The impact of prolonged mechanical ventilation after acute type A aortic dissection repair.
Patients with type A aortic dissection have increased resource use. The objective of this study was to describe the relationship between prolonged mechanical ventilation and longitudinal survival in patients undergoing type A aortic dissection repair. We conducted a retrospective analysis of patients with type A aortic dissection undergoing repair from 2010 to 2018; Kaplan-Meier function and adjusted Cox regression analysis were used to compare in-hospital mortality and longitudinal survival accounting for time on mechanical ventilatory support. A total of 552 patients were included. The study population was divided into 12 hours or less (n = 291), more than 12 to 24 or less hours (n = 101), more than 24 to 48 hours or less (n = 60), and more than 48 hours (n = 100) groups. Patients within the 12 or less hours group were the youngest (60.0 vs 63.5 years vs 63.6 vs 62.8 years; P = .03) and less likely to be female (31.6% vs 43.6% vs 46.7% vs 56.0%; P < .001). On the other hand, the more than 48 hours group presented with malperfusion syndrome at admission more often (24.4% vs 29.7% vs 28.3% vs 53.0%; P < .001) and had longer cardiopulmonary and ischemic times (P < .05). In-hospital mortality was significantly higher in the more than 48 hours group (5.2% vs 6.9% vs 3.3% vs 30.0%; P < .001). Multivariable analysis demonstrated worse longitudinal survival for the 24 to 48 hours group (hazard ratio, 1.94, confidence interval, 1.10-3.43) and more than 48 hours ventilation group (hazard ratio, 2.25, confidence interval, 1.30-3.92). The need for prolonged mechanical ventilatory support is prevalent and associated with other perioperative complications. More important, after adjusting for other covariates, prolonged mechanical ventilation is an independent factor associated with increased longitudinal mortality.


[Centering angles of the femoral head and neck in the dysplastic hip].
Centering angle of the femoral head determining relation of the head and acetabulum depending on the epiphyseal plane and acetabular roof coverage of the head is described. Centering angles of the neck indicating cranial or lateral dislocation of the proximal femur in relation to apparent shaft-neck angle and anteversion angle are also described. The parameters proved useful in grading of the dysplastic hip.


The perinuclear space of pancreatic acinar cells and the synthetic pathway of zymogen in Scorpaena scrofa L.: ultrastructural aspects.
Electron microscopic examination of exocrine pancreatic tissues from the fish Scorpaena scrofa L., probably captured while replenishing the acinar cells, shows two main functional cell morphologies of the same cell type. One cell functional aspect contains numerous well-contrasted small vesicles, the zymogenic vesicles. The other functional morphology is mainly represented by a few cells containing large apical zymogen vesicles with many empty RER cisterns. In our observations, the zymogenic vesicles are always studded with ribosomes. The main cytological finding is to report that zymogenic vesicles can be extruded from the perinuclear space and it confirms the suspected, synthetic activity of this cell compartment. The pool of zymogenic vesicles, maintaining their coat of ribosomes, then fuses and transfers their content into the cis Golgi complex network. Finally, the zymogen vesicles are produced following the classical secretory pathway from the trans Golgi saccular network into the supranuclear, apical region of the acinar cells where the largest vesicles concentrate their content until secretion.


A Comparison of Insulin Doses for the Treatment of Hyperkalemia in Patients with Renal Insufficiency.
To compare the safety and efficacy of 5 units versus 10 units of insulin for the treatment of hyperkalemia in patients with renal insufficiency. Retrospective cohort study. Large academic medical center emergency department. Between March 1, 2008, and February 29, 2016, 675 patients met the inclusion criteria of age 18 years and older, serum potassium greater than 5 mEq/L, renal insufficiency, 5 units or 10 units of intravenous regular insulin administered in the emergency department, and blood glucose documented within 5 hours after insulin administration. Of these patients, 133 (19.7%) received 5 units of insulin and 542 (80.3%) received 10 units of insulin. The primary outcome was incidence of hypoglycemia (blood glucose < 70 mg/dl). Secondary outcomes were incidence of severe hypoglycemia (blood glucose < 40 mg/dl) and change in serum potassium after insulin therapy. Hypoglycemia occurred in 26 of 133 patients receiving 5 units of insulin (19.5%) and in 155 of 542 patients receiving 10 units (28.6%) (difference = -9.1%, 95% confidence interval [CI] -16.8% to -1.3%). Severe hypoglycemia occurred in 4 of 133 patients (3.0%) and 37 of 542 patients (6.8%) receiving insulin 5 units and 10 units, respectively (difference = -3.8%, 95% CI -7.4% to 0%). Change in serum potassium was similar between groups (-1.0 ± 0.8 vs -1.0 ± 0.7 mEq/L, difference = 0, 95% CI -0.1 to 0.1). In patients with renal insufficiency and hyperkalemia, 5 units of insulin reduced serum potassium to the same extent as 10 units of insulin but with a lower rate of hypoglycemia. Further controlled studies are needed to confirm these findings.


Teleneurology clinics for polyneuropathy: a pilot study.
Polyneuropathy (PN) is a common condition with significant morbidity. We developed tele-polyneuropathy (tele-PN) clinics to improve access to neurology and increase guideline-concordant PN care. This article describes the mixed-methods evaluation of pilot tele-PN clinics at three community sites within the Greater Los Angeles VA Healthcare System. For the first 25 patients (48 scheduled visits), we recorded the duration of the tele-PN visit and exam; the performance on three guideline-concordant care indicators (PN screening labs, opiate reduction, physical therapy for falls); and patient-satisfaction scores. We elicited comments about the tele-PN clinic from patients and the clinical team. We combined descriptive statistics with qualitative themes to determine the feasibility and acceptability of the tele-PN clinics. The average tele-PN encounter and exam times were 28.5 and 9.1 min, respectively. PN screening lab completion increased from 80 to 100%. Opiate freedom improved from 68 to 88%. Physical therapy for patients with recent falls increased from 58 to 100%. The tele-PN clinic was preferred for follow-up over in-person clinics in 86% of cases. Convenience was paramount to the clinic's success, saving an average of 231 min per patient in round-trip travel. The medical team's caring and collaborative spirit received high praise. While the clinic's efficiency was equal or superior to in-person care, the limited treatment options for PN and the small clinical exam space are areas for improvement. In this pilot, we were able to efficiently see and examine patients remotely, promote guideline-concordant PN care, and provide a high-satisfaction encounter.


Stromal cell-derived inducing activity does not promote dopaminergic differentiation, but enhances differentiation and proliferation of neural stem cell-derived astrocytes.
Previous evidence has shown that stromal cell-derived inducing activity (SDIA), produced by the mouse PA6 stromal cell line, promotes dopaminergic differentiation of mouse, monkey and human embryonic stem cells in vitro. To examine whether PA6 stromal cells can enhance the yield of dopaminergic differentiation from neural progenitors, we generated neurospheres from embryonic day 11.5 (E11.5) (midbrain and forebrain) and E14.5 (ventral mesencephalon and cortex) rat embryos and allowed them to differentiate in co-culture with PA6 cells or poly-l-lysine/laminin-coated dishes. We observed that SDIA did not promote dopaminergic differentiation of E11.5 and E14.5 neurospheres but more prominently, enhanced astrocyte differentiation, cell survival and astrocyte proliferation. Our results suggest that PA6 cells do not have a general capacity to promote differentiation into dopaminergic neurons from all types of stem cells, but that they may specifically induce dopaminergic differentiation of highly uncommitted stem cells such as embryonic stem cells.


DPC 817: a cytidine nucleoside analog with activity against zidovudine- and lamivudine-resistant viral variants.
Highly active antiretroviral therapy (HAART) is the standard treatment for infection with the human immunodeficiency virus (HIV). HAART regimens consist of protease inhibitors or nonnucleoside reverse transcriptase inhibitors combined with two or more nucleoside reverse transcriptase inhibitors (NRTIs). DPC 817, 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (PSI 5582 D-D4FC) is a potent inhibitor of HIV type 1 replication in vitro. Importantly, DPC 817 retains activity against isolates harboring mutations in the reverse transcriptase gene that confer resistance to lamivudine (3TC) and zidovudine (AZT), which are frequent components of initial HAART regimens. DPC 817 combines this favorable resistance profile with rapid uptake and conversion to the active metabolite DPC 817-triphosphate, which has an intracellular half-life of 13 to 17 h. Pharmacokinetics in the rhesus monkey suggest low clearance of parent DPC 817 and a plasma half-life longer than that of either AZT or 3TC. Together, these properties suggest that DPC 817 may be useful as a component of HAART regimens in individuals with resistance to older NRTI agents.


Efficient radiation production in long implosions of structured gas-puff Z pinch loads from large initial radius.
We have proposed and demonstrated successfully a new approach for generating high-yield K-shell radiation with large-diameter gas-puff Z pinches. The novel load design consists of an outer region plasma that carries the current and couples energy from the driver, an inner region plasma that stabilizes the implosion, and a high-density center jet plasma that radiates. It increased the Ar K-shell yield at 3.46 MA in 200 ns implosions from 12 cm initial diameter by a factor of 2, to 21 kJ, matching the yields obtained earlier on the same accelerator with 100 ns implosions. A new "pusher-stabilizer-radiator" physical model is advanced to explain this result.


[Device for studying the kinematics of movement of closing elements in artificial heart valves].
A device designed for studying the motion kinematics of locking elements in the artificial cardiac valves is described. The principle of its operation is based on the photoelectric registration with subsequent electronic differentiation of the electric displacement signal. The length of measurable linear displacement is 0+20 mm. The amplitudinal-frequency characteristics of the differentiator is linear within the range of 0+120 Hz. The error of the displacement and speed error--not more than 5 per cent.


The systematical analysis of oriental pulse waveform: a practical approach.
With the view to set up the oriental pulse database as well as objective diagnosis standards, this study has designed and manufactured a digital pulse diagnosis system that uses a high-performance microprocessor on the basis of systematic pulse diagnosis methodology. The algorithm for extracting significant points has been proposed to precisely interpret the pulse signals that have various kinds of noises, and pulse measurement tests were conducted on many patients at a hospital. Much of the clinical data attained by the digital pulse diagnosis system has been compared with the clinical findings made by the doctors in charge of patients. As a result of this comparison and analysis, the study has found out that the two findings showed almost identical opinions. On this basis, an objective diagnostic parameter clinical diagnosis has been presented.


