Valinomycin inhibition of the electrical activity of mouse pancreatic beta-cells.
The effect of the K-ionophore valinomycin (VAL) on the electrical activity of single mouse pancreatic beta-cells was measured using the glass micro-electrode technique. In the presence of 11.1 mM glucose, after 4 min of exposure to 10 nM VAL the spike activity was abolished, bursts became irregular and after 10 min the membrane hyperpolarized 4 mV. The electrical activity was completely blocked by 100 nM VAL within 3 min and the membrane hyperpolarization averaged 10 mV. The effect of VAL was irreversible. VAL (100 nM) also inhibited the electrical activity induced by 11.1 mM glucose plus 10 mM tetraethylammonium chloride (TEA), a specific blocker of the voltage sensitive PK. Total inhibition was observed 6-7 min after VAL addition and the cell hyperpolarized 14 mV. With the simultaneous application of 10 mM TEA and 100 microM quinine, a specific blocker of the [Ca2+]i-dependent PK, in the presence of 16.7 mM glucose, the membrane showed continuous activity and progressive depolarization from -45 to -5 mV within 23 min. The subsequent addition of 100 nM VAL also hyperpolarized the cell, with the membrane potential reaching -17 mV after 7 min. On the basis of these data, we suggest that VAL affects the glucose-dependent depolarization of the beta-cell membrane by increasing K+ permeability.


Lactic acidosis associated with phenformin therapy. Evidence that inhibited lactate oxidation is the causative factor.
Using uniformly labeled 14C L-lactate, we have studied the turnover and oxidation of lactic acid in a patient who presented with a mild lactic acidosis while on phenformin medication. As with other cases of lactic acidosis associated with phenformin therapy, this subject had impaired renal function as evidenced by serum creatinine levels of 2 mg./100 ml. and BUNs of 40 mg./100 ml. Comparison of the rate of lactate oxidation relative to the rate of lactate turnover in this subject while on and off phenformin therapy suggests that a prime factor leading to the elevated lactate levels in this situation in impaired peripheral aerobic metabolism. Although lactate oxidation was increased in the presence of phenformin, the control studies clearly demonstrate that aerobic metabolism was not keeping pace with the increased level of anaerobic carbohydrate metabolism brought on by the drug. It is concluded that it is this imbalance in lactate metabolism that is responsible for the lactic acidosis that accompanies phenformin therapy.


Laryngeal Embryonal Rhabdomyosarcoma: A rare adult neoplasm.
The embryonal subtype of rhabdomyosarcoma is the most frequent, commonly seen in children. However, it is uncommon to discover this subtype in adults, especially in the larynx. We presented a rare case of a 63 years old man who presented with worsening hoarseness, dysphagia for solids, and dyspnea and was later diagnosed with embryonal rhabdomyosarcoma of the larynx.


Lack of interaction between diazepam and nimodipine during chronic oral administration to healthy elderly subjects.
1. Nimodipine (30 mg three times daily) and diazepam (10 mg once daily), were given orally to 24 elderly healthy subjects in a randomized, non-blinded, threefold-crossover study. Each of the three treatment periods lasted 5 days separated by 2 week washout phases. 2. Plasma concentrations of nimodipine and diazepam were not affected by the combined treatment. 3. No clinically relevant changes in haemodynamics, ECG recordings, clinical chemistry or haematology were observed after all of the three treatments. The overall frequency of side effects was lowest during monotherapy with nimodipine and highest during diazepam monotherapy. 4. In the test of subjective rating of tiredness (VAS) and the Pauli calculation test, diazepam, alone and with nimodipine co-medication, produced an increase in tiredness and a clear reduction in performance and endurance. After nimodipine monotherapy an improvement was observed only in the Pauli test. Using the critical flicker fusion frequency test (CFF) significant decrements in performance were found after diazepam monotherapy only. 5. In summary, there was no evidence that either nimodipine or diazepam affected the pharmacokinetics, safety and tolerance of each other. However, the CNS-effects of diazepam were compensated partially by nimodipine.


Flow cytometric double labeling technique for screening of multidrug resistance.
We investigated the capabilities of flow cytometry in the analysis of a multidrug resistant (MDR) human ovarian cancer cell line 2780AD and its drug sensitive parental A2780. A functional assay using daunorubicin (DNR) as a fluorescent probe was combined with an immunofluorescence assay of P-glycoprotein (P-gp) using the monoclonal antibody MRK-16. Functionally MDR could be demonstrated by the lower DNR-content of MDR cells compared to DNR-content of drug sensitive cells. When incubation was performed with DNR in the presence of verapamil, DNR-content increased in the MDR cells. However the content of the A2780 cells was never attained. Differences in DNR-content were not related to differences in DNA-content. In experimental cell lines immunofluorescence data were inversely related with those of DNR-content: MDR cells had high levels of P-gp expression and low levels of DNR-content (and vice versa in drug sensitive cells). Both assays can be easily combined in a multiparametric flow cytometric procedure to evaluate both parameters simultaneously in the same cells. Analysis of clinical samples demonstrates the existence of aberrant subpopulations which would not be detected by using a single parameter assay.


Glycogen synthase kinase 3 controls migration of the neural crest lineage in mouse and Xenopus.
Neural crest migration is critical to its physiological function. Mechanisms controlling mammalian neural crest migration are comparatively unknown, due to difficulties accessing this cell population in vivo. Here we report requirements of glycogen synthase kinase 3 (GSK3) in regulating the neural crest in Xenopus and mouse models. We demonstrate that GSK3 is tyrosine phosphorylated (pY) in mouse neural crest cells and that loss of GSK3 leads to increased pFAK and misregulation of Rac1 and lamellipodin, key regulators of cell migration. Genetic reduction of GSK3 results in failure of migration. We find that pY-GSK3 phosphorylation depends on anaplastic lymphoma kinase (ALK), a protein associated with neuroblastoma. Consistent with this, neuroblastoma cells with increased ALK activity express high levels of pY-GSK3, and blockade of GSK3 or ALK can affect migration of these cells. Altogether, this work identifies a role for GSK3 in cell migration during neural crest development and cancer.


Psychological assessment and management in diabetes.
Though the importance of psychological factors in the natural history, and the management of diabetes, cannot be overstated, these factors are sometimes not discussed adequately in current literature. Lack of trained manpower, time, and other resources, tends to detract diabetes care professionals from paying attention to this field. This review discusses simple, practical ways of psychological assessment and psychological management, in a manner relevant not only to Pakistan, but to other resource challenged settings as well. The paper underscores the fact that improvements in our understanding of psychological aspects of diabetes should be considered worthy of inclusion in the column: recent advances in endocrinology.


Management of the unstable prosthetic shoulder arthroplasty.
Instability is the most common complication of shoulder arthroplasty. An understanding of the predisposing factors for developing instability is critical to the avoidance of this complication. Soft-tissue balance and proper component positioning must be attained during the index procedure to minimize the risk of developing postoperative instability. Once the shoulder does become unstable, the reason for the instability must be determined. Is the instability secondary to soft-tissue imbalance, component malposition, bony deformity, or a combination of these? Next, a decision must be made as to how to treat the instability. Nonsurgical treatment may be tried if no obvious cause is present. However, if the instability fails to resolve or recurs, surgical intervention should be undertaken early. If the instability is not treated, it may result in loosening of the prosthesis and early wear of the components. Once surgical intervention is undertaken, all elements of the instability must be recognized and treated.


Incidence and economic implications of heparin-induced thrombocytopenia in medical patients receiving prophylaxis for venous thromboembolism.
To determine the incidence of heparin-induced thrombocytopenia (HIT) in patients admitted to a medical service who were given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) to prevent venous thromboembolism, the incremental cost of developing HIT, and the cost consequences of using LMWH to prevent venous thromboembolism in medical patients. Retrospective analysis with a nested case-control. University-affiliated tertiary-care hospital. A total of 10,121 adult medical patients admitted between August 1, 2000, and November 2, 2004, received UFH or LMWH to prevent venous thromboembolism during their admission. From these, patients with immune-mediated HIT were identified and served as case patients, and 3-5 matched control patients were identified for each case patient. The development of HIT was determined for patients who received LMWH and for patients who received UFH. Costs were compared between the patients with HIT and the matched control patients. The cost of using LMWH to prevent venous thromboembolism was compared with the cost of using UFH. In patients receiving UFH and those receiving LMWH, the incidence of HIT was 0.51% (43/8420) and 0.084% (1/1189), respectively (p=0.037), with an overall incidence of 0.43% (44/10,121). Admissions that included development of HIT incurred an average cost of 56,364 dollars compared with 15,231 dollars (p<0.001) for admissions without HIT. Using LMWH to prevent venous thromboembolism in medical patients cost 13.88 dollars less per patient than using UFH. For the prophylaxis of venous thromboembolism, LMWH was associated with a lower incidence of HIT than UFH in medical patients. An admission during which the patient develops HIT costs significantly more than an admission during which the patient does not develop HIT. Low-molecular-weight heparin is cost-effective for prevention of venous thromboembolism in medical patients.


A new Culeolus species (Ascidiacea) from the NE Pacific, California.
The paper describes Culeolus barryi n. sp. (Ascidiacea: Pyuridae), a species photographically documented in situ and collected in the northeast Pacific, off the coast of California (USA). This species of stalked tunicate inhabits deepwater (1200 m) and is characterized by numerous gonads on each side of the body. It is most similar to C. nadejdae from the Sea of Okhotsk and C. sluiteri from Aleutian Islands. A brief overview of all Culeolus species is provided.


Hash Bit Selection Based on Collaborative Neurodynamic Optimization.
Hash bit selection determines an optimal subset of hash bits from a candidate bit pool. It is formulated as a zero-one quadratic programming problem subject to binary and cardinality constraints. In this article, the problem is equivalently reformulated as a global optimization problem. A collaborative neurodynamic optimization (CNO) approach is applied to solve the problem by using a group of neurodynamic models initialized with particle swarm optimization iteratively in the CNO. Lévy mutation is used in the CNO to avoid premature convergence by ensuring initial state diversity. A theoretical proof is given to show that the CNO with the Lévy mutation operator is almost surely convergent to global optima. Experimental results are discussed to substantiate the efficacy and superiority of the CNO-based hash bit selection method to the existing methods on three benchmarks.


