for hiding a spread-spectrum watermark of variable amplitude and density in an image. The model takes into account the sensitivity and masking behavior of the human visual system by means of a local isotropic contrast measure and a masking model. We compare the insertion of this watermark in luminance images and in the blue channel of color images. We also evaluate the robustness of such a watermark with respect to its embedding density. Our results show that this approach facilitates the insertion of a more robust watermark while preserving the visual quality of the original. Furthermore, we demonstrate that the maximum watermark density generally does not provide the best detection performance.


Alcohol impairs skeletal muscle protein synthesis and mTOR signaling in a time-dependent manner following electrically stimulated muscle contraction.
Alcohol (EtOH) decreases protein synthesis and mammalian target of rapamycin (mTOR)-mediated signaling and blunts the anabolic response to growth factors in skeletal muscle. The purpose of the current investigation was to determine whether acute EtOH intoxication antagonizes the contraction-induced increase in protein synthesis and mTOR signaling in skeletal muscle. Fasted male mice were injected intraperitoneally with 3 g/kg EtOH or saline (control), and the right hindlimb was electrically stimulated (10 sets of 6 contractions). The gastrocnemius muscle complex was collected 30 min, 4 h, or 12 h after stimulation. EtOH decreased in vivo basal protein synthesis (PS) in the nonstimulated muscle compared with time-matched Controls at 30 min, 4 h, and 12 h. In Control, but not EtOH, PS was decreased 15% after 30 min. In contrast, PS was increased in Control 4 h poststimulation but remained unchanged in EtOH. Last, stimulation increased PS 10% in Control and EtOH at 12 h, even though the absolute rate remained reduced by EtOH. The stimulation-induced increase in the phosphorylation of S6K1 Thr(421)/Ser(424) (20-52%), S6K1 Thr(389) (45-57%), and its substrate rpS6 Ser(240/244) (37-72%) was blunted by EtOH at 30 min, 4 h, and 12 h. Phosphorylation of 4E-BP1 Ser(65) was also attenuated by EtOH (61%) at 4 h. Conversely, phosphorylation of extracellular signal-regulated kinase Thr(202)/Tyr(204) was increased by stimulation in Control and EtOH mice at 30 min but only in Control at 4 h. Our data indicate that acute EtOH intoxication suppresses muscle protein synthesis for at least 12 h and greatly impairs contraction-induced changes in synthesis and mTOR signaling.


[Cell cycle clock and its dysregulation in bronchopulmonary cancers].
The cell cycle is the process in which two daughter cells are produced with a strictly identical genetic makeup to the mother cell. Several genes are implicated in activating (oncogenes) or inhibiting (tumor suppressor genes) the cycle. Abnormal gene function can contribute to development of cancer. We describe here the normal cell cycle, its regulation and dysregulation in bronchogenic cancer.


Assessment of Indian wheat germplasm for Septoria nodorum blotch and tan spot reveals new QTLs conferring resistance along with recessive alleles of Tsn1 and Snn3.
The leaf blight diseases, Septoria nodorum blotch (SNB), and tan spot (TS) are emerging due to changing climatic conditions in the northern parts of India. We screened 296 bread wheat cultivars released in India over the past 20 years for seedling resistance against SNB (three experiments) and TS (two experiments). According to a genome-wide association study, six QTLs on chromosome arms 1BL, 2AS, 5BL, and 6BL were particularly significant for SNB across all three years, of which Q.CIM.snb.1BL, Q.CIM.snb.2AS1, Q.CIM.snb.2AS.2, and Q.CIM.snb.6BL appeared novel. In contrast, those on 5BS and 5BL may correspond to Snn3 and Tsn1, respectively. The allelic combination of tsn1/snn3 conferred resistance to SNB, whereas that of Tsn1/Snn3 conferred high susceptibility. As for TS, Tsn1 was the only stably significant locus identified in this panel. Several varieties like PBW 771, DBW 277, and HD 3319, were identified as highly resistant to both diseases that can be used in future wheat improvement programs as resistant donors.


HIV, Sexually Transmitted Infections, and Sexuality in Later Life.
In this article, we review recent evidence indicating that people over the age of 50 years are increasingly at risk of HIV and sexually transmitted infections, and that-thanks to the success of highly active antiretroviral therapies-those infected with HIV are now living into older age. We show that health professionals and society in general have been reluctant to acknowledge sexuality in older adults. Sexuality until recently has been regarded as merely a matter of male potency and sexual function, whereas older women's sexuality and desires have been ignored. Changing patterns of sexual practices, including high rates of divorce and partner change in the older age groups, indicate that focus and concern with sex and sexuality in later life will become part of routine prevention and maintenance of sexual health.


Are Homeostatic States Stable? Dynamical Stability in Morphoelasticity.
Biological growth is often driven by mechanical cues, such as changes in external pressure or tensile loading. Moreover, it is well known that many living tissues actively maintain a preferred level of mechanical internal stress, called the mechanical homeostasis. The tissue-level feedback mechanism by which changes in the local mechanical stresses affect growth is called a growth law within the theory of morphoelasticity, a theory for understanding the coupling between mechanics and geometry in growing and evolving biological materials. This coupling between growth and mechanics occurs naturally in macroscopic tubular structures, which are common in biology (e.g., arteries, plant stems, airways). We study a continuous tubular system with spatially heterogeneous residual stress via a novel discretization approach which allows us to obtain precise results about the stability of equilibrium states of the homeostasis-driven growing dynamical system. This method allows us to show explicitly that the stability of the homeostatic state depends nontrivially on the anisotropy of the growth response. The key role of anisotropy may provide a foundation for experimental testing of homeostasis-driven growth laws.


Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets.
Hypocalcemic vitamin D-resistant rickets is a human genetic disease resulting from target organ resistance to the action of 1,25-dihydroxyvitamin D3. Two families with affected children homozygous for this autosomal recessive disorder were studied for abnormalities in the intracellular vitamin D receptor (VDR) and its gene. Although the receptor displays normal binding of 1,25-dihydroxyvitamin D3 hormone, VDR from affected family members has a decreased affinity for DNA. Genomic DNA isolated from these families was subjected to oligonucleotide-primed DNA amplification, and each of the nine exons encoding the receptor protein was sequenced for a genetic mutation. In each family, a different single nucleotide mutation was found in the DNA binding domain of the protein; one family near the tip of the first zinc finger (Gly----Asp) and one at the tip of the second zinc finger (Arg----Gly). The mutant residues were created in vitro by oligonucleotide directed point mutagenesis of wild-type VDR complementary DNA and this cDNA was transfected into COS-1 cells. The produced protein is biochemically indistinguishable from the receptor isolated from patients.


