Unilateral mydriasis after induction of anaesthesia.
Unilateral mydriasis is a disturbing finding during anaesthesia and may indicate serious neurological injury. In addition, the assessment of abnormal neurological findings is limited during general anaesthesia, and therefore requires special consideration. I report finding a dilated right pupil (7 mm, nonreactive to light) after bronchoscopic tracheal intubation and induction of general anaesthesia in a frail, 74-yr-old woman with cervical subluxations and spinal cord impingement. The possible aetiology of the unilateral mydriasis includes the effects of anaesthetic agents, stellate ganglion block, impaired venous return from the head and neck, acute intracranial mass lesion or an haemorrhagic event, direct eye trauma, pre-existing medical or surgical conditions, and inadvertent direct deposition of alpha-adrenergic or anticholinergic agents in the eye. Consideration of these factors, the autonomic innervation of the eye, and an intraoperative "wake-up" test allowed satisfactory neurological assessment in this patient and surgery to proceed. Unilateral mydriasis, while unusual, may be seen during general anaesthesia and requires thorough knowledge of autonomic nerve pathways and pharmacology of the eye for correct diagnosis. In this case, mydriasis was considered to result from phenylephrine/lidocaine spray which was used to provide topical anaesthesia to the airway.


Prognostic significance of forkhead box M1 (FoxM1) expression and antitumour effect of FoxM1 inhibition in melanoma.
Forkhead box M1 (FoxM1) is a transcription factor that regulates cell-cycle progression and tumour progression, but limited information is available regarding its clinical significance in melanoma. The aim of this study was to investigate the potency of FoxM1 as a therapeutic target in melanoma. We investigated 60 melanoma clinical samples and a melanoma WM266-4 cell line using immunohistochemical staining and molecular biological approaches. Patients with a FoxM1-overexpressing melanoma had significantly shorter survival [both for melanoma-specific survival (MSS) and disease-free survival (DFS)] than the other patients (P < 0.001, respectively). The FoxM1 overexpression was also an adverse prognostic factor for both MSS and DFS on the Cox multivariate analyses [hazard ratio (HR): 3.96, 95% confidence interval (CI): 1.12-14.27, P = 0.032; HR: 3.21, 95% CI: 1.08-9.67, P = 0.037, respectively). FoxM1 inhibition using siRNA and an inhibitor (thiostrepton) each suppressed the cell proliferation of the melanoma cell line. Furthermore, FoxM1 inhibition improved chemosensitivity to dacarbazine, whereas it reduced cell migration and invasion. These results suggest that FoxM1 plays important roles in tumour progression and the chemoresistance of melanoma. We have shown the prognostic impact of FoxM1 on melanoma patients. FoxM1 inhibition may be a potential therapeutic option for advanced melanoma.


Hepatitis C viraemic organs in solid organ transplantation.
Although rates of organ donation and solid organ transplantation have been increasing over the last few decades, demand for organs still greatly exceeds supply. Several strategies have been utilised to increase organ supply, including utilisation of high-risk (e.g. HCV antibody-positive) donors. In this context, organs from HCV antibody-positive donors have been used in recipients with chronic HCV since the early 1990s. Recently, transplantation of HCV-viraemic organs into HCV-naïve recipients has garnered significant interest, owing to the development of safe and highly effective direct-acting antivirals and increased experience of treating HCV in the post-transplant setting. Preliminary studies based largely in the US have shown excellent outcomes in kidney, liver, heart, and lung transplantation. This practice has the potential to significantly increase transplantation rates and decrease waitlist mortality; however, intentionally transmitting an infectious disease to recipients has important practical and ethical implications. Further, the generalisability of the US experience to other countries is limited by significant differences in HCV-viraemic donor populations. This review summarises the current data on this practice, discusses barriers to implementation, and highlights areas that warrant further study.


Approach to renal tubular disorders.
The renal tubule plays an important role in fluid and electrolyte homeostasis. Renal tubular disorders may affect multiple ( e.g., Fanconi syndrome) or specific (e.g., nephrogenic diabetes insipidus, renal glucosuria) tubular functions. Most conditions are primary and monogenic but occasionally are secondary to other disorders (focal segmental glomerulosclerosis, cystinosis, Lowe syndrome). Tubular dysfunction should be considered in all children with failure to thrive, polyuria, refractory rickets, hypokalemia and metabolic acidosis. Careful clinical and laboratory evaluation is essential for appropriate diagnosis and specific management of these conditions.


Prevention of ventricular extrasystole by mexiletine in patients with normal QT intervals is associated with a reduction of transmural dispersion of repolarization.
Antiarrhythmic potential of mexiletine in patients with congenital and acquired long-QT syndrome (LQTS) has been attributed to a reduction of transmural dispersion of repolarization (TDR). A similar mechanism could be involved in the antiarrhythmic activity of the drug in patients with normal QT intervals, but the issue remains to be investigated. We analyzed 24-h Holter ECG recordings from 17 patients in sinus rhythm showing premature ventricular complexes (PVCs) with normal QT intervals (age, 62+/-10 years, mean+/-S.D.). Treatment of the patients with oral mexiletine (300 mg/day for 21-40 days) resulted in a significant reduction of PVCs (from 13899+/-18887 to 6949+/-12822 beats/24 h, p<0.01). Rate-dependent behavior of ventricular repolarization was analyzed by plotting QT intervals (QT(peak), QT(end)), and the interval from T-wave peak to T-wave end (TPE) against preceding respective RR intervals of sinus beats. Both the QT(peak) and QT(end) tended to be shortened by mexiletine at RR intervals from 600 ms to 1000 ms, although the changes did not reach statistical significances. TPE, which reflects TDR, was shortened significantly at relatively long RR intervals (by 14+/-9% at RR of 900 ms, p<0.05). There was a linear relationship between the percentage shortening of TPE and the percentage reduction of PVCs (r=0.86, p<0.04). TPE> or =70 ms was significantly associated with PVC suppression >75% with an odds ratio of 0.60 (95% confidence interval 0.36-0.98, per 1 ms increment). Inhibitory effect of mexiletine against PVCs in patients with normal QT intervals is mediated at least in part by a reduction of TDR. Mexiletine may be effective in patients exhibiting longer baseline TPE.


Different types of small granule-containing cells and neurons in the guinea-pig adrenal medulla.
An electron microscopic, histo- and biochemical study was carried out on the adrenal medulla of newborn and adult guinea-pigs giving special emphasis to small granule-containing (SGC) cells. Adrenaline (A) was the predominating catecholamine (CA) both in newborn (70-90% of total CA) and adult (85-90%) guinea-pig adrenals. In analogy to the biochemical findings electron microscopy revealed a high predominance of A cells, which contained large granular vesicles with an average diameter of 180 nm. Most noradrenaline (NA) storing cells showed granular vesicles of a considerably smaller average diameter (80 nm) and had a higher nuclear-cytoplasmic ratio. These cells were termed SGC-NA cells. NA cells with large granular vesicles (average diameter 170 nm) were extremely rare. Another type of SGC cells contained granular vesicles with cores of low to medium electron-density (SGC-NA-negative cells). Biochemical determinations made it unlikely that these cells contained predominantly dopamine (DA). SGC cells were scarcely innervated by cholinergic nerves. They formed processes, which were found both in the adrenal cortex and medulla contacting blood vessels including sinusoid capillaries, steroid producing cells of the reticularis and fasciculata zone and processes, which were interpreted to belong to medullary nerve cells. Two types of neurons were present in the guinea-pig adrenal medulla, one resembling the principal neurons in sympathetic ganglia, the other, which, principal neurons and SGC cells. In adrenomedullary grafts under the kidney capsule, which were studied three weeks after transplantation, "ordinary" A cells resembled SGC-NA negative cells with respect to their ultramorphology. Processes of transplanted principal neurons showed uptake of 5-hydroxydopamine and, hence, were considered to be adrenergic. Despite the lack of extrinsic nerves to the transplants, few principal neurons received cholinergic synapses, the origin of which is uncertain to date.


Preventing aneuploidy: the contribution of mitotic checkpoint proteins.
Aneuploidy, an abnormal number of chromosomes, is a trait shared by most solid tumors. Chromosomal instability (CIN) manifested as aneuploidy might promote tumorigenesis and cause increased resistance to anti-cancer therapies. The mitotic checkpoint or spindle assembly checkpoint is a major signaling pathway involved in the prevention of CIN. We review current knowledge on the contribution of misregulation of mitotic checkpoint proteins to tumor formation and will address to what extent this contribution is due to chromosome segregation errors directly. We propose that both checkpoint and non-checkpoint functions of these proteins contribute to the wide array of oncogenic phenotypes seen upon their misregulation.


Proton magnetic resonance spectroscopy in frontotemporal dementia.
This study of frontotemporal dementia (FTD) was carried out to determine whether MR spectroscopy can provide an in vivo marker for the neuronal loss and gliosis that occur in this condition. We compared spectra in frontal and temporal regions known to be affected early in the course of the disease with spectra in the parietal lobe that is spared until late stages of FTD. We were interested in the relative concentrations of two compounds, NAA (a marker of neuronal integrity) and mI (a marker of gliosis), expressed as ratios to creatine (a relatively stable brain constituent). MR spectroscopy was performed on the temporal, parietal, and anterior cingulate cortices of five patients with the established semantic dementia form of FTD, two patients with the frontal form of FTD and 13 age matched controls. Structural MRI and neuropsychometry were also performed. Patients with FTD had reduced NAA/Cr in frontal and temporal, but not parietal lobes. The two patients with the frontal form of FTD had increased mI/Cr in their cingulate cortices. These data show for the first time that MR spectroscopy can reveal regionally selective abnormalities in patients with FTD. This opens up the possibility of using MR spectroscopy as a clinical tool to identify earlier presentations of the condition.


Thyroid autoimmunity and polyglandular endocrine syndromes.
Even though autoimmune thyroiditis is considered as the most emblematic type of organ-specific autoimmune disorder of autoimmunity, autoimmune thyroid diseases can be associated with other autoimmune endocrine failures or non-endocrine diseases (namely vitiligo, pernicious anemia, myasthenia gravis, autoimmune gastritis, celiac disease, hepatitis). Thyroid disorders, which are the most frequent expression of adult polyendocrine syndrome type 2, occur concomitantly with or secondarily to insulinodependent diabetes, premature ovarian failure, Addison's disease (Schmidt syndrome, or Carpenter syndrome if associated with diabetes). Testicular failure and hypoparathyroidism are unusual. The disease is polygenic and multifactorial. Disorders of thyroid autoimmunity are, surprisingly, very rare in polyendocrine syndrome type 1 (or APECED) beginning during childhood. They are related to mutations of the AIRE gene that encodes for a transcriptional factor implicated in central and peripheral immune tolerance. Hypothyroidism can also be observed in the very rare IPEX and POEMS syndromes.