Comparison of intra-ocular pressure changes with liquid or flat applanation interfaces in a femtosecond laser platform.
Cataract surgery is the most common surgical procedure and femtosecond laser assisted cataract surgery (FLACS) has gained increased popularity. FLACS requires the application of a suction device to stabilize the laser head and focus the laser beam accurately. This may cause a significant escalation in intra-ocular pressure (IOP), which poses potential risks for patients undergoing cataract surgery. In this study we aimed to assess the effect of the Ziemer LDV Z8 femtosecond cataract machine on IOP. We demonstrated through a porcine model that IOP was significantly higher with a flat interface but could be abrogated by reducing surgical compression and vacuum. Pressure was lower with a liquid interface, and further altering angulation of the laser arm could reduce the IOP to 36 mmHg. A pilot series in patients showed comparable pressure rises with the porcine model (30 mmHg). These strategies may improve the safety profile in patients vulnerable to high pressure when employing FLACS with the Ziemer LDV Z8.


[Professor GUAN Ji-duo: a well-renowned acupuncturist in Sichuan province].
As a famous TCM physician and acupuncturist in our country, professor GUAN Ji-duo, who was determined to study medicine and save life from a child, has been engaged in teaching and clinical work of acupuncture and moxibustion for more than sixty years. With a lifetime writing and tireless teaching, he has made every effect, from small clue to see what is coming, to be well-versed in the learning of both ancient and modern times and learn widely from others' points to devote all his life for the development and innovation of acupuncture and moxibustion. With deep study on syndrome differentiation of meridians, he has focused on acupoint combination, advocated on painless insertion of needle, and made "smokeless moxa-stick" to form a unique academic thought. At the age of more than 90, professor GUAN still insists on outpatient clinic, which is highly respected.


Transcription of the kalilo linear senescence plasmid from Neurospora intermedia.
The 8.6-kb kalilo linear mitochondrial plasmid of Neurospora intermedia was found to give rise to multiple transcripts of 8.6, 4.4, 4.0, 1.3, 1.2, and 0.9 kb. Plasmid transcripts were found in all the developmental stages tested and were present in cells with and without plasmid integration into mtDNA. The 4.4- and 4.0-kb transcripts corresponded to the two known ORFs in size, position, and polarity. An analysis of RNA fractions has confirmed the mitochondrial location of kalilo. The kalilo-specific RNA appears to be selectively unstable in affected strains of N. intermedia; this may be a general property of linear plasmid RNA. Transcripts are most likely initiated from near the termini of the linear plasmid. Primer extension and sequencing showed a clear 5' RNA end at nucleotide 101. However, the sequence in this region does not show homology with any known mitochondrial, plasmid, or nuclear promoter. The sequence does show homology with the tip of the plasmid and marks the border of a long series of direct repeats. Possibly the plasmid RNA polymerase may be bifunctional, recognizing sequences at the plasmid tip as well as the promoter.


Structure of Mixed Acid/Decyl Monolayers Grafted on Oxide-Free Si(111) Surfaces.
The structure of mixed acid/decyl monolayers (MLs) grafted on oxide-free Si(111) surfaces by photochemical hydrosilylation in a mixture of neat undecylenic acid and 1-decene is studied in detail. After appropriate surface cleaning of the as-grafted surfaces, atomic force microscopy (AFM) (topography and phase imaging) and calibrated FTIR analysis demonstrate that a mixed monolayer is formed, free of residue. When the acid-molecule fraction (ΓSOL) is >0.1, mixed MLs are homogeneous on the scale of observations and they are only slightly enriched in acid chains with respect to the solution. Conversely, when ΓSOL < 0.1, the acid chain fraction within the ML becomes quasi-independent of the solution composition and may become much larger than ΓSOL. In addition, dark domains are observed in AFM phase images. Correlations between the characteristic parameters of νCO IR bands and AFM phase images suggest a strong phase separation of acid and alkyl chains at various length scales. A model involving a structuration of the grafting solution is proposed to explain observations.


Population flow drives spatio-temporal distribution of COVID-19 in China.
Sudden, large-scale and diffuse human migration can amplify localized outbreaks of disease into widespread epidemics1-4. Rapid and accurate tracking of aggregate population flows may therefore be epidemiologically informative. Here we use 11,478,484 counts of mobile phone data from individuals leaving or transiting through the prefecture of Wuhan between 1 January and 24 January 2020 as they moved to 296 prefectures throughout mainland China. First, we document the efficacy of quarantine in ceasing movement. Second, we show that the distribution of population outflow from Wuhan accurately predicts the relative frequency and geographical distribution of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) until 19 February 2020, across mainland China. Third, we develop a spatio-temporal 'risk source' model that leverages population flow data (which operationalize the risk that emanates from epidemic epicentres) not only to forecast the distribution of confirmed cases, but also to identify regions that have a high risk of transmission at an early stage. Fourth, we use this risk source model to statistically derive the geographical spread of COVID-19 and the growth pattern based on the population outflow from Wuhan; the model yields a benchmark trend and an index for assessing the risk of community transmission of COVID-19 over time for different locations. This approach can be used by policy-makers in any nation with available data to make rapid and accurate risk assessments and to plan the allocation of limited resources ahead of ongoing outbreaks.


Pharmacological and nonpharmacological methods for rate control.
In many patients with atrial fibrillation, the most appropriate strategy is 'rate control', designed to slow down the rapid ventricular rates often seen with atrial fibrillation. Based on the hypothesis that symptoms, especially palpitations and exercise intolerance, are due to rapid ventricular rates with activity, optimum rate control usually requires reducing ventricular rates at rest and during activity. Beta-blockers and nondihydropyridine calcium channel blockers are likely more effective than digoxin alone, and the adequacy of rate control is best assessed with heart rate measurement during activity or with ambulatory electrocardiographic monitoring. Taking a patient's symptoms into account, reasonable target ventricular rates are less than 80 beats/min at rest and less than 100 beats/min, on average, over 24 h.


Alternative structures of the cauliflower mosaic virus 35 S RNA leader: implications for viral expression and replication.
The CaMV 35 S RNA functions as both messenger and pregenomic RNA under the control of its 600 nts leader, which contains regulatory elements involved in splicing, polyadenylation, translation, reverse transcription, and probably also packaging. The structure of the leader has been characterized theoretically and experimentally. The predicted conformation, a low-energy elongated hairpin, base-pairing the two halves of the leader, with a cross-like structure at the top, is strongly supported by enzymatic probing, chemical modification, and phylogenetic comparison. The elongated hairpin is stabilized by strong base-pairing between the ends of the leader, regions which are important in allowing translation downstream of the leader via the ribosome shunt mechanism. At high ionic strength the 35 S RNA leader exhibits additional higher order structures of low electrophoretic mobility: (1) a long-range pseudoknot connecting central and terminal parts of the leader; (2) a dimer. Alternative structures of the CaMV 35 S RNA leader may co-exist and have specialized functions. Their potential impact on CaMV life cycle regulation is discussed.


Measuring beliefs about orthodontic treatment: a questionnaire approach.
Few studies have examined what parents and orthodontists expect from and value about orthodontic treatment. In this study, we designed and tested a questionnaire to outline what drives consumer demand for children's orthodontic care. Further, we present data from the questionnaire to illustrate how expectations and values pertaining to orthodontic treatment relate to sociodemographic variables. Subjects were 220 Pennsylvania orthodontists and 220 parents at a university orthodontic clinic who were administered a questionnaire designed to assess what parents and orthodontists value about and expect from orthodontic treatment. Items for the questionnaire were developed via a qualitative, telephone interview process. Data were analyzed using factor analysis and reliability analysis for scale development, and analysis of variance for preliminary validity assessment. Through factor analysis, the questionnaire was reduced from 84 to 52 items, and eight scales were examined: expected treatment benefits, expected treatment risks (short- and long-term), expected treatment inconveniences, value of treatment benefits, value of risks (short- and long-term), and value of treatment inconveniences. For parents, the reliability for all scales was in the acceptable range. For orthodontists, only the "short-term risks" scale failed to attain an acceptable reliability. Preliminary validity was assessed through examining relationships between demographic variables and subscale scores. For parents, income, father's education level, and sex of respondent were related to treatment expectations and values. For orthodontists, age, sex, and patient volume were related to treatment values. The questionnaire developed in the present study was found to be practical and reliable for use with providers and consumers of orthodontic care and can be used to explore factors affecting the demand for orthodontic care. Implications of possible unrealistic treatment expectations on the part of orthodontists and parents also are discussed.


Application of magnetic field for biological response modification.
The study of magnetic effects on biological system was started in response to Dr. Nose's wish for the development of extracorporeal immunomodulation therapy. In the extracorporeal immunomodulation system, monocytes or lymphocytes in blood are stimulated by the interactions with immune-active materials. The concept of magnetic field application was introduced in order to enhance the cell activation. Therefore, the applicability of magnetic field was studied. This paper was concerned with in vitro study of magnetic field effects on macrophage/monocytes and lymphocytes activations. Time-varying magnetic field could enhance macrophages/monocytes and lymphocytes activations.


[Stimulatory response to the oxidation of benzidine and other xenobiotics mediated by lipoxygenase in the presence of phenothiazines].
To test the possibility that certain efficient substrates for lipoxygenase (LOX) produce shuttle oxidants that stimulate the generation of reactive oxygen species from other chemicals. Metabolic interactions were conducted in vitro between chlorpromazine (BZ) or other phenothiazines and benzidine or other xenobiotics mediated by soybean lipoxygenase (SLO) or purified human term placental lipoxygenase (HTPLO) in the presence of hydrogen peroxide, and the rates of xenobiotics oxidation were measured by spectroscopic analysis. Chlorpromazine cation radical (CPZ(*+)) generated by lipoxygenase triggered a rapid oxidation of benzidine to benzidine diimine cation. Under the experimental conditions used, the metabolic interaction resulted in a 42-fold greater stimulation than BZ alone in the rate of BZ oxidation. The magnitude of stimulation of benzidine oxidation exhibited a dependence on the pH of the reaction medium, amount of the enzyme, and concentration of chlorpromazine, BZ, and hydrogen peroxide. A number of other phenothiazines were also found to stimulate BZ oxidation, albeit to a lesser degree. Chlorpromazine cation radical stimulated the oxidation of all six other xenobiotics tested. The highest stimulation (94-fold) was noted in the oxidation of tetramethyl phenylenediamine to Wursters blue radical, while the lowest stimulatory response (2-fold) was observed in guaiacol. Preliminary data showed that purified HTPLO also displayed a similar stimulatory response to benzidine oxidation in the presence of chlorpromazine. Both soybean lipoxygenase and purified human term placental lipoxygenase can mediate stimulatory response to the oxidation of benzidine and other xenobiotics in the presence of phenothiazines.