Structure of the parathyroid glands, as revealed by different methods of fixation. A quantitative light- and electron-microscopic study in untreated Mongolian gerbils.
Stereology and semi-automatic image analysis were used with the aim of comparing the structure of parathyroid glands from untreated adult Mongolian gerbils fixed by immersion with those fixed by perfusion. Subclassification of the chief cells based upon the staining affinity or electron density of the cytoplasm was readily performed only in glands fixed by immersion, and so-called atrophic cells were observed only in these glands. The atrophic cells were often surrounded by "light" chief cells. In glands fixed by perfusion, "light" chief cells were only rarely encountered. A significant difference between glands fixed by immersion and those fixed by perfusion was found only with regard to the form of cells and nuclei, those fixed by perfusion being more spherical. When comparing individual cells within glands fixed by immersion, "light" chief cells were more spherical and had a significantly larger nuclear and cellular size, and a lower mitochondrial volume density than the "intermediate"/"dark" chief cells. Otherwise there were no significant differences in any of the parameters investigated. These data indicate that occurrence of so-called "light" chief cells and atrophic cells is a result of improper fixation. The results of this study do not favour the concept of a functional cycle with a simultaneous occurrence of active and inactive cells within parathyroid glands.


Motivation as a Mechanism for Daily Experiences' Effects on HIV Medication Adherence.
Medication adherence is a challenge for people living with HIV (PLWH), who may experience a gap between their intentions and everyday behaviors. We measured PLWH's (n = 87) daily experiences and tested a model to explain the intention-behavior gap. Participants completed baseline questionnaires, then used a smartphone-based survey and an electronic pill bottle to provide daily data for the next 10 weeks. These PLWH, with generally well-controlled HIV, were nevertheless adherent on only 73% of study days. Multilevel analyses were used to test predicted relationships between variables (n = 58). Four of five theory-based daily measures predicted motivation for antiretroviral therapy (betas = 0.06-0.10), and motivation, in turn, predicted adherence. Consistent with our theory, control beliefs, mood, and social support had indirect effects on adherence. However, stress and coping did not. Daily experiences affect adherence, even in PLWH with well-controlled HIV. Providers should ask about everyday changes in motivation.


Parental awareness and child abuse: a cognitive-developmental analysis of urban and rural samples.
A cognitive-developmental analysis of parental reasoning on child-rearing issues is presented and applied in two controlled studies of parents of abused or neglected children. Significant differences in parental awareness were found between urban parents and their controls; this relationship is sustained in a rural sample, controlling for child handicap as well as for other familial characteristics.


A computerized medical record for clinical management of children with cerebral palsy.
Computerization has numerous applications in the administrative, business, and personal arenas. Applications in the medical field have produced a myriad of programs with varying degrees of impact on direct patient care. A recent Institute of Medicine report states that a computer-based medical record should become the standard for medical records.


Preparation interval and cue utilization in the prevention of distraction.
Maintaining a selective attention set allows us to efficiently perform sensory tasks despite the multitude of concurrent sensory stimuli. Unpredictably occurring, rare events nonetheless capture our attention, that is, we get distracted. The present study investigated the efficiency of control over distraction as a function of preparation time available before a forthcoming distracter. A random sequence of short and long tones (100 or 200 ms with 50-50 % probability) was presented. Independently from tone duration, occasionally (13.3 % of the time), the pitch of a tone was changed. Such rare pitch variants (distracters) usually lead to delayed and less precise discrimination responses, and trigger a characteristic series of event-related potentials (ERPs) reflecting the stages of distraction-related processing: starting with negative ERPs signaling the sensory registration of the distracter; a P3a-usually interpreted as a reflection of involuntary attention change and finally the so-called reorienting negativity signaling the restoration of the task-optimal attention set. In separate conditions, 663 or 346 ms before each tone (long or short cue-tone interval), a visual cue was presented, which signaled whether the forthcoming tone was a distracter (rare pitch variant), with 80 % validity. As reflected by reduced reaction time delays and P3a amplitudes, valid cues led to the prevention of distraction, but only in the long cue-tone interval condition. The analyses of the cue-related P3b and contingent negative variation showed that participants made more effort to utilize cue information to prevent distraction in the long cue-tone than in the short cue-tone interval condition.


Novel SCN2A mutation in a family associated with juvenile-onset myoclonus: Case report.
The phenotypic spectrum caused by SCN2A mutations includes benign neonatal/infantile seizures, Ohtahara syndrome, infantile spasms, West syndrome, and other unclassified epileptic phenotypes. Mutations in SCN2A have been implicated in neonatal seizure cases. Here, we described a Chinese family with 2 members having juvenile-onset myoclonus and identified a novel SCN2A point mutation within this family. The 21-year-old male proband suffered from frequent myoclonus at 11 years old with subsequent progressive ataxia. His elder maternal half-sister also experienced myoclonus. Genomic DNA of the patients was extracted from the peripheral blood cells of the proband, elder maternal half-sister, parents, and uncle of the proband. Targeted next-generation sequencing was used to screen gene mutations in the proband. The potential functional effects of mutations within SCN2A were predicted In silico analyses. Genetic testing revealed a novel SCN2A variant, c.T4820C, which contains a highly conserved amino acid substitution within segment S5 (p.V1607A). This mutation was predicted to produce a dysfunctional Nav1.2 protein by Mutation Taster and Protein Variation Effect Analyzer (PROVEAN). Genotype-phenotype correlation showed an incomplete penetrance of p.V1607A. The proband was treated by multiple antiepileptic drugs. These included carbamazepine, oxcarbazepine, valproate, and topiramate. The duration of follow up was 2 years, and the proband developed drug-resistant epilepsy. The case gives us the lesson that SCN2A mutation can contribute to juvenile-onset myoclonus. Our findings extend the spectrums of SCN2A mutations and the clinical features of patients with SCN2A mutations.


The Prognostic Role of Mismatch Repair Status and CDX-2 Expression with Inflammatory Markers and Pathological Risk Factors in Stage II and III Colon Cancer: Multicenter Real-Life Data.
Colorectal cancer is common worldwide, and adjuvant treatment's benefit is still controversial. We designed this study to determine the role of MSI and CDX-2 status determined by immunohistochemistry (IHC) combined with the inflammatory markers and pathological parameters in predicting disease recurrence in stage II and III colon cancer. A total of 226 stage II/III colon cancer patients with a median age of 59 years who underwent initial surgery were included in this retrospective study. The pathologic assessment of MSI and CDX-2 was performed twice by immunohistochemistry (IHC) and two different pathologists. No staining/weak staining below 10% of the tumor was accepted as CDX-2 negative, and any MSI clones with weak staining below 10% were accepted as MSI-H. The laboratory parameters were noted at the initial diagnosis. One hundred twenty-one and 105 patients were diagnosed with stage III and II colon cancer. 58.0% of patients were male, 46 (20.4%) of tumor tissue were MSS, and 17 (7.5%) were CDX-2 negative. One hundred twenty-nine tumors were localized in the right colon. Disease recurrence was significantly correlated with tumor localization, CDX-2 status, stage at diagnosis, and preoperatively median CRP and CEA levels. DFS rates for MSS patients with CDX-2 negative and positive were 36.7% and 98.1%, respectively [p < 0.001]. There was no significant correlation between MSI status and CDX-2 status. MSI status, the presence of adjuvant treatment, and systemic inflammatory markers were not significant prognostic factors for DFS. CDX-2 status [HR:0.08, CI 95% 0.03-0.17, p < 0.001 HR: 1.7, CI 95% 1.1-3.0, p = 0.03], disease stage [HR:2.6, CI 95% 1.43-4.74], and preoperatively CEA levels [HR:4.1 CI 95% 2.18-785, p < 0.001 were independent significant prognostic factors for DFS. CDX-2 loss was an independent prognostic factor for DFS and disease recurrence in early-stage colon cancer. MSS patients with CDX-2 loss had significantly worse survival outcomes, and this might be the reason for deciding on adjuvant chemotherapy.


Water and national identity in the Netherlands; the history of an idea.
According to a popular Dutch theory, water has shaped the Dutch national identity. The Dutch fight against the water would have stimulated perseverance, ingenuity, cooperation and an egalitarian and democratic society. Despite the long water management history of the Netherlands, water became an important part of the self-images of the nation only in the eighteenth Century. In the 1780s the idea that the Dutch had wrung their country from the sea became popular. Initially, this idea was especially popular among the (proto-)liberal opposition, who emphasised the importance of the nation and its achievements. By the end of the nineteenth Century, water had become a national symbol for orthodox Calvinists, Roman Catholics and Socialists too, despite their different views on the nation. Whenever there was fast social change, political turmoil or external threats, as in the late eighteenth Century, the 1930s and 1940s and since the 1990s, the link between water and the Netherlands was used to promote national pride and unity and stimulate action. This link has also been used to promote specific hydraulic works, but it is a topic for further research how widespread and effective this practice was. As this paper is part of a special issue, Water History in the time of COVID-19, it has undergone modified peer review.


Local administration of cells containing an inserted IL-2 gene and producing IL-2 inhibits growth of human tumours in nu/nu mice.
We have prepared a retroviral expression construct, pPS-IL-2, in which human IL-2 cDNA has been inserted into the polylinker region, and have used the retroviral vector to introduce the functional IL-2 gene into a fibroblast cell line, RAT-1. Peritumoral administration of IL-2-producing RAT-1 cells into congenitally athymic (nu/nu) mice carrying subcutaneous transplants of human carcinoma cells inhibited the growth of the human tumour xenografts.


Determination of Angiotensin-(1-7) with HPLC/Fluorescence-Detection.
Angiotensin-(1-7) is an important active component in the renin-angiotensin-system. Due to its cardio protective effects it is now under investigation in combination with antioxidants as a reperfusion solution. The combination showed impressive effects on isolated hearts of male Wistar rats after induced ischemia. In this work a high performance liquid chromatography method with fluorescence detection was developed for the first time for in-process measurements as well as for stability tests of the peptide in the novel antioxidant-containing Karal® solution. For fluorescence detection of angiotensin-(1-7) fluorescamine as derivatization dye was applied. Under optimized conditions the method showed linearity over the range of 50 to 5000 ng/mL with R(2) of 0.9988 and an overall precision better than 5.0 %. LOD and LOQ were determined to be in the femtomol range on column. It was found that stability of angiotensin-(1-7) could be significantly improved in the antioxidant containing preparation compared to aqueous solutions.


Brownian motion in non-equilibrium systems and the Ornstein-Uhlenbeck stochastic process.
The Ornstein-Uhlenbeck stochastic process is an exact mathematical model providing accurate representations of many real dynamic processes in systems in a stationary state. When applied to the description of random motion of particles such as that of Brownian particles, it provides exact predictions coinciding with those of the Langevin equation but not restricted to systems in thermal equilibrium but only conditioned to be stationary. Here, we investigate experimentally single particle motion in a two-dimensional granular system in a stationary state, consisting of 1 mm stainless balls on a plane circular surface. The motion of the particles is produced by an alternating magnetic field applied perpendicular to the surface of the container. The mean square displacement of the particles is measured for a range of low concentrations and it is found that following an appropriate scaling of length and time, the short-time experimental curves conform a master curve covering the range of particle motion from ballistic to diffusive in accordance with the description of the Ornstein-Uhlenbeck model.