Disruption of Src Is Associated with Phenotypes Related to Williams-Beuren Syndrome and Altered Cellular Localization of TFII-I
Src is a nonreceptor protein tyrosine kinase that is expressed widely throughout the central nervous system and is involved in diverse biological functions. Mice homozygous for a spontaneous mutation in Src (Src (thl/thl) ) exhibited hypersociability and hyperactivity along with impairments in visuospatial, amygdala-dependent, and motor learning as well as an increased startle response to loud tones. The phenotype of Src (thl/thl) mice showed significant overlap with Williams-Beuren syndrome (WBS), a disorder caused by the deletion of several genes, including General Transcription Factor 2-I (GTF2I). Src phosphorylation regulates the movement of GTF2I protein (TFII-I) between the nucleus, where it is a transcriptional activator, and the cytoplasm, where it regulates trafficking of transient receptor potential cation channel, subfamily C, member 3 (TRPC3) subunits to the plasma membrane. Here, we demonstrate altered cellular localization of both TFII-I and TRPC3 in the Src mutants, suggesting that disruption of Src can phenocopy behavioral phenotypes observed in WBS through its regulation of TFII-I.


Thermodynamic modeling of contact angles on rough, heterogeneous surfaces.
Theoretical modelling for contact angle hysteresis carried out to date has been mostly limited to several idealized surface configurations, either rough or heterogeneous surfaces. This paper presents a preliminary study on the thermodynamics of contact angles on rough and heterogeneous surfaces by employing the principle of minimum free energy and the concept of liquid front. Based on a two-dimensional regular model surface, a set of relations were obtained, which correlate advancing, receding and system equilibrium contact angles to surface topography, roughness and heterogeneity. It was found that system equilibrium contact angles (theta(ES)) can be expressed as a function of surface roughness factor (delta) and the Cassie contact angle (theta(C)): costheta(ES) = deltacostheta(C). This expression can be reduced to the classical Wenzel equation.: theta(ES) = theta(W) for rough but homogeneous surfaces, and the classical Cassie equation theta(ES) = theta(C) for heterogeneous but smooth surfaces. A non-dimensional parameter called surface feature factor (omega) was proposed to classify surfaces into three categories (types): roughness-dominated, heterogeneity-dominated and mixed-rough-heterogeneous. The prediction of advancing and receding contact angles of a surface is dependent on which category the surface belongs to. The thermodynamic analysis of contact angle hysteresis was further extended from the regular model surface to irregular surfaces; consistent results were obtained. The current model not only agrees well with the models previously studied by other researchers for idealized surfaces, but also explores more possibilities to explain the reported experimental results/observations that most existing theories could not explain.


Irreversible inhibition of hexosaminidase C by medium-chain monocarboxylic acids and Triton X-100.
The neutral beta-N-acetylhexosaminidase (hexosaminidase C) from human brain was partially purified (separated from lysosomal beta-N-acetylhexosaminidases by chromatography on a Con A-Sepharose column). Hexosaminidase C was inhibited by medium-chain fatty acids (monocarboxylic acids with chain-length between C6 and C9), whereas shorter-chain monocarboxylic acids showed no inhibitory effect. Studies on the inhibition mechanism showed an irreversible and pH-dependent inhibition which progresses with time and which is not reversed by the removal of fatty acids (by Bio-Beads SM-2). Similar inhibitory effects were also obtained using Triton X-100 (but not with homologous alkylamines). These results suggest that the hexosaminidase C inactivation is related to the hydrophobic properties of the inhibitor which acts as a denaturing agent mainly at acidic pH. The possibility has been discussed that this inactivation effect of monocarboxylic acid on hexosaminidase C could constitute a molecular model of the toxicity of medium-chain-length fatty acids.


Expert agreement in prior elicitation and its effects on Bayesian inference.
Bayesian inference requires the specification of prior distributions that quantify the pre-data uncertainty about parameter values. One way to specify prior distributions is through prior elicitation, an interview method guiding field experts through the process of expressing their knowledge in the form of a probability distribution. However, prior distributions elicited from experts can be subject to idiosyncrasies of experts and elicitation procedures, raising the spectre of subjectivity and prejudice. Here, we investigate the effect of interpersonal variation in elicited prior distributions on the Bayes factor hypothesis test. We elicited prior distributions from six academic experts with a background in different fields of psychology and applied the elicited prior distributions as well as commonly used default priors in a re-analysis of 1710 studies in psychology. The degree to which the Bayes factors vary as a function of the different prior distributions is quantified by three measures of concordance of evidence: We assess whether the prior distributions change the Bayes factor direction, whether they cause a switch in the category of evidence strength, and how much influence they have on the value of the Bayes factor. Our results show that although the Bayes factor is sensitive to changes in the prior distribution, these changes do not necessarily affect the qualitative conclusions of a hypothesis test. We hope that these results help researchers gauge the influence of interpersonal variation in elicited prior distributions in future psychological studies. Additionally, our sensitivity analyses can be used as a template for Bayesian robustness analyses that involve prior elicitation from multiple experts.


Usability and safety of the new 5 French air-charged catheter for performing urodynamic studies on pediatric patients.
To assess the performance and safety of the T-DOC® 5 French air-charged urodynamic catheters in pediatric patients and obtain feedback from providers related to usability performance. Patients ages 12 years and younger undergoing urodynamics were prospectively recruited from two institutions. The T-DOC® 5 French air-charged catheters were used. Issues with catheter placement, adverse events (AEs), and pain scores were assessed. A follow-up telephone call was made to assess for post-urodynamic AEs. Providers completed a clinical user questionnaire. Likert scale was used (1 = most negative and 5 = most positive response) and reported in mean (range). A total of 28 patients completed the study. The mean age was 55 months (5-130) (10 females, 18 males). One problem was noted with the insertion of an abdominal catheter, secondary to stool impaction. Catheters stayed in place on all subjects, except for one related to patient hyperactivity. There were no AEs during the studies. In total four reported post-urodynamics AEs (one hematochezia, three dysuria). Among nine patients, pain level on the bladder and abdominal insertion was 3.6/10 (0-10) and 3.1/10 (0-10). Five providers completed the questionnaire. The overall ease of use was rated 4.3/5 (3-5). The ease of insertion was 4.1/5 (2-5) and set-up/clean-up time was 4.4/5 (3-5). Tracing stability, subtraction accuracy, and artifact sensitivity were all perceived favorably (respectively 4.8/5 [4-5], 4.6/5 [4-5], and 4.4/5 [4-5]). The T-DOC® 5 French air-charged catheter was considered safe and effective in pediatric patients. No AEs occurred during the studies. Providers, using the catheters, reported favorably on catheter usage.


Making lemonade from SARS coronavirus-2 lemons: Transitioning a smoking cessation trial to a virtual platform.
Clinical trials represent an essential component of improving treatment for substance use disorders (SUD). The SARS coronavirus-2 pandemic disrupted our ongoing clinical trial of smoking cessation and forced us to rapidly implement changes to assure participants access to ongoing counseling and monitoring via telephone calls and/or video chat sessions. Our experiences suggest that this pandemic will lead to changes for both future clinical trial participants and project staff. While challenges remain, it will be important to assessing the impact of these changes with regard to participant experiences and treatment outcomes.


Paraneoplastic pemphigus presenting as erythrodermic lichenoid dermatitis with concomitant features of pemphigus foliaceus.
We describe a patient with paraneoplastic pemphigus who presented with erythrodermic lichenoid dermatitis, later developing blisters of pemphigus foliaceus type and oral erosive lesions. In addition to antibodies against the plakin family proteins, the patient's serum was positive for anti-desmoglein 1 antibodies without coexisting anti-desmoglein 3 activities by enzyme-linked immunosorbent assay, which is a very rare autoantibody profile in paraneoplastic pemphigus.


Morphological alterations of retinal cells accompanying inhibition of axonal transport by kainic acid.
The effect of kainic acid (KA) on rat retinal morphology was investigated with emphasis on the ganglion cell layer. Two hours after intraocular injection of KA, 70% of the neurones in the ganglion cell layer display morphological alterations. These alterations at the ultrastructural level include the absence of identifiable Golgi complexes and the presence of abundant round empty vacuoles among other nuclear and cytoplasmic modifications. These alterations of the Golgi complex are discussed in relation to axoplasmic transport inhibition by kainic acid. Seven days after KA treatment the retina showed a decreased number of cells in the inner nuclear layer and ganglion cell layer and the inner plexiform layer had virtually disappeared. Despite the disappearance of cells from the ganglion cell layer a week after KA injection, abundant ganglion cells could be retrogradely labelled with horseradish peroxidase. Thus although retinal ganglion cells seem to be sensitive to KA most of them survive KA treatment.


A direct projection from the perirhinal cortex (area 35) to the subiculum in the rat.
An efferent projection from the perirhinal cortex (area 35) in the rat was studied using the anterograde transport of tritiated amino acids as well as horseradish peroxidase (HRP). Following injections of either tracer in either the dorsal or ventral parts of area 35, anterogradely transported label was observed in the molecular layer of the subiculum, adjacent prosubiculum and CAla. Regardless of the dorsoventral level of the injection, the label was most dense at mid-dorsoventral levels of the subiculum and decreased in density in both the septal and temporal directions. Small injections of the same tracers made into the surrounding entorhinal, ectorhinal or prepiriform cortices did not reproduce this pattern. While the entorhinal cortex is the main cortical source of afferent input to the molecular layer of the subiculum as well as the hippocampus and dentate gyrus, the perirhinal cortex appears to constitute a complementary cortical pathway for afferent input to the subiculum.


c-erbB-2 oncoprotein, CEA, and CA 15.3 in patients with breast cancer: prognostic value.
The diagnostic value of a new tumor marker, c-erbB-2, was studied in the sera of 50 healthy subjects, 58 patients with benign breast diseases, and 413 patients with breast cancer (186 locoregional, 185 with advanced disease, and 42 with no evidence of disease). Using 15 U/ml as the cut-off, no healthy subjects or patients with benign diseases and only 2.4% of no evidence of disease patients had elevated serum levels. Abnormal c-erbB-2 levels were found in 29% (101/370) of the patients with breast carcinoma (locoregional 9%, metastases 45.4%). CEA (cut-off 5 U/ml) and CA 15.3 (cut-off 35 U/ml) sensitivity was 18% and 16% in patients with locoregional disease and 61% and 70% in those patients with advanced disease, respectively. A trend toward higher serum levels of all three tumor markers in patients with nodal involvement or greater tumor size was found, but was statistically significant only with CEA (p < 0.01). By contrast, c-erbB-2 was related to steroid receptors, in both locoregional and metastatic tumors. When the prognostic value of these markers was evaluated, patients with abnormally high presurgical CEA and c-erbB-2 had a worse prognosis than those patients with normal values, in both node-negative (p < 0.05 and p < 0.001, respectively) and node-positive patients (p < 0.556 and p < 0.001, respectively). By contrast, no relationship was found between CA 15.3 values and prognosis. Multivariate analysis showed that CEA and c-erbB-2 were also prognostic factors. The correlation between serum and tissue levels of c-erbB-2 was studied in the tumors of 161 patients. Significantly higher c-erbB-2 serum levels were found in patients with overexpression in tissue by immunohistochemistry, in both locoregional and advanced disease (p = 0.0001). Serum concentrations in patients with advanced disease were related to the site of recurrence, with significantly higher values in patients with metastases (mainly in those with liver metastases) than in those with locoregional recurrence. In summary, c-erbB-2 serum levels seem to be a useful tumor marker in the prognosis of patients with breast cancer. Using all three tumor markers, sensitivity was 35% in patients with locoregional breast cancer and 88% in patients with recurrence.


