Specificity of cellular retinol-binding protein in the transfer of retinol to nuclei and chromatin.
We have reported previously that cellular retinol-binding protein (CRBP) is able to transfer retinol to specific binding sites in nuclei and chromatin. In this report, we have examined the specificity of the interaction of the protein moiety of retinol-CRBP (R-CRBP) with chromatin and nuclei in the transfer process. We first determined the ability of apo-CRBP, apo-serum retinol-binding protein (RBP), and apo beta-lactoglobulin (BLG), all capable of retinol binding, to compete with R-CRBP in the transfer of retinol to chromatin and nuclei. Apo-CRBP was an effective competitor but apo-RBP and apo-BLG showed no competitive ability. On the other hand, cellular retinol-binding protein type II (CRBP(II], whose amino acid sequence shows a considerable similarity to CRBP, did compete for the transfer of retinol from the R-CRBP complex, but less effectively than CRBP. These results demonstrate that the interaction of the protein moiety of the R-CRBP complex with nuclei and chromatin is quite specific.


Impairment of corneal epithelial barrier function in diabetics.
Corneal epithelial permeability was determined using an automatic fluorophotometer in 80 consecutive diabetic patients. The corneal epithelium, which is the most important part of the corneal diffusion barrier, showed a significant increase of permeability to watery, ionic substances (natrium fluorescein). The permeability was increased 5.4 times in comparison with nondiabetic individuals and a distinct correlation of increased permeability with the presence and duration of retinal nonperfusion areas was observed.


Heart failure and socioeconomic status: accumulating evidence of inequality.
Socioeconomic status (SES) is a powerful predictor of incident coronary disease and adverse cardiovascular outcomes. Understanding the impact of SES on heart failure (HF) development and subsequent outcomes may help to develop effective and equitable prevention, detection, and treatment strategies A systematic literature review of electronic databases including PubMed, EMBASE, CINAHL, and the Cochrane Library, restricted to human subjects, was carried out. The principal outcomes were incidence, prevalence, hospitalizations, mortality, and treatment of HF. Socioeconomic measures included education, occupation, employment relations, social class, income, housing characteristics, and composite and area level indicators. Additional studies were identified from bibliographies of relevant articles and reviews. Twenty-eight studies were identified. Lower SES was associated with increased incidence of HF, either in the community or presenting to hospital. The adjusted risk of developing HF was increased by ∼30-50% in most reports. Readmission rates following hospitalization were likewise greater in more deprived patients. Although fewer studies examined mortality, lower SES was associated with poorer survival. Evidence defining the equity of medical treatment of patients with HF was scarce and conflicting. Socioeconomic deprivation is a powerful independent predictor of HF development and adverse outcomes. However, the precise mechanisms accounting for this risk remain elusive. Heart failure represents the endpoint of numerous different pathophysiological processes and 'chains of events', each modifiable throughout the disease trajectories. The interaction between SES and HF is accordingly complex. Disentangling the many and varied life course processes is challenging. A better understanding of these issues may help attenuate the health inequalities so clearly evident among patients with HF.


Hypoglycaemia-induced changes in regional brain volume and memory function.
Hypoglycaemic events can be a serious complication of insulin therapy in Type 1 diabetes mellitus. Severe hypoglycaemic exposure can lead to episodic memory impairments, including anterograde amnesia. However, relatively little is known regarding the long-term impact of severe hypoglycaemia on brain structure in Type 1 diabetes mellitus. The goals of the present study were to gain a greater understanding of the long-term effects of severe hypoglycaemia exposure on brain structure and the neural correlates of memory impairments in Type 1 diabetes mellitus. Regional grey and white matter volume and total white matter lesion volume were quantified in an individual with long-standing hypoglycaemia-induced anterograde amnesia and compared with age- and gender-matched healthy controls. Our patient has significant reductions in grey matter volume in the hippocampus, thalamus and pallidum, and significant reductions in white matter volume in the splenium, isthmus of the cingulate and cerebellum. He also has a significantly larger total white matter lesion volume than controls. This case study highlights the potential of hypoglycaemia for permanent deleterious effects on brain structure and memory function. Our results suggest that subcortical grey matter, periventricular white matter and posterior white matter may be most susceptible to injury from hypoglycaemia exposure, and that structural damage to the hippocampus and isthmus of the cingulate may play a central role in hypoglycaemia-induced memory impairments.


A new antisickling agent: in vitro studies of its effect on S/S erythrocytes and on hemoglobin S.
2-(benzoylamino) pyridinium benzoate (BAPB) has exhibited an antisickling effect with homozygous S/S erythrocytes in vitro. This study suggests that BAPB prevents sickling by inhibiting the gelation of hemoglobin S.


Initial test of emergency procedure performance in temporary negative pressure isolation by using simulation technologies.
The potential of infectious disease spread in diseases such as tuberculosis, infectious disease epidemic such as avian flu and the threat of terrorism with agents capable of airborne transmission have focused attention on the need for increased surge capacity for patient isolation. Total negative pressure isolation using portable bioisolation tents may provide a solution. The study assesses the ability of health care workers to perform emergency procedures in this environment. Physician performance in completing predetermined critical actions in 5 emergency care scenarios inside and outside of a bioisolation tent ("setting") was studied in an advanced medical simulation laboratory. By design, no pretraining of subjects about total negative pressure isolation use occurred. Impact of setting on time to completion of predetermined critical actions was the primary outcome measured. Secondary variables studied included impact of study groups, scenarios, and run order (inside or outside of the tent first). Subjective assessments were obtained through questionnaires. Four teams of 3 physicians completed 5 emergency patient care scenarios during 2 4-hour sessions. Mean time to completion of critical actions was for tent/no tent 298 seconds/284 seconds (P=.69, one way ANOVA), respectively. Mean time to completion for first versus second performance of a scenario in the crossover design was 338 versus 243 (P=.01). The mean score for self-assessed performance did not differ according to setting. The ability of physicians naive to the total negative pressure isolation environment to perform emergency medical critical actions was not significantly degraded by a simulated bioisolation tent patient care environment.


A Myb enhancer-guided analysis of basophil and mast cell differentiation.
The transcription factor MYB is a crucial regulator of hematopoietic stem and progenitor cells. However, the nature of lineage-specific enhancer usage of the Myb gene is largely unknown. We identify the Myb -68 enhancer, a regulatory element which marks basophils and mast cells. Using the Myb -68 enhancer activity, we show a population of granulocyte-macrophage progenitors with higher potential to differentiate into basophils and mast cells. Single cell RNA-seq demonstrates the differentiation trajectory is continuous from progenitors to mature basophils in vivo, characterizes bone marrow cells with a gene signature of mast cells, and identifies LILRB4 as a surface marker of basophil maturation. Together, our study leads to a better understanding of how MYB expression is regulated in a lineage-associated manner, and also shows how a combination of lineage-related reporter mice and single-cell transcriptomics can overcome the rarity of target cells and enhance our understanding of gene expression programs that control cell differentiation in vivo.


Phenylarsine oxide inhibits ex vivo HIV-1 expression.
Phenylarsine oxide (PAO), which is described as an inhibitor of tyrosine phosphatase activity, inhibits H2O2 release from human peripheral blood mononuclear cells (PBMCs) as measured by electrochemistry. Since human immunodeficiency virus type 1 (HIV-1) replication is known to be favored under oxidative stress conditions, ex vivo experiments using uninfected PBMCs, primary monocytes or a latently infected promonocytic U1 cell line show that HIV-1 replication and reactivation, monitored by p24 antigen measurement, are inhibited by PAO in a time- and concentration-dependent manner. These observations can be linked with the inhibition of NF-kappa B activation when uninfected monocytes are induced by either tumor necrosis factor alpha (TNF-alpha) phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS).


The anti-retinotopic organization of the frog's optic nerve.
In Rana pipiens, axons marked by the intraretinal application of horseradish peroxidase (HRP) were traced within the optic nerve and tract. Axons arising from dorsal regions of the peripheral retina collect at the dorsal end of the elongate optic disc and form a compact group on the dorsal side of the nerve. Correspondingly, ventral axons locate on the ventral side of the nerve. However, nasal and temporal peripheral axons share passage on both the nasal and temporal sides of the nerve, segregating only upon reaching the brain. The ultimate sorting of nasal and temporal axons in the brain, following their intermingling in the optic nerve, supports the operation of a chemoaffinity mechanism, rather than passive mechanical guidance.


Intra-articular ganglion cyst of the knee.
Ganglion cysts of the knee are extremely uncommon. They usually cause non-specific symptoms and do not produce classical signs. Advances in imaging techniques as well as widespread use of arthroscopy have made detection of these cysts easier, and most can be treated arthroscopically. Ganglion cysts arising within the infrapatellar fat pad are even more uncommon. We report a case of a young lady with a giant intra-articular ganglion within the infrapatellar fat pad that was treated by open excision.


Carcinoma in situ in testicular biopsies.
Carcinoma in situ of the testis is an abnormality of the seminiferous epithelium characterized by aneuploid cells with clear cytoplasm located along the tubular basement membrane or in the lumina of tubules. Morphological, cytogenetic, and histochemical features of this anomaly are presented. An adequate fixation of testicular tissue samples is necessary for correct diagnosis. The fact that approximately 50% of carcinoma in situ may develop into malignant germ cell tumours of the testis in 5 years and the investigations of the testicular tissue adjacent to these tumours support the malignant nature and invasive potential of testicular carcinoma in situ. The incidence of carcinoma in situ in persons at risk is reviewed.


The major intrinsic protein (MIP) of the bovine lens fiber membrane: characterization and structure based on cDNA cloning.
Synthetic oligonucleotide probes have been used to identify two overlapping cDNA clones that represent the entire coding region of the mRNA for the major intrinsic protein (MIP) of bovine lens cell membrane. Hybridization studies indicate that bovine MIP is encoded by a single-copy gene. The cDNA hybridizes to the rat genome, but MIP mRNA is not detected in rat liver. Analysis of the deduced amino acid sequence provides support for the potential role of MIP as a junctional protein. The structure predicted for MIP suggests that it traverses the lipid bilayer six times with both carboxy and amino termini on the cytoplasmic side, and that it has at least one amphiphilic transmembrane segment, as expected if the protein were to participate in the formation of an aqueous channel.