Effect of phentolamine on wakefulness and sleep during recovery from REM sleep deprivation in cats.
Adult cats with permanent EEG, EMG, EOG, and PGO electrodes were recorded for 24 hours started at the end of a 72-hour REMS deprivation induced by a platform-water-tank procedure and after receiving IP injections of phentolamine (20 mg/kg) or saline. Exposure of the cats to the platform-REMS deprivation procedure increased the percentage of REMS during the subsequent 24 hours. Phentolamine interacted with the platform REMS deprivation causing the peak of REMS percentage to occur during recovery hours 5-12. These findings indicate that blockade of alpha-receptors has an additive effect on platform-REMS deprivation induced REMS rebound in cats.


How Clinically Relevant Are Treatment Comparisons of Topical Calcineurin Inhibitor Trials for Atopic Eczema?
We sought to explore the architecture of trials of calcineurin inhibitors for atopic eczema to document the extent to which comparisons with active treatments such as topical corticosteroids might have been included or avoided. We identified all eligible randomized controlled trials using the Global Resource for EczemA Trials (GREAT) database. Network plots were produced where the nodes represented a treatment type and the lines between the nodes represented the number of trials or participants involved in the various treatment comparisons. A total of 174 randomized controlled trials for atopic eczema treatments were identified in which pimecrolimus, tacrolimus, or topical corticosteroids were compared with another intervention or a vehicle/emollient. Of 39 trials involving pimecrolimus and 41 trials involving tacrolimus, 8 (20.5%) and 13 (31.7%), respectively, made comparisons with topical corticosteroids, and 25 (64.1%) and 15 (36.6%), respectively, were vehicle-controlled studies. The high rate of comparisons with vehicle controls in randomized controlled trials that assessed the efficacy of pimecrolimus or tacrolimus long after efficacy had been established is a matter of concern. Active comparators (mild topical corticosteroids for pimecrolimus and moderate to potent topical corticosteroids for tacrolimus) are best placed to determine how topical calcineurin inhibitors compare with established clinical practice.


Conditional Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 MAP Kinase Is Not Associated with Anxiety/Depression-Like Behaviors
Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question. To address this issue, we utilized a transgenic mouse strain in which adult neurogenesis was specifically and conditionally impaired by Nestin-CreER-driven, inducible knockout (icKO) of erk5 MAP kinase in Nestin-expressing neural progenitors of the adult mouse brain upon tamoxifen administration. Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal's susceptibility to depression after chronic unpredictable stress treatment. Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression.


[From a mixed couple to a mixed family].
The arrival of a baby, in all cultures, is a special moment for the parents, which brings with it numerous changes. The specificity of mixed couples magnifies these changes and requires certain elements to be negotiated in order to help the new family blend together. A clinical story shows how to envisage a creative way of constituting a mixed family.


[Iron deficiency in chronic heart failure: from diagnosis to therapy].
Anaemia and iron deficiency are frequent co-morbidities in patients with chronic heart failure. Both are bound to worsen an already reduced exercise capacity in these patients. Recent data have demonstrated that iron deficiency alone, i.e. without concomitant anaemia, reduces quality of life, exercise capacity and likely also survival. Two clinical entities should be differentiated in this context: absolute and functional iron deficiency, the first being an absolute deficiency of iron, the second representing a disturbed mobilisation capacity. The FAIR-HF study has shown that intravenous iron administration can improve quality of life and exercise capacity in affected patients. A correct diagnosis can easily be arrived at using parameters such as serum ferritin and transferrin saturation. Replenishing iron stores is most useful using the intravenous route, and administered doses need to be adjusted to individual needs.


Posidonia oceanica (L.) Delile: A Mediterranean seagrass with potential applications but regularly and erroneously referred to as an algal species.
Posidonia oceanica (L.) Delile is one of the most abundant aquatic vascular higher plants in the Mediterranean Sea belonging to Posidoniaceas family. It is considered as a valuable natural source for multiple uses either for ecological functions or industrial applications. Nevertheless, this marine phanerogam is commonly confused with macroalgae, or seaweeds, known also as cryptogams. The present note intends to discuss the mis-use of the associated terminology of P. oceanica as algae in the scientific literature in order to avoid the widespread of this issue in the future. Thus, an extensive assessment of some important published woks has been conducted. This note will certainly allow the accurate nomenclature of this promising endemic species, which will continue its valorizations' ascension in several potential applications.


Narciclasine, a novel topoisomerase I inhibitor, exhibited potent anti-cancer activity against cancer cells.
DNA topoisomerases are essential nuclear enzymes in correcting topological DNA errors and maintaining DNA integrity. Topoisomerase inhibitors are a significant class of cancer chemotherapeutics with a definite curative effect. Natural products are a rich source of lead compounds for drug discovery, including anti-tumor drugs. In this study, we found that narciclasine (NCS), an amaryllidaceae alkaloid, is a novel inhibitor of topoisomerase I (topo I). Our data demonstrated that NCS inhibited topo I activity and reversed its unwinding effect on p-HOT DNA substrate. However, it had no obvious effect on topo II activity. The molecular mechanism of NCS inhibited topo I showed that NCS did not stabilize topo-DNA covalent complexes in cells, indicating that NCS is not a topo I poison. A blind docking result showed that NCS could bind to topo I, suggesting that NCS might be a topo I suppressor. Additionally, NCS exhibited a potent anti-proliferation effect in various cancer cells. NCS arrested the cell cycle at G2/M phase and induced cell apoptosis. Our study reveals the antitumor mechanisms of NCS and provides a good foundation for the development of anti-cancer drugs based on topo I inhibition.


Limited efficacy of experimental anti-epileptic drugs in refractory temporal lobe epilepsy: implications for patient management and study recruitment.
Patients with refractory temporal lobe epilepsy (TLE) are commonly recruited for investigational anti-epileptic drug (XAED) studies. However, the long-term outcome of TLE after exposure to XAEDs is poorly documented. In this pilot study, we report the USC Epilepsy Center's experience of 19 patients with TLE enrolled in three XAED trials. The data reinforce that TLE is a drug-resistant epilepsy, and referral of good surgical candidates for surgery rather than XAED trials is more likely to result in remission.


In vivo quinolinic acid increases synaptosomal glutamate release in rats: reversal by guanosine.
Glutamate, the main excitatory neurotransmitter in the mammalian central nervous system (CNS), plays important role in brain physiological and pathological events. Quinolinic acid (QA) is a glutamatergic agent that induces seizures and is involved in the etiology of epilepsy. Guanine-based purines (GBPs) (guanosine and GMP) have been shown to exert neuroprotective effects against glutamatergic excitotoxic events. In this study, the influence of QA and GBPs on synaptosomal glutamate release and uptake in rats was investigated. We had previously demonstrated that QA "in vitro" stimulates synaptosomal L-[3H]glutamate release. In this work, we show that i.c.v. QA administration induced seizures in rats and was able to stimulate synaptosomal L-[3H]glutamate release. This in vivo neurochemical effect was prevented by i.p. guanosine only when this nucleoside prevented QA-induced seizures. I.c.v. QA did not affect synaptosomal L-[3H]glutamate uptake. These data provided new evidence on the role of QA and GBPs on glutamatergic system in rat brain.


'Drug holidays' in the treatment of Parkinson's disease. A brief review.
"Drug holiday," the withdrawal of levodopa for a variable period of time, is a controversial method of treating patients with Parkinson's disease who have levodopa-related complications. Only four studies have been published in which patients were observed for one year or longer. Although it is extremely beneficial for some patients, this treatment provides a sustained one-year benefit for only a minority of patients.


TCD Cerebral Hemodynamic Changes during Moderate-Intensity Exercise in Older Adults.
Exercise plays an important role in supporting overall brain health. However, the mechanisms by which exercise supports brain health are imprecisely defined. Further, brain hemodynamic changes during exercise are not clearly understood, especially in older adults. The primary aim of this study was to compare cerebral blood flow velocity and pulsatility index (PI) during moderate-intensity exercise between older adults with normal pulsatile flow (normal PI) and older adults with elevated pulsatile flow (elevated PI). Secondary aims were to compare cardiovascular disease risk and cognitive function between individuals with elevated and nonelevated PI. Using transcranial Doppler ultrasound (TCD), middle cerebral artery blood velocity (MCAv) and PI were recorded during the rest and moderate-intensity exercise. End tidal carbon dioxide (PET CO2 ) and beat-to-beat mean arterial blood pressure were also recorded. We enrolled 104 older adults into the study. The change in PI was greater in normal PI group (35.5% vs. 21.3%, P = .005). The change in MCAv was similar in both groups (11.6% for normal PI vs. 10.6% for elevated PI; P = .22). There was no significant difference in cardiovascular disease risk between the two groups (P = .77). Individuals with elevated PI performed significantly worse in WAIS-R Digit Symbol and Trail Making Test A (P = .04 and = .01, respectively). The percent increase in PI from rest to moderate-intensity exercise was attenuated in the older adults with elevated resting PI. Higher resting PI may negatively affect brain health as evidenced by the slower processing speed scores.


Molecular characterization of mtDNA depleted and repleted NT2 cell lines.
Transmitochondrial cytoplasmic hybrids (cybrids) enable functional assessment of mitochondrial DNA (mtDNA)-encoded proteins. Cybrid production often utilizes cell lines depleted of endogenous mtDNA (rho0 cells), and a number of suitable rho0 cell lines exist for this purpose. We now provide molecular data characterizing an NT2 human teratocarcinoma rho0 cell line, as well as NT2 cybrid derivatives. NT2 rho0 cells contained no detectable mtDNA on a sensitive PCR assay. Eight weeks after exogenous mtDNA transfer cybrids showed no evidence of endogenous mtDNA reversion, and heteroplasmic ratios of a single nucleotide substitution roughly reflected that of the blood samples used to repopulate their mtDNA.


Correlation of urethral physiology and skin collagen in postmenopausal women.
Connective tissue collagen is thought to contribute to the generation of urethral pressure. It has been previously shown that skin collagen and urethral pressure are oestrogen dependent. This study demonstrates a correlation between urethral pressure measurements and skin collagen content. It is suggested that the beneficial effect of oestrogens on urethral function may be mediated by collagen.


