Clinical acceptance of single-unit crowns and its association with impression and tissue displacement techniques: Findings from the National Dental Practice-Based Research Network.
The definitive impression for a single-unit crown involves many material and technique factors that may affect the success of the crown. The purpose of this prospective cohort study was to determine whether impression technique (tray selection), impression material, or tissue displacement technique are associated with the clinical acceptability of the crown (CAC). Dentists in the National Dental Practice-Based Research Network documented details of the preparation, impression, and delivery of 3730 consecutive single-unit crowns. Mixed-effects logistic regression analyses were performed to evaluate associations between impression techniques and materials and the CAC and to assess associations between the presence of a subgingival margin with the displacement technique and the outcome variables CAC and number of impressions required. Of the 3730 crowns, 3589 (96.2%) were deemed clinically acceptable. A significant difference in the CAC was found with different impression techniques (P<.001) and different impression materials (P<.001). The percentage of the CAC for digital scans was 99.5%, 95.8% for dual-arch trays, 95.2% for quadrant trays, and 94.0% for complete-arch impression trays. Although no statistically significant difference was found in the CAC produced with dual-arch trays without both mesial and distal contacts, crowns fabricated under these conditions were less likely to achieve excellent occlusion. The percentage of the CAC for digital scans was 99.5%, 97.0% for polyether impressions, 95.5% for polyvinyl siloxane impressions, and 90.5% for other impression materials. Accounting for the location of the margin, the use of a dual-cord displacement technique was significantly associated with lower rates of requiring more than 1 impression (P=.015, odds ratio=1.43). Dual-arch trays produced clinically acceptable crowns; however, if the prepared tooth was unbounded, the occlusal fit was more likely to have been compromised. Digital scans produced a slightly higher rate of CAC than conventional impression materials. The use of a dual-cord technique was associated with a decreased need to remake impressions when the margins were subgingival.


Enisoprost in renal transplantation. The Enisoprost Renal Transplant Study Group.
Prostaglandins of the E-series (PGE) mediate a wide variety of physiologic processes and have been shown to have regulatory roles in cell immunity. Previous animal and human trials have shown lower incidence of acute rejection when prostaglandins are administered in conjunction with standard immunosuppressives. This study evaluated the effects of the PGE analogue, enisoprost (EP), in a multicenter (39 centers) prospective, randomized, double-blind trial in 374 patients undergoing renal transplantation. Groups were placebo, enisoprost 50 micrograms p.o. q.i.d. (EP-50 micrograms), and enisoprost 100 micrograms p.o. q.i.d. (EP-100 micrograms). Patients received cyclosporine, azathioprine, corticosteroids, and Minnesota antilymphocyte globulin or OKT3 according to each center's protocol. Prophylactic antibody therapy (MALG or OKT3) was not randomized. Two hundred fifty-five patients completed the 8-week study period. Of the 119 patients who were withdrawn, 73 did so because of an adverse event. Rejection episodes occurred in 98 of 374 patients (26%). There was no statistically significant difference in the incidence of rejection between placebo- and EP-treated patients (P = 0.782). There was no significant difference in episodes of cyclosporine nephrotoxicity between placebo- and EP-treatment groups (P = 0.883). There was also no difference between incidence of acute tubular necrosis, duration of initial hospitalization, or need for rehospitalization between placebo- and EP-treated groups. Administration of EP was associated with frequent adverse events including elevation of body temperature, dyspepsia, and diarrhea. Antibody-treated patients had a higher percentage of black recipients, higher mean body weight, greater cold ischemic times, fewer living-related donors, and higher panel reactivity. Patients not receiving antibody prophylaxis were better matched immunologically than those receiving either MALG or OKT3. Despite these immunologic differences, there was no significant difference in the incidence of rejection in patients who did or did not receive antibody prophylaxis. Cyclosporine toxicity was more common in MALG-treated patients (P = 0.02). Renal function was worse in antibody-treated patients. There was no detectable effect of enisoprost on the incidence of acute rejection, renal function, or hospitalization in a multicenter prospective, randomized, double-blind trial in 374 patients undergoing renal transplantation.


Clinical applications of transcranial Doppler sonography.
Transcranial Doppler sonography (TCD) is used to assess cerebral blood flow velocity in basal cerebral arteries and is a common tool for the diagnosis and follow-up of cerebrovascular disease. With more than 200 clinical studies using TCD published annually, indications for its use are expanding. The current article critically reviews standard and recent clinical applications for TCD including delayed vasospasm after subarachnoid hemorrhage, sickle cell disease, atherosclerosis of cranial vessels, ischemic stroke, brain trauma, brain death, carotid artery disease, cerebral venous thrombosis, intraoperative TCD monitoring, arteriovenous malformations, cardiac shunts and preeclampsia.


A hybrid solid-fluorous phase radioiodination and purification platform.
A new class of fluorous materials was developed to create a hybrid solid-solution phase strategy for the expedient preparation and HPLC-free purification of (125) I-labeled compounds. The system is referred to as a hybrid platform in that it combines solution phase labeling and fluorous solid-phase purification in one step as opposed to two separate individual processes. Treatment of fluorous arylstannanes coated on fluorous silica with [(125) I]NaI and the appropriate oxidant made it possible to produce and selectively isolate the nonfluorous radiolabeled products in high purity (>98%) free from excess starting material and unreacted radioiodine. Examples included simple aryl and heterocyclic (click) derivatives, known radiopharmaceuticals including meta-iodobenzylguanidine (MIBG) and iododeoxyuridine (IUdR), and a new agent with high affinity for prostate-specific membrane antigen. The coated fluorous silica kits are simple to prepare, and reactions can be performed at room temperature using different oxidants generating products in minutes in biocompatible solutions.


The use of conventional EEG for the assessment of hypoxic ischaemic encephalopathy in the newborn: a review.
Neonatal hypoxic ischaemic encephalopathy continues to be one of the leading causes of morbidity and mortality among neonates around the globe. With the advent of therapeutic hypothermia, the need to accurately classify the severity of injury in the early neonatal period is of great importance. As clinical measures cannot always accurately estimate the severity early enough for treatment to be initiated, clinicians have become more dependent on conventional and amplitude integrated EEG. Despite this, there is currently no single agreed classification scheme for the neonatal EEG in hypoxic ischaemic encephalopathy. In this review we discuss classification schemes of neonatal background EEG, published over the past 35 years, highlighting the urgent need for a universal visual analysis scheme.


[Diagnosis and therapy for ureteral endometriosis].
To discuss the therapy for ureteral endometriosis. The clinical data of 25 cases of histopathologically confirmed ureteral endometriosis during 2001-2015 were retrospectively analyxed. In the 25 cases, all the patients took urinary ultrasound for examination before surgery, of whom 21 (84%) were examined by CT and 5 (20%) by MRI. Three (12%) cases underwent preoperative KUB and intravenous pyelogram (IVP) examination. Four (16%) cases were examined by retrograde pyelography before surgery. Eight (32%) of them took cystoscope for examination and 11 (44%) took preoperative radionuclide renal dynamic imaging examination. All of these cases were affected with unilateral ureter, 13 (52%) in the right and 12 (48%) in the left. The ureter lesions were at the upper part in 21 (84%) cases and at the middle part in 4 (16%) cases. In these cases, 11 (44%) received partial ureteral resection and end-to-end ureteral anastomosis, 10 (40%) received partial ureteral resection and ureterocystoneostomy, 3 (12%) received retroperitoneal laparoscopic nephroureterectomy, and 1 (4%) received endoscopic resection of ureteral endometriosis lesion. All of these cases were confirmed with ureteral endometriosis by post-surgery pathology results, with the expression of CA125 and ER in the glandular tissue and expression of PR in the mesenchymal tissue inside the ureteral muscle detected by immunohistochemistry. Four (16%) cases took postoperative adjuvant hormonal therapy. And no recurrence was found among 16 (64%) cases with the successful follow-up which ranged from 3 to 76 months and the median follow up was 28 months. Fifteen cases were submitted to the follow-up by urinary ultrasound (93.8%) and 5 (31.3%) underwent CT for examination. All the cases relieved from hydronephrosis, and symptoms of 10 (63.5) cases disappeared. The cases with double-J stent all had the stent removed within 3 to 6 weeks. Surgical procedures should be considered as the main therapy for ureteral endometriosis. We recommend ureterolysis for patients with mild ureteral obstruction and hydronephrosis. As for those with moderate and severe ureteral obstruction and hydronephrosis, we recommend partial ureteral resection. When the situation comes to patients with little renal function of the affected side, the recommended management is nephroureterectomy.


Ambient and focal visual processing of naturalistic activity.
When people inspect a picture, they progress through two distinct phases of visual processing: an ambient, or exploratory, phase that emphasizes input from peripheral vision and rapid acquisition of low-frequency information, followed by a focal phase that emphasizes central vision, salient objects, and high-frequency information. Does this qualitative shift occur during dynamic scene viewing? If so, when? One possibility is that shifts to exploratory processing are triggered at subjective event boundaries. This shift would be adaptive, because event boundaries typically occur when activity features change and when activity becomes unpredictable. Here, we used a perceptual event segmentation task, in which people identified boundaries between meaningful units of activity, to test this hypothesis. In two studies, an eye tracker recorded eye movements and pupil size while participants first watched movies of actors engaged in everyday activities and then segmented them into meaningful events. Saccade amplitudes and fixation durations during the initial viewings suggest that event boundaries function much like the onset of a new picture during static picture presentation: Viewers initiate an ambient processing phase and then progress to focal viewing as the event progresses. These studies suggest that this shift in processing mode could play a role in the formation of mental representations of the current environment.