EFFECT OF O-METHYL-DL-THREONINE AND O-METHYL-DL-SERINE ON GROWTH AND PROTEIN SYNTHESIS IN ESCHERICHIA COLI.
Neale, S. (Department of Botany, University College, London, England), and H. Tristram. Effect of O-methyl-dl-threonine and O-methyl-dl-serine on growth and protein synthesis in Escherichia coli. J. Bacteriol. 86:1241-1250. 1963.-Addition of either O-methyl-dl-threonine or O-methyl-dl-serine to exponentially growing cultures of Escherichia coli resulted in "linear" increases in optical density. The total cell count, however, remained constant, the increase in optical density being accompanied by a marked increase in cell length. In the presence of O-methyl-dl-serine, a phase of "linear" growth was followed by exponential growth, which was maintained during a second passage through analogue-containing medium but not after a subsequent passage through normal medium, suggesting phenotypic adaptation to the analogue. The differential rate of incorporation of amino acids into trichloroacetic acid-insoluble material was unaffected by growth in the presence of either O-methyl-dl-threonine or O-methyl-dl-serine. Neither analogue was incorporated into E. coli protein. The effect of the analogues on the production of alkaline phosphatase and beta-galactosidase was examined. The precise point and mode of action of the analogues have not been determined, but available evidence suggests that the growth-inhibitory effects of both substances are due to interference with the biosynthesis of threonine and methionine.


Uncommon co-infection due to Moniezia expansa and Moniezia benedeni in young goats from Romania: morphological and histopathological analysis.
Digestive parasitoses negatively affect the goat's health, the gain weight of the kids, the efficiency of food conversion, fertility, and productivity, causing important economic losses. This investigation was carried out on a group of goats, Carpathian breed, in the hill area of Tg. Frumos-Iași, to specify the etiology of the acute digestive syndrome, triggered towards the end of the pasturing season, in the young goats. In this context, four sick animals, aged 6-8 months, were slaughtered. Morphological, pathological, and parasitological examination of dissected animals was conducted. Multiple tapeworms belonging to Moniezia expansa and Moniezia benedeni species were found. From the duodenum, jejunum, ileum, fragments were taken for the histopathological processing. The identification of the tapeworm species was carried out through morphological differentiation. The prevalence of tapeworm infection in the examined animals was 100% of which M. expansa was 56.10% and M. benedeni was 43.90%. The average infection intensity was 10.25 tapeworms/animal. The average intensity of infection with M. expansa was 7.5 tapeworms/ animal, and with M. benedeni it was 4.5 tapeworms/animal. Severe pathological lesions in the small intestine such as occlusion, intestinal obstruction, catarrhal inflammation, total atrophy of intestinal villi, ulcerations were produced by the parasites, which led to the clinical expression of the disease and to direct economic losses. The infection with the Moniezia benedeni species is noticed for the first time in Romania, in young goats.


Transfer of defined numbers of chloroplasts into albino protoplasts using an improved subprotoplast/protoplast microfusion procedure: transfer of only two chloroplasts leads to variegated progeny.
A procedure is described by which it is possible to perform controlled microfusion of microscopically selected protoplast fusion partners with high efficiencies. The procedure is applied to fusion of Nicotiana tabacum (line 92V37. N. undulata cytoplasm) plastid albino protoplasts as a recipient and spontaneously formed subprotoplasts of green N. tabacum (line SR1) as donor. Products of individual electrofusion events are cloned via single cell nurse culture and the derived cell lines are analysed for the occurrence of variegated or green regenerating shoots, which are indicative of the establishment of the transferred organelles in the cell progeny. The plastid population in green regenerants recovered after the transfer of only two chloroplasts was demonstrated to have originated from the donor subprotoplast organelles by restriction analysis of total DNA using a plastome-specific probe.


Gaussian mixture model for the identification of psychogenic non-epileptic seizures using a wearable accelerometer sensor.
Any abnormal hypersynchronus activity of neurons can be characterized as an epileptic seizure (ES). A broad class of non-epileptic seizures is comprised of Psychogenic non-epileptic seizures (PNES). PNES are paroxysmal events, which mimics epileptic seizures and pose a diagnostic challenge with epileptic seizures due to their clinical similarities. The diagnosis of PNES is done using video-electroencephalography (VEM) monitoring. VEM being a resource intensive process calls for alternative methods for detection of PNES. There is now an emerging interest in the use of accelerometer based devices for the detection of seizures. In this work, we present an algorithm based on Gaussian mixture model (GMM's) for the identification of PNES, ES and normal movements using a wrist-worn accelerometer device. Features in time, frequency and wavelet domain are extracted from the norm of accelerometry signal. All events are then classified into three classes i.e normal, PNES and ES using a parametric estimate of the multivariate normal probability density function. An algorithm based on GMM's allows us to accurately model the non-epileptic and epileptic movements, thus enhancing the overall predictive accuracy of the system. The new algorithm was tested on data collected from 16 patients and showed an overall detection accuracy of 91% with 25 false alarms.


Mining the ovarian cancer ascites proteome for potential ovarian cancer biomarkers.
Current ovarian cancer biomarkers are inadequate because of their relatively low diagnostic sensitivity and specificity. There is a need to discover and validate novel ovarian cancer biomarkers that are suitable for early diagnosis, monitoring, and prediction of therapeutic response. We performed an in-depth proteomics analysis of ovarian cancer ascites fluid. Size exclusion chromatography and ultrafiltration were used to remove high abundance proteins with molecular mass >/=30 kDa. After trypsin digestion, the subproteome (</=30 kDa) of ascites fluid was determined by two-dimensional liquid chromatography-tandem mass spectrometry. Filtering criteria were used to select potential ovarian cancer biomarker candidates. By combining data from different size exclusion and ultrafiltration fractionation protocols, we identified 445 proteins from the soluble ascites fraction using a two-dimensional linear ion trap mass spectrometer. Among these were 25 proteins previously identified as ovarian cancer biomarkers. After applying a set of filtering criteria to reduce the number of potential biomarker candidates, we identified 52 proteins for which further clinical validation is warranted. Our proteomics approach for discovering novel ovarian cancer biomarkers appears to be highly efficient because it was able to identify 25 known biomarkers and 52 new candidate biomarkers that warrant further validation.


Searching for DFT-based methods that include dispersion interactions to calculate the physisorption of H2 on benzene and graphene.
Simulations of the hydrogen storage capacities of nanoporous carbons require an accurate treatment of the interaction of the hydrogen molecule with the graphite-like surfaces of the carbon pores, which is dominated by the dispersion forces. These interactions are described accurately by high level quantum chemistry methods, like the Coupled Cluster method with single and double excitations and a non-iterative correction for triple excitations (CCSD(T)), but those methods are computationally very expensive for large systems and for massive simulations. Density functional theory (DFT)-based methods that include dispersion interactions at different levels of complexity are less accurate, but computationally less expensive. In order to find DFT-methods that include dispersion interactions to calculate the physisorption of H2 on benzene and graphene, with a reasonable compromise between accuracy and computational cost, CCSD(T), Møller-Plesset second-order perturbation theory method, and several DFT-methods have been used to calculate the interaction energy curves of H2 on benzene and graphene. DFT calculations are compared with CCSD(T) calculations, in the case of H2 on benzene, and with experimental data, in the case of H2 on graphene. Among the DFT methods studied, the B97D, RVV10, and PBE+DCACP methods yield interaction energy curves of H2-benzene in remarkable agreement with the interaction energy curve obtained with the CCSD(T) method. With regards to graphene, the rev-vdW-DF2, PBE-XDM, PBE-D2, and RVV10 methods yield adsorption energies of the lowest level of H2 on graphene, very close to the experimental data.


Optimal bladder filling during high-dose-rate intracavitary brachytherapy for cervical cancer: a dosimetric study.
The aim of this study is to compare 3D dose volume histogram (DVH) parameters of bladder and other organs at risk with different bladder filling protocol during high-dose-rate intracavitary brachytherapy (HDR-ICBT) in cervical cancer, and to find optimized bladder volume. This dosimetric study was completed with 21 patients who underwent HDR-ICBT with computed tomography/magnetic resonance compatible applicator as a routine treatment. Computed tomography planning was done for each patient with bladder emptied (series 1), after 50 ml (series 2), and 100 ml (series 3) bladder filling with a saline infusion through the bladder catheter. Contouring was done on the Eclipse Planning System. 7 Gy to point A was prescribed with the standard loading patterns. Various 3D DVH parameters including 0.1 cc, 1 cc, 2 cc doses and mean doses to the OAR's were noted. Paired t-test was performed. The mean (± SD) bladder volume was 64.5 (± 25) cc, 116.2 (± 28) cc, and 172.9 (± 29) cc, for series 1, 2, and 3, respectively. The 0.1 cm3,1 cm3, 2 cm3 mean bladder doses for series 1, series 2, and series 3 were 9.28 ± 2.27 Gy, 7.38 ± 1.72 Gy, 6.58 ± 1.58 Gy; 9.39 ± 2.28 Gy, 7.85 ± 1.85 Gy, 7.05 ± 1.59 Gy, and 10.09 ± 2.46 Gy, 8.33 ± 1.75 Gy, 7.6 ± 1.55 Gy, respectively. However, there was a trend towards higher bladder doses in series 3. Similarly, for small bowel dose 0.1 cm3, 1 cm3, and 2 cm3 in series 1, 2, and 3 were 5.44 ± 2.2 Gy, 4.41 ± 1.84 Gy, 4 ± 1.69 Gy; 4.57 ± 2.89 Gy, 3.78 ± 2.21 Gy, 3.35 ± 2.02 Gy, and 4.09 ± 2.38 Gy, 3.26 ± 1.8 Gy, 3.05 ± 1.58 Gy. Significant increase in small bowel dose in empty bladder (series 1) compared to full bladder (series 3) (p = 0.03) was noted. However, the rectal and sigmoid doses were not significantly affected with either series. Bladder filling protocol with 50 ml and 100 ml was well tolerated and achieved a reasonably reproducible bladder volume during cervical brachytherapy. In our analysis so far, there is no significant impact of bladder filling on DVH parameters, although larger bladders tend to have higher doses. Small bowel doses are lesser with higher bladder volumes. Further evaluation and validation are necessary.


