Description of sorbing tracers transport in fractured media using the lattice model approach.
The transport of contaminants in fractured media is a complex phenomenon with a great environmental impact. It has been described with several models, most of them based on complex partial differential equations, that are difficult to apply when equilibrium and nonequilibrium dynamics are considered in complex boundaries. With the aim of overcoming this limitation, a combination of two lattice Bathnagar, Gross and Krook (BGK) models, derived from the lattice Boltzmann model, is proposed in this paper. The fractured medium is assumed to be a single fissure in a porous rock matrix. The proposed approach permits us to deal with two processes with different length scales: advection-dispersion in the fissure and diffusion within the rock matrix. In addition to the mentioned phenomena, sorption reactions are also considered. The combined model has been tested using the experimental breakthrough curves obtained by Garnier et al. (Garnier, J.M., Crampon, N., Préaux, C., Porel, G., Vreulx, M., 1985. Traçage par 13C, 2H, I- et uranine dans la nappe de la craie sénonienne en écoulement radial convergent (Béthune, France). J. Hidrol. 78, 379-392.) giving acceptable results. A study on the influence of the lattice BGK models parameters controlling sorption and matrix diffusion on the breakthrough curves shape is included.


Bioavailability of copper to rats from various foodstuffs and in the presence of different carbohydrates.
Copper bioavailability was studied in rats using an extrinsic Cu label. Copper absorption from sunflower seeds (46%), peanuts (41%), cooked shrimp (50%), and cooked beef (40%) was as good or better than copper sulfate (46%). Copper from plant foods (sunflower seeds, garbanzo beans, peanuts) was absorbed equally as well as copper from animal foods (beef, shrimp, chicken liver), 39 +/- 7% vs 43 +/- 7%, P greater than 0.05. There was no significant difference in percentage Cu absorption between intrinsically labeled chicken liver and extrinsically labeled chicken liver. In a second experiment, Cu absorption was measured in the presence of glucose, fructose, sucrose, or cornstarch. There were no significant differences in Cu absorption due to different carbohydrates in a single meal.


Denosumab or romosozumab therapy and risk of cardiovascular events in patients with primary osteoporosis: Systematic review and meta- analysis.
Osteoporosis and cardiovascular (CV) diseases are closely correlated. RANKL/RANK/OPG pathway and Wnt signalling pathway both implicated in the pathogenesis of osteoporosis and cardiovascular diseases. We aimed to investigate the effect of denosumab or romosozumab therapy on cardiovascular outcomes in patients with primary osteoporosis. PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to June 4, 2019. Randomized clinical trials evaluating the effect of denosumab or romosozumab versus active comparators or placebo for at least 6 months in patients with primary osteoporosis or osteopenia were included. Two investigators independently extracted data for study characteristics, outcomes of interest, and risk of bias in accordance with PRISMA guidelines. 17 relevant studies (denosumab: n=11, 13615 participants; romosozumab: n=6, 12219 participants) were included. No associations between denosumab therapy and risk of a composite cardiovascular outcome (1.06 [95 % CI, 0.88-1.28], p=0.54), three-point major adverse cardiovascular event (3P MACE, 1.01 [95 % CI, 0.83-1.23], p=0.93), and four-point major adverse cardiovascular event (4P MACE, 0.99 [95 % CI, 0.83-1.18], p=0.89) were identified. Romosozumab therapy did not increase the risk of composite cardiovascular outcome (1.26 [95 % CI, 0.95-1.68], p=0.11), and 3P MACE (1.41 [95 % CI, 0.99-2.02], p=0.06), while increased the risk of 4P MACE (1.39 [95 % CI, 1.01-1.90], p=0.04) among elderly men and postmenopausal woman with osteoporosis over a period of 12-36 months. Denosumab or romosozumab did not increase or reduce specific cardiovascular outcomes, including CV death or death, myocardial infarction, stroke, atrial fibrillation, heart failure, aortic and intracranial aneurysm, aortic dissection, aortic valve disease and hypertension (all p>0.05). Sensitivity analysis conducted by random effects model altered the result of 4P MACE in romosozumab (1.36 [0.99-1.87], p=0.06). No other significant difference was detected in the sensitivity analyses and subgroup analyses. Denosumab therapy was not associated with any risk of composite and specific cardiovascular outcomes among patients with primary osteoporosis than active comparators or placebo, while romosozumab therapy might increase the risk of 4P MACE.


How we do it: the Bradford grommet trainer: a model for training in myringotomy and grommet insertion.
Myringotomy and grommet insertion is the most common operative procedure in otological practice. We describe a simple, cheap and effective model for the junior trainee to develop the skills required for myringotomy and grommet insertion without compromising patient safety. As the materials required for our model are more readily available, it is more likely to gain widespread acceptance in ENT training.


Relationship between mechanical ankle joint laxity and subjective function.
An increase in ankle joint laxity has been reported in patients with chronic ankle instability (CAI). However, it is not known if this increase in joint laxity is responsible for the subjective level of functional deficits also reported in these patients. One hundred twenty subjects with unilateral CAI (55 males, 65 females; age, 20.6 ± 1.5 years; mass, 74.5 ± 13.6 kg; height, 174.2 ± 9.7 cm) participated in the study. Mechanical joint stability was measured with an instrumented ankle arthrometer. The arthrometer measured ankle joint motion for anterior/posterior translation and inversion/eversion angular displacement. Subjective level of function was assessed with the foot and ankle disability index (FADI) and foot and ankle disability index sport (FADIS). Bivariate correlations using Pearson Product Moments were made between all dependent variables taken on the unstable ankles. The strongest relationship was between anterior laxity and the FADIS (r = -0.88, p < 0.0001). As scores on the FADIS decreased, anterior laxity increased. Similar significant results were reported for anterior laxity and the FADI (r = -0.65, p = 0.013), as well as inversion laxity and the FADI (r = -0.53, p = 0.017) and FADIS (r = -0.45, p = 0.013). These data demonstrate that there appears to be a relationship between anterior and inversion ankle laxity and subjective function in those with CAI. Although numerous insufficiencies develop after an ankle sprain, increased laxity may cause some of the subjective functional deficits reported in those with CAI. Strategies to prevent increased laxity following ankle sprain may improve the patient's subjective level of function.


HTLV-I-associated lymphoma presenting as mycosis fungoides in an HTLV-I non-endemic area: a viro-molecular study.
Human T-lymphotropic virus type I (HTLV-I) is endemic in the Caribbean region, south-western Japan and Africa, and is associated with tropical spastic paraparesis and adult T-cell leukaemia/lymphoma (ATLL). Cutaneous forms of ATLL are sometimes indistinguishable from other cutaneous T-cell lymphomas (CTCL). We report a woman living in a non-endemic area for HTLV-I, with no risk factors for viral infection, who developed mycosis fungoides-like ATLL. The findings underline the usefulness of molecular biological techniques in distinguishing between mycosis fungoides and ATLL. We emphasize the need to establish the HTLV-I status of patients with CTCL, even in HTLV-I non-endemic areas, not only to establish a preventive policy in these countries, but also to further our knowledge of the lymphoproliferation spectrum associated with human retroviruses.


Myelination in the CNS of mld mutant mice: comparison between composition and structure.
Myelination was studied between 15 and 135 days postnatally in the brain and optic nerves of myelin deficient (mld) mutant mice. Between 15 and 30 days almost no myelin basic protein (MBP) could be detected in mld myelin. The axons were loosely wrapped by membranes which only fused at the extracellular sites forming the intraperiod line. At this age the major dense line was absent. At 25-30 days, purified myelin contained extremely high 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) (EC 184.108.40.206) activities which could be related to the redundant paranodal-like structures observed at this age in mld CNS. Therefore, it can be suggested that CNP is probably localized in such paranodal loops. After the active phase of myelin deposition was completed in controls, mld mutants showed important increases of MBP concentration in myelin with the concomitant appearance of the major electron dense line and better compaction of the myelin lamellae. The yield of myelin increased from 5 to 14% of control values during the period of 30 to 135 days. Since the recovery phase occurred at the time when myelin lipid synthesizing enzymes are at low residual activities, the myelin deficit could only be partially corrected. This study indicates that there is a delay of MBP synthesis in mld mice and the decrease of other myelin proteins could be secondary to the assumed primary defect involving MBP.


NMR studies of the stable mismatch purine-thymine in the self-complementary d(CGPuAATTTCG) duplex in solution.
One- and two-dimensional nuclear Overhauser effect experiments demonstrate that a single hydrogen bond between a T imino proton and purine N3 is sufficient to hold the base pair dPu.dT in d(CGPuAATTTCG) by a Watson-Crick fashion rather than a Hoogsteen type. In addition, the dPu.dT base pair is well stacked with neighboring base pairs. The spin-lattice relaxation measurements at 30 and 35 degrees C of two decamers, d(CGPuAATTTCG) and d(CGAAATTTCG), reveal that the elimination of two single hydrogen bonds of dA.dT base pairs (due to the substitution of adenine for purine) in the sequence results in an increase in the overall imino proton exchange rate from 7 to 36 s-1 at the site of mismatch.


Strong Raman-induced noninstantaneous soliton interactions in gas-filled photonic crystal fibers.
We have developed an analytical model based on the perturbation theory to study the optical propagation of two successive solitons in hollow-core photonic crystal fibers filled with Raman-active gases. Based on the time delay between the two solitons, we have found that the trailing soliton dynamics can experience unusual nonlinear phenomena, such as spectral and temporal soliton oscillations and transport toward the leading soliton. The overall dynamics can lead to a spatiotemporal modulation of the refractive index with a uniform temporal period and a uniform or chirped spatial period.