Enhancing Residents' Warmth in Greeting Caregivers: An Inpatient Intervention to Improve Family-Centered Communication.
Hospitals are increasingly motivated to improve the patient and family experience and increase patient satisfaction scores. The manner by which a provider greets patients and their families sets the tone for the hospital stay. This study aimed to improve residents' greetings of caregivers in the inpatient pediatric setting to improve family-centered communication. The study was conducted from October 2017 to April 2018 at a single, urban children's hospital on a unit with patients primarily <5 years old. The intervention consisted of posting a prominent board outside of patients' rooms that (1) listed caregivers' preferred names (e.g., Mom/Dad, first names), (2) instructed residents to greet caregivers warmly by their preferred names, and (3) identified residents for families by name and photograph. During implementation, we conducted 5 Plan-Do-Study-Act cycles and surveyed 114 caregivers. Improvement was assessed using run charts. The primary outcome was the percentage of caregivers who rated residents' warmth of greetings as "excellent." This measure increased from a baseline median of 62.5%-84.4% with ≥6 consecutive postintervention points above the baseline median. The intervention improved caregiver-perceived quality of residents' greetings and could serve as a model for other hospitals to enhance provider-family rapport and improve communication.


Enhanced skin wound healing by a sustained release of growth factors contained in platelet-rich plasma.
Platelet-rich plasma (PRP) contains growth factors that promote tissue regeneration. Previously, we showed that heparin-conjugated fibrin (HCF) exerts the sustained release of growth factors with affinity for heparin. Here, we hypothesize that treatment of skin wound with a mixture of PRP and HCF exerts sustained release of several growth factors contained in PRP and promotes skin wound healing. The release of fibroblast growth factor 2, platelet-derived growth factor-BB, and vascular endothelial growth factor contained in PRP from HCF was sustained for a longer period than those from PRP, calcium-activated PRP (C-PRP), or a mixture of fibrin and PRP (F-PRP). Treatment of full-thickness skin wounds in mice with HCF-PRP resulted in much faster wound closure as well as dermal and epidermal regeneration at day 12 compared to treatment with either C-PRP or F-PRP. Enhanced skin regeneration observed in HCF-PRP group may have been at least partially due to enhanced angiogenesis in the wound beds. Therefore, this method could be useful for skin wound treatment.


Residue 182 influences the second step of protein-tyrosine phosphatase-mediated catalysis.
Previous enzyme kinetic and structural studies have revealed a critical role for Asp181 (PTP1B numbering) in PTP (protein-tyrosine phosphatase)-mediated catalysis. In the E-P (phosphoenzyme) formation step, Asp181 functions as a general acid, while in the E-P hydrolysis step it acts as a general base. Most of our understanding of the role of Asp181 is derived from studies with the Yersinia PTP and the mammalian PTP1B, and to some extent also TC (T-cell)-PTP and the related PTPa and PTPe. The neighbouring residue 182 is a phenylalanine in these four mammalian enzymes and a glutamine in Yersinia PTP. Surprisingly, little attention has been paid to the fact that this residue is a histidine in most other mammalian PTPs. Using a reciprocal single-point mutational approach with introduction of His182 in PTP1B and Phe182 in PTPH1, we demonstrate here that His182-PTPs, in comparison with Phe182-PTPs, have significantly decreased kcat values, and to a lesser degree, decreased kcat/Km values. Combined enzyme kinetic, X-ray crystallographic and molecular dynamics studies indicate that the effect of His182 is due to interactions with Asp181 and with Gln262. We conclude that residue 182 can modulate the functionality of both Asp181 and Gln262 and therefore affect the E-P hydrolysis step of PTP-mediated catalysis.


Oncogene activation of HIV-LTR-driven expression via the NF-kappa B binding sites.
The Raf-1 proto-oncogene product is a highly regulated serine/threonine kinase that functions in signal transduction downstream from growth factor receptors and upstream from nuclear proto-oncogene products. Using a transient cotransfection assay we have found that activated Raf-1 activates expression from the HIV-LTR. Analysis of a series of 5' deletion and point mutations revealed the NF-kappa B motifs as the Raf-responsive element in the HIV-LTR. Moreover, Raf-BXB activated expression from heterologous promoters driven by the HIV NF-kappa B binding sites. In addition to Raf, we show that v-Src, v-H-Ras and v-Mos activate HIV-LTR expression through the NF-kappa B binding sites and v-H-Ras-induced HIV-LTR expression is mediated by Raf-1. These findings may have implications for the involvement of the cellular homologues of these oncogenes in the switch from latent to productive infection by HIV in response to T-cell activation.


[Analysis of gait disorders in Parkinson's disease assessed with an accelerometer].
The objective of this study was to analyse stabilized gait disorders in newly diagnozed Parkinson patients using an accelerometric device, which had been previously validated for human locomotion analysis (Auvinet et al., 1999), and to compare Parkinson's gait variables with those obtained in a matched normal population (same gender, age, height and weight). The patient group included 22 subjects (women: 9, men: 13; age: 69+/-9 y; height: 164+/-9 cm; weight: 71+/-15 kg) with motor score from 4 to 59 (mean: 23.5+/-3.0). Gait analysis system included two accelerometers held over the middle of the low back by means of a semi-elastic belt, cranio-caudal and side to side accelerations were recorded at a frequency of 50 Hz. Subjects were asked to walk at their own speed along a straight 40 meter long corridor. A 20 second period of stabilized walking was used to calculate stride frequency, step symmetry, stride regularity and cranio-caudal activity (related to hypokinesia). The walking speed was measured with an electronic stop watch. Parkinson's gait was characterized by a reduction of walking velocity (p<0.0001) which was explained by reduction of stride frequency (p<0.001) and step length (p<0.001), but mainly we noticed a reduction of walking regularity (p<0.0001) and of the cranio-caudal activity (p<0.0001). These two last variables were strongly correlated to the motor score ((r=-0.59 (p<0.01); r=-0.65 (p<0.003), respectively)). In conclusion regularity and cranio-caudal activity appeared as the most interesting variables to characterize stabilized Parkinson's gait.


Mapping muscle protein genes by in situ hybridization using biotin-labeled probes.
The genes coding for the myosin heavy chain isoforms (unc-54, myo-1, myo-2 and myo-3) and the actins (act-1,2,3 and act-4) have been mapped on the embryonic metaphase chromosomes of Caenorhabditis elegans by in situ hybridization. The genes were cloned in a cosmid vector and the entire cosmid was nick translated to incorporate biotin-labeled dUTP. This produced a probe DNA complementary to a 35-45 kb length of chromosomal DNA. The hybridization signal from the cosmid probe, detected by immunofluorescence, could be easily seen by eye. The clear signals and the specific hybridization of the cosmid probes provided a faster means of mapping these single copy genes than small probes cloned in plasmid or lambda vectors. The myosin heavy chain genes are not clustered. Only unc-54 and myo-1 mapped to the same chromosome; the unc-54 locus is at the extreme right end of linkage group I and myo-1 mapped 40-50% from the left end of linkage group I. Myo-2 mapped to the X, 52-75% from the left end. The myo-3 gene mapped to the middle of linkage group V near the cluster of three actin genes (act-1,2,3). The fourth actin gene, act-4 mapped to 20-35% from the left end of X.


Does mode of administration matter? Comparison of online and face-to-face administration of a time trade-off task.
Developments in electronic data collection methods have allowed researchers to generate larger datasets at lower costs, but relatively little is known about the comparative performance of the new methods. This paper considers the comparability of two modes of administration (face-to-face and remote electronic) for the time trade-off. Data were collected from a convenience sample of adults (n = 135) randomised to either a face-to-face time trade-off or a remote electronic tool. Patterns of responses were considered. For each sample, standard regression analysis was undertaken to generate a valuation set, which were then contrasted. The pattern of responses differed by mode of administration, with the electronic tool yielding larger standard deviations and higher proportions of responses at -1, 0 and 1. The impact of this on the regression was difficult to disentangle from the high variability around individual scores of states, which is a common feature of responses to time trade-off tasks. Under the scoring algorithms generated by mode of administration, the difference between scores exceeded 0.1 for 100 of the 243 EQ-5D health states. This comparison demonstrates that variability arising from mode of administration needs to be considered in developing health state valuations. While electronic administration has considerable cost advantages, particular attention to the design of the task is required. This has wider implications, as all modes of administration may have mode-specific impacts on the distribution of valuation responses.


PACAP stimulates biosynthesis and release of endozepines from rat astrocytes.
Astrocytes synthesize and release endozepines, a family of neuropeptides related to diazepam-binding inhibitor (DBI). Astroglial cells also express the receptors of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). In the present article, we show that PACAP dose dependently increases DBI gene expression and stimulates endozepine release through activation of PAC1-R. PACAP increases cAMP formation, enhances polyphosphoinositide turnover, and evokes calcium mobilization from intracellular Ca2+ pools. The effect of PACAP on endozepine release is mediated through the adenylyl cyclase/PKA pathway while the downregulation of astrocyte response to PACAP can be ascribed to activation of the PLC/PKC pathway.


Current status of marine protected areas in latin america and the Caribbean.
Marine protected areas (MPAs), including no-take marine reserves (MRs), play an important role in the conservation of marine biodiversity. We document the status of MPAs and MRs in Latin America and the Caribbean, where little has been reported on the scope of such protection. Our survey of protected area databases, published and unpublished literature, and Internet searches yielded information from 30 countries and 12 overseas territories. At present more than 700 MPAs have been established, covering more than 300,000 km(2) or 1.5% of the coastal and shelf waters. We report on the status of 3 categories of protection: MPAs (limited take throughout the area), MRs (no-take throughout the area), and mixed-use (a limited-take MPA that contains an MR). The majority of protected areas in Latin America and the Caribbean are MPAs, which allow some or extensive extractive activities throughout the designated area. These 571 sites cover 51,505 km(2) or 0.3% of coastal and shelf waters. There are 98 MRs covering 16,862 km(2) or 0.1% of the coastal and shelf waters. Mixed-use MPAs are the fewest in number (87), but cover the largest area (236,853 km(2), 1.2%). Across Latin America and the Caribbean, many biogeographic provinces are underrepresented in these protected areas. Large coastal regions remain unprotected, in particular, the southern Pacific and southern Atlantic coasts of South America. Our analysis reveals multiple opportunities to strengthen marine conservation in Latin America and the Caribbean by improving implementation, management, and enforcement of existing MPAs; adding new MPAs and MRs strategically to enhance connectivity and sustainability of existing protection; and establishing new networks of MPAs and MRs or combinations thereof to enhance protection where little currently exists.