Genome-wide profiling of prime editor off-target sites in vitro and in vivo using PE-tag.
Prime editors have a broad range of potential research and clinical applications. However, methods to delineate their genome-wide editing activities have generally relied on indirect genome-wide editing assessments or the computational prediction of near-cognate sequences. Here we describe a genome-wide approach for the identification of potential prime editor off-target sites, which we call PE-tag. This method relies on the attachment or insertion of an amplification tag at sites of prime editor activity to allow their identification. PE-tag enables genome-wide profiling of off-target sites in vitro using extracted genomic DNA, in mammalian cell lines and in the adult mouse liver. PE-tag components can be delivered in a variety of formats for off-target site detection. Our studies are consistent with the high specificity previously described for prime editor systems, but we find that off-target editing rates are influenced by prime editing guide RNA design. PE-tag represents an accessible, rapid and sensitive approach for the genome-wide identification of prime editor activity and the evaluation of prime editor safety.


Frequency of Aedes sp. Linnaeus (Diptera: Culicidae) and Associated Entomofauna in Bromeliads from a Forest Patch within a densely Urbanized Area.
Little is known about the relationship between the presence of Aedes, abiotic factors and the entomofauna existing in phytotelmatas. The aim of this study was to identify biotic and abiotic factors associated with the presence of Aedes in bromeliads sites located in a forest fragment in Rio de Janeiro, Brazil. In the study area, eight bromeliads from the Aechmea genus were chosen and kept in landscape form. Physical and chemical variables were measured. Collected aquatic insects were identified according to the literature. A total of 3102 immature insects were collected. The presence of Aedes aegypti (Linnaeus) (2.29%) was rare. Few specimens were found concentrated in urban-adjacent areas during summer. On the other hand, Aedes albopictus (Skuse) (17.57%) was found throughout the year in 0%-80% of the sites, averaging 1.0 mosq/bromelia. Aedes albopictus was found predominantly in central sites of the forest fragment. The Canonical Correspondence Analysis indicates that most taxa had a moderate association with temperature, dissolved oxygen, and pH. The abiotic variables, such as temperature and dissolved oxygen, affect the distribution of the genus Aedes vectors, while most of the other variables did not.


Improved adaptation to heat, cold, and solvent tolerance in Lactobacillus plantarum.
The effect of overproducing each of the three small heat shock proteins (Hsp; Hsp 18.5, Hsp 18.55, and Hsp 19.3) was investigated in Lactobacillus plantarum strain WCFS1. Overproduction of the three genes, hsp 18.5, hsp 18.55, and hsp 19.3, translationally fused to the start codon of the ldhL gene yielded a protein of approximately 19 kDa, as estimated from Tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis in agreement with the predicted molecular weight of small Hsps. Small Hsp overproduction alleviated the reduction in growth rate triggered by exposing exponentially growing cells to heat shock (37 or 40 degrees C) and cold shock (12 degrees C). Moreover, overproduction of Hsp 18.55 and Hsp 19.3 led to an enhanced survival in the presence of butanol (1% v/v) or ethanol (12% v/v) treatment suggesting a potential role of L. plantarum small Hsps in solvent tolerance.


The role of protein arginine deiminase 4-dependent neutrophil extracellular traps formation in ulcerative colitis.
Neutrophil extracellular traps (NETs) play an important role in the development and progression of ulcerative colitis (UC). Peptidyl arginine deiminase 4 (PAD4) is essential for the formation of NETs via catalyzing histone citrullination. This study mainly to explore the role of PAD4-mediated NETs in intestinal inflammation of dextran sulfate sodium (DSS)-induced UC. Acute and chronic colitis mouse models were established by supplementing DSS in drinking water. Colon tissues from colitis mice were analyzed for the level of PAD4 expression, citrullinated histone H3(Cit-H3), intestinal histopathology, and inflammatory cytokines secretion. Serum samples were tested for systemic neutrophil activation biomarkers. Colitis mice administered with Cl-amidine, a PAD4 inhibitor, and PAD4 knockout mice were investigated to detect NETs formation, intestinal inflammation, and barrier function. We found the formation of NETs significantly increased in DSS-induced colitis mice and was correlated with disease markers. Blocking NETs formation by Cl-amidine or PAD4 genetic knockout could alleviate clinical colitis index, intestinal inflammation, and barrier dysfunction. This study provided a research basis for the role of PAD4-mediated NETs formation in the pathogenesis of UC and suggested that inhibition of PAD4 activity and the formation of NETs may be helpful for the prevention and treatment of UC.


High-efficiency artificial enzyme cascade bio-platform based on MOF-derived bimetal nanocomposite for biosensing.
In this paper, a high-performance enzyme cascade bio-platform has been developed for biosensing by combining MOFs-based nanozyme and natural enzymes. Firstly, a novel porous mixed bi-metal oxide (MnCo2O4) derived from MOF with rod-like nanostructures was synthesized. Based on this, the nanozyme of bovine serum albumin-Pt nanoparticles@mesoporous MnCo2O4 (BSA-PtNP@MnCo2O4) was successfully synthesized and used to construct enzyme cascade bio-platform. The nanozyme had unique physicochemical surface properties and hierarchical structure. Due to the synergistic effect of protein, bimetal oxide and PtNP, the nanozyme presented excellent dual enzyme activity. On the one hand, BSA-PtNP@MnCo2O4 can be used as nanozyme with oxidase activity to achieve superior detection of glutathione with detection limit of 0.42 μM. On the other hand, BSA- PtNP@MnCo2O4 can also be used both as the nanozyme with great peroxidase activity and as a scaffold for immobilization of glucose oxidase (GOx), guiding an organized high-efficiency enzyme cascade bio-platform. The platform combined advantages of nanozyme and natural enzyme, and provided excellent glucose detection with the detection limit of 8.1 μM. The tandem catalytic system not only broadened the application of nanozyme in natural enzyme catalysis, but also provided a simple, efficient and organized enzyme cascade bio-platform for biosensing and other applications.


Lysosomes and pancreatic islet function. Glucose-dependent alterations of lysosomal morphology.
The relation between qualitative and quantitative glucose-dependent alterations of lysosomes in pancreatic islets and the function of the islets was studied. Isolated islets of the mouse were maintained in tissue culture for one week in either 28, 5.5 or 3.3 mmol/l glucose. Insulin biosynthesis, insulin secretion and insulin content of the cultured islets were determined. After culture, the islets were subjected to acid phosphatase cytochemistry and examined by electron microscopy and ultrastructural morphometry. Islets cultured in 28 mmol/l glucose both produced and secreted insulin rapidly. Such islets seemed, however, unable to maintain more than small amounts of granule-stored insulin. Islets cultured at the lower concentrations of glucose displayed a reduced insulin secretion, which apparently resulted in considerable amounts of intracellularly stored insulin. In all cultured islets different types of lysosomes, identified by their acid phosphatase reactivity, could be seen. Dense bodies, i.e., lysosomes characterized by a homogeneous, very fine, particulate content of high density, seemed to predominate at all concentrations of glucose. It is suggested that, in the islets, the dense bodies correspond morphologically to primary lysosomes. Other types of lysosomes with inclusions of various kinds, which were frequent at the two lower concentrations of glucose, may correspond to secondary lysosomes. Morphometry revealed differences between the size distributions of lysosomes in the three experimental groups. Thus, the average lysosomal size was inversely proportional to the concentration of glucose in the culture medium. However, the numerical density of lysosomes was greatest at the highest glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)


Soy Protein Compared with Milk Protein in a Western Diet Increases Gut Microbial Diversity and Reduces Serum Lipids in Golden Syrian Hamsters.
Diet is a major factor influencing the composition and metabolic activity of the gut microbiota. This study investigated the effect of soy compared with dairy protein on the gut microbiota of hamsters to determine whether changes in microbiota could account for soy protein's lipid lowering properties. Thirty-two 6- to 8-wk-old, male Golden Syrian hamsters were fed a Western diet containing 22% (%wt) milk protein isolate (MPI) as the single protein source for 3 wk followed by 6 wk of one of 4 diets containing either [22% protein (%wt)]: MPI, soy protein concentrate (SPC), partially hydrolyzed soy protein isolate (SPI1), or intact soy protein isolate. Serum lipids, hepatic gene expression, and gut microbial populations were evaluated. Serum total and LDL-cholesterol concentrations were lower in the SPC-fed group (183 ± 9.0 and 50 ± 4.2 mg/dL, respectively) than in the MPI group (238 ± 8.7 and 72 ± 3.9 mg/dL, respectively) (P< 0.05). Triglyceride (TG) concentrations were lower (P< 0.05) in the SPI1-fed group (140 ± 20.8 mg/dL) than in the MPI-fed group (223 ± 14.2 mg/dL). VLDL and non-HDL-cholesterol concentrations were lower (by 40-49% and 17-33%, respectively) in all soy-fed groups than in the MPI-fed group (P< 0.05). Sequencing of the 16S ribosomal RNA gene revealed greater microbial diversity in each soy-fed group than in the MPI-fed group (P< 0.05). The cholesterol- and TG-lowering effect of soy protein was associated with higher expression of 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), lanosterol synthase (Lss), and farnesyl-diphosphosphate farnesyl-transferase 1 (Fdft1) (1.6-2.5-fold higher), and lower steroyl-CoA desaturase-1 (Scd1) expression (37-46% lower) in all soy-fed groups (P< 0.05) compared with the MPI-fed group. Gut microbes that showed significant diet differences were significantly correlated (ρ = -0.68 to 0.65,P< 0.05) with plasma lipids and hepatic gene expression. Dietary protein sources in male Golden Syrian hamsters fed a Western diet affect the gut microbiota, and soy protein may reduce lipogenesis through alterations of the gut microbial community.


Dissimilar effects of lithium isotopes on motility in rats.
Male Wistar rats were injected twice daily with chlorides of pure lithium isotopes, either Li-6 or Li-7. While both salts decreased mobility, the salt of Li-6 initially produced a more profound effect than the salt of Li-7. This differential effect of the isotopes proved to be time dependent and was most evident on the third day of treatment. Li-6 is likely to become a valuable tool in basic psychopharmacological research. It may possess therapeutic and/or toxic properties that are different from those of lithium salts currently used in treatment of mania.


Experimental measurement and quantification of frictional contact between biological surfaces experiencing large deformation and slip.
Interactions between contacting biological surfaces may play significant roles in physiological and pathological processes. Theoretical models have described some special cases of contact, using one or more simplifying assumptions. Experimental quantification of contact could help to validate theoretical analyses. The objective of this study was to develop a general mathematical approach describing the dynamics of deformation and relative surface motion between contacting bodies and to implement this approach to describe the contact between two experimentally tracked tissue surfaces. A theoretical formulation (in 2-D and 3-D) of contact using the movement of discrete tissue markers is described. The method was validated using theoretically generated 3-D datasets, with <1% error for a wide range of parameters. The method was applied to the contact loading of opposing articular cartilage tissues, where displacements of cell nuclei were tracked optically and used to quantify the movements and deformations of the surfaces. Compared to tissues with matched material properties, tissues with mismatched material properties exhibited increased disparities in lateral expansion and relative motion (sliding) between the contacting surfaces.