C9orf72-G4C2 Intermediate Repeats and Parkinson's Disease; A Data-Driven Hypothesis.
Pathogenic C9orf72-G4C2 repeat expansions are associated with ALS/FTD, but not with Parkinson's disease (PD); yet the possible link between intermediate repeat lengths and PD remains inconclusive. We aim to study the potential involvement of these repeats in PD. The number of C9orf72-repeats were determined by flanking and repeat-primed PCR assays, and the risk-haplotype was determined by SNP-array. Their association with PD was assessed in a stratified manner: in PD-patients-carriers of mutations in LRRK2, GBA, or SMPD1 genes (n = 388), and in PD-non-carriers (NC, n = 718). Allelic distribution was significantly different only in PD-NC compared to 600 controls when looking both at the allele with higher repeat's size (p = 0.034) and at the combined number of repeats from both alleles (p = 0.023). Intermediate repeats (20-60 repeats) were associated with PD in PD-NC patients (p = 0.041; OR = 3.684 (CI 1.05-13.0)) but not in PD-carriers (p = 0.684). The C9orf72 risk-haplotype, determined in a subgroup of 588 PDs and 126 controls, was observed in higher frequency in PD-NC (dominant model, OR = 1.71, CI 1.04-2.81, p = 0.0356). All 19 alleles within the risk-haplotype were associated with higher C9orf72 RNA levels according to the GTEx database. Based on our data, we suggest a model in which intermediate repeats are a risk factor for PD in non-carriers, driven not only by the number of repeats but also by the variants' genotypes within the risk-haplotype. Further studies are needed to elucidate this possible role of C9orf72 in PD pathogenesis.


Pearls and pitfalls of intraarterial chemotherapy for retinoblastoma.
Retinoblastoma is a deadly eye cancer in children, leading to death in 50%-70% of children in undeveloped nations who are diagnosed with it. This malignancy is the most common intraocular tumor in childhood worldwide. The good prognosis in developed nations is related to early detection and advanced treatments. With the advent of intraarterial chemotherapy, neurosurgeons have taken a central role in the treatment of this pediatric condition. Intraarterial chemotherapy is a novel treatment for retinoblastoma whereby chemotherapeutic agents are precisely delivered into the ophthalmic artery, minimizing systemic toxicity. This procedure has shown impressive results and has allowed a dramatic decrease in the rate of enucleation (eye removal) in advanced and refractory retinoblastoma. Recent reports have raised some concerns about the risk of ocular vasculopathy, radiation-related toxicity, and the potential for metastatic disease after intraarterial chemotherapy. In the authors' experience of more than 3 years, tumor control is excellent with globe salvage at 67% and vascular events less than 5%, mostly related to improvement in technique. The role of this novel approach in the management of retinoblastoma has yet to be defined. As more centers are adopting the technique, the topic will decidedly become the focus of intensive future research. In this paper, the authors review and discuss current data regarding intraarterial chemotherapy for retinoblastoma.


Basis for physician recommendations for adjuvant radioiodine therapy in early-stage thyroid carcinoma: principal findings of the Canadian-American thyroid cancer survey.
To explore physician recommendations regarding radioiodine remnant ablation (RRA) as adjuvant treatment in early-stage well-differentiated thyroid carcinoma (WDTC), their rationale for administration of RRA, and their willingness to involve patients' opinions in decision making about the use of RRA. We surveyed a representative sample of specialty physicians in Canada and the United States and asked survey participants whether they would recommend adjuvant RRA after thyroidectomy for a 1.6-cm papillary thyroid carcinoma (Likert scale of agreement responses from 1 to 7; strong agreement >or=6). Factor analysis was performed to explore the rationale for recommendations. We asked whether physicians accepted the role of patients' preferences in decision making about administration of RRA, and backward conditional logistic regression analysis was used to identify predictors of strong acceptance. The effective response rate for the survey was 56.3% (486 of 864), with 62.8% (295 of 470 respondents) strongly recommending RRA. Strong RRA recommendations were founded in opinions that RRA (1) decreases WDTC-related mortality and recurrence and (2) facilitates WDTC follow-up at low risk of adverse effects. Approximately a third of the survey respondents (152 of 474) strongly agreed with incorporation of patients' preferences in decision making regarding the use of RRA. Physicians without firm convictions about the efficacy of RRA in decreasing disease-related outcomes and those practicing in the United States were most likely to indicate strong support for incorporating patients' preferences in decision making about RRA. The recommendations of physicians regarding use of adjuvant RRA are founded in beliefs in intervention efficacy and follow-up practices. Physicians in medical practice in the United States and those without strong convictions about RRA efficacy are most likely to incorporate patients' views in individualizing decisions about RRA therapy.


Rho-independent termination: dyad symmetry in DNA causes RNA polymerase to pause during transcription in vitro.
Termination of transcription by RNA polymerase at rho-independent sites appears to depend primarily upon two structural features, a region of GC-rich dyad symmetry in the DNA preceding the stop point and a stretch of uridines at the 3' end of the transcript. The possibility that the former might be responsible for slowing elongation prompted us to perform a kinetic analysis of transcription across the leader and terminator regions of the E. coli tryptophan (trp) operon. Regions where the elongation rate is dramatically slowed or stopped are identifiable because they generate discrete transcript hands on a gel. Species derived from pause sites, unlike those resulting from termination sites, are transient and detectable only within the first two minutes of transcription, since polymerase eventually resumes elongation. At two mutant trp attenuator sites (trp a135 and trp a1419), where termination is incomplete or absent in vitro, a substantial pause is nevertheless observed. Likewise, a significant pause occurs at trp t, the termination site at the end of the operon. Our experiments also reveal a major pause site at about position 90 in the trp leader sequence, just past a region of dyad symmetry. The RNA hairpin corresponding to this site is U-rich, and pausing is strongly enhanced by incorporation of BrUTP. In contrast, this analog does not affect pausing at the attenuator or terminator sites with hairpins that are GC-rich. These results strongly support the hypothesis that pausing of the polymerase is an obligatory prelude to rho-independent termination. Moreover, the termination event evidently results from consecutive but discrete responses to separate structural features of these sites.


Inflammation-related genetic variations and survival in patients with advanced non-small cell lung cancer receiving first-line chemotherapy.
Accurate prognostic prediction is challenging for patients with advanced-stage non-small cell lung cancer (NSCLC). We systematically investigated genetic variants within inflammation pathways as potential prognostic markers for advanced-stage NSCLC patients treated with first-line chemotherapy. A discovery phase in 502 patients and an internal validation phase in 335 patients were completed at the MD Anderson Cancer Center. External validation was performed in 371 patients at Harvard University. A missense single-nucleotide polymorphism (SNP) in the gene encoding the major histocompatibility complex class II, DO-β chain (HLA-DOB:rs2071554), predicted to influence protein function, was significantly associated with poor survival in the discovery (hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02-2.09), internal validation (HR: 1.51; 95% CI: 1.02-2.25), and external validation (HR: 1.52; 95% CI: 1.01-2.29) populations. KLRK1:rs2900420 was associated with reduced risk in the discovery (HR: 0.76; 95% CI: 0.60-0.96), internal validation (HR: 0.77; 95% CI: 0.61-0.99), and external validation (HR: 0.80; 95% CI: 0.63-1.02) populations. A strong cumulative effect on overall survival was observed for these SNPs. Genetic variations in inflammation-related genes could have potential to complement prediction of prognosis.