IALP and the world: global perspectives. International Association of Logopedics and Phoniatrics.
IALP is an association that guards, coordinates, and enhances internationally the field of communicative sciences and disorders. On the occasion of its 75th anniversary an attempt is made in this presentation to introduce the Association and the lines of possible future development in relation to its global responsibilities. An introduction to human communication aims at highlighting the importance of the field of interest of IALP. The history and present status of IALP is given. Future development focuses on aspects of the specialty and on promotion of the goals of IALP with reference to the importance of developing international contacts. Finances, an important aspect in the development of any establishment, are referred to, stressing their sound features at present. Suggested global tasks are put forward as a visionary and even a missionary plan for IALP in its coming decades.


Considering non-hospital data in clinical informatics use cases, a review of the National Emergency Medical Services Information System (NEMSIS).
The National Emergency Medical Services (EMS) Information System (NEMSIS) Technical Assistance Center (TAC) collects and curates EMS activation level records for the United States. Originated as an outcomes assessment and service comparison tool, NEMSIS may have other high value clinical and public health uses. This study acquired a 100% activation level public dataset for 2019 from NEMSIS TAC and assessed item response quantities. Subsumption of NEMSIS terms within other controlled clinical vocabularies was also considered. None of the assessed terminologies (LOINC, ICD10-CM, SNOMED-CT) could describe meaningful volumes of NEMSIS item response codes. The 2019 activation year dataset included 36,525 non-date/time or calculated distinct item responses for 43 activation descriptive items. Said item responses yielded 2,101,844,053 activation distinct non-blank responses. Several NEMSIS item responses had high clinical and public health value. NEMSIS can support multiple public health use cases in addition to EMS outcomes assessment. A comprehensive custom value set is appropriate to integrate NEMSIS item response codes into controlled terminologies, FHIR or hospital Electronic Health Record applications.


5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer.
We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m(2)), modulated by MTX (24 h earlier, 200 mg/m(2)) were alternated with a 3-week continuous infusion of FU (200 mg/m(2)daily), modulated by LV (20 mg/m(2)weekly bolus). Mito, 7 mg/m(2), was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28-46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III-IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents.


Topical application of valrubicin has a beneficial effect on developing skin tumors.
Valrubicin is a second generation anthracycline characterized by an excellent safety profile presenting no skin toxicity or necrosis upon contact. In its current liquid formulation (Valstar; Indevus Pharmaceuticals, Lexington, MA), it is approved solely for the treatment of bladder cancer. Recently, valrubicin was incorporated in a cream formulation rendering this drug available for topical application. The cytostatic property of valrubicin can, thus, be employed for treating hyperproliferative skin diseases as was recently described for psoriasis. In the present study, the effect of topical application of valrubicin was investigated in skin tumor development; we hypothesized that valrubicin may be employed in treating actinic keratosis, a hyperproliferative skin condition that may transform into malignancy. A two-stage chemical mouse skin carcinogenesis model that represents the multistage etiology of human skin cancer-from developing papillomas to squamous cell carcinoma (SCC) was used. Moreover, two human skin SCC cell lines: DJM-1 and HSC-1 were cultured, to further investigate the effect of valrubicin in vitro. Cell viability was assessed by adenosine triphosphate presence, proliferation as proliferative cell nuclear antigen expression and apoptosis as cytokeratin 18 cleavage, caspase activation, poly-adenosine diphosphate-ribose-polymerase cleavage and bax and bcl-2 regulation. Valrubicin significantly inhibited tumor formation in the mouse skin carcinogenesis model and significantly decreased cell viability of the cultured human skin SCC cells. In both mouse skin and SCC cells, proliferation was significantly decreased. Apoptosis was significantly increased in SCC cells but unchanged in the treated mouse skin at study completion. This study demonstrated that topical application of valrubicin has a beneficial effect in treating developing skin tumors.


A New Functional Magnetic Resonance Imaging Localizer for Preoperative Language Mapping Using a Sentence Completion Task: Validity, Choice of Baseline Condition, and Test-Retest Reliability.
To avoid post-neurosurgical language deficits, intraoperative mapping of the language function in the brain can be complemented with preoperative mapping with functional magnetic resonance imaging (fMRI). The validity of an fMRI "language localizer" paradigm crucially depends on the choice of an optimal language task and baseline condition. This study presents a new fMRI "language localizer" in Russian using overt sentence completion, a task that comprehensively engages the language function by involving both production and comprehension at the word and sentence level. The paradigm was validated in 18 neurologically healthy volunteers who participated in two scanning sessions, for estimating test-retest reliability. For the first time, two baseline conditions for the sentence completion task were compared. At the group level, the paradigm significantly activated both anterior and posterior language-related regions. Individual-level analysis showed that activation was elicited most consistently in the inferior frontal regions, followed by posterior temporal regions and the angular gyrus. Test-retest reliability of activation location, as measured by Dice coefficients, was moderate and thus comparable to previous studies. Test-retest reliability was higher in the frontal than temporo-parietal region and with the most liberal statistical thresholding compared to two more conservative thresholding methods. Lateralization indices were expectedly left-hemispheric, with greater lateralization in the frontal than temporo-parietal region, and showed moderate test-retest reliability. Finally, the pseudoword baseline elicited more extensive and more reliable activation, although the syllable baseline appears more feasible for future clinical use. Overall, the study demonstrated the validity and reliability of the sentence completion task for mapping the language function in the brain. The paradigm needs further validation in a clinical sample of neurosurgical patients. Additionally, the study contributes to general evidence on test-retest reliability of fMRI.


Prevalence and factors associated with sleep disturbances among early-treated HIV-infected persons.
Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0-142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4-5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7-.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.


Renal dysfunction in acute stroke: an independent predictor of long-term all combined vascular events and overall mortality.
Acute stroke is the third leading cause of death in western societies after ischemic heart disease and cancer. Although it is an emergency disease sharing the same atherosclerotic risk factors with ischemic heart disease, the association of renal function and stroke is poorly investigated. The present study aims at assessing renal function status in patients with acute stroke and investigate any prognostic significance on the outcome. This is a prospective study of hospitalized first-ever stroke patients over 10 years. The study population comprised 1350 patients admitted within 24 h from stroke onset and followed up for 1 to 120 months or until death. Patients were divided in 3 groups on the basis of the estimated Glomerular Filtration Rate (eGFR) that was calculated from the abbreviated equation of the Modification Diet for Renal Disease in ml/min/1.73 m(2) of body surface area: Group-A comprised patients who had eGFR > 60, group-B those with 30 <or= eGFR <or= 60 and group-C patients with eGFR < 30. Patients with Acute Kidney Injury (AKI) were excluded from the study. The main outcome measures were overall mortality and the composite new cardiovascular events (myocardial infarction, recurrent stroke, vascular death) among the 3 groups during the follow-up period. Almost 1/3 (28.08%) of our acute stroke patients presented with moderate (group B) or severe (group C) renal dysfunction as estimated by eGFR. After adjusting for basic demographic, stroke risk factors and stroke severity on admission, eGFR was an independent predictor of stroke mortality at 10 years. Patients in groups B and C had an increased probability of death during follow-up: Hazard ratio = 1.21 with 95% CI 1.01-1.46, p < 0.05 and Hazard ratio = 1.76 with 95% CI 1.14-2.73, p < 0.05 respectively, compared to patients belonging to group A. The probability of death from any cause was significantly different among groups (log rank test 55.4, p = 0.001) during the follow-up period: in group-A patients it was 62.8 (95% CI 57.6-68.1), in group-B 77.3 (95% CI 68.5-86.1) and in group-C 89.2 (95% CI 75.1-100). During the follow-up period 336 new cardiovascular events occurred. The probability to have a new composite cardiovascular event was also significantly different among the 3 groups (log rank test 21.1, p = 0.001): in group-A patients it was 45.2 (95% CI 38.7-51.7), in group-B 67.4 (95% CI 56.2-78.6) and in group-C 77.6 (95% CI 53.5-100). Renal function on admission appears to be a significant independent prognostic factor for long term mortality and new cardiovascular morbidity over a 10-year period.


Interaction of neurotransmitter systems in the hippocampus: a study of some behavioral effects of hippocampal sympathetic ingrowth.
Recent research has suggested that normal learning/memory may depend upon the balance between central noradrenergic and cholinergic systems. This hypothesis has particular relevance to the study of the neuronal rearrangement that follows cholinergic denervation of hippocampus. In this, peripheral noradrenergic fibers, originating from the superior cervical ganglion, grow into the hippocampus in response to lesions of the medial septal (MS) cholinergic cell bodies. To understand further the influence of hippocampal sympathetic ingrowth (HSI) on behavior, gustatory neophobia, passive avoidance (PA) learning, and open field activity were studied. Male Sprague-Dawley rats underwent one of four surgical procedures: MS lesions and sham ganglionectomy (ingrowth group; MS/HSI group), sham MS lesions and ganglionectomy (Gx group), MS lesions and ganglionectomy (no-ingrowth group; MS/Gx group), or sham MS lesions and sham ganglionectomy (CON group). Behavioral testing began 4 weeks following surgery. The time to acquire the PA task was similar among all groups; however, the initial latency to enter the dark chamber of the PA apparatus was longer, and the number of partial reentries greatest, for MS/HSI animals. Retention testing at 24 hr revealed that MS/HSI animals were significantly impaired when compared to the CON and MS/Gx groups. The MS/Gx and the CON groups demonstrated gustatory neophobia, preferring water to saccharin solution, while gustatory neophobia was absent in the MS/HSI and Gx groups. MS/HSI animals were found to be more active in the open field than the other groups. Biochemical studies revealed the expected loss of ChAT activity in the dorsal and ventral hippocampi of lesioned animals along with elevated levels of norepinephrine (NE) in the dorsal hippocampus of MS/HSI animals.(ABSTRACT TRUNCATED AT 250 WORDS)


Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors.
Most solid malignancies display interstitial hypertension and a poor uptake of anticancer drugs. Platelet-derived growth factor (PDGF) and the cognate tyrosine kinase receptors are expressed in many tumors. Signaling through PDGFbeta receptors was shown recently to increase interstitial fluid pressure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this study, we show that treatment with the selective PDGF receptor kinase inhibitor, STI571, formerly known as CGP57148B, decreased the interstitial hypertension and increased capillary-to-interstitium transport of 51Cr-EDTA in s.c. growing rat PROb colonic carcinomas. Furthermore, treatment with an antagonistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension in these tumors. PDGFbeta receptors were expressed in blood vessels and stromal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biology, although similar effects of PDGF on IFP have been demonstrated previously in the dermis. The data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy.