Development of a robust mapping between AIS 2+ and ICD-9 injury codes.
Motor vehicle crashes result in millions of injuries and thousands of deaths each year in the United States. While most crash research datasets use Abbreviated Injury Scale (AIS) codes to identify injuries, most hospital datasets use the International Classification of Diseases, version 9 (ICD-9) codes. The objective of this research was to establish a one-to-one mapping between AIS and ICD-9 codes for use with motor vehicle crash injury research. This paper presents results from investigating different mapping approaches using the most common AIS 2+ injuries from the National Automotive Sampling System-Crashworthiness Data System (NASS-CDS). The mapping approaches were generated from the National Trauma Data Bank (NTDB) (428,637 code pairs), ICDMAP (2500 code pairs), and the Crash Injury Research and Engineering Network (CIREN) (4125 code pairs). Each approach may pair given AIS code with more than one ICD-9 code (mean number of pairs per AIS code: NTDB=211, ICDMAP=7, CIREN=5), and some of the potential pairs are unrelated. The mappings were evaluated using two comparative metrics coupled with qualitative inspection by an expert physician. Based on the number of false mappings and correct pairs, the best mapping was derived from CIREN. AIS and ICD-9 codes in CIREN are both manually coded, leading to more proper mappings between the two. Using the mapping presented herein, data from crash and hospital datasets can be used together to better understand and prevent motor vehicle crash injuries in the future.


Study of allosteric communication between protomers by immunotagging.
Ligand-induced allosteric changes in proteins are important in their cellular functions and regulation, and both concerted and sequential examples are known. The distinction has entailed elaborate analysis, however, and only a few systems have been unequivocally analysed. We have investigated the coupling between ATP usage and DNA transport by type II DNA topoisomerases, and one key question concerning allostery in these dyadic enzymes is whether ATP binding to one protomer can induce a concerted conformational change in the entire enzyme. Here we use an enzyme with one immunotagged subunit defective in ATP binding and one wild-type subunit to show that it can. Our approach should be generally applicable in the study of allostery and communication between members of a macromolecular assembly.


Management of agricultural biomass wastes: preliminary study on characterization and valorisation in clay matrix bricks.
In this work the feasibility of using woody agricultural biomass wastes as grapes and cherries seeds, sawdust, as pore forming agent, and sugar cane ash, as silica precursor, in bricks, were reported. Sawdust and grapes and cherries seeds, thanks to their organic substances content, during their combustion, bring an energetic support in the bricks firing phase and act as pore forming agent. Usually the addition of this kind of waste is limited to 10wt.% in order to reach an equilibrium between positive (weight and shrinkage decrease and porosity increase) and negative (increase of water absorption and mechanical resistance decrease) effects. The results show that grapes and cherries seeds, added in a percentage of 5wt.% to a brick formulation, have better influence with respect to the sawdust, maintaining the mechanical properties of the fired brick (950°C), showing modulus of rupture around 21-23MPa with a weight reduction of 3-10% (respect to the standard one). Regarding the sugar cane ash, the addition of 5wt.% improves the mechanical properties (modulus of rupture around 27MPa) and no weight decrease is observed. These results confirmed the role played by this kind of agricultural waste, which thanks to its high silica content (61wt.%) is capable to demonstrate a filler and plasticity reducing effect on the brick bodies. Tests carried out highlighted that the addition of these by-products (5wt.%) do not change negatively the main technological properties measured (water absorption, linear shrinkage, flexural resistance, etc.) and permit to hypothesize their use to obtain bricks with both insulating and higher mechanical properties using a pore agent forming or silica carrier alternative raw materials, respectively.


A multilevel examination of the association between COVID-19 restrictions and residence-to-crime distance.
Restrictions resulting from the COVID-19 pandemic interrupted people's daily routine activities. Rooted in crime pattern and routine activity theories, this study tests whether the enactment of a Safer-at-Home mandate was associated with changes in the distance between individuals' home addresses and the locations of where they committed crimes (i.e., residence-to-crime distance). Analyses are based on violent (N = 282), property (N = 1552), and disorder crimes (N = 1092) reported to one police department located in a United States' Midwest suburb. Multilevel models show that residence-to-crime distances were significantly shorter during the Safer-at-Home order, compared to the pre- and post-Safer-at-Home timeframes, while controlling for individual and neighborhood characteristics. Additionally, these relationships varied by crime type. Consistent with the literature, the findings support the argument that individuals tend to offend relatively near their home address. The current findings extend the state of the literature by highlighting how disruptions to daily routine activities stemming from the COVID-19 pandemic led to alterations in crime patterns, in which analyses indicated shorter distances between home address and offense locations. The online version contains supplementary material available at 10.1186/s40163-022-00172-1.


Atypical hemispheric language dominance in left temporal lobe epilepsy as a result of the reorganization of language functions.
Hemispheric language dominance, as determined by intracarotid short-acting barbiturate injections (Wada testing), was retrospectively evaluated in 44 right-handed patients with medically intractable left (n=26) or right (n=18) temporal lobe epilepsy (TLE). Atypical hemispheric language dominance (right or bilateral) was revealed in 13.6% of all patients investigated. A significantly higher rate of deviance from complete left hemisphere dominance was observed in left TLE (23.1%) than in right TLE (0%). Patient age at the time of seizure onset was proven a critical variable affecting atypical speech development in left TLE. The mean patient age at the time of seizure onset in left TLE patients with atypical language representation was 5.61 years, but was 13.13 years in patients with left hemisphere language dominance. Our results strongly support the influential impact of epileptiform activity spreading from the left temporal lobe structures on the reorganization of language functions in patients with early brain injury.


Treatment of anterior open bite by posterior maxillary segmental osteotomy and miniplates: a case report.
Anterior open bite is a challenging malocclusion to correct orthodontic treatment. Anterior open bite associated with over-erupted posterior teeth and long lower facial height should be treated by reduction of posterior dimension for esthetic results. Although the possibility of orthodontic treatment of an anterior open bite has increased with the introduction of skeletal anchorage, there are still cases requiring surgery for various reasons. This case report covers an anterior open bite of a 25-year-old man successfully treated with the posterior maxillary segmental osteotomy (PMSO) and miniplates. After the pre-surgical orthodontic treatment, the PMSO between canines and first premolars was performed under local anesthesia and miniplates were placed on the zygomatic buttress. As a result of 28 months of treatment, an impaction amount of 3.5 mm was obtained in the maxillary posterior teeth, and the facial esthetics improved at rest and smile. The impaction of the posterior dentoalveolar segment using the PMSO can be a good treatment option in patients with anterior open bite showing long lower facial height.


Epithelia under metabolic stress perceive commensal bacteria as a threat.
The normal gut flora has been implicated in the pathophysiology of inflammatory bowel disease and there is increased interest in the role that stress can play in gut disease. The chemical stressor dinitrophenol (DNP, uncouples oxidative phosphorylation) was injected into the ileum of laparotomized rats and mitochondria structure, epithelial permeability, and inflammatory cell infiltrate were examined 6 and 24 hours later. Monolayers of human colonic epithelial cells (T84, HT-29) were treated with DNP +/- commensal Escherichia coli, followed by assessment of epithelial permeability, bacterial translocation, and chemokine (ie, interleukin-8) synthesis. Delivery of DNP into rat distal ileum resulted in disruption of epithelial mitochondria; similar changes were noted in mildly inflamed ileal resections from patients with Crohn's disease. Also, DNP-treated ileum displayed increased gut permeability and immune cell recruitment. Subsequent studies revealed deceased barrier function, increased bacterial translocation, increased production of interleukin-8, and enhanced mobilization of the transcription factor AP-1 in the model epithelial cell lines exposed to commensal bacteria (E. coli strains HB101 or C25), but only when the monolayers were pretreated with DNP (0.1 mmol/L). These data suggest that enteric epithelia under metabolic stress perceive a normally innocuous bacterium as threatening, resulting in loss of barrier function, increased penetration of bacteria into the mucosa, and increased chemokine synthesis. Such responses could precipitate an inflammatory episode and contribute to existing enteric inflammatory disorders.


13-cis-retinoic acid and interferon-alpha 2a therapy in locally advanced squamous cell carcinoma of the cervix: p53 alteration, proliferating cell nuclear antigen expression and angiogenesis response.
To evaluate prognostic importance of p53, PCNA and vascularization alteration in patients with locally advanced cervical squamous cell carcinoma (SCC) after combination therapy with 13-cis-retinoic acid (13cRA) and interferon-alpha 2a (IFN-alpha 2a). 13cRA and IFN-alpha 2a were administered to patients with locally advanced cervical SCC. Formalin fixed, paraffin embedded tissues sections obtained at pre- and post-therapy, respectively, were stained immunohistochemically with anti-p53, anti-PCNA and anti CD31. p53 alteration was demonstrated in 5/10 patients and 3/10 patients pre- and post-therapy, respectively. There was no correlation between p53 alteration and prognosis. After therapy, two patients with complete response had lower PCNA expression whereas the non-responders demonstrated the opposite result. The vascularization showed a correlation with PCNA and prognosis. In the response group, patients had lower microvessel count while the metastatic group exhibited higher count. The present study suggests that p53 alteration is neither related to the prognosis of cervical SCC nor is it influenced by the combination therapy while PCNA expression and vascularization might be constitute potential markers for tumorigenesis, prognosis and responsiveness to this novel regimen.