Changes in nerve conduction velocity after six weeks of glucoregulation with portable insulin infusion pumps.
Near normal glucoregulation was maintained in 10 patients with insulin-dependent (type I) diabetes mellitus for 6 wk with preprogrammed continuous subcutaneous insulin infusion using a portable battery-powered infusion pump (CSII). This form of therapy resulted in a statistically significant increase in motor nerve conduction velocity in the median and peroneal nerves compared with baseline values. There was no significant change in the motor nerve conduction velocity in the ulnar nerve or in the sensory nerve conduction studies. No changes occurred in five additional patients studied in similar fashion while on a conventional insulin regimen. These results suggest that the prevention of sustained hyperglycemia with CSII could theoretically result in the prevention of diabetic neuropathy. However, only long-term studies of CSII will provide the information necessary to determine the clinical relevance of the findings.


Cloning, Expression, and Characterization of a Novel Thermophilic Monofunctional Catalase from Geobacillus sp. CHB1.
Catalases are widely used in many scientific areas. A catalase gene (Kat) from Geobacillus sp. CHB1 encoding a monofunctional catalase was cloned and recombinant expressed in Escherichia coli (E. coli), which was the first time to clone and express this type of catalase of genus Geobacillus strains as far as we know. This Kat gene was 1,467 bp in length and encoded a catalase with 488 amino acid residuals, which is only 81% similar to the previously studied Bacillus sp. catalase in terms of amino acid sequence. Recombinant catalase was highly soluble in E. coli and made up 30% of the total E. coli protein. Fermentation broth of the recombinant E. coli showed a high catalase activity level up to 35,831 U/mL which was only lower than recombinant Bacillus sp. WSHDZ-01 among the reported catalase production strains. The purified recombinant catalase had a specific activity of 40,526 U/mg and K m of 51.1 mM. The optimal reaction temperature of this recombinant enzyme was 60°C to 70°C, and it exhibited high activity over a wide range of reaction temperatures, ranging from 10°C to 90°C. The enzyme retained 94.7% of its residual activity after incubation at 60°C for 1 hour. High yield and excellent thermophilic properties are valuable features for this catalase in industrial applications.


Fluid hydration to prevent post-ERCP pancreatitis in average- to high-risk patients receiving prophylactic rectal NSAIDs (FLUYT trial): study protocol for a randomized controlled trial.
Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost-effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer's solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs. EudraCT: 2015-000829-37 . Registered on 18 February 2015. 13659155 . Registered on 18 May 2015.


Phosphorylation at the D53 but Not the T65 Residue of CovR Determines the Repression of rgg and speB Transcription in emm1- and emm49-Type Group A Streptococci.
CovR/CovS is a two-component regulatory system in group A Streptococcus and primarily acts as a transcriptional repressor. The D53 residue of CovR (CovRD53) is phosphorylated by the sensor kinase CovS, and the phosphorylated CovRD53 protein binds to the intergenic region of rgg-speB to inhibit speB transcription. Nonetheless, the transcription of rgg and speB is suppressed in covS mutants. The T65 residue of CovR is phosphorylated in a CovS-independent manner, and phosphorylation at the D53 and T65 residues of CovR is mutually exclusive. Therefore, how phosphorylation at the D53 and T65 residues of CovR contributes to the regulation of rgg and speB expression was elucidated. The transcription of rgg and speB was suppressed in the strain that cannot phosphorylate the D53 residue of CovR (CovRD53A mutant) but restored to levels similar to those of the wild-type strain in the CovRT65A mutant. Nonetheless, inactivation of the T65 residue phosphorylation in the CovRD53A mutant cannot derepress the rgg and speB transcription, indicating that phosphorylation at the T65 residue of CovR is not required for repressing rgg and speB transcription. Furthermore, trans complementation of the CovRD53A protein in the strain that expresses the phosphorylated CovRD53 resulted in the repression of rgg and speB transcription. Unlike the direct binding of the phosphorylated CovRD53 protein and its inhibition of speB transcription demonstrated previously, the present study showed that inactivation of phosphorylation at the D53 residue of CovR contributes dominantly in suppressing rgg and speB transcription.IMPORTANCE CovR/CovS is a two-component regulatory system in group A Streptococcus (GAS). The D53 residue of CovR is phosphorylated by CovS, and the phosphorylated CovRD53 binds to the rgg-speB intergenic region and acts as the transcriptional repressor. Nonetheless, the transcription of rgg and Rgg-controlled speB is upregulated in the covR mutant but inhibited in the covS mutant. The present study showed that nonphosphorylated CovRD53 protein inhibits rgg and speB transcription in the presence of the phosphorylated CovRD53in vivo, indicating that nonphosphorylated CovRD53 has a dominant role in suppressing rgg transcription. These results reveal the roles of nonphosphorylated CovRD53 in regulating rgg transcription, which could contribute significantly to invasive phenotypes of covS mutants.


[Mirizzi Syndrome without Cholecystolithiasis].
Mirizzi syndrome is a rare cause of biliary symptoms and jaundice. It describes an obstruction of the common hepatic bile duct by external compression caused by an impacted gallstone in the gallbladder neck or cystic duct. This setting is usually associated with cholecystolithiasis. A 64-year-old caucasian woman with intermittent abdominal pain and newly diagnosed jaundice was admitted to our clinic. An ERC was performed a few weeks earlier because of similar complaints without jaundice. At that time there was no evidence of choledocholithiasis. Now ERC surprisingly showed a gallstone impacted in the cystic duct, leading to an external compression of the common hepatic bile duct (Mirizzi syndrome). Since an endoscopic stone extraction failed, surgical intervention was performed. A laparoscopic cholecystectomy was performed without trans-cystic stone removal. After removal of the bile duct drainage it became evident that the impacted stone was still located in the remaining part of the cystic duct. After successful endoscopic extraction of the impacted stone the patient remained free of symptoms without recurrent jaundice. In rare cases Mirizzi syndrome without cholecystolithiasis can cause biliary symptoms. A close interdisciplinary cooperation is necessary in order to guarantee an excellent therapeutic management.


Chest CT abnormalities in COVID-19: a systematic review.
Computed tomography (CT) of the chest is one of the main diagnositic tools for coronavirus disease 2019 (COVID-19) infection. To document the chest CT findings in patients with confirmed COVID-19 and their association with the clinical severity, we searched related literatures through PubMed, MEDLINE, Embase, Web of Science (inception to May 4, 2020) and reviewed reference lists of previous systematic reviews. A total of 31 case reports (3768 patients) on CT findings of COVID-19 were included. The most common comorbid conditions were hypertension (18.4%) and diabetes mellitus (8.3%). The most common symptom was fever (78.7%), followed by cough (60.2%). It took an average of 5.6 days from symptom onset to admission. The most common chest CT finding was vascular enlargement (84.8%), followed by ground-glass opacity (GGO) (60.1%), air-bronchogram (47.8%), and consolidation (41.4%). Most lung lesions were located in the lung periphery (72.2%) and involved bilateral lung (76%). Most patients showed normal range of laboratory findings such as white blood cell count (96.4%) and lymphocyte (87.2%). Compared to previous published meta-analyses, our study is the first to summarize the different radiologic characteristics of chest CT in a total of 3768 COVID-19 patients by compiling case series studies. A comprehensive diagnostic approach should be adopted for patients with known COVID-19, suspected cases, and for exposed individuals.