MRI findings, including diffusion-weighted imaging, in seven cats with nasal lymphoma and two cats with nasal adenocarcinoma.
Primary nasal tumours in cats are rare, with lymphoma being the most common feline nasal tumour, followed by adenocarcinoma. Although CT can reliably detect feline nasal tumours, there are no specific CT features that identify each tumour type. To our knowledge, there have been no reports describing MRI findings, including diffusion-weighted imaging (DWI), for nasal lymphomas and adenocarcinomas in cats. Therefore, this retrospective study aimed to evaluate the MRI findings of nasal lymphoma and adenocarcinoma, including qualitative and quantitative analysis of DWI. MRI examination was performed on seven cats with histologically confirmed lymphoma and on two with adenocarcinoma. The MRI protocol included T2-weighted imaging (T2WI), T1-weighted imaging (T1WI) and DWI. Apparent diffusion coefficient (ADC) values were measured using DWI. Contrast agent was not used in one cat with lymphoma. Of the cats with lymphoma, three (43%) were iso- and hyperintense on T2WI, seven (100%) were isointense on T1WI, five (83%) exhibited mild heterogeneous enhancement, including a prominent region of non-enhancement on post-contrast T1WI, and seven (100%) cats exhibited hyperintensity on DWI. The median ADC values were 0.45 × 10-3 mm2/s (range 0.37-0.53 × 10-3 mm2/s). For adenocarcinoma, two (100%) were iso- and hyperintense on T2WI, two (100%) were isointense on T1WI, two (100%) exhibited marked heterogeneous enhancement on post-contrast T1WI and two (100%) were isointense on DWI. The median ADC values were 1.08 × 10-3 mm2/s (range 0.88-1.27 × 10-3 mm2/s). The median ADC values of lymphoma tended to be lower than adenocarcinoma (P = 0.056). Determining ADC value and tumours with a large area of non-enhancement may be helpful in differentiating nasal lymphoma from nasal adenocarcinoma.


External validation of the CREST model to predict early circulatory-etiology death after out-of-hospital cardiac arrest without initial ST-segment elevation myocardial infarction.
The CREST model is a prediction model, quantitating the risk of circulatory-etiology death (CED) after cardiac arrest based on variables available at hospital admission, and intend to guide the triage of comatose patients without ST-segment-elevation myocardial infarction after successful cardiopulmonary resuscitation. This study assessed performance of the CREST model in the Target Temperature Management (TTM) trial cohort. We retrospectively analyzed data from resuscitated out-of-hospital cardiac arrest (OHCA) patients in the TTM-trial. Demographics, clinical characteristics, and CREST variables (history of coronary artery disease, initial heart rhythm, initial ejection fraction, shock at admission and ischemic time > 25 min) were assessed in univariate and multivariable analysis. The primary outcome was CED. The discriminatory power of the logistic regression model was assessed using the C-statistic and goodness of fit was tested according to Hosmer-Lemeshow. Among 329 patients eligible for final analysis, 71 (22%) had CED. History of ischemic heart disease, previous arrhythmia, older age, initial non-shockable rhythm, shock at admission, ischemic time > 25 min and severe left ventricular dysfunction were variables associated with CED in univariate analysis. CREST variables were entered into a logistic regression model and the area under the curve for the model was 0.73 with adequate calibration according to Hosmer-Lemeshow test (p = 0.602). The CREST model had good validity and a discrimination capability for predicting circulatory-etiology death after resuscitation from cardiac arrest without ST-segment elevation myocardial infarction. Application of this model could help to triage high-risk patients for transfer to specialized cardiac centers.


Metallomacrocycles as anion receptors: combining hydrogen bonding and ion pair based hosts formed from Ag(I) salts and flexible bis- and tris-pyrimidine ligands.
Two self-assembled hosts are formed from Ag(I) salts and bis-pyrimidyl ligands and X-ray characterized. Both are able to incorporate two anions into the structure combining hydrogen bonding and electrostatic interactions.


Effects of formulation and process variables on the release of a weakly basic drug from single unit extended release formulations.
A new commercially available extended release matrix material, Kollidon SR, composed of polyvinylacetate (PVA) and polyvinylpyrrolidone (PVP), was evaluated with respect to its ability to modulate the in vitro release of the weakly basic drug ZK 811 752. The effect of different formulation and process parameters on the release kinetics of ZK 811 752 from PVA/PVP based matrix tablets was investigated as a function of the (i) nature of excipient added to the drug-polymer mixtures, (ii) method of manufacturing (direct compression versus wet granulation), and (iii) effect of a post-compression curing step. ZK 811 752 containing extended release matrix tablets were successfully prepared by using Kollidon SR. The drug release from the matrix tablets increased by the addition of excipients such as maize starch, lactose and calcium phosphate. Addition of the highly swellable maize starch and the water-soluble lactose accelerated the drug release in a more pronounced manner compared to the water-insoluble calcium phosphate. Compound release from matrix tablets prepared by wet granulation was faster compared to the drug release from tablets prepared by direct compression. Post compression curing did not influence the drug release rate from drug-lactose-Kollidon SR formulations. Stability studies demonstrated no degradation of the drug substance and reproducible drug release patterns for matrix tablets stored at 25 degrees C/60% RH and 30 degrees C/70% RH for up to 6 months.


[The combination of nifedipine and a low sodium diet with potassium supplement in the therapy of essential arterial hypertension].
Moderate dietary sodium restriction with moderate dietary potassium supplementation was used in patients with essential hypertension who were treated with nifedipine retard by mouth every twelve hours. Combination therapy of this diet with the nifedipine retard produced a significantly greater decrease in both lying and standing blood pressure that with the drug alone. No noticeable side effects were observed.


Berberine ameliorates chronic kidney disease through inhibiting the production of gut-derived uremic toxins in the gut microbiota.
At present, clinical interventions for chronic kidney disease are very limited, and most patients rely on dialysis to sustain their lives for a long time. However, studies on the gut-kidney axis have shown that the gut microbiota is a potentially effective target for correcting or controlling chronic kidney disease. This study showed that berberine, a natural drug with low oral availability, significantly ameliorated chronic kidney disease by altering the composition of the gut microbiota and inhibiting the production of gut-derived uremic toxins, including p-cresol. Furthermore, berberine reduced the content of p-cresol sulfate in plasma mainly by lowering the abundance of g_Clostridium_sensu_stricto_1 and inhibiting the tyrosine-p-cresol pathway of the intestinal flora. Meanwhile, berberine increased the butyric acid producing bacteria and the butyric acid content in feces, while decreased the renal toxic trimethylamine N-oxide. These findings suggest that berberine may be a therapeutic drug with significant potential to ameliorate chronic kidney disease through the gut-kidney axis.


A high-fiber diet synergizes with Prevotella copri and exacerbates rheumatoid arthritis.
Both preclinical and established rheumatoid arthritis (RA) patients display alterations in the gut microbiome. Prevotella spp. are preferentially enriched in a subset of RA patients. Here, we isolated a Prevotella strain, P. copri RA, from the feces of RA patients and showed that colonization of P. copri RA exacerbated arthritis in a collagen-induced arthritis (CIA) model. With the presence of P. copri RA colonization, a high-fiber diet exacerbated arthritis via microbial alterations and intestinal inflammation. Colonization of P. copri together with a high-fiber diet enabled the digestion of complex fiber, which led to the overproduction of organic acids, including fumarate, succinate and short-chain fatty acids. Succinate promoted proinflammatory responses in macrophages, and supplementation with succinate exacerbated arthritis in the CIA model. Our findings highlight the importance of dysbiosis when evaluating the effects of dietary interventions on RA pathogenesis and provide new insight into dietary interventions or microbiome modifications to improve RA management.


Hunger and food security in the times of Covid-19.
This paper discusses the situation of hunger and malnutrition in India during the times of the Covid-19, the associated lockdown and the aftermath. The economic slowdown and loss of employment have resulted in widespread food insecurity. There are also concerns that this might have long-lasting effects on the nutrition status of the population. In this context, government support through schemes such as the PDS plays an important role. While there have been some interventions through these schemes towards providing food and cash support to people, there are many gaps. The availability of high food stocks can be used as an opportunity to provide a universal PDS which is the need of the hour. Other issues such as expanding the PDS to include pulses and oils, decentralised procurement, universal food support through school meals and ICDS, and enhanced cash transfers through social security schemes also need to be ensured.


Enhanced protective immunity against spring viremia of carp virus infection can be induced by recombinant subunit vaccine conjugated to single-walled carbon nanotubes.
As a successful prevention strategy for controlling the highly contagious and pathogenic disease of spring viremia of carp (SVC), DNA vaccines reported in recent years could trigger protective responses against SVC with the means of injection. However, there remains many concerns and uncertainties related to DNA vaccination as well as injection is labor intensive, costly and not suitable to vaccinate large numbers of fish. Therefore, more efficient and safe prophylactic measures should be urgently investigated. In this research, single-walled carbon nanotubes (SWCNTs) as the candidate SWCNTs-pET32a-G subunit vaccine carrier were administrated via bath (1, 5, 10, 20, 40 mg L-1) or injection (1, 4, 8, 12, 20 μg) in common carp juvenile, and the different immune treatments to induce immunoprotective effect were analyzed. The results showed that SWCNTs-pET32a-G could enter fish body after immersion for 10 h, furthermore, compared to control groups, antibody levels, the non-specific immune parameters (complement activity, superoxide dismutase activity and alkaline phosphatase activity), and immune-related genes (especially the TNF-α and IFNg2b) in vaccinated groups were significantly enhanced in fish immunized with SWCNTs-subunit vaccine. In addition, as a promising carrier, SWCNTs can increase the immune protective effect of naked subunit vaccine by ca. 16% in bath immunization group and by ca. 23% in injection group. This study suggests that SWCNTs-vaccine may represent a potentially efficient immersion vaccine against viral pathogens of fish in the future.


Antiinflammatory 2-benzyl-4-sulfonyl-4H-isoquinoline-1,3-diones: novel inhibitors of COX-2.
A series of 2-benzyl-4-sulfonyl-4H-isoquinoline-1,3-diones was prepared. Members of this series are potent and selective inhibitors of cyclooxygenase-2 (COX-2) in both microsomal and cellular assays. Two representatives demonstrated activity in the carrageenan-induced paw edema model in rats upon oral administration.


Body dysmorphic disorder and dermatologists.
The aim of this study was to determine the frequency of body dysmorphic disorder (BDD) identified by Polish dermatologists and to evaluate the treatment modalities applied by them. A specially designed questionnaire was distributed to 172 dermatologists. A total of 118 doctors responded (68.6%). The dermatologists were asked regarding demographic data, frequency of BDD in their everyday practice and methods of treatment they used in managing BDD patients. During the whole working period, over the half of dermatologists (64%) had observed at least one BDD patient in their practice. One fifth (20%) of the respondents observed 1 or 2 BDD cases during the past 5 years, 14% observed 3 to 5 such patients, 7% observed 5 to 10 BDD cases, and 5% of the doctors reported seeing more than 10 BDD patients within this period. Almost 18% of dermatologists were currently treating a BDD patient. Our data show that 40.7% of the respondents always ask and 28.8% often ask for a psychiatric opinion. More experienced dermatologists statistically more frequently (P < 0.05) obtained a psychiatric opinion about their patients. Only a small group of dermatologists (15.3%) use their own pharmacological treatment. If they do so, they first use anxiety-relieving drugs and placebo. BDD is a quite common disorder; however, not all dermatologists are sufficiently prepared to treat it. There is an urgent need for training of dermatologists on the effective approach to psychodermatoses.