Blended learning: Improving the diabetes mellitus counseling skills of German pharmacy students.
Pharmacists have the responsibility to conduct medication therapy management and appropriately counsel patients and physicians on medicines. Blended learning and objective structured clinical examinations (OSCEs) may have the potential to address these skills. This study aimed to assess whether a blended learning program consisting of e-learning and OSCEs could enhance pharmacy students' abilities to conduct pharmaceutical consultations with type 2 diabetes mellitus patients. The blended learning program consisted of e-learning, formative OSCEs, and summative OSCEs. The e-learning aimed to bring the students to the same level of diabetes knowledge. The students' baseline consultation skills were measured by a summative pre-training OSCE. After the formative OSCEs, a summative post-training OSCE quantified the change in performance. During the pre- and post-training OSCEs, analytical checklists were used to assess consultation skills and a global rating scale assessed communication skills. Surveys were used to measure students' self-assessment and satisfaction. The study demonstrated significant improvement in students' pharmaceutical knowledge of diabetes mellitus, consultation performances on diabetes mellitus, and self-assessment scores. Most students responded positively on the satisfaction survey. This study demonstrated that a blended learning approach with e-learning and OSCEs can improve students' diabetes consultations and communication skills. These results support the use of this instructional technique for teaching patient counseling. Further studies should consider a control group to assess whether the improvement of the consultation performance is a result of the training or solely a learning effect due to the repetition of summative OSCEs.


Chemotherapy in recurrent epithelial ovarian cancer (EOC): an analysis of prognostic factors.
Prognosis of patients with recurrent epithelial ovarian cancer (EOC) is generally poor. Cisplatin is the most effective drug. We used three cisplatin based chemotherapeutic (CT) regimens and retrospectively analyzed the data to determine the response rate, toxicity, survival and the impact of various prognostic factors on the outcome. Between August, 1989 and September, 1997, 102 patients were diagnosed to have recurrent EOC. Sixty-five of 102 patients received CT every 3 weeks using cisplatin 75 mg/m2 i.v. day 1 plus cyclophosphamide 750 mg/m2 i.v. day 1 (CP, Group A, n = 29), cisplatin 75 mg/m2 i.v. day 1, plus adriamycin 40 mg/m2 i.v. day 1 and cyclophosphamide (CAP, Group B, n = 22) and paclitaxel 135 mg/m2 i.v. day 1 plus cisplatin 75 mg/m2 i.v. day 1 (TP, Group C, n = 14). Twelve patients received single agent CT and were not analyzed. Remaining 25 patients refused CT treatment and were followed for survival. The overall response rate (complete and partial) was 59.2% for patients receiving CP (Group A), 45% for CAP (Group B) and 76.9% for those receiving TP (Group C), p = ns. Response rate was significantly higher for patients with platinum sensitive disease compared to those with platinum resistant disease; 55.76 vs 39%, p < 0.007. CT was generally tolerated well; 2 patients died of CT toxicity, one each in Group A (CP) and C (TP), respectively. The median survival from the date of relapse for patients receiving chemotherapy was 15 months compared to 4 months for those who did not receive chemotherapy, p < 0.001. Chemotherapy responders had a significantly higher median survival than chemotherapy non-responders, 24 months vs 10 months, p < 0.01. The median overall survival was not significantly different in the 3 groups; Group A--15 months, Group B--12 months and 15 months in Group C, p = 0.738. On univariate analysis--time since last CT (< 6 months vs > 6 months, p < 0.037, response to previous CT, p < 0.0183, cisplatinum sensitivity vs resistance, p < 0.032, number of sites (< 2 vs > 2) of recurrence, p < 0.004 and response to salvage CT, p < 0.01 were associated with survival benefit. On multivariate analysis, 2 factors--platinum sensitivity and response to salvage CT attained significance. Our study confirms the benefit of platinum based chemotherapy in recurrent EOC. Patients with platinum sensitive disease, and those responding to salvage chemotherapy benefit most.


A novel ladderlectin from hybrid crucian carp possesses antimicrobial activity and protects intestinal mucosal barrier against Aeromonas hydrophila infection.
Ladderlectin is a pattern recognition receptor (PRR) in fish that is critical for rapid detection of bacteria in vitro, but the immunological function of ladderlectin in vivo is essentially unknown. In this study, we examined the expression and function of a ladderlectin homologue (WR-ladderlectin) from hybrid crucian carp. WR-ladderlectin contains 157 amino acids and possesses the conserved C-type lectin domain. WR-ladderlectin is mainly expressed in the intestine and is upregulated by bacterial infection. Recombinant WR-ladderlectin (rWR-ladderlectin) agglutinated Aeromonas hydrophila and Escherichia coli. rWR-ladderlectin also bound the A. hydrophila and E. coli in a protein dose-dependent manner. As well as its ability to bind bacterial cells, rWR-ladderlectin displayed apparent bactericidal activity against A. hydrophila and E. coli in vitro. When introduced in vivo, rWR-ladderlectin induced significant expression of the antimicrobial molecules and tight junctions in the intestine. In addition, rWR-ladderlectin prevented significant decrease in the length of intestine villus and enhanced the host's resistance to bacterial infection. These results indicate that WR-ladderlectin is a classic pattern recognition molecule that protects intestinal mucosal barrier against bacterial infection.


Low-Dose CCT to Exclude Contraindications to Lumbar Puncture : Benefits and Limitations.
Low-dose cranial computed tomography (LD-CCT) based on iterative reconstruction has been shown to have sufficient image quality to assess cerebrospinal fluid spaces (CSF) and midline structures but not to exclude subtle parenchymal pathologies. Patients without focal neurological deficits often undergo CCT before lumbar puncture (LP) to exclude contraindications to LP including brain herniation or increased CSF pressure. We performed LD-CCT to assess if image quality is appropriate for this indication. A total of 58 LD-CCT (220 mA/120 kV) of patients before LP were retrospectively evaluated and compared to 79 normal standard dose cranial computed tomography (SD-CCT) (350 mA/120 kV). Iterative reconstruction used for both dose levels was increased by one factor for LD-CCT. We assessed the signal-to-noise (SNR) and contrast-to-noise ratio (CNR), the dose estimates and scored diagnostic image quality by two raters independently. Significance level was set at p < 0.05. The inner and outer CSF spaces except the sulci were equally well depicted by the LD-CCT and SD-CCT; however, depiction of the subtle density differences of the brain parenchyma and the sulci was significantly worse in the LD-CCT (p < 0.0001). The SNR in the gray matter (9.35 vs. 10.61, p < 0.05) and white matter (7.23 vs. 8.15, p < 0.001) were significantly lower in LD-CCT than in SD-CCT with significantly lower dose estimates (1.04 vs. 1.69 mSv, respectively p < 0.0001). The use of LD-CCT with a dose reduction of almost 50% is sufficient to exclude contraindications to LP; however, LD-CCT cannot exclude subtle parenchymal pathologies. Therefore, in patients with suspected parenchymal pathology, SD-CCT is still the method of choice.


One Piece Immediately Loaded Implants Versus 1 Piece or 2 Pieces Delayed: 3 Years Outcome.
To compare time-dependent outcome of immediately loaded 1-piece (1P) implants with delayed loaded 1P and 2-piece (2P) implants. A cohort of 33 patients divided into 3 groups: group A, 13 patients, 49 immediately placed and loaded 1P implants; group B, 11 patients, immediately placed and delayed loaded 1P implants; and group C, 10 patients, 39 2P implants delayed placed and loaded in a two-stage procedure. Marginal bone loss (MBL) was analyzed using x-ray radiography every 6 months, 1 year, and 3 years. A statistically significant mean MBL was observed between baseline, 6 months, 1 year, and 3 years in all groups. There was no statistical significant difference in MBL between immediate and delayed loaded 1P implants. MBL around mandibular implants was lower compared with maxillary implants. 2P implants showed less MBL compared with 1P implants in both maxilla and mandible. There was no statistical difference in MBL between immediate and delayed loaded 1P implants. Immediate loaded implants show more MBL in maxilla.


Synthesis of simplified tedanolide analogues--connecting tedanolide to myriaporone and gephyronic acid.
Southern belles! Simplified analogues of tedanolide, a natural product with picomolar activity against a range of tumor cell lines, were synthesized and evaluated for potency in mammalian cancer cells. The truncated analogues were found to retain significant activity in vitro (23 μmol mL(-1) for the example shown) compared with the parent compound tedanolide (0.33 nmol mL(-1)), and represent potential leads for the development of novel anticancer agents.


Health needs of migrant female head porters in Ghana: evidence from the Greater Accra and Greater Kumasi Metropolitan areas.
In low-and middle-income countries, migrants are confronted with health needs which affect the promotion of their well-being and healthy lives. However, not much is known about the health needs of migrant female head porters (Kayayei) in Ghana. This study assesses the health needs of migrant female head porters in the Greater Kumasi Metropolitan Area (GKMA) and Greater Accra Metropolitan Area (GAMA). The study adopted a convergent mixed methods design where both qualitative and quantitative data were used. A representative sample size of 470 migrant female head porters was used for the study. The study revealed that ante-natal care, post-natal care, treatment of malaria, treatment of diarrhoea diseases, mental health, sexual health, and cervical cancer were health needs of migrant female head porters. The findings showed that participants from the GAMA significantly have greater cervical cancer needs (71.6% vrs 67.1%, p = 0.001) compared to those from the GKMA. Kayeyei from the GKMA significantly have greater mental health needs than those from the GAMA (84.6% vrs 79.2%, p = 0.031). Also, Kayeyei from the GKMA significantly have higher attendance of post-natal care compared to those from the GAMA (99.4% vrs 96.2%, p = 0.013). The findings underscore differential health needs across geographical localities. Based on the findings of the study, specific health needs such as ante-natal care and post-natal care should be included in any health programmes and policies that aim at addressing health needs of migrant female head porters in the two metropolitan areas of Ghana.