[The Immunomodulatory and Anti-allergy Effects of Lactobacilli].
This study was conducted to evaluate the potent immunomodulatory effects of Lactobacilli and their possible anti-allergic effects. Lactobacillus plantarum LP45 (LP45), Lactobacillus acidophilus La28 (La28), Lactobacillus acidophilus 6091 (6091), Lactobacillus rhamnosus GG (LGG) were orally administrated to male BALB/C mice, respectively for 28 d. The immune organ index, serum Th1 cytokines [interferon-γ (IFN-γ), interleukin-12 (IL-12)] and Th2 cytokines IL-6 of the tested mice were analyzed with ELISA after intervention. Furthermore, La28, 6901 were also orally fed to ovalbumin (OVA)-sensitized male BALB/C. The serum total IgE of the tested mice was analyzed with ELISA after intervention. No statistical difference was found in immune organ index among the tested four strains. La28 significantly decreased serum IL-6 of the tested mice after 14 d and 28 d compared to those in control (P < 0.05). After 28 d, 6091 also significantly reduced serum IL-6 of the tested mice (P < 0.05). La28 significantly suppressed the increase of serum total IgE of the tested mice (P < 0.05). The present study indicates that the immunomodulatory effects of Lactobacilli might be strain-dependent. Among the tested strains of Lactobacilli, La28 and 6091 may have possibility to influence the Th2 immunity of host animal. La28 may also posse potent ability to alter IgE mediated allergy by the way to affect Th1/Th2 balance of host animal.


Passive transfer studies in Guillain-Barré polyneuropathy.
Serum and lymphocytes from patients with acute Guillain-Barré polyneuropathy were injected into rat sciatic nerves. Serum from 13 of 17 patients produced perivenular demyelination, associated with lymphocytic infiltration. The pattern of demyelination differed from that caused by experimental allergic neuritis serum. The level of serum demyelinating activity as greatest early in the disease and then decreased. The demyelinating factor was heat-labile but not complement-dependent. Circulating lymphocytes did not cause demyelination in eight patients.


High-resolution daily profiles of tissue adrenal steroids by portable automated collection.
Rhythms are intrinsic to endocrine systems, and disruption of these hormone oscillations occurs at very early stages of the disease. Because adrenal hormones are secreted with both circadian and ultradian periods, conventional single-time point measurements provide limited information about rhythmicity and, crucially, do not provide information during sleep, when many hormones fluctuate from nadir to peak concentrations. If blood sampling is attempted overnight, then this necessitates admission to a clinical research unit, can be stressful, and disturbs sleep. To overcome this problem and to measure free hormones within their target tissues, we used microdialysis, an ambulatory fraction collector, and liquid chromatography-tandem mass spectrometry to obtain high-resolution profiles of tissue adrenal steroids over 24 hours in 214 healthy volunteers. For validation, we compared tissue against plasma measurements in a further seven healthy volunteers. Sample collection from subcutaneous tissue was safe, well tolerated, and allowed most normal activities to continue. In addition to cortisol, we identified daily and ultradian variation in free cortisone, corticosterone, 18-hydroxycortisol, aldosterone, tetrahydrocortisol and allo-tetrahydrocortisol, and the presence of dehydroepiandrosterone sulfate. We used mathematical and computational methods to quantify the interindividual variability of hormones at different times of the day and develop "dynamic markers" of normality in healthy individuals stratified by sex, age, and body mass index. Our results provide insight into the dynamics of adrenal steroids in tissue in real-world settings and may serve as a normative reference for biomarkers of endocrine disorders (ULTRADIAN, NCT02934399).


Resistive index of central retinal artery is a bioimaging biomarker for severity of diabetic retinopathy.
The present study was undertaken to assess the resistive index (RI) of central retinal artery (CRA) as a bioimaging biomarker for the severity of diabetic retinopathy (DR), for the first time. Eighty-one consecutive patients of type 2 diabetes mellitus between the ages of 40 and 70 years were included in a tertiary care center-based cross sectional study. Severity of retinopathy was assessed according to Early Treatment Diabetic Retinopathy Study (ETDRS) classification: diabetes mellitus with no retinopathy (No DR) (n = 26); non-proliferative diabetic retinopathy (NPDR) (n = 29); and proliferative diabetic retinopathy (PDR) (n = 26). Twenty-six healthy controls of similar age were also included. Resistive index of CRA was studied using color Doppler and gray scale sonography. Central subfield thickness (CST), cube average thickness (CAT), retinal photoreceptor ellipsoid zone (EZ) disruption, and retinal nerve fiber layer (RNFL) thickness were evaluated using spectral domain optical coherence tomography. Sensitivity and specificity were assessed by receiver operating characteristic (ROC) curve. Mean RI of CRA for the study groups revealed significant increase with severity of diabetic retinopathy (F = 10.24, P < 0.001). The ROC curve analysis showed diagnostic accuracy of RI of CRA (area under curve = 0.841-0.999; sensitivity = 76-100%, specificity = 95.45-100%, P < 0.001) in discriminating controls and patients. Univariate regression analysis revealed significant association between the study groups and RI of CRA (P < 0.001). RI of CRA correlated positively with CST (r = 0.37), CAT (r = 0.45), EZ disruption (r = 0.43) and negatively with RNFL thickness (r = - 0.35) (P < 0.001). Resistive index of CRA is a reliable bioimaging biomarker for the severity of DR.


The Long Road to Equality: A Meta-Regression Analysis of Changes in the Black Test Score Gap over Time.
We analyze changes in test score gaps between Black students and their peers from 1979 to 2010 and examine how observable factors contribute to the gap. Using meta-regression, we examine the relationship between African American racial status and achievement in United States K-12 education in 165 published studies. The absolute relationship between Black status and achievement decreased during the 1980s and early 1990s, but was stagnant from the late 1990s through 2010. Socioeconomic status explained more than half of the gap, and the influence of socioeconomic status on the gap did not changed significantly over time. Schooling characteristics explained relatively little of the gap, but school-level factors increased in importance over time. Black test score gap closure stagnated in an era when federal education policy sought to close racial achievement gaps. Observable factors explain more of the gap than has been previously recognized.


How should I tell you this? The effects of the image used to convey that a natural yogurt is sweetened on consumer expectations and willingness to buy.
This study aimed to assess how packaging imagery used to convey that a natural yogurt is sweetened influences consumer expectations and willingness to buy. Four packages of sweetened natural yogurt were designed, in which the message that they were sweetened was conveyed through three different images (sugar cubes, a sack of sugar and a spoon of sugar) and through only text. The results of a pretest consisting of a word association task and a main experiment consisting of an online survey show that packages in which the message that the yogurt is sweetened is conveyed by using an image together with a textual claim instead of just a textual claim are expected to be sweeter. However, some differences can be appreciated depending on the specific image that is depicted (with the package showing an image of sugar cubes raising the higher sweetness expectations). Moreover, results show that Willingness to buy is positively associated with the attributes Natural Ingredients, Healthy and Quality, and in a slightly negative way with the attribute Sweet. Overall, these results suggest that although using packaging imagery to convey a message may enhance consumer expectations and willingness to buy, its effect on consumers' attitude towards the product may ultimately depend on the subject of the image that is depicted and in the valence of the message to be conveyed. These findings are discussed in the context of packaging design and consumer research, and directions for further research are provided. This study may help packaging designers and dairy companies to better communicate the desired message to consumers and to improve the marketing performance of their products.


In Vitro Functional Assessment of Adult Spiral Ganglion Neurons (SGNs).
Spiral ganglion neurons (SGNs) faithfully encode acoustic waves from hair cells to the cochlear nucleus (CN) using voltage-dependent ion channels. A sizable portion of our knowledge on SGN functions have been derived from pre-hearing neurons. In post-hearing SGNs, the mechanisms of how they encode the massive sound information without delay and precisely are largely unknown. Mature SGNs are housed in the central bony labyrinth of the cochlea, protected by a well-insulated myelin sheath, making it a technical feat to isolate viable neurons for rigorous functional electrophysiology. Recently, we have overcome the previous intractable hindrance in SGN functional analyses. We provide a step-by-step user-friendly protocol with practical applications, including patch-clamp recordings and imaging by using cultured SGNs.


Randomized clinical trial.
The randomized clinical trial has a minimum of four elements. These are: 1. The use of control patients who either receive no treatment, the conventional treatment, or a placebo. 2. The use of random assignment of treatment to be tested. 3. The avoidance of investigator bias by single or double masking procedures. 4. The development of a sound ethical basis for the conduct of the research. These elements are discussed and the principles illustrated by a brief discussion of the diabetic retinopathy study conducted by the National Eye Institute.


Triclosen and Its Alternatives in Antibacterial Soaps.
In 2017, the Food and Drug Administration banned the marketing of triclosan and triclocarban in antibacterial soaps, citing inefficacy and concerns of systemic absorption and antibacterial resistance. As a result, there is an anticipated decrease in the number of triclosan-containing products on the market with an associated increase in antibacterial alternatives (eg, benzalkonium chloride, benzethonium chloride, chloroxylenol, chlorhexidine) and cases of allergic and irritant contact dermatitis. The aims of the study were to determine the extent that triclosan and triclocarban are being used in the consumer and medical industries after the Food and Drug Administration marketing ban and to appraise the risk of allergic contact dermatitis to triclosan alternatives. The National Drug Code Directory (NDCD), Google, Amazon, Target, Walgreens, Walmart, CVS, and Colorado hospitals were surveyed for antibacterial soap use. Antibiotics surveyed include triclosan, triclocarban, benzalkonium chloride, benzethonium chloride, chloroxylenol, and chlorhexidine. The most common antibiotics reported by the NDCD, consumer sites, and Colorado hospitals were benzalkonium chloride, chloroxylenol, and triclosan, respectively. Triclosan accounted for the second most prevalent antibacterial in the NDCD- and consumer site-surveyed products. The triclosan marketing ban may instigate increased exposure to triclosan alternatives. The addition of antibacterial products to hand soaps does not improve soap effectiveness and may cause harm by contributing to antibiotic resistance and the development of allergic conditions. Additional studies are needed to elucidate the benefits and harms of antibacterial soaps.