Innovative training modality for sacral neuromodulation (SNM): Patient-specific computerized tomography (CT) reconstructed 3D-printed training system: ICS School of Modern Technology novel training modality.
Sacral neuromodulation (SNM) is an effective treatment of urinary and bowel dysfunction, including secondary to neurological disorders. The learning curve for the optimal electrode placement for SNM is steep, expensive, and limited by patient factors such as obesity and previous injuries. We aim to create a patient specific 3-dimensional (3D) model for successful SNM training. A total of 26 urology residents who had different level of knowledge and experience were enrolled to the 3D SNM training program. The creation of 3D sacrum model has been started with evaluation of real patient computerized tomography images and creation of Digital Imaging and Communications in Medicine files. The segmented anatomic structures from the files then edited and stereolithographic files were generated for 3D-model prints via Mimics© software. The 3D-printed models were used for training and evaluation of participants during the SNM intervention was performed. The evaluation of 3D SNM model training was led by one mentor who is expert on SNM. On the preprinted 3D sacrum model all 26 participants were requested to perform the essential steps to complete a SNM procedure and individual procedure time was recorded. The mean and median scores were 18.8 and 19, respectively according to Likert scores (min 11 max 28). SNM is increasing in popularity as a treatment option with physicians and patients with refractory symptoms. Few experienced specialists exist, and more effective training methods are needed to tackle the increasing demand, and individual patient anatomy.


Associations of sleep characteristics in late midlife with late-life hearing loss in the Atherosclerosis Risk in Communities-Sleep Heart Health Study (ARIC-SHHS).
This study investigated associations of late midlife sleep characteristics with late-life hearing, which adds to the existing cross-sectional evidence and is novel in examining polysomnographic sleep measures and central auditory processing. A subset of Atherosclerosis Risk in Communities Study participants underwent sleep assessment in the Sleep Heart Health Study in 1996-1998 and hearing assessment in 2016-2017. Peripheral hearing thresholds (0.5-4kHz) assessed by pure-tone audiometry were averaged to calculate speech-frequency pure-tone average in better-hearing ear (higher pure-tone average=worse hearing). Central auditory processing was measured by the Quick Speech-in-Noise Test (lower score=worse performance). Sleep was measured using polysomnography (time spent in stage 1, stage 2, stage 3/4, rapid eye movement sleep; sleep-disordered breathing [apnea-hypopnea index ≥5]) and self-report (habitual sleep duration; excessive daytime sleepiness [Epworth Sleepiness Scale 10]). Linear regression models adjusted for demographic and lifestyle factors with additional adjustment for cardiovascular factors. Among 719 Atherosclerosis Risk in Communities-Sleep Heart Health Study participants (61 ± 5years, 54% female, 100% White), worse speech-frequency pure-tone average was found with sleep-disordered breathing (2.51dB, 95% confidence interval: 0.27, 4.75) and excessive daytime sleepiness (3.35 dB, 95% confidence interval: 0.81, 5.90). Every additional hour of sleep when sleeping >8 hours was associated with worse Quick Speech-in-Noise score (1.61 points, 95% confidence interval: 0.03, 3.19). Every 10-minute increase in rapid eye movement sleep was associated with 0.14-point better Quick Speech-in-Noise score (95% confidence interval: 0.02, 0.25). Sleep abnormalities might be risk factors for late-life hearing loss. Future longitudinal studies are needed to confirm these novel findings and clarify the mechanisms.


Modulation of human T lymphocyte functions by isoprinosine.
Isoprinosine was shown to alter certain T cell functions. In vitro, it has previously been shown to induce suppressor cell activity in both mouse and human lymphocytes. Our in vitro results suggest that Isoprinosine acts on immune balance by increasing the number of non-suppressor T cells and, at least partially blocks Con A induced suppressor activity. In vitro NK activity remained unaltered.


Two cases of mucopolysaccharidosis type III (Sanfilippo). An anatomopathological study.
Anatomopathological studies of one case of Sanfilippo disease types A and C, respectively, are presented. The storage phenomenon is very severe in the central as well as in the peripheral nervous system of both patients. Light microscopy does not show significant differences between the two cases. Electron microscopy of the nervous system reveals in both cases the presence of variable amounts of zebra bodies and of membrano-granulo-vacuolar inclusions. The presence of larger amounts of zebra bodies in the type A case and of larger quantities of membrano-granulo-vacuolar inclusions in the type C case constitute probably a nondistinctive feature between the two types. Light and electron microscopic studies of visceral organs do not disclose significant differences either. It is concluded that no major morphological differences between Sanfilippo disease types A and C can be observed.


Evaluating Surgical Outcomes of Robot Assisted Simple Prostatectomy in the Retreatment Setting.
To report perioperative and postoperative outcomes in men who undergo salvage RASP (sRASP) following some other endoscopic outlet procedure for benign prostate enlargement (BPE) compared to those undergoing RASP for primary treatment (pRASP). A prospectively maintained database consisting of all RASP surgeries (December 2014-October 2019) performed at our institution by 3 different urologists was used. Patients who had received an endoscopic procedure for BPE prior to their RASP (sRASP) were compared to those who had not had a prior outlet procedure (pRASP). In total, 310 men underwent RASP during the study period. Of those, 30 (9.7%) had undergone an endoscopic procedure prior to surgery. There were no significant differences in age, race, ASA, BMI, prostate volume, PSA or rates of preoperative retention (P> .05 for all). Men who were treatment-naive had significantly higher preoperative International Prostate Symptom Scores (IPSS) than men who had a prior procedure (18.3 ± 7.7 vs 13.6 ± 6.2, P = .008). However, there were no significant differences in functional or quality of life outcomes between the 2 groups (P > .05 for all). There were no significant differences in perioperative or post-operative outcomes between the 2 groups. Furthermore, rates of post-operative complications and incontinence were similar between groups (11% vs 10%, P = .9 and 2% vs 0%, P = 1 respectively). Performing a RASP after prior endoscopic procedure for BPE was found to be safe and effective. Success and complication rates were similar to patients with no prior procedures.


Peripheral nerve fibres regenerate through myenteric plexus.
The ability of myenteric glia and neurons to support peripheral nerve regeneration was tested by grafting pieces of muscularis externa 5 mm long from the distal colon of inbred CBA mice adjacent to the proximal stump of cut common peroneal nerves. By two weeks after operation many axons had invaded the plexus and after 3 weeks regeneration common peroneal nerve fibres could be identified in all parts of the plexus throughout the grafts. Some axonal profiles within the plexus appeared to be in the early stages of myelination by enteric glia. Axons surrounded by compact myelin were found at the periphery of ganglia, but the cells involved resembled Schwann cells and could not be positively identified as enteric glia. Profiles similar to those of regenerating axons were only very rarely seen in control experiments in which grafts were placed adjacent to intact common peroneal nerves. It is suggested that the cellular elements of the myenteric plexus can support peripheral nerve regeneration.


Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors.
A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (K(i)=0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo.


Chronic nitric oxide synthase blockade desensitizes the heart to the negative metabolic effects of nitric oxide.
The consequences of chronic nitric oxide synthase (NOS) blockade on the myocardial metabolic and guanylyl cyclase stimulatory effects of exogenous nitric oxide (NO) were determined. Thirty-three anesthetized open-chest rabbits were randomized into four groups: control, NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 10(-4 )M), NOS blocking agent N(G)-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg/day) for 10 days followed by a 24 hour washout and L-NAME for 10 days followed by a 24 hour washout plus SNAP. Myocardial O(2) consumption was determined from coronary flow (microspheres) and O(2) extraction (microspectrophotometry). Cyclic GMP and guanylyl cyclase activity were determined by radioimmunoassay. There were no baseline metabolic, functional or hemodynamic differences between control and L-NAME treated rabbits. SNAP in controls caused a reduction in O(2) consumption (SNAP 5.9+/-0.6 vs. control 8.4+/-0.8 ml O(2)/min/100 g) and a rise in cyclic GMP (SNAP 18.3+/-3.8 vs. control 10.4+/-0.9 pmol/g). After chronic L-NAME treatment, SNAP caused no significant changes in O(2) consumption (SNAP 7.1+/-0.8 vs. control 6.4+/-0.7) or cyclic GMP (SNAP 14.2+/-1.8 vs. control 12.1+/-1.3). In controls, guanylyl cyclase activity was significantly stimulated by SNAP (216.7+/-20.0 SNAP vs. 34.4+/-2.5 pmol/mg/min base), while this increase was blunted after L-NAME (115.9+/-24.5 SNAP vs. 24.9+/-4.7 base). These results demonstrated that chronic NOS blockade followed by washout blunts the response to exogenous NO, with little effect on cyclic GMP or myocardial O(2) consumption. This was related to reduced guanylyl cyclase activity after chronic L-NAME. These results suggest that, unlike many receptor systems, the NO-cyclic GMP signal transduction system becomes downregulated upon chronic inhibition.


A case report demonstrating spontaneous change in tachycardia terminating window.
A patient who received a patient-activated pacemaker system for termination of paroxysmal, drug-resistant, ventricular tachycardia is described. During the pre-implant invasive electrophysiological (EP) study and the three post-implant non-invasive EP studies, tachycardias were easily and reproducibly terminated by two stimuli using the interval scanning mode. On the fourth day post-implant, this pacing mode no longer terminated tachycardia at rest. A new pacing mode using more stimuli was then found to terminate the tachycardia reproducibly under various physiological conditions. This case report demonstrated a spontaneous change in the tachycardia terminating window and the usefulness of versatility in antitachycardia pacemaker systems.


First large-scale ecological impact study of desalination outfall reveals trade-offs in effects of hypersalinity and hydrodynamics.
Desalination is an increasingly common method of meeting potable water demands, but the associated ecological risks are not well understood. Seawater desalination plants discharge large volumes of hypersaline brine directly into the ocean, raising concerns about potential impacts to marine life. In order to reduce impacts of brine, newer desalination outfalls are often fitted with high-pressure diffusers that discharge brine at high velocity into the water column, increasing the mixing and dilution of brine with ocean water. However, there are few published studies of marine impacts of desalination brine, and no well replicated before-after designs. Here we report a six-year study testing for impacts and subsequent recovery of sessile marine invertebrate recruitment near a desalination outfall with high-pressure diffusers. We used a Multiple Before-After-Control-Impact (MBACI) design to test for impacts and recovery at two distances (30 m and 100 m) from a 250 ML/day plant outfall, as well as a gradient design to test the strength of impacts relative to distance from the outfall. The diffusers achieved the target of less than 1 psμ salinity difference to surrounding ambient waters within 100 m of the discharge outfall, but sessile invertebrates were nonetheless impacted. Polychaetes, bryozoans and sponges reduced in cover as far as 100 m from the outfall, while barnacles showed the opposite pattern and were more abundant near the discharging outfall. Ecological impacts were disproportionate to the relatively minor change in salinity (∼1 psμ), suggesting a mechanism other than salinity. We propose that impacts were primarily driven by changes in hydrodynamics caused by the diffusers, such as higher near-bed flow away from the outfall. This is consistent with flow preferences of various taxonomic groups, which differ due to differences in settlement and feeding abilities. High-pressure diffusers designed to reduce impacts of hypersalinity may inadvertently cause impacts through hydrodynamics, leading to a trade-off in minimizing combined salinity and hydrodynamic stress. This study provides the first before-after test of ecological impacts of desalination brine on sessile marine communities, and rare insight into mechanisms behind impacts of a growing form of human disturbance.


