Gliadel wafer in initial surgery for malignant glioma: long-term follow-up of a multicenter controlled trial.
Adjuvant systemic chemotherapy increases survival of primary malignant glioma patients beyond 12-18 months. The only interstitial chemotherapy treatment approved for malignant glioma is Gliadel wafer containing carmustine (BCNU) placed in the resection cavity at surgery. Analysis of a large trial by Westphal and colleagues (n = 240) showed a 29% risk reduction (P = 0.03) in the BCNU wafer-treated group over the course of the 30-month trial. Long-term follow-up of these patients was undertaken to determine the survival benefit at 2 and 3 years. Survival proportions for the placebo and treatment groups over the 56-month study were estimated by the Kaplan-Meier method. Multiple-regression analyses using the Cox proportional hazards model included prognostic factors of age, KPS, and tumor type. A secondary analysis was conducted for 207 GBM patients. Of the 59 patients available for long-term follow-up, 11 were alive at 56 months: 9 had received BCNU wafers and 2 had received placebo wafers. Median survival of patients treated with BCNU wafers was 13.8 months vs 11.6 months in placebo-treated patients (P = 0.017) with a hazard ratio of 0.73 (P = 0.018), representing a 27% significant risk reduction. This survival advantage was maintained at 1, 2, and 3 years and was statistically significant (P = 0.01) at 3 years. Two of 207 GBM patients remained alive at the end of the follow-up period, both in the BCNU wafer-treated group. Malignant glioma patients treated with BCNU wafers at the time of initial surgery in combination with radiation therapy demonstrated a survival advantage at 2 and 3 years follow-up compared with placebo.


Insights on the seasonal variations of reproductive features in the Eastern Atlantic Bluefin Tuna.
The Atlantic Bluefin Tuna (ABFT, Thunnus thynnus) is one of the most intensely exploited fisheries resources in the world. In spite of the years of studies on ABFT, basic aspects of its reproductive biology remain uncertain. To gain insight regarding the seasonal changes of the reproductive characteristics of the eastern stock of ABFT, blood and tissue samples were collected from mature specimens caught in the Mediterranean basin during the reproductive (May-June) and non-reproductive season (Oct-Nov). Histological analysis of the gonads of May-June samples indicated that there were females which were actively spawning (contained post-ovulatory follicles) and females that were not actively spawning that had previtellogenic and fully vitellogenic oocytes. In males, testis were at early or late stage of spermatogenesis during the reproductive season. In Oct-Nov, ovaries contained mostly previtellogenic oocytes as well as β and α atretic follicles while the testis predominantly contained spermatogonia and few cysts with spermatocytes and spermatozoa. Gonadosomatic index (GSI) in females was highest among the actively spawning individuals while in males GSI was higher in early and late spermatogenic individuals compared to those that were spent. Plasma sex steroids levels varied with the reproductive season. In females, estradiol (E2), was higher in May-June while testosterone (T) and progesterone (P) did not vary. In males, E2 and T were higher in May-June while P levels were similar at the two sampling points. Circulating follicle stimulating hormone (FSH) was higher in Oct-Nov than in May-June both in males and females. Vitellogenin (VTG) was detected in plasma from both males and females during the reproductive season with levels in females significantly higher than in males. VTG was undetected in Oct-Nov samples. Since choriogenesis is an important event during follicle growth, the expression of three genes involved in vitelline envelope formation and hardening was measured and results showed significantly higher levels in ovaries in fish caught in May-June with respect to those sampled in Oct-Nov. In addition, a set of genes encoding for ion channels that are responsible for oocyte hydration and buoyancy, as well as sperm viability, were characterized at the two time points, and these were found to be more highly expressed in females during the reproductive season. Finally, the expression level of three mRNAs encoding for different lipid-binding proteins was analyzed with significantly higher levels detected in males, suggesting sex-specific expression. Our findings provide additional information on the reproductive biology of ABFT, particularly on biomarkers for the assessment of the state of maturation of the gonad, highlighting gender-specific signals and seasonal differences.


New 2-stage buccal mucosal graft urethroplasty.
Previously buccal mucosal grafts used for repairing adult bulbourethral stricture with the 1-stage dorsal technique has provided a satisfactory outcome in our experience. We present the wider use of buccal mucosal grafts for 2-stage urethroplasty. A total of 24 men 25 to 60 years old (median age 45) with a complex bulbar stricture underwent 2-stage urethroplasty using a buccal mucosal graft to repair the perineostomy. The primary etiology of stricture was traumatic in 4 cases, inflammatory in 16 and unknown in 4. The 2 x 6 cm. graft was harvested from the inner cheek and sutured to the left margin of the urethral mucosal plate with running 6-zero polyglactin suture. Patients were discharged from the hospital within 3 days with a 14Fr silicone urethral catheter in place. Radiological studies and urethroscopy were done 1 year after closure. A final successful outcome with no recurrent stricture was achieved in 23 of 24 men (92.8%) at a median followup of 18 months (range 13 to 32). In 1 case a urethrocutaneous fistula at the initial radiological assessment closed spontaneously after 14 days of catheterization. No urethral diverticula developed. The mean postoperative peak flow rate is 22 ml. per second (range 18 to 25). Our new 2-stage buccal mucosal graft urethroplasty may be an excellent technique for complex bulbar urethral stricture disease. Our suggestions may increase usefulness of the 2-stage technique for repairing complex strictures due to the avoidance of classic complications.