Preparation and characterization of alloys of the Ti-15Mo-Nb system for biomedical applications.
In the development of new metallic biomaterials, the Ti-15Mo alloy has great prominence because of its excellent corrosion resistance and good combination of mechanical properties. In this study, the element niobium was added to the Ti-15Mo alloy, forming the Ti-15Mo-Nb system for the purpose of improving their properties and promoting its application as a biomaterial. These alloys are very promising to use as biomedical implants, because they integrate a new class of titanium alloys without the presence of aluminum and vanadium, which may cause cytotoxic effects. The alloys were produced by arc-melting and characterized by density, X-ray diffraction, scanning electron microscopy, microhardness, elastic modulus, corrosion, and cytotoxicity assays. The developed alloys have β phase predominance (with bcc crystalline structure). The addition of niobium decreases the microhardness and elastic modulus, with values around 80 GPa, which is well below that of the metallic alloys used commercially for this type of application. Very low passive current densities were found for all alloys studied showing that the passive film on these alloys is highly protective. In vitro cytotoxicity tests revealed that the introduction of niobium did not cause cytotoxic effects in the studied alloys. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 639-648, 2018.


Rabbits (Oryctolagus cuniculus) increase caecal calcium absorption at increasing dietary calcium levels.
Hindgut fermenting herbivores from different vertebrate taxa, including tortoises, and among mammals some afrotheria, perissodactyla incl. equids, several rodents as well as lagomorphs absorb more calcium (Ca) from the digesta than they require, and excrete the surplus via urine. Both proximate and ultimate causes are elusive. It was suggested that this mechanism might ensure phosphorus availability for the hindgut microbiome by removing potentially complex-building Ca from the digesta. Here we use Ussing chamber experiments to show that rabbits (Oryctolagus cuniculus) maintained on four different diets (six animals/diet) increase active Ca absorption at increasing Ca levels. This contradicts the common assumption that at higher dietary levels, where passive uptake should be more prevalent, active transport can relax and hence supports the deliberate removal hypothesis. In the rabbits, this absorption was distinctively higher in the caecum than in the duodenum, which is unexpected in mammals. Additional quantification of the presence of two proteins involved in active Ca absorption (calbindin-D9K CB; vitamin D receptor, VDR) showed higher presence with higher dietary Ca. However, their detailed distribution across the intestinal tract and the diet groups suggests that other factors not investigated in this study must play major roles in Ca absorption in rabbits. Investigating strategies of herbivores to mitigate potential negative effects of Ca in the digesta on microbial activity and growth might represent a promising area of future research.


Partners HealthCare Center for Connected Health.
This article reviews the history, current status, and future plans of the Partners HealthCare Center for Connected Health (the Center). Established in 1995 by Harvard Medical School teaching hospitals, the Center develops strategies to move healthcare from the hospital and doctor's office into the day-to-day lives of patients. It leverages information technology to help manage chronic conditions, maintain health and wellness, and improve adherence to prescribed regimen, patient engagement, and clinical outcomes. Since inception, it has served over 30,000 patients. The Center's core functions include videoconference-based real-time virtual visits, home vital sign monitoring, store-and-forward online consultations, social media, mobile technology, and other novel methods of providing care and enabling health and wellness remotely and independently of traditional time and geographic constraints. It offers a wide range of services, programs, and research activities. The Center comprises over 40 professionals with various technical and professional skills. Internally within Partners HealthCare, the role of the Center is to collaborate, guide, advise, and support the experimentation with and the deployment and growth of connected health technologies, programs, and services. Annually, the Center engages in a deliberative planning process to guide its annual research and operational agenda. The Center enjoys a diversified revenue stream. Funding sources include institutional operating budget/research funds from Partners HealthCare, public and private competitive grants and contracts, philanthropic contributions, ad hoc funding arrangements, and longer-term contractual arrangements with third parties.


Evolution of Aging Theories: Why Modern Programmed Aging Concepts Are Transforming Medical Research.
Programmed aging refers to the idea that senescence in humans and other organisms is purposely caused by evolved biological mechanisms to obtain an evolutionary advantage. Until recently, programmed aging was considered theoretically impossible because of the mechanics of the evolution process, and medical research was based on the idea that aging was not programmed. Theorists struggled for more than a century in efforts to develop non-programmed theories that fit observations, without obtaining a consensus supporting any non-programmed theory. Empirical evidence of programmed lifespan limitations continued to accumulate. More recently, developments, especially in our understanding of biological inheritance, have exposed major issues and complexities regarding the process of evolution, some of which explicitly enable programmed aging of mammals. Consequently, science-based opposition to programmed aging has dramatically declined. This progression has major implications for medical research, because the theories suggest that very different biological mechanisms are ultimately responsible for highly age-related diseases that now represent most research efforts and health costs. Most particularly, programmed theories suggest that aging per se is a treatable condition and suggest a second path toward treating and preventing age-related diseases that can be exploited in addition to the traditional disease-specific approaches. The theories also make predictions regarding the nature of biological aging mechanisms and therefore suggest research directions. This article discusses developments of evolutionary mechanics, the consequent programmed aging theories, and logical inferences concerning biological aging mechanisms. It concludes that major medical research organizations cannot afford to ignore programmed aging concepts in assigning research resources and directions.


Cytotoxic epimeric withaphysalins from leaves of Acnistus arborescens.
Phytochemical analysis of the leaves of Acnistus arborescens (Solanaceae) resulted in the isolation of two new epimeric withaphysalins (17S,20R,22R)-5beta,6beta: 18,20-diepoxy-4beta,18-dihydroxy-1-oxowitha-24-enolide (2, 18R and 18S), together with the known withaphysalin F (1, 18R and 18S). Their structures were established by spectroscopic methods, including 2D NMR data and comparison with literature data. Compounds 1 and 2 dis-played potent cytotoxic activities against several cancer cell lines with IC50 values in the range of 0.20 to 1.46 microg/mL for 1 and 0.89 to 8.08 microg/mL for 2. The strong cytotoxicity presented by 1 suggests that in this series of compounds, the 2,3-unsaturated ketone moiety is an important pharmacophoric unit. The cytotoxic activity seemed to be related to DNA synthesis inhibition, as revealed by the reduction of 5-bromo-2'-deoxyuridine incorporation after 24 hours of incubation on leukemic cells.


Chloroquine resistance and the pH of the malaria parasite's digestive vacuole.
The molecular mechanisms underlying chloroquine resistance in the malaria parasite are not well understood. Recent studies have focused attention on the role of the pH of the parasite's 'digestive vacuole', an internal acidic compartment in which ingested host cell proteins are degraded. In these studies, vacuolar pH was estimated from measurements of fluorescence from parasites stained with acridine orange. The validity of the method, and the conclusions drawn, have been challenged. Nevertheless, the correlation observed between acridine orange fluorescence and chloroquine resistance is intriguing and may well provide insights into the resistance mechanism. Whether vacuolar pH plays a role in chloroquine resistance remains an open question.


Stigmata in the history: between faith, mysticism and science.
Stigmata are one of the most ancient and fascinating mysteries of the Christian religion. The word "stigmata" derives by the Greek "stigma", that means sign, mark. Classically, stigmata are the sores inflicted on Jesus Christ during his passion and crucifixion. Today, the term stigmatized has been extended to designate several cases of individuals, who show skin sores similar to those of Christ. The Authors report a brief history of stigmata, trying to give an explanation to such a fascinating phenomenon.


An unusual, His-dependent family I pyrophosphatase from Mycobacterium tuberculosis.
Soluble inorganic pyrophosphatases (PPases) comprise two evolutionarily unrelated families (I and II). These two families have different specificities for metal cofactors, which is thought to be because of the fact that family II PPases have three active site histidines, whereas family I PPases have none. Here, we report the structural and functional characterization of a unique family I PPase from Mycobacterium tuberculosis (mtPPase) that has two His residues (His21 and His86) in the active site. The 1.3-A three-dimensional structure of mtPPase shows that His86 directly interacts with bound sulfate, which mimics the product phosphate. Otherwise, mtPPase is structurally very similar to the well studied family I hexameric PPase from Escherichia coli, although mtPPase lacks the intersubunit metal binding site found in E. coli PPase. The cofactor specificity of mtPPase resembles that of E. coli PPase in that it has high activity in the presence of Mg2+, but it differs from the E. coli enzyme and family II PPases because it has much lower activity in the presence of Mn2+ or Zn2+. Replacements of His21 and His86 in mtPPase with the residues found in the corresponding positions of E. coli PPase had either no effect on the Mg2+- and Mn2+-supported reactions (H86K) or reduced Mg2+-supported activity (H21K). However, both replacements markedly increased the Zn2+-supported activity of mtPPase (up to 11-fold). In the double mutant, Zn2+ was a 2.5-fold better cofactor than Mg2+. These results show that the His residues in mtPPase are not essential for catalysis, although they determine cofactor specificity.


Increased thyroxine turnover and thyroidal function after stimulation of hepatocellular binding of thyroxine by phenobarbital.
Administration of phenobarbital to rats in a dosage schedule previously demonstrated to increase hepatocellular binding of thyroxine results in increased hormonal turnover, due both to increased deiodination and to fecal disposition of thyroxine iodine. The rate of biliary excretion of thyroxine iodine is roughly proportional to the hepatic content of exchangeable thyroxine. The enhanced peripheral disposition of thyroxine appears to lead to increased thyroidal function, as measured by isotopic iodine studies, and the maintenance of a normal nonradioactive serum PBI. On the other hand, thyroidectomized animals maintained on a constant replacement dose of L-thyroxine and treated with phenobarbital exhibit a marked fall in serum PBI. These findings suggest that increased thyroxine flux in phenobarbital-treated animals is secondary to primary stimulation of hepatocellular binding. Exchangeable intracellular thyroxine may thus be an important determinant of hormone turnover and, possibly, of hormonal action.


Is the gram stain useful in the microbiologic diagnosis of VAP? A meta-analysis.
In a meta-analysis examining respiratory specimen Gram stain for diagnosis of ventilator-associated pneumonia, absence of bacteria on Gram stain had a high negative predictive value, but a positive Gram stain correlated poorly with organisms recovered in culture. Rapid and accurate diagnosis of ventilator-associated pneumonia (VAP) is a major challenge and no generally accepted gold standard exists for VAP diagnosis. We conducted a meta-analysis to examine the role of respiratory specimen Gram stain to diagnose VAP, and the correlation with final culture results. In 21 studies, pooled sensitivity of Gram stain for VAP was 0.79 (95% confidence interval [CI], .77-0.81; P < .0001) and specificity was 0.75 (95% CI, .73-.78; P < .0001). Negative predictive value of Gram stain for a VAP prevalence of 20%-30% was 91%, suggesting that VAP is unlikely with a negative Gram stain but the positive predictive value of Gram stain was only 40%. Pooled kappa was 0.42 for gram-positive organisms and 0.34 for gram-negative organisms, suggesting fair concordance between organisms on Gram stain and recovery by culture. Therefore, a positive Gram stain should not be used to narrow anti-infective therapy until culture results become available.