Search of the 5' untranslated region of the human cardiac actin gene for segments controlling translation.
We have examined the possibility that the 5'-UT region of the human cardiac actin (CH-actin) mRNA is responsible for regulating translation of this transcript during skeletal myogenesis. Genes were constructed which consisted of the murine leukaemia virus promoter driving the Escherichia coli LacZ coding region with and without the CH-actin 5'-UT region. These constructs were transfected into L6 myoblasts that were subsequently differentiated into myotubes. The presence of the CH-actin 5'-UT region appeared to have no effect on expression of the LacZ reporter gene. EGTA blocks myogenesis and inhibits translation of muscle-specific transcripts (Endo, T. and Nadal-Ginard, B. (1987) Cell 49, 515-526) but EGTA had no effect on expression of the chimaeric LacZ transcripts. Thus, if the CH-actin transcript is subject to translational regulation, it must be mediated by sequences other than those of the 5'-UT region.


What are the influencing factors on the outcome in lateral incisional hernia repair? A registry-based multivariable analysis.
Incisional hernias following lateral abdominal wall incisions with an incidence of 1-4% are less common than following medial incisions at 14-19%. The proportion of lateral incisional hernias in the total collective of all incisional hernias is around 17%. Compared to midline defects, lateral incisional hernias are more difficult to repair because of the more complex anatomy and localization. A recent systematic review identified only 11 publications with a total of 345 patients reporting on lateral incisional hernia repair. Therefore, further studies are urgently needed. Multivariable analysis of the data available for 6,306 patients with primary elective lateral incisional hernia repair was performed to assess the confirmatory pre-defined potential influence factors and their association with the perioperative and one-year follow-up outcomes. In primary elective lateral incisional hernia repair, open onlay, open IPOM and suture procedures were found to have an unfavorable effect on the recurrence rate. This was also true for larger defect sizes and higher BMI. A particularly unfavorable relationship was identified between larger defect sizes and perioperative complications. Laparoscopic-IPOM presented a higher risk of intraoperative, and open sublay of postoperative, complications. The chronic pain rates were especially unfavorably influenced by the postoperative complications, preoperative pain and female gender. Open-onlay, open IPOM and suture procedures, larger defect sizes, female gender, higher BMI, preoperative pain and postoperative complications are associated with unfavorable outcomes following primary elective lateral incisional hernia repair.


Recombinant activated factor VII for treatment of refractory hemorrhage after surgery for acute aortic dissection.
Despite appropriate treatment, surgery for aortic dissection is frequently associated with bleeding problems. In these series we report on the employment of recombinant activated factor VII (rFVIIa) for refractory hemorrhage after emergency surgery for acute type A aortic dissection, used to face the problems of postoperative blood loss and transfusion requirements. Despite the good results of the therapy, a patient presented with thrombosis of the left cavernous sinus. Although a risk of thromboembolic complications has to be considered, rFVIIa is a reasonable rescue option in life-threatening hemorrhage and enlarges our hemostatic armamentarium in surgery for acute aortic dissection.


An examination of associations between the inability to taste phenylthiocarbamide (PTC) and clinical characteristics and trait markers in first-episode, nonaffective psychotic disorders.
Research findings are mixed as to whether or not the inability to taste phenylthiocarbamide (PTC) might represent an endophenotypic trait marker for schizophrenia. We hypothesized associations between PTC-tasting status and select clinical characteristics and trait markers in patients with psychotic disorders that, if present, would provide support for the inability to taste PTC as a trait marker. In a first-episode psychosis sample (n=93), we measured PTC tasting, family history of psychosis, age at onset of prodrome and psychosis, severity of positive and negative symptoms, global impairment in functioning, neurological soft signs, and four neurocognitive domains (verbal learning/memory, visual learning/memory, verbal working memory, and spatial working memory). Associations between PTC-non-tasting and clinical/neurocognitive variables were examined with χ(2) tests and independent samples t tests. Among participants, 67.7% tasted PTC in comparison to a strip of control paper, and 25.8% were non-tasters. Tasters and non-tasters did not show statistically significant differences with respect to family history, age at onset, severity of symptoms, neurological soft signs, or the four neurocognitive domains. In conjunction with other findings, it is unlikely that PTC-non-tasting is a trait marker of schizophrenia, though a conclusive study is warranted.


Differences between the pre-menopausal and post-menopausal uterine fibroid vasculature.
To quantitatively examine differences in microvascular density between fibroid and myometrial tissue from fibroid uteri removed at hysterectomy, both before and after the menopause, and with hormone replacement therapy. Factor VIII immunostaining of formalin fixed tissues was used to identify blood vessels, and the vessels counted by an investigator blinded to tissue type or menopausal status. The mean myometrial: fibroid MVD ratio was 2.38 higher in the post-menopausal group (95% CI: 0.12, 4.65, p=0.0474) than in the pre-menopausal group, with the hormone therapy (HT)-using post-menopausal group lying in between. An increase in microvascular density in the myometrium after the menopause was responsible for most of the change in ratios seen between the pre and post-menopausal pairs. There was a trend to increasing myometrial MVD with increasing number of years post-menopause. Myometrial microvascular density increases markedly after the menopause, while fibroid microvascular density does not alter. Thus, the difference between myometrial and fibroid vasculature becomes greater after the menopause. The implications of this for the treatment of fibroids in post-menopausal women is discussed.


Investigating high throughput phenotyping based morpho-physiological and biochemical adaptations of indian pennywort (Centella asiatica L. urban) in response to different irrigation regimes.
Indian pennywort (Centella asiatica L. Urban; Apiaceae) is a herbaceous plant used as traditional medicine in several regions worldwide. An adequate supply of fresh water in accordance with crop requirements is an important tool for maintaining the productivity and quality of medicinal plants. The objective of this study was to find a suitable irrigation schedule for improving the morphological and physiological characteristics, and crop productivity of Indian pennywort using high-throughput phenotyping. Four treatments were considered based on irrigation schedules (100, 75, 50, and 25% of field capacity denoted by I100 [control], I75, I50, and I25, respectively). The number of leaves, plant perimeter, plant volume, and shoot dry weight were sustained in I75 irrigated plants, whereas adverse effects on plant growth parameters were observed when plants were subjected to I25 irrigation for 21 days. Leaf temperature (Tleaf) was also retained in I75 irrigated plants, when compared with control. An increase of 2.0 °C temperature was detected in the Tleaf of plants under I25 irrigation treatment when compared with control. The increase in Tleaf was attributed to a decreased transpiration rate (R2 = 0.93), leading to an elevated crop water stress index. Green reflectance and leaf greenness remained unchanged in plants under I75 irrigation, while significantly decreased under I50 and I25 irrigation. These decreases were attributed to declined leaf osmotic potential, increased non-photochemical quenching, and inhibition of net photosynthetic rate (Pn). The asiatic acid and total centellosides in the leaf tissues, and centellosides yield of plants under I75 irrigation were retained when compared with control, while these parameters were regulated to maximal when exposed to I50 irrigation. Based on the results, I75 irrigation treatment was identified as the optimum irrigation schedule for Indian pennywort in terms of sustained biomass and a stable total centellosides. However, further validation in the field trials at multiple locations and involving different crop rotations is recommended to confirm these findings.


Fighting killer worms.
Parasitic worms known as schistosomes are a major cause of disability and death in many parts of the world, especially sub-Saharan Africa. Although a treatment exists, reinfection is the rule. A vaccine would make a world of difference, but none has yet proved effective. Genetic and other tools hold promise for generating new candidates.


A highly stable 3D acentric zinc metal-organic framework based on two symmetrical flexible ligands: high second-harmonic-generation efficiency and tunable photoluminescence.
A 3D metal-organic framework (MOF), [Zn(BPHY)(SA)]n (1; BPHY = 1,2-bis(4-pyridyl)hydrazine, H2SA = succinic acid), which crystallizes in a noncentrosysmmetric space group (Cc), has been solvothermally obtained and testified to be a good nonlinear-optical material with the largest second-harmonic-generation response among the known MOFs based on sysmmetric ligands and high stability. Ultraviolet-to-visible tunable emission for 1 is observed.


Transferrin-binding proteins isolated from Neisseria meningitidis elicit protective and bactericidal antibodies in laboratory animals.
Transferrin-binding proteins (Tbps) were affinity-isolated from group B Neisseria meningitidis strain B16B6 and used to raise specific antisera. Administration of the antisera to mice loaded with human transferrin before bacterial challenge significantly protected the animals from death. In active immunization studies, mice received three 25 micrograms injections of purified Tbps over a period of 28 days, 7 days after which they were challenged with N. meningitidis. The survival rate in immunized mice was much higher than in control groups. In both active and passive immunization experiments mice were protected against at least 100 LD50. A specific Tbp antiserum was highly bactericidal against the parent strain and against approximately half of the strains tested.


Role of arteries in oxygen induced vaso-obliteration.
In mice the retinal vasculature develops in the first postnatal week by spreading from the optic nerve head towards the retinal periphery. During this growth period, exposure to hyperoxia causes vaso-obliteration of capillaries in the retinal center but not in peripheral regions. High oxygen levels lead to downregulation of vascular endothelial growth factor (VEGF), an important survival factor for vascular endothelial cells, which could explain the vaso-obliteration caused by hyperoxia. However, it is not clear why only capillaries in the center of the retina are affected. We therefore investigated how capillary obliteration correlates with VEGF mRNA distribution by in situ hybridization in retinal whole mount preparations. In mouse pups reared under normoxic conditions VEGF mRNA was detectable across the entire vascular network but was virtually absent in the immediate vicinity of arteries. This was true along developing retinal arteries but also around the optic nerve head through which the entire arterial blood supply for the retinal and hyaloid vasculature passes. In these areas capillaries were absent, resulting in so-called capillary free zones. Exposure to hyperoxia caused an expansion of areas with low VEGF mRNA which correlated with capillary obliteration in these regions. Combined capillary obliteration around the optic nerve head and along retinal arteries lead to a large capillary free zone in the center of the retina. Thus, our observations suggest that hyperoxia affects the retinal vasculature by reducing VEGF mRNA levels near arteries and causing a widening of capillary free zones.


Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.
Amyloid-like protein aggregation is associated with neurodegeneration and other pathologies. The nature of the toxic aggregate species and their mechanism of action remain elusive. Here, we analyzed the compartment specificity of aggregate toxicity using artificial β-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP-43). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases.


Targeting non-coding RNAs in sEVs: The biological functions and potential therapeutic strategy of diabetic cardiomyopathy.
Diabetic cardiomyopathy (DCM) is defined as abnormalities in myocardial structure and function in the setting of diabetes and in the absence of cardiovascular diseases, such as coronary artery disease, hypertension, and valvular heart disease. DCM is one of the leading causes of mortality in patients with diabetes. However, the underlying pathogenesis of DCM has not been fully elucidated. Recent studies have revealed that non-coding RNAs (ncRNAs) in small extracellular vesicles (sEVs) are closely associated with DCM and may act as potential diagnostic and therapeutic targets. Here, we introduced the role of sEV-ncRNAs in DCM, summarized the current therapeutic advancements and limitations of sEV-related ncRNAs against DCM, and discussed their potential improvement.