Myocardial Contrast Defect Associated with Thrombotic Coronary Occlusion: Pre-Autopsy Diagnosis of a Cardiac Death with Post-Mortem CT Angiography.
We report the case of a female who died of suspected acute myocardial infarction. Post-mortem CT angiography (PMCTA) was performed with intravascular contrast infusion before the standard autopsy, and it successfully demonstrated the complete thrombotic occlusion of a coronary artery and also a corresponding perfusion defect on myocardium. We herein describe the PMCTA findings of a cardiac death with special emphasis on the potential benefits of this novel CT technique in forensic practice.


Molecular combing and its application in clinical settings.
Molecular combing technology (MCT) is an effective means for stretching DNA molecules and making them thus accessible for in situ studies. MCT uses the force exerted in the process of liquid flow via surface tension to stretch DNA molecules and spread them on solid surfaces, i.e. glass cover slips. Many DNA molecules can be stretched at the same time in parallel and neatly arranged side-by-side, making the approach convenient for statistical analysis. Accordingly, DNA replication and transcription can be studied at the single molecule level. In this paper, the principle, experimental methods, important applications, advantages and shortcuts of MCT in medical field are presented and discussed.


Change in pharmacokinetic and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels.
The in vivo pharmacokinetics (PK), biodistribution and antitumor activity of a new liposomal formulation of gemcitabine (GemLip) were compared to the conventional (clinical) formulation of gemcitabine (GemConv). Gemcitabine was entrapped in a vesicular phospholipid gel (VPG) consisting of densely packed liposomes. Redispersed VPG containing GemLip consisted of 33% liposomally entrapped and 67% free gemcitabine. The in vivo efficacies of GemLip and GemConv were compared using the subcutaneously growing human soft tissue sarcoma SXF 1301 and the orthotopically growing human bladder cancer BXF 1299T. PK and biodistribution were evaluated using radiolabeled drug and lipid in SXF 1301 tumor-bearing nude mice. GemLip was highly active in SXF 1301 at a gemcitabine dose of 6-9 mg/kg (days 1, 8 and 15; dose near the MTD). In the 6-mg/kg groups, complete tumor remissions were observed in seven of eight mice. Equimolar doses of GemConv resulted in only moderate tumor growth inhibition. Even at equitoxic doses (360 mg/kg given on days 1, 8 and 15, or 120 mg/kg on days 1, 5 and 8) GemConv was less active than GemLip. Furthermore, GemLip was active in the orthotopically growing BXF 1299T bladder cancer model at 6 mg/kg and prevented distant organ metastasis. In the PK study, GemLip achieved a 35-fold higher plasma AUC (1680 mg x h/ml) than GemConv (47.6 mg x h/ml). The serum half-lives were 0.15 h for free gemcitabine and 13.3 h for liposomal gemcitabine (6 mg/kg each i.v.). Moreover, gemcitabine levels in tumors were fourfold higher following injection of GemLip than following injection of GemConv. GemLip is a highly effective gemcitabine delivery system which results in superior gemcitabine pharmacodynamics and PK than GemConv. The enhanced in vivo efficacy might be explained by sustained release and passive tumor targeting.


Five methodological challenges in cognitive electrophysiology.
Here we discuss five methodological challenges facing the current cognitive electrophysiology literature that address the roles of brain oscillations in cognition. The challenges focus on (1) unambiguous and consistent terminology, (2) neurophysiologically meaningful interpretations of results, (3) evaluation and comparison of different spatial filters often used in M/EEG research, (4) the role of multiscale interactions in brain and cognitive function, and (5) development of biophysically plausible cognitive models. We also suggest research directions that will help address these challenges. We hope that this paper will help foster discussions and debates about important themes in the study of how the brain's rhythmic patterns of spatiotemporal electrophysiological activity support cognition.


Pathology of the vestibulocochlear nerve.
Imaging of the vestibulocochlear nerve has evolved dramatically over the past few decades. The imaging specialist now is involved in the diagnosis of far more diagnostic entities than ever before. With this increased involvement comes the responsibility to increase collective knowledge regarding the pathophysiology of these diagnostic entities. This article is organized in a conventional way and covers congenital deformity of the internal auditory canal, neoplastic and pseudoneoplastic lesions, with special detailed emphasis on schwannoma of the eight cranial nerves (acoustic neuroma), nonneoplastic IAC/CPA pathology, including vascular loops, and numerous additional differential diagnostic entities, with particular emphasis on non-neoplastic meningeal disease. Lesions of the auditory pathway and an overview of cochlear implant surgery are also included in this discussion.


Hierarchical tensile structures with ultralow mechanical dissipation.
Structural hierarchy is found in myriad biological systems and has improved man-made structures ranging from the Eiffel tower to optical cavities. In mechanical resonators whose rigidity is provided by static tension, structural hierarchy can reduce the dissipation of the fundamental mode to ultralow levels due to an unconventional form of soft clamping. Here, we apply hierarchical design to silicon nitride nanomechanical resonators and realize binary tree-shaped resonators with room temperature quality factors as high as 7.8 × 108 at 107 kHz frequency (1.1 × 109 at T = 6 K). The resonators' thermal-noise-limited force sensitivities reach 740 zN/Hz1/2 at room temperature and 90 zN/Hz1/2 at 6 K, surpassing state-of-the-art cantilevers currently used for force microscopy. Moreover, we demonstrate hierarchically structured, ultralow dissipation membranes suitable for interferometric position measurements in Fabry-Pérot cavities. Hierarchical nanomechanical resonators open new avenues in force sensing, signal transduction and quantum optomechanics, where low dissipation is paramount and operation with the fundamental mode is often advantageous.


Single Hepatocyte Hepatitis B Virus Transcriptional Landscape in HIV Coinfection.
Hepatitis B virus (HBV) is a leading cause of liver failure and hepatocellular carcinoma. Approximately 10% of people with HIV also have HBV and are at higher risk of liver disease progression than in HBV monoinfection. Antivirals, common to HIV and HBV, suppress HBV DNA levels but do not eradicate virus because the transcriptional template, covalently closed circular DNA (cccDNA), is long lived in infected hepatocytes. Using single-cell laser capture microdissection, we isolated >1100 hepatocytes from 5 HIV/HBV coinfected persons with increasing exposure to HBV antivirals (HB1-HB5; no exposure to >7 years exposure), quantifying cccDNA and pregenomic RNA (pgRNA) in each cell using droplet digital polymerase chain reaction. The proportion of infected hepatocytes decreased with antiviral exposure from 96.4% (HB1) to 29.8% (HB5). Upper cccDNA range and median pgRNA decreased from HB1 to HB5 (P < .05 for both). The amount of pgRNA transcribed per cccDNA also decreased from HB1 to HB5 (P < .05). Cells with inactive pgRNA transcription were enriched from 0% (HB1) to 14.3% (HB5) of infected hepatocytes. cccDNA transcription is reduced in HIV/HBV coinfected people with longer antiviral duration. Understanding HBV transcriptional regulation may be critical to develop a functional cure.


A review on processing techniques of bast fibers nanocellulose and its polylactic acid (PLA) nanocomposites.
The utilization of nanocellulose has increasingly gained attentions from various research fields, especially the field of polymer nanocomposites owing to the growing environmental hazardous of petroleum based fiber products. Meanwhile, the searching of alternative cellulose sources from different plants has become the interests for producing nanocellulose with varying characterizations that expectedly suit in specific field of applications. In this content the long and strong bast fibers from plant species was gradually getting its remarkable position in the field of nanocellulose extraction and nanocomposites fabrications. This review article intended to present an overview of the chemical structure of cellulose, different types of nanocellulose, bast fibers compositions, structure, polylactic acid (PLA) and the most probable processing techniques on the developments of nanocellulose from different bast fibers especially jute, kenaf, hemp, flax, ramie and roselle and its nanocomposites. This article however more focused on the fabrication of PLA based nanocomposites due to its high firmness, biodegradability and sustainability properties in developed products towards the environment. Along with this it also explored a couple of issues to improve the processing techniques of bast fibers nanocellulose and its reinforcement in the PLA biopolymer as final products.


Social-psychologic perspective in motivating changes in eating behavior.
Some reasons for difficulties in motivating changes in eating behavior are outlined, and the application of the major principles of social psychology relevant to dietary management are reviewed. Locus of control and varying communication models are discussed in the context of nutritional counseling. The importance of the patient assuming responsibility for his/her own behavioral change is reviewed in terms of attribution theory. Specific suggestions for helping nutritionists motivate patients to change their eating behavior are made.


Association between behavioural risks and Alzheimer's disease: Elucidated with an integrated analysis of gene expression patterns and molecular mechanisms.
Alzheimer's disease (AD) remains a global health challenge. Previous studies have reported linkages between AD and multiple behavioural risk exposures, however, the underlying biological mechanisms and crucial genes of gene expression patterns driven by behavioural risks on the onset or progression of AD remains ambiguous. In this study, we performed an integrated analysis on the influence of behavioural risks including smoking, excessive alcohol consumption, physical inactivity, and non-healthy dietary pattern on AD with a comprehensive strategy. Our results demonstrated that multiple behavioural risk exposures could independently or collectively influence diverse hierarchical levels of gene expression patterns through multiple biological mechanisms such as Wnt, mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), nuclear factor (NF)-κB, phosphatidylinositol 3-kinase (PI3K)-Akt, and insulin (INS) signalling pathways-mediated pathological processes, thereby prodromally or intermediately impacting AD. Our study provided insights into understanding the association of behavioural risk exposures with AD and informative support for further studies.


Preparation of Mitotic Chromosomes with the Dropping Technique.
The quality of chromosome preparation influences all downstream analyses and is therefore crucial. Hence, numerous protocols exist to produce microscopic slides with mitotic chromosomes. Nevertheless, due to the high content of fibers in and around a plant cell, preparation of plant chromosomes is still far from trivial and needs to be fine-tuned for each species and tissue type. Here, we outline the "dropping method," a straightforward and efficient protocol to prepare multiple slides with uniform quality from a single chromosome preparation. In this method, nuclei are extracted and cleaned to produce a nuclei suspension. In a drop-by-drop manner, this suspension is then applied from a certain height onto the slides, causing the nuclei to rupture and the chromosomes to spread. Due to the physical forces that accompany the dropping and spreading process, this method is best suited for species with small- to medium-sized chromosomes.