Coping with a possible breast cancer diagnosis: demographic factors and social support.
This paper reports a study examining the relationships between demographic characteristics, social support, anxiety, coping and defence among women with possible breast cancer. Awaiting a possible breast cancer diagnosis is an anxiety-provoking situation that demands coping. Social support and demographic characteristics have been reported to influence coping and well-being, but the interconnection is insufficiently understood. A survey design was used, and self-administrated questionnaires were returned by a convenience sample of 117 women in Norway who had undergone breast biopsy. The data were collected from September 1998 to February 2000. The instruments consisted of: the Social Provisions Scale, State-Trait Anxiety Scale, Utrecht Coping List and Defence Mechanisms Inventory. In addition, data on age, level of education, employment, marital status, and household status were collected. Social support was positively related to instrumental-oriented coping and emotion-focused coping, unrelated to cognitive defence and defensive hostility. Educational level was positively related to instrumental-oriented coping. Educational level, employment and marital status were negatively related to cognitive defence. Educational level was the most important contributor to social support. Attachment and education were the most important contributors to instrumental-oriented coping, with education as the strongest predictor. Better coping was linked primarily to education, and secondly to attachment. Unemployment, low level of education and single/divorced/widowed status were related to greater use of cognitive defence. Women who used a defensive hostile style tended to receive poor social support. Nurses need to be aware of the influence of demographic characteristics on social support, coping and defence and to identify poor copers, as these patients are most in need of professional support.


Preoperative MRI sphincter morphology and anal manometry: can they be markers of functional outcome following anterior resection for rectal cancer?
Good functional outcome following anterior resection (AR) for rectal cancer is an important clinical goal, but its prediction has proven difficult. Assessments such as anal manometry have been advocated as a potential tool but functional anatomy as depicted on MRI has not been investigated. This study looked at whether sphincter complex measurements recorded from preoperative staging MRIs and preoperative anal manometry have any correlation with functional outcome. Consecutive patients with rectal adenocarcinoma underwent preoperative manometric assessment and MRI staging. MRIs were assessed with regard to anorectal angle, puborectalis thickness, canal length and external and internal anal sphincter thickness. Functional outcome was categorized into three groups according to the number of adverse postoperative symptoms (frequency, urgency, leakage, diarrhoea, use of pads, use of antidiarrhoeal medication): 0, 1 and ≥ 2. This was evaluated 1 year following surgery and 6 months following stoma reversal where applicable. Univariate analysis of an ordinal regression model was performed with significance at the 5% level. Thirty patients were assessed. No single preoperative manometric parameter proved significant (P > 0.05). Only puborectalis thickness showed a significant (P = 0.01) relationship with the number of adverse symptoms suffered postoperatively. On receiver operating characteristics analysis, a cut-off value of 3.5 mm gave an optimal sensitivity of 0.5 (95% CI, 0.17-0.83) and specificity of 0.86 (95% CI, 0.64-0.96). Measurements of the puborectalis thickness on preoperative staging MRIs for rectal cancer may help predict functional outcome following AR. Prospective assessment of larger numbers with a fully validated continence score are required to evaluate these findings further.


Curriculum label distribution learning for imbalanced medical image segmentation.
Label distribution learning (LDL) has the potential to resolve boundary ambiguity in semantic segmentation tasks. However, existing LDL-based segmentation methods suffer from severe label distribution imbalance: the ambiguous label distributions contain a small fraction of the data, while the unambiguous label distributions occupy the majority of the data. The imbalanced label distributions induce model-biased distribution learning and make it challenging to accurately predict ambiguous pixels. In this paper, we propose a curriculum label distribution learning (CLDL) framework to address the above data imbalance problem by performing a novel task-oriented curriculum learning strategy. Firstly, the region label distribution learning (R-LDL) is proposed to construct more balanced label distributions and improves the imbalanced model learning. Secondly, a novel learning curriculum (TCL) is proposed to enable easy-to-hard learning in LDL-based segmentation by decomposing the segmentation task into multiple label distribution estimation tasks. Thirdly, the prior perceiving module (PPM) is proposed to effectively connect easy and hard learning stages based on the priors generated from easier stages. Benefiting from the balanced label distribution construction and prior perception, the proposed CLDL effectively conducts a curriculum learning-based LDL and significantly improves the imbalanced learning. We evaluated the proposed CLDL using the publicly available BRATS2018 and MM-WHS2017 datasets. The experimental results demonstrate that our method significantly improves different segmentation metrics compared to many state-of-the-art methods. The code will be available.1.


DNA and cholesterol biosynthesis in synchronized embryonic rat fibroblasts. I. Temporal relationships between HMG-CoA reductase activity, sterol biosynthesis and thymidine incorporation into DNA.
Temporal relationships between hydroxymethylglutaryl-CoA reductase activity, biosynthesis of C27 sterols, and [3H]thymidine incorporation into DNA were studied in a rat embryo fibroblast cell line synchronized by double thymidine block and cultured in cholesterol-containing medium. Cyclic variations of HMG-CoA reductase activity and C27 sterols occurred, with two maxima in S and G2M phases; the relative shortness of the G1 phase (3 h) in these cells could be responsible for the shift of sterol synthesis in the S phase. No noticeable variation of the individual C27 sterols was observed during the entire cell cycle. In each experiment, there was a good linear correlation between HMG-CoA reductase activity and C27 sterol synthesis, but from one experiment to another, a given level of enzymatic activity led to varying levels of [2-14C]acetate incorporation into sterols. In our experimental conditions, total HMG-CoA reductase activity is measured, and the preceding observation could be explained by a varying degree of phosphorylation of the enzyme depending on the metabolic state of the cells at the start of the experiment. The cyclic variations of the enzyme activity seem to be due more to increased synthesis at given times of the cycle than to periodic dephosphorylation. We question the existence of a relationship between cell division and cyclic sterol synthesis occurring in cells cultured in cholesterol-containing medium.


Cancer in pregnancy and the risk of adverse pregnancy and neonatal outcomes: A nationwide cohort study.
To investigate the obstetrical management of cancer in pregnancy and to determine adverse pregnancy and neonatal outcomes. A nationwide cohort study. We included all pregnancies (n = 4 071 848) in Denmark from 1 January 1973 to 31 December 2018. Exposure was defined as pregnancies exposed to maternal cancer (n = 1068). The control group comprised pregnancies without cancer. The groups were compared using logistic regression analysis and adjusted for potential confounders. The outcomes were induced abortion, preterm birth and adverse neonatal outcomes. More women with cancer in pregnancy, as compared with the control group, experienced induced abortion (24.8% vs. 20.0%); first-trimester induced abortion adjusted odds ratio (aOR) 3.5 (95% confidence interval [CI] 2.7-4.5), second-trimester induced abortion; aOR 8.8 (95% CI 6.3-12.3), planned preterm birth (11.8% vs. 1.3%); aOR 10.8 (95% CI 8.0-14.6) and planned preterm birth at <32 gestational weeks; aOR 16.3 (95% CI 8.3-31.7). Neonates born to mothers with cancer in pregnancy had a higher risk of respiratory distress syndrome; aOR 3.5 (95% CI 2.8-4.4), low birthweight; aOR 3.8 (95% CI 3.1-4.8), admission to neonatal intensive care unit for >7 days; aOR 5.1 (95% CI 3.9-6.6), neonatal infection; aOR 1.8 (95% CI1.1-3.1) and neonatal mortality; aOR 4.7 (95% CI 2.7-8.2), but not of SGA; aOR 1.0 (95% CI 0.6-1.5) and malformations; 1.2 (95% CI 0.9-1.7). Cancer in pregnancy increases the risk of induced abortion and planned premature birth. Neonates born to mothers with cancer in pregnancy had an increased risk of neonatal morbidity and mortality, presumably due to prematurity. Cancer in pregnancy is associated with an increased risk of premature birth leading to adverse neonatal outcomes.


Mucormycosis: A 14-Year Retrospective Study from a Tertiary Care Center in Lebanon.
Mucormycosis (MCM) is a serious invasive fungal disease (IFD) that is associated with high mortality, particularly in immunocompromised patients. A global surge in MCM cases was reported with the COVID-19 pandemic. We analyzed all recorded cases of MCM at the American University of Beirut Medical Center (AUBMC), a tertiary care center in Lebanon, over 14 years. We aimed to identify the incidence, seasonal variation, clinical characteristics of the patients, and predictors of mortality. We conducted a retrospective chart review between 1 January 2008 and 1 January 2023. All patients with proven or probable MCM were included in the study. Proven or probable MCM was defined by positive histopathology and/or positive cultures. A total of 43 patients were identified as having MCM. Their median age was 53 years, and the majority were males (58.1%). Most of the cases were diagnosed in the autumn season. In total, 67.4% of the patients had hematological malignancies (HMs), and 34.9% had uncontrolled diabetes mellitus (DM). The most common site of involvement was rhino-orbital-cerebral MCM (ROCM) (74%). The annual cases of MCM per 100,000 patient days increased markedly during the years of the COVID-19 pandemic (from 0 to 4.4 cases/100,000 patient days to 7.5 cases/100,000 during 2020 and 2021). Liposomal amphotericin (Ampho) B was used as a first-line agent in most of the patients (86%). The median duration of total in-hospital antifungal therapy was 21 days and 51.2% of the patients received step-down therapy with azoles. Surgical debridement and isolated ROCM were significantly associated with survival (p-value: 0.02 and <0.001, respectively). All-cause mortality was 46.7%, with chronic renal disease being significantly associated with mortality (p-value < 0.05). The incidence of MCM has been increasing at our institution, particularly since the COVID-19 pandemic. Early diagnosis, treatment, and surgical debridement improve patient outcomes and overall survival.