Effect of laser pulse energy on orthogonal double femtosecond pulse laser-induced breakdown spectroscopy.
In this paper, the effect of laser pulse energy on orthogonal double femtosecond pulse laser induced breakdown spectroscopy (LIBS) in air is studied. In the experiment, the energy of the probe pulse is changeable, while the pump pulse energy is held constant. At the same time, a systematic study of the laser induced breakdown spectroscopy signal dependence on the inter-pulse delay between the two pulses is performed. It is noted that the double pulse orthogonal configuration yields 2-32 times signal enhancement for the ionic and atomic lines as compared to the single pulse LIBS spectra when an optimum temporal separation between the two pulses is used, while there is no significant signal enhancement for the molecular lines in the studied range of the delay. It is also noted that the dependence of the enhancement factor for ionic and atomic lines on the inter-pulse delay can be fitted by Gaussian function. Furthermore, the electron temperature obtained by the relative line-to-continuum intensity ratio method was used to explain the LIBS signal enhancement.


Using Data to Improve Programs: Assessment of a Data Quality and Use Intervention Package for Integrated Community Case Management in Malawi.
Health Surveillance Assistants (HSAs) have been providing integrated community case management (iCCM) for sick children in Malawi since 2008. HSAs report monthly iCCM program data but, at the time of this study, little of it was being used for service improvement. Additionally, HSAs and facility health workers did not have the tools to compile and visualize the data they collected to make evidence-based program decisions. From 2012 to 2013, we worked with Ministry of Health staff and partners to develop and pilot a program in Dowa and Kasungu districts to improve data quality and use at the health worker level. We developed and distributed wall chart templates to display and visualize data, provided training to 426 HSAs and supervisors on data analysis using the templates, and engaged health workers in program improvement plans as part of a data quality and use (DQU) package. We assessed the package through baseline and endline surveys of the HSAs and facility and district staff in the study areas, focusing specifically on availability of reporting forms, completeness of the forms, and consistency of the data between different levels of the health system as measured through results verification ratio (RVR). We found evidence of significant improvements in reporting consistency for suspected pneumonia illness (from overreporting cases at baseline [RVR=0.82] to no reporting inconsistency at endline [RVR=1.0]; P=.02). Other non-significant improvements were measured for fever illness and gender of the patient. Use of the data-display wall charts was high; almost all HSAs and three-fourths of the health facilities had completed all months since January 2013. Some participants reported the wall charts helped them use data for program improvement, such as to inform community health education activities and to better track stock-outs. Since this study, the DQU package has been scaled up in Malawi and expanded to 2 other countries. Unfortunately, without the sustained support and supervision provided in this project, use of the tools in the Malawi scale-up is lower than during the pilot period. Nevertheless, this pilot project shows community and facility health workers can use data to improve programs at the local level given the opportunity to access and visualize the data along with supervision support.


Isolation and embryonic expression of an abdominal-A-like gene from the lepidopteran, Manduca sexta.
Using sequence homology to the Drosophila Antennapedia gene, we isolated a homeobox-containing gene from the lepidopteran, Manduca sexta. Sequence analysis and in situ hybridizations to tissue sections suggest that the Manduca gene encodes a lepidopteran homologue of the Drosophila Bithorax complex gene abdominal-A. The predicted amino acid sequence of a 76 amino acid region that includes the homeobox and the regions immediately flanking it are identical between the Manduca and Drosophila genes. Northern blots reveal that the manduca abd-A gene is expressed first in the early embryo and continues to be expressed throughout later embryonic and larval stages. In situ hybridizations show that the posterior half of the first abdominal segment marks the anterior border of the Manduca abd-A expression. This expression pattern demonstrates the conservation of parasegments as domains of gene activity in the lepidopteran embryo. The Manduca abd-A expression extends from the posterior half of the first abdominal segment through the tenth abdominal segment, a domain that is greater than that of the Drosophila abd-A expression, and reflects the difference in visible segment number between the two insects.


Video Gaming Disorder and Sport and Exercise in Emerging Adulthood: A Longitudinal Study.
Among the negative consequences of video gaming disorder, decreased participation in sport and exercise has received little attention. This study aimed to assess the longitudinal association between video gaming disorder and the level of sport and exercise in emerging adult men. A questionnaire was completed at baseline and 15-month follow-up by a representative national sample of 4,933 respondents. The seven items of the Game Addiction Scale were used to construct a latent variable representing video gaming disorder. Level of sport and exercise was also self-reported. Cross-lagged path modeling indicated a reciprocal causality between video gaming disorder and the level of sport and exercise, even after adjusting for a large set of confounders. These findings support the need for better promotion of sport and exercise among emerging adults in order to contribute to the prevention of video gaming disorder, and to raise the level of sport and exercise activity in addicted gamers.


Persistent staining of lattice lines after intraoperative trypan blue use in patients with lattice corneal dystrophy.
The aim of this study was to report the persistent staining of corneal lattice lines resulting from the intraoperative use of trypan blue. This is a case series. Four patients with lattice corneal dystrophy (LCD) who underwent either deep anterior lamellar keratoplasty or cataract extraction with intraoperative trypan blue use demonstrated persistent, postoperative trypan staining of lattice lines on slit-lamp examination out to final follow-up (range, 176 to 541 days postoperatively). This case series demonstrates the previously unreported finding that intraoperative trypan blue stains corneal lattice lines in LCD. Trypan blue staining, localized in previous laboratory studies to amyloid deposits, seems to persist for months or longer and may be permanent in human tissue. Although the staining was not visually significant, animal models suggest a stimulatory effect on progression of amyloidosis. Clinicians should be aware of the potential for permanent corneal staining and possible disease progression with the use of intraoperative trypan blue in patients with LCD.


Long noncoding RNAs and their proposed functions in fibre development of cotton (Gossypium spp.).
Long noncoding RNAs (lncRNAs) are transcripts of at least 200 bp in length, possess no apparent coding capacity and are involved in various biological regulatory processes. Until now, no systematic identification of lncRNAs has been reported in cotton (Gossypium spp.). Here, we describe the identification of 30 550 long intergenic noncoding RNA (lincRNA) loci (50 566 transcripts) and 4718 long noncoding natural antisense transcript (lncNAT) loci (5826 transcripts). LncRNAs are rich in repetitive sequences and preferentially expressed in a tissue-specific manner. The detection of abundant genome-specific and/or lineage-specific lncRNAs indicated their weak evolutionary conservation. Approximately 76% of homoeologous lncRNAs exhibit biased expression patterns towards the At or Dt subgenomes. Compared with protein-coding genes, lncRNAs showed overall higher methylation levels and their expression was less affected by gene body methylation. Expression validation in different cotton accessions and coexpression network construction helped to identify several functional lncRNA candidates involved in cotton fibre initiation and elongation. Analysis of integrated expression from the subgenomes of lncRNAs generating miR397 and its targets as a result of genome polyploidization indicated their pivotal functions in regulating lignin metabolism in domesticated tetraploid cotton fibres. This study provides the first comprehensive identification of lncRNAs in Gossypium.