Experiences of Oncology and Palliative Care Nurses When Supporting Parents Who Have Cancer and Dependent Children.
It is important not to ignore the impact of parental cancer on children, and this is where oncology and palliative care nurses can play a key role, providing support to parents as a regular aspect of oncological nursing care. This study explored the experience, needs, and confidence of nurses working in acute cancer services when supporting parents with cancer who have dependent children. Two focus group interviews were conducted with oncology and palliative care nurses in 1 acute hospital trust in the south of England. Nurses described how they identified with their patients as a parent themselves. This identification with patients added to the emotionally charged context of care and resulted in nurse avoidance of the troubling issue of dependent children. Nurses identified the importance of peer support with regular opportunities to reflect on practice when dealing with issues relevant to parents and children. Oncology and palliative care nurses take a reactive approach to family centred care, taking their cue from patients to initiate or request support for their children. Guidance was needed on children's developmental stages and how to communicate with children of different ages. In addition, guidance was needed on assessing family needs and access to up to date resources. To enable nurses to engage with the issue of children, strategies of peer support and further educational opportunities need to be implemented.


The effects of combining Web-based eHealth with telephone nurse case management for pediatric asthma control: a randomized controlled trial.
Asthma is the most common pediatric illness in the United States, burdening low-income and minority families disproportionately and contributing to high health care costs. Clinic-based asthma education and telephone case management have had mixed results on asthma control, as have eHealth programs and online games. To test the effects of (1) CHESS+CM, a system for parents and children ages 4-12 years with poorly controlled asthma, on asthma control and medication adherence, and (2) competence, self-efficacy, and social support as mediators. CHESS+CM included a fully automated eHealth component (Comprehensive Health Enhancement Support System [CHESS]) plus monthly nurse case management (CM) via phone. CHESS, based on self-determination theory, was designed to improve competence, social support, and intrinsic motivation of parents and children. We identified eligible parent-child dyads from files of managed care organizations in Madison and Milwaukee, Wisconsin, USA, sent them recruitment letters, and randomly assigned them (unblinded) to a control group of treatment as usual plus asthma information or to CHESS+CM. Asthma control was measured by the Asthma Control Questionnaire (ACQ) and self-reported symptom-free days. Medication adherence was a composite of pharmacy refill data and medication taking. Social support, information competence, and self-efficacy were self-assessed in questionnaires. All data were collected at 0, 3, 6, 9, and 12 months. Asthma diaries kept during a 3-week run-in period before randomization provided baseline data. Of 305 parent-child dyads enrolled, 301 were randomly assigned, 153 to the control group and 148 to CHESS+CM. Most parents were female (283/301, 94%), African American (150/301, 49.8%), and had a low income as indicated by child's Medicaid status (154/301, 51.2%); 146 (48.5%) were single and 96 of 301 (31.9%) had a high school education or less. Completion rates were 127 of 153 control group dyads (83.0%) and 132 of 148 CHESS+CM group dyads (89.2%). CHESS+CM group children had significantly better asthma control on the ACQ (d = -0.31, 95% confidence limits [CL] -0.56, -0.06, P = .011), but not as measured by symptom-free days (d = 0.18, 95% CL -0.88, 1.60, P = 1.00). The composite adherence scores did not differ significantly between groups (d = 1.48%, 95% CL -8.15, 11.11, P = .76). Social support was a significant mediator for CHESS+CM's effect on asthma control (alpha = .200, P = .01; beta = .210, P = .03). Self-efficacy was not significant (alpha = .080, P = .14; beta = .476, P = .01); neither was information competence (alpha = .079, P = .09; beta = .063, P = .64). Integrating telephone case management with eHealth benefited pediatric asthma control, though not medication adherence. Improved methods of measuring medication adherence are needed. Social support appears to be more effective than information in improving pediatric asthma control. Clinicaltrials.gov NCT00214383; http://clinicaltrials.gov/ct2/show/NCT00214383 (Archived by WebCite at http://www.webcitation.org/68OVwqMPz).


Utilization trends at a multidisciplinary prostate cancer clinic: initial 5-year experience from the Duke Prostate Center.
The multidisciplinary approach is becoming increasingly encouraged but little is known about the multidisciplinary experience compared to routine care. For patients with prostate cancer the goal is to provide evaluations by urologists, medical and radiation oncologists at a single visit. Although additional resources are required, this strategy may enhance the overall health care experience. We compared utilization determinants between a multidisciplinary and a urology prostate cancer clinic at Duke University Medical Center and identified factors associated with pursuing treatment at the university medical center for multidisciplinary clinic patients. We retrospectively analyzed data on patients referred for primary prostate cancer treatment evaluation at Duke University Medical Center from 2005 to 2009. Comparisons between 701 multidisciplinary clinic and 1,318 urology prostate cancer clinic patients were examined with the rank sum and chi-square tests. Predictive factors for pursuing treatment at the university medical center were assessed using multivariate adjusted logistic regression. Compared to patients at the urology prostate cancer clinic those at the multidisciplinary clinic were more likely to be younger and white, have a higher income and travel a longer distance for evaluation. Of multidisciplinary clinic patients 58% pursued primary treatment at the university medical center. They were more likely to be younger, black and physician referred, have a lower income and reside closer to the medical center. Factors predictive of pursuing treatment at the medical center included high risk disease and physician referral. Factors predictive of not receiving care at the university medical center were income greater than $40,000 and a distance traveled of greater than 100 miles. A different patient demographic is using the multidisciplinary approach. However, when treatment is pursued at the institution providing multidisciplinary services, the patient demographic resembles that of the treating institution.


A Review of GNSS/GPS in Hydrogeodesy: Hydrologic Loading Applications and Their Implications for Water Resource Research.
Hydrogeodesy, a relatively new field within the earth sciences, is the analysis of the distribution and movement of terrestrial water at Earth's surface using measurements of Earth's shape, orientation, and gravitational field. In this paper, we review the current state of hydrogeodesy with a specific focus on Global Navigation Satellite System (GNSS)/Global Positioning System measurements of hydrologic loading. As water cycles through the hydrosphere, GNSS stations anchored to Earth's crust measure the associated movement of the land surface under the weight of changing hydrologic loads. Recent advances in GNSS-based hydrogeodesy have led to exciting applications of hydrologic loading and subsequent terrestrial water storage (TWS) estimates. We describe how GNSS position time series respond to climatic drivers, can be used to estimate TWS across temporal scales, and can improve drought characterization. We aim to facilitate hydrologists' use of GNSS-observed surface deformation as an emerging tool for investigating and quantifying water resources, propose methods to further strengthen collaborative research and exchange between geodesists and hydrologists, and offer ideas about pressing questions in hydrology that GNSS may help to answer.


The burden of very early dropout in infertility care: a nationwide population-based cohort study.
What is the frequency and the associated factors of very early dropout following unsuccessful clomiphene citrate (CC)/gonadotropin treatment in the context of full coverage of treatment cost. Despite free treatment, almost one in four women had a very early dropout following unsuccessful CC/gonadotropin treatment, with patients below the poverty line being more likely to drop out early. Success of infertility care is tarnished by very high dropout rates. Infertility care dropout has been considered as resulting principally from financial barriers because of the high cost of treatment. Nearly all previous work addressed dropout following IVF/ICSI. Factors associated with dropout following CC/gonadotropins may be different and also need to be investigated. Nationwide population-based cohort study. Using the French national health insurance and hospital databases, we included in the cohort 27 416 women aged 18-49 years unsuccessfully treated with CC/gonadotropins in 2017. The main outcome was very early dropout, defined as discontinuation of all infertility treatment after unsuccessful treatment for 1-3 months. Very early treatment dropout was analysed by multivariate logistic regression. Among women unsuccessfully treated with CC/gonadotropins, 22% dropped out of infertility care within 3 months. In multivariate analysis, higher early dropout following unsuccessful CC/gonadotropin treatment was associated with older and younger ages (≥35 and <25 years), being below the poverty line, being treated with CC prescribed by a general practitioner and lack of infertility tests or monitoring. This study is based on health administrative data that do not include reasons for dropout and record only a limited amount of information. It is thus not possible to analyse the reason for early dropout. Despite full coverage of all infertility treatment, women under the poverty line have a higher risk of very early dropout following unsuccessful CC/gonadotropin treatment. Better understanding is needed of the non-financial barriers and difficulties faced by these patients. To address disparities in infertility treatment, practitioner training could be reinforced to adapt to patients from different social and cultural backgrounds. This work was supported by the ANR StimHo project, grant ANR-17-CE36-0011-01 from the French Agence Nationale de la Recherche. The authors have no conflict of interest to declare. N/A.