Development of a 3D disposable device for the electrochemical determination of diclofenac in different matrices.
In this work, the development of a disposable electrochemical device (US$ 0.02 per electrode) using a 3D printed support (3Ds) of acrylonitrile butadiene styrene (ABS) insulating filament with a composite material (CM) based on graphite and nail polish, immobilized on the support surface, was described for the electrochemical determination of diclofenac (DCF). The device was compared to the commercial glassy carbon electrode (GCE) and showed superior electroanalytical performance with approximately 1.8-fold higher current density. Additionally, an amperometric method for DCF determination in tap water, synthetic urine, and pharmaceutical formulation samples with the proposed electrode, using a flow injection analysis (FIA-AD) system, was developed. The optimized method presented excellent detectability (LOD = 0.47 µmol L-1), with excellent precision and accuracy (relative standard deviation < 5.6%) and percent recovery from spiked samples ranging from 89 to 106%. In addition, the sensor showed optimal analytical frequency with approximately 108 injections per hour, which demonstrates the potential of this system using the proposed disposable electrode for implementation in routine analysis and quality control with good selectivity and sensitivity.


Paediatric talus fractures: A guide to management based on a review of the literature.
Talus fractures are devastating injuries in both adults and children. Well recognised complications such as avascular necrosis (AVN), post-traumatic arthritis and non-union contribute to patient morbidity. This systematic review aimed to assess the literature on these injuries in children and their associated incidence, classification, management and outcome. A systematic review of Embase and Medline databases was carried out in accordance with PRISMA guidelines. Inclusion criteria were clinically orientated studies looking at talus fractures in paediatric patients (less than 18 years old). Exclusion criteria were conference abstracts, opinion-based reports, articles not published in English and articles published prior to 1980. Data extracted included patient demographics, fracture classification, management and outcomes. 31 studies were included encompassing 143 patients and 167 fractures with a mean age of 11.9 years (1.2-18). The majority of fractures (43.7%, n = 73) were of the talar neck. 70.6% (n = 101) were managed operatively. The overall rate of AVN was 15.4% (n = 22), with a 96.5% union rate. Observed rates of AVN were 5.7% in Hawkin's 1, 11.8% in Hawkin's 2, 53.3% in Hawkin's 3 and 0 in Hawkin's 4 injuries. All cases of non-union occurred in children over 12 years, and seven children required arthrodesis (1x pantalar, 1x subtalar and 5x subtalar and tibiotalar) with a mean age of 14.4 years (9-17). Talus fractures are rare but potentially devastating injuries in children. This systematic review has shown comparable rates of AVN in children to their adult counterparts, with higher rates of non-union and arthrodesis in adolescent patients. A lower threshold for operative intervention to achieve anatomical reduction in these patients should be considered.


Cytotoxic and immunomodulatory effects of polyhydroxyoctane isolated from Lentinus polychrous mycelia.
A polyhydroxyoctane, 6-methylheptane-1,2,3,4,5-pentaol (MHP), was first isolated from mycelia of the Thai edible mushroom Lentinus polychrous. MHP was evaluated for its cytotoxic and immunomodulatory effects in vitro. MHP was slightly cytotoxic to murine splenocytes but not to RAW264.7 cells or peripheral blood mononuclear cells. MHP decreased nitric oxide and intracellular O2 (-) production from lipopolysaccharide- and phorbol-12-myristate-13-acetate-activated RAW264.7 cells at levels of 78.98 ± 4.72 and 78.48 ± 2.41 % of controls, respectively. The mRNA expression of pro-inflammatory mediators, including iNOS, TNF-α, IL-1β, IL-6, COX-1 and COX-2, were significantly suppressed by MHP. In addition, MHP significantly increased the proliferation of phytohemagglutinin and pokeweed mitogen-induced splenocytes. These results indicate that MHP is able to modulate inflammatory responses and the proliferation of both T- and B-lymphocyte cells, suggesting that MHP may be a good natural immunomodulator.


Inhibition of SAPK/JNK leads to enhanced IL-1-induced IL-6 synthesis in osteoblasts.
Stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)(1) which belongs to the MAP kinase superfamily regulates many cellular events. We previously reported that interleukin 1 (IL-1) stimulates the synthesis of interleukin 6 (IL-6) through activation of ERK and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that AMP-activated protein kinase (AMPK) negatively regulates the IL-1-induced IL-6 synthesis through IκB/NF-κB pathway. In the present study, we investigated the role of SAPK/JNK in the IL-1-stimulated IL-6 synthesis in these cells. IL-1 induced the phosphorylation of SAPK/JNK. SP600125, an inhibitor of SAPK/JNK, increased the release and the mRNA expression levels of IL-6 induced by IL-1. IL-1-stimulated IL-6 release was significantly up-regulated in SAPK/JNK-knocked down cells. SP600125 remarkably suppressed the IL-1-induced phosphorylation of both IκB and NF-κB, whereas SP600125 failed to affect the IL-1-induced phosphorylation of AMPK, STAT3 or Src. Compound C, an AMPK inhibitor, attenuated the IL-1-induced phosphorylation of SAPK/JNK. SP600125 enhanced IL-1-stimulated IL-6 release also in normal human osteoblasts. These results strongly suggest that SAPK/JNK negatively regulates IL-1-stimulated IL-6 synthesis and acts at the point between AMPK and IκB/NF-κB in osteoblasts.


The position of tropomyosin in muscle thin filaments.
The contraction of vertebrate skeletal muscle is controlled by the action of Ca2+ on muscle thin filaments. At low Ca2+ concentrations (less than 10(-6)M) the regulatory proteins of the thin filament, tropomyosin and troponin, relax muscle by preventing the interaction of myosin and actin. At higher Ca2+ levels this inhibition is removed, when Ca2+ binds to troponin. Tropomyosin, a long coiled-coil alpha-helical molecule, is located in each of the two long-pitch helical grooves of actin, but troponin, a globular molecule, is attached at intervals of 38 nm (refs 1, 2). By combining evidence from X-ray diffraction studies of muscle and from electron microscopy, several authors have proposed that tropomyosin moves to block or allow attachment of myosin heads to actin. We investigate here an alternative way of combining the data, which if valid may have important consequences for our understanding of the regulation of muscle contraction.


Metabolic Syndrome and Its Components: A Cross-Sectional Analysis of Its Distribution among Pre- and Post-Menopausal Women from Northern India.
This study aims to determine the prevalence of Metabolic Syndrome (MS) and recognize its abnormal components in pre and postmenopausal women. We also aim to recognize the abnormal components in postmenopausal women with regard to duration since menopause. The cross-sectional study was undertaken among pre- and post-menopausal women between 40 and 65 years. Women with MS were identified as per the modified National Cholesterol Education Program Adult Treatment Panel III. A total of 220 women were enrolled comprising 112 premenopausal and 108 postmenopausal women, the prevalence of MS among them being 33% and 51.85%, respectively. Postmenopausal status was found to be independently associated with MS when adjusted for potential confounders (adjusted odds ratios = 14.77, 95% confidence intervals: 1.77-23.33). All the components were proportionately higher in postmenopausal group, the rise in blood pressure (BP) (P = 0.003) and low high-density lipoprotein (HDL) (0.027) being statistically significant. The risk of MS, abdominal obesity, and high BP were highest in <5 years since menopause and decreased thereafter. The risk for low HDL and high triglyceride increased with the number of years since menopause, reaching the peak level in the 5-9-year group and then decreased while the risk of high fasting blood sugar increased reaching peak in the 10-14 years' group. The prevalence of MS is significantly high in postmenopausal women. Screening of women in premenopausal period will give an opportunity to intervene and prevent the menace of MS in Indian women predisposed to abdominal obesity, insulin resistance, and cardiovascular adverse events.


[On the use of fenoterolhydrobromide in the treatment of imminent abortion (author's transl)].
A report was made about the retrospective comparison of a purely hormonal and a hormonal-tocolytic therapy of abortus imminens in 153 patients. The statistical comparison of the two groups was later specified. As a successful criterion, the successful childbirth was based upon. In this case it was found out, that an additional tocolytic medication of the final result was insignificantly affected, rather the hospital admittance under the tocolysis was significantly lengthened and the number of pregnancies which ended through abortion was reduced. Through this clear indication, it could be said, that pregnancies with delicate prognosis through tocolytic therapy are possibly unnecessarily lengthened and the final result is not better.


Accuracy, uncertainty, and adaptability of automatic myocardial ASL segmentation using deep CNN.
To apply deep convolution neural network to the segmentation task in myocardial arterial spin labeled perfusion imaging and to develop methods that measure uncertainty and that adapt the convolution neural network model to a specific false-positive versus false-negative tradeoff. The Monte Carlo dropout U-Net was trained on data from 22 subjects and tested on data from 6 heart transplant recipients. Manual segmentation and regional myocardial blood flow were available for comparison. We consider 2 global uncertainty measures, named "Dice uncertainty" and "Monte Carlo dropout uncertainty," which were calculated with and without the use of manual segmentation, respectively. Tversky loss function with a hyperparameter β was used to adapt the model to a specific false-positive versus false-negative tradeoff. The Monte Carlo dropout U-Net achieved a Dice coefficient of 0.91 ± 0.04 on the test set. Myocardial blood flow measured using automatic segmentations was highly correlated to that measured using the manual segmentation (R2 = 0.96). Dice uncertainty and Monte Carlo dropout uncertainty were in good agreement (R2 = 0.64). As β increased, the false-positive rate systematically decreased and false-negative rate systematically increased. We demonstrate the feasibility of deep convolution neural network for automatic segmentation of myocardial arterial spin labeling, with good accuracy. We also introduce 2 simple methods for assessing model uncertainty. Finally, we demonstrate the ability to adapt the convolution neural network model to a specific false-positive versus false-negative tradeoff. These findings are directly relevant to automatic segmentation in quantitative cardiac MRI and are broadly applicable to automatic segmentation problems in diagnostic imaging.


Sirolimus reduces the incidence and progression of UVB-induced skin cancer in SKH mice even with co-administration of cyclosporine A.
Transplant immunosuppressants have been implicated in the increased incidence of non-melanoma skin cancer in transplant recipients, most of whom harbor considerable UVB-induced DNA damage in their skin prior to transplantation. This study was designed to evaluate the effects of two commonly used immunosuppressive drugs, cyclosporine A (CsA) and sirolimus (SRL), on the development and progression of UVB-induced non-melanoma skin cancer. SKH-1 hairless mice were exposed to UVB alone for 15 weeks, and then were treated with CsA, SRL, or CsA+SRL for 9 weeks following cessation of UVB treatment. Compared with vehicle, CsA treatment resulted in enhanced tumor size and progression. In contrast, mice treated with SRL or CsA+SRL had decreased tumor multiplicity, size, and progression compared with vehicle-treated mice. CsA, but not SRL or combined treatment, increased dermal mast cell numbers and TGF-beta1 levels in the skin. These findings demonstrate that specific immunosuppressive agents differentially alter the cutaneous tumor microenvironment, which in turn may contribute to enhanced development of UVB-induced skin cancer in transplant recipients. Furthermore, these results suggest that CsA alone causes enhanced growth and progression of skin cancer, whereas co-administration of SRL with CsA causes the opposite effect. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article please go to http://network.nature.com/group/jidclub


Comparison of the crystal and solution structures of two RNA oligonucleotides.
Until recently, there were no examples of RNAs whose structures had been determined by both NMR and x-ray crystallography, and thus there was no experimental basis for assessing the accuracy of RNA solution structures. A comparison of the solution and the crystal structures of two RNAs is presented, which demonstrates that NMR can produce solution structures that resemble crystal structures and thus validates the application to RNA of a methodology developed initially for the determination of protein conformations. Models for RNA solution structures are appreciably affected by the parameters used for their refinement that describe intramolecular interactions. For the RNAs of interest here, the more realistic those parameters, the greater the similarity between solution structures and crystal structures.


Pancreatitis and altered glucose tolerance in mice infected with coxsackie B4 virus.
CD1 mice infected with Coxsackie B4 virus showed an early polymorph infiltration of the pancreas, which later changed to a mononuclear exudate. A state of glucose tolerance developed concurrently and both events coincided with the inhibition of migration of spleen cells in the presence of the virus. The relevance of these findings to human juvenile-onset diabetes mellitus is discussed.


Characterization and fabrication of zinc oxide nanoparticles by gum Acacia modesta through green chemistry and impregnation on surgical sutures to boost up the wound healing process.
In the present research, we developed zinc oxide nanoparticles (ZnO-NPs) based surgical sutures for the accelerated wound healing process. Color change from transparent to dark, surface plasmon response with a peak at 270 nm and infra-red spectra with ZnO-bond stretches at 489.6831 cm-1 confirmed the synthesis of NPs. Rod shape ZnO-NPs with an ideal size of 70 ± 03 nm were noted with uniform distribution. X-rays diffraction patterns revealed sharp peaks which was a clear indication of the crystalline nature of NPs. The energy dispersive X-ray analysis of synthesized nanoparticles reveals that the expected stoichiometric mass percent of zinc and oxygen is 77.55% and 22.45% respectively. Disc-diffusion antibacterial assay revealed that synthesized NPs hold good anti-bacterial potential against the Escherichia coli and Methicillin-resistant staphylococcus aureus (MRSA). Gum based ZnO-NPs coated suture revealed good tensile strength which is considered as a necessary parameter for suturing purposes. The designed suture showed excellent wound healing potential in Sprague-dawley rats through the incision wound model. Overall, in rats, rapid rate of epithelialization, wound contraction, mild inflammation and absence of any infection on the wounded site were recorded. Additionally, histopathology showed enhanced collagen fibers, fibroblast cells, lower inflammatory cells and rapid angiogenesis at healed tissues as compared to standard surgical treatment. Conclusively, the improved wound healing responses of the AM-ZnO-NPs were obtained due to the higher antibacterial activity of NPs.


The "tear-drop" bladder due to bilateral pelvic lymphocoeles. Aspirations under imaging control.
The description "tear-drop" or "pear-shaped" bladder is applied to a bladder with a narrow base and elongated body (1). Though first described in patients with a pelvic haematoma, pelvic lymphocoele is a recognised though uncommon cause. This case report demonstrates the characteristic ultrasonic appearance that led to successful aspiration of the bilateral fluid collection.


Muscle-enriched microRNA miR-486 decreases in circulation in response to exercise in young men.
MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. miRNAs are taken in by intracellular exosomes, secreted into circulation, and taken up by other cells, where they regulate cellular functions. We hypothesized that muscle-enriched miRNAs existing in circulation mediate beneficial metabolic responses induced by exercise. To test this hypothesis, we measured changes in muscle-enriched circulating miRNAs (c-miRNAs) in response to acute and chronic aerobic exercise. Eleven healthy young men (age, 21.5 ± 4.5 y; height, 168.6 ± 5.3 cm; and body weight, 62.5 ± 9.0 kg) performed a single bout of steady-state cycling exercise at 70% VO2max for 60 min (acute exercise) and cycling training 3 days per week for 4 weeks (chronic exercise). Blood samples were collected from the antecubital vein before and after acute and chronic exercise. RNA was extracted from serum, and the levels of muscle-enriched miRNAs (miR-1, miR-133a, miR-133b, miR-206, miR-208b, miR-486, and miR-499) were measured. All of these miRNAs, except for miR-486, were found at too low copy numbers at baseline to be compared. miR-486 was significantly decreased by both acute (P = 0.013) and chronic exercise (P = 0.014). In addition, the change ratio of miR-486 due to acute exercise showed a significant negative correlation with VO2max for each subject (R = 0.58, P = 0.038). The reduction in circulating miR-486 may be associated with metabolic changes during exercise and adaptation induced by training.


Predicting aperture crossing behavior from within-trial metrics of motor control reliability.
Actors utilize intrinsically scaled information about their geometric and dynamic properties when perceiving their ability to pass through openings. Research about dynamic factors of affordance perception have shown that the reliability of a given movement, or the precision of one's motor control for that movement, increase the buffer space used when interacting with the environment. While previous work has assessed motor control reliability as a person-level variable (i.e., behavior is aggregated across many trials), the current study assessed how characteristics of motor control and movement reliability within a single trial impact real-time action strategies for passing through apertures. Participants walked 5 m and then passed through apertures of various widths while their motions were tracked. For each trial, we collected walking time-series data, then calculated the magnitude and complexity of the lateral sway. Assessing two behavioral measures of the buffer, we found that trial-level metrics of motor control reliability, in addition to the person-level metrics previously studied, significantly predicted the buffer on each trial. This study supports previous claims that actors pick up real-time information about their dynamic capabilities in order to perceive and act within their environment. Further, the study recommends that future affordance research consider trial-level movement data, including nonlinear analyses that inform the pattern and structure of motor control reliability.


Oral naftidrofuryl prevents platelet hyperreactivity ex vivo and inhibits functional desensitization to prostacyclin in hypercholesterolemic rabbits.
Among other mediators, platelet-derived serotonin (5-HT) may contribute to thromboembolic complications of atherosclerosis. We determined whether long-term oral treatment with the 5-HT2 antagonist naftidrofuryl (NAF, 50 mg/kg daily for 12 weeks) alters platelet function in cholesterol-fed (1%) rabbits. Hypercholesterolemia resulted in marked platelet hyperreactivity to collagen and ADP. This included increased aggregation, ATP secretion, and thromboxane formation; e.g., collagen-induced (1.2 micrograms/ml) platelet aggregation was stimulated to 210 +/- 10 mm/30 s in cholesterol-fed rabbits as compared with 108 +/- 9 mm/30 s in rabbits fed a standard diet (p < 0.05). Inhibition of ADP-stimulated platelet activation by the prostacyclin mimetic iloprost was significantly reduced. NAF did not reduce plasma cholesterol in hypercholesterolemia, but prevented enhanced platelet aggregation, thromboxane formation, and ATP secretion. NAF treatment significantly reduced collagen-induced (1.2 micrograms/ml) aggregation to 81 +/- 20 mm/30 s in these animals (p < 0.05). NAF also inhibited functional desensitization of platelets to iloprost, but did not alter the impaired binding of [3H]iloprost to platelet membranes in hypercholesterolemic animals. NAF also did not change any of these parameters in normocholesterolemic rabbits. These data suggest beneficial effects of NAF on platelet hyperreactivity in experimental hypercholesterolemia which may also be relevant for its clinical use.


Prognostic value of platelet to lymphocyte ratio in non-small cell lung cancer: a systematic review and meta-analysis.
The prognostic value of the platelet-to-lymphocyte ratio (PLR) in non-small cell lung cancer (NSCLC) remains controversial. We therefore conducted a meta-analysis of published studies to determine the prognostic value of PLR in NSCLC. A systematic search was performed in PubMed, Web of Science and Embase for relevant studies. The data and characteristics of each study were extracted, and the hazard ratio (HR) at a 95% confidence interval (CI) was calculated to estimate the effect. We also performed subgroup and meta-regression analyses. A total of 2,889 patients in 12 studies were enrolled in this meta-analysis, and the pooled HR of 1.492 (95% CI: 1.231-1.807, P < 0.001) indicated that patients with an elevated PLR are expected to have a shorter overall survival (OS) after treatment. This meta-analysis indicates that a high PLR might be a predictive factor of poor prognosis in NSCLC. Further large-cohort studies are needed to confirm these findings.


In situ gelling hydrogels for pharmaceutical and biomedical applications.
Since Wichterle et al. introduced hydrogels as novel materials possibly suitable for a variety of biomedical applications, hydrogel research has become a fast-developing and exciting research field. The soft and hydrophilic nature of hydrogels makes them particularly suitable as protein delivery system or as cell-entrapping scaffold in tissue engineering. Traditional hydrogels were formed by chemical crosslinking of water-soluble polymers or by polymerization (of mixtures) of water-soluble monomers. Because of incompatibility of these crosslinking methods with fragile molecules like pharmaceutical proteins and living cells, in recent years research interest has been focused on hydrogels that gel spontaneously under physiological conditions. In these systems, hydrogel formation occurs in situ, at the site of injection, without the aid of potentially toxic or denaturizing crosslinking agents. This review provides an overview of in situ gelling systems and their potential in biomedical applications. Both photopolymerizable as well as self-assembling hydrogels, based on either chemical crosslinks or physical interactions will be addressed.


Review of the Oriental genus Platysodes Westwood (Coleoptera: Scarabaeidae: Cetoniinae: Cremastocheilini) with a redescription of Platysodes madoni Bourgoin.
The genus Platysodes Westwood, 1873 (Coleoptera: Scarabaeidae: Cetoniinae: Cremastocheilini) is reviewed, with an identification key, images, and distributional map for all species. Platysodes madoni Bourgoin, 1923 is newly recorded from southern China, and a lectotype is designated for this species. The year of publication of Platysodes is corrected to 1873.


Pentylenetetrazol-induced seizures are associated with Na⁺,K⁺-ATPase activity decrease and alpha subunit phosphorylation state in the mice cerebral cortex.
The present study aimed to investigate whether Na(+),K(+)-ATPase activity and phosphorylation state of the catalytic α subunit are altered by pentylenetetrazol (PTZ)-induced seizures. PTZ (30, 45 or 60 g/kg, i.p.) was administered to adult male Swiss mice, and Na(+),K(+)-ATPase activity and phosphorylation state were measured in the cerebral cortex 15 min after PTZ administration. Na(+),K(+)-ATPase activity significantly decreased after PTZ-induced seizures (60 mg/kg). Immunoreactivity of phosphorylated Ser943 at α subunit was increased after PTZ-induced seizures. A significant positive correlation between Na(+),K(+)-ATPase activity and latency to myoclonic jerks and generalized seizures was found. Conversely, a strong negative correlation between Ser943 phosphorylation and latency to generalized seizures was detected. Given the role of Na(+),K(+)-ATPase as a major regulator of brain excitability, Ser943 at Na(+),K(+)-ATPase α subunit may represent a potentially valuable new target for drug development for seizure disorders.


Celiac disease and dermatitis herpetiformis in Brazilian twins: a long-term follow-up and screening of their relatives.
To investigate three pairs of twins with celiac disease (CD) concerning clinical presentation, diagnostic procedures, and long-follow-up, besides screening CD in their first-degree relatives. CD was diagnosed in childhood by endoscopic duodenal biopsy in two monozygotic (MZ) female pairs (A1 and A2, B1 and B2) and one dizygotic (DZ) pair, in which the male (C1) had CD and the female (C2) was negative. The patients had periodic evaluations after a gluten-free diet (GFD) for 16 to 21 years. Nine first-degree relatives were screened by serological tests and when positive, referred for intestinal biopsies. At diagnosis, all CD patients had the classic presentation. A1/A2: scalloped duodenal mucosa with atrophic areas, Marsh III-b, after 16 years of GFD was antiendomysium antibody (EmA) negative, normal mucosa. B1/B2 at diagnosis: mucosal atrophy, Marsh III-b, after 21 years was EmA negative, decreased folds. Patient C1: decreased folds, Marsh III-b, after 16 years was EmA positive, decreased folds, admitted to gluten ingestion. A1, A2, and B1 presented dermatitis herpetiformis. The father of A1/A2 and the mother of C1/C2 were celiac. The long-term follow-up of the patients allowed some observations such as the concordance for CD in MZ twins, both in relation to the time of onset and the severity of the disease. Also, the findings of serological, endoscopic, and histological analyses were similar. Dermatitis herpetiformis was present in patients with CD, with partial concordance in MZ twins.


Glycated haemoglobin and other biochemical parameters in Sudanese diabetics.
Fasting levels of glycated haemoglobin, cholesterol and triglycerides were studied in 44 patients with non-insulin-dependent diabetes mellitus (NIDDM), 31 patients with insulin-dependent diabetes mellitus (IDDM) and 28 healthy Sudanese individuals. Results confirmed previous observations showing correlation of glycated haemoglobin with fasting blood glucose in NIDDM (r = 0.634; P less than 0.001), and with cholesterol in IDDM (r = 0.355; P less than 0.05). No correlation of glycated haemoglobin with triglycerides was observed in either group of diabetics. A negative correlation was demonstrated between glycated haemoglobin and the duration of diabetes (r = -0.552; P less than 0.01) in IDDM. It seemed that control improved in these patients as their diabetes progressed, probably through self-education.


Calcium, calmodulin and 3',5'-cyclic nucleotide phosphodiesterase activity in human muscular disorders.
3',5'-Cyclic nucleotide phosphodiesterase (PDE) is known to play an important role in the regulation of cyclic nucleotide levels in various tissues including the muscle. Previous studies have estimated the level of this enzyme in several neuromuscular disorders but the results have been variable. Moreover, there was no attempt made to correlate the enzyme levels with the levels of calcium and calmodulin, both of which regulate diverse biological processes including muscle contraction. In the present study we have estimated phosphodiesterase in the muscle of normal controls as well as patients with myotonic (MyD) and Duchenne muscular dystrophy (DMD) and amyotrophic lateral sclerosis (ALS). PDE was found to be increased significantly in all of the diseased muscles as compared to controls (P less than 0.01). But the increase could be coupled with an increase in calcium and calmodulin only in Duchenne dystrophic muscle.


Gas-liquid chromatographic method for the assay of aminoglycoside antibiotics in serum.
A gas-liquid chromatographic (GLC) method is presented for the rapid analysis of gentamicin, tobramycin, netilmicin, and amikacin from human serum. This procedure may have application to all aminoglycoside drugs. The three isomers of gentamicin are resolved as two bands, while tobramycin, netilmicin, and amikacin appear in this system as single bands. Normal serum constituents do not interfere with chromatograms. Thus far, no assay interference has been found in cases where other drugs and antibiotics were administered concurrently with aminoglycoside therapy. Dose-response data demonstrating linear recovery are included for all four aminoglycosides as well as a comparison of the GLC method with the microbiological method for the assay of gentamicin and amikacin. Quantitation is based upon the relative response of the antibiotics to a fixed amount of the internal standards, either kanamycin A or paromomycin B. These standards are clearly resolved as symmetrical peaks from the antibiotics of assay interest. Isothermal chromatographic analysis time is less than 8 min, while total assay time per single serum specimen is approximately 50 min. Preparation of serum includes: precipitation, evaporative drying of the supernatant, a two-stage derivatization (N-trimethylsilylimidazole, N-heptafluorobutyrylimidazole), and a single hexane extraction with a water wash. The methodology described may be applied to the analysis of other compounds (e.g., saccharides, amino-saccharides, amino acids, etc.) which do not rapidly partition into an organic phase.


Colon wall motility: comparison of novel quantitative semi-automatic measurements using cine MRI.
Recently, cine magnetic resonance imaging (MRI) has shown promise for visualizing movement of the colonic wall, although assessment of data has been subjective and observer dependent. This study aimed to develop an objective and semi-automatic imaging metric of ascending colonic wall movement, using image registration techniques. Cine balanced turbo field echo MRI images of ascending colonic motility were acquired over 2 min from 23 healthy volunteers (HVs) at baseline and following two different macrogol stimulus drinks (11 HVs drank 1 L and 12 HVs drank 2 L). Motility metrics derived from large scale geometric and small scale pixel movement parameters following image registration were developed using the post ingestion data and compared to observer grading of wall motion. Inter and intra-observer variability in the highest correlating metric was assessed using Bland-Altman analysis calculated from two separate observations on a subset of data. All the metrics tested showed significant correlation with the observer rating scores. Line analysis (LA) produced the highest correlation coefficient of 0.74 (95% CI: 0.55-0.86), p < 0.001 (Spearman Rho). Bland-Altman analysis of the inter- and intra-observer variability for the LA metric, showed almost zero bias and small limits of agreement between observations (-0.039 to 0.052 intra-observer and -0.051 to 0.054 inter-observer, range of measurement 0-0.353). The LA index of colonic motility derived from cine MRI registered data provides a quick, accurate and non-invasive method to detect wall motion within the ascending colon following a colonic stimulus in the form of a macrogol drink.


Changes in renal dimensions evaluated by magnetic resonance imaging and ultrasonography during long-term ciclosporin-A treatment.
To investigate changes in renal dimensions during long-term treatment with ciclosporin-A (CsA). Five mini-Göttingen pigs were treated with CsA (10 mg kg(-1) day(-1)) for 6 months; 3 untreated animals served as controls. Renal length was measured by magnetic resonance imaging (MRI) and ultrasonography (US); renal volume by MRI. Examinations were performed at baseline (0 weeks) and after the start of CsA treatment at intervals of 5 weeks (5-25 weeks). Comparison of baseline and end-point data (0 weeks vs. 25 weeks) revealed a statistically significant increase in renal volume in CsA-treated animals (87.1 cm3 vs. 55.9 cm3, P=0.002). Renal volume remained unchanged in the control group. A significant increase in renal length was found both in the CsA-treated pigs (MRI: 96 mm vs. 84 mm, P<0.001; US: 94 mm vs. 81 mm, P<0.001) and in the control group (MRI: 97 mm vs. 85 mm, P<0.001; US: 89 mm vs. 81 mm, P=0.018). No difference was found between MRI and US measurements based on 40 paired units (MRI variance: 2.4-30.3% and US variance: -5.1-40.6%, P=0.133). During long-term CsA treatment, renal volume increases in mini-pigs, but there is no correlation between the increase in volume and the increase in length in this pig model.


The non-specific enhancement of allergy. II. Precipitation of anaphylactic in vitro response capacity and serum IgE and IgG2a antibody synthesis in primed but non-responding rats by injection of alum.
PVG rats given injections of 1 microgram ovalbumin (OA) together with 10 mg Silica gel failed to provide serosal mast cells or lung tissue with the capacity to release histamine on in vitro challenge with the antigen. However, if such animals were injected i.p. with 100 mg of alum (without any further antigen addition) 3-9 weeks after the primary antigen injection, their mast cells and lung tissue showed a clear-cut capacity to respond in vitro, when examined 1 week after the alum injection. Injection of only 15 mg alum did not induce such a response capacity. The fading of the reactivity induced by an alum injection could be prevented by a repeated injection of the adjuvant alone. Pretreatment of the rats with cyclophosphamide (33 mg/kg) 2 days before the primary antigen injection did not affect the response capacity induced by a booster injection 3 weeks later. S.c. injection of alum also precipitated response capacity in animals primed by i.p. injection of antigen and Silica gel. The anaphylactic response capacity induced by injection(s) of alum was generally accompanied by increased levels of OA-IgE and especially OA-IgG2a antibody; however, a clear-cut correlation between either serosal mast cell or lung tissue response capacity and serum OA-IgE or IgG2a antibody titer could not be demonstrated. These data show that in primed animals, which do not express allergic response capacity, such a capacity can be induced by injecting adjuvant alone, even several weeks after the primary antigen injection.


VWA3A-derived ependyma promoter drives increased therapeutic protein secretion into the CSF.
Recombinant adeno-associated viral vectors (rAAVs) are a promising strategy to treat neurodegenerative diseases because of their ability to infect non-dividing cells and confer long-term transgene expression. Despite an ever-growing library of capsid variants, widespread delivery of AAVs in the adult central nervous system remains a challenge. We have previously demonstrated successful distribution of secreted proteins by infection of the ependyma, a layer of post-mitotic epithelial cells lining the ventricles of the brain and central column of the spinal cord, and subsequent protein delivery via the cerebrospinal fluid (CSF). Here we define a functional ependyma promoter to enhance expression from this cell type. Using RNA sequencing on human autopsy samples, we identified disease- and age-independent ependyma gene signatures. Associated promoters were cloned and screened as libraries in mouse and rhesus macaque to reveal cross-species function of a human DNA-derived von Willebrand factor domain containing 3A (VWA3A) promoter. When tested in mice, our VWA3A promoter drove strong, ependyma-localized expression of eGFP and increased secreted ApoE protein levels in the CSF by 2-12× over the ubiquitous iCAG promoter.