Functional expression of a vacuolar-type H+-ATPase in the plasma membrane and intracellular vacuoles of Trypanosoma cruzi.
Acid-loaded Trypanosoma cruzi amastigotes and trypomastigotes regained normal cytoplasmic pH (pHi), as measured in cells loaded with 2',7'-bis-(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), by a process that was sensitive to bafilomycin A1 at concentrations comparable to those that inhibited vacuolar (V) H+-ATPases from different sources. Steady-state pHi was also decreased by similar concentrations of bafilomycin A1 in a concentration-dependent manner. The efflux of H+ equivalents from amastigotes and trypomastigotes was measured by following changes in the fluorescence of extracellular BCECF. Basal H+ extrusion in the presence of glucose was 15.4+/-2.8 (S.D.) nmol of H+/min per 10(8) amastigotes and 6. 37+/-0.8 nmol of H+/min per 10(8) trypomastigotes. Bafilomycin A1 treatment significantly decreased the efflux of H+ equivalents by amastigotes (8.9+/-2.2 nmol of H+/min per 10(8) cells), but not by trypomastigotes (5.1+/-1.7 nmol of H+/min per 10(8) cells). The localization of the V-H+-ATPase of T. cruzi was investigated by immunocytochemistry. Confocal and electron microscopy indicated that, in addition to being located in cytoplasmic vacuoles, the V-H+-ATPase of different stages of T. cruzi is also located in the plasma membrane. However, no labelling was detected in the plasma membrane lining the flagellar pocket of the different developmental stages. Surface localization of the V-H+-ATPase was confirmed by experiments involving the biotinylation of cell surface proteins and immunoprecipitation with antibodies against the V-H+-ATPase. Taken together, the results are consistent with the presence of a functional V-H+-ATPase in the plasma membrane of amastigotes and with an important role for intracellular acidic compartments in the maintenance of pHi in different stages of T. cruzi.


[Dilation of the ventriculus terminalis, an infrequent cause of lower back pain. Magnetic resonance findings].
Ventriculus terminalis is the name given to a congenital disorder that consists in the appearance of a small oval ependymal cystic cavity in the conus medullaris. It is formed during embryogenesis as a result of the differentiation between the canalisation and regression of the spinal cord. The aim of this study is to describe the findings obtained by magnetic resonance (MR) imaging concerning the dilation of the ventriculus terminalis in a symptomatic patient. A 41-year-old female with a three-year history of lower back pain and irradiated pain in the left leg, together with paresthesias. The physical exploration revealed hypoesthesia with a low level of sensitivity in D12, L1 and L2. MR images revealed the presence of a cystic lesion located in the conus medullaris, with a well defined outline, and which was not enhanced following contrast IV. The ventriculus terminalis is the ependymal cavity that lies in the conus medullaris. It may present an abnormal dilation and we need to know of its existence, where it is typically located and its signal characteristics in MR in order to be able to diagnose and differentiate it from cystic tumours situated in the same place, which can display a similar appearance in MR images. The therapeutic management of these patients will depend on their clinical progress. MR scanning is fundamental for diagnosing and monitoring symptomatic patients.


Effects of repetitive transcranial magnetic stimulation combined with cognitive training on resting-state brain activity in Alzheimer's disease.
Repetitive transcranial magnetic stimulation (rTMS) is a promising tool to modulate brain plasticity, but the neural basis has been little addressed. The purpose was to investigate the effects of rTMS on resting-state brain activity in patients with Alzheimer's disease (AD). Seventeen patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS combined with cognitive training (real group, n = 9); (2) sham rTMS with cognitive training (sham group, n = 8). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex and then the left lateral temporal lobe for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment and resting-state functional magnetic resonance imaging (rsfMRI) before and after treatment. The fractional amplitude of low frequency fluctuation (fALFF) of rsfMRI data in real group were: (1) compared to sham; (2) correlated with rTMS-induced cognitive alterations. Significantly increased fALFF in right cerebellum/declive, left lingual/cuneus and left cingulate gyrus, as well as decreased fALFF in left middle frontal gyrus were found after 10 Hz rTMS, but not after sham stimulation. Using these suprathreshold regions, we found that rTMS increased functional connectivity between the right cerebellum/declive and left precentral/postcentral gyrus. The fALFF increase in left lingual/cuneus and right cerebellum/declive was associated with significant improvement in cognitive function. rTMS combined with cognitive training induced increased low frequency fluctuation neural oscillations and functional connectivity in brain regions subserving cognition, suggesting a possible neuronal mechanism of the beneficial effects of rTMS.


Structural comparison of tRNA m(1)A58 methyltransferases revealed different molecular strategies to maintain their oligomeric architecture under extreme conditions.
tRNA m(1)A58 methyltransferases (TrmI) catalyze the transfer of a methyl group from S-adenosyl-L-methionine to nitrogen 1 of adenine 58 in the T-loop of tRNAs from all three domains of life. The m(1)A58 modification has been shown to be essential for cell growth in yeast and for adaptation to high temperatures in thermophilic organisms. These enzymes were shown to be active as tetramers. The crystal structures of five TrmIs from hyperthermophilic archaea and thermophilic or mesophilic bacteria have previously been determined, the optimal growth temperature of these organisms ranging from 37°C to 100°C. All TrmIs are assembled as tetramers formed by dimers of tightly assembled dimers. In this study, we present a comparative structural analysis of these TrmIs, which highlights factors that allow them to function over a large range of temperature. The monomers of the five enzymes are structurally highly similar, but the inter-monomer contacts differ strongly. Our analysis shows that bacterial enzymes from thermophilic organisms display additional intermolecular ionic interactions across the dimer interfaces, whereas hyperthermophilic enzymes present additional hydrophobic contacts. Moreover, as an alternative to two bidentate ionic interactions that stabilize the tetrameric interface in all other TrmI proteins, the tetramer of the archaeal P. abyssi enzyme is strengthened by four intersubunit disulfide bridges. The availability of crystal structures of TrmIs from mesophilic, thermophilic or hyperthermophilic organisms allows a detailed analysis of the architecture of this protein family. Our structural comparisons provide insight into the different molecular strategies used to achieve the tetrameric organization in order to maintain the enzyme activity under extreme conditions.