Clinical needs finding: developing the virtual experience-a case study.
We describe an innovative program at the University of California, Davis for students to engage in clinical needs finding. Using a team-based approach, students participated in clinical rotations to observe firsthand the needs of clinicians at the university affiliated medical center. The teams were asked to develop documentary-style videos to capture key experiences that would allow future viewers to use the videos as "virtual" clinical rotations. This was conceived as a strategy to allow students in prohibitively large classes, or students in programs at institutions without associated medical or veterinary school programs, to experience clinical rotations and perform needs assessments. The students' perspectives on the experience as well as instructor analysis of best practices for this type of activity are presented and discussed. We found that the internship experience was valuable to the students participating, by not only introducing the practice of needs finding but also increasing the students' confidence in the practice of engineering design and their ability to work independently. The videos produced were of such high quality that instructors from other institutions have requested copies for instructional use. Virtual clinical rotations through video experiences may provide a reasonable substitute for students who do not have the ability to participate in rotations in person.


Bit vector architecture for computational mathematical morphology.
A real-time, compact architecture is presented for translation-invariant windowed nonlinear discrete operators represented in computational mathematical morphology. The architecture enables output values to be computed in a fixed number of operations and thus can be pipelined. Memory requirements for an operator are proportional to its basis size. An operator is implemented by three steps: 1) each component of a vector observation is used as an index into a table of bit vectors; 2) all retrieved bit vectors are "ANDed" together; and 3) the position of the first nonzero bit is used as an index to a table of output values. Computational mathematical morphology is described, the new architecture is illustrated through examples, and formal proofs are given. A modification of the basic architecture provides for increasing operators.


Cluster and network analysis of non-headache symptoms in migraine patients reveals distinct subgroups based on onset age and vestibular-cochlear symptom interconnection.
The present study endeavors to identify natural subgroups of migraine patients based on the patterns of non-headache symptoms, utilizing cluster analysis. Subsequently, network analysis was performed to estimate the structure of symptoms and explore the potential pathophysiology of these findings. A total of 475 patients who met the diagnostic criteria for migraine were surveyed face-to-face during the period of 2019 to 2022. The survey included collecting demographic and symptom data. Four different solutions were generated by the K-means for mixed large data (KAMILA) clustering algorithm, from which the final cluster solutions were selected based on a series of cluster metrics. Subsequently, we performed network analysis using Bayesian Gaussian graphical models (BGGM) to estimate the symptom structure across subgroups and conducted global and pairwise comparisons between structures. Cluster analysis identified two distinct patient groups, and the onset age of migraine proved to be an effective characteristic differentiating the two patient groups. Participants assigned to late-onset group showed a longer course of migraine, higher frequency of monthly headache attacks, and greater tendency toward medication overuse. In contrast, patients in early-onset group exhibited a higher frequency of nausea, vomiting, and phonophobia compared to their counterparts in the other group. The network analysis revealed a different symptom structure between the two groups globally, while the pairwise differences indicated an increasing connection between tinnitus and dizziness, and a decreasing connection between tinnitus and hearing loss in the early-onset group. Utilizing clustering and network analysis, we have identified two distinct non-headache symptom structures of migraine patients with early-onset age and late-onset age. Our findings suggest that the vestibular-cochlear symptoms may differ in the context of different onset ages of migraine patients, which may contribute to a better understanding of the pathology of vestibular-cochlear symptoms in migraine.


[Prevalence of hemoglobin S in the State of Paraná, Brazil, based on neonatal screening].
The Brazilian Ministry of Health created the National Neonatal Screening Program under ruling no. 822/2001, including neonatal screening for hemoglobinopathies. In the State of Paraná, neonatal screening is conducted by the Ecumenical Foundation for the Protection of the Handicapped. The prevalence rates were determined for homozygous and heterozygous hemoglobin S and Sbeta-thalassemia. Blood samples drawn on filter paper were examined by isoelectric focusing (IEF) and high-performance liquid chromatography (HPLC). From January 2002 to December 2004, 548,810 newborns were screened, with the detection of 21 with FS, two FSA/FS, and four FSA. After confirmatory tests at six months of age, 12 were defined as sickle-cell anemia, or a prevalence of 2.2:100,000 newborns; Sbeta-thalassemia was confirmed in 15 (2.7:100,000 newborns); and 8,321 newborns were diagnosed as heterozygous HbS (1,500:100,000 newborns). HbS prevalence in Paraná (in southern Brazil) is lower than in the Central-West, North, and Northeast of the country. Ethnic origin of the population, fetal deaths, and non-random procreation may contribute to the relatively low number of homozygous individuals in the State. Sbeta-thalassemia interaction suggests the presence of Euro-Mediterranean peoples in this population's miscegenation.


Trait-mediated indirect interactions: Moose browsing increases sawfly fecundity through plant-induced responses.
Induced responses in plants, initiated by herbivory, create potential for trait-mediated indirect interactions among herbivores. Responses to an initial herbivore may change a number of plant traits that subsequently alter ecological processes with additional herbivores. Although common, indirect interactions between taxonomically distant herbivores, such as mammals and insects, are less studied than between taxonomically related species (i.e., insect-insect). In terms of mammal-insect interactions, effects on insect numbers (e.g., density) are relatively well studied, whereas effects on performance (e.g., fecundity) are rarely explored. Moreover, few studies have explored mammal-insect interactions on coniferous plants.The aim of this study was to investigate the effect of mammalian induced responses on insect performance. We specifically investigated the effect of moose (Alces alces) browsing on Scots pine (Pinus sylvestris) and subsequent effects on sawfly (Neodiprion sertifer) performance.Sawfly larvae were reared on browsed, clipped, and unbrowsed control pine trees in a controlled field experiment. Afterward, cocoon weight was measured. Needle C:N ratio and di-terpene content were measured in response to browsing.Sawfly performance was enhanced on trees browsed by moose. Cocoon weight (proxy for fecundity) was 9 and 13% higher on browsed and clipped trees compared to unbrowsed trees. Cocoon weight was weakly related to needle C:N ratio, and browsed trees had lower a C:N ratio compared to unbrowsed trees. Needle di-terpene content, known to affect sawfly performance, was neither affected by the browsing treatments nor did it correlate with sawfly weight.We conclude that mammalian herbivory can affect insect herbivore performance, with potential consequences for ecological communities and with particular importance for insect population dynamics. The measured plant variables could not fully explain the effect on sawfly performance providing a starting point for the consideration of additional plant responses induced by mammalian browsing affecting insect performance.


[Intravascular ultrasound (IVUS): the assessment of tumor infiltration into the vascular wall].
The demonstration or exclusion of tumour infiltration into a vessel wall is made possible by IVUS. This was performed 25 times in 23 patients using a 20 MHz probe where there was suspicion of tumour infiltration on the basis of CT, MRI or angiography. IVUS proved very suitable for clarifying the situation, making direct intravascular evaluation of the affected vessel possible. In 10 cases where surgery was performed, the demonstration or exclusion of tumour infiltration into a vein was confirmed operatively in every case. Further experience is necessary before the value of the method for diagnosing early arterial infiltration can be judged.


Human semen cryopreservation: a sperm DNA fragmentation study with alkaline and neutral Comet assay.
Sperm cryopreservation is widely used for both research and reproduction purposes, but its effect on sperm DNA damage remains controversial. Sperm DNA fragmentation (SDF) has become an important biomarker to assess male infertility. In particular, the differentiation between single- and double-stranded DNA fragmentation (ssSDF and dsSDF) has clinical implications for male infertility where ssSDF is associated with reduced fertility, whereas dsSDF is associated with increased risk of miscarriage. In this study, semen samples from 30 human males have been analysed in both fresh and cryopreserved using the alkaline and neutral Comet assays. Results show an increase of about 10% of ssSDF, assessed by the alkaline Comet assay, regardless of the male fertility status. Neutral Comet analysis of dsSDF does not show any statistical increase when comparing fresh and cryopreserved samples in any of the patient groups. Results support previous reports that oxidative stress is the major effector in DNA damage during sample cryopreservation, as, on one hand, ssSDF has previously been related to oxidative damage and, on the other hand, we have not found any effect on dsSDF. Therefore, there might be a slight risk of decreased fertility after using a freezed sample, but no evidence for increased miscarriage risk from cryopreserved spermatozoa should be expected.


Development of a method for the measurement of primary cilia length in 3D.
Primary cilia length is an important measure of cell and tissue function. While accurate length measurements can be calculated from cells in 2D culture, measurements in tissue or 3D culture are inherently difficult due to optical distortions. This study uses a novel combination of image processing techniques to rectify optical distortions and accurately measure cilia length from 3D images. Point spread functions and experimental resolutions were calculated from subresolution microspheres embedded in 3D agarose gels for both wide-field fluorescence and confocal laser scanning microscopes. The degree of axial smearing and spherical aberration was calculated from xy:xz diameter ratios of 3D image data sets of 4 μm microspheres that had undergone deconvolution and/or Gaussian blurring. Custom-made 18 and 50 μm fluorescent microfibers were also used as calibration objects to test the suitability of processed image sets for 3D skeletonization. Microfiber length in 2D was first measured to establish an original population mean. Fibers were then embedded in 3D agarose gels to act as ciliary models. 3D image sets of microfibers underwent deconvolution and Gaussian blurring. Length measurements within 1 standard deviation of the original 2D population mean were deemed accurate. Finally, the combined method of deconvolution, Gaussian blurring and skeletonization was compared to previously published methods using images of immunofluorescently labeled renal and chondrocyte primary cilia. Deconvolution significantly improved contrast and resolution but did not restore the xy:xz diameter ratio (0.80). Only the additional step of Gaussian blurring equalized xy and xz resolutions and yielded a diameter ratio of 1.02. Following image processing, skeletonization successfully estimated microfiber boundaries and allowed reliable and repeatable measurement of fiber lengths in 3D. We also found that the previously published method of calculating length from 2D maximum projection images significantly underestimated ciliary length. This study used commercial and public domain image processing software to rectify a long-standing problem of 3D microscopy. We have shown that a combination of deconvolution and Gaussian blurring rectifies optical distortions inherent in 3D images and allows accurate skeletonization and length measurement of microfibers and primary cilia that are bent or curved in 3D space.