Transactivation of Abl by the Crk II adapter protein requires a PNAY sequence in the Crk C-terminal SH3 domain.
To gain a better understanding of how Crk II regulates the function of the Abl tyrosine kinase, we explored the function of the C-terminal linker and SH3 domain, a region of Crk II that is still poorly understood. Molecular modeling, tryptophan fluorescence, and covariation sequence alignment indicate that the Crk-SH3-C has a unique binding groove and RT loop not observed in typical SH3 domains. Based on these models, we made a series of mutations in the linker and in residues predicted to destabilize the putative binding pocket and RT loop. In Abl transactivation assays, Y222F and P225A mutations in the linker resulted in strong transactivation of Abl by Crk II. However, mutations predicted to be at the surface of the Crk SH3-C were not activators of Abl. Interestingly, combinations of activating mutations of Crk II with mutations in the highly conserved PNAY sequence in the SH3-C inactivated the activating mutations, suggesting that the SH3-C is necessary for activation. Our data provide insight into the role of highly conserved residues in the Crk-SH3-C, suggesting a mechanism for how the linker and the Crk-SH3-C function in the transactivation of the Abl tyrosine kinase.


Spatial heterogeneity in epithelial to mesenchymal transition properties of circulating tumor cells associated with distant recurrence in pancreatic cancer patients.
The spatial heterogeneity of epithelial to mesenchymal transition (EMT)-related circulating tumor cells (CTCs) within the circulatory system and its potential clinical relevance remain unclear in pancreatic cancer (PC) patients. We aimed to map the distribution of EMT-related CTCs along the spreading pathway and investigate the prognostic significance due to the potential spatial heterogeneity in the count and phenotypic properties of CTCs. Both portal vein (PoV) and peripheral vein (PV) blood samples were collected from 39 PC patients. CTCs were isolated by using a CD45 negative enrichment method, and EMT-related phenotypes in CTCs were analyzed by 4-channel immunofluorescence. The correlations of CTCs with patient characteristics and recurrence-free survival (RFS) were analyzed. Both the number {median CTC total count, 10 [6-16] in PoV vs. 5 [1-7] in PV per mL, P<0.0001} and EMT status of CTCs [median mesenchymal CTC (M-CTC) percentage, 0.33 (0.13-0.52) in PoV vs. 0.2 (0-0.4) in PV, P=0.0211] showed significant spatial heterogeneity during dissemination from the PoV to the PV. Univariate analysis adjusting for patient age and sex revealed that CTC total count and M-CTC percentage in PoV samples could be risk factors for RFS in PC patients (P=0.003 and P=0.001, respectively), and ROC curve analysis found that both of these factors had good performance in distinguishing patients with early distant recurrence (within 6 months), with the optimal cut-off values of 14 cells/mL (AUROC =0.893, sensitivity =0.857, specificity =0.813, P=0.001) and 0.545 (AUROC =0.795, sensitivity =0.714, specificity =0.906, P=0.016), respectively. Multivascular assessment of EMT-related CTCs suggested profound dynamic alterations in total count and phenotypes during dissemination, and the spatial heterogeneity of CTCs in circulation could help establish novel prognosis markers in PC patients.


Metabolomic profile of amniotic fluid to evaluate lung maturity: the diaphragmatic hernia lamb model.
Tracheal occlusion (TO) stimulates lung growth in fetuses affected with congenital diaphragmatic hernia (CDH) although the processes involved in lung maturation still remain unknown. The objective of this study was to evaluate the metabolomic profile of amniotic fluid (AF) following TO in fetal lamb model in order to obtain an indirect view of mechanisms involved in pulmonary reversal hypoplasia and biochemical maturity in response to fetal TO. Liquid Chromatography Mass Spectrometry was performed on lamb AF samples at: age I (70 days' gestation); age II (102 days' gestation); age III (136 days' gestation). CDH was induced at age I and TO at age II. Betaine, choline, creatinine were found significantly increased during gestation in the control group. The CDH group showed choline (p =0.007) and creatinine (p =0.004) decreases during pregnancy. In the TO group choline and creatinine profiles were restored. Alveolar tissue and fetal global growth ameliorated after TO. Metabolomics provided useful information on biochemical details during lung maturation. Metabolomic profiling would help to identify the best time to perform TO, in order to increase survival of CDH affected patients.


Immuno-profiling of Brucella proteins for developing improved vaccines and DIVA capable serodiagnostic assays for brucellosis.
Brucellosis remains a worldwide zoonotic disease with a serious impact on public health and livestock productivity. Controlling brucellosis in livestock is crucial for limiting human infections in the absence of effective human vaccines. Brucellosis control measures are majorly dependent on rigorous monitoring of disease outbreaks and mass vaccination of livestock. Live attenuated vaccines are available for livestock vaccination that play a vital role in brucellosis control programs in many countries. Even though the existing animal vaccines confer protection against brucellosis, they carry some drawbacks, including their infectivity to humans and interference with sero-monitoring. The available serodiagnostic assays for brucellosis depend on detecting anti-LPS antibodies in the serum. Since diagnosis plays a vital role in controlling brucellosis, developing improved serodiagnostic assays with enhanced specificity, sensitivity and DIVA capability is required. Therefore, it is essential to identify novel antigens for developing improved vaccines and serodiagnostic assays for brucellosis. In the present study, we performed a high throughput immunoprofiling of B. melitensis protein microarray using brucellosis-positive human and animal serum samples. The screening identified several serodominant proteins of Brucella that exhibited common or differential reactivity with sera from animals and humans. Subsequently, we cloned, expressed, and purified ten serodominant proteins, followed by analyzing their potential to develop next-generation vaccines and improved serodiagnostic assays for brucellosis. Further, we demonstrated the protective efficacy of one of the serodominant proteins against the B. melitensis challenge in mice. We found that the seroreactive protein, Dps (BMEI1980), strongly reacted with brucellosis-positive serum samples, but it did not react with sera from B. abortus S19-vaccinated cattle, indicating DIVA capability. A prototype lateral flow assay and indirect ELISA based on Dps protein exhibited high sensitivity, specificity, and DIVA capability. Thus, the present study identified promising candidates for developing improved vaccines and affordable, DIVA-capable serodiagnostic assays for animal and human brucellosis.


Analysis of codon usage pattern in the viral proteins of chicken anaemia virus and its possible biological relevance.
Chicken anaemia virus (CAV) is an important poultry pathogen. CAV infection can lead to severe immunosuppression and mortality in birds. The viral proteins (VP1, VP2 and VP3) are major protective immunogens that determine the pathotype of CAV strains. The factors influencing the synonymous codon usage bias and the nucleotide composition of the viral protein genes of CAV have not been studied. In the present study, we have analysed the synonymous codon usage pattern in VP1, VP2 and VP3 genes of CAV. Our results showed that all the genes have a low codon usage bias; however, this bias was slightly higher in the VP2 gene as compared to VP1 and VP3. The major contributing factor for this pattern of codon usage bias in CAV is mutational pressure followed by the host factors. The conclusion was drawn based on codon usage, correspondence analysis, ENC-GC3 plot and correlation analyses among different indices. The study will help us to understand the codon usage bias of CAV and related single-stranded DNA viruses which could further be used to explore their biology.


Retrospective study of rare cutaneous malignant adnexal tumors of the head and neck in a tertiary care cancer hospital: a case series.
Adnexal tumors of the skin are a large and diverse group of benign and malignant neoplasms, which exhibit morphological differentiation toward one of the different types of adnexal epithelium present in normal skin and they pose a diagnostic challenge. The purpose of this study is to share our experience with these rare but aggressive tumors at a tertiary care cancer hospital in a developing country. A retrospective review of 11 patients diagnosed with rare adnexal tumors and their variants from January 2005 to December 2014, treated either surgically or non-surgically, was performed to describe the clinicopathological characteristics and outcome of the disease. A total of 11 patients were diagnosed with adnexal carcinoma and its variants: a 34-year-old Sindhi man, a 59-year-old Punjabi woman, a 32-year-old woman from Khyber Pakhtunkhwa, a 43-year-old Punjabi woman, a 64-year-old Punjabi man, a 51-year-old man from Khyber Pakhtunkhwa, a 51-year-old Punjabi woman, a 74-year-old Punjabi woman, a 75-year-old Punjabi man, a 61-year-old man from Khyber Pakhtunkhwa, and a 53-year-old man from Khyber Pakhtunkhwa. The male to female ratio was 1.2:1. The histological variations were sebaceous differentiation (n = 4), microcystic adnexal carcinoma (n = 4), trichilemmal carcinoma (n = 1), pilomatrix carcinoma (n = 1), and hidradenocarcinoma (n = 1). The mean age at presentation was 54 years (range 32 to 75). The primary subsite of involvement was the scalp in nine patients followed by eyelids in two patients. Surgery was the primary treatment modality in almost all patients; postoperative radiotherapy (PORT) was offered to eight patients. The median dose of radiation was 45 Gy to the primary site. Indications for radiotherapy included close margins (n = 2), positive margins (n = 1), high grade histology (n = 4), and multifocal disease (n = 1). On follow-up, two patients presented with local, one regional and two patients developed distant metastasis. Adnexal carcinomas are rare tumors with diverse histological patterns and a tendency for locoregional and distant metastasis. Surgery should be the mainstay of treatment reserving radiotherapy for adjuvant, palliative, and re-treatment scenarios.


Overview: Dietary fat and atherosclerosis.
Research on the effects of dietary fat on cholesterolemia and coronary risk began with comparisons of the amount and type of fat (saturated vs unsaturated). It then became clear that not all fatty acids had similar cholesterolemic effects and equations were derived which gave different weights to saturated and unsaturated fatty acids. We now find that the triglyceride structure also plays a role in cholesterolemia as suggested by the studies of Kritchevsky and Tepper in rabbits and McGandy et al. in human subjects.