[Dana Point: what is new in the treatment of pulmonary hypertension?].
The treatment algorithm that has recently been developed at the 4th World Conference on Pulmonary Hypertension (PH) in Dana Point will contain a number of important innovations for patients with pulmonary arterial hypertension (PAH), but also for those with other forms of PH. In PAH patients, a targeted therapy with ERA or PDE5 inhibitors is now recommended for patients in functional class II. Combination therapy (ERA and/or PDE5i and/or prostanoids) is proposed if the clinical response to monotherapy is not adequate. In addition, supervised training programs are recommended for patients with PAH. For other forms of PH such as PH due to left heart disease or chronic lung disease, it remains valid that the underlying disease should be treated as efficiently as possible. However, a targeted PAH therapy may be beneficial in selected patients with "out of proportion PH", but these treatments should exclusively be initiated in expert centers. Pulmonary endarterectomy (PEA) remains the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH). If patients are inoperable and/or if surgical treatment is not an option, targeted PAH therapy may be considered, but these patients should at present be included into clinical trials. Since there is currently no cure for PH/PAH, further development and progress in medical treatment are highly desirable. A number of promising novel compounds are currently under investigation. These include sGC stimulators, tyrosine kinase inhibitors, and serotonin antagonists.


Identifying deprived areas using indices from the 1991 census and information about the recipients of community charge and council tax benefit.
To assess the level of agreement between those small areas selected as materially deprived by indicators derived from the 1991 census and those indicators derived from local authority benefit data. Census indices of deprivation and local authority benefits data were collected, compiled, and correlated for three districts in Yorkshire at enumeration district (ED) level. The composition of the "most deprived" quintiles of pairs of indicators was compared. Data were obtained from the 1991 census for the Bradford, Kirklees, and Rotherham districts. Community charge benefit and council tax benefit data were also obtained for all claimants in the three districts. Correlation coefficients between indicators of deprivation from the census and from the benefits data were shown to be quite high. However, the composition of EDs in the highest quintiles of pairs of indicators showed marked differences. Census indicators of deprivation and local authority benefits data select broadly similar groups of "deprived" EDs. Where deprivation indicators disagree is in the composition of specific quintiles which is due partly to methodological differences in the construction of the indicators, partly to deficiencies of the benefit data, and partly to the different aspects of deprivation which the various indicators measure.


Supraclinoid Internal Carotid Artery Aneurysm Clipping Complicated by Aneurysm Dome Origin of the Anterior Choroidal Artery: 2-Dimensional Operative Video.
Supraclinoid internal carotid artery (ICA) aneurysms most commonly arise at the origin of the posterior communicating or anterior choroidal artery. The unique angioarchitecture presented in this case involved the anterior choroidal artery (AChA) originating from the dome of a supraclinoid ICA aneurysm. Treatment is associated with high morbidity because of the eloquent parenchyma perfused by the AChA. Therefore, the preservation of flow within the AChA during clipping is paramount. Anterior choroidal syndrome, comprising hemiplegia, hemianesthesia, and hemianopsia, conveys a significant morbidity. This syndrome is observed in the setting of AChA sacrifice and can be observed in a delayed manner after clipping. Anterior choroidal syndrome is of uncertain etiology but is associated with AChA infarction. This patient presented with tinnitus and was found to have an incidental supraclinoid ICA aneurysm with AChA originating from the aneurysmal dome. A right orbitozygomatic craniotomy was performed for a transsylvian approach to the aneurysm. A fenestrated clip was applied to occlude the aneurysmal portion of the ICA up to the point of AChA origin. A curved clip was then used to occlude the AChA segment of the aneurysm, providing patency to the AChA takeoff along the ICA. Patency of the AChA and ICA was confirmed with intraoperative angiography, and the patient had a favorable clinical outcome. This case exemplified an excellent surgical clipping of a challenging supraclinoid ICA aneurysm involving the need to preserve a vessel off the aneurysm dome. The patient gave informed consent for surgery and video recording. Institutional review board approval was deemed unnecessary. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.


Correlations between computerized tomography of the head and motor developmental disturbances of children with cerebral palsy.
Two hundred and eight-two children with cerebral palsy (C.P.) and thirty-seven normal children were studied by computerized tomography (C.T.) of the head for finding out the correlations between the organic damage of the brain and the motor developmental disturbance. The abnormal findings of C.T. were: enlargement of the ventricular system, high density area, low density area and porencephalus, enlargement of the sulcus and anomaly of the medial structure. Enlargement of the ventricular system seemed to have correlation with spasticity; the portion and the extent of the enlargement corresponded to the affected extremities and the severity of the spasticity. Children of other types also showed various abnormal C.T. findings but, in general, less than that of spastic types. The prognosis of the motor development of C.P. children cannot be predicted by serial C.T. examinations strictly, because early treatment could cause improvement to that of these children. However, it is of worthy notice that C.T. is an effective method of helping to diagnose the motor developmental disturbance in earlier childhood.


Acute intraoperative brain herniation during elective neurosurgery: pathophysiology and management considerations.
To describe operative procedures, pathophysiological events, management strategies, and clinical outcomes after acute intraoperative brain herniation during elective neurosurgery. Review of clinical diagnoses, operative events, postoperative CT findings, intracranial pressure, and arterial blood pressure changes and outcomes in a series of patients in whom elective neurosurgery had to be abandoned because of severe brain herniation. Acute intraoperative brain herniation occurred in seven patients. In each patient subarachnoid or intraventricular haemorrhage preceded the brain herniation. The haemorrhage occurred after intraoperative aneurysm rupture either before arachnoidal dissection (three) or during clip placement (one); after resection of 70% of a recurrent hemispheric astroblastoma; after resection of a pineal tumour; and after a stereotactic biopsy of an AIDS lesion. In all patients the procedure was abandoned because of loss of access to the intracranial operating site, medical measures to control intracranial pressure undertaken (intravenous thiopentone), an intraventricular catheter or Camino intracranial pressure monitor inserted, and CT performed immediately after scalp closure. The patients were transferred to an intensive care unit for elective ventilation and multimodality physiological monitoring. Using this strategy all patients recovered from the acute ictus and no patient had intracranial pressure > 35 mm Hg. Although one patient with an aneurysm rebled and died three days later the other six patients did well considering the dramatic and apparently catastrophic nature of the open brain herniation. There are fundamental differences in the pathophysiological mechanisms, neuroradiological findings, and outcomes between open brain herniation occurring in post-traumatic and elective neurosurgical patients. The surprisingly good outcomes in this series may have occurred because the intraoperative brain herniation was secondary to extra-axial subarachnoid or intraventricular haemorrhage rather than intraparenchymal haemorrhage or acute brain oedema. Expeditious abandonment of the procedure and closure of the cranium may also have contributed to the often very satisfactory clinical outcome.


Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma.
We examined the utility of post-therapy surveillance imaging in a large, prospectively enrolled cohort of patients with diffuse large B-cell lymphoma (DLBCL) from the United States and confirmed our results in an independent cohort of patients from France. Patients with newly diagnosed DLBCL and treated with anthracycline-based immunochemotherapy were identified from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence and the Léon Bérard Cancer Center, Lyon, France. In those with relapse, details at relapse and outcomes were abstracted from records. 680 individuals with DLBCL were identified from the MER, 552 (81%) of whom achieved remission after induction. 112 of the 552 patients (20%) suffered a relapse. The majority (64%) of relapses were identified before a scheduled follow-up visit. Surveillance imaging detected DLBCL relapse before clinical manifestations in nine out of 552 patients (1.6%) observed after therapy. In the Lyon cohort, imaging identified asymptomatic DLBCL relapse in four out of 222 patients (1.8%). There was no difference in survival after DLBCL relapse in patients detected at scheduled follow-up versus before scheduled follow-up in both the MER (P = .56) and Lyon cohorts (P = .25). The majority of DLBCL relapses are detected outside of planned follow-up, with no difference in outcome in patients with DLBCL detected at a scheduled visit compared with patients with relapse detected outside of planned follow-up. These data do not support the use of routine surveillance imaging for follow-up of DLBCL.


Intermittent hypoxia regulates vasoactive molecules and alters insulin-signaling in vascular endothelial cells.
Vascular dysfunction and insulin resistance (IR) are associated with obstructive sleep apnea (OSA), which is characterized by frequent episodes of nocturnal intermittent hypoxia (IH). While it is recognized that the balance between vasoconstrictive (endothelin-1) and vasodilatory molecules (nitric oxide, NO) determine vascular profile, molecular mechanisms contributing to vascular dysfunction and IR in OSA are not completely understood. Caveolin-1 is a membrane protein which regulates endothelial nitric oxide synthase (eNOS) activity which is responsible for NO generation and cellular insulin-signaling. Hence, we examined the effects of IH on caveolin-1, eNOS, and endothelin-1 in human coronary artery endothelial cells in the context of IR. Chronic 3-day IH exposure up-regulated caveolin-1 and endothelin-1 expression while reducing NO. Also, IH altered insulin-mediated activation of AKT but not ERK resulting in increased endothelin-1 transcription. Similarly, caveolin-1 overexpression attenuated basal and insulin-stimulated NO synthesis along with impaired insulin-dependent activation of AKT and eNOS, with no effect on insulin-stimulated ERK1/2 phosphorylation and endothelin-1 transcription. Our data suggest that IH contributes to a vasoconstrictive profile and to pathway-selective vascular IR, whereby insulin potentiates ET-1 expression. Moreover, IH may partly mediate its effects on NO and insulin-signaling via upregulating caveolin-1 expression.


Mouse urothelial cells in early postnatal development--proliferation and apical plasma membrane specialization.
The purpose of this work was to investigate proliferation and differentiation of the mouse urothelial cells from the day of birth until the 5th postnatal day. The expression of proliferating cell nuclear antigen (PCNA) was studied immunocytochemically and the differentiation of apical plasma membrane of superficial cells was analysed by scanning microscopy. It was established that proliferation activity is very high during all five days since PCNA positive cells are seen in the superficial and in basal cell layer of the urothelium. Results of scanning microscopy show that the differentiation of superficial urothelial cells is a nonsynchronous process, which gradually progresses from the day of birth and leads into homogeneous population of terminally differentiated superficial cells on the 5th postnatal day.


The polar ionosphere of venus near the terminator from early pioneer venus orbiter radio occultations.
Fourteen profiles of electron density in the ionosphere of Venus were obtainecd by the dual-frequency radio occulation method with the Pioneer Venus orbiter between 5 and 30 December 1978. The solar zenith angles for these measurements were between about 85 degrees and 92 degrees , and the latitudes ranged from about 81 degrees to 88 degrees (ecliptic north). In addition to the expected decreasein peak electron density from about 1.5 x 10(3) to 0.5 x 10(3) per cubic centimeter with increasing solar zenith angle, a region of almost constant electron density above about 250 kilometers was observed. The ionopause height varies from about 300 to 700 kilometers and seems to be influenced by diurnal changes in solar wind conditions. The structures of the profiles are consistent with models in which O(2)(+) dominates near the ionization peak and is replaced by O(+) at higher altitudes.


Criteria for the selection of single nucleotide polymorphisms in pathway pharmacogenetics: TNF inhibitors as a case study.
Pharmacogenetics aims to identify genetic variation to predict drug response or to establish an individual optimal dose. Classically, explorative pharmacogenetic studies are performed concerning a limited number of SNPs in genes encoding enzymes involved in the drug's metabolic route. Alternatively, potential markers across the genome are elucidated by the performance of the hypothesis-free genome-wide method. Besides their successful use, both methods provide substantial disadvantages. A solution toward these difficulties is the pathway pharmacogenetic approach, which considers variability in the entire pathway without restricting the analysis to only one gene. In this article, we present selection criteria for this approach to effectively explore potential associating SNPs. As an illustration, the method is applied to the biological adalimumab as a case study.


Negative Symptoms in Schizophrenia: Where We have been and Where We are Heading.
This review traces the history of negative symptom profiles in neuropsychiatry from their earliest emergence in the 19th century to the current psychiatric concepts and therapeutic approaches. Recent investigations performing exploratory and confirmatory factor analysis have suggested that negative symptoms are multidimensional, including evidence for at least two distinct negative symptom subdomains: diminished expression and amotivation. Preliminary studies have demonstrated the clinical validity of this distinction. Several potential pathophysiological validating factors based on brain imaging analysis of emotional experiences and expressions in individuals with schizophrenia are examined. Finally, the potential of different treatment strategies, including medications and various psychotherapeutic techniques, to most favorably treat each of these subdomains is discussed.


Sequence analysis of the gamma-globin gene locus from a patient with the deletion form of hereditary persistence of fetal hemoglobin.
The gamma-globin genes from a patient homozygous for a deletion form of hereditary persistence of fetal hemoglobin (HPFH-1) have been cloned and sequenced. The DNA sequence of the patient's gamma-globin genes corresponds to a previously identified sequence framework (chromosome A) with the exception of 10 base changes. Seven of these base changes can be attributed to normal allelic variation generated by small gene conversion events. The remaining three base changes are present in a 0.76 kb HindIII fragment containing a putative enhancer located 3' to the A gamma-globin gene. The same three base changes have also been described in the Seattle variant of nondeletion HPFH. We have analyzed 16 alleles from non-HPFH individuals and five alleles from individuals with nondeletion or deletion HPFH for the presence of these base changes by polymerase chain reaction amplification of cloned or chromosomal DNA and hybridization to allele-specific oligonucleotide probes. Although these base changes were found in an individual with HPFH-2, they were not found in the DNA from two patients with nondeletion HPFH. More importantly, all three base changes were detected in DNA from five non-HPFH individuals and appear to be common in blacks. We conclude that these base changes do not correlate with an HPFH phenotype and that the significant mutation in HPFH-1 is the deletion of over 100 kb of genomic DNA.


Pulmonary microthrombi syndrome in newborn infants with unresponsive persistent pulmonary hypertension.
Some newborn infants with either primary or secondary persistent pulmonary hypertension (PPHN) remain hypoxemic, hypercarbic, and acidotic despite therapeutic efforts. In autopsies of 23 infants who had PPHN, diffuse platelet-fibrin thrombi were present in the pulmonary microcirculation of eight (15.2 +/- 18.1 thrombi/cm2 lung tissue) and absent in 15 (0.2 +/- 0.3 thrombi/cm2 lung tissue), (P less than 0.004). Diagnoses in group A (thrombi) were pneumonia and sepsis (four patients), meconium inhalation (3), and primary PPHN (1); and in group B (no thrombi) pneumonia and sepsis (4), meconium inhalation (4), primary PPHN (4), hyaline membrane disease (2), and diaphragmatic hernia (1). The only significant differences between the two groups were the response to tolazoline infusion as assessed by changes in partial pressure of arterial oxygen (PaO2) and the platelet counts. Group A responded less favorably to tolazoline (14.8 mm Hg vs 83.6 mm Hg; P less than 0.05) and had lower platelet counts (51,000/microliter vs 128,000/microliter) (P less than 0.01) than group B. No significant differences could be detected in Apgar scores, duration or mode of mechanical ventilation, oxygen requirements, arterial blood gas tensions or pH, systemic arterial blood pressure, coagulation profile, amount of blood product transfusions, or intravascular catheter use. Pulmonary microthrombi should be added to the list of mechanisms for PPHN and may explain why some infants do not respond well to therapeutic efforts aimed at vasodilation. Thrombocytopenia and failure to respond to pulmonary vasodilators might suggest the diagnosis.


Primary choriocarcinoma metastasizing to skeletal muscles, presenting as an abdominal wall mass: A rare presentation.
Choriocarcinoma is a highly malignant tumor of the trophoblastic origin. Most cases are present within 1 year of antecedent pregnancy. We present an extremely rare case of choriocarcinoma of the anterior abdominal muscle in a 41-year-old female who presented as mass in anterior abdominal wall 4 months after undergoing a total abdominal hysterectomy with bilateral salpingo oophorectomy for a diagnosis of fibroid uterus. Laparotomy done for the mass revealed it to be an extraperitoneal mass within the rectus muscle that on histopathological examination was confirmed to be primary choriocarcinoma. Computed tomography scan revealed pulmonary metastases and patient was given combination chemotherapy to which she responded well.


Evaluating Current Practices in Shelf Life Estimation.
The current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) methods for determining the supported shelf life of a drug product, described in ICH guidance documents Q1A and Q1E, are evaluated in this paper. To support this evaluation, an industry data set is used which is comprised of 26 individual stability batches of a common drug product where most batches are measured over a 24 month storage period. Using randomly sampled sets of 3 or 6 batches from the industry data set, the current ICH methods are assessed from three perspectives. First, the distributional properties of the supported shelf lives are summarized and compared to the distributional properties of the true shelf lives associated with the industry data set, assuming the industry data set represents a finite population of drug product batches for discussion purposes. Second, the results of the ICH "poolability" tests for model selection are summarized and the separate shelf life distributions from the possible alternative models are compared. Finally, the ICH methods are evaluated in terms of their ability to manage risk. Shelf life estimates that are too long result in an unacceptable percentage of nonconforming batches at expiry while those that are too short put the manufacturer at risk of possibly having to prematurely discard safe and efficacious drug product. Based on the analysis of the industry data set, the ICH-recommended approach did not produce supported shelf lives that effectively managed risk. Alternative approaches are required.


A prospective study of the introduction of complementary foods in contemporary Australian infants: What, when and why?
To accurately establish the extent to which breastfeeding exclusivity and duration and the introduction of foods other than breast milk are congruous with Australian infant feeding guidelines among a cohort of primiparous women and their infants in Australia. The Feeding Queensland Babies Study is primarily a questionnaire-based prospective birth cohort study of infant feeding attitudes and behaviours but also collected significant data on feeding patterns in infancy. These data were extracted from the demographic questionnaire and from questionnaires administered at 4 and 6 months of infant age. Participants were healthy primiparous Australian women aged between 18 and 40 years, recruited by convenience sampling in Queensland, Australia. Data were collected by self-administered questionnaire both online and on paper between October 2010 and September 2011. Breastfeeding initiation in this cohort is high; however, by 4 months of age, 15.4% of mothers had completely ceased any breastfeeding, 28.7% of infants had been given formula and 18.5% had been introduced to baby cereal. By 6 months of age, 98.4% of infants had been introduced to non-milk foods, most commonly at a rate of one new food every 4 to 5 days. Contemporary prospective data on infant feeding have value in describing trends that may influence the health outcomes of a generation of Australian children. Even in this group of relatively well-educated Australian women, premature cessation of breastfeeding and the early introduction of foods other than breast milk to infants demonstrate behaviours not congruous with evidence-based guidelines.


Earth's Bow Shock: Elapsed-Time Observations by Two Closely Spaced Satellites.
Coordinated observations of the earth's bow shock were made as Vela 3A and Explorer 33 passed within 6 earth radii of each other. Elapsed time measurements of shock motion give directly determined velocities in the range 1 to 10 kilometers per second and establish the existence of two regions, one of large amplitude magnetic "shock" oscillations and another of smaller, sunward, upstream oscillations. Each region is as thick as 1 earth radius, or more.


CAR T cells in solid tumors: challenges and opportunities.
CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as "living drugs" presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.


A paradigm shift for cardiovascular outcome evaluation in diabetes: Major adverse cardiovascular events (MACE) to major adverse vascular events (MAVE).
Drugs for diabetes are required to demonstrate cardiovascular safety through CV outcome trials (CVOT). The pre-defined end-points for cardiovascular outcome studies may not be sufficient to capture all clinically relevant atherosclerotic cardio vascular disease (ASCVD) events particularly peripheral arterial disease (PAD). We planned a scoping review and searched database to identify CVOT conducted in population with diabetes measuring lower limb events due to PAD as the primary outcome measure. We also searched CVOT for reported differential cardiovascular outcomes in population with PAD. We identified that CV outcomes are measured as 3 point major adverse cardiovascular outcomes (3P-MACE) that includes nonfatal MI and nonfatal stroke or 4P-MACE that included additional unstable angina which is further expanded to 5P-MACE by the inclusion of hospitalization for heart failure (HHF). These CV end points are captured as surrogate for CV mortality based on the biological plausibility of relation between the surrogate and final outcome from pathophysiological studies. We found the prevalence of PAD is no lesser than other CV events in people with diabetes. Moreover, PAD contributes to the significant morbidity associated with diabetes as a surrogate for mortality. However, none of the CVOT with anti-diabetic drugs include PAD events as primary outcome measure despite the inclusion of 6-25 % participants with PAD in major CVOT. PAD outcomes are objectively measurable with tibial arterial waveforms and clinical end-point as lower extremity amputation. PAD outcomes do improve with treatment including intensive glycemic control and novel oral anticoagulants. We suggest the inclusion of PAD to MACE as a pre-specified outcome for a comprehensive capture of major adverse vascular event in future studies for people with diabetes. MACE should be expanded to include PAD event as major adverse vascular event in cardiovascular outcome studies since PAD is clinically relevant and objectively measurable in diabetes.