Risk factors for adverse drug reactions during thiacetazone treatment of pulmonary tuberculosis in human immunodeficiency virus infected adults.
Prospective randomised clinical trial comparing the safety and efficacy of rifampicin- and thiacetazone-containing regimens in human immunodeficiency virus (HIV)-infected adults with pulmonary tuberculosis (TB) at the National Tuberculosis Treatment Centre, Kampala, Uganda. To assess demographic, clinical and laboratory risk factors associated with toxicity during treatment with streptomycin, thiacetazone and isoniazid (STH) of HIV-1 infected adults with pulmonary TB. Nested case-control study of all subjects randomized to the STH treatment arm. Baseline demographic, clinical, microbiological, hematological and radiographic characteristics were compared between subjects who developed and those who did not develop adverse drug reactions (ADR). Of the 90 subjects randomized to STH, 13 developed ADR yielding an incidence rate of 19.6 events per 100 person years of observation (PYO). Eleven of the 13 ADR were cutaneous hypersensitivity reactions, including one fatal case of Stevens-Johnson syndrome. Eight of 13 patients who developed ADR were tuberculin anergic, compared to 12 of 77 patients who did not develop ADR (P < 0.001). An absolute lymphocyte count below 2000 cells/mm3 was also associated with ADR (P = 0.02). Initial anergy to tuberculin and lymphocytopenia, markers of advanced HIV infection and immunosuppression, were associated with increased risk for adverse drug reactions during STH chemotherapy.


Dissolution and homogeneous photocatalysis of polymeric carbon nitride.
As a metal-free conjugated polymer, carbon nitride (CN) has attracted tremendous attention as a heterogeneous (photo)catalyst. By following the example of enzymes, making all of the catalytic sites accessible via homogeneous reactions is a promising approach toward maximizing CN activity, but hindered due to the poor solubility of CN. Herein, we report the dissolution of CN in environmentally friendly methanesulfonic acid, and homogeneous photocatalysis (two biomimetic/pharmaceutical photocatalytic oxidation reactions) driven by CN for the first time with the activity boosted up to 10-times compared to the heterogeneous counterparts. Moreover, facile recycling and reusability, the hallmarks of heterogeneous catalysts, were kept for the homogeneous CN photocatalyst via reversible precipitation using poor solvents. This study opens a new vista for CN in homogeneous catalysis and offers a successful example of a polymeric catalyst that bridges the gap between homo/heterogeneous catalysis.


Silencing Lnc-HES1-10 Inhibits Osteosarcoma Cells Proliferation, Invasive Ability, and Metastasis.
Long noncoding RNA (LncRNA) play a vital role in the development and pathophysiology of osteosarcoma (OS). However, the LncRNA activated by HES1-10 in OS has not been furthered investigated. This present study aims to show the possible function of Lnc-HES1-10 in OS. Cell proliferation in vitro were assessed by the MTT assay, whereas the migration and invasion abilities of OS cell lines were measured by wound-healing migration assay and transwell invasion assay, respectively. Quantitative reverse transcriptase polymerase chain reaction and western blot analysis was used to detected the expression level of HES1-10. The present study demonstrated that the Lnc-HES1-10 is overexpressed in OS and associated with poor prognosis of patients. In addition, the results revealed that Lnc-HES1-10 is overexpressed in MG63 and 143B OS cell lines and promote proliferation on both cell lines in vitro. Furthermore, migration and invasion abilities of MG63 and 143B cells are suppressed after silencing Lnc-HES1-10. Our finding demonstrates that HES1-10 plays a crucial role in regulating OS growth and metastasis.


Three sea urchin actin genes show different patterns of expression: muscle specific, embryo specific, and constitutive.
The expression of three different actin genes in the sea urchin, Strongylocentrotus purpuratus, was monitored in embryos and adult tissues by using untranslated mRNA sequences as specific hybridization probes. Three distinct patterns of expression were found: muscle specific, embryo specific, and constitutive (i.e., present in all tissues examined). The actin genes encoding the muscle-specific and constitutively expressed genes were each found to be present once in the haploid genome. The embryo-specific probe could derive from either a single gene or a small subset of actin genes. These data demonstrate that at least three members of the sea urchin actin gene family are expressed in distinct ways and thus are probably associated with different regulatory programs of gene expression necessary for development of this metazoan.


Outcomes following deep brain stimulation lead revision or reimplantation for Parkinson's disease.
OBJECTIVEThe number of patients who benefit from deep brain stimulation (DBS) for Parkinson's disease (PD) has increased significantly since the therapy was first approved by the FDA. Suboptimal outcomes, infection, or device failure are risks of the procedure and may require lead removal or repositioning. The authors present here the results of their series of revision and reimplantation surgeries.METHODSThe data were reviewed from all DBS intracranial lead removals, revisions, or reimplantations among patients with PD over a 6-year period at the authors' institution. The indications for these procedures were categorized as infection, suboptimal outcome, and device failure. Motor outcomes as well as lead location were analyzed before removal and after reimplant or revision.RESULTSThe final sample included 25 patients who underwent 34 lead removals. Thirteen patients had 18 leads reimplanted after removal. There was significant improvement in the motor scores after revision surgery among the patients who had the lead revised for a suboptimal outcome (p = 0.025). The mean vector distance of the new lead location compared to the previous location was 2.16 mm (SD 1.17), measured on an axial plane 3.5 mm below the anterior commissure-posterior commissure line. When these leads were analyzed by subgroup, the mean distance was 1.67 mm (SD 0.83 mm) among patients treated for infection and 2.73 mm (SD 1.31 mm) for those with suboptimal outcomes.CONCLUSIONSPatients with PD who undergo reimplantation surgery due to suboptimal outcome may experience significant benefits. Reimplantation after surgical infection seems feasible and overall safe.


Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-matched analysis from the STS database.
Several single-institution series have demonstrated that compared with open thoracotomy, video-assisted thoracoscopic lobectomy may be associated with fewer postoperative complications. In the absence of randomized trials, we queried the Society of Thoracic Surgeons database to compare postoperative mortality and morbidity following open and video-assisted thoracoscopic lobectomy. A propensity-matched analysis using a large national database may enable a more comprehensive comparison of postoperative outcomes. All patients having lobectomy as the primary procedure via thoracoscopy or thoracotomy were identified in the Society of Thoracic Surgeons database from 2002 to 2007. After exclusions, 6323 patients were identified: 5042 having thoracotomy, 1281 having thoracoscopy. A propensity analysis was performed, incorporating preoperative variables, and the incidence of postoperative complications was compared. Matching based on propensity scores produced 1281 patients in each group for analysis of postoperative outcomes. After video-assisted thoracoscopic lobectomy, 945 patients (73.8%) had no complications, compared with 847 patients (65.3%) who had lobectomy via thoracotomy (P < .0001). Compared with open lobectomy, video-assisted thoracoscopic lobectomy was associated with a lower incidence of arrhythmias [n = 93 (7.3%) vs 147 (11.5%); P = .0004], reintubation [n = 18 (1.4%) vs 40 (3.1%); P = .0046], and blood transfusion [n = 31 (2.4%) vs n = 60 (4.7%); P = .0028], as well as a shorter length of stay (4.0 vs 6.0 days; P < .0001) and chest tube duration (3.0 vs 4.0 days; P < .0001). There was no difference in operative mortality between the 2 groups. Video-assisted thoracoscopic lobectomy is associated with a lower incidence of complications compared with lobectomy via thoracotomy. For appropriate candidates, video-assisted thoracoscopic lobectomy may be the preferred strategy for appropriately selected patients with lung cancer.


Chemically Modified Antisense Oligonucleotide Against ARL4C Inhibits Primary and Metastatic Liver Tumor Growth.
ADP-ribosylation factor-like 4c (ARL4C) is identified as a small GTP-binding protein, which is expressed by Wnt and EGF signaling and plays an important role in tubulogenesis of cultured cells and the ureters. ARL4C is little expressed in adult tissues, but it is highly expressed in lung cancer and colorectal cancer and shown to represent a molecular target for cancer therapy based on siRNA experiments. This study revealed that ARL4C is highly expressed in primary hepatocellular carcinoma (HCC) tumors and colorectal cancer liver metastases, and that ARL4C expression is associated with poor prognosis for these cancers. Chemically modified antisense oligonucleotides (ASO) against ARL4C effectively reduced ARL4C expression in both HCC and colorectal cancer cells and inhibited proliferation and migration of these cancer cells in vitro ARL4C ASOs decreased the PIK3CD mRNA levels and inhibited the activity of AKT in HCC cells, suggesting that the downstream signaling of ARL4C in HCC cells is different from that in lung and colon cancer cells. In addition, subcutaneous injection of ARL4C ASO was effective in reducing the growth of primary HCC and metastatic colorectal cancer in the liver of immunodeficient mice. ARL4C ASO accumulated in cancer cells more efficiently than the surrounding normal cells in the liver and decreased ARL4C expression in the tumor. These results suggest that ARL4C ASO represents a novel targeted nucleic acid medicine for the treatment of primary and metastatic liver cancers.