BCG Δzmp1 vaccine induces enhanced antigen specific immune responses in cattle.
Mycobacterium bovis (M. bovis) causes major economy and public health problem in numerous countries. In Great Britain, despite the use of a test-and-slaughter strategy, the incidence of bovine tuberculosis (bTB) in cattle has steadily risen in recent years. One strategy being considered to reduce the burden of bTB in cattle is the development of an efficient vaccine. The only current potentially available vaccine against tuberculosis, live attenuated M. bovis bacille Calmette-Guérin (BCG), has demonstrated variable efficacy in both humans and cattle and the development of improved vaccination strategies for cattle is a research priority. In this study we assessed the immunogenicity in cattle of two recombinant BCG strains, namely BCG Pasteur Δzmp1::aph and BCG Danish Δzmp1. By applying a recently defined predictive immune-correlate of protection (T cell memory responses measured by cultured ELISPOT), we have compared these two recombinant BCG with wild-type BCG Danish SSI. Our results demonstrated that both strains induced superior T cell memory responses compared to wild-type BCG. These data provide support for the prioritisation of testing BCG Danish Δzmp1 in vaccination/M. bovis challenge studies to determine its protective efficacy.


Two TPL-Binding Motifs of ARF2 Are Involved in Repression of Auxin Responses.
Auxin signaling is finalized by activator auxin response factors (aARFs) that are released from Auxin/Indole-3-Acetic Acid (Aux/IAA) repressors and directly activate auxin-responsive genes. However, it remains to be answered how repressor ARFs (rARFs) exert their repression function. In this study, we assessed the molecular and biological functions of two putative co-repressor-binding motifs (EAR and RLFGI) of ARF2 (a rARF) in Arabidopsis thaliana. In the yeast two-hybrid assay, the EAR mutation moderately and the RLFGI mutation, or both motifs, almost completely disrupted the interaction between the co-repressor TOPLESS (TPL) and the repressive motifs-containing middle domain (MD) of ARF2. The ARF2-MD interacted not only with TPL but also with TPL homologs (TPRs). Root hair-specific overexpression of rARFs (ARF1-4, 9-11, and 16) considerably inhibited root hair growth, suggesting that rARFs generally function as repressors in the auxin-responsive root hair single cell. Individual mutation of the ARF2 EAR or RLFGI motif slightly and both mutations greatly compromised ARF2-mediated inhibition of root hair growth and auxin-responsive gene expression. In addition, flowering time and seed size, two representative arf2 mutant phenotypes, were examined to assess the function of the repressive motifs in mutant-complementation experiments. ARF2-mediated inhibition of flowering and seed growth was suppressed considerably by the individual mutation of EAR or RLFGI and almost completely by both mutations. These results suggest that EAR and RLFGI work together as major repressive motifs for ARF2 to recruit TPL/TPR co-repressors and to exhibit its repressive biological functions.


Auxin represses stomatal development in dark-grown seedlings via Aux/IAA proteins.
Stomatal development is tightly regulated through internal and external factors that are integrated by a complex signalling network. Light represents an external factor that strongly promotes stomata formation. Here, we show that auxin-resistant aux/iaa mutants, e.g. axr3-1, exhibit a de-repression of stomata differentiation in dark-grown seedlings. The higher stomatal index in dark-grown axr3-1 mutants when compared with the wild type is due to increased cell division in the stomatal lineage. Excessive stomata in dark-grown seedlings were also observed in mutants defective in auxin biosynthesis or auxin perception and in seedlings treated with the polar auxin transport inhibitor NPA. Consistent with these findings, exogenous auxin repressed stomata formation in light-grown seedlings. Taken together, these results indicate that auxin is a negative regulator of stomatal development in dark-grown seedlings. Epistasis analysis revealed that axr3-1 acts genetically upstream of the bHLH transcription factors SPCH, MUTE and FAMA, as well as the YDA MAP kinase cascade, but in parallel with the repressor of photomorphogenesis COP1 and the receptor-like protein TMM. The effect of exogenous auxin required the ER family of leucine-rich repeat receptor-like kinases, suggesting that auxin acts at least in part through the ER family. Expression of axr3-1 in the stomatal lineage was insufficient to alter the stomatal index, implying that cell-cell communication is necessary to mediate the effect of auxin. In summary, our results show that auxin signalling contributes to the suppression of stomatal differentiation observed in dark-grown seedlings.


The course of retinal vasculitis.
To determine if characteristics of retinal vasculitis correlate with ocular complications, or the response to different lines of treatment. We performed a computerised database analysis of 56 patients evaluated for uveitis at the Casey Eye Institute from September 1985 until May 2010. All patients had non-infectious retinal vasculitis and at least 1 year of follow-up. Although occlusive vasculitis was rare, retinal neovascularisation occurred much more commonly in the occlusive vasculitis subgroup than among the non-occlusive vasculitis subgroup (p<0.01). Epiretinal membrane (ERM) was found more commonly in the retinal vasculitis patients who presented with cotton wool spots and intraretinal haemorrhage compared to retinal vasculