Differential diagnosis of hepatic tumors: value of contrast-enhanced harmonic sonography using the newly developed contrast agent, Sonazoid.
To clarify the value of contrast-enhanced harmonic ultrasonography (US) with Sonazoid, a second-generation US contrast agent, in the differential diagnosis of liver tumors compared to dynamic CT. A total of 249 hepatic nodules in 214 patients were studied; these included 177 hepatocellular carcinomas (HCCs), 42 liver metastases, 20 liver hemangiomas, 6 dysplastic nodules and 4 focal nodular hyperplasias (FNHs). After the injection of Sonazoid, nodules were scanned using real-time contrast-enhanced harmonic US in the vascular phases, i.e. the early and late vascular phases, and the Kupffer phase. Six enhancement patterns were identified to be significant for the differential diagnosis of hepatic tumors. In HCCs, the presence of intratumoral vessels supplied from the periphery and fast washout (sensitivity, 96.6%; specificity, 94.4%) were the most typical characteristics. In metastases, the presence of rim-like enhancement with peripheral tumor vessels (sensitivity, 88.1%; specificity, 100%) was the typical pattern. In hemangiomas, the presence of intratumoral hypoperfusion images with globular or cotton wool-like pooling, which continue to the late vascular phase (sensitivity, 90.0%; specificity, 99.6%), was typical. In dysplastic nodules, the presence of portal enhancement without arterial supply in the early vascular phase and the presence of intratumoral uptake in the Kupffer phase (sensitivity, 83.3%; specificity, 100%) were the most typical patterns. In FNHs, the presence of a spoke-wheel pattern in the early vascular phase with dense staining in the late vascular phase, and positive uptake within the nodule in the Kupffer phase (sensitivity, 100%; specificity, 100%) were the most typical patterns. Contrast-enhanced harmonic US with Sonazoid allowed intimate vascular and Kupffer imaging and, therefore, is useful for the differential diagnosis of hepatic tumors.


New bioengineering insights into human neural precursor cell expansion in culture.
Understanding initial cell growth, interactions associated with the process of expansion of human neural precursor cells (hNPCs), and cellular events pre- and postdifferentiation are important for developing bioprocessing protocols to reproducibly generate multipotent cells that can be used in basic research or the treatment of neurodegenerative disorders. Herein, we report the in vitro responses of telencephalon hNPCs grown in a serum-free growth medium using time-lapse live imaging as well as cell-surface marker, aggregate size, and immunocytochemical analyses. Time-lapse analysis of hNPC initial expansion indicated that cell-surface attachment in stationary culture and the frequency of cell-cell interaction in suspension conditions are important for subsequent aggregate formation and hNPC growth. In the absence of cell-surface attachment in low-attachment stationary culture, large aggregates of cells were formed and expansion was adversely affected. The majority of the telencephalon hNPCs expressed CD29, CD90, and CD44 (cell surface markers involved in cell-ECM and cell-cell interactions to regulate biological functions such as proliferation), suggesting that cell-surface attachment and cell-cell interactions play a significant role in the subsequent formation of cell aggregates and the expansion of hNPCs. Before differentiation, about 90% of the cells stained positive for nestin and expressed two neural precursor cells surface markers (CD133 and CD24). Upon withdrawal of growth cytokines, hNPCs first underwent cell division and then differentiated preferentially towards a neuronal rather than a glial phenotype. This study provides key information regarding human NPC behavior under different culture conditions and favorable culture conditions that are important in establishing reproducible hNPC expansion protocols.


Combined external beam irradiation and external regional hyperthermia for locally advanced adenocarcinoma of the prostate.
To determine the safety and efficacy of combined external beam irradiation and external regional hyperthermia in the treatment of adenocarcinoma of the prostate. From 1987 to 1994, 30 patients received combined external beam irradiation and external regional hyperthermia for locally advanced prostate cancer. The results of the 21 patients with newly diagnosed (n = 18) or locally recurrent (n = 3) adenocarcinoma are reported herein. No patient had evidence of distant metastases. Total radiotherapy doses of 65-70 Gy to the prostate were planned using a four-field box technique. Hyperthermia treatments were delivered using an annular phased array microwave device. The treatment goal was to achieve temperatures > or = 42 degrees C in all measured points within the prostate. Of the newly diagnosed patients, 16 out of 18 (89%) had T3 or T4 tumors, 11 out of 18 (61%) had Gleason scores of 7-9, and the mean pretreatment Prostate Specific Antigen (PSA) was 69 ng/ml. The median follow-up of all 21 patients was 36 months. None of the patients achieved the treatment goal of all intratumoral temperatures > or = 42 degrees C. The mean CEM 43 T90 was 2.34 min. The disease-free survival at 36 months is 25%; 12 out of 18 (67%) of the patients have relapsed. The only significant predictor of relapse was pretreatment PSA. There were no complications > Grade 3. In spite of the inability to achieve high tumor temperatures, the relapse-free survival rate in this population of patients with very advanced localized prostate cancer treated with radiation therapy plus hyperthermia compares favorably with most series using radiation therapy alone. Further studies aimed at improving the ability to deliver hyperthermia to the prostate are warranted.


Computer-Aided Three-Dimensional Virtual Surgical Planning in Complex Skull Base Reconstruction for Sphenoid Wing Dysplasia in Neurofibromatosis Type 1.
Unilateral sphenoid dysplasia is a rare but distinctive manifestation of neurofibromatosis type 1, causing pulsatile exophthalmos, decreased vision, and facial deformity. Surgical intervention is required to prevent visual deterioration. However, the reconstruction of a complex cranial base defect while fulfilling cosmetic needs is challenging. The asymmetric anatomy impedes identification and preservation of vital structures, and the use of bone grafts is often unsustainable due to resorption. Here we demonstrate a multimodal technique combining mirror-image-based virtual surgical planning, stereolithography, and neuronavigation to achieve skull base reconstruction and restore facial symmetry in an neurofibromatosis type 1 patient with sphenoid dysplasia. Preoperative surgical planning involved mirror-image simulation based on the unaffected contralateral counterpart and a stereolithographic skull-base model fabricated to design a patient-specific titanium mesh. Surgical reconstruction via the transcranial approach under intraoperative neuronavigation was performed. Immediate resolution of pulsatile proptosis was observed postoperatively. With the help of virtual surgical planning, stereolithography, and neuronavigation, precise and sustainable reconstruction with patient-specific implants can be tailored for a complex skull base defect.


Differences in mood and cortisol by menstrual phase during acute smoking abstinence: A within-subject comparison.
There is evidence that smoking-cessation success differs by menstrual phase and sex hormone levels; however, the biological mechanisms underlying these differences are not clear. One possibility is that variation in cortisol throughout the menstrual cycle and early smoking abstinence may be partly responsible. The goal of this secondary-data analysis was to conduct a within-subject examination of the effects of menstrual phase and smoking abstinence on salivary cortisol and mood. Data are from a controlled crossover trial, in which participants completed 2 testing weeks during their follicular and luteal phases. During each testing week, they smoked ad libitum during the first 2 days and then abstained from smoking during the next 4 days. Salivary cortisol and self-reported mood were collected 5 times on the day before abstinence (D0) and the first (D1) and third (D3) days of abstinence. Participants (n = 125) were, on average (mean ± SE), 29.4 ± 0.6 years old and smoked 12.6 ± 0.5 cigarettes/day. Whereas salivary cortisol varied significantly by time of day (p < .0001) and smoking abstinence (D0 to D1: β = -0.06 ± 0.02 log[ng/ml], p = .0074 and D3: β = -0.05 ± 0.02 log[ng/ml], p = .0117). no significant differences by menstrual phase were observed. Craving increased from D0 to D1 during the follicular phase but decreased in the luteal phase (+0.31 vs. -0.15, β = 0.46 ± 0.19, p = .0162). This work builds on prior observations in demonstrating a decrease in cortisol in acute smoking abstinence and menstrual phase differences in craving. The results provide further evidence that cortisol levels do not vary by menstrual phase in the first few days of abstinence. (PsycINFO Database Record


Clinical and pathologic characteristics of familial prostate cancer in Asian population.
We investigated prevalence of familial and hereditary prostate cancer (PCa) in Asian population, and compared clinical characteristics between familial and sporadic disease. Pedigrees of 1102 patients who were treated for PCa were prospectively acquired. Clinical and pathologic characteristics and biochemical recurrence (BCR)-free survival were compared between familial PCa and sporadic PCa in patients who underwent radical prostatectomy (RP; n = 751). The prevalence of familial, first-degree familial, and hereditary PCa was found to be 8.4%, 6.7%, and 0.9%, respectively; similar result was obtained in patients who underwent RP (8.4%, 6.4%, and 0.9%). Patients with familial PCa were significantly younger than those with sporadic PCa (63.3 vs 65.6 years; P = .015). However, preoperative variables (prostate-specific antigen, clinical stage, biopsy Gleason score [GS], and percentage of positive biopsy cores) and postoperative variables (surgical GS, upgrading rate, pathologic stage, and percentage of tumor volume) did not correlate with family history (P range: .114-.982). Kaplan-Meier analysis of 5-year BCR-free survival revealed no significant difference between sporadic (82.7%), familial (89.4%; P = .594), and first-degree familial (87.1%; P = .774) PCa. Analysis of p53, Bcl-2, Ki67, and other immunohistochemistry biomarkers revealed that only increasing p53 expression and first-degree familial PCa approached significance (P = .059). The prevalence of familial PCa was somewhat lower in the Asian population than in other ethnic groups. Clinical and pathologic variables and selected histologic biomarker abnormalities were not significantly different in patients with and without a family history of PCa. BCR-free survival following RP was also unaffected by family history.


Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer.
To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer. Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m(2) by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m(2) increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed. The dose-limiting toxicities at 60 mg/m(2) given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m(2) dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression. A dose of twice-weekly gemcitabine at 40 mg/m(2) produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.


Sound component duration of healthy human pharyngoesophageal swallowing: a gender comparison study.
Cervical auscultation is a noninvasive technique for studying swallowing that was first used in the 1960s. The aim of our study was to use the numeric acoustic recording technique for analyzing swallowing sound signals in healthy subjects while they ingested a defined volume and consistency of a specific substance. Twenty males and ten females were included in the study and given 10 ml of a barium suspension to swallow. A microphone was placed on the skin overlying the lateral border of the trachea, directly under the inferior border of the cricoid, and connected to a computer. For each sound recording, the total duration of the sound (td), the number (n) of sound components (SC), the duration of each SC (c1, c2, c3,...), and the intervals (i1, i2,...) between the SCs were measured. For all the recordings, the mean durations of acoustic parameters (TDm, C1m, C2m, C3m, I1m, I2m) were calculated and compared by using Student's t test. In the 20 male subjects, the mean acoustic parameters were calculated (MTDm, MC1m, MC2m, MC3m, MI1m, MI2m) and compared with the mean acoustic parameters (FTDm, FC1m, FC2m, FC3m, FI1m, FI2m) in the ten females by using a Wilcoxon nonparametric statistical test. We were able to interpret 80% of the recordings. The TDm was 710 +/- 28 ms. Three main SCs were detected: C1m = 100 +/- 56, C2m = 150 +/- 90, C3m = 80 +/- 54 ms; I1m = 100 +/- 66, I2m = 190 +/- 120 ms. No significant difference in these parameters was observed with respect to gender. This study enabled us to decompose the swallowing sounds into three main SCs and to quantify their normal durations. These results should prove useful for the assessment of sound variations in pathologic conditions.


Broader leaves result in better performance of indica rice under drought stress.
Leaf growth is one of the first physiological processes affected by changes in plant water status under drought. A decrease in leaf expansion rate usually precedes any reduction in stomatal conductance or photosynthesis. Changes in leaf size and stomatal opening are potential adaptive mechanisms, which may help avoid drought by reducing transpiration rate, and can be used to improve rice genotypes in water-saving cultivation. The indica rice cultivar IR64 and four of its near-isogenic lines (NILs; BC(3)-derived lines) unique for leaf size traits, YTK 124 (long leaves), YTK 127 (broad leaves), YTK 205 (short leaves) and YTK 214 (narrow leaves), were compared in this study for changes in leaf growth and its water status. The plants were subjected to two soil water regimes, well-watered and progressive soil drying measured by the fraction of transpirable soil water (FTSW). Applied drought reduced leaf number, total leaf area, specific leaf area, plant biomass, tiller number, plant height, stomatal conductance, amount of water transpired, leaf relative water content, and leaf water potential more in IR64 and the NILs than in the respective controls; nonetheless, transpiration efficiency (TE) was slightly higher under drought than in the well-watered controls. NILs with broader leaves had higher biomass (and its individual components), less stomatal conductance, and higher TE under drought than NILs with narrow and shorter leaves. Under drought, leaf number was positively correlated with tiller number and plant height; nonetheless, root weight and total biomass, water transpired and TE, and plant height and TE were positively correlated with each other. However, a negative correlation was observed between stomatal conductance and the FTSW threshold at which normalized transpiration started to decline during soil drying. Overall, the IR64-derived lines with broader leaves performed better than NILs with narrow and short leaves under drought.


Molecular cloning and immunologic characterization of a novel cDNA coding for progesterone-induced blocking factor.
Previous studies from our laboratory showed that the immunomodulatory effects of progesterone are mediated by a 34-kDa protein, named the progesterone-induced blocking factor (PIBF). Lymphocytes of women with threatened abortion fail to produce this factor. Via inducing a Th2 biased cytokine production and blocking of NK activity, PIBF prevents induced pregnancy loss in mice, suggesting that substitution therapy with PIBF could be useful as an alternative treatment of certain forms of recurrent spontaneous abortions. Our study was aimed at mapping the sequence and structure of PIBF coding cDNA and characterizing the encoded protein product. Screening of a human liver cDNA library revealed a 2765-bp clone with a 2271-bp open reading frame. The PIBF1 cDNA encodes a protein of 757 amino acid residues with an 89-kDa predicted molecular mass, which shows no significant amino acid sequence homology with any known protein. PIBF produced via recombinant technique is recognized by the Ab specific for the secreted lymphocyte PIBF Ab, and possesses the biological activities of the secreted lymphocyte PIBF. The full-length PIBF is associated with the nucleus, whereas secretion of shorter forms, such a 34-kDa protein is induced by activation of the cell. The 48-kDa N-terminal part of PIBF is biologically active, and the part of the molecule, responsible for modulating NK activity is encoded by exons 2-4. These data provide an initial step for exploiting the possible diagnostic and therapeutic potential of this immunomodulatory molecule.


Transcription and Signaling Regulators in Developing Neuronal Subtypes of Mouse and Human Enteric Nervous System.
The enteric nervous system (ENS) regulates gastrointestinal function via different subtypes of neurons, organized into fine-tuned neural circuits. It is not clear how cell diversity is created within the embryonic ENS; information required for development of cell-based therapies and models of enteric neuropathies. We aimed to identify proteins that regulate ENS differentiation and network formation. We generated and compared RNA expression profiles of the entire ENS, ENS progenitor cells, and non-ENS gut cells of mice, collected at embryonic days 11.5 and 15.5, when different subtypes of neurons are formed. Gastrointestinal tissues from R26ReYFP reporter mice crossed to Sox10-CreERT2 or Wnt1-Cre mice were dissected and the 6 populations of cells were isolated by flow cytometry. We used histochemistry to map differentially expressed proteins in mouse and human gut tissues at different stages of development, in different regions. We examined enteric neuronal diversity and gastric function in Wnt1-Cre x Sox6fl/fl mice, which do not express the Sox6 gene in the ENS. We identified 147 transcription and signaling factors that varied in spatial and temporal expression during development of the mouse ENS. Of the factors also analyzed in human ENS, most were conserved. We uncovered 16 signaling pathways (such as fibroblast growth factor and Eph/ephrin pathways). Transcription factors were grouped according to their specific expression in enteric progenitor cells (such as MEF2C), enteric neurons (such as SOX4), or neuron subpopulations (such as SATB1 and SOX6). Lack of SOX6 in the ENS reduced the numbers of gastric dopamine neurons and delayed gastric emptying. Using transcriptome and histochemical analyses of the developing mouse and human ENS, we mapped expression patterns of transcription and signaling factors. Further studies of these candidate determinants might elucidate the mechanisms by which enteric stem cells differentiate into neuronal subtypes and form distinct connectivity patterns during ENS development. We found expression of SOX6 to be required for development of gastric dopamine neurons.


[Usefulness of Fenestrated Catheters for i.v. Contrast Infusion Cardiac CT Angiography for Newborn Patients during the Congenital Heart Disease].
A three-dimensional (3D) image from computed tomography (CT) angiography is a useful method for evaluation of complex anatomy such as congenital heart disease. However, 3D imaging requires high contrast enhancement for distinguishing between blood vessels and soft tissue. To improve the contrast enhancement, many are increasing the injection rate. However, one method is the use of fenestrated catheters, it allows use of a smaller gauge catheter for high-flow protocols. The purpose of this study was to compare the pressure of injection rate and CT number of a 24-gauge fenestrated catheter with an 22-gauge non-fenestrated catheter for i.v. contrast infusion during CT. Between December 2014 and March 2015, 50 newborn patients were randomly divided into two protocols; 22-gauge conventional non-fenestrated catheter (24 newborn; age range 0.25-8 months, body weight 3.6±1.2 kg) and 24-gauge new fenestrated catheter (22 newborn; age range 0.25-12 months, body weight 3.3±0.9 kg). Helical scan of the heart was performed using a 64-detector CT (LightSpeed VCT, GE Healthcare) (tube voltage 80 kV; detector configuration 64×0.625 mm, rotation time 0.4 s/rot, helical pitch 1.375, preset noise index for automatic tube current modulation 40 at 0.625 mm slice thickness). We compared the maximum pressure of injection rate, CT number of aortic enhancement, and CT number of pulmonary artery enhancement between both protocols. The median injection rate, CT number of aortic enhancement, and CT number of pulmonary artery enhancement were 0.9 (0.5-3.4) ml/s, 455.5 (398-659) HU, and 500.0 (437-701) HU in 22-gauge conventional non-fenestrated catheter and 0.9 (0.5-2.0) ml/s, 436.5 (406-632) HU, and 479.5 (445-695) HU in the 24-gauge fenestrated catheter, respectively. There are no significantly different between a 24-gauge fenestrated catheter and 22-gauge non-fenestrated catheters at injection rate and CT number. Maximum pressure of injection rate was lower with 24-gauge non-fenestrated catheters (0.33 kg/cm2) than 22-gauge non-fenestrated catheters (0.55 kg/cm2) (p<0.01Conclusion: A 24-gauge fenestrated catheter performs similarly to an 22-gauge non-fenestrated catheter with respect to i.v. contrast infusion and aortic enhancement levels and can be placed in most subjects whose veins are deemed insufficient for an 22-gauge catheter.


Sit-to-Stand Video Analysis-Based App for Diagnosing Sarcopenia and Its Relationship With Health-Related Risk Factors and Frailty in Community-Dwelling Older Adults: Diagnostic Accuracy Study.
Probable sarcopenia is determined by a reduction in muscle strength assessed with the handgrip strength test or 5 times sit-to-stand test, and it is confirmed with a reduction in muscle quantity determined by dual-energy X-ray absorptiometry or bioelectrical impedance analysis. However, these parameters are not implemented in clinical practice mainly due to a lack of equipment and time constraints. Nowadays, the technical innovations incorporated in most smartphone devices, such as high-speed video cameras, provide the opportunity to develop specific smartphone apps for measuring kinematic parameters related with sarcopenia during a simple sit-to-stand transition. We aimed to create and validate a sit-to-stand video analysis-based app for diagnosing sarcopenia in community-dwelling older adults and to analyze its construct validity with health-related risk factors and frailty. A total of 686 community-dwelling older adults (median age: 72 years; 59.2% [406/686] female) were recruited from elderly social centers. The index test was a sit-to-stand video analysis-based app using muscle power and calf circumference as proxies of muscle strength and muscle quantity, respectively. The reference standard was obtained by different combinations of muscle strength (handgrip strength or 5 times sit-to-stand test result) and muscle quantity (appendicular skeletal mass or skeletal muscle index) as recommended by the European Working Group on Sarcopenia in Older People-2 (EWGSOP2). Sensitivity, specificity, positive and negative predictive values, and area under the curve (AUC) of the receiver operating characteristic curve were calculated to determine the diagnostic accuracy of the app. Construct validity was evaluated using logistic regression to identify the risks associated with health-related outcomes and frailty (Fried phenotype) among those individuals who were classified as having sarcopenia by the index test. Sarcopenia prevalence varied from 2% to 11% according to the different combinations proposed by the EWGSOP2 guideline. Sensitivity, specificity, and AUC were 70%-83.3%, 77%-94.9%, and 80.5%-87.1%, respectively, depending on the diagnostic criteria used. Likewise, positive and negative predictive values were 10.6%-43.6% and 92.2%-99.4%, respectively. These results proved that the app was reliable to rule out the disease. Moreover, those individuals who were diagnosed with sarcopenia according to the index test showed more odds of having health-related adverse outcomes and frailty compared to their respective counterparts, regardless of the definition proposed by the EWGSOP2. The app showed good diagnostic performance for detecting sarcopenia in well-functioning Spanish community-dwelling older adults. Individuals with sarcopenia diagnosed by the app showed more odds of having health-related risk factors and frailty compared to their respective counterparts. These results highlight the potential use of this app in clinical settings. ClinicalTrials.gov NCT05148351; https://clinicaltrials.gov/study/NCT05148351. RR2-10.3390/s22166010.


Improving reversal median computation using commuting reversals and cycle information.
In the past decade, genome rearrangements have attracted increasing attention from both biologists and computer scientists as a new type of data for phylogenetic analysis. Methods for reconstructing phylogeny from genome rearrangements include distance-based methods, MCMC methods, and direct optimization methods. The latter, pioneered by Sankoff and extended with the software suites GRAPPA and MGR, is the most accurate approach, but is very limited due to the difficulty of its scoring procedure--it must solve multiple instances of the reversal median problem to compute the score of a given tree. The reversal median problem is known to be NP-hard and all existing solvers are extremely slow when the genomes are distant. In this paper, we present a new reversal median heuristic for unichromosomal genomes. The new method works by applying sets of reversals in a batch where all such reversals both commute and do not break the cycle of any other. Our testing using simulated datasets shows that this method is much faster than the leading solver for difficult datasets with only a slight accuracy penalty, yet retains better accuracy than other heuristics with comparable speed, and provides the additional option of searching for multiple medians. This method dramatically increases the speed of current direct optimization methods and enables us to extend the range of their applicability to organellar and small nuclear genomes with more than 50 reversals along each edge.


Mechanisms of the Beneficial Effects of Exercise on Brain-Derived Neurotrophic Factor Expression in Alzheimer's Disease.
Brain-derived neurotrophic factor (BDNF) is a key molecule in promoting neurogenesis, dendritic and synaptic health, neuronal survival, plasticity, and excitability, all of which are disrupted in neurological and cognitive disorders such as Alzheimer's disease (AD). Extracellular aggregates of amyloid-β (Aβ) in the form of plaques and intracellular aggregates of hyperphosphorylated tau protein have been identified as major pathological insults in the AD brain, along with immune dysfunction, oxidative stress, and other toxic stressors. Although aggregated Aβ and tau lead to decreased brain BDNF expression, early losses in BDNF prior to plaque and tangle formation may be due to other insults such as oxidative stress and contribute to early synaptic dysfunction. Physical exercise, on the other hand, protects synaptic and neuronal structure and function, with increased BDNF as a major mediator of exercise-induced enhancements in cognitive function. Here, we review recent literature on the mechanisms behind exercise-induced BDNF upregulation and its effects on improving learning and memory and on Alzheimer's disease pathology. Exercise releases into the circulation a host of hormones and factors from a variety of peripheral tissues. Mechanisms of BDNF induction discussed here are osteocalcin, FNDC5/irisin, and lactate. The fundamental mechanisms of how exercise impacts BDNF and cognition are not yet fully understood but are a prerequisite to developing new biomarkers and therapies to delay or prevent cognitive decline.


Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter.
Presynaptic nerve terminals are formed from preassembled vesicles that are delivered to the prospective synapse by kinesin-mediated axonal transport. However, precisely how the various cargoes are linked to the motor proteins remains unclear. Here, we report a transport complex linking syntaxin 1a (Stx) and Munc18, two proteins functioning in synaptic vesicle exocytosis at the presynaptic plasma membrane, to the motor protein Kinesin-1 via the kinesin adaptor FEZ1. Mutation of the FEZ1 ortholog UNC-76 in Caenorhabditis elegans causes defects in the axonal transport of Stx. We also show that binding of FEZ1 to Kinesin-1 and Munc18 is regulated by phosphorylation, with a conserved site (serine 58) being essential for binding. When expressed in C. elegans, wild-type but not phosphorylation-deficient FEZ1 (S58A) restored axonal transport of Stx. We conclude that FEZ1 operates as a kinesin adaptor for the transport of Stx, with cargo loading and unloading being regulated by protein kinases.


Preoperative carcinoembryonic antigen levels correlated with postoperative pathological staging in bronchial carcinoma.
Serum carcinoembryonic antigen (CEA) levels were obtained before operation in 214 patients undergoing diagnostic tests for suspected bronchial carcinoma, and the results correlated with the postoperative, pathological stage of disease. Positive CEA levels (greater than 10 ng/ml) were observed in 40% (8/20) of stage 1, 58.5% (31/53) of stage 2, 85.2% (69/81) of stage 3, and 92.3% (24/26) of stage 4 patients with bronchial carcinoma. Furthermore, the mean CEA levels increased with stage of disease, and the differences between mean levels were found to be significant in stages 1 and 2 versus 3 and 4 (p less than 0.001). This suggests a positive correlation between the preoperative CEA level and tumour burden defined by pathological staging. When the results were compared with the histological type of lung carcinoma, CEA elevations occurred most frequently with adenocarcinoma, followed by undifferentiated and squamous cell carcinoma, reflecting perhaps the origin of this oncofetal antigen from the endodermally derived bronchial mucosa. These data indicate that preoperative serum CEA levels quantitatively reflect the extent of tumour assessed pathologically at operation and confirm the potential usefulness of this antigen as a biological tumour marker in the management of bronchial neoplasms.


Visuospatial reaching preferences of common marmosets (Callithrix jacchus): an assessment of individual biases across a variety of tasks.
Using multiple measures of hand preference, the authors investigated lateralization at an individual level in 21 common marmosets. Despite showing group biases for sensory and communication functions, these same marmosets did not show a group bias in direction of lateralized hand use. Hand preferences were recorded on four novel reaching tasks requiring different levels of visual guidance and postural control. As found for simple food holding (with the same subjects), they displayed strong individual hand preferences but no group bias indicative of handedness. The strength of hand preference was influenced by task demands: stronger preferences were expressed when subjects adopted a suspended posture, and when "successful" versus "unsuccessful" foraging strategies were compared. Comparisons between visuospatial reaching and simple food holding preferences also revealed that half of the subjects displayed a division of function between the hands/hemispheres; subjects displayed opposing preferences in simple and visuospatial reaching, which would be beneficial for the performance of coordinated bimanual tasks. Given the apparent absence of a selective advantage for handedness, the authors suggest that hand preferences may reflect hemispheric dominance of other cognitive domains (i.e., temperament).


Enhancing the effectiveness of community stroke risk screening: a randomized controlled trial.
Stroke risk factors are routinely assessed in community screening programs; however, the rate of patient follow-up for health care once risk factors are identified is known to be low. This study was conducted to test the effectiveness of a brief behavioral telephonic intervention in an ongoing community stroke prevention screening program on health care seeking for stroke risk. A total of 227 participants with 2 or more stroke risk factors were randomly allocated to either an attention control arm or a behavioral intervention arm. The control group received standard information on risk and advice, whereas the intervention group received a brief Health Belief Model telephonic intervention designed to motivate care-seeking. The effect of treatment on the participants who completed a health care visit for stroke risk concerns was assessed using logistic regression. Cox survival analysis was used to compare time to physician visit between the 2 groups. Participants in the intervention arm were 1.85 times more likely to visit a primary care physician than controls. At 3 months, 69.2% of subjects in the intervention arm and 52.9% of those in the controls arm reported a new primary care visit after screening (P = .02), with 56.0% in the intervention arm and 38.4% in the control arm reporting a primary care visit specifically to discuss the stroke screening results (P < .01). Our data indicate that the brief, low-cost, motivational intervention effectively promoted adherence to screening advice and merits further testing.


[Distribution of transferable trimethoprim and gentamicin resistance plasmids in Enterobacteriaceae].
Following the employment of trimethoprim/sulfonamid and gentamicin in the general clinical praxis transferable plasmids with respective resistance function were identified at first in enteric bacteria from sewage before they could be detected in patient strains. Whereas the trimethoprim resistance plasmids represent different incompatibility groups (C, FII, I5, K, M, N, S, U) the gentamicin resistance plasmids are very similar IncM members of 62 MD in size. Therefore a clonal distribution of a particular gentamicin resistance plasmid has to be taken into consideration.


Insertion of MAP4-VP1 peptide into lipid monolayers and bilayers.
Myscibility of dipalmitoylphosphatidylcholine (DPPC) with dipalmitoylphosphatidylglycerol (DPPG), cardiolipine (CL) and dipalmitoylphosphatidylethanolamine (DPPE) was studied using monomolacular layers of different compositions. The influence of MAP4-VP1 peptide construct related to HAV protein in mixed monolayers of the above cited lipid components was determined following penetration kinetics and compression isotherms. Moreover, liposomes with the same composition as monolayers were saturated with ANS or DPH and incubated with MAP4VP1, and polarization values as well as transition temperatures were determined. In general interaction is maximum with DPPC/DPPG mono and bilayers, followed by DPPC/CL. In these systems electrostatic repulsive forces seem to play a strong role.


Deterioration of diabetic patients' knowledge and management skills as determined during outpatient visits.
A checklist of 22 items that diabetic persons need to perform correctly in order to carry out adequate home management was analyzed for 30 patients in an outpatient clinic. Both a recording of correct performance (baseline assessment) and a reassessment 3--17 mo later were obtained for each item included in the study. An 8 1/2% error rate occurred on reassessment. Approximately one-third of the patients had an error rate of 10% or more. No significant relationship was found between the percentage of error and age, interval between assessments, years of diabetes, or past performance on the checklist. Nor did a majority of the errors occur on items that showed an error immediately before the correct baseline assessment. This error rate is less than in reports not including a correct baseline performance. However, it is high enough to indicate that reassessment is needed more frequently than is generally done.


Molecular genetics of acute myeloid leukemia.
Recurring chromosomal abnormalities are detected in most patients with acute myeloid leukemia (AML). They may be associated with a distinct AML FAB subtype or may identify distinct clinicobiological entities within the same FAB subtype. Therefore, cytogenetic investigation has a pivotal role in AML diagnosis. In addition, it is one of the most valuable prognostic determinants of the disease, as recently demonstrated. The development of new molecular techniques, such as reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization, has allowed perfect definition of the chromosome regions containing genes with a crucial role in normal hemopoiesis and leukemia. Understanding the action of such genes provides new insights into AML pathogenesis and has led us to envisage new therapeutic options.


Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells.
Contrary to cell cycle-associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-dependent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks.


Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire: feasibility of utilizing one-day versus seven-day symptom reporting.
Patient-reported outcomes are important measures to include in pulmonary arterial hypertension clinical trials but are not widely utilized in clinical practice. Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire (PAH-SYMPACT) is the only pulmonary arterial hypertension-specific patient-reported outcomes instrument developed and validated in accordance with the US Food and Drug Administration guidance on patient-reported outcomes development. The PAH-SYMPACT tool measures pulmonary arterial hypertension-related symptoms and impact of pulmonary arterial hypertension on daily life. Symptoms are reported each day for seven consecutive days, and the impact of pulmonary arterial hypertension over one week is recalled and reported on day 7; however, daily symptom reporting may overburden patients and healthcare resources, limiting the practicality of PAH-SYMPACT outside of clinical trials. To determine the practicability of an abridged version of PAH-SYMPACT for which all reporting is completed on one day, symptom data from the SYMPHONY trial (NCT01841762; PAH-SYMPACT validation study) were retrospectively analyzed to assess whether symptoms reported on each day correlated with the weekly average and whether one-day symptom scores were sensitive to disease severity. Correlation coefficients comparing the weekly average and individual day symptom scores were mostly high or very high regardless of the day they were measured. Findings were similar when using either Spearman's rank correlation or weighted kappa method. One-day symptom scores differentiated well between World Health Organization functional classes II and III/IV pulmonary arterial hypertension and were sensitive to change in disease severity as measured by the Patient Global Assessment of Disease Severity. These data suggest that the one-day PAH-SYMPACT is feasible and appropriate for routine implementation in clinical practice.


Should Kiribati continue to aim for 100% voluntary non-remunerated blood donation as recommended by the WHO?
Setting: Tungaru Central Hospital Blood Bank Laboratory, Nawerewere, Tarawa, Kiribati. Objective: To determine characteristics, deferrals and reasons for deferral amongst blood donors from 2011 to 2016. Design: A cross-sectional study using routinely collected data. Results: From January 2011 to March 2016, 8531 potential blood donors were registered. For each full year, the proportion of voluntary non-remunerated blood donors (VNRBD) was below 10%, although it increased to 13% in 2015. The overall proportion of blood donors deferred increased each year over the 5-year period, from 44% to 57%, with similar increases in deferrals in VNRBD and family replacement donors (FRD). Among all blood donors, a higher proportion of females than males (59% vs. 43%) and VNRBD than FRD (56% vs. 44%) were deferred (P < 0.001). Deferrals were due to 1) failing the medical questionnaire (53%), 2) having anaemia and/or high white cell count (26%), or 3) transfusion-transmissible infections (21%). More VNRBD were deferred due to failing the medical questionnaire, while more FRD were deferred due to anaemia and/or high white-cell count; the number of deferrals was similar for transfusion-transmissible infections. Conclusion: This 5-year study showed that the proportion of VNRBD is low and deferrals are higher for this group than for FRD. There is a strong case for encouraging both types of donor in the country.


Benzimidazole Derivatives as Novel Zika Virus Inhibitors.
We have synthesized 50 benzimidazole (BMZ) derivatives with 1,2-phenylenediamines and aromatic aldehydes under mild oxidation conditions by using inexpensive, nontoxic inorganic salt sodium metabisulfite in a one-pot condensation reaction and screened their ability to interfere with Zika virus (ZIKV) infection utilizing a cell-based phenotypic assay. Seven BMZs inhibited an African ZIKV strain with a selectivity index (SI=CC50 /EC50 ) of 9-37. Structure-activity relationship analysis demonstrated that substitution at the C-2, N-1, and C-5 positions of the BMZ ring were important for anti-ZIKV activity. The hybrid structure of BMZ and naphthalene rings was a structural feature responsible for the high anti-ZIKV activity. Importantly, BMZs inhibited ZIKV in human neural stem cells, a physiologically relevant system considering the severe congenital anomalies, like microcephaly, caused by ZIKV infection. Compound 39 displayed the highest antiviral efficacy against the African ZIKV strain in Huh-7 (SI>37) and neural stem cells (SI=12). Compound 35 possessed the highest activity in Vero cells (SI=115). Together, our data indicate that BMZs derivatives have to be considered for the development of ZIKV therapeutic interventions.


Human health risk assessment due to global warming--a case study of the Gulf countries.
Accelerated global warming is predicted by the Intergovernmental Panel on Climatic Change (IPCC) due to increasing anthropogenic greenhouse gas emissions. The climate changes are anticipated to have a long-term impact on human health, marine and terrestrial ecosystems, water resources and vegetation. Due to rising sea levels, low lying coastal regions will be flooded, farmlands will be threatened and scarcity of fresh water resources will be aggravated. This will in turn cause increased human suffering in different parts of the world. Spread of disease vectors will contribute towards high mortality, along with the heat related deaths. Arid and hot climatic regions will face devastating effects risking survival of the fragile plant species, wild animals, and other desert ecosystems. The paper presents future changes in temperature, precipitation and humidity and their direct and indirect potential impacts on human health in the coastal regions of the Gulf countries including Yemen, Oman, United Arab Emirates, Qatar, and Bahrain. The analysis is based on the long-term changes in the values of temperature, precipitation and humidity as predicted by the global climatic simulation models under different scenarios of GHG emission levels. Monthly data on temperature, precipitation, and humidity were retrieved from IPCC databases for longitude 41.25 degrees E to 61.875 degrees E and latitude 9.278 degrees N to 27.833 degrees N. Using an average of 1970 to 2000 values as baseline, the changes in the humidity, temperature and precipitation were predicted for the period 2020 to 2050 and 2070 to 2099. Based on epidemiological studies on various diseases associated with the change in temperature, humidity and precipitation in arid and hot regions, empirical models were developed to assess human health risk in the Gulf region to predict elevated levels of diseases and mortality rates under different emission scenarios as developed by the IPCC.The preliminary assessment indicates increased mortality rates due to cardiovascular and respiratory illnesses, thermal stress, and increased frequency of infectious vector borne diseases in the region between 2070 and 2099.


Coping strategies and emotional wellbeing among HIV-infected men and women experiencing AIDS-related bereavement.
AIDS influences the psychological coping not only of the person with the disease but also those close to that individual. Following a death from AIDS, family members and friends may experience atypical bereavement. Bereavement coping challenges can be especially difficult and pronounced for persons who are themselves HIV-positive. The prevalence of AIDS-related bereavement and psychosocial predictors of grief severity were examined in an ethnically diverse sample of 199 HIV-infected men and women. Eighty per cent of HIV-positive respondents had experienced the loss of someone close to AIDS, the majority of whom had sustained multiple and repetitive losses. Two-thirds of the participants who had experienced an AIDS-related loss reported grief symptoms in the past month. Hierarchical regression analyses revealed that grief was most closely associated with emotional suppression and avoiding coping strategies, with residual variance related to depression. Interventions for AIDS-related bereavement that reduce distress and maladaptive ways of coping are needed in order to meet the secondary prevention needs of bereaved people living with HIV/AIDS.


Antiemetic effect of droperidol after ophthalmic surgery.
Postoperative nausea with emesis is an undesirable side effect of general anesthesia in patients who have undergone ophthalmic surgery. The antiemetic effect of intravenous droperidol (Inapsine) was measured in a double-blind, controlled study of 78 patients undergoing general (enflurane [Ethrane]) anesthesia for a variety of ophthalmic procedures. There was a significant difference in the incidence of postoperative nausea and/or emesis in the droperidol-treated group, 13 of 78 (16%) as compared with the control population (37 of 87 [42%]). No complications of droperidol administration were observed. Droperidol may be an effective antiemetic drug if used prophylactically in patients who receive general anesthesia for ophthalmic surgery.


Outcome reporting in randomised controlled trials and meta-analyses of appendicitis treatments in children: a systematic review.
Acute appendicitis is the most common surgical emergency in children. Despite this, there is no core outcome set (COS) described for randomised controlled trials (RCTs) in children with appendicitis and hence no consensus regarding outcome selection, definition and reporting. We aimed to identify outcomes currently reported in studies of paediatric appendicitis. Using a defined, sensitive search strategy, we identified RCTs and systematic reviews (SRs) of treatment interventions in children with appendicitis. Included studies were all in English and investigated the effect of one or more treatment interventions in children with acute appendicitis or undergoing appendicectomy for presumed acute appendicitis. Studies were reviewed and data extracted by two reviewers. Primary (if defined) and all other outcomes were recorded and assigned to the core areas 'Death', 'Pathophysiological Manifestations', 'Life Impact', 'Resource Use' and 'Adverse Events', using OMERACT Filter 2.0. A total of 63 studies met the inclusion criteria reporting outcomes from 51 RCTs and nine SRs. Only 25 RCTs and four SRs defined a primary outcome. A total of 115 unique and different outcomes were identified. RCTs reported a median of nine outcomes each (range 1 to 14). The most frequently reported outcomes were wound infection (43 RCTs, nine SRs), intra-peritoneal abscess (41 RCTs, seven SRs) and length of stay (35 RCTs, six SRs) yet all three were reported in just 25 RCTs and five SRs. Common outcomes had multiple different definitions or were frequently not defined. Although outcomes were reported within all core areas, just one RCT and no SR reported outcomes for all core areas. Outcomes assigned to the 'Death' and 'Life Impact' core areas were reported least frequently (in six and 15 RCTs respectively). There is a wide heterogeneity in the selection and definition of outcomes in paediatric appendicitis, and little overlap in outcomes used across studies. A paucity of studies report patient relevant outcomes within the 'Life Impact' core area. These factors preclude meaningful evidence synthesis, and pose challenges to designing prospective clinical trials and cohort studies. The development of a COS for paediatric appendicitis is warranted.


[A new surgical treatment for syringomyelia, scoliosis, Arnold-Chiari malformation, kinking of the brainstem, odontoid recess, idiopathic basilar impression and platybasia].
Based on medullary traction as responsible for idiopathic syringomyelia (SMI), idiopathic scoliosis (ESCID), Arnold Chiari malformation (ARCH), platybasia (PTB), basilar impression (IMB), odontoid recess (RTO) kinking of the brain stem (KTC) and considering the medullary traction to be transmitted by the filum terminale (FT), a surgical technique for the section of FT (SFT) is described in three cases of SMI, one of ESCID, and one of ARCH with no lumbar dysraphia. A 34-year-old woman with cervico-brachialgias, paresthesias, bilateral babinski and a centro-medullary cavity C3-C7. A 26-year-old male with cervico-brachialgias, hypoestesia in left hemybody, and cervicobulbar cavity. A 19-year-old female with ESCID since the age of 14th, with episodes of reacuting, and 38o of dorsolumbar curvature. A 67-year-old woman with intense headache, hypoesthesia of the hands, paraparesia and ARCH. A 23-year-old man with marked tetraparesia, bilateral babinski, anesthesia of both legs, SMI, ESCID, ARCH and hydrocephaly. After SFT: in the SMIs the thermo-algesic, disesthetic and algic dissociation disappeared. In ESCID there was a reduction to 31o in the curvature in nine months. On ARCH the headaches ceased and there was recovery of touch and paraparesia. SFT is a useful etiological treatment for SMI, ESCID, ARCH. Also, in ESCID it is possible to avoid stress on the medulla due to its surgical reduction.


Washoff behavior of in-sewer deposit in combined sewer system through artificial flushing experiment.
In-sewer deposits in combined sewer systems (CSSs) are closely related with the behavior of first foul flush and combined sewer overflows. However, the research paying attention to the role of in-sewer deposits is quite rare, furthermore, their contributions for the washoff patterns of each pollutant including pathogenic microorganisms are almost never discussed so far. The artificial flushing experiment separating the washoff of in-sewer deposits from the inflow of surface pollutants was carried out to simulate the first foul flush in a CSS. The washoff behaviors of each pollutant including bacterial indicators and enteric viruses were investigated. Several morphological analyses for the concentration and load curves of each parameter were conducted and all patterns were classified according to their washoff characteristics and first foul flush patterns. The washoff behaviors of each pollutant and microorganism are different from each other and categorized into several groups according to their (i) time-series concentration and load curves and (ii) concentration vs. flow rate curves, respectively. The first foul flush patterns of each parameter were to be categorized into typical 3 groups; strong-, partial-, and no first foul flush group. The order of these groups signifies the strength of the first foul flush phenomena and the runoff priority as well.


Vitex agnus castus effects on hyperprolactinaemia.
Vitex agnus castus (VAC), also known as chaste tree, is a plant from the Mediterranean area, Crimea, and central Asia. Its fruit has been used for more than 2500 years as phytotherapic agent. In the last century, VAC has been mostly used for the treatment of premenstrual syndrome (PMS), menstrual irregularities, fertility disorders, and symptoms of menopause. Since some degree of hyperprolactinaemia may be observed in patients with such disorders, VAC effects on hyperprolactinaemia have been assessed in a small number of studies and in some patient series or single case reports. It has been postulated that the diterpenes contained in VAC extract may interact with dopamine D2 receptors (D2R) and inhibit prolactin release via dopamine D2R activation in the anterior pituitary. Most of the published papers focus on the use of VAC for the management of PMS or infertility. However, due to its action on D2R, VAC could have a role in the treatment of mild hyperprolactinaemia, including patients with idiopathic hyperprolactinaemia, microprolactinoma, drug-induced hyperprolactinaemia, or polycystic ovary syndrome. We have reviewed and analysed the data from the literature concerning the use of VAC extracts in patients with hyperprolactinaemia. Some evidence suggests a possible role of VAC for the management of hyperprolactinaemia in selected patients, though in an inhomogeneous way. However, there are not any large randomized controlled trials supporting the same and the precise pharmacological aspects of VAC extract in such a clinical setting still remain obscure. It appears that VAC may represent a potentially useful and safe phytotherapic option for the management of selected patients with mild hyperprolactinaemia who wish to be treated with phytotherapy. However, larger studies of high quality are needed to corroborate it.


Chordoma: demographics and survival analysis with a focus on racial disparities and the role of surgery, a U.S. population-based study.
Chordoma is a rare malignant tumor of notochordal origin that may appear anywhere in the axial skeleton from the skull base to the sacrum. This study presents findings from a large database query to highlight the demographic, clinical, and pathological factors, prognosis, and survival of chordomas. The Surveillance, Epidemiology, and End Results (SEER) data based was used to identify patients with a "chordoma" diagnosis from 200 to 2018. In a total of 1600 cases, the mean age at diagnosis was 54.47 years (standard deviation, SD ± 19.62 years). Most cases were male (57.1%) and white (84.5%). Tumor size was found to be > 4 cm in 26% of cases. Histologically, 33% with known features had well-differentiated Grade I tumors, and 50.2% of the tumors were localized. Metastasis at the time of to the bone, liver, and lung was observed at a rate of 0.5%, 0.1%, and 0.7%, respectively. The most common treatment received was surgical resection (41.3%). The overall 5-year overall survival observed was 39% (confidence interval, CI 95% 37-41; p = 0.05) with patients who received surgery having a 5-year survival rate of 43% (CI 95% 40-46; p = 0.05). Multivariate analysis showed independent factors that contributed to worse prognosis chemotherapy only as a treatment modality and no surgery as a treatment modality. Chordomas are more common in white males and appear between the 5th and 6th decades of life. Factors that contributed to a worse prognosis were Asian, Pacific Islander, American Indian, or Alaska Native races.


Quantum Dot Nanotoxicity Investigations Using Human Lung Cells and TOXOR Electrochemical Enzyme Assay Methodology.
Recent studies have suggested that certain nanomaterials can interfere with optically based cytotoxicity assays resulting in underestimations of nanomaterial toxicity. As a result there has been growing interest in the use of whole cell electrochemical biosensors for nanotoxicity applications. Herein we report application of an electrochemical cytotoxicity assay developed in house (TOXOR) in the evaluation of toxic effects of mercaptosuccinic acid capped cadmium telluride quantum dots (MSA capped CdTe QDs), toward mammalian cells. MSA capped CdTe QDs were synthesized, characterized, and their cytotoxicity toward A549 human lung epithelial cells investigated. The internalization of QDs within cells was scrutinized via confocal microscopy. The cytotoxicity assay is based on the measurement of changes in cellular enzyme acid phosphatase upon 24 h exposure to QDs. Acid phosphatase catalyzes dephosphorylation of 2-naphthyl phosphate to 2-naphthol (determined by chronocoulometry) and is indicative of metabolic activity in cells. The 24 h IC50 (concentration resulting in 50% reduction in acid phosphatase activity) value for MSA capped CdTe QDs was found to be 118 ± 49 μg/mL using the TOXOR assay and was in agreement with the MTT assay (157 ± 31 μg/mL). Potential uses of this electrochemical assay include the screening of nanomaterials, environmental toxins, in addition to applications in the pharmaceutical, food, and health sectors.


Optimizing Early-Stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.
We describe the clinical pharmacology characterization of giredestrant in a first-in-human study. This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily (QD). The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg QD. Dose-escalation and expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg. Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 h at steady state was 4320 ng·h/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients. This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development.


Cissus quadrangularis inhibits IL-1β induced inflammatory responses on chondrocytes and alleviates bone deterioration in osteotomized rats via p38 MAPK signaling.
Inflammatory mediators are key players in the pathogenesis of osteoarthritis (OA) and bone destruction. Conventional drugs suppress symptomatic activity and have no therapeutic influence on disease. Cissus quadrangularis and Withania somnifera are widely used for the treatment of bone fractures and wounds; however, the cellular and molecular mechanisms regulated by these herbals are still unclear. We established an in vitro OA culture model by exposing human chondrocytes to proinflammatory cytokine and interleukin (IL)-1β for 36 hours prior to treatment with the herbals: C. quadrangularis, W. somnifera, and the combination of the two herbals. Cell viability, toxicity, and gene expression of OA modifying agents were examined. In addition, expression of survivin, which is crucial for cell growth, was analyzed. In vivo work on osteotomized rats studied the bone and cartilage regenerative effects of C. quadrangularis, W. somnifera, and the combination therapy. Exposure of chondrocytes to IL-1β induced significant toxicity and cell death. However, herbal treatment alleviated IL-1β induced cell toxicity and upregulated cell growth and proliferation. C. quadrangularis inhibited gene expression of cytokines and matrix metalloproteinases, known to aggravate cartilage and bone destruction, and augmented expression of survivin by inhibiting p38 MAPK. Interestingly, osteotomized rats treated with C. quadrangularis drastically enhanced alkaline phosphatase and cartilage tissue formation as compared to untreated, W. somnifera only, or the combination of both herbals. Our findings demonstrate for the first time the signaling mechanisms regulated by C. quadrangularis and W. somnifera in OA and osteogenesis. We suggest that the chondroprotective effects and regenerative ability of these herbals are via the upregulation of survivin that exerts inhibitory effects on the p38 MAPK signaling pathway. These findings thus validate C. quadrangularis as a potential therapeutic for rheumatic disorders.


Therapeutic RNA interference targeting CKIP-1 with a cross-species sequence to stimulate bone formation.
Casein kinase 2 interacting protein 1 (CKIP-1) is a newly discovered intracellular negative regulator of bone formation without affecting bone resorption. In this study, we aimed to identify a cross-species siRNA sequence targeting CKIP-1 to facilitate developing a novel RNAi-based bone anabolic drug for reversing established osteoporosis. Eight specifically designed cross-species CKIP-1 siRNA sequences were screened in human, rhesus, rat and mouse osteoblast-like cells in vitro to identify the optimal sequence with the highest knockdown efficiency. The effect of this optimal siRNA sequence on osteogenic differentiation and matrix mineralization was further examined in osteoblast-like cells across different species, followed by an immunogenicity assessment in human peripheral blood mononuclear cells in vitro. The intra-osseous localization and silencing efficiency of the optimal siRNA were examined in vivo using a biophotonic system and real-time polymerase chain reaction, respectively. The RNAi-mediated cleavage of the CKIP-1 transcript was confirmed by rapid amplification of the 5' cDNA ends in vivo. Furthermore, the effect of the optimal siRNA sequence on osteogenic differentiation, bone turnover biomarkers, bone mass and micro-architecture parameters was investigated in healthy and osteoporotic rodents. The CKIP-1 siRNA sequence (si-3) was identified as the optimal sequence, which consistently maintained CKIP-1 mRNA/protein expression at the lowest level across species in vitro. The si-3 significantly increased mRNA expression levels of osteoblast phenotypic genes and matrix mineralization across species without inducing an immunostimulatory activity in vitro. The intra-osseous localization and RNAi-mediated CKIP-1 silencing with high efficiency were confirmed in vivo. Periodic intravenous injections of si-3 promoted mRNA expression of osteoblast phenotypic genes, enhanced bone formation, increased bone mass and elevated serum level of bone formation marker without raising urine level of bone resorption marker in the healthy rodents. Moreover, the si-3 treatment promoted bone formation, improved trabecular micro-architecture and reversed bone loss in the osteoporotic mice. The identified optimal CKIP-1 siRNA sequence (si-3) could promote osteogenic differentiation across species in vitro, stimulate bone formation in the healthy rodents and reverse bone loss in the osteoporotic mice.


Reversible photochromic properties of TiO2-polymer nanocomposites.
Composite films of nanosized TiO2 particles, which contained rutile as the only detected crystal modification, and poly(vinyl alcohol), poly(vinyl pyrrolidone) or poly(4-vinylpyridine) were prepared from aqueous dispersions. During exposure to UV irradiation the nanocomposites comprising poly(vinyl alcohol) or poly(vinyl pyrrolidone) turned blue as a consequence of a partial reduction of TiIV to TiIII. The color intensity increased with increasing TiO2 content and irradiation time. This color did not fade after removal of the UV source in spite of the sensitivity of TiIII to atmospheric oxygen. By contrast, exposure to water caused the nanocomposites to adopt their original colorless appearance. These colorization-decolorization cycles could be repeated more than 10 times without apparent loss of intensity. Due to the small size of the TiO2 nanoparticles (ca. 3 nm), patterned blue structures of high resolution could be created in the polymeric materials, for instance with simple masking methods.


Five-Year Outcomes and Prognostic Value of Feature-Tracking Cardiovascular Magnetic Resonance in Patients Receiving Early Prereperfusion Metoprolol in Acute Myocardial Infarction.
The aim of the present study was to investigate the long-term impact of early intravenous metoprolol in ST-segment elevation myocardial infarction (STEMI) patients in terms of left ventricular (LV) strain with feature-tracking cardiovascular magnetic resonance (CMR) and its association with prognosis. A total of 270 patients with first anterior STEMI enrolled in the randomized METOCARD-CNIC clinical trial, assigned to receive up to 15 mg intravenous metoprolol before primary percutaneous coronary intervention versus conventional STEMI therapy, were included. LV global circumferential (GCS) and longitudinal (GLS) strain were assessed with feature-tracking CMR at 1 week after STEMI in 215 patients. The occurrence of major adverse cardiac events (MACE) at 5-year follow-up was the primary end point. Among 270 patients enrolled, 17 of 139 patients assigned to metoprolol arm and 31 of 131 patients assigned to control arm experienced MACE (hazard ratio [HR] 0.500, 95% confidence interval [CI] 0.277 to 0.903; p = 0.022). Impaired LV GCS and GLS strain were significantly associated with increased occurrence of MACE (GCS: HR 1.208, 95% CI 1.076 to 1.356, p =0.001; GLS: HR 1.362, 95% CI 1.180 to 1.573, p < 0.001). On multivariable analysis, LV GLS provided incremental prognostic value over late gadolinium enhancement (LGE) and LV ejection fraction (LVEF) (LGE + LVEF chi-square = 12.865, LGE + LVEF + GLS chi-square = 18.459; p =0.012). Patients with GLS ≥-11.5% (above median value) who received early intravenous metoprolol were 64% less likely to experience MACE than their counterparts with same degree of GLS impairment (HR 0.356, 95% CI 0.129 to 0.979; p = 0.045). In conclusion, early intravenous metoprolol has a long-term beneficial prognostic effect, particularly in patients with severely impaired LV systolic function. LV GLS with feature-tracking CMR early after percutaneous coronary intervention offers incremental prognostic value over conventional CMR parameters in risk stratification of STEMI patients.


Echocardiographic values in clinically healthy adult dogue de Bordeaux dogs.
To assess the influence of body surface area, age and gender on echocardiographic parameters and to establish echocardiographic reference values for dogue de Bordeaux dogs. Thirty-nine healthy dogue de Bordeaux dogs of both sexes, older than one year, were recruited and 31 of these were included in the study. The classic linear regression model proved to be the best way to analyse the data. The reference limits of the echocardiographic measurements were calculated using the regression equations. The difference between the mean values of body surface area in both gender groups was evaluated by using one-way ANOVA. A significant correlation was seen between several echocardiographic parameters and body surface area or body surface area and age, and high coefficients of determination (R2) were found. No effect of gender was detected on echocardiographic variables, except for the thickness of the left ventricular posterior wall at end diastole. The echocardiographic parameters related to body surface area, in the absence of correlation with other independent variables (gender and age) should be interpreted with caution because their variation could be significant for the presence of heart disease. The proposed statistical model allows estimation of echocardiographic parameters in dogue de Bordeaux dogs with different body surface areas and ages.


A Theoretically Informed Approach to Support the Implementation of Pre-Operative Anemia and Iron Deficiency Screening, Evaluation, and Management Pathways: Protocol for a Type Two Hybrid-Effectiveness Study.
Blood transfusions are a risk factor for increased morbidity, mortality, and length of hospital stay. Patient blood management guidelines provide guidance to reduce risk and improve patient outcomes. They outline steps to help prevent transfusions and considerations for when deciding to transfuse. One recommendation to prevent unnecessary transfusion is to optimize patients using Pre-operative Anemia and Iron Deficiency Screening, Evaluation and Management Pathways (PAIDSEM-P). The uptake of these recommendations is highly variable, and an effective approach to implementing them in a tailored and context-specific manner remains elusive. A mixed-methods, interventional study, using a type two-hybrid effectiveness-implementation design, will evaluate the impact of a change package to improve the uptake of PAIDSEM-P. The change package consists of the intervention (PAIDSEM-P) supported by theoretically informed implementation strategies. Pre- and post-implementation, retrospective health record reviews will determine the effect of the change package on provider outcomes, including compliance with guideline recommendations as measured by the proportion of patients who have the appropriate tests performed, and, if required, appropriate treatment and/or referrals. Patient outcomes will be measured by checking for any difference in the proportion of patients with anemia on the day of surgery and the proportion of patients who receive a blood transfusion during the peri-operative period. An economic evaluation will be conducted to compare health outcomes and costs. The feasibility, acceptability and appropriateness of the PAIDSEM-P will be assessed using a quantitative, validated survey to measure implementation outcomes. Testing of implementation theory is required to advance understanding of what works, in what context, and the impact on implementation success. This study aims to evaluate the impact of a theoretically informed change package on improving the uptake of PAIDSEM-P. If successful, it will also provide a framework for health care facilities to follow when addressing other evidence-practice gaps.


Stereochemical aspects of the oxidation of 4-ethylphenol by the bacterial enzyme 4-ethylphenol methylenehydroxylase.
The O2-independent hydroxylase 4-ethylphenol methylenehydroxylase (4EPMH) from Pseudomonas putida JD1 catalysed the complete conversion of 4-ethylphenol into 1-(4-hydroxyphenyl)ethanol together with a small amount of 4-hydroxyacetophenone, but with no formation of the side product 4-vinylphenol reported to be formed when the similar enzyme p-cresol methylhydroxylase (PCMH) catalyses this reaction. The enantiomer of 1-(4-hydroxyphenyl)ethanol produced by 4EPMH was R(+) when horse heart cytochrome c or azurin was used as electron acceptor for the enzyme. PCMHs from various bacterial strains produced the S(-)-alcohol. Both enantiomers of 1-(4-hydroxyphenyl)ethanol were substrates for conversion into 4-hydroxyacetophenone by 4EPMH, but the S(-)-isomer was preferred. The Km and kcat. were 1.2 mM and 41 s-1 respectively for the S(-)-alcohol and 4.7 mM and 22 s-1 for the R(+)-alcohol. In addition to the 1-(4-hydroxyphenyl)ethanol dehydrogenase activity of 4-EPMH, NAD(+)-linked dehydrogenase activity for both enantiomers of the alcohol was found in extracts of Ps. putida JD1.


Visual assessment versus quantitative three-dimensional stereotactic surface projection fluorodeoxyglucose positron emission tomography for detection of mild cognitive impairment and Alzheimer disease.
We examined the clinical impact of commercially available quantitation software using 3-dimensional stereotactic surface projection (3D-SSP) on the diagnostic accuracy of 18F fluorodeoxyglucose positron emission tomography (18F FDG PET) in mild cognitive impairment (MCI) and Alzheimer disease (AD). Enrollees underwent clinical evaluation to determine cognitive status and subsequent 18F FDG PET neuroimaging. Four blinded readers (2 novices and 2 experts) rated the images for degree of abnormality and interpretive confidence without and with 3D-SSP. Diagnostic accuracy was determined with area under the curve (area under the curve) of a receiver operating characteristic (receiver operating characteristic) curve analysis and change in confidence with model-based means (LSMeans). Twenty-three normal controls and 31 patients with cognitive impairment (18 MCI and 13 AD) were enrolled (28 female and 26 male; mean age 74 years). During follow-up (mean 3.6 years), all normal participants remained normal, 12 of 18 participants with MCI progressed to dementia, and all participants with baseline dementia progressed. The area under the curve with 3D-SSP (0.88; 95% CI: 0.76-0.95) was significantly higher than without it (0.72; 95% CI: 0.55-0.83). The specificity increased from 26% to 63% for novices and from 56% to 87% for experts with addition of 3D-SSP, whereas the sensitivity was essentially unchanged at 86% and 86% for the beginners and 81% and 79% for the experts. The interpretive confidence increased significantly from 3.3 to 4.0 (maximum value = 5, P = 0.048). The use of commercially available 3D-SSP quantitation improved diagnostic accuracy for evaluation of MCI and AD with 18F FDG PET.


Statistical patterns of visual search for hidden objects.
The movement of the eyes has been the subject of intensive research as a way to elucidate inner mechanisms of cognitive processes. A cognitive task that is rather frequent in our daily life is the visual search for hidden objects. Here we investigate through eye-tracking experiments the statistical properties associated with the search of target images embedded in a landscape of distractors. Specifically, our results show that the twofold process of eye movement, composed of sequences of fixations (small steps) intercalated by saccades (longer jumps), displays characteristic statistical signatures. While the saccadic jumps follow a log-normal distribution of distances, which is typical of multiplicative processes, the lengths of the smaller steps in the fixation trajectories are consistent with a power-law distribution. Moreover, the present analysis reveals a clear transition between a directional serial search to an isotropic random movement as the difficulty level of the searching task is increased.


Detection and isolation of fetal cells from maternal blood using the flourescence-activated cell sorter (FACS).
The presence of fetal cells in the maternal circulation during pregnancy has been suggested by repeated observations of small numbers of cells containing Y chromatin or a Y chromosome in the blood of pregnant women. With the fluorescence-activated cell sorter (FACS), we have used antibodies to a paternal cell surface (HLA) antigen, not present in the mother, to select fetal cells from the lymphocyte fractions of a series of maternal blood samples, collected as early as 15 weeks of gestation. These sorted cells have been examined for a second paternal genetic marker, Y chromatin. Y chromatin-containing cells were found among the sorted cells from prenatal maternal blood specimens in 8 pregnancies subsequently producing male infants whose lymphocytes reacted with the same antibodies to paternal antigen used for sorting with the FACS. In each of 17 pregnancies resulting in male infants who failed to inherit the antigen detected by the antibodies used for cell sorting, Y chromatin-containing cells were not found prenatally. The use of two paternal genetic markers, a cell surface antigen and nuclear Y chromatin, to identify fetal cells in maternal blood permits us to conclude that these cells are present in the mother's circulation, as early as 15 weeks gestation. Further development of the techniques reported here could lead to widespread screening of maternal blood samples during pregnancy for detection of fetal genetic abnormalities.


Integrated Real-Time Digital Measurement During Ureteroscopic Procedures for Nephrolithiasis: A Workflow Feasibility Study.
Introduction: Accurate estimation of stone fragment size during ureteroscopic lithotripsy procedures facilitates operative efficiency and predicts the safety of fragment extraction or spontaneous passage. Using a novel stone measurement software application, this study assesses the feasibility of performing integrated real-time digital stone measurement during ureteroscopy. Methods: This workflow feasibility study was conducted in two phases. First, in the ex vivo simulation, mock stone fragments were placed in a renal collecting system training model. A basket extraction task was performed using a digital ureteroscope, with and without digital stone measurement. The time required to perform the tasks was recorded and compared. Second, in the in vivo workflow trial, adult patients undergoing ureteroscopic stone procedures were prospectively enrolled. Intraoperative measurements of stone fragments were performed to determine the time required to complete the measurements. Technical failures and perioperative complications were recorded. Results: In the ex vivo simulation, 20 mock stones mimicking varied fragmentation conditions were tested in the training model. The mean completion time of the basketing task without vs with digital stone measurement was 16.5 seconds (range 10.2-33.7) vs 38.9 seconds (range 27.2-60.0). Mean additional time required to measure stones was 22.3 seconds (range 8.4-42.7). In the in vivo workflow trial, nine patients undergoing ureteroscopy were enrolled. A median of five fragments (range 3-10) were measured in each patient. Mean completion time for each measurement was 10.1 seconds (range 8.2-12.8). Mean total time required to perform digital measurement per procedure was 50.8 seconds (range 25.9-99.0). No technical failures or clinical complications were observed. Conclusions: Integrating real-time digital stone measurement during ureteroscopy is safe and feasible. The findings support clinical trials of digital stone measurement to enhance intraoperative decision-making during ureteroscopy.


Microneedle-mediated Intratumoral Delivery of Anti-CTLA-4 Promotes cDC1-dependent Eradication of Oral Squamous Cell Carcinoma with Limited irAEs.
Head and neck squamous cell carcinoma (HNSCC) ranks sixth in cancer incidence worldwide and has a 5-year survival rate of only 63%. Immunotherapies-principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity-offer the greatest promise for HNSCC treatment. Anti-PD-1 has been recently approved for first-line treatment of recurrent and metastatic HNSCC; however, less than 20% of patients show clinical benefit and durable responses. In addition, the clinical application of ICI has been limited by immune-related adverse events (irAE) consequent to compromised peripheral immune tolerance. Although irAEs are often reversible, they can become severe, prompting premature therapy termination or becoming life threatening. To address the irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Using our recently reported syngeneic, tobacco-signature murine HNSCC model, we found that both systemic and local-MN anti-CTLA-4 therapy lead to >90% tumor response, which is dependent on CD8 T cells and conventional dendritic cell type 1 (cDC1). However, local-MN delivery limited the distribution of anti-CTLA-4 antibody from areas distal to draining lymphatic basins. Employing Foxp3-GFPDTR transgenic mice to interrogate irAEs in vivo, we found that local-MN delivery of anti-CTLA-4 protects animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of MN-intratumoral ICI delivery as a viable strategy for HNSCC treatment with reduced irAEs, and the opportunity to target cDC1s as part of multimodal treatment options to boost ICI therapy.


Small bowel malignant melanoma--report of three cases and review of literature.
Malignant melanomas have a predilection to metastasize to the small bowel. Three patients with malignant melanoma involving the small bowel are reported. Two patients were operated on for small bowel obstruction and the third for gastrointestinal bleeding with anemia. Two patients remained well 6 month and 2 years, respectively, after surgery. One patient died of metastatic cerebral melanoma 6 months postoperatively. One should suspect small bowel metastasis in every patient with malignant melanoma in his past medical history, who presents with recent changes in bowel habits, intestinal obstruction or gastrointestinal bleeding. Preoperative assessment can only raise the suspicion, even with advanced imaging methods: capsule endoscopy, enteroscopy, CT or PET-CT. The only therapeutic procedure is surgical resection, offering both short term survival as well as an improvement in the quality of life. Although prognosis is dismal there are factors associated with prolonged survival: complete surgical resection with no residual primary or metastatic tumor, so-called primary small bowel tumors in patients aged more then 60 years, LDH < 200 U/L, lack of tumor spread in mesenteric lymph nodes.


Danger and loss events and the incidence of anxiety and depressive disorders: a prospective-longitudinal community study of adolescents and young adults.
There are inconclusive findings regarding whether danger and loss events differentially predict the onset of anxiety and depression. A community sample of adolescents and young adults (n = 2304, age 14-24 years at baseline) was prospectively followed up in up to four assessments over 10 years. Incident anxiety and depressive disorders were assessed at each wave using the DSM-IV/M-CIDI. Life events (including danger, loss and respectively mixed events) were assessed at baseline using the Munich Event List (MEL). Logistic regressions were used to reveal associations between event types at baseline and incident disorders at follow-up. Loss events merely predicted incident 'pure' depression [odds ratio (OR) 2.4 per standard deviation, 95% confidence interval (CI) 1.5-3.9, p < 0.001] whereas danger events predicted incident 'pure' anxiety (OR 2.3, 95% CI 1.1-4.6, p = 0.023) and 'pure' depression (OR 2.5, 95% CI 1.7-3.5, p < 0.001). Mixed events predicted incident 'pure' anxiety (OR 2.9, 95% CI 1.5-5.7, p = 0.002), 'pure' depression (OR 2.4, 95% CI 1.6-3.4, p < 0.001) and their co-morbidity (OR 3.6, 95% CI 1.8-7.0, p < 0.001). Our results provide further evidence for differential effects of danger, loss and respectively mixed events on incident anxiety, depression and their co-morbidity. Since most loss events referred to death/separation from significant others, particularly interpersonal loss appears to be highly specific in predicting depression.