Detrimental influences of intraluminally-administered sclerotic agents on surrounding tissues and peripheral nerves: an experimental study.
The minimally-invasive nature of sclerotherapy makes it one of the first treatment options for venous malformations, although treatment-related complications, such as peripheral nerve paralysis, have been reported in some clinical cases. However, no studies of the aetiology of the detrimental effects of intraluminally-administered sclerotic agents on the surrounding tissues, including the peripheral nerves, have yet been published. This study therefore investigated the influences of intraluminally-administered sclerotic agents on the tissues surrounding the injection site using a newly-developed rat femoral vein model. Using this model, the effects of absolute ethanol, 5% ethanolamine oleate, and 1% polidocanol were compared histologically with those of normal saline controls. Fluorescein isothiocyanate-conjugated agents were administered and the leakage of sclerotic agents through the venous wall was evaluated by fluorescence microscopy. Damage to the adjacent femoral nerve was quantitatively evaluated by counting the numbers of axons in cross-sections. All the sclerotic agents caused vascular wall injuries and leakage into the surrounding tissues. The number of axons in the femoral nerve was significantly reduced following administration of absolute ethanol or 5% ethanolamine oleate, compared with normal saline. The results of this study suggest that sclerotic agents commonly leak out the vascular lumen, and some agents can cause adjacent nerve injury. It is important to be aware of this type of complication of sclerotherapy for venous malformations when selecting appropriate therapeutic interventions.


Unilateral upper extremity edema. A case report.
A case report of a 28-year-old Hispanic male with a 5-month history of left arm, face and supraclavicular edema is presented. Chest radiography revealed bilateral pleural effusions. Thoracentesis was negative for malignant cells. Left arm venogram demonstrated compression of the left subclavian vein and lymphangiogram was consistent with perilymphatic stasis. Computerized tomography and magnetic resonance imaging demonstrated a questionable mass in the left side of the neck. On exploration of the left supraclavicular fossa, a severely fibrotic thoracic duct was encountered as well as a prominent scalene lymph node. Pathological section revealed an adenocarcinoma in both specimens which was positive for keratin and carcinoembryonic antigen. Chemotherapy was begun, however, the patient died 3 months later secondary to a respiratory arrest. This presentation of an adenocarcinoma arising from an unknown gastrointestinal source is unusual. A search should be made to locate the primary site. Prognosis is unclear but presumed poor due to the rarity of this presentation.


Modulation of attention networks serving reorientation in healthy aging.
Orienting attention to behaviorally relevant stimuli is essential for everyday functioning and mainly involves activity in the dorsal and ventral frontoparietal networks. Many studies have shown declines in the speed and accuracy of attentional reallocation with advancing age, but the underlying neural dynamics remain less understood. We investigated this age-related decline using magnetoencephalography (MEG) and a Posner task in 94 healthy adults (22-72 years old). MEG data were examined in the time-frequency domain, and significant oscillatory responses were imaged using a beamformer. We found that participants responded slower when attention reallocation was needed (i.e., the validity effect) and that this effect was positively correlated with age. We also found age-related validity effects on alpha activity in the left parietal and beta in the left frontal-eye fields from 350-950 ms. Overall, stronger alpha and beta responses were observed in younger participants during attention reallocation trials, but this pattern was reversed in the older participants. Interestingly, this alpha validity effect fully mediated the relationship between age and behavioral performance. In conclusion, older adults were slower in reorienting attention and exhibited age-related alterations in alpha and beta responses within parietal and frontal regions, which may reflect increased task demands depleting their compensatory resources.


The hunt for protective correlates of immunity to Plasmodium falciparum malaria.
Determining an immunologic correlate of protection against Plasmodium falciparum malaria has been the holy grail of natural infection studies, and sought after as an endpoint for malaria vaccine trials. An in vitro assay that provides an accurate and precise assessment of protective immunity to malaria would make smaller, short-duration studies feasible, rather than the currently powered study designs that use morbidity or mortality as outcomes. Such a biomarker would be especially desirable in situations where malaria control measures that result in decreases in clinical endpoints and putatively waning protective immunity have been implemented. In an article published in BMC Medicine, Osier and colleagues addressed this problem, and demonstrated that antibodies promoting opsonic phagocytosis of merozoites provide a functional link between antigen-specific responses and protection. Understanding the mechanisms conferring protection against malaria not only improves our knowledge of basic human immunology, but promises to help in the design of an effective malaria vaccine.


[Dosimetric consequences of the application of a rectum hull-planning volume for treatment planning of intensity modulated radiotherapy of prostate cancer].
The present study evaluated a hull-volume definition strategy for the planning organ at risk volume (PRV) for the rectum in the planning of radiotherapy of prostate cancer. The bounding volumes of rectum contours of 1 to 5 CT scans were compared on the basis of the rectum coverage probabilities for 5 patients. In addition, IMRT treatment plans were optimized using the rectum hull PRV5 of 5 CTs and each of the conventional rectum contours PRV1. The plans were compared on the basis of the organ doses caused by the individual organ motion. PRV5 allowed to cover the rectum with a probability of nearly 90% (PRV1 67%). Rectal wall dose showed a great variability for PRV1, while planned and treatment dose agreed well for PRV5 due to the improved geometric information which resulted in a better rectal sparing. In conclusion, the rectum hull-volume PRV5 is a well suited PRV for planning of IMRT dose distributions allowing dose escalation as well as rectal sparing.


Implantable volume monitor and miniaturized stimulator dedicated to bladder control.
This paper describes a new miniaturized implantable bladder controller that is composed of 4 main parts: a volume monitoring device based on the tomography approach, a fully programmable miniaturized central processor and stimulator, a bidirectional data and power link, and an external controller. The proposed system is intended to restore both normal bladder functions (retention and voiding) to spinal cord injured patients. The system contains a mixed-signal (analog/digital) feedback loop to command the bladder functions through neuromuscular stimulation techniques. The implantable circuitry is powered by a single encoded radiofrequency carried and may have up to 8 independently controlled monopolar (4 bipolar) channels. The microstimulator is able to generate a wide range of stimulation patterns, including selective stimulation waveforms. In addition, an optical link transmits the state of the implant and volume monitoring results to the external controller.


Identification of prognostic risk factors for pancreatic cancer using bioinformatics analysis.
Pancreatic cancer is one of the most common malignant cancers worldwide. Currently, the pathogenesis of pancreatic cancer remains unclear; thus, it is necessary to explore its precise molecular mechanisms. To identify candidate genes involved in the tumorigenesis and proliferation of pancreatic cancer, the microarray datasets GSE32676, GSE15471 and GSE71989 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between Pancreatic ductal adenocarcinoma (PDAC) and nonmalignant samples were screened by GEO2R. The Database for Annotation Visualization and Integrated Discovery (DAVID) online tool was used to obtain a synthetic set of functional annotation information for the DEGs. A PPI network of the DEGs was established using the Search Tool for the Retrieval of Interacting Genes (STRING) database, and a combination of more than 0.4 was considered statistically significant for the PPI. Subsequently, we visualized the PPI network using Cytoscape. Functional module analysis was then performed using Molecular Complex Detection (MCODE). Genes with a degree ≥10 were chosen as hub genes, and pathways of the hub genes were visualized using ClueGO and CluePedia. Additionally, GenCLiP 2.0 was used to explore interactions of hub genes. The Literature Mining Gene Networks module was applied to explore the cocitation of hub genes. The Cytoscape plugin iRegulon was employed to analyze transcription factors regulating the hub genes. Furthermore, the expression levels of the 13 hub genes in pancreatic cancer tissues and normal samples were validated using the Gene Expression Profiling Interactive Analysis (GEPIA) platform. Moreover, overall survival and disease-free survival analyses according to the expression of hub genes were performed using Kaplan-Meier curve analysis in the cBioPortal online platform. The relationship between expression level and tumor grade was analyzed using the online database Oncomine. Lastly, the eight snap-frozen tumorous and adjacent noncancerous adjacent tissues of pancreatic cancer patients used to detect the CDK1 and CEP55 protein levels by western blot. Altogether, the DEGs and hub genes identified in this work can help uncover the molecular mechanisms underlying the tumorigenesis of pancreatic cancer and provide potential targets for the diagnosis and treatment of this disease.


Genome-Wide Identification and Characterization of UTR-Introns of Citrus sinensis.
Introns exist not only in coding sequences (CDSs) but also in untranslated regions (UTRs) of a gene. Recent studies in animals and model plants such as Arabidopsis have revealed that the UTR-introns (UIs) are widely presented in most genomes and involved in regulation of gene expression or RNA stability. In the present study, we identified introns at both 5'UTRs (5UIs) and 3'UTRs (3UIs) of sweet orange genes, investigated their size and nucleotide distribution characteristics, and explored the distribution of cis-elements in the UI sequences. Functional category of genes with predicted UIs were further analyzed using GO, KEGG, and PageMan enrichment. In addition, the organ-dependent splicing and abundance of selected UI-containing genes in root, leaf, and stem were experimentally determined. Totally, we identified 825 UI- and 570 3UI-containing transcripts, corresponding to 617 and 469 genes, respectively. Among them, 74 genes contain both 5UI and 3UI. Nucleotide distribution analysis showed that 5UI distribution is biased at both ends of 5'UTR whiles 3UI distribution is biased close to the start site of 3'UTR. Cis- elements analysis revealed that 5UI and 3UI sequences were rich of promoter-enhancing related elements, indicating that they might function in regulating the expression through them. Function enrichment analysis revealed that genes containing 5UI are significantly enriched in the RNA transport pathway. While, genes containing 3UI are significantly enriched in splicesome. Notably, many pentatricopeptide repeat-containing protein genes and the disease resistance genes were identified to be 3UI-containing. RT-PCR result confirmed the existence of UIs in the eight selected gene transcripts whereas alternative splicing events were found in some of them. Meanwhile, qRT-PCR result showed that UIs were differentially expressed among organs, and significant correlation was found between some genes and their UIs, for example: The expression of VPS28 and its 3UI was significantly negative correlated. This is the first report about the UIs in sweet orange from genome-wide level, which could provide evidence for further understanding of the role of UIs in gene expression regulation.


Macroanatomy of the renicule of the bowhead whale (Balaena mysticetus).
The macroanatomy of renicules and surrounding tissues from the kidneys of five Eskimo-harvested bowhead whales, Balaena mysticetus , was examined. These renicules are similar in overall structure to those of other cetaceans and intermediate in size. There are several important differences including the presence of arcuate vessels within the sporta perimedullaris , the extension of connective tissue from the sporta deep into the peripheral cortex, and the presence of very large, thin-walled veins that occupy the interrenicular spaces. Arterial and venous plexuses outside the substance of the sporta reported in other cetaceans were not observed in the bowhead .