Development, validity and reliability of the 'Sitting Balance Measure' (SBM) in spinal cord injury.
This is a methodological research design. Spinal cord injury (SCI) may result in the inability to sit unsupported. This may lead to difficulty performing daily living activities. To make the subjects with SCI independent in their daily living to the maximum possible extent, therapists provide them balance training for which they may require to assess the sitting balance. This study aims to develop an objective measure 'Sitting Balance Measure' (SBM) for the assessment of sitting balance of the subjects with SCI, and to determine its content validity and internal consistency reliability. This study was conducted in New Delhi, India. The study was conducted in three phases, namely planning, construction and quantitative evaluation phase. Thirty-six items were generated through the review of literature and semistructured interviews. Qualitative and quantitative content validation through the expert opinion and the content validity ratio (CVR) method resulted in the 24-item scale, which was pilot-tested on a purposive sample of 30 subjects with SCI. Item analysis was conducted to determine internal consistency reliability. CVR method and qualitative review by the experts validated the content of SBM. The SBM has high internal consistency reliability (Cronbach's alpha=0.96). SBM is a valid scale for the assessment of sitting balance in subjects with SCI. Internal consistency reliability of SBM is high. This may be indicative of item redundancy, which necessitates the need for the second pilot test to refine the scale further.


Circ_0075825 promotes gastric cancer progression via adsorbing miR-432-5p to modulate SOX9.
Circ_0075825 expression in adjacent tissues and GC tissues was evaluated by bioinformatics method and quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). How circ_0075825 regulated GC cell growth, migration, invasion, and apoptosis were investigated by cell counting kit-8 assay, transwell assay and flow cytometry. The targeted interplays among circ_0075825, and miR-432-5p and Sex-Determining Region Y-related high-mobility group box 9 (SOX9) were explored by bioinformatics analysis and luciferase reporter gene assay. The regulatory effects of circ_0075825 and miR-432-5p on SOX9 protein expression were probed by western blot. Circ_0075825 expression was raised in GC tissues and cell lines. Circ_0075825 overexpression promoted the proliferative, migrative and invasive abilities of GC cells, while inhibiting apoptosis, while depletion of circ_0075825 suppressed the malignant biological behaviors of GC cells. SOX9 was identified as one of the direct target genes of miR-432-5p, and circ_0075825 repressed the expression of miR-432-5p, to induce the expression of SOX9. Furthermore, miR-432-5p overexpression counteracted the promoting effect of circ_0075825 on the malignancy of GC cells. Circ_0075825 promotes GC progression via sponging miR-432-5p to regulate SOX9 expression level, and it may be a novel therapeutic target for treating GC.


Potential role of ghrelin in the regulation of inflammation.
Several diseases are caused or progress due to inflammation. In the past few years, accumulating evidence suggests that ghrelin, a gastric hormone of 28-amino acid residue length, exerts protective effects against inflammation by modulating the related pathways. This review focuses on ghrelin's anti-inflammatory and potential therapeutic effects in neurological, cardiovascular, respiratory, hepatic, gastrointestinal, and kidney disorders. Ghrelin significantly alleviates excessive inflammation and reduces damage to different target organs mainly by reducing the secretion of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), and inhibiting the nuclear factor kappa-B (NF-κB) and NLRP3 inflammasome signaling pathways. Ghrelin also regulates inflammation and apoptosis through the p38 MAPK/c-Jun N-terminal kinase (JNK) signaling pathway; restores cerebral microvascular integrity, and attenuates vascular leakage. Ghrelin activates the phosphoInositide-3 kinase (PI3K)/protein kinase B (Akt) pathway and inhibits inflammatory responses in cardiovascular diseases and acute kidney injury. Some studies show that ghrelin exacerbates colonic and intestinal manifestations of colitis. Interestingly, some inflammatory states, such as non-alcoholic steatohepatitis, inflammatory bowel diseases, and chronic kidney disease, are often associated with high ghrelin levels. Thus, ghrelin may be a potential new therapeutic target for inflammation-related diseases.


Human mesenchymal stem-derived extracellular vesicles improve body growth and motor function following severe spinal cord injury in rat.
Spinal cord injury (SCI) in young adults leads to severe sensorimotor disabilities as well as slowing of growth. Systemic pro-inflammatory cytokines are associated with growth failure and muscle wasting. Here we investigated whether intravenous (IV) delivery of small extracellular vesicles (sEVs) derived from human mesenchymal stem/stromal cells (MSC) has therapeutic effects on body growth and motor recovery and can modulate inflammatory cytokines following severe SCI in young adult rats. Contusional SCI rats were randomized into three different treatment groups (human and rat MSC-sEVs and a PBS group) on day 7 post-SCI. Functional motor recovery and body growth were assessed weekly until day 70 post-SCI. Trafficking of sEVs after IV infusions in vivo, the uptake of sEVs in vitro, macrophage phenotype at the lesion and cytokine levels at the lesion, liver and systemic circulation were also evaluated. An IV delivery of both human and rat MSC-sEVs improved functional motor recovery after SCI and restored normal body growth in young adult SCI rats, indicating a broad therapeutic benefit of MSC-sEVs and a lack of species specificity for these effects. Human MSC-sEVs were selectively taken up by M2 macrophages in vivo and in vitro, consistent with our previous observations of rat MSC-sEV uptake. Furthermore, the infusion of human or rat MSC-sEVs resulted in an increase in the proportion of M2 macrophages and a decrease in the production of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 at the injury site, as well as a reduction in systemic serum levels of TNF-α and IL-6 and an increase in growth hormone receptors and IGF-1 levels in the liver. Both human and rat MSC-sEVs promote the recovery of body growth and motor function after SCI in young adult rats possibly via the cytokine modulation of growth-related hormonal pathways. Thus, MSC-sEVs affect both metabolic and neurological deficits in SCI.


Bridging barriers to clinic-based HIV testing with new technology: translating self-implemented testing for African American youth.
Numerous barriers to clinic-based HIV testing exist (e.g., stigmatization) for African American youth. These barriers may be addressed by new technology, specifically HIV self-implemented testing (SIT). We conducted a series of formative phase 3 translation studies (49 face-to-face interviews, 9 focus groups, 1 advisory panel review) among low-income African American youth (15-19 years) and providers of adolescent services in two US cities to identify potential translation difficulties of the OraQuick SIT. Based on content analysis, we found that providers and African American youth viewed SITs positively compared to clinic-based testing. Data suggest that SITs may reduce social stigma and privacy concerns and increase convenience and normalization of HIV testing. Challenges with SIT implementation include difficulties accessing confirmatory testing, coping with adverse outcomes, and instructional materials that may be inappropriate for low socioeconomic status (SES) persons. Study results underscore the need for translation studies to identify specific comprehension and implementation problems African American youth may have with oral SITs.


A bipolar electrode for peripheral nerve stimulation.
The construction of a bipolar electrode for the stimulation of peripheral nerves is described. The electrode was designed for acute stimued in which the effects of peripheral nerve stimulation on central neural activity in rats were determined. Since the electrode can be secured into a fixed position, neural recordings can be made during the stimulation of various visceral nerves and the electrode can be easily adapted for chronic behavioral studies.


[Security agents on the front line against Ebola: roles, perceptions and knowledge in Fann Teaching Hospital, Dakar, Senegal].
Security agents are on the front line when patients arrive at health facilities, giving them a potential role to play in an Ebola virus disease (EVD) outbreak. The position of security agents within health services is poorly documented. A survey was conducted to clarify their understanding of Ebola pathology, to assess their need for information and to determine their role in patient management. The survey included both qualitative and quantitative aspects. 80 security agents of the Fann teaching hospital (Dakar) completed questionnaires, and 11 were interviewed. Qualitative analysis was performed with Dedoose and the quantitative analysis using Excel. The results show that security agents' activities go beyond their mission of security and control. They are involved in informing, orienting and assisting patients and those accompanying them in the hospital. The security agents have basic knowledge of EVD, but overestimate the risk of transmission. They want to be more informed and to have access to protective material. These results suggest that these professionals should be taken into account when developing response strategies to Ebola outbreaks. Their knowledge of and protection against the disease must be strengthened. Non-health professionals working in health facilities should be trained in order to be able to relay information to the public.


Meta-analysis of the efficacy of acupuncture in the treatment of the vascular cognitive impairment associated with cerebral small vessel disease.
To systematically evaluate the efficacy and safety of acupuncture in the treatment of the vascular cognitive impairment (VCI) associated with cerebral small vessel disease (CSVD-VCI) and to provide a theoretical basis for clinical acupuncture treatment for CSVD-VCI. Various databases, including China National Knowledge Infrastructure, Wanfang Data, Chinese Science and Technology Journal Database, Chinese BioMedical Literature Service System, PubMed, the Cochrane Library, and EBSCOhost, were searched for randomized controlled trials (RCTs) related to acupuncture treatment for CSVD-VCI. The quality of the included trials was evaluated, and a meta-analysis was conducted using the Review Manager 5.4 software. Ten articles on RCTs were included, involving 761 patients, i.e., 381 in the acupuncture group and 380 in the control group. The meta-analysis results indicated that the use of acupuncture alone and acupuncture alongside other therapies for CSVD-VCI could improve the overall clinical response rate [odds ratio = 3.51, 95% confidence interval (CI) = (2.05, 6.00), P < 0.00001], increase the patients' Montreal Cognitive Assessment scores [mean difference (MD) = 3.33, 95%CI (2.98, 3.68), P < 0.00001], Mini-Mental State Examination scores [MD = 2.78, 95%CI (2.51, 3.06), P < 0.00001], and activities of daily living scores [MD = 6.30, 95%CI (4.22, 8.37), P < 0.00001], and shorten the latency of auditory evoked potential P300 [MD = -14.67, 95%CI (-19.54, -9.80), P < 0.00001]. Acupuncture alone and acupuncture alongside other therapies are superior to non-acupuncture-based therapies in the treatment of CSVD-VCI. However, due to the small number of relevant available articles and their general low quality, this conclusion may be biased. More clinical RCTs with a larger sample size and higher quality are needed to support this theory.


Facilitating reproducible research through direct connection of data analysis with manuscript preparation: StatTag for connecting statistical software to Microsoft Word.
To enhance reproducible research by creating a broadly accessible, free, open-source software tool for connecting Microsoft Word to statistical programs (R/R Markdown, Python, SAS, Stata) so that results may be automatically updated in a manuscript. We developed StatTag for Windows as a Microsoft Word plug-in using C# and for macOS as a native application using Objective-C. Source code is available under the MIT license at https://github.com/stattag. StatTag links analysis file(s) (R/R Markdown, SAS, Stata, or Python) and a Word document, invokes the statistical program(s) to obtain results, and embeds selected output in the document. StatTag can accommodate multiple statistical programs with a single document and features an interface to view, edit, and rerun statistical code directly from Word. StatTag may facilitate reproducibility within increasingly multidisciplinary research teams, improve research transparency through review and publication, and complement data-sharing initiatives.