Preparation and use of Leadfluor-1, a synthetic fluorophore for live-cell lead imaging.
Leadfluor-1 (LF1) is a small-molecule fluorescent sensor for detecting lead in biological and environmental samples, including live cells. This dye uses a xanthenone fluorescent scaffold coupled to a dicarboxylate pseudocrown ether receptor to achieve selective detection of Pb(2+) in the presence of biologically relevant metal ions, including divalent calcium, magnesium and zinc. LF1 fluorescence increases by up to 18-fold on binding Pb(2+). In this protocol, we describe the synthesis and application of LF1 to imaging lead accumulation within live cells. The preparation of LF1 is anticipated to take 14-21 d, and the imaging assays can be performed in 1-2 d with cultured cells.


Bronchopneumonia disguising lung metastases of a painless central chondrosarcoma of pubis.
Chondrosarcoma is a generally locally malignant chondroid-forming bone tumor with a low potential for distant metastases. A small and completely painless central chondrosarcoma of pubis metastasizing to the lungs in a 63-year-old woman with bronchopneumonia is reported. Here we emphasize the mimicry and low growth of the chondrosarcoma and the easiness with which the diagnosis in completely asymptomatic patients can be missed. Although painless chondrosarcoma metastasizing to lung is rather rare, this tumor should be always included in the differential diagnosis of malignancies in this age category.


From P4 medicine to P5 medicine: transitional times for a more human-centric approach to AI-based tools for hospitals of tomorrow.
Within the debate on shaping future clinical services, where different robotics and artificial intelligence (AI) based technologies are integrated to perform tasks, the authors take the chance to provide an interdisciplinary analysis required to validate a tool aiming at supporting the melanoma cancer diagnosis. In particular, they focus on the ethical-legal and technical requirements needed to address the Assessment List on Trustworthy AI (ALTAI), highlighting some pros and cons of the adopted self-assessment checklist. The dialogue stimulates additionally remarks on the EU regulatory initiatives on AI in the healthcare systems.


Partial attenuation of hemodynamic responses to rapid sequence induction and intubation with labetalol.
The effectiveness of labetalol (a combination nonselective beta and alpha-1-adrenergic receptor antagonist) in modifying hemodynamic responses associated with rapid sequence induction and tracheal intubation was evaluated. In a double-blind study, 24 ASA physical status I or II male patients scheduled for elective surgery were given either IV labetalol, 0.25 mg/kg (n = 8) or 0.75 mg/kg (n = 8), or a saline placebo (n = 8). Five minutes later, patients were given oxygen by mask and IV vecuronium, 0.01 mg/kg. Ten minutes after giving labetalol or placebo, cricoid pressure was applied and anesthesia was induced with IV sodium thiopental (4 mg/kg) and succinylcholine (1.5 mg/kg) 1 minute prior to intubation. The mean duration of laryngoscopy was 17 +/- 3 seconds. Prior to induction, the 0.25 mg/kg and 0.75 mg/kg doses of labetalol significantly (p less than 0.05) reduced mean arterial pressure by 4.4 +/- 1.9 and by 8.6 +/- 2.0 mmHg, respectively, but did not significantly alter heart rate or cardiac output. The 0.75 mg/kg dose of labetalol also significantly (p less than 0.05) decreased total peripheral resistance by 10.1 +/- 3.0%. Within 30 seconds after intubation, patients in all three groups exhibited increases in heart rate, mean arterial pressure, total peripheral resistance, and rate pressure product and a decrease in stroke volume. However, patients in the 0.25 and 0.75 mg/kg labetalol groups, compared to those in the placebo group, had significantly lower increases in peak heart rate (33 +/- 2 and 27 +/- 3 vs. 44 +/- 7 beats/minute), peak mean arterial pressure (38 +/- 6 and 38 +/- 7 vs. 58 +/- 7 mmHg), and peak rate pressure product (7,726 +/- 260 and 7,215 +/- 300 vs. 14,023 +/- 250 units). The results show that these doses of labetalol significantly blunt, but do not completely block, autonomic responses to rapid sequence induction and intubation.


Implementation of the use of SPECT-portable for evaluation of surgical margins in breast cancer with indication of ROLL: First results.
Main objective: To compare the effectiveness for checking surgical margins between SPECT-portable and mammography of the piece (RxM). To standardize a pre-operative protocol using SPECT-portable and to evaluate the time required in the use of this technique. Prospective longitudinal study with 36 patients (39 lesions) diagnosed with breast cancer (CM) with criteria for SNOLL/ROLL. A pre-surgical study of the tumor lesion was performed, after the eco-guided administration of 99mTc-nanocolloids of albumin/99mTc-macroaggregates of albumin, in the tumor lesion. Hybrid images (optical + SPECT) and 3D navigation images with gamma probe are obtained using freehandSPECT. In the operating room, 4-5 images are obtained with freehandSPECT, (I) on skin for tumor location, (II) after exposure of surgical bed for resection guide, (III) of the surgical bed after exeresis, (IV and V) the anterior-posterior and lateral surface of the surgical specimen. The three criteria to decide to extend the margins are: (a) residual activity (cps) at the edges of the surgical bed resection; (b) visual analysis of the uptake in the specimen; (c) a minimum distance of 10 mm from the edges of the specimen to the center of greatest uptake, plus the radius of the lesion. We study the concordance of: the depth measurement between ultrasound and freehandSPECT; the surgical margins between freehandSPECT vs. mammography of the specimen (RxM), considering anatomical pathology (AP) as the gold standard technique as reference; surgical time used with freehandSPECT and RxM. Intraoperative localization was performed in all cases. False negative (FN: no detection margin affected) with freehandSPECT: 9 margins; with RxM: 8. True positive (TP: detection margin affected) with freehandSPECT: 5 margins, with RxM: 6. True negative (TN: consider free margin when healthy) with freehandSPECT: 213 margins; with RxM: 196. Negative predictive value (NPV: probability of negative margin on unaffected part) with freehandSPECT: 95.9%, with RxM: 96.07%. Specificity with freehandSPECT: 96.8%, with RxM: 97%. The concordance of surgical bed margins between freehandSPECT and RxM: 94.5%. Between freehandSPECT and AP: 93.1%. Between RxM and PA: 93.5%, being all statistically significant (p-value <0.000), so we can affirm that both techniques are related or dependent on the reference technique, the PA. Degree of correlation between SPECT-portable and low PA (Kappa index: 0.34, 95% CI [0.22-0.47], and between RxM and moderate PA (Kappa index: 0.42, 95% CI [0.29-0.56], p-value <0.001. Comparison of the successes and failures of both techniques (SPECT-portable and RxM) and PA: Distribution χ2: 0.023 with degree of freedom 1, with value <0.05, so we can affirm that both techniques are similar, since there are no significant statistical differences. Median total OR time: 60.25 min (30-145). Mean freehandSPECT OR time: 5 scans = 10 min. There are no statistically significant differences in the probability to rule out affective margins that require a second surgery between both techniques (SPECT-portable and RxM) so, the technique performed with SPECT-Portable is a useful and effective procedure, which requires specific training with an optimized and multidisciplinary protocol. The time spent with SPECT-portable is feasible for daily practice.


Atrial fibrillation signal organization predicts sinus rhythm maintenance in patients undergoing cardioversion of atrial fibrillation.
Electrical remodelling is believed to influence the outcome following cardioversion of patients with persistent atrial fibrillation (AF). However, the results in clinical studies are conflicting. We assessed the hypothesis that non-invasively obtained atrial fibrillatory organization can be used as a predictor of sinus rhythm (SR) maintenance. Fifty-four patients (37 men, age 67+/-11) with persistent AF (median duration 3 months, 1 day to 18 months), without anti-arrhythmic drug treatment, referred for cardioversion were studied. Assessment of the atrial harmonic decay was made by time-frequency analysis of the ECG. At 1-month follow-up, 30 patients had relapsed into AF. The mean harmonic decay at inclusion of those relapsing into AF was 1.5+/-0.3 compared with 1.1+/-0.3 among those maintaining SR (P=0.0004). Using a cut-off value of harmonic decay <or=1.5 to determine suitability for cardioversion would have resulted in a clinically useful discriminator (sensitivity=92%, specificity=47%, PPV=59%, and NPV=88%). This study shows that patients relapsing rapidly to AF have a higher harmonic decay than those maintaining SR. The degree of AF signal organization (harmonic decay) was a superior discriminator to other patient parameters. Further studies are needed to confirm these results and to determine the electrophysiological correlate of harmonic decay.


Experimental and numerical analysis of metal leaching from fly ash-amended highway bases.
A study was conducted to evaluate the leaching potential of unpaved road materials (URM) mixed with lime activated high carbon fly ashes and to evaluate groundwater impacts of barium, boron, copper, and zinc leaching. This objective was met by a combination of batch water leach tests, column leach tests, and computer modeling. The laboratory tests were conducted on soil alone, fly ash alone, and URM-fly ash-lime kiln dust mixtures. The results indicated that an increase in fly ash and lime content has significant effects on leaching behavior of heavy metals from URM-fly ash mixture. An increase in fly ash content and a decrease in lime content promoted leaching of Ba, B and Cu whereas Zn leaching was primarily affected by the fly ash content. Numerically predicted field metal concentrations were significantly lower than the peak metal concentrations obtained in laboratory column leach tests, and field concentrations decreased with time and distance due to dispersion in soil vadose zone.


Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data.
A critical and comprehensive review of the safety information on erythritol was undertaken. Numerous toxicity and metabolic studies have been conducted on erythritol in rats, mice and dogs. The toxicity studies consist of long-term feeding studies conducted to determine carcinogenic potential, intravenous and oral teratogenicity studies to determine the potential for effects on the foetus, oral studies in which erythritol was administered over one or two generations to determine the potential for reproductive effects, and studies in bacterial and mammalian systems to determine mutagenic potential. The majority of the safety studies conducted were feeding studies in which erythritol was mixed into the diet at concentrations as high as 20%. The metabolic studies in animals have shown that erythritol is almost completely absorbed, not metabolized systemically and is excreted unchanged in the urine. The safety studies have demonstrated that erythritol is well tolerated and elicits no toxicological effects. The clinical program for erythritol involved a series of single-dose and repeat-dose, short-duration studies which have been used to investigate the human correlates to the physiological responses seen in the preclinical studies. The clinical studies showed erythritol to be well tolerated and not to cause any toxicologically relevant effects, even following high-dose exposure. Erythritol administered orally to humans was rapidly absorbed from the gastrointestinal tract and quantitatively excreted in the urine without undergoing metabolic change. At high oral doses, urinary excretion accounted for approximately 90% of the administered dose with minimal amounts appearing in the faeces. A comparison of the human and animal data indicated a high degree of similarity in the metabolism of erythritol and this finding supports the use of the animal species used to evaluate the safety of erythritol for human consumption. It can be concluded, based on the available studies that erythritol did not produce evidence of toxicity.