Incident microalbuminuria and complement factor mannan-binding lectin-associated protein 19 in people with newly diagnosed type 1 diabetes.
Evidence links the lectin pathway of complement activation to diabetic kidney disease. Upon carbohydrate-recognition by pattern-recognition molecules, eg, mannan-binding lectin (MBL), the MBL-associated serine protease (MASP-2) is activated and initiates the complement cascade. The MASP2 gene encodes MASP-2 and the alternative splice product MBL-associated protein 19 (MAp19). Both MAp19 and MASP-2 circulate in complex with MBL. We tested the hypothesis that MAp19 and MASP-2 concentrations predict the risk of incident microalbuminuria. Baseline MAp19 and MASP-2 were measured in 270 persons with newly diagnosed type 1 diabetes tracked for incidence of persistent microalbuminuria in a prospective observational 18-year-follow-up study. Seventy-five participants (28%) developed microalbuminuria during follow-up. MBL-associated protein 19 concentrations were higher in participants that later progressed to microalbuminuria as compared with those with persistent normoalbuminuria (268 ng/mL [95% CI, 243-293] vs 236 ng/mL [95% CI, 223-250], P = .02). Participants with MAp19 concentration within the highest quartile of the cohort had an increased risk of microalbuminuria as compared with participants with MAp19 concentration within the combined lower 3 quartiles in unadjusted Cox analysis, hazard ratio 1.86 ([95% CI, 1.17-2.96], P = .009). This remained significant in adjusted models, eg, adjusting for age, sex, HbA1c , systolic blood pressure, urinary albumin excretion, smoking, serum creatinine, and serum cholesterol. MBL-associated serine protease concentration was not associated with incidence of microalbuminuria. In conclusion, the results show an association between baseline MAp19 concentration and the incidence of microalbuminuria in an 18-year-follow-up study on persons with newly diagnosed type 1 diabetes.


[Efficacy of transarterial embolization combined with percutaneous ethanol injection therapy for recurrent hepatocellular carcinoma].
One hundred and eighty-nine patients with hepatocellular carcinoma (HCC) underwent hepatectomy since 1987 to 1992 in our institute. Recurrences were detected on residual liver in 84 patients up to December 1993. Sixty-seven of 84 patients were treated with re-resection (group-O, n = 11), transarterial embolization (TAE) combined with percutaneous ethanol injection therapy (PEIT) (group-TP, n = 13), TAE alone (group-T, n = 34) and intraarterial chemotherapy (group-IA, n = 9). Among these 67 cases, the efficacy of treatment for recurrences was investigated. There was no significant difference in age, positive ratio of hepatitis B virus, ICG R15 and percentage of underlying liver cirrhosis among the 4 groups. However, the frequency of patients with 2 nodules or less, was significantly higher in group-O than in other groups. Cumulative 1-, 2- and 3-year survival rates (%) were 88.9, 64.8 and 51.9 in group-O, 92.1, 55.4 and 55.4 in group-TP, 70.9, 49.6 and 31.0 in group-T, and 16.9, 0 and 0 in group-IA, respectively. The survival rate after recurrences in group-TP was higher than in group-IA and group-T, and almost equivalent to that of group-O. Either re-resection or TAE combined with PEIT might assure- a favorable prognosis in patients with recurrent HCC.


CV-4151--a potent, selective thromboxane A2 synthetase inhibitor.
(E)-7-Phenyl-7-(3-pyridyl)-6-heptenoic acid (CV-4151) inhibited horse platelet microsomal thromboxane (TX) A2 synthetase with an IC50 of 2.6 X 10(-8) M, but even at a high concentration of 10(-4) M it had little effect on cyclooxygenase, PGI2 synthetase and 5-lipoxygenase in in vitro enzymatic assays. CV-4151 did not affect PGI2 release from rat and rabbit aortic tissues in in vitro (10(-4) M) and ex vivo (10 and 100 mg/kg, p.o.) experiments, whereas aspirin (10(-4) M or 10 and 100 mg/kg, p.o.) markedly inhibited PGI2 release in these preparations. When given orally to rats and dogs, CV-4151 markedly inhibited blood TXA2 synthetase activity: the ID50 values (mg/kg, 2 hr later) were 0.05 in rats and 0.17 in dogs. The inhibitory effects at an oral dose of 1 mg/kg lasted more than 24 hr in both species; the inhibition was 41% in rats and 32% in dogs 24 hr after the administration. When injected i.v. to rats and dogs, CV-4151 caused inhibitory effects on TXA2 synthetase equipotent to those observed with the oral administration. In both species, CV-4151 given orally increased concentration of serum immunoreactive 6-keto-PGF1 alpha concomitant with a decrease of serum TXB2-8 concentration. CV-4151 was equipotent to OKY-1580 (IC50: 2.3 X 10 M), a well documented TXA2 synthetase inhibitor, in an in vitro TXA2 synthetase assay. However, CV-4151, given orally or i.v. to rats and dogs, was much more potent and longer acting in inhibition of blood TXA2 production than OKY-1580. Dazoxiben was less potent than these compounds in vitro. In rats, serial oral administration of CV-4151 (10 mg/kg) once daily for 14 days produced a constant and marked reduction of serum TXB2 concentration with concomitant increase of serum immunoreactive 6-keto-PGF1 alpha concentration. No rebound phenomenon in inhibition of TXA2 synthetase was observed after the dosing was stopped. These findings indicate that CV-4151 is a potent and long acting selective inhibitor of TXA2 synthetase and may reorient the metabolism of PG endoperoxides to PGI2.


The association between peri-operative acute risk change (ARC) and long-term survival after cardiac surgery.
Acute risk change has been described as the difference in calculated mortality risk between the pre-operative and postoperative periods of cardiac surgery. We aimed to assess whether this was associated with long-term survival after cardiac surgery. We retrospectively analysed 22,570 cardiac surgical patients, with minimum and maximum follow-up of 1.0 and 6.7 years. Acute risk change was calculated as the arithmetic difference between pre- and postoperative mortality risk. 'Rising risk' represented an increase in risk from pre- to postoperative phase. The primary outcome was one-year mortality. Secondary outcomes included mortality at 3 and 5 years and time to death. Univariable and multivariable analyses were undertaken to examine the relationship between acute risk change and outcomes. Rising risk was associated with higher mortality (5.6% vs. 3.5%, p < 0.001). After adjusting for baseline risk, rising risk was independently associated with increased 1-year mortality (OR 2.6, 95%CI 2.2-3.0, p < 0.001). The association of rising risk with long-term survival was greatest in patients with highest baseline risk. Cox regression confirmed rising risk was associated with shorter time to death (HR 1.86, 1.68-2.05, p < 0.001). Acute risk change may represent peri-operative clinical events in combination with unmeasured patient risk and noise. Measuring risk change could potentially identify patterns of events that may be amenable to investigation and intervention. Further work with case review, and risk scoring with shared variables, may identify mechanisms, including the interaction between miscalibration of risk and true differences in peri-operative care.


6,11-Dihydro-11-oxodibenz [b,e] oxepinacetic acids with potent antiinflammatory activity.
A series of 6,11-dihydro-11-oxodibenz[b,e]oxepinacetic acids was synthesized and the antiinflammatory activity determined. Studies on 29 compounds revealed certain structure-activity relationships. In the carrageenan edema test, eight compounds exhibited higher antiinflammatory activities than did indomethacin. Several compounds (2, 9, 14, 22, 25) also proved to have activities superior or comparable to indomethacin in suppressing chronic as well as acute inflammation and carrageenan-induced hyperesthesia. Gastric irritation and lethality rates were less frequently observed with these compounds.


Transcatheter aortic valve replacement: current perspectives and future implications.
Transcatheter aortic valve replacement (TAVR) or transcatheter aortic valve implantation (TAVI) has emerged as an attractive treatment strategy for the treatment of patients with severe symptomatic aortic stenosis (AS), particularly those who are inoperable or at high risk for surgical aortic valve replacement. Several multicentre registries and randomised trials have demonstrated the safety and efficacy of this technology in improving the survival as well as functional capacity of patients with AS. Most of the elderly patients with severe AS have multiple non-cardiac comorbidities, which might limit survival and impede the improvement in functional capacity afforded by TAVR. Therefore, optimal patient selection based on precise risk assessment is currently the cornerstone of evaluation of patients for TAVR. Due to the need for a multifaceted approach in patient evaluation, procedural conduct as well as postprocedure management, multidisciplinary heart valve teams have assumed a paramount role in the TAVR process. This review presents the current perspectives in patient selection, risk assessment, procedural considerations and outcomes following TAVR, along with implications for the future.


Pre-papillary vitreous opacities associated with Behçet's disease: a case series and review of the literature.
To present pre-papillary vitreous opacity as an uncommon manifestation of inflammation in Behçet's disease that may be specific to this uveitic entity. We retrospectively reviewed the charts of 67 patients with Behçet's disease examined at our clinic between 2005 and 2016. Behçet's disease was diagnosed based on established clinical criteria of inflammation involving the eyes, mucocutaneous junctions, and skin. Patients with Behçet's disease who presented with papillitis and a pre-papillary vitreous opacity were identified. Response to anti-inflammatory treatment on examination and optical coherence tomography imaging were evaluated. PubMed searches were performed for (1) other cases with pre-papillary vitreous opacities in uveitic entities and (2) reports of optic nerve involvement specifically in Behçet's disease. We identified three patients with Behçet's disease who presented with unilateral papillitis and a pre-papillary vitreous opacity. The pre-papillary vitreous opacity had a funnel-shaped appearance on optical coherence tomography. All patients were initially treated with steroids, which led to resolution of the opacity clinically and on imaging. We identified one previous report of such a pre-papillary opacity in a patient with Behçet's disease, and no reports of this finding in other uveitic entities. This study expands the number of Behçet's disease cases presenting with a pre-papillary vitreous opacity and demonstrates novel optical coherence imaging of this finding. This finding may be specific to Behçet's disease as it was not identified in other uveitic entities in a review of the existing literature.


Modified interactive Q-learning for attenuating the impact of model misspecification with treatment effect heterogeneity.
A sequential multiple assignment randomized trial, which incorporates multiple stages of randomization, is a popular approach for collecting data to inform personalized and adaptive treatments. There is an extensive literature on statistical methods to analyze data collected in sequential multiple assignment randomized trials and estimate the optimal dynamic treatment regime. Q-learning with linear regression is widely used for this purpose due to its ease of implementation. However, model misspecification is a common problem with this approach, and little attention has been given to the impact of model misspecification when treatment effects are heterogeneous across subjects. This article describes the integrative impact of two possible types of model misspecification related to treatment effect heterogeneity: omitted early-stage treatment effects in late-stage main effect model, and violated linearity assumption between pseudo-outcomes and predictors despite non-linearity arising from the optimization operation. The proposed method, aiming to deal with both types of misspecification concomitantly, builds interactive models into modified parametric Q-learning with Murphy's regret function. Simulations show that the proposed method is robust to both sources of model misspecification. The proposed method is applied to a two-stage sequential multiple assignment randomized trial with embedded tailoring aimed at reducing binge drinking in first-year college students.