Oxygen partial pressure distribution within skeletal muscle: indicator of whole body oxygen delivery in patients?
Simultaneously with determination of cardiac output, the distribution of oxygen partial pressure within biceps muscle was measured during and after open heart surgery in 29 patients. During extracorporeal circulation (ECC) mean muscular oxygen partial pressure (MPO2m) decreased from 25 mmHg to 14 mmHg with an increase of MPO2 values below 5 mmHg from 4% to 20%. Sustained decrease of MPO2m (greater than 1h) did not occur after ECC. Before ECC and in the postoperative period, MPO2m was lineary correlated (r = 0.85) to whole body oxygen delivery (Ox. offer) suggesting that local oxygen delivery within biceps muscle was sufficiently indicated only by systemic parameters of oxygen transport which require determination of cardiac output. Particularly with regard to relative changes, MPO2m might be used for estimation of whole body oxygen offer clinically.


R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse.
(±)-Modafinil has piqued interest as a treatment for attention-deficit/hyperactivity disorder and stimulant dependence. The R-enantiomer of modafinil might have unique pharmacological properties that should be further investigated. (±)-Modafinil and its R-(-)- and S-(+)-enantiomers were synthesized and tested for inhibition of [(3)H] dopamine (DA) uptake and [(3)H]WIN 35428 binding in human dopamine transporter (DAT) wild-type and mutants with altered conformational equilibria. Data were compared with cocaine and the atypical DA uptake inhibitor, JHW 007. R- and S-modafinil were also evaluated in microdialysis studies in the mouse nucleus accumbens shell and in a cocaine discrimination procedure. (±)-, R-, and S-modafinil bind to the DAT and inhibit DA uptake less potently than cocaine, with R-modafinil having approximately threefold higher affinity than its S-enantiomer. Molecular docking studies revealed subtle differences in binding modes for the enantiomers. R-modafinil was significantly less potent in the DAT Y156F mutant compared with wild-type DAT, whereas S-modafinil was affected less. Studies with the Y335A DAT mutant showed that the R- and S-enantiomers tolerated the inward-facing conformation better than cocaine, which was further supported by [2-(trimethylammonium)ethyl]-methanethiosulfonate reactivity on the DAT E2C I159C. Microdialysis studies demonstrated that both R- and S-modafinil produced increases in extracellular DA concentrations in the nucleus accumbens shell less efficaciously than cocaine and with a longer duration of action. Both enantiomers fully substituted in mice trained to discriminate cocaine from saline. R-modafinil displays an in vitro profile different from cocaine. Future trials with R-modafinil as a substitute therapy with the potential benefit of cognitive enhancement for psychostimulant addiction are warranted.


Association of GDF-5 rs143383 polymorphism with radiographic defined knee osteoarthritis: A systematic review and meta-analysis.
To assess the association of GDF-5 rs143383 polymorphism with radiographic defined knee osteoarthritis (OA), a systematic review and meta-analysis was conducted. A total of 17 relevant case-control studies with 7424 cases and 11,310 controls was collected from several electronic databases up to June 2018. The pooled results showed that GDF-5 rs143383 polymorphism was significantly associated with radiographic defined knee OA in overall and stratified analysis by ethnicity, source of controls and genotyping techniques. The GDF-5 rs143383 polymorphism might be used as a relevant risk estimate for radiographic defined Knee OA.


MicroRNA-146a and hemopoietic disorders.
MicroRNAs (MiRNAs) are a class of small non-coding regulatory RNAs that repress protein expression at the posttranscriptional level and play important roles in hematopoiesis processes. MiR-146a is a miRNA that is thought to regulate physiological and pathophysiological pathways in hematopoietic cells. In this review, we focus on recent progress in analyzing the functional roles of miR-146a in normal hematopoiesis and hematopoietic disease. We suggest that manipulation of miR-146a expression may represent a potential new therapy for several hematopoietic diseases, and may further serve as a biomarker for diagnosis, prevention, and treatment of such disease.


Steric control in the thermal rearrangement of a bicyclo[3.1.0]hex-2-ene substituted at a radical-nonstabilizing position.
Introduction into the long-known bicyclo[3.1.0]hex-2-ene system of a large substituent in an electronically inactive, interconnected pair of positions brings to light the importance of sterics as a major factor in the determination of products. Far from the "flat" surface that so well describes the caldera of diradicals of the archetype, a "bumpy" surface is required as the conceptual scheme. The relief of "compressional" strain serves to explain the dramatic effect on kinetics and composition at equilibrium.


Effects of the free radical scavenger, edaravone, on the development of postoperative cognitive impairment in patients undergoing carotid endarterectomy.
Some patients undergoing carotid endarterectomy (CEA) experience postoperative cognitive impairment. The purpose of the present case cohort study with historical control was to determine whether pretreatment with a novel free radical scavenger, edaravone, could prevent development of cognitive impairment after CEA. Fifty-five patients with ipsilateral internal carotid artery (ICA) stenosis (> or =70%) underwent CEA with administration of edaravone before ICA clamping. Neuropsychological testing was performed preoperatively and at the first postoperative month. Cerebral blood flow was also measured using single-photon emission computed tomography before and immediately after CEA and on the third postoperative day. Postoperative cognitive impairment was observed in only 1 (2%) patient, who exhibited postoperative cerebral hyperperfusion (cerebral blood flow increase > or =100% compared with preoperative values). Incidence of postoperative cognitive impairment in the control group (92 CEA patients without administration of edaravone) was significantly higher (12%) (P = .0298, control vs treatment group). Logistic regression analysis demonstrated that postoperative cerebral hyperperfusion and absence of pretreatment with edaravone were significant independent predictors of postoperative cognitive impairment. Pretreatment with edaravone can prevent development of cognitive impairment after CEA.


Retracted: Visual Resolve of Modern Educational Technology Based on Artificial Intelligence under the Digital Background.
[This retracts the article DOI: 10.1155/2022/1924138.].


Underwater Hearing in Turtles.
The hearing of turtles is poorly understood compared with the other reptiles. Although the mechanism of transduction of sound into a neural signal via hair cells has been described in detail, the rest of the auditory system is largely a black box. What is known is that turtles have higher hearing thresholds than other reptiles, with best frequencies around 500 Hz. They also have lower underwater hearing thresholds than those in air, owing to resonance of the middle ear cavity. Further studies demonstrated that all families of turtles and tortoises share a common middle ear cavity morphology, with scaling best suited to underwater hearing. This supports an aquatic origin of the group. Because turtles hear best under water, it is important to examine their vulnerability to anthropogenic noise. However, the lack of basic data makes such experiments difficult because only a few species of turtles have published audiograms. There are also almost no behavioral data available (understandable due to training difficulties). Finally, few studies show what kinds of sounds are behaviorally relevant. One notable paper revealed that the Australian snake-necked turtle (Chelodina oblonga) has a vocal repertoire in air, at the interface, and under water. Findings like these suggest that there is more to the turtle aquatic auditory scene than previously thought.


Transition to intensive care nursing: a state-wide, workplace centred program-12 years on.
In November 1999, the Queensland Health (QH) Transition to Practice Nurse Education Program - Intensive Care (TPNEP-IC) was initiated in QH Intensive Care Units (ICUs) across Queensland. This 12-month, state-wide, workplace based education program has set minimum standards for intensive care nursing education and therefore minimum standards for intensive care nursing practice in QH. In the 12 years of operation, 824 nurses have completed TPNEP-IC, 761 achieving academic credit status and 453 utilising this academic credit status to undertake postgraduate study in critical/intensive care nursing at three Queensland universities. These outcomes were achieved through the appointment of nurse educators within ICUs who, through a united and strong commitment to this state-wide approach formed collaborative professional networks, which resulted in the development, implementation and maintenance of the program. Furthermore, these networks enabled a framework of support for discussion and dissemination of evidence based practice, to endorse quality processes for TPNEP-IC and to nurture leadership potential among educators. Challenges to overcome included obtaining adequate resources to support all aspects of the program, gaining local management and administrative support, and embedding TPNEP-IC within ICU culture. The 12 years of operation of the program have demonstrated its long term sustainability. The program is being launched through a new blended learning approach utilising e-learning strategies. To capitalise on the current success, a strong commitment by all stakeholders will be required to ensure the ongoing sustainability of the program.


Osteosarcoma exocytosis of soluble LGALS3BP mediates macrophages toward a tumoricidal phenotype.
This study aimed to elucidate the interactions between osteosarcoma (OS) and M1 macrophages infiltrated into the tumor microenvironment and to explore the underlying mechanisms whereby M1 macrophages influence the growth of OS, so that novel treatments of OS can be developed. A transwell co-culture system, an indirect conditioned medium culture system and two orthotopic bearing OS models were established to assess for the interplay between M1 macrophages and OS. We found that the co-culture of M1 macrophages with OS cells significantly inhibited the growth of the tumor cells by inducing apoptosis. Furthermore, HSPA1L secreted by M1 macrophages exerted this anti-tumor effect through the IRAK1 and IRAK4 pathways. LGALS3BP secreted by OS cells bound to the ligand LGALS3 on M1 macrophages and thereby induced the secretion of Hspa11 via Akt phosphorylation. In vivo experiments demonstrated that the culture supernatant of OS-stimulated M1 macrophages significantly inhibited the growth of OS, whereas silencing Lgals3bp promoted the progression of OS. In conclusion, OS modifies the phenotype of tumor-associated macrophages (TAMs) and thereby influences the apoptosis of OS cells through soluble factors. The modulation of TAMs may be a promising and effective therapeutic approach in OS.