Outcomes of endovascular treatment of basilar artery occlusion in the stent retriever era: a systematic review and meta-analysis.
Stent retriever thrombectomy has recently been found to be effective for anterior circulation strokes, but its efficacy for basilar artery occlusion (BAO) is unclear. To carry out a systematic review and meta-analysis to analyze the available evidence for the use of stent retrievers for BAO. Two independent reviewers searched six databases for studies reporting outcomes following endovascular treatment for BAO. A total of 17 articles (6 prospective and 11 retrospective) were included. The weighted mean age of patients was 67 years (range 59-82) and 59% were male. Thrombolytic drugs were administered intravenously and intra-arterially in 46% (range 0-88%) and 38% (range 0-90%) of patients, respectively. Weighted pooled estimates of successful recanalization (TICI 2b-3) and good outcome (modified Rankin Scale ≤2) were 80.0% (95% CI 70.7% to 88.0%; I2=80.28%; p<0.001) and 42.8% (95% CI 34.0% to 51.8%; I2=61.83%; p=0.002), respectively. Pooled mortality was 29.4% (95% CI 23.9% to 35.3%; I2=37.01%; p=0.087). Incidence of procedure-related complications and symptomatic hemorrhage was 10.0% (95% CI 3.7% to 18.3%; I2=61.05%; p=0.017) and 6.8% (95% CI 3.5% to 10.8%; I2=37.99%; p=0.08), respectively. Stent retriever thrombectomy achieves a high rate of recanalization and functional independence while being relatively safe for patients with BAO. Future prospective studies with long-term follow-up are warranted.


A mechanical pivot-shift device for continuously applying defined loads to cadaveric knees.
Current techniques to study the biomechanics of the pivot-shift utilize either static or poorly defined loading conditions. Here, a novel mechanical pivot-shift device that continuously applies well-defined loads to cadaveric knees is characterized and validated against the manual pivot-shift. Six fresh-frozen human lower limb specimens were potted at the femur, mounted on a hinged testing base, and fitted with the mechanical device. Five mechanical and manual pivot-shift tests were performed on each knee by two examiners before and after transecting the ACL. Three-dimensional kinematics (anterior and internal-rotary displacements, and posterior and external-rotary velocities) and kinetics (forces and moments applied to the tibia by the device) were recorded using an optical navigation system and 6-axis load cell. Analysis of variance and Bland-Altman statistics were used to gauge repeatability within knees, reproducibility between knees, agreement between the mechanical and manual test methods, and agreement between examiners. The forces and moments applied by the device were continuous and repeatable/reproducible to within 4/10 % of maximum recorded values. Kinematic variables (excluding external-rotary velocity) were qualitatively and quantitatively similar to manual pivot-shift kinematics, and were more repeatable and reproducible. The presented device induces pivot-shift-like kinematics by applying highly repeatable three-dimensional loads to cadaver knees. It is based on a simple mechanical principle and designed using easily obtainable components. Consequently, the device enables orthopaedic biomechanists to easily and reliably quantify the effect of ACL injury and reconstruction on pivot-shift kinematics.


Enhanced solubility and antibacterial activity of lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazoles by complexation with β-cyclodextrins.
Some lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazole antibacterial agents have been evaluated for their activity in the presence of cyclodextrins (CDs) containing aqueous solutions where CDs are adopted as solubilizing excipients for improving the poor water solubility of these compounds. For such purpose both the natural β-CD and one of FDA/EMA approved CDs for parenteral use (i.e. HP-β-CD) have been employed. The solubility rank order observed was accounted for by thermal analysis (Differential Scanning Calorimetry) and FT-IR spectroscopy. The most promising compound was subjected to further NMR spectroscopic studies and molecular modelling simulations to verify the interactions between the guest molecule and the CD cavity. The assessment of the antibacterial activity of such compounds against selected Gram positive and Gram negative bacterial strains clearly showed that their antimicrobial effectiveness may, quite in all instances, be positively affected by complexation with β-CD and HP-β-CD. These results, which are in some ways in contrast with those already reported in the literature, are herein discussed on the basis of plausible mechanisms. Moreover, this investigation also reveals that the described methodology of complexing both lipophilic and hydrophilic antimicrobial agents with CDs may be an useful approach to enhance their effectiveness as well as a promising strategy to overcome even the microbial resistance problem.


IL-5, IL-8 and MMP -9 levels in exhaled breath condensate of atopic and nonatopic asthmatic children.
Asthma is a heterogeneous disease, and a great majority of pediatric patients with asthma demonstrate atopic characteristics and develop a Th2 type cytokine response. Nonatopic asthma, on the other hand, is seen more rarely. In this study, levels of IL-5, IL-8 and MMP-9 were measured in exhaled breath condensate (EBC) of the subjects to demonstrate the extent of tissue damage as well as eosinophilic and neutrophilic inflammation in children with atopic and nonatopic asthma. A total of 37 children with atopic asthma and 37 children with nonatopic asthma were enrolled in the study. Patients who exhibited protease positive aeroallergen (House dust mite, mould mix, olea, grass mix) sensitivity in allergen skin prick test were included in the atopic asthma group. To evaluate the EBC, the fluid content of the breath was collected by having the patients exhale into an EBC device, after which the IL-5, IL-8 and MMP-9 levels were assayed using the ELISA method. The atopic asthmatics exhibited significantly higher IL-5 levels in their EBC samples than the nonatopic asthmatics (0.271 [0.198-0.489] pg/ml and 0.198 [0.125-0.344] pg/ml, respectively, p = 0.04), while no significant differences were observed in the levels of IL-8 and MMP-9 in the EBC samples of the atopic and nonatopic asthmatics. IL-5 levels, as a marker of eosinophilic inflammation, were demonstrated to be higher in the children with atopic asthma when compared to those with nonatopic asthma in EBC. The fact that no significant difference was apparent in the IL-8 levels between the groups suggests that it is the severity of the disease rather than the atopic state that plays an important role in IL-8 levels. Since no difference was recorded between the groups in terms of MMP-9 levels, lung damage in asthma sufferers seems to develop independent of atopia.


Construction and in vitro testing of a novel fab-hirudin-based fusion protein that targets fibrin and inhibits thrombin in a factor xa-dependent manner.
Fibrin targeting of the thrombin inhibitor hirudin via chemical coupling is effective in vitro and in vivo. However, since chemical coupling has limitations, a recombinant approach was taken to improve the fibrin-targeting ability of hirudin. Additionally, to activate hirudin selectively at the target area and thereby limit side effects in an in vivo setting, the authors aimed to construct an inactive precursor molecule that is converted into an active thrombin inhibitor only upon cleavage by factor Xa. Using PCR, the coding region for hirudin was fused to parts of the genomic DNA of the IgG heavy chain that was cloned from the antifibrin antibody-producing hybridoma cell line 59D8. Additionally, a factor Xa recognition site was introduced between the antibody and the hirudin sequence. The fusion construct was then transfected into a heavy-chain loss variant of the hybridoma cell line 59D8. After selection of stable hybridoma clones, the expressed fusion protein was evaluated for its molecular size (57 kd) and its binding ability to the fibrin-specific peptide Bbeta 15-22. The cleavage of the fusion protein by factor Xa was demonstrated by HPLC. The recombinant anticoagulant revealed antithrombin activity only after cleavage by factor Xa. Thus, the newly designed hirudin fusion protein revealed the anticipated functions in vitro. Further experiments are needed to prove whether this precursor anticoagulant allows a highly clot-specific and efficient thrombin inhibition in vivo.


Echocardiographic indices of left ventricular function. A comparison.
Multiple M-mode echocardiographic indices of left ventricular function are currently in use, but their reliability is disputed. Therefore, we correlated echo ejection fraction (EF) using quadratic (Q) and cubic (C) formulae, percentage of minor axis shortening (%S), mean velocity of circumferential fiber shortening (mVCF), and peak VCF with angiographic EF in 37 subjects, including 10 normal subjects. None had echocardiographic segmental wall motion abnormalities. Significant linear correlations were found between angiographic EF and EFc (r = 0.78), %S (r = 0.77), EFQ(r = 0.68), peak VCF (r = 0.68), and mVCF (r = 0.58). However, for all indices, the scatter was too great to permit reliable quantitative estimations of angiographic EF based on echo date. Peak VCF was qualitatively the most reliable predictor of ventricular function, being greater than or equal to 2.00 circumference per second in 23 of 25 patients with angio EF greater than or equal to 55 percent and less than 2.00 circumferences per second in 11 of 12 with EF less than 55 (sensitivity [sens] 92 percent, specificity [spec] 92 percent). Mean VCF (sens 83 percent, spec 80 percent), %S (sens 50 percent, spec 96 percent), EFC (senc 58 percent, spec 96 percent), and EFQ (sens 58 percent, spec 92 percent) were less satisfactory. We conclude that echo indices are reliable only as qualitative parameters of ventricular function. Peak VCF appears to be the most sensitive and specific qualitative index now available.


Revision and Replacement of Spinal Cord Stimulator Paddle Leads.
Paddle leads for spinal cord stimulation (SCS) offer more efficient energy delivery and advantages in some patients. However, there is concern for how safely SCS paddles can be replaced once previously implanted because of scar tissue and the relative vulnerability of the thoracic cord. In this study, we share our experience on SCS paddle replacement. Participants who underwent SCS replacement at Albany Medical Center between 2011 and 2020 were identified. The medical records were reviewed for demographic data and information regarding initial complications, reason for removal or revision, subsequent complications of replacement surgery and its timing, and whether the implant was ultimately removed. Percutaneous lead replacement cases performed over the same period were used as a comparison group. A total of 1265 patients were identified to have had an SCS-related procedure based on billing codes. Of these, 73 involved replacement of epidural leads (51 paddles, 22 percutaneous). Most paddles (48/51) were replaced at the time of removal. A total of 30 of the 51 paddle replacements required additional lamina removal. Re-operations that occurred more than one year after initial implant were significantly more likely to require additional bone removal (p < 0.001). Paddle re-operations lasted in general 1.7 ± 0.2 hours and had 35 ± 5 mL of blood loss, whereas percutaneous operations lasted 1.3 ± 0.2 hours and had 12.5 ± 2 mL of blood loss. Despite the invasive nature of paddle replacement, there was no difference in complications (p = 0.23) compared with that in percutaneous leads. This study characterizes the safety profile of SCS paddle replacement surgeries. Here, we demonstrate that the replacement of paddle leads at the time of removal, with additional lamina removal if needed because of scar, is associated with low rates of complications. This validates the feasibility and low-risk profile of replacing paddle leads when clinically indicated for experienced surgeons with specialization in SCS.