Altered Time Awareness in Dementia.
Our awareness of time, specifically of longer intervals spanning hours, days, months, and years, is critical for ensuring our sense of self-continuity. Disrupted time awareness over such intervals is a clinical feature in a number of frontotemporal dementia syndromes and Alzheimer's disease, but has not been studied and compared systematically in these diseases. We used a semi-structured caregiver survey to capture time-related behavioral alterations in 71 patients representing all major sporadic and genetic syndromes of frontotemporal dementia, in comparison to 28 patients with typical Alzheimer's disease and nine with logopenic aphasia, and 32 healthy older individuals. Survey items pertained to apparent difficulties ordering past personal events or estimating time intervals between events, temporal rigidity and clockwatching, and propensity to relive past events. We used a logistic regression model including diagnosis, age, gender, and disease severity as regressors to compare the proportions of individuals exhibiting each temporal awareness symptom between diagnostic groups. Gray matter associations of altered time awareness were assessed using voxel-based morphometry. All patient groups were significantly more prone to exhibit temporal awareness symptoms than healthy older individuals. Clinical syndromic signatures were identified. While patients with typical and logopenic Alzheimer's disease most frequently exhibited disturbed event ordering or interval estimation, patients with semantic dementia were most prone to temporal rigidity and clockwatching and those with behavioral variant frontotemporal dementia commonly exhibited all these temporal symptoms as well as a propensity to relive past events. On voxel-based morphometry, the tendency to relive past events was associated with relative preservation of a distributed left-sided temporo-parietal gray matter network including hippocampus. These findings reveal a rich and complex picture of disturbed temporal awareness in major dementia syndromes, with stratification of frontotemporal dementia syndromes from Alzheimer's disease. This is the first study to assess symptoms of altered temporal awareness across frontotemporal dementia syndromes and provides a motivation for future work directed to the development of validated clinical questionnaires, analysis of underlying neurobiological mechanisms and design of interventions.


Monitoring ceramic hydroxyapatite media degradation using dynamic image analysis and uniaxial confined bulk compression.
Ceramic hydroxyapatite (CHT) is a multimodal chromatographic medium widely used in the pharmaceutical industry for the purification of biomolecules. CHT is a sintered form of hydroxyapatite crystals with moderate stability at acidic conditions. This moderate stability may lead to underperformance of CHT packed bed lifetime, especially under acidic conditions, which should be monitored by diagnostic tools to design optimal buffer systems for the step. This study presents the application of dynamic image analysis (DIA) and uniaxial confined bulk compression (UCBC) to monitor CHT particle degradation as a function of buffer composition. DIA was used to evaluate changes in solidity and morphology, while UCBC was used to evaluate changes in resistance to uniaxial compression. All properties were studied as a function of bed position and operational parameters. Results show that when CHT is exposed to acidic pH, adding phosphate and/or calcium at concentrations of 1 mM minimizes changes in particle solidity and mechanical strength. Changes in CHT morphological properties (i.e., convexity, aspect ratio) are also affected by the presence of calcium and/or phosphate in the inlet buffers. Furthermore, calcium and phosphate have a positive effect on the mechanical behavior of CHT, which is related to changes in the CHT particle solidity.


Sequence alignments and validation of PCR primers used to detect phylogenetically diverse nrfA genes associated with dissimilatory nitrate reduction to ammonium (DNRA).
PCR primer sets were designed to target nrfA, the gene encoding the pentaheme nitrite reductase NrfA that catalyzes the nitrite ammonification step in the process of dissimilatory nitrate reduction to ammonium (DNRA). Details of the nucleotide alignments of the primer target regions of 271 nrfA sequences from reference genomes representing 18 distinct clades of NrfA are shown here along with validation of application to PCR-based methodology including the use of amplified fragment length polymorphism (AFLP) profiling and Illumina platform amplicon-based sequencing of environmental samples and selected reference strains. Summary data tables illustrate the specificity of forward primers nrfAF2awMOD and nrfAF2awMODgeo when paired with the new reverse primer nrfAR1MOD in relation to consensus target reference sequences associated with members of 18 NrfA clades. Specificity of the new primers to nrfA sequences in environmental samples is shown in AFLP analysis and amino acid-translated amplicon sequences obtained with the new primer sets. We also provide sequence alignment files of the full length nrfA genes, PCR reference amplicon alignment, NrfA amino-acid alignment and NrfA translated PCR amplicon-amino acid alignment. The full nucleotide and protein alignments contain 271 reference genomes that represent the 18 identified NrfA clades as a tool to further aid practitioners in examining new sequences corresponding to the primer target regions and allow further primer design modifications if deemed pertinent to specific studies. A more comprehensive analysis of this data may be obtained from ("Optimization of PCR primers to detect phylogenetically diverse nrfA genes associated with nitrite ammonification" Cannon et al., 2019).


Examining the Canadian 24-Hour Movement Guidelines among Adults with Intellectual Disability: A Pilot Study.
The purpose of this pilot study was to investigate the extent to which adults with intellectual disability (ID) met the 2020 Canadian 24-Hour Movement Guidelines. Fifteen adults (six females and nine males) participated in this nine-day observational study (age = 20-64 years) in 2021-2022, during the COVID-19 pandemic. Moderate-to-vigorous physical activity (MVPA), sedentary time, and total sleep time were measured with a smartwatch to compare to the guidelines. A diary subjectively tracked physical activity. Of the 15 participants, 11 met the MVPA guidelines (73%), 4 met the sedentary behaviour guidelines (27%), 7 met the sleep guidelines (47%), and only 1 participant met all 3 of the guidelines (7%). There were no differences in physical activity or sleep between weekends and weekdays, or between males and females. Walking, cleaning dishes, and swimming were the most common types of physical activity performed by the participants. The findings of this pilot study indicate the need to improve sleep and reduce sedentary time in adults with ID. As most participants met the MVPA guidelines, few met the sedentary behaviour guidelines, and nearly half met the sleep guidelines, these data also demonstrate how important it is to assess all three aspects of the movement guidelines. All these behaviours have independent health benefits and risks, which interact to influence overall health.


Pairwise and Multi-chain Protein Docking Enhanced Using LZerD Web Server.
Interactions of proteins with other macromolecules have important structural and functional roles in the basic processes of living cells. To understand and elucidate the mechanisms of interactions, it is important to know the 3D structures of the complexes. Proteomes contain numerous protein-protein complexes, for which experimentally determined structures often do not exist. Computational techniques can be a practical alternative to obtain useful complex structure models. Here, we present a web server that provides access to the LZerD and Multi-LZerD protein docking tools, which can perform both pairwise and multi-chain docking. The web server is user-friendly, with options to visualize the distribution and structures of binding poses of top-scoring models. The LZerD web server is available at https://lzerd.kiharalab.org . This chapter dictates the algorithm and step-by-step procedure to model the monomeric structures with AttentiveDist, and also provides the detail of pairwise LZerD docking, and multi-LZerD. This also provided case studies for each of the three modules.


Re-examination of the cranial osteology of the Arctic Alaskan hadrosaurine with implications for its taxonomic status.
Hadrosaurid fossils from the Liscomb Bonebed (Prince Creek Formation, North Slope, Alaska) were the first dinosaur bones discovered from the Arctic. While the Prince Creek Formation hadrosaurids were long identified as Edmontosaurus, a member of the sub-clade Hadrosaurinae, they were recently assigned to a newly-erected taxon, Ugrunaaluk kuukpikensis. However, taxonomic status of the new taxon is ambiguous largely due to the immature nature of the specimens upon which it was based. Here we reexamine cranial elements of the Prince Creek Formation hadrosaurine in order to solve its taxonomic uncertainties. The Prince Creek Formation hadrosaurine possesses a short dorsolateral process of the laterosphenoid, one of the diagnostic characters of Edmontosaurus. The Prince Creek Formation hadrosaurine also shows affinity to Edmontosaurus regalis in the presence of a horizontal shelf of the jugal. Our morphological comparisons with other North American Edmontosaurus specimens and our phylogenetic analyses demonstrate that the Prince Creek Formation hadrosaurine should be re-assigned to Edmontosaurus. Because the Prince Creek Formation Edmontosaurus shows differences with lower latitude Edmontosaurus in a dorsoventrally short maxilla, presence of a secondary ridge on the dentary teeth, and the absence of the transverse ridge between basipterygoid processes of the basisphenoid, we consider that the Prince Creek Formation Edmontosaurus should be regarded as Edmontosaurus sp. until further discoveries of mature hadrosaurines from the Prince Creek Formation Bonebed and/or equivalently juvenile Edmontosaurus specimens from the lower latitudes allow direct comparisons. The retention of the Prince Creek Formation hadrosaurine as Edmontosaurus re-establishes a significant latitudinal distribution for this taxon. Despite the large latitudinal distribution of the taxon, the morphological disparity of Edmontosaurus is small within Hadrosaurinae. The small morphological disparity may be related to the relatively low latitudinal temperature gradient during the latest Cretaceous compared to present day, a gradient which might not have imposed significant pressure for much morphological adaptations across a broad latitudinal range.


Antibacterial effect of green tea infusion used as a mouthwash on saliva and bacterial plaque: a randomized controlled trial.
The objective of this study was to evaluate the antibacterial effect of a green tea infusion used as a mouthwash. In this double-blind, randomized controlled study, simple randomization was used to divide 28 students, 18 to 40 years of age, into 2 groups (n = 14): green tea (intervention) or distilled water (placebo). A 13% green tea infusion was prepared with 13 g of green tea (commercially fractionated) in 100 mL of saline solution at a temperature of approximately 90°C. The liquid was poured into sterile glass containers, as was the distilled water for the control group. The antibacterial effect was determined by counting the colony-forming units in cultures of plaque and saliva samples, which were obtained before and immediately after the students rinsed their mouth once with 10 mL of the green tea or control solution. The data were subjected to t tests to analyze differences before and after the intervention and between groups (green tea versus distilled water) (P < 0.05). The analysis showed statistically significant differences between the groups (P < 0.05), with participants in the green tea group demonstrating greater reductions in the numbers of colony-forming units. Green tea mouthwash had an antibacterial effect on saliva and bacterial plaque, suggesting that green tea mouthwash could be a beneficial addition to standard oral hygiene measures. Trial registration: ClinicalTrials.gov Identifier NCT04410666.