Dutasteride: a review of its use in the management of prostate disorders.
Dutasteride (Avodart), an oral synthetic 4-azasteroid, is a potent, selective, irreversible inhibitor of type 1 and type 2 5alpha-reductase (5AR), the enzyme that converts testosterone to dihydrotestosterone (DHT) intracellularly. Although type 2 5AR predominates, both isoenzymes are overexpressed in prostate tissue in benign prostatic hyperplasia (BPH) and at all stages in some prostate cancers. Oral dutasteride 0.5 mg once daily is approved for the treatment of moderate to severe symptomatic BPH in men with an enlarged prostate to improve symptoms, and to reduce the risk of acute urinary retention (AUR) and the need for BPH-related surgery.In pivotal 2-year phase III trials, oral dutasteride 0.5 mg once daily improved urinary symptoms, decreased total prostate volume (TPV), and reduced the risk of AUR and BPH-related surgery in men with moderate to severe symptoms of BPH and prostate enlargement. The good efficacy and tolerability of dutasteride was maintained for up to 4 years in open-label extension studies. Results of the pre-planned, 2-year interim analysis of the CombAT trial showed that the combination of dutasteride and tamsulosin was superior to either drug as monotherapy in improving BPH-related symptoms, peak urinary flow and BPH-related health status. The overall adverse event profile for combination therapy was consistent with those reported for both monotherapies. Although drug-related adverse events were more frequent with combination therapy versus both monotherapies, most did not result in treatment cessation. Dutasteride is being investigated for its efficacy in reducing the risk of prostate cancer in at-risk men in the 4-year REDUCE study and as treatment to extend the time to progression in men with low-risk localized prostate cancer who would otherwise undergo watchful waiting in the 3-year REDEEM study. Thus, dutasteride is an effective treatment option in patients with moderate to severe symptomatic BPH and demonstrable prostatic enlargement, and may have potential to reduce the risk of developing biopsy-detectable prostate cancer in at-risk individuals or extending the time to progression in low-risk localized prostate cancer.


Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency.
Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessively inherited inborn error of folate metabolism. We report a new patient with severe MTHFR deficiency who presented at age 4 months with early onset severe scoliosis associated with severe hypotonia. Markedly decreased MTHFR enzyme activity (0.3 nmoles CHO/mg protein/h; reference range>9) and compound heterozygous mutations (c. 1304T>C; p.Phe435Ser and c.1539dup; p.Glu514Argfs∗24) in the MTHFR gene confirmed the diagnosis. She was treated with vitamin B12, folic acid and betaine supplementation and showed improvements in her developmental milestones and hypotonia. To the best of our knowledge, this is the first patient with MTHFR deficiency reported with severe early onset scoliosis. Despite the late diagnosis and treatment initiation, she showed favorable short-term neurodevelopmental outcome. This case suggests that homocysteine measurement should be included in the investigations of patients with developmental delay, hypotonia and scoliosis within first year of life prior to organizing genetic investigations.


Radiotherapy for benign achillodynia. Long-term results of the Erlangen Dose Optimization Trial.
The aim of this study was to evaluate the long-term efficacy of two dose-fractionation schedules for radiotherapy of achillodynia. Between February 2006 and February 2010, 112 evaluable patients were recruited for this prospective trial. All patients received orthovoltage radiotherapy. One course consisted of 6 fractions/3 weeks. In the case of insufficient remission of pain after 6 weeks, a second series was performed. Patients were randomly assigned to receive either single doses of 0.5 or 1.0 Gy. The endpoint was pain reduction. Pain was measured before, right after (early response), 6 weeks after (delayed response), and approximately 2 years after radiotherapy (long-term response) with a questionnaire-based visual analogue scale (VAS) and a comprehensive pain score (CPS). The median follow-up was 24 months (range, 11-56). The overall early, delayed, and long-term response rates for all patients were 84 %, 88 %, and 95 %, respectively. The mean VAS values before treatment for early, delayed, and long-term responses for the 0.5-Gy and 1.0-Gy groups were 55.7 ± 21.0 and 58.2 ± 23.5 (p = 0.53), 38.0 ± 23.2 and 30.4 ± 22.6 (p = 0.08), 35.5 ± 25.9 and 30.9 ± 25.4 (p = 0.52), and 11.2 ± 16.4 and 15.3 ± 18.9 (p = 0.16), respectively. The mean CPS values before treatment for early, delayed, and long-term responses were 8.2 ± 3.0 and 8.9 ± 3.3 (p = 0.24), 5.6 ± 3.1 and 5.4 ± 3.3 (p = 0.76), 4.4 ± 2.6 and 5.3 ± 3.8 (p = 0.58), and 2.2 ± 2.9 and 2.8 ± 3.3 (p = 0.51), respectively. No significant differences in long-term response quality between the two arms was found (p = 0.73). Radiotherapy is a very effective treatment for the management of benign achillodynia. For radiation protection, the dose for a radiotherapy series should not exceed 3.0 Gy.


Circulating ADAMTS13 Levels Are Associated with an Increased Occurrence of Obstructive Sleep Apnea.
Obstructive sleep apnea (OSA) is strongly associated with obesity, metabolic diseases, coronary artery disease (CAD), stroke, hypertension, and other disorders. This study assessed the relationship between circulating a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) levels and the presence of OSA. This cross-sectional study included a total of 223 patients. We used a powerful high-throughput multiplexed immunobead-based assay to detect circulating levels of ADAMTS13. The associations between circulating ADAMTS13 levels and OSA were evaluated by multivariate logistic regression analysis. Circulating ADAMTS13 levels were significantly elevated in patients with OSA compared with controls (0.8 vs. 2.7 μg/mL, respectively, P < 0.001). After adjusting for confounding factors, circulating ADAMTS13 levels were significantly independently associated with the presence of OSA (odds ratio = 9.96, 95% confidence interval (CI) =4.11-24.13, P < 0.001). Furthermore, circulating ADAMTS13 levels showed discriminatory accuracy in assessing the presence of OSA (area under the curve: 0.87, 95% CI 0.81-0.93, P < 0.001). Circulating ADAMTS13 levels were significantly correlated with the presence of OSA. ADAMTS13 may therefore function as a novel biomarker for monitoring the development and progression of OSA.


NADH-peroxidase activity and H2O2 decomposition in a peroxidogenic strain of Streptococcus durans.
Streptococcus durans S-76 can accumulate hydrogen peroxide to high concentrations under aerobic conditions when it is previously grown anaerobically. An NADH-peroxidase enzyme protects this bacterium from the bactericidal effect of H2O2. The relationship between oxygen uptake and H2O2 excretion into the medium has been investigated in cultures containing or lacking glucose under various conditions of incubation. The results obtained suggest that neither oxygen nor H2O2 regulate the cellular levels of NADH-peroxidase whose activity seems to be controlled exclusively by the availability of reduced NADH.


Antero-posterior and vertical facial type variations influence the aesthetic preference of the antero-posterior lip positions.
SummaryObjectives: The purposes of this study were to investigate whether the antero-posterior and vertical facial type variations influenced the favoured lip positions and to elucidate whether the favoured lip positions differed between orthodontists and laypersons. An average profile was constructed from a Japanese female with Class I occlusion and a well-balanced profile, as assessed by several cephalometric analyses. Nine facial types were composed by morphing the chin antero-posteriorly and/or vertically. Thirteen morphed lip profiles were constructed by moving the lips antero-posteriorly in the nine facial types, respectively. Seventy-seven Japanese laypersons and 30 orthodontists were asked to choose the top three most-favoured lip positions for each facial type. The protruded lip positions were significantly favoured for all the mandibular protrusive facial types. The retruded lip positions were significantly favoured for the short facial type of the antero-posteriorly average and mandibular retrusive-short facial types. Among the mandibular protrusive facial types, the protruded lip positions were significantly favoured for the long facial type. The retruded lip positions were statistically more attractive for orthodontists than laypersons on the antero-posteriorly average-short, mandibular protrusive-short, mandibular retrusive-vertically average, antero-posteriorly average-vertically average, and mandibular retrusive-long facial types. Our data were limited by the specific ethnic groups and variety of facial types. The favoured antero-posterior lip position was affected by not only the antero-posterior facial disproportion but also by the vertical dimensions. The favoured lip positions differed between orthodontists and laypersons. These results might be helpful in deciding between extraction and non-extraction treatment in borderline cases.


Plasmonic and catalytic AuPd nanowheels for the efficient conversion of light into chemical energy.
Reinventing the wheel: Bimetallic AuPd nanowheels, a freestanding form of 2D AuPd nanostructures, were synthesized in a one-pot process. The well-defined and tunable surface plasmon resonance displayed by these nanowheels was exploited in a unique catalytic process in which light energy was used to drive catalytic reactions, such as the Suzuki coupling, with much higher efficiency than that of the conventional heating process.


Carcinoembryonic antigen as an adjunct to determination of clinical stage in prostate cancer.
CEA level has been measured in a series of prostate cancer patients. Data are presented to show CEA correlation with clinical course and acid phosphatase level.


Prevalence of Having Advance Directives and a Signed Power of Attorney in Nova Scotia.
Advance directives are statements that allow a person to express his or her wishes for medical treatment in advance of needing it or to appoint someone else if they are unable to do so. To estimate the prevalence of decedents having a documented advance directive (AD) and a signed enduring power of attorney (SPoA) and to determine the degrees to which characteristics of decedents and their informant and the care the decedent received were predictive of the decedents having a documented AD and a SPoA. A population-based mortality follow-back survey was conducted in Nova Scotia, Canada. Informants who were knowledgeable of a decedents' death were invited to participate in a telephone interview based on the After-Death Bereaved Family Member Interview. Regression analyses were used to assess factors that were predictive of having an AD or SPoA. Overall, 56.3% of decedents had a documented AD, and 67.6% had an SPoA. Significant predictors of a decedent having a documented AD were their age, where they received the majority of their end-of-life care, whether they received specialized palliative care, whether they were aware they were dying, and the informant's age. Significant factors in predicting whether a person had a SPoA were whether the decedent received specialized palliative care, where they received the majority of their care, and the age and education level of their informant. These results may be used to better target and tailor future efforts to promote use of AD and SPoA.


Acyclic antimetabolite therapy of experimental herpes simplex keratitis.
In a masked controlled study we compared 3% acycloguanosine, 0.5% idoxuridine, and 3% vidarabine ointments in therapy of experimental herpes simplex virus keratitis in rabbits. The results of the acycloguanosine group were significantly better than the control groups and both other treatment groups, while producing none of the toxic side effects of increasing iritis, conjunctivitis or stromal keratitis, with continued drug application.