Development, standardization and refinement of procedures for evaluating effects of endocrine active compounds on development and sexual differentiation of Xenopus laevis.
Xenopus laevis has been introduced as a model to study effects of endocrine-active compounds (EAC) on development and sexual differentiation. However, variable and inconsistent data have raised questions about the reliability of the test methods applied. The current study was conducted in two laboratories to develop, refine, and standardize procedures and protocols. Larvae were exposed in flow-through systems to 17beta-estradiol (E2), at concentrations from 0.2 to 6.0 microg E2 L(-1) in Experiment 1A, and 0.015 to 2.0 microg E2 L(-1) in Experiment 1B. In both studies survival (92%, 99%) and percentage of animals that completed metamorphosis (97%, 99%) indicated reproducible biological performance. Furthermore, minor variations in husbandry led to significant differences in snout-to-vent length, weight, and gonad size. In Experiment 1A, almost complete feminization occurred in all E2 treatment groups whereas a concentration response was observed in Experiment 1B resulting in an EC(50) of 0.12 microg E2 L(-1). The final verified protocol is suitable for determining effects of EAC on development and sexual differentiation in X. laevis.


Risks of Hypoparathyroidism After Total Thyroidectomy in Children: A 21-Year Experience in a High-Volume Cancer Center.
Hypoparathyroidism occurs relatively frequently after thyroid surgery in children. However, few studies have reported risk factors. We aimed to identify risk factors for hypoparathyroidism that occurred after total thyroidectomy for proven or suspected malignancy in children. Children (aged ≤ 18 years) who underwent total thyroidectomy for neoplasm or RET germline mutation at our institution between 1997 and 2018 were included. We retrospectively reviewed demographics, surgical indications, perioperative and follow-up laboratory results, pathologic results, and duration of calcium/calcitriol supplementation. Risk factors for hypoparathyroidism were identified by multivariate analysis. Of 184 consecutive patients, 111 had undergone surgery for neoplasm; these diseases were primarily malignancies (106, 95.5%), predominantly papillary carcinoma (103, 92.8%). The remaining 73 patients had undergone early thyroidectomy for RET germline mutation. Among all patients, 67 (36.4%) had hypoparathyroidism: 61 transient and 6 permanent. In a multivariate analysis, central neck dissection (odds ratio 4.3, 95% confidence interval 2.0-9.1) and gross extrathyroidal extension (odds ratio 4.9, 95% confidence interval 2.0-12.1) predicted overall hypoparathyroidism; however, no significant factors were associated with permanent hypoparathyroidism. Most patients with permanent hypoparathyroidism (5 of 6) had undergone therapeutic central neck dissection. When central neck dissection was performed, younger children had a higher risk of overall hypoparathyroidism. In pediatric total thyroidectomies, central neck dissection and gross extrathyroidal extension were major predictors for overall hypoparathyroidism. Surgeons performing thyroidectomy in such patients should be aware of the relatively high risk, preserve parathyroid tissue to the extent possible, and be conscientious regarding postoperative calcium monitoring and replacement.


Mandibular Tissue Engineering: Past, Present, Future.
Almost 2 decades ago, the senior author's (M.T.J.) first article was with our mentor, Dr Leonard B. Kaban, a review article titled "Distraction Osteogenesis: Past, Present, Future." In 1998, many thought it would be impossible to have a remotely activated, small, curvilinear distractor that could be placed using endoscopic techniques. Currently, a U.S. patent for a curvilinear automated device and endoscopic techniques for minimally invasive access for jaw reconstruction exist. With minimally invasive access for jaw reconstruction, the burden to decrease donor site morbidity has increased. Distraction osteogenesis (DO) is an in vivo form of tissue engineering. The DO technique eliminates a donor site, is less invasive, requires a shorter operative time than usual procedures, and can be used for multiple reconstruction applications. Tissue engineering could further reduce morbidity and cost and increase treatment availability. The purpose of the present report was to review our experience with tissue engineering of bone: the past, present, and our vision for the future. The present report serves as a tribute to our mentor and acknowledges Dr Kaban for his incessant tutelage, guidance, wisdom, and boundless vision.


Tuning cell cycle of insect cells for enhanced protein production.
The eukaryotic cell cycle consists of many checkpoints during which certain conditions must be met before passing to subsequent stages. These safeguards ensure cells' integrity and survival, but may also limit growth and protein synthesis in protein production processes. In this work, we employ metabolic engineering principles to "tune" the cell cycle to overcome checkpoint processes in order to facilitate faster cell growth, and independently, arrest the cell cycle in gap1 (G1) phase for greater protein productivity. Specifically, we identified the complete cyclin E (cycE) cDNA sequence from industrially relevant, Trichoplusia ni (T. ni) derived High Five™ genomes. We then both knocked down (through RNA interference; RNAi) and overexpressed (on an expression plasmid) cycE gene expression to tune the cell phenotype. We successfully up- and down-regulated cycE transcription, enhancing and hindering cell growth, respectively. We also measured the effects of titrated cycE expression on the cell cycle phase distribution. Finally, we investigated the dose-dependent effects of dsCycE on recombinant protein production using the baculovirus expression system and demonstrated a nearly 2-fold increase in expression of model protein (GFPuv).


Lipid and lipoprotein synthesis in isolated and cultured hepatocytes from lean and obese Zucker rats.
Hepatocytes were isolated by EDTA perfusion of livers from lean (Fa/-) and obese (fa/fa) Zucker rats. Triacylglycerol (TG) and sn-glycerol 3-phosphate were increased in fa/fa hepatocytes, but free fatty acids, cholesterol and phospholipid concentrations were similar in both groups. In spite of an identical fatty acid uptake rate, glycerolipid synthesis was higher in obese compared to lean rat hepatocytes, and this difference remained for at least 2-3 days of culture. Triacylglycerol mass secretion was 2-fold higher in obese than in lean rat hepatocytes. This was confirmed by the higher incorporation of labeled glycerol and oleic acid into the medium TG fraction floating at density 1.006 g/ml. Density gradient ultracentrifugation of [14C]oleate-labeled lipoproteins showed that fa/fa hepatocytes secreted more TG-rich lipoproteins, and that 87% of the label was in the VLDL fraction compared with 67% in the medium of Fa/- hepatocytes. Decreased utilisation of leucine for protein synthesis in obese rat compared to lean rat hepatocytes was associated with enhanced leucine oxidation to CO2. [35S]Methionine incorporation showed an identical cell protein synthesis rate. Autoradiography after PAGE separation of secreted apolipoproteins (apoBh, Bl, apoA-VI, apoE, apoA-I, apoC) showed an identical pattern in both cell types.


Doctor of pharmacy as a career option: a cross-sectional study exploring PharmD students and practitioners expectations in Jordan.
This study aimed to (1) investigate the expectations and preferences of PharmD students and practitioners regarding their role in the health care system, and (2) to contrast those expectations and preferences of PharmD practitioners with real-life practice in Jordan. Two cross-sectional descriptive questionnaires were used to collect data from PharmD students and PharmD practitioners in Jordan. A total number of 330 students and 280 practitioners were interviewed. The responses to all questions were encoded, entered, and summarized as frequencies and percentages or as means and standard deviations. Comparisons between groups were performed using Chi-square test. A p-value of < 0.05 was considered significant. Both PharmD students and practitioners chose working as a clinical pharmacist in a hospital as their first-choice job. However, their second and third jobs choices were significantly different as practitioners opted for income as a main criterion for job selection. Interestingly, salary expectations by PharmD students were significantly higher than the reality as reported by PharmD practitioners. Both students and practitioners placed the work environment as the highest priority criterion for making a work choice on the work environment. In general, both students and practitioners agree on the ideal roles of PharmD graduate with the issues of prescribing and compounding responsibilities being the ones with the highest disparity between practitioners and students. Significant differences were found between the student's and practitioner's perceptions of the ideal role of a PharmD in and the current professional practice in Jordan. Job preferences and salary expectations differ significantly between students and practitioners. Professional orientation of PharmD. students should be implemented to minimize misconceptions of their job nature, availability, and compensations. The fact that students do not prefer to work in a community pharmacy should be addressed by educational institutions and professional organizations. The prescribing and compounding responsibilities of pharmacists should be also emphasized in the curricula of pharmacy schools and worked in by professional organization to achieve optimal implementation in real-life practice.


Clinical relevance of pedal pulse palpation in patients suspected of peripheral arterial insufficiency.
Previous studies in patients with peripheral arterial disease (PAD) have shown that the prognosis is relatively good when the distal systolic ankle index (ankle systolic pressure/arm systolic pressure) is above 50% and the distal toe systolic pressure is above 40 mmHg. In 132 patients suspected of PAD in the legs we investigated the relationship between the presence of pedal pulse and the distal systolic pressure in order to discover what diagnostic and prognostic information could be found from pulse palpation alone. The prospective study consisted of three consecutive series (A, 51 patients; B, 42 patients; and C, 39 patients); three of the authors palpated the arteries of the patients' feet: one author in each series. The palpatory findings were related to the distal systolic pressures. When pedal pulses were present we found: (a) ankle indices above 50%; and (b) toe systolic pressures above 40 mmHg. These minimal pressure values were reproducible in the three series. Furthermore, patients lacking palpable pulses in both feet had ankle indices below 90%. We conclude: (a) if pulses are palpable on both feet of a patient the prognosis for progression is relatively good regarding the patient's PAD; (b) if pedal pulse is palpable an arteriosclerotic ulcer on the foot will heal; and (c) patients lacking palpable pulses in both feet actually suffer from PAD.


Structural and dynamical characterization of the Miz-1 zinc fingers 5-8 by solution-state NMR.
Myc-interacting zinc finger protein-1 (Miz-1) is a BTB/POZ transcription factor that activates the transcription of cytostatic genes, such as p15(INK4B) or p21(CIP1). The C-terminus of Miz-1 contains 13 consensus C2H2 zinc finger domains (ZF). ZFs 1-4 have been shown to interact with SMAD3/4, while the remaining ZFs are expected to bind the promoters of target genes. We have noted unusual features in ZF 5 and the linker between ZFs 5 and 6. Indeed, a glutamate is found instead of the conserved basic residue two positions before the second zinc-coordinating histidine on the ZF 5 helix, and the linker sequence is DTDKE in place of the classical TGEKP sequence. In a canonical ββα fold, such unusual primary structure elements should cause severe electrostatic repulsions. In this context, we have characterized the structure and the dynamics of a Miz-1 construct comprising ZFs 5-8 (Miz 5-8) by solution-state NMR. Whilst ZFs 5, 7 and 8 were shown to adopt the classical ββα fold for C2H2 ZFs, the number of long-range NOEs was insufficient to define a classical fold for ZF 6. We show by using (15)N-relaxation dispersion experiments that this lack of NOEs is due to the presence of extensive motions on the μs-ms timescale. Since this negatively charged region would have to be located near the phosphodiester backbone in a DNA complex, we propose that in addition to promoting conformational searches, it could serve as a hinge region to keep ZFs 1-4 away from DNA.


Cellular retinol-binding protein-1 in hepatocellular carcinoma correlates with beta-catenin, Ki-67 index, and patient survival.
The cellular retinol-binding protein-1 (CRBP-1) plays a key role in the esterification and intercellular transfer of retinol. By in situ hybridization, immunohistochemistry, and confocal laser scanning microscopy (CLSM), we show that, in normal liver, CRBP-1 is strongly expressed in the cytoplasm of hepatic stellate cells (HSCs) and myofibroblasts (MFs) with only low CRBP-1 levels in hepatocytes. By contrast, in 196 hepatocellular carcinoma (HCC) specimens CRBP-1 expression in MFs was down-regulated in 83%. Patients with high CRBP-1 expression in MFs had a significantly higher 2-year survival as compared with patients with low CRBP-1 expression (52% vs. 29%, respectively; P =.034). An aberrant nuclear CRBP-1 accumulation resulting from cytoplasmic invagination was found in 29% of HCCs. Nuclear CRBP-1 staining correlated positively with a favorable tumor stage (Okuda stage I; P =.01) and negatively with the Ki-67(+) proliferation fraction (PF). A Ki-67(+) PF of > or =10% was associated with a lower 2-year survival probability as compared with patients with a Ki-67(+) PF of <10% (12% vs. 40%, respectively; P =.015). Prognosis did not correlate with the nuclear beta-catenin expression. There was, however, a close correlation between nuclear CRBP-1 inclusions and nuclear beta-catenin staining in HCCs (P =.008), suggesting a cross talk between CRBP-1 and the Wnt/wingless signal transduction pathway. In conclusion, our findings demonstrate that CRBP-1 detection may be useful for the discrimination between nonneoplastic and neoplastic liver cells and suggest that modulation of CRBP-1 expression in HCCs contributes to tumor growth and progression via retinoid-mediated signaling and disruption of cellular vitamin A homeostasis.


Effects of capacity demands on picture viewing.
Effects of cognitive-resource demands on picture-viewing patterns were investigated. The eye fixations of 72 subjects were recorded as the subjects viewed pictures and concurrently performed one of three listening tasks. Half of the subjects were asked to remember certain objects from the pictures and half had no-memory instructions. Concurrent auditory monitoring increased interfixation distances and the frequency of fixations on regions of high informativeness, and decreased the area of the pictures explored and the memory for objects in the scenes. It is suggested that the demands on cognitive resources influenced subjects' ability to encode and integrate fixated information and therefore prolonged the normal first phase of viewing, described by Buswell (1935).


Complement system and immunological mediators: Their involvements in the induced inflammatory process by Androctonus australis hector venom and its toxic components.
Androctonus australis hector scorpion venom is well known by its high toxicity, it induces massive release of neurotransmitters that lead to pathophysiological disorders in cardiovascular, neuro-hormonal and immune systems. Previous studies have shown the relationship between the severity of scorpion envenoming and immune system activation. This study was assessed to investigate the involvement of complement system and inflammatory mediators after sublethal injection of Aah venom, its toxic fraction (FtoxG50) and its main toxins (AahI and AahII) into NMRI mice. The Activation complement system by the venom is also compared to that induced of lipopolysaccharides (LPS). Obtained results showed that seric complement system (CS) is activated by the venom and by its toxic components; this activation is more pronounced into liver tissue when toxic components (FtoxG50, AahI or AahII) are used. Increase of cytokine levels (IL1β, TNFα and ICAM) into hepatic tissue induced by AahI or AahII neurotoxins is correlated with tissue alterations. Aprotinin, a non specific inhibitor of complement system seems to be able to reduce CS consumption and to restore partially the induced tissue damage by venom. The mechanisms by which toxic fraction or LPS induced the activation of complement system seem to be different. Sensitivity of hepatic tissue is more pronounced after FtoxG50 injection; however lung tissue is more sensible to LPS than FoxG50.


Therapeutic targeting of organelles for inhibition of Zika virus replication in neurons.
Zika virus (ZIKV) is an arbovirus belonging to the family Flaviviridae. Since 2015, ZIKV infection has emerged as a leading cause of virus-induced placental insufficiency, microcephaly and other neuronal complications. Currently, no therapeutics have been approved to treat ZIKV infection. In this study, we examined how targeted inhibition of cellular organelles or trafficking processes affected ZIKV infection and replication in neural progenitor cells. We found that blocking endocytosis, Golgi function or structural filaments like actin or microtubules had moderate effects on virus replication. However, inducing endoplasmic reticulum (ER) stress by treatment with Thapsigargin substantially inhibited virus production, suggesting the ER might be a candidate cellular target. Further analysis showed that sarcoplasmic/endoplasmic reticulum Ca2+-ATPases (SERCA) was important for ZIKV inhibition. Collectively, these studies indicate that targeting the SERCA-dependent ER stress pathway may be useful to develop antivirals to inhibit ZIKV replication.


Metabolomics as a powerful tool for molecular quality assessment of the fish Sparus aurata.
The molecular profiles of perchloric acid solutions extracted from the flesh of Sparus aurata fish specimens, produced according to different aquaculture systems, have been investigated. The (1)H-NMR spectra of aqueous extracts are indicative of differences in the metabolite content of fish reared under different conditions that are already distinguishable at their capture, and substantially maintain the same differences in their molecular profiles after sixteen days of storage under ice. The fish metabolic profiles are studied by top-down chemometric analysis. The results of this exploratory investigation show that the fish metabolome accurately reflects the rearing conditions. The level of many metabolites co-vary with the rearing conditions and a few metabolites are quantified including glycogen (stress indicator), histidine, alanine and glycine which all display significant changes dependent on the aquaculture system and on the storage times.


Expression with early postnatal peak and female-dominant sexual dimorphism of phospholipase D (PLD) 2 in submandibular gland ducts in situ of mice.
In the present study, expression and localization of PLD2 were examined in mouse submandibular glands in situ in comparison with those of PLD1 previously reported by the present authors. In immunoblots, PLD2-expression was high at postnatal 0 week (P0W) and P2W, and at P4W decreased considerably with the decrease of the male gland more marked, and at P8W it was undetectable in the male gland, but remained faint in the female. In the male gland at P8W after castration at P6W, PLD2-expression reappeared faintly. In the female glands with daily injections of testosterone started at P6W, at P8W the expression was undetectable. In immunohistochemistry, PLD2 was localized throughout immature duct epithelia without distinct regional differences in its intensity at P0W and P2W. PLD2-localization was weak and diffuse in granular convoluted tubules at P4W and negligible there at P8W in the female gland, while it was at negligible levels in the tubules at P4W and at undetectable levels there at P8W in the male gland. The expression changes detected in immunoblots after castration or testosterone injection were duplicated in granular convoluted tubules in immunohistochemistry. The present findings suggest that PLD2 is dominantly involved in proliferation/differentiation/apoptosis of most immature ductal cells at early postnatal and at least perinatal stages, different from PLD1. This also indicates that the female-dominant sexual dimorphism of PLD2-expression occurs in synchrony of differentiation of granular convoluted tubules at puberty and at young adulthood, similar to PLD1 though at much lower levels.


Lysosomal enzyme activities in normals and in patients with chronic liver diseases.
The maximal activities of liver lysosomal enzymes (acid phosphatase and cathepsin D) were found to be increased in patients with chronic active hepatitis, cirrhosis and primary hepatocellular carcinoma. The ratio between maximal and basal activity (an expression of the degree of retention of the enzymes to lysosome) of acid phosphatase was significantly decreased in patients with chronic active hepatitis and cirrhosis whereas that of cathepsin D did not show any significant changes between normal and various liver disorders. Serum levels of both the enzymes were elevated significantly in patients with cirrhosis and primary hepatocellular carcinoma.


Hydrophobic similarity between molecules: a MST-based hydrophobic similarity index.
A similarity index based on the hydrophilic/hydrophobic properties of molecules is presented. Such an index is defined based on the fractional partition of the free energy of solvation developed within the framework of the self-consistent reaction field MST model, which divides the free energy of solvation or the free energy of transfer into contributions assigned to the surface elements defining the solute/solvent interface. These surface contributions can be integrated to derive atomic or group contributions. The suitability of the index to compute the molecular similarity based on hydrophobic/hydrophilic properties is examined by considering their application in a variety of test systems, including structure-activity relationships, absorption properties, and molecular recognition. The similarity index is expected to be a very powerful tool in molecular similarity studies for compounds of chemical, biochemical, and pharmaceutical interest.


Ionic lanthanum passage across cerebral endothelium exposed to hyperosmotic arabinose.
Hyperosmotic media infused into the cerebral circulation open the blood-brain barrier to protein and colloid. The mechanism whereby such substances cross the affected vessels is still disputed. We describe here the transendothelial route taken by ionic lanthanum (La3+), a small electron-dense tracer which, unlike colloidal lanthanum, can be administered to the living animal. In adult rats, 2.9 ml of hyperosmotic (1.4 M) arabinose was infused into the internal carotid artery as a 30-s bolus, followed by 5 mM LaCl3. To find the extravasated La3+, which is invisible by light microscopy, horseradish peroxidase (HRP) was injected simultaneously into the femoral vein. The hyperosmotic treatment resulted in exudation of both HRP and La3+ primarily around cerebral arterioles. The La3+ crossed arterioles through successive tight junctions between endothelial cells. Although the tight junctions were not discernibly opened, they must have become permeable because the extracellular pools between successive tight junctions were penetrated by the La3+. These pools are normally inaccessible to La3+. Luminal and abluminal pits and cytoplasmic vesicles, some of them containing La3+, formed intraendothelial clusters. Their role, if any, in the transfer of ion remains uncertain.