CHEMORESISTANCE RELATED TO HYPOXIA ADAPTATION IN MESOTHELIOMA CELLS FROM TUMOR SPHEROIDS.
Hypoxia has been noted as a key factor for induction and maintenance of cancer stemness thereby leading to therapy resistance. Three-dimensional (3D) spheroid models demonstrate a heterogeneity of hypoxic regions replicating the in vivo situation within tumors. Utilizing an established 3D spheroid model, we investigated whether extrinsic hypoxia reinforced chemoresistance in malignant pleural mesothelioma (MPM) spheroids. Tumor spheres were generated from Meso-1 (a typical human MPM cell line) cells having high spheroid-forming ability. To induce hypoxia condition, we utilized a hypoxia chamber with regulation of O2 and CO2 levels. Cell viability was estimated by a WST-8 assay. Real-time polymerase chain reaction and Western blot were performed to evaluate the expression at mRNA and protein levels. Compared with cells cultured in the two-dimensional monolayer model, tumor sphere cells showed elevated mRNA levels of cancer stemness markers (CD26, CD44 and ABCG2) and protein levels of the stemness and hypoxia adaptation markers (ABCG2, ALDH1A1 and HIFs). Correlating with this, 3D spheroid cells were more resistant to permetrexed and topotecan than the two-dimensional cells, indicative of their potential for hypoxic adaptation. Furthermore, significantly stronger resistance to both chemotherapeutic agents was observed in spheroid cells upon hypoxic challenge compared to spheroid cells under normoxia. From the present data, it is concluded that hypoxia adaptation of MPM cells from tumor spheres could enhance their chemoresistance.


NIR Light-Activated Mitochondrial RNA Cross-Linking Strategy for H2S Monitoring and Prolonged Colorectal Tumor Imaging.
Molecular diffusion and leakage impede the long-term retention of probes/drugs and may cause potential adverse effects in theranostic fields. Spatiotemporally manipulating the organelle-immobilization behavior of probes/drugs for prolonged tumor retention is indispensable to achieving effective cancer diagnosis and therapy. Herein, we propose a rational strategy that could realize near-infrared light-activated ribonucleic acids (RNAs) cross-linking for prolonged tumor retention and simultaneously endogenous hydrogen sulfide (H2S) monitoring in colorectal tumors. Profiting from efficient singlet oxygen (1O2) generation from Cy796 under 808 nm light irradiation, the 1O2-animated furan moiety in Cy796 could covalently cross-link with cytoplasmic RNAs via a cycloaddition reaction and realize organelle immobilization. Subsequently, specific thiolysis of Cy796 assisted with H2S resulted in homologous product Cy644 with reduced 1O2 generation yields and enhanced absolute fluorescence quantum yields (from 7.42 to 27.70%) with blue-shifted absorption and emission, which avoided the molecular oxidation fluorescence quenching effect mediated by 1O2 and validated fluorescence imaging. Furthermore, studies have demonstrated that our proposed strategy possessed adequate capacity for fluorescence imaging and endogenous H2S detection in HCT116 cells, particularly accumulated at the tumor sites, and retained long-term imaging with excellent biocompatibility. The turn-on fluorescence mode and turn-off 1O2 generation efficiency in our strategy successfully realized a diminished fluorescence cross-talk and oxidation quenching effect. It is adequately envisioned that our proposed strategy for monitoring biomarkers and prolonged tumor retention will contribute tremendous dedication in the clinical, diagnostic, and therapeutic fields.


Chronic hepatitis B virus infection: treatment strategies for the next millennium.
Chronic hepatitis B virus (HBV) infection is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Its prevalence approaches 10% in hyperendemic areas, such as southeast Asia, China, and Africa. Although chronic HBV infection is seen less frequently in North America and Europe, an estimated 1.25 million persons in the United States are infected. In the past decade, revolutionary strides have been made toward the treatment of chronic HBV infection. Interferon-alpha was once the only available therapy but has recently been joined by the nucleoside analogues, the most extensively studied of which is lamivudine. Interferon therapy continues to have a role in the treatment of a carefully selected group of patients. Lamivudine therapy, which has less stringent selection criteria, suppresses HBV DNA in almost all treated patients: Seventeen percent to 33% experience loss of hepatitis B e antigen, and 53% to 56% have a histologic response. Extended lamivudine treatment leads to the development of a specific lamivudine-resistant virus with base-pair substitutions at the YMDD locus of the DNA polymerase. Newer nucleoside analogues and other immunomodulator therapies are being investigated. In the future, combination therapy with different classes of agents may yield improved response rates and delay the development of resistance.


Clonal analyses in the anterior pre-placodal region: implications for the early lineage bias of placodal progenitors.
Cranial ectodermal placodes, a vertebrate innovation, contribute to the adenohypophysis and peripheral nervous system of the head, including the paired sense organs (eyes, nose, ears) and sensory ganglia of the Vth, VIIth, IXth and Xth cranial nerves. Fate-maps of groups of cells in amphibians, teleosts and amniotes have demonstrated that all placodes have a common origin in a horseshoe shaped territory, known as the preplacodal region (PPR), which surrounds the presumptive neural plate of the late gastrula/early neurula stage embryo. Given the extensive regional overlap of progenitors for different placodes in the chick embryo, it has been a matter of debate as to whether individual cells in the PPR are truly multipotent progenitors, with regard to placodal identity, or rather are lineage-biased or restricted to a specific placodal type prior to overt differentiation. Utilizing clonal analyses in vivo, we demonstrate here that the anterior PPR comprises some precursors that contribute either to the olfactory or lens placode well before they are spatially segregated or committed to either of these placodal fates. This suggests that lineage bias towards a specific placodal fate may coincide with induction of the PPR.


Pathophysiology of Keratoconus: What Do We Know Today.
Keratoconus is a common corneal ectasia that leads to progressive visual impairment. Numerous studies have shown abnormal protein expression patterns in keratoconic corneas. However, the specific mechanisms causing this disease remain ambiguous. This review aims to provide an update on morphological studies of the keratoconic cornea, relate these early studies with current findings from proteomic, biochemical and cell culture studies and to postulate possible pathogenic pathways.


Cerebral air embolism via port catheter and endoscopic retrograde cholangio-pancreatography.
Cerebral air embolism (CAE) is a critical clinical condition necessitating rapid diagnosis and therapeutic measures. The authors describe two patients with lethal CAE. An 81-year-old man rapidly developed coma with tetraplegia. CT-scan revealed prominent CAE whereby the entry of the air was via a port catheter for parenteral nutrition. A 45-year-old man with severe alcohol-toxic multiple organ damage needed endoscopic retrograde cholangio-pancreatography (ERCP) and a second esophagogastroscopy. After an epileptic seizure, the CT-scan of the brain showed small amounts of cerebral air in the posterior right hemisphere and in the sagittal superior sinus. Despite critical care the patient died. CAE is a neurocritical emergency case. Early CT-scan of the brain can detect air, guide further therapy, and contribute to the assessment of the prognosis.


Targeting of host cell receptor tyrosine kinases by intracellular pathogens.
Intracellular pathogens use complex and tightly regulated processes to enter host cells. Upon initial interactions with signaling proteins at the surface of target cells, intracellular microbes activate and co-opt specific host signaling pathways that mediate cell surface-cytosol communications to facilitate pathogen internalization. Here, we discuss the roles of host receptor tyrosine kinases (RTKs) in the establishment of productive infections by major intracellular pathogens. We evaluate the gaps in the current understanding of this process and propose a comprehensive approach for assessing the role of host cell signaling in the biology of intracellular microorganisms and viruses. We also discuss RTK-targeting strategies for the treatment of various infections.


Choline metabolism in the cerebral cortex of guinea pigs. Phosphorylcholine and lipid choline.
1. The labelling of phosphorylcholine and choline-containing phospholipids in the subcellular fractions of guinea-pig cerebral cortex after the intraventricular injection of [N-Me-(3)H]choline into conscious animals has been studied. Special emphasis was placed upon the synaptosome fraction and early time-periods after administration. 2. The labelling of phosphorylcholine was rapid compared with that of phospholipid and was confined to two distinct subcellular fractions: the soluble cytoplasmic fraction and the synaptosome fraction. Most of the labelled phosphorylcholine of the synaptosome fraction was readily released by osmotic rupture indicating location in the nerve-ending cytoplasm. The two pools of phosphorylcholine had similar specific radioactivities at all observed times. 3. (3)H-labelled phospholipid was found in all membranous fractions. The labelling was confined to choline-containing phospholipids, notably phosphatidylcholine. 4. The labelling of the different membranous fractions was similar. 5. The half-life of the choline-containing phospholipids in the synaptic vesicle fraction was very much greater than the acetylcholine in this fraction. 6. Evidence is presented that synthesis de novo of phosphatidylcholine at nerve terminals occurs in vivo.


Transient activation of hematopoietic stem and progenitor cells by IFNγ during acute bacterial infection.
How hematopoietic stem cells (HSCs) respond to inflammatory signals during infections is not well understood. Our studies have used a murine model of ehrlichiosis, an emerging tick-born disease, to address how infection impacts hematopoietic function. Infection of C57BL/6 mice with the intracellular bacterium, Ehrlichia muris, results in anemia and thrombocytopenia, similar to what is observed in human ehrlichiosis patients. In the mouse, infection promotes myelopoiesis, a process that is critically dependent on interferon gamma (IFNγ) signaling. In the present study, we demonstrate that E. muris infection also drives the transient proliferation and expansion of bone marrow Lin-negative Sca-1(+) cKit(+) (LSK) cells, a population of progenitor cells that contains HSCs. Expansion of the LSK population in the bone marrow was associated with a loss of dormant, long-term repopulating HSCs, reduced engraftment, and a bias towards myeloid lineage differentiation within that population. The reduced engraftment and myeloid bias of the infection-induced LSK cells was transient, and was most pronounced on day 8 post-infection. The infection-induced changes were accompanied by an expansion of more differentiated multipotent progenitor cells, and required IFNγ signaling. Thus, in response to inflammatory signals elicited during acute infection, HSCs can undergo a rapid, IFNγ-dependent, transient shift from dormancy to activity, ostensibly, to provide the host with additional or better-armed innate cells for host defense. Similar changes in hematopoietic function likely underlie many different infections of public health importance.