Left atrium measurement in patients suspected of having heart failure with preserved ejection fraction.
The pathophysiological model of heart failure (HF) with preserved ejection fraction (HFPEF) focuses on the presence of diastolic dysfunction, which causes left atrial (LA) structural and functional changes. The LA size, an indicator of the chronic elevation of the left ventricular (LV) filling pressure, can be used as a marker of the presence of HFPEF, and it is easily obtained. To estimate the accuracy of measuring the LA size by using indexed LA volume and diameter (ILAV and ILAD, respectively) for diagnosing HFPEF in ambulatory patients. This study assessed 142 patients (mean age, 67.3 ± 11.4 years; 75% of the female sex) suspected of having HF, divided into two groups: with HFPEF (n = 35) and without HFPEF (n = 107). The diastolic function, assessed by use of Doppler echocardiography, showed a significant difference between the groups regarding the parameters assessing ventricular relaxation (E': 6.9 ± 2.0 cm/s vs. 9.3 ± 2.5 cm/s; p < 0.0001) and LV filling pressure (E/E' ratio: 15.2 ± 6.4 vs. 7.6 ± 2.2; p < 0.0001). The ILAV cutoff point of 35 mL/m² best correlated with the diagnosis of HFPEF, showing sensitivity, specificity, and accuracy of 83%. The ILAD cutoff point of 2.4 cm/m² showed sensitivity of 71%, specificity of 66%, and accuracy of 67%. For diagnosing HFPEF in ambulatory patients, the ILAV proved to be a more accurate parameter than ILAD. On echocardiographic assessment, ILAV, rather than ILAD, should be routinely measured.


Increased serum carcinoembryonic antigen level can predict poor survival of patients with small cell lung cancer.
Increased serum tumor biomarkers are usually associated with huge tumor burden, but the prognostic value of these markers remains controversial. The serum levels of carcinoembryonic antigen (CEA), nerve cell-specific enolase, and lactate dehydrogenase in 281 patients with small cell lung cancer (SCLC) were analyzed in this study. Increased serum CEA levels were observed in 92 (32.7%) patients. Survival was superior in patients with normal serum CEA levels compared with those with increased serum CEA levels. The median survival time, 2-year overall survival (OS) rate, and 3-year OS rate were 19.1 months vs 14.6 months, 42.7% vs 28.3%, and 30.6% vs 14.1%, respectively (P = 0.002). In multivariate analysis, extensive-stage (ES)-SCLC (hazard ratio [HR] = 1.936, P = 0.001), an increased serum CEA level (HR = 1.432, P = 0.021) at diagnosis, and <4 cycles of chemotherapy (ChT) (HR = 0.432, P = 0.001) were independent negative prognostic factors for the OS. Additionally, normal CEA level (HR = 1.678, P = 0.012), treatment modalities including surgery (HR = 1.595, P = 0.049), and ≥ 4 cycles of ChT (HR = 1.880, P = 0.004) were independent positive prognostic factors for OS in patients with local disease. In the subgroup with ES-SCLC, normal serum CEA level (HR = 1.608, P = 0.043), thoracic radiation therapy (HR = 1.744, P = 0.005), and ≥ 4 cycles of ChT (HR = 2.626, P = 0.001) were independent positive prognostic factors for OS.


Ants on featureless saltpans build tall nest mounds.
North African desert ants Cataglyphis fortis living on a featureless saltpan far from the shoreline build a mound at their nest entrance. Experimental manipulations show that they do this purposefully to make it easier for returning foragers to find their nest.


Transpopliteal stenting of femoral occlusions in patients with critical limb ischemia using a 4-French system.
In many patients with critical limb ischemia (CLI), transfemoral endovascular recanalization is the preferred treatment. Transpopliteal treatment may be used in patients with inaccessible groins. This retrospective study regards transpopliteal stenting of superficial femoral artery (SFA) occlusions using a 4F system. Eleven patients (4 male and 7 female [mean age 77 years]) underwent 12 attempts of transpopliteal recanalization of long SFA occlusions (Trans-Atlantic InterSociety Consensus B through D). All patients had CLI (Rutherford 4 to 6) and were nonoperable due to poor general condition. Indications for transpopliteal access were proximal/flush SFA occlusions (n = 5), failure of antegrade recanalization (n = 4), infected femoral-femoral crossover bypass (n = 2), and occlusion of both the native SFA and the femoral-popliteal bypass (n = 1). The popliteal artery was punctured under ultrasound guidance. Occlusions were recanalized subintimally, and 4F compatible stents were implanted. Technical success rate (<30 % residual stenosis) was achieved in 83 % of cases. In two patients, stent dislocation occurred while the sheath was removed. One arteriovenous fistula was successfully treated with additional stenting. During 6-month follow-up, there were no major amputations, and three patients died from nonrelated causes. Fifty percent of patients alive after 6 months improved to Rutherford score ≤3. The duplex restenosis (>50 %) rate at 6 months was 50 %. Transpopliteal primary stenting of complex SFA lesions in CLI for a temporary bypass is now technically feasible using a 4F system. Technical results are promising. Clinical results after 6 months are acceptable when taking into consideration that this approach may be the last option for limb salvage.


Ameliorative effects of Osteo-F, a newly developed herbal formula, on osteoporosis via activation of bone formation.
The fruit of Schizandra chinensis and Lycium chinense, and the root of Eucommia ulmoides, components of Osteo-F, has traditionally been used for treating bone diseases in Korean Medicine. The exact role and underlying mechanism of Osteo-F herbal formula on bone formation in osteoporosis was investigated in the present study. OVX mice were treated with 0.9, 9 and 90 mg/kg of Osteo-F for 4 weeks. Bone tissues including fourth to sixth lumbar vertebrae (LV) and femur were collected to analyze the bone mineral density (BMD). In addition, serum biomarkers were estimated by enzyme-linked immunosorbent assay. The expressions of collagen, BMP-2 and osteopontin were determined in tibia to clarify the bone anabolic effects of Osteo-F in osteoporosis. The levels of BMD in both of fourth to sixth LV and femur were significantly increased by Osteo-F treatment in OVX mice. Bone mineral content (BMC) was also elevated in Osteo-F-treated LV and femoral bone tissues. In addition, serum osteocalcin was markedly increased by Osteo-F in osteoporotic mice. Serum ALP and bALP levels were neutralized in Osteo-F 90 mg/kg-administered mice. Furthermore, Osteo-F treatment dramatically increased the mRNA expressions of collagen type I, BMP-2 and OPN in tibial bone specimens. Osteo-F ameliorated bone loss by increasing bone forming molecules including BMP-2 and OPN in osteoporosis. Osteo-F, a newly developed herbal formula, may be an alternative material for the management of osteoporosis with bone anabolic effects.


Optical correlation by use of partial phase-only modulation with VGA liquid-crystal displays.
The development of liquid-crystal panels for use in commercial equipment has been aimed at improving the pixel resolution and the display efficiency. These improvements have led to a reduction in the thickness of such devices, among other outcomes, that involves a loss in phase modulation. We propose a modification of the classical phase-only filter to permit displays in VGA liquid-crystal panels with a constant amplitude modulation and less than a 2pi phase modulation. The method was tested experimentally in an optical setup.


Management Strategies for Rotator Cuff Defects After Calcific Tendinitis Debridement.
Management of rotator cuff defects that are created in the process of excising calcific deposits for patients undergoing surgical intervention for symptomatic calcific tendinitis is not well defined. Such defects can vary considerably in depth, size, and location, and surgical treatment of these rotator cuff lesions depends on a number of factors. Accurately identifying the location and extent of these calcific deposits is important in ensuring their complete removal, and techniques designed to consistently localize these calcific deposits are also described.


Biobibliometrics (UGDH-TP53-BRCA1) Genes Connections in the Possible Relationship Between Breast Cancer and EEG.
In recent years there has been an increasingly amount of data stored in biomedical Databases due to the breakthroughs in biology and bioinformatics, biomedical information is growing exponentially making efficient information retrieval from scientist more and more challenging. New Scientific fields as Bioinformatics seem to be the tool needed to extract scientifically important data based on experimental results and information provided by papers and journals. In this paper we are going to implement a custom made IT system in order to find connections between genes in the breast cancer pathways such the BRCA1 with the electrical energy in the human brain with UGDH gene via the TP53 tumor gene. The proposed system will be able to identify the appearance of each gene ID and compare the coexistence of two genes in PubMed articles/papers. The final system could become a useful tool against the struggle of scientists and medical professionals in the near future.


The 206 kbp mitochondrial genome of Phanerochaete carnosa reveals dynamics of introns, accumulation of repeat sequences and plasmid-derived genes.
In this study, the mitogenome of Phanerochaete carnosa was sequenced and assembled by the next-generation sequencing. The P. carnosa mitogenome was composed of circular DNA molecules, with a total size of 206,437 bp. Intron sequence, repeat sequence and plasmid-derived genes together promoted the P. carnosa mitogenome to become the second largest mitogenome in Basidiomycota. Gene arrangement analysis revealed large-scale gene rearrangements between Polyporales mitogenomes, and P. carnosa contained a unique gene order. The number and position classes of introns varied between 14 Polyporales species tested, indicated numerous intron loss/gain events occurred in the evolution of Polyporales. Most core PCGs in the 14 Polyporales species we tested were found subjected to purifying selection. However, the Ka/Ks values of rps3 gene were found >1 between some Polyporales species, indicating pressure of positive selection may exist. Phylogenetic analysis based on the combined mitochondrial gene set obtained well-supported tree topologies, and P. carnosa was identified as a sister species to Phlebia radiata. This study served as the first report on the mitogenome in the family Phanerochaetaceae, which will promote the understanding of the phylogeny, population genetics, and evolution of this white-rot fungus and related fungi.


Simultaneous high-performance liquid chromatographic analysis of carbidopa, levodopa and 3-O-methyldopa in plasma and carbidopa, levodopa and dopamine in urine using electrochemical detection.
Two assay procedures are described for the analysis of levodopa, carbidopa and 3-O-methyldopa in plasma and levodopa, carbidopa and dopamine in urine. The methods are suitable for quantifying the analytes following therapeutic administration of levodopa and carbidopa. Both were based on reversed-phase high-performance liquid chromatography (HPLC) with electrochemical detection and with methyldopa as the internal standard. Plasma samples were prepared by perchloric acid precipitation followed by the direct injection of the supernatant. Urine was prepared by alumina adsorption, and the analytes were desorbed with perchloric acid solution containing disodium EDTA and sodium metabisulfite prior to injection into the HPLC system. The methods have been utilized to evaluate the pharmacokinetics and bioavailability of oral dosage forms containing levodopa and carbidopa.