Hereditary lysozyme amyloidosis with sicca syndrome, digestive, arterial, and tracheobronchial involvement: case-based review.
Lysozyme amyloidosis (ALys) is a rare autosomal dominant hereditary systemic amyloidosis associated with a large spectrum of clinical manifestations. ALys phenotype mainly involves the digestive tract, liver and spleen, kidneys, lymph nodes, skin, and lachrymal and salivary glands. Very recently, cardiac involvement and peripheral neuropathy associated with a new p.Leu102Ser variant of lysozyme have been documented. In the present observation, we extend the phenotypic heterogeneity of ALys to the tracheobronchial tree with histologically proven bronchial ALys-amyloid deposits. We report the case of a 62-year-old man of Italian origin (Piedmont) diagnosed with ALys associated with the p.Trp82Arg variant. The patient complained of upper digestive symptoms, sicca syndrome, and lately recurrent pulmonary infections. Thoracic endoscopy revealed a fragile, inflammatory, and granulomatous aspect of the bronchi. Amyloid deposits were observed in the upper digestive tract, salivary glands, temporal artery, and tracheobronchial tree. Symptomatic treatment was offered. Recurrent pulmonary infections occurred during the follow-up. Lung involvement in hereditary ALys has only been exceptionally described. Although vascular involvement has already been reported in ALys in many organs, it never concerned cranial arteries. This case highlights the systemic nature of the amyloid protein variant deposits and expands the spectrum of clinical manifestations to chest involvement. The literature review highlights that hereditary ALys with the p.Trp82Arg variant is frequent in patients coming from Piedmont (Italy). Due to diffuse organs involvement related to ALys, it is important not to misdiagnose ALys for AL amyloidosis, the most frequent form of amyloidosis.


Hematopoietic cell transplantation for patients with myelodysplastic syndromes (MDS): when, how and for whom?
Hematopoietic cell transplantation (HCT) offers potentially curative therapy for patients with myelodysplastic syndromes (MDS). However, who should and can be transplanted, with which approach, and when is a matter of debate. Various classification schemes and prognostic scoring systems have helped in the decision-making process. Offering HCT to patients who were not considered transplant candidates in the past is now possible with the development of new transplant strategies. In addition to disease stage, patient age, comorbid conditions, preHCT chemotherapy, type of donor, source of stem cells, and possibly other factors, need to be considered prior to transplant. Patients without substantial comorbid conditions up to 60 years with the availability of unrelated donor grafts or 65 years with related donor grafts can be transplanted with more conventional (higher dose) regimens (e.g. targeted BU/CY; Flu/BU). Older patients and patients with comorbid conditions should be enrolled in trials aimed at optimizing RIC/nonmyeloablative HCT (e.g. Flu/melphalan; Flu/low dose TBI). Patients who present with 'advanced' MDS or are transfusion dependent, and do not have a del(5q), should probably be transplanted early in their course. GVHD (in all patients) and post-HCT relapse (in patients with high risk disease) remain major problems. Modifications of transplant conditioning regimens have reduced transplant-related mortality and allow successful HCT even in older patients. However, prospective randomized trials are needed to determine the role of pre-HCT chemotherapy and the type of transplant conditioning regimen best suited for a given patient.


Characterization of Extracellular Vesicles by Transmission Electron Microscopy and Immunolabeling Electron Microscopy.
Transmission electron microscopy (TEM) is currently the only method that enables the observation of extracellular vesicles (EVs) at a nanometer scale. Direct visualization of the whole content of EV preparation provides not only crucial insights on the morphology of EVs but also an objective evaluation of the content and purity of the preparation. Coupled to immunogold labeling, TEM allows the detection and association of proteins at the surface of EVs. In these techniques, EVs are deposited on grids and are chemically immobilized and contrasted to withstand a high-voltage electron beam. Under high vacuum, the electron beam hits the sample and the electrons that scatter forward are collected to form an image. Here, we describe the steps needed to observe EVs by classical TEM and the extra steps required to label proteins through immunolabeling electron microscopy (IEM).


Cadmium bioaccumulates after acute exposure but has no effect on locomotion or shelter-seeking behaviour in the invasive green shore crab (Carcinus maenas).
Cadmium (Cd2+) is a non-essential metal ubiquitous in the environment due to industrial processes. However, little is known regarding the ability of Cd2+ to impact the behaviour of aquatic animals in receiving environments. Green shore crabs (Carcinus maenas) were exposed to waterborne Cd2+ [control (no Cd2+), low (0.30 μmol/L), medium (3.3 μmol/L) and high (63 μmol/L)], for 24 h, then, crabs were placed in an open field and shelter test to determine potential changes in locomotion and preference for shelter. Tissues (gill, haemolymph, stomatogastric ganglion) were taken for bioaccumulation analysis of Cd2+ and ion content. Behavioural testing was recorded with a motion-tracking software system and showed no impact of Cd2+ on any variable in either of the tests used. All three tissues accumulated Cd2+ in a concentration-dependent manner. Crabs exposed to low Cd2+ showed a small but significant decrease in haemolymph Ca2+, however, this effect was not present at higher Cd2+ exposures. Overall, the results indicate that short-term Cd2+ exposure, and the resulting Cd2+ accumulation, had no effect on locomotor and anxiety-related behaviour of green shore crabs.


Chronic manganism: A long-term follow-up study with a new dopamine terminal biomarker of 18F-FP-(+)-DTBZ (18F-AV-133) brain PET scan.
Recent experimental studies revealed that dopamine neuron dysfunction in chronic manganism may be due to a reduced capacity of dopamine release in the striatum. The findings imposed further difficulty in the differential diagnosis between manganism and IPD. We conducted a long-term clinical follow-up study of 4 manganism patients, applying a new tracer (18)F-9-fluoropropyl-(+)-dihydrotetrabenazine ((18)F-AV-133) with positron emission tomography (PET). Twenty age-matched subjects including 4 manganism patients, 8 idiopathic Parkinson's disease (IPD) patients, and 8 healthy controls were enrolled for comparison. Volumes of interest of the bilateral putamen, caudate nuclei and occipital cortex as the reference region were delineated from individual magnetic resonance images. The clinical features of the manganism patients still progressed, with increased scores on the Unified Parkinson Disease Rating Scale. The (18)F-AV-133 uptake in the IPD patients decreased at the bilateral striatum, compared with the healthy controls. In the manganism patients, there was no decreased uptake of radioactivity involving the bilateral striatum, except Patient 4, who had a stroke with decreased uptake in the right posterior putamen. The (18)F-AV-133 PET finding reveals that nigrostriatum neurons are not degenerated in chronic manganism and can provide a useful neuroimage biomarker in the differential diagnosis.


Periodic eyelid opening associated with burst-suppression electroencephalography due to hypoxic ischemic injury.
We report four patients who developed periodic eyelid opening following hypoxic ischemic injury. This manuscript reviews the clinical course of our patients as well as previously published cases and discusses the neuroanatomical basis of eyelid opening. Data were collected from the patients' electronic medical record and digital electroencephalography recordings. In all patients, periodic eyelid opening was associated with a burst-suppression pattern on electroencephalography (EEG). Rapid eyelid opening appeared with the onset of bursts, while slow eyelid closure coincided with periods of suppression. Progressive rostrocaudal deterioration in brainstem function ensued, in each case culminating in brain death. Our experience and prior reports suggest that periodic eyelid opening following cardiac arrest is associated with a burst-suppression pattern on EEG. Since burst-suppression is highly (though not invariably) predictive of a poor outcome in this patient population, intensivists should be familiar with this neurological sign. Prospective studies are needed to define the neurophysiology of this phenomena and clarify its clinical significance.


Oligo-1,6-glucosidase from a thermophile, Bacillus thermoglucosidasius KP1006, was efficiently produced by combinatorial expression of GroEL in Escherichia coli.
To improve the production of oligo-1,6-glucosidase from the obligately thermophilic Bacillus thermoglucosidasius KP1006 in Escherichia coli, the combined expression of oligo-1,6-glucosidase with various chaperone proteins of Hsp (heat-shock protein) 60 team proteins (GroES and GroEL) or Hsp70 team proteins (GrpE, DnaK and DnaJ) from the same thermophile was examined. This attempt was based on the facts that, (i) among glycosyl hydrolases of Family 13, bacillary oligo-1,6-glucosidases share highest homology with yeast alpha-glucosidase, and (ii) this yeast enzyme interacts with GroEL. In B. thermoglucosidasius Hsp60 team proteins, in particular, GroEL brought about a remarkable rise in expression of B. thermoglucosidasius oligo-1,6-glucosidase, while Hsp70 team proteins had no significant effect. The effect of B. thermoglucosidasius GroEL on oligo-1,6-glucosidase expression was supported by the finding that thermally inactivated B. thermoglucosidasius oligo-1,6-glucosidase was revived by B. thermoglucosidasius GroEL. Although the molecular mass of B. thermoglucosidasius oligo-1,6-glucosidase (66 kDa) exceeds the major range of substrates for GroEL proteins, the GroEL molecules probably recognized the alpha/beta motifs contained in the N-terminal domain and the subdomain of the oligo-1,6-glucosidase. Here we show that (i) the production of B. thermoglucosidasius oligo-1,6-glucosidase in E. coli was improved 3.8-fold by Hsp60 team proteins, (ii) the system can function for the expression of other glycosyl hydrolases of Family 13 that have defects in expression and (iii) the combinatorial expression of thermostable proteins with GroEL from the same thermophile in E. coli can increase the production of thermostable enzymes, preventing problems derived from differences in protein biogenesis.


Biological and chemical inhibitors of NF-kappaB sensitize SiHa cells to cisplatin-induced apoptosis.
Cisplatin, a chemotherapeutic agent, is known to induce apoptosis of cancer cells. We examined the role of NF-kappaB during cisplatin-induced apoptosis in two human cervical cancer cell lines, HeLa and SiHa, known to differ in their response to cisplatin treatment. We found that SiHa cells were relatively more resistant than HeLa cells to the cytotoxic effects induced by cisplatin as measured by MTT assays. HeLa cells were more sensitive to the apoptotic effects induced by cisplatin as shown by increases in annexin staining, DNA fragmentation, and loss of mitochondrial membrane potential. Similarly the activities of caspases 3, 8, and 9 and cleavage of PARP induced by cisplatin were more in HeLa than SiHa cells. Cisplatin induced NF-kappaB DNA binding activity in HeLa and SiHa cells but not in primary cervical cells and the active DNA binding complex in SiHa cells consists of p50 and RelA heterodimers. However, when NF-kappaB DNA binding activity was blocked by chemical (curcumin, PDTC, or salicylic acid) or biological inhibitors (NIK-KM or IKK-beta DN), the cell viability was less in SiHa cells with cisplatin treatment, but these effects were not observed in HeLa cells. Similarly upon treatment with cisplatin SiHa cells had more activation of caspases compared to that seen in HeLa cells under conditions of NF-kappaB inhibition by biological or chemical inhibitors. These results suggest that NF-kappaB may contribute to the resistance of human cervical cancer cells to cisplatin and highlight the potential use of combination therapy involving cisplatin and NF-kappaB inhibitors.