A Population-Based Approach to Reporting System-Level Performance Measures for Rheumatoid Arthritis Care.
To operationalize and report on nationally endorsed rheumatoid arthritis (RA) performance measures (PMs) using health administrative data for British Columbia (BC), Canada. All patients with RA in BC ages ≥18 years were identified between January 1, 1997 and December 31, 2009 using health administrative data and followed until December 2014. PMs tested include: the percentage of incident patients with ≥1 rheumatologist visit within 365 days; the percentage of prevalent patients with ≥1 rheumatologist visit per year; the percentage of prevalent patients dispensed disease-modifying antirheumatic drug (DMARD) therapy; and time from RA diagnosis to DMARD therapy. Measures were reported on patients seen by rheumatologists, and in the total population. The cohort included 38,673 incident and 57,922 prevalent RA cases. The percentage of patients seen by a rheumatologist within 365 days increased over time (35% in 2000 to 65% in 2009), while the percentage of RA patients under the care of a rheumatologist seen yearly declined (79% in 2001 to 39% in 2014). The decline was due to decreasing visit rates with increasing follow-up time rather than calendar effect. The percentage of RA patients dispensed a DMARD was suboptimal over follow-up (37% in 2014) in the total population but higher (87%) in those under current rheumatologist care. The median time to DMARD in those seen by a rheumatologist improved from 49 days in 2000 to 23 days in 2009, with 34% receiving treatment within the 14-day benchmark. This study describes the operationalization and reporting of national PMs using administrative data and identifies gaps in care to further examine and address.


Saccorhiza polyschides-A Source of Natural Active Ingredients for Greener Skincare Formulations.
The growing knowledge about the harmful effects caused by some synthetic ingredients present in skincare products has led to an extensive search for natural bioactives. Thus, this study aimed to investigate the dermatological potential of five fractions (F1-F5), obtained by a sequential extraction procedure, from the brown seaweed Saccorhiza polyschides. The antioxidant (DPPH, FRAP, ORAC and TPC), anti-enzymatic (collagenase, elastase, hyaluronidase and tyrosinase), antimicrobial (Staphylococcus epidermidis, Cutibacterium acnes and Malassezia furfur), anti-inflammatory (nitric oxide, tumor necrosis factor-α, interleukin-6 and interleukin-10) and photoprotective (reactive oxygen species) properties of all fractions were evaluated. The ethyl acetate fraction (F3) displayed the highest antioxidant and photoprotective capacity, reducing ROS levels in UVA/B-exposed 3T3 fibroblasts, and the highest anti-enzymatic capacity against tyrosinase (IC50 value: 89.1 µg/mL). The solid water-insoluble fraction (F5) revealed the greatest antimicrobial activity against C. acnes growth (IC50 value: 12.4 µg/mL). Furthermore, all fractions demonstrated anti-inflammatory potential, reducing TNF-α and IL-6 levels in RAW 264.7 macrophages induced with lipopolysaccharides. Chemical analysis of the S. polyschides fractions by NMR revealed the presence of different classes of compounds, including lipids, polyphenols and sugars. The results highlight the potential of S. polyschides to be incorporated into new nature-based skincare products.


Therapeutic Evaluation of Computed Tomography Findings for Efficacy of Prone Ventilation in Acute Respiratory Distress Syndrome Patients with Abdominal Surgery.
In Acute Respiratory Distress Syndrome (ARDS), the heterogeneity of lung lesions results in a mis-match between ventilation and perfusion, leading to the development of hypoxia. The study aimed to examine the association between computed tomographic (CT scan) lung findings in patients with ARDS after abdominal surgery and improved hypoxia and mortality after prone ventilation. A single site, retrospective observational study was performed at the Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan, between 1st January 2004 and 31st October 2018. Patients were allocated to one of two groups after CT scanning according to the presence of ground-glass opacity (GGO) or alveolar shadow with predominantly dorsal lung atelectasis (DLA) on lung CT scan images. Also, Patients were divided into a prone ventilation group and a supine ventilation group when the treatment for ARDS was started. We analyzed data for fifty-one patients with ARDS following abdominal surgery. CT scans confirmed GGO in five patients in the Group A and in nine patients in the Group B, and DLA in 17 patients in the Group A and nine patients in the Group B. Both GGO and DLA were present in two patients in the Group A and nine patients in the Group B. Prone ventilation significantly improved patients' impaired ratio of arterial partial pressure of oxygen to fraction of inspired oxygen from 12 h after prone positioning compared with that in the supine position. Weaning from mechanical ventilation occurred significantly earlier in the Group A with DLA vs the Group B with DLA (P < 0.001). Twenty-eight-day mortality was significantly lower for the Group A with DLA vs the Group B with DLA (P = 0.035). These results suggest that prone ventilation could be effective for treating patients with ARDS as showing the DLA.


A review of epidemiological data on epilepsy, phenobarbital, and risk of liver cancer.
Phenobarbital is not genotoxic, but has been related to promotion of liver cancer (as well as inhibition) in rodents. In October 2012, we carried out a systematic literature search in the Medline database and searched reference lists of retrieved publications. We identified 15 relevant papers. Epidemiological data on epileptics/anticonvulsant use and liver cancer were retrieved from eight reports from seven cohort (record linkage) studies of epileptics, and data on phenobarbital use from a pharmacy-based record linkage investigation of patients treated with phenobarbital (three reports), plus a case-control study nested in one of the cohort studies and including information on phenobarbital use. Of the studies of cancer in epileptics, two showed no excess risk of liver cancer. A long-term (1933-1984) Danish cohort study of epileptics found relative risks (RRs) of 4.7 [95% confidence interval (CI) 3.2-6.8] of liver cancer and of 2.2 (95% CI 1.2-3.5) of biliary tract cancers. Such apparent excess risks could, however, be largely or completely attributed to thorotrast, a contrast medium used in the past in epileptic patients for cerebral angiography. A Finnish cohort study of epileptics obtained an RR of 1.7 (95% CI 1.2-2.4). Such an apparent excess risk, however, was not related to phenobarbital or to any specific anticonvulsant drug. The long-term follow-up of two UK cohorts found some excess risk of liver cancer among severe, but not among mild, epileptics. Some excess risk of liver cancer was also found in cohort studies of patients hospitalized for epilepsy in Sweden and Taiwan, in the absence, however, of association with any specific drugs. A UK General Practice database, comparing epileptics treated with valproate with unexposed ones, found a very low incidence of liver cancer. Of the studies of cancer in patients treated with phenobarbital, a large US pharmacy-based cohort investigation showed no excess risk of liver cancer. In a case-control study, nested in the Danish cohort of epileptics, no association was observed between phenobarbital and liver cancer among patients who had not received thorotrast (RR=1.0 for liver and 0.8 for biliary tract cancers). Thus, some, although not all, studies reported excess risk of all cancers and liver cancer in severe, but not in milder epileptics. There is no evidence of a specific role of phenobarbital in human liver cancer risk, but data on the topic are limited.


[Pathogenicity of the Lassa virus for laboratory mice].
Pathogenicity for randombred and inbred mice of various age groups of the standard Lassa virus and the virus enriched with defective interfering particles (DIP) was studied. The standard Lassa virus inoculated intracerebrally caused 100% death of C3H/Sn mice aged up to 4 weeks and 60%-70% death of randombred white mice aged 3-4 weeks. BALB/C mice were found to be nonsusceptible to the virus, and its lethality for C57BL/6 and AKR mice varied within the range of 30%-60%. Lassa virus enriched with DIP caused no death of the susceptible animals and showed poor protective activity against the standard virus.


Characterization of Spanish grapevine cultivar diversity using sequence-tagged microsatellite site markers.
A broad germplasm bank collection containing most of the autochthonous Spanish grapevine cultivars was analyzed using six sequence-tagged microsatellite site (STMS) loci: VVS2, VVMD5, VVMD7, ssrVrZAG47, ssrVrZAG62, and ssrVrZAG79. The number of alleles obtained ranged from 9 in ssrVrZAG47 to 13 in VVS2, and the observed genotypes per locus varied between 24 (ssrVrZAG47) and 41 (VVSS2). A total of 57 unique genotypes were obtained considering all 6 loci, and 40 varieties presented at least 1 of these specific genotypes. The genotypic combinations for the 6 loci have generated 163 different profiles in the 176 cultivars. Ten pairs of accessions and one group of four Garnacha's cultivars can not be differentiated. The observed heterozygosity varied between 75.6 (VVMD7) and 90.9% (VVMD5), without significant differences from the expected values for any loci. The VVMD5 locus was the most informative, and also showed the highest discrimination power. The cumulative discrimination power for all six loci was practically 1; however, in fact, these STMS loci have differentiated only about 93% of the accessions, probably owing to high relatedness of the plant material. Usefulness of this STMS set for characterization of a Spanish grapevine collection is emphasized, as well as the elaboration of databases with these molecular markers.


Higher order structures in purine and pyrimidine metabolism.
The recent discovery of several forms of higher order protein structures in cells has shifted the paradigm of how we think about protein organization and metabolic regulation. These dynamic and controllable protein assemblies, which are composed of dozens or hundreds of copies of an enzyme or related enzymes, have emerged as important players in myriad cellular processes. We are only beginning to appreciate the breadth of function of these types of macromolecular assemblies. These higher order structures, which can be assembled in response to varied cellular stimuli including changing metabolite concentrations or signaling cascades, give the cell the capacity to modulate levels of biomolecules both temporally and spatially. This provides an added level of control with distinct kinetics and unique features that can be harnessed as a subtle, yet powerful regulatory mechanism. Due, in large part, to advances in structural methods, such as crystallography and cryo-electron microscopy, and the advent of super-resolution microscopy techniques, a rapidly increasing number of these higher order structures are being identified and characterized. In this review, we detail what is known about the structure, function and control mechanisms of these mesoscale protein assemblies, with a particular focus on those involved in purine and pyrimidine metabolism. These structures have important implications both for our understanding of fundamental cellular processes and as fertile ground for new targets for drug discovery and development.