Patterns of Performance and Symptom Validity Test Findings After Mild Traumatic Brain Injury.
The purpose of this study was to evaluate the presence of demographic, injury and neuropsychological correlates of distinct patterns of performance validity test and symptom validity test results in persons with mild traumatic brain injury (mTBI). One hundred and seventy-eight persons with mTBI completed the Test of Memory Malingering (TOMM; performance validity) and the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF; symptom validity) within 1-12 months postinjury. Four groups were compared: (a) pass both TOMM and MMPI-2-RF validity criteria, (b) pass TOMM and fail MMPI-2-RF, (c) fail TOMM and pass MMPI-2-RF, and (d) fail both TOMM and MMPI-2-RF. Compared to Group a, participants in combined Groups b-d were more than twice as likely to be engaged in financial compensation-seeking and about four times less likely to have neuroimaging evidence of an intracranial lesion. The average performance of Group d on an independent test of verbal learning was more than 1.5 standard deviations below that of Group a. Participants in Group b were more likely to have intracranial lesions on neuroimaging than participants in Group c. Performance and symptom validity tests provide complementary and non-redundant information in persons with mTBI. Whereas financial compensation-seeking is associated with increased risk of failure of either PVT or SVT, or both, the presence of intracranial findings on neuroimaging is associated with decreased risk of such.


Study of common bile duct exploration and endoscopic sphincterotomy in a consecutive series of 438 patients.
The outcome of 438 consecutive patients who had exploration of the common bile duct and/or endoscopic sphincterotomy (ES) in a 5-year period was reviewed. Patients were analysed according to four groups: 59 patients had planned ES followed by surgery resulting in 14 major complications (23.7 per cent) including 3 deaths (5.1 per cent) (group 1); 248 patients had surgery alone with 21 major complications (8.5 per cent) including 10 deaths (4.0 per cent) (group 2); 114 patients with gallbladder in situ underwent ES alone with 22 major complications (19.3 per cent) including 9 deaths (7.9 per cent) (group 3); 17 patients with remote cholecystectomy also had ES alone with 3 major complications (17.6 per cent) including 3 deaths (17.6 per cent) (group 4). There was no difference in mortality between the groups. Compared with group 2, major complications were significantly higher in group 1 (chi 2 = 11.0, d.f. = 1, P less than 0.001) and in group 3 (chi 2 = 8.6, d.f. = 1, P less than 0.003). Patients in group 3, however, were significantly older than those in groups 1 and 2, and the former also had higher medical and total risk factor scores than the latter (all P less than 0.001). The results indicate that routine pre-operative ES is of questionable value. ES alone is justified in elderly high risk patients; mortality in this group might be reduced by improved management of post-ES complications.


Functional implications of hippocampal adult neurogenesis in intellectual disabilities.
The development of strategies capable to promote nervous system plasticity in adulthood is nowadays an important aim in neuroscience to improve not only cognitive abilities but also to ameliorate pathological dysfunctions. Several studies have demonstrated that adult neurogenesis is regulated by many physiological and pathological stimuli at almost every stage, from proliferation of neuronal precursors until integration and activation of newly formed neurons in the preexisting network. We review the process of generating functional neurons from precursors in the adult brain and its implications in intellectual disability disorders.


The differential diagnostic value of selected cardiovascular biomarkers in Takotsubo syndrome.
Takotsubo syndrome (TTS) is clinically indistinguishable from an acute coronary syndrome (ACS). In the absence of valid markers for differential diagnosis, coronary angiography has been indispensable. In our study, we evaluated the serum levels of sST-2, GDF-15, suPAR and H-FABP in 92 patients with the suspicion of TTS (51 TTS and 41 ACS patients) and 40 gender matched controls (no coronary artery disease or signs of heart failure) at baseline. H-FABP was significantly higher in ACS patients compared to TTS patients. Even in in propensity score matching for left ventricular ejection fraction, sex and cardiovascular risk factors, differences in the plasma levels of H-FABP in the matched cohort of TTS vs ACS remained statistically significant. Whereas, sST-2 was significantly elevated in TTS patients. H-FABP was superior for prediction of an ACS with even higher accuracy than hs troponin in differential diagnosis (AUC 0.797, p ≤ 0.0001); the optimal cut off for discrimination towards a TTS was calculated as 2.93 ng/ml (sensitivity 70.0%, specificity 82.4%, PPV 75.7%, NPV 77.4%). sST-2 seemed most appropriate for identification of a TTS (AUC 0.653, p = 0.012). The optimal cut off for differential diagnosis was 11018.06 pg/ml (sensitivity 82.0%, specificity 51.2%, PPV 69.4%, NPV 71.9 %). H-FABP and sST-2 are the most promising markers with better accuracy than preexisting biomarkers in differential diagnosis in our study and therefore, could be crucial for the guidance of treatment in patients with high bleeding risk, advanced renal failure or multimorbidity.


The preoperative assessment of deep myometrial invasion by three-dimensional ultrasound versus MRI in endometrial carcinoma.
To evaluate the usefulness of three-dimensional ultrasound (3D US), magnetic resonance imaging (MRI) and three-dimensional power Doppler angiography (3D-PDA) in the preoperative assessment of myometrial invasion in endometrial carcinoma. A prospective observational study. University hospital. Twenty consecutive patients diagnosed with endometrial carcinoma. Preoperative 3 T MRI and 3D US examinations were performed, and the depth of myometrial invasion was assessed. The vascularity indices, vascularization index, flow index and vascularization flow index, were calculated by 3D-PDA. The results were compared with the final histopathology report after a surgical staging. In detecting deep myometrial invasion, the sensitivity of 3D US, MRI and their combination was 50, 91.7 and 100%, respectively. The specificity was 87.5, 50 and 50%, respectively. There were no significant differences in the 3D-PDA vascularity indices between the two groups. MRI appears to be more sensitive than 3D US in detecting deep invasion, while 3D US has a better specificity.


Metagenomics reveals microbial community differences lead to differential nitrate production in anammox reactors with differing nitrogen loading rates.
Nitrate production during anammox can decrease total nitrogen removal efficiency, which will negatively impact its usefulness for the removal of nitrogen from waste streams. However, neither the performance characteristics nor physiological shifts associated with nitrate accumulation in anammox reactors under different nitrogen loading rates (NLRs) is well understood. Consequently, these parameters were studied in a lower NLR anammox reactor, termed R1, producing higher than expected levels of nitrate and compared with a higher NLR reactor, termed R2, showing no excess nitrate production. While both reactors showed high NH4+-N removal efficiencies (>90%), the total nitrogen removal efficiency (<60%) was much lower in R1 due to higher nitrate production. Metagenomic analysis found that the number of reads derived from anammox bacteria were significantly higher in R2. Another notable trend in reads occurrence was the relatively higher levels of reads from genes predicted to be nitrite oxidoreductases (nxr) in R1. Binning yielded 27 high quality draft genomes from the two reactors. Analysis of bin occurrence found that R1 showing both a decrease in anammox bacteria and an unexpected increase in nxr. In-situ assays confirmed that R1 had higher rates of nitrite oxidation to nitrate and suggested that it was not solely due to obligate NOB, but other nxr-containing bacteria are important contributors as well. Our results demonstrate that nitrate accumulation can be a serious operational concern for the application of anammox technology to low-strength wastewater treatment and provide insight into the community changes leading to this outcome.


The increased prevalence of myopia in Finland.
To study change in the prevalence of myopia in Finland during the 20th century. A review of the literature on the prevalence of myopia in Finland. During the 20th century, the prevalence of myopia among 7- to 8-year-old schoolchildren did not increase in Finland and varied between 0.5% and 1.9%. Among 14- to 15-year-old school children, myopia doubled to about 21%. Among adults born during the first three decades of the 20th century, the prevalence of myopia was <10%, whereas among those born during the second half of the 20th century, the prevalence rose to 21-30%. The change in mean refraction was towards myopia. During the course of the 20th century, myopia among teenagers and adults in Finland significantly increased and the mean change in refraction was towards myopia. Increased education is proposed as the main reason behind these changes.


Ras does not contribute to the facilitation of hippocampal synaptic plasticity enabled by environmental enrichment.
Environmental enrichment (EE), which mimics the wealth of sensory, motor and cognitive stimuli that arise through intense interactions with the ambient environment, results in enhanced hippocampal long-term potentiation (LTP) and spatial learning. A key molecular factor in the mediation of these changes is the brain-derived neurotrophic factor (BDNF). One of the downstream cascades that is activated by BDNF is the cascade linked to the small GTPase, Ras, that triggers mitogen-activated protein kinase (MAPK) activity and is part of the cAMP response element-binding protein (CREB) pathway that can lead to synaptic restructuring to support LTP. Here, we explored whether persistent activation of Ras in neurons further enhances LTP following EE of rodents. Immediately following weaning, transgenic mice that expressed constitutively activated neuronal Ras, or their wildtype (Wt) littermates, underwent 3weeks of constant EE. In the absence of EE, theta burst stimulation (TBS) evoked LTP in the CA1 region of transgenic mice that was not significantly different from LTP in Wts. After 3weeks of EE, hippocampal LTP was improved in Wt mice. Enriched transgenic mice showed an equivalent level of LTP to enriched Wts, but it was not significantly different from non-enriched synRas controls. Western blot analysis performed after a pull-down assay showed that non-enriched transgenic mice expressed higher Ras activity compared to non-enriched Wts. Following EE, Ras activity was reduced in transgenics to levels detected in Wts. These results show that constitutive activation of Ras does not mimic the effects of EE on LTP. In addition, EE results in an equivalent enhancement of LTP transgenics and Wts, coupled with a decrease in Ras activity to Wt levels. This suggests that permanent activation of Ras in neurons of synRas animals following EE results in an altered feedback regulation of endogenous Ras activity that is not a key factor in LTP enhancements. The maintenance of Ras within a physiological range may thus be required for the optimization of LTP in the hippocampus.