Emergency transanal haemorrhoidal Doppler guided dearterialization for acute and persistent haemorrhoidal bleeding.
The effectiveness of Doppler guided transanal haemorrhoidal dearterialization (THD) for arresting persistent haemorrhoidal bleeding in patients admitted as an emergency was studied. Eleven patients with severe anal bleeding underwent emergency THD as definitive treatment for haemorrhoids. In the majority of patients antiplatelet or anticoagulant therapy was ongoing and severe anaemia was present in six patients. The mean operative time was 39.7 min. Six to nine feeding arteries were ligated. Intra-operative blood loss was nil. Bleeding was well controlled in all patients. No blood transfusion was required. Mean pain score per verbal numeric scale was 3.6 and 1.4 on day 1 and day 3 respectively. The mean time to resumption of normal activities was 8 days. No major complications were experienced. Six months follow-up demonstrated good control of haemorrhoidal disease. THD is effective in controlling acute haemorrhoidal bleeding with a low incidence of postoperative complications.


Monocytopoiesis in malignant melanoma: untreated, during immunotherapy and chemoimmunotherapy.
Monocytopoiesis and blood monocytes were investigated in patients with superficial spreading melanoma stages I and II. Monocyte production was moderately increased in 4 of 9 untreated patients. Postoperative prophylactic BCG-vaccination gave rise to increased proliferation activity in 3 of 4 patients with previously normal monocytopoiesis. However, monocyte production returned to normal between the 4th and 6th month of BCG immunotherapy. Monocytopoietic hyperproliferation did not occur if DTIC was administered simultaneously with BCG. These results indicate that BCG-vaccination increases monocytopoiesis during the first months of treatment only. This effect is abrogated by concomitant chemotherapy.


High-resolution array-CGH profiling of germline and tumor-specific copy number alterations on chromosome 22 in patients affected with schwannomas.
Schwannomas may develop sporadically or in association with NF2 and schwannomatosis. The fundamental aberration in schwannomas is the bi-allelic inactivation of the NF2 gene. However, clinical and molecular data suggest that these tumors share a common pathogenetic mechanism related to as yet undefined 22q-loci. Linkage studies in schwannomatosis, a condition related to NF2, have defined a candidate 22q-locus and excluded the NF2 gene as the causative germline mutation. Thus, analysis of aberrations in schwannomas may lead to the identification of putative gene(s) involved in the development of schwannoma/schwannomatosis. We profiled a series of 88 schwannomas and constitutional DNA using a tiling path chromosome 22 array. Array-CGH is a suitable method for high-resolution discrimination between germline and tumor-specific aberrations. Previously reported frequencies of 22q-associated deletions in schwannomas display large discrepancies, ranging from 30% to 80%. We detected heterozygous deletions in 53% of schwannomas and the predominant pattern was monosomy 22. In addition, three tumors displayed terminal deletions and four harbored overlapping interstitial deletions of various sizes encompassing the NF2 gene. When profiling constitutional DNA, we identified eight loci that were affected by copy number variation (CNV). Some of the identified CNVs may not be phenotypically neutral and the possible role of these CNVs in the pathogenesis of schwannomas should be studied further. We observed a correlation between the breakpoint position, present in tumor and/or constitutional DNA and the location of segmental duplications. This association implicates these unstable regions in rearrangements occurring both in meiosis and mitosis.


Draft Genome Sequence of Kerstersia gyiorum CG1, Isolated from a Leg Ulcer.
We report the first draft genome sequence of Kerstersia gyiorum from a leg ulcer of a patient with diabetes and osteomyelitis. The 3.94-Mb genome assembly included 3,428 annotated coding sequences with an N50 of 223,310 bp and a plasmid encoding a type IV secretion system gene and two antitoxin genes.


[The anatomy of the laryngeal ventricle and its importance in carcinoma of the vocal cords (author's transl)].
An anatomical study was made of the sinus of Morgagni (laryngeal ventricle) in 10 normal larynges and 15 larynges with vocal cord carcinoma. The most striking difference in those patients with malignancy was the relatively greater goblet cell population found. It is assumed that these anatomical changes reflect a disturbed function of the laryngeal ventricle. The epithelial metaplasia and the high goblet cell count probably indicate an increased risk of vocal cord carcinoma.


The peak force-resting membrane potential relationships of mouse fast- and slow-twitch muscle.
We endeavored to understand the factors determining the peak force-resting membrane potential (EM) relationships of isolated slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles from mice (25°C), especially in relation to fatigue. Interrelationships between intracellular K+ activity ([Formula: see text]), extracellular K+ concentration ([K+]o), resting EM, action potentials, and force were studied. The large resting EM variation was mainly due to the variability of [Formula: see text]. Action potential overshoot-resting EM relationships determined at 4 and 8-10 mM [K+]o after short (<5 min) and prolonged (>50 min) depolarization periods revealed a constant overshoot from -90 to -70 mV providing a safety margin. Overshoot decline with depolarization beyond -70 mV was less after short than prolonged depolarization. Inexcitable fibers occurred only with prolonged depolarization. The overshoot decline during action potential trains (2 s) exceeded that during short depolarizations. Concomitant lower extracellular [Na+] and raised [K+]o depressed the overshoot in an additive manner and peak force in a synergistic manner. Raised [K+]o-induced force loss was exacerbated with transverse wire versus parallel plate stimulation in soleus, implicating action potential propagation failure in the surface membrane. Increasing stimulus pulse parameters restored tetanic force at 9-10 mM [K+]o in soleus but not EDL, indicative of action potential failure within trains. The peak tetanic force-resting EM relationships (determined with resting EM from deeper rather than surface fibers) were dynamic and showed pronounced force depression over -69 to -60 mV in both muscle types, implicating that such depolarization contributes to fatigue. The K+-Na+ interaction shifted this relationship toward less depolarized potentials, suggesting that the combined ionic effect is physiologically important during fatigue.


Myelin regeneration in multiple sclerosis: targeting endogenous stem cells.
Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.


Application of diaza-18-crown-6-capped beta-cyclodextrin bonded silica particles as chiral stationary phases for ultrahigh pressure capillary liquid chromatography.
Two bonded chiral stationary phases (CSPs), 8-aminoquinoline-2-ylmethyl- and 8-aminoquinoline-7-ylmethyl-diaza-18-crown-6-capped [3-(2-O-beta-cyclodextrin)-2-hydroxypropoxy]propylsilyl silica particles (non-porous, 1.5 microm), have been prepared and evaluated using capillary liquid chromatography at high pressures (> or = 8000 p.s.i.). High column efficiency (up to 400 000 plates m(-1)) was achieved for chiral separations. These CSPs with two recognition sites, i.e. substituted-diaza-18-crown-6 and beta-cyclodextrin combined with high chromatographic efficiency provide good resolution of a variety of enantiomers and positional isomers in relatively short times under reversed-phase conditions. After inclusion of a Ni (II) ion from the mobile phase, the positively charged crown ether-capped beta-cyclodextrin facilitates specific static, dipolar, and host-guest complexation interactions with solutes.


Dampening, Positive Rumination, and Positive Life Events: Associations with Depressive Symptoms in Children at Risk for Depression.
Blunted positive affect is characteristic of depression. Altered positive affect regulation may contribute to this blunting, and two regulation strategies, dampening positive affect and positive rumination, have been implicated in depression. However, the conditions under which these strategies impart risk/protective effects prior to onset of depression are unknown. The current study examined 81 healthy children (age 7-10) at low and high risk for depression on the basis of maternal history of depression and tested how dampening and positive rumination interacted with the experience of recent positive life events to predict depressive symptoms. Children at high and low risk did not differ in their use of dampening or positive rumination. However, elevated use of dampening in the context of many positive life events predicted current depressive symptoms, and specifically anhedonic symptoms, in children at low-risk for depression. These findings held when controlling for negative rumination and negative life events. Positive rumination did not interact with positive life events but was associated with higher depressive symptoms in high-risk children. Results indicate that prior to the onset of depression, positive life events may impart risk when dampening positive affect is utilized in this context, while positive rumination may increase risk for depressive symptoms.


Insulin Sensitivity and β-Cell Function Improve after Gastric Bypass in Severely Obese Adolescents.
To test the hypothesis that insulin secretion and insulin sensitivity would be improved in adolescents after Roux-en-Y gastric bypass (RYGB). A longitudinal study of 22 adolescents and young adults without diabetes undergoing laparoscopic RYGB (mean age 17.1 ± 1.42 years; range 14.5-20.1; male/female 8/14; Non-Hispanic White/African American 17/5) was conducted. Intravenous glucose tolerance tests were done to obtain insulin sensitivity (insulin sensitivity index), insulin secretion (acute insulin response to glucose ), and the disposition index as primary outcome variables. These variables were compared over the 1 year of observation using linear mixed modeling. In the 1-year following surgery, body mass index fell by 38% from a mean of 61 ± 12.3 to 39 ± 8.0 kg/m(2) (P < .01). Over the year following surgery, fasting glucose and insulin values declined by 54% and 63%, respectively. Insulin sensitivity index increased 300% (P < .01), acute insulin response to glucose decreased 56% (P < .01), leading to a nearly 2-fold increase in the disposition index (P < .01). Consistent with improved β-cell function, the proinsulin to C-peptide ratio decreased by 21% (P < .01). RYGB reduced body mass index and improved both insulin sensitivity and β-cell function in severely obese teens and young adults. These findings demonstrate that RYGB is associated with marked metabolic improvements in obese young people even as significant obesity persists. ClinicalTrials.gov: NCT00360373.


Pain Management for Persons Living With HIV Disease: Experience With Interprofessional Education in Nigeria.
Pain management (PM) has not been routinely incorporated into HIV/AIDS care and treatment in resource-constrained settings. We describe training for multidisciplinary teams tasked with integrating care management into HIV clinics to address pain for persons living with HIV in Nigeria. Education on PM was provided to mixed-disciplinary teams including didactic and iterative sessions following home and hospital visits. Participants identified challenges and performed group problem solving. HIV trainers identified barriers to introducing PM reflecting views of the patient, providers, culture, and the health environment. Implementation strategies included (1) building upon existing relationships; (2) preliminary advocacy; (3) attention to staff needs; and (4) structured data review. Implementing PM in Nigerian HIV clinics requires recognition of cultural beliefs.


Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs.
Approximately 60-70% of EWSR1-negative small blue round cell sarcomas harbour a rearrangement of CIC, most commonly CIC-DUX4. CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo. Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.


Acro-mesomelic dysplasia--a new type. Report of two siblings.
Two siblings who represent a new type of acro-mesomelic dysplasia are reported. The unique pattern of the acro-mesomelic hypoplastic/dysplastic changes allows us to designate them as a new syndrome.


Theta oscillations as a substrate for medial prefrontal-hippocampal assembly interactions.
The execution of cognitive functions requires coordinated circuit activity across different brain areas that involves the associated firing of neuronal assemblies. Here, we tested the circuit mechanism behind assembly interactions between the hippocampus and the medial prefrontal cortex (mPFC) of adult rats by recording neuronal populations during a rule-switching task. We identified functionally coupled CA1-mPFC cells that synchronized their activity beyond that expected from common spatial coding or oscillatory firing. When such cell pairs fired together, the mPFC cell strongly phase locked to CA1 theta oscillations and maintained consistent theta firing phases, independent of the theta timing of their CA1 counterpart. These functionally connected CA1-mPFC cells formed interconnected assemblies. While firing together with their CA1 assembly partners, mPFC cells fired along specific theta sequences. Our results suggest that upregulated theta oscillatory firing of mPFC cells can signal transient interactions with specific CA1 assemblies, thus enabling distributed computations.


Hospitalized chronic alcoholic patients without field-dependent performance in the rod-and-frame test.
Hospitalized male chronic alcoholics (n = 60) fully employed and with no history of malnutrition were compared with matched nonalcoholic controls (n = 50) on the Rod-and-Frame Test (RFT). The RFT scores of the alcoholics were not significantly worse than those of the controls. This is in marked contrast to earlier reports of RFT field dependence in unemployed, indigent alcoholics and supports Burdick's findings with the Embedded Figures Test.


A systematic review of studies examining the rate of lung function decline in patients with cystic fibrosis.
A systematic review was performed (i) to describe the reported overall rate of progression of CF lung disease quantified as FEV1%predicted decline with age, (ii) to summarise identified influencing risk factors and (iii) to review methods used to analyse CF lung disease progression data. A search of publications providing FEV1%predicted values over age was conducted in PUBMED and EMBASE. Baseline and rate of FEV1%predicted decline were summarised overall and by identified risk factors. Thirty-nine studies were included and reported variable linear rates of lung function decline in patients with CF. The overall weighted mean FEV1%predicted over age was graphically summarised and showed a nonlinear, time-variant decline of lung function. Compared to their peers, Pseudomonas aeruginosa infection and pancreatic insufficiency were most commonly associated with lower baseline and more rapid FEV1%predicted declines respectively. Considering nonlinear models and drop-out in lung disease progression, analysis is lacking and more studies are warranted.


Ultrastructure of human preovulatory granulosa cells in follicular fluid aspirates.
The ultrastructure of preovulatory granulosa cells may be distinct in follicles containing competent as opposed to non-competent oocytes. To test this assumption, granulosa cells were looked for in 36 follicular fluid aspirates from 8 patients taking part in an in vitro fertilization and embryo transfer program. Granulosa cells were absent from 16 aspirates and present in 20. Both aspirate types contained oocytes able to develop in culture. Granulosa cells were subdivided into three developmental stages. Stage 1 (5% of aspirates) showed proliferating cells, while stage 2 (60% of aspirates) and 3 (35% of aspirates) cells were in the preluteinization stage. These cells were recognizable by their number of lipid droplets and differentiated according to possession of a rough (stage 2) or smooth (stage 3) endoplasmic reticulum. Luteinization did not occur in these cells. All stages displayed desmosomes, gap junctions, and annular junctions. The structure of Call-Exner bodies and of fibrin deposits were unexpected findings. Our study indicates that there is no correlation between the previously used morphological parameters of granulosa cells and oocyte maturity.


Neuropeptide Y levels are associated with nutritional status and cardiovascular events in adults with chronic kidney disease.
Neuropeptide Y (NpY) is an important factor in neuropeptide signalling, and significantly change in the blood and cerebrospinal fluid (CSF) during chronic kidney disease (CKD) progression. However, the role of NpY remains unclear. We aimed to investigate the associations between NpY levels, nutritional status and cardiovascular disease (CVD) in patients with CKD. In this cohort study, we performed Pearson's correlation analysis and multiple linear regressions to assess the relationship between CSF and serum NpY levels, as well as nutritional indices. Receiver operating characteristic curves were used to evaluate the sensitivity and specificity of CSF NpY levels. As NpY affects the cardiovascular system, Kaplan-Meier analysis was used to investigate the relationship between serum NpY levels and CVD. CSF NpY levels and nutritional indices were related during CKD progression (energy intake: β=0.236, P<0.001; mid-arm muscle circumference: β=0.953, P=0.014; prealbumin: β=0.067, P<0.001), and had high specificity (79.9%). High serum NpY levels may be a risk factor associated with CVD (relative risk=1.8015, 95% confidence interval: 1.0509-3.0881). Our results suggested a relationship between CSF NpY levels and nutritional indices in CKD patients. High serum NpY concentrations may be a risk factor associated with CVD.


Regulation of plasma membrane H+-ATPase activity by the membrane environment.
The plant plasma membrane H(+)-ATPase is a proton pump which plays a central role in physiological functions such as nutrient uptake and intracellular pH regulation. This pump belongs to the P(3)-type ATPase family and creates an electrochemical gradient across the plasma membrane. The generation of this gradient has a major role in providing the energy for secondary active transport across the plasma membrane. The activity of the proton pump is regulated by the transcriptional and post-translational levels and by membrane environmental factors such as membrane lipids. Several reviews have appeared during the last few years concerning the regulatory mechanism at transcriptional and post-translational levels. The plasma membrane H(+)-ATPase requires lipids for activity. This lipid dependency suggests a possible mode of regulation of the H(+)-ATPase via modification of its lipid environment. This review focuses on the regulation of plasma membrane H(+)-ATPase by membrane lipids surrounding H(+)-ATPase molecules.


Synthesis and aldose reductase inhibitory activities of novel thienocinnolinone derivatives.
A novel series of tetrahydrothieno[2,3-h]cinnolinone derivatives were synthesized and evaluated in vitro for their ability to inhibit aldose reductase (ALR2), an enzyme involved in the appearance of diabetic complications. Compounds 2e and 2j exert a remarkable inhibitory effect, with IC(50) of 7.6 and 18 microM, respectively. These compounds incorporate a valid pharmacophore for aldose reductase inhibitory activity represented by a thienocinnolinone template linked through a pentamethylene spacer to a carboxylic function.


Meatal stenosis following three types of circumcision with frenular artery preservation (FAP), the Plastibell device (PD), and frenular artery ligation (FAL): a long-term follow-up.
Despite the simplicity of male circumcision, complications occur frequently. Post-circumcision meatal stenosis is a concerning complication that might require several interventions. This study aims to evaluate the incidence of meatal stenosis in long-term follow-up, following three common circumcision methods: frenular artery preservation, frenular ligation, and the Plastibell device. This study is the continuation of the previous randomized clinical trial, the preliminary abstract of which has been accepted in the annual meeting of the American Urological Association in 2011. However, in this paper, we only included the patients with results of long-term follow-up. Patients were followed for a median of 11 years (range, 7-17). Follow-ups were recorded by evaluation of meatus and signs and symptoms of meatal stenosis. Two hundred six boys (80 neonates and 126 non-neonates) at the time of procedure were included in this study. The circumcision was conducted on 23.3% (48/206) of boys with the Plastibell device (PD) and 39.3% (81/206) of cases with frenular artery preservation (FAP) and 37.4% (77/206) of cases with frenular artery ligation (FAL). Meatal stenosis presented in 13 children during follow-up. Considering the three methods of circumcision, a significant difference in the incidence of meatal stenosis among the types of circumcisions was observed (6.3% in PD and 1.2% in FAP, 11.7% in FAL, P = 0.026). The present study revealed that the technique preserving the frenular artery is associated with a significantly lower incidence of meatal stenosis. Hence, the FAP is the recommended technique for circumcision as compared to two other methods.


N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning.
The present study demonstrates that impairments of spatial learning and hippocampal long-term potentiation in rats chronically exposed to lead are associated with changes in gene and protein expression of N-methyl-D-aspartate receptor subunits. Rats exposed to 750 and 1500 ppm lead acetate were found to exhibit deficits in acquisition of a water maze spatial learning task. Furthermore, lead-exposed rats show dose-dependent reductions in the maintenance of in vivo hippocampal long-term potentiation induced in entorhinal cortex-dentate gyrus synapses. We found an unexpected, but significant (P<0.05), correlation between spatial learning and long-term potentiation when control and lead-exposed rats were analysed as a single, combined population. Dentate gyrus NR1 subunit messenger RNA was reduced 18% and 28% by exposure to 750 and 1500 ppm lead acetate, respectively. NR2A subunit messenger RNA was reduced 18% but only in the dentate gyrus of rats exposed to 1500 ppm lead acetate. No significant changes in dentate NR2B messenger RNA expression were measured in either of the lead-exposed groups. NR1 subunit protein was reduced 24% and 58% in hippocampal homogenates from rats exposed to 750 and 1500 ppm lead acetate. In contrast, no changes in NR2A or NR2B subunit protein were observed in the same hippocampal homogenates. These data show that reductions of specific N-methyl-D-aspartate receptor subunits are associated with deficits of both hippocampal long-term potentiation and spatial learning, induced in rats by chronic exposure to environmentally relevant levels of lead. These findings strongly suggest that the effects of lead on N-methyl-D-aspartate receptors may be the mechanistic basis for lead-induced deficits in cognitive function.


Administrative simplification: adoption of standards for health care electronic funds transfers (EFTs) and remittance advice. Interim final rule with comment period.
This interim final rule with comment period implements parts of section 1104 of the Affordable Care Act which requires the adoption of a standard for electronic funds transfers (EFT). It defines EFT and explains how the adopted standards support and facilitate health care EFT transmissions.