Association between vitamin D and ovarian cancer development in BRCA1 mutation carriers.
Women with inherited mutations in BRCA1 gene have a high (40-70%) genetic risk of developing ovarian cancer. Epidemiological studies suggest an inverse correlation between serum vitamin D (VD) levels and the risk of ovarian cancer, but there is a lack of data from BRCA1 mutation (BRCA1 mut) carriers. Therefore, we investigated VD levels and actions in cancer free women with BRCA1 mutations. Blood, ovary and fallopian tube samples were collected from healthy pre-menopausal women with BRCA1 mut and without BRCA1 mutations (BRCA wt). Serum calcifediol (major circulating form of VD) concentrations were measured by electrochemiluminescence immunoassay. Immunohistochemistry was performed on paraffin-embedded ovarian and fallopian tube sections to determine vitamin D receptor (VDR) expression. Ovarian surface epithelial cells (OSEs) from BRCA1 mut carriers were cultured with or without calcitriol supplementation for 72 hrs. VDR protein levels, cell proliferation and cell viability were analyzed. BRCA1 mut women had lower serum calcifediol levels compared to BRCA wt women (p = 0.003). VDR protein expression was evident in ovarian and the fallopian tube epithelium of BRCA wt patients, but was reduced in BRCA1 mut women. Calcitriol (biologically active VD) supplementation elevated VDR expression in cultured BRCA1 mut OSEs (p = 0.005) and decreased cell proliferation rates in a dose-dependent manner without inducing apoptosis. VD biosynthesis and signaling via VDR in the ovarian and fallopian tube epithelium are impaired in BRCA1 mut women. VD treatment may limit BRCA1 mut epithelial cell proliferation without affecting cell viability, providing a rationale for exploring the potential for VD in ovarian cancer prevention in BRCA1 mut carriers.


Genetic association studies.
We review the rationale behind and discuss methods of design and analysis of genetic association studies. There are similarities between genetic association studies and classic epidemiological studies of environmental risk factors but there are also issues that are specific to studies of genetic risk factors such as the use of particular family-based designs, the need to account for different underlying genetic mechanisms, and the effect of population history. Association differs from linkage (covered elsewhere in this series) in that the alleles of interest will be the same across the whole population. As with other types of genetic epidemiological study, issues of design, statistical analysis, and interpretation are very important.


Mast cells and IgE-bearing cells in lungs of RAO-affected horses.
Recurrent airway obstruction (RAO) is a common condition in stabled horses characterised by small airway inflammation and obstruction following exposure of susceptible horses to mouldy hay and straw. The aim of the present study was to investigate whether lung tissue from horses with RAO contains higher numbers of IgE-protein positive (+) cells and mast cells compared to controls after mouldy hay challenge. Furthermore, mast cell subtypes in lung tissue were investigated. IgE+ cells were detected in most lung tissue samples but no significant differences between RAO-affected and control horses were found. In the wall of the bronchi and bronchioli of both RAO-affected and control horses, mainly chymase+ mast cells (MC(C)) were present (85% in the bronchial wall and 77% in the wall of the bronchioli), while 73% of the mast cells (MC) around blood vessels were tryptase+ mast cells (MC(T)). No double stained MCs were detected. RAO-affected horses had significantly more MC(C) than controls in the wall of the bronchi (median=7.6 and 1.7 cell/mm(2), respectively, P< or =0.05). They also showed a tendency for more MC(C) in the wall of the bronchioli than controls (median=21 and 2.9 cells/mm(2), respectively, P=0.07) but there were no differences in MC(T) numbers. The data suggest an involvement of MC(C) in the pathogenesis of RAO. Independently of the clinical diagnosis, there was a significant relationship between high MC(C) numbers in the bronchial wall and lung fibrosis, suggesting that these MC(C) may be involved in tissue remodelling. Furthermore, high MC(C) numbers were also associated with increased infiltration with lymphocytes and neutrophils.


Metabolic Stress Triggers Immune Escape by Tumors.
There is major interest in understanding the role of the tumor microenvironment in immune escape. In a recent report, Marijt et al. shed light on the signaling cascade that leads to decreased surface expression of MHC class I by tumor cells triggered by low oxygen and glucose availability, revealing new opportunities for therapeutic intervention.


Activation of platelets by heparin-induced thrombocytopenia antibodies in the serotonin release assay is not dependent on the presence of heparin.
The serotonin release assay (SRA) tests for antibodies responsible for heparin-induced thrombocytopenia (HIT). By definition, SRA-positive antibodies cause platelet serotonin release in vitro, in the presence of low concentrations of heparin, but not with excess heparin. Many SRA-positive sera activate platelets in the presence of saline without drug, either as a result of residual heparin in the specimen, or because of intrinsic features of the HIT antibodies. The present experiments show that neither exhaustive heparinase treatment, nor chromatographic removal of heparin abrogates the spontaneous platelet activation caused by these HIT antibodies. This is the first study to systematically demonstrate that in vitro activity of HIT antibodies can be independent of heparin. In addition, T-gel chromatography demonstrated differences among fractions of enzyme-linked-immunosorbent assay (ELISA)-positive HIT antibodies within individual specimens. Certain ELISA-positive fractions had SRA activity while others did not, and the SRA activity was not proportional to HIT antibody ELISA titer. These data suggest that antibodies formed as a result of heparin treatment are heterogeneous, and that some can contribute to the pathogenesis of HIT even when heparin is no longer present.


Variation of indoor radon concentration and ambient dose equivalent rate in different outdoor and indoor environments.
Subject of this study is an investigation of the variations of indoor radon concentration and ambient dose equivalent rate in outdoor and indoor environments of 40 dwellings, 31 elementary schools and five kindergartens. The buildings are located in three municipalities of two, geologically different, areas of the Republic of Macedonia. Indoor radon concentrations were measured by nuclear track detectors, deployed in the most occupied room of the building, between June 2013 and May 2014. During the deploying campaign, indoor and outdoor ambient dose equivalent rates were measured simultaneously at the same location. It appeared that the measured values varied from 22 to 990 Bq/m(3) for indoor radon concentrations, from 50 to 195 nSv/h for outdoor ambient dose equivalent rates, and from 38 to 184 nSv/h for indoor ambient dose equivalent rates. The geometric mean value of indoor to outdoor ambient dose equivalent rates was found to be 0.88, i.e. the outdoor ambient dose equivalent rates were on average higher than the indoor ambient dose equivalent rates. All measured can reasonably well be described by log-normal distributions. A detailed statistical analysis of factors which influence the measured quantities is reported.


Tissue cathepsins as tumor markers.
In the metastatic process, proteolytic enzymes play an important role in mediating passage of the malignant cell through the cell membrane. The cathepsins are ubiquitous lysosomal proteases and are classified both functionally and according to their active site. Cathepsin D, cathepsin B and to a lesser extent other cathepsins have been described as prognostic markers in cancer. Measurements of cathepsin D in breast tissue may be significant in predicting recurrence as well as disease free and overall survival. Reported differences concerning the role of cathepsin D as a prognostic marker may be related in part to the methodology used and the employment in the assays of antibodies prepared to different portions of the molecule. The general consensus is that elevated concentrations of cathepsin D in breast cancer tissue are highly significant indicators of the potential for recurrence. Cathepsin B, which catalyzes the degradation of laminin, may play a role in the rupture of the basement membrane and may be of importance in pancreatic and colorectal cancer.


An improved arbitrary primed PCR method for rapid characterization of transposon insertion sites.
Modifications were made to published arbitrary primed polymerase chain reaction (AP-PCR) procedures that resulted in increased specificity and sensitivity. Several arbitrary primer sequences were also evaluated, resulting in recommendations for primer design.


Lewis Lung Cancer Cells Promote SIGNR1(CD209b)-Mediated Macrophages Polarization Induced by IL-4 to Facilitate Immune Evasion.
Tumor-associated macrophages are a prominent component of lung cancer and contribute to tumor progression by facilitating the immune evasion of cancer cells. DC-SIGN (CD209) assists in the immune evasion of a broad spectrum of pathogens and neoplasms by inhibiting the maturation of DCs and subsequent cytokines production. However, the expression of DC-SIGN in macrophages and its role in mediating immune evasion in lung cancer and the underlying mechanism remain unclear. Our study aimed to identify the immunosuppressive role of SIGNR1 in murine macrophage differentiation and lung cancer progression. We found that SIGNR1-positive RAW264.7 macrophages were enriched in mixed cultures with Lewis lung cancer cells (LLC) (ratio of RAW 264.7 to LLC being 1:1) after stimulation with IL-4. Moreover, LLC-educated macrophages exhibited significantly higher levels of IL-10 but lower IL-12 in response to IL-4 treatment as determined by RT-PCR and ELISA. However, inhibition of SIGNR1 markedly hampered the production of IL-10, indicating that SIGNR1 was indispensable for IL-4+LLC induced macrophage polarization towards the M2 subtype. Furthermore, polarized M2 cells immersed in a tumor microenvironment promoted the migration of LLCs, as measured by transwell assays, but migration was suppressed after blockade of SIGNR1 using CD209b antibody. In addition, IL-4+LLC-educated macrophages reduced the proliferation of the activated T cells and reduced IFN-γ-mediated Th1 response in T cells, while SIGNR1 inhibition rescued Th1 cell functions. In conclusion, murine SIGNR1 expressed in LLC-educated macrophages appears to mediate IL-4-induced RAW264.7 macrophage polarization and thus facilitate lung cancer evasion.


Chromatographic retention relationships between aliphatic tertiary amines and their putative N-oxide metabolites--preliminary results.
The chromatography of a series of tertiary amines and the corresponding N-oxides have been studied and the Functional Group Contribution Approach used to describe retention correlations between them. Good correlations are observed between the behaviour of compounds on HPLC and with the exception of some alicyclic nitrogen compounds also on thin layer chromatography. The models produced are used to predict k' and Rf values for ranitidine N-oxide and tamoxifen N-oxide based upon those for the parent molecule. The deviation between actual and predicted values was larger than expected, presumably due to the structural or physico-chemical differences of ranitidine and tamoxifen compared to the model compounds.


Left-sided hepatic hydrothorax diagnosed by contrast-enhanced ultrasonography with intraperitoneal injection of Levovist.
A 62-year-old Japanese woman was admitted to our hospital with dyspnea. Chest X-ray revealed massive pleural effusion on the left side. Contrast-enhanced ultrasonography using Levovist was performed to confirm the transdiaphragmatic passage of ascitic fluid into the pleural cavity. After injection of Levovist into the peritoneal cavity, an enhanced pulsative flow into the pleural cavity was detected. This is the first report of hepatic hydrothorax diagnosed by contrast-enhanced ultrasonography. This method is safe and useful for the diagnosis of hepatic hydrothorax, and it allows observation of the real-time movement of ascitic fluid from the peritoneal cavity to the pleural space and detection of the site of the peritoneopleural communication.