Hypercalcemia in cancer patients: pathobiology and management.
Hypercalcemia is the most common life-threatening metabolic disorder associated with cancer, occurring in approximately 10-30% of all patients with neoplastic disease, although it occurs much less often in the pediatric setting. Hypercalcemia can emerge in hematologic malignancies, particularly multiple myeloma, as well as assorted solid tumors, primarily lung and breast cancers, and can even dominate the clinical picture in select patients. Early diagnosis and treatment with fluids and drugs that lower calcium levels in the blood can improve symptoms in a few days, ameliorate the quality of life of these patients, and avoid delays in the implementation of further anticancer treatments. Occasionally, the symptoms of hypercalcemia can appear gradually, and may be non-specific, resembling symptoms of many cancers and other comorbidities, especially in the elderly, thus resulting in an underestimated incidence of hypercalcemia in cancer patients. Of note, there is an increasing number of antineoplastic compounds that can interfere with calcium metabolism. Taking into consideration both the severity of hypercalcemia and the tumor status, health care providers should determine and apply appropriate treatment measures. We provide a comprehensive subjective synthesis of peer-reviewed evidence on the pathophysiology and treatment of hypercalcemia in cancer patients.


Enabling Trade in Gene-Edited Produce in Asia and Australasia: The Developing Regulatory Landscape and Future Perspectives.
Genome- or gene-editing (abbreviated here as 'GEd') presents great opportunities for crop improvement. This is especially so for the countries in the Asia-Pacific region, which is home to more than half of the world's growing population. A brief description of the science of gene-editing is provided with examples of GEd products. For the benefits of GEd technologies to be realized, international policy and regulatory environments must be clarified, otherwise non-tariff trade barriers will result. The status of regulations that relate to GEd crop products in Asian countries and Australasia are described, together with relevant definitions and responsible regulatory bodies. The regulatory landscape is changing rapidly: in some countries, the regulations are clear, in others they are developing, and some countries have yet to develop appropriate policies. There is clearly a need for the harmonization or alignment of GEd regulations in the region: this will promote the path-to-market and enable the benefits of GEd technologies to reach the end-users.


Reduced Risk of Reoperations With Modern Deep Brain Stimulator Systems: Big Data Analysis From a United States Claims Database.
Objective: There have been significant improvements in the design and manufacturing of deep brain stimulation (DBS) systems, but no study has considered the impact of modern systems on complications. We sought to compare the relative occurrence of reoperations after de novo implantation of modern and traditional DBS systems in patients with Parkinson's disease (PD) or essential tremor (ET) in the United States. Design: Retrospective, contemporaneous cohort study. Setting: Multicenter data from the United States Centers for Medicare and Medicaid Services administrative claims database between 2016 and 2018. Participants: This population-based sample consisted of 5,998 patients implanted with a DBS system, of which 3,869 patients had a de novo implant and primary diagnosis of PD or ET. Follow-up of 3 months was available for 3,810 patients, 12 months for 3,561 patients, and 24 months for 1,812 patients. Intervention: Implantation of a modern directional (MD) or traditional omnidirectional (TO) DBS system. Primary and Secondary Outcome Measures: We hypothesized that MD systems would impact complication rates. Reoperation rate was the primary outcome. Associated diagnoses, patient characteristics, and implanting center details served as covariates. Kaplan-Meier analysis was performed to compare rates of event-free survival and regression models were used to determine covariate influences. Results: Patients implanted with modern systems were 36% less likely to require reoperation, largely due to differences in acute reoperations and intracranial lead reoperations. Risk reduction persisted while accounting for practice differences and implanting center experience. Risk reduction was more pronounced in patients with PD. Conclusions: In the first multicenter analysis of device-related complications including modern DBS systems, we found that modern systems are associated with lower reoperation rates. This risk profile should be carefully considered during device selection for patients undergoing DBS for PD or ET. Prospective studies are needed to further investigate underlying causes.


Algorithmic bias and research integrity; the role of nonhuman authors in shaping scientific knowledge with respect to artificial intelligence: a perspective.
Artificial intelligence technologies were developed to assist authors in bettering the organization and caliber of their published papers, which are both growing in quantity and sophistication. Even though the usage of artificial intelligence tools in particular ChatGPT's natural language processing systems has been shown to be beneficial in research, there are still concerns about accuracy, responsibility, and transparency when it comes to the norms regarding authorship credit and contributions. Genomic algorithms quickly examine large amounts of genetic data to identify potential disease-causing mutations. By analyzing millions of medications for potential therapeutic benefits, they can quickly and relatively economically find novel approaches to treatment. Researchers from several fields can collaborate on difficult tasks with the assistance of nonhuman writers, promoting interdisciplinary research. Sadly, there are a number of significant disadvantages associated with employing nonhuman authors, including the potential for algorithmic prejudice. Biased data may be reinforced by the algorithm since machine learning algorithms can only be as objective as the data they are trained on. It is overdue that scholars bring forth basic moral concerns in the fight against algorithmic prejudice. Overall, even if the use of nonhuman authors has the potential to significantly improve scientific research, it is crucial for scientists to be aware of these drawbacks and take precautions to avoid bias and limits. To provide accurate and objective results, algorithms must be carefully designed and implemented, and researchers need to be mindful of the larger ethical ramifications of their usage.


Photodynamic Therapy Using Photosensitizer-Encapsulated Polymeric Nanoparticle to Overcome ATP-Binding Cassette Transporter Subfamily G2 Function in Pancreatic Cancer.
Chlorin-based photosensitizers are commonly used in photodynamic therapy (PDT). These drugs are effluxed by cell membrane transporters, such as the ATP-binding cassette subfamily G member 2 (ABCG2). PDT efficacy is limited in tumor cells expressing high levels of these proteins. Pancreatic cancer cell lines AsPC-1 and MIA PaCa-2, which have high and low ABCG2 expression, respectively, were used, and ABCG2-overexpressing MIA PaCa-2 cells were generated. We compared PDT efficacy between chlorin e6 (Ce6) and cationic photosensitizer-encapsulated polymeric nanoparticle (PS-pNP), which is comprised with Ce6, polyethylene glycol, and polyethylenimine. The intracellular concentration of Ce6 was significantly higher in MIA PaCa-2 cells than in AsPC-1 or ABCG2-overexpressing MIA PaCa-2 cells. PS-pNP increased intracellular levels of the photosensitizer in all cell lines. The cell viability experiments indicated increased Ce6 resistance in ABCG2-overexpressing cells. In contrast, PS-pNP produced similar levels of cytotoxicity in each of the cancer cell lines tested. Singlet oxygen production was higher in cells treated with PS-pNP than in those treated with Ce6. Furthermore, in heterotopic and orthotopic AsPC-1 xenograft mouse models, PDT using PS-pNP significantly reduced tumor volume in comparison with that of Ce6 treatment. PS-pNP could increase intracellular Ce6 concentration, which was related with reduced ABCG2-mediated efflux of Ce6, thereby enhancing the effects of PDT in pancreatic cancer cells. Mol Cancer Ther; 16(8); 1487-96. ©2017 AACR.


Learning reaching strategies through reinforcement for a sensor-based manipulator.
This paper presents a neural controller that learns goal-oriented obstacle-avoiding reaction strategies for a multilink robot arm. It acquires these strategies on-line from local sensory data. The controller consists of two neural modules: an actor-critic module and a module for differential inverse kinematics (DIV). The input codification for the controller exploits the inherent symmetry of the robot arm kinematics. The actor-critic module generates actions with regard to the Shortest Path Vector (SPV) to the closest goal in the configuration space. However, the computation of the SPV is cumbersome for manipulators with more than two links. The DIV module aims to overcome the SPV calculation. This module provides a goal vector by means of the inversion of a neural network that has been trained previously to approximate the manipulator forward kinematics. Results for a two-link robot arm show that the combination of both modules speeds up the learning process.


Zatariamultiflora ameliorates cisplatin-induced testicular damage via suppression of oxidative stress and apoptosis in a mice model.
Cisplatin (CP), as an anti-neoplastic drug, causes testicular damage. Zataria multiflora Boiss (ZM), a medicinal plant, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effects of ZM against CP-induced testicular toxicity. In this experimental study, thirty-two adult male mice were randomly divided into four groups. The control group received normal saline with oral gavage during 7 days; ZM group received ZM (200 mg/kg) during 7 days by gavage; CP group received CP (10 mg/kg) intraperitoneally (IP) in the 5th day of study; ZM + CP group received ZM during 7 days and CP was injected in 5th day. Sperm parameters, biochemical (MDA, GSH, and PC) levels, serum testosterone levels, and histopathological and immunohistochemical assays of testis were examined one day after the last drug treatment. CP treatment caused significant damage via changed sperm parameters (sperm motility, count, viability rate, and abnormalities), increased oxidative stress (increased MDA and PC levels, and decreased GSH level), histological changes (degeneration, necrosis, arrest of spermatogenesis, congestion, and decrease in thickness of the germinal epithelium, diameter of seminiferous tubules, and Johnsen's Score), decreased serum testosterone level, and increased caspase-3 immunoreactivity. ZM preserved spermatogenesis and mitigated the toxic effects of CP on the testis tissue. In addition, treatment with ZM significantly reduced caspase-3 immunoreactivity. The findings of this study suggest that ZM as a potential antioxidant compound and due to free radicals scavenging activities has a protective effect against CP-induced testicular toxicity.


Ethical issues in child and adolescent psychotherapy: a clinical review.
Child and adolescent psychotherapy has made great progress in recent years. With this progress, ethical issues have emerged that need to be addressed in the Indian setting. This article looks at various ethical issues in child and adolescent psychotherapy specific to Indian practitioners. The involvement of parents in psychotherapy often blurs therapeutic boundaries and issues related to confidentiality. Practitioners working in hospital and school settings are faced with similar problems. The advent of the internet and e-mail has resulted in new concerns for psychiatrists, related to communication via those media. Issues related to parenting, culture and development patterns, along with personal issues for the therapist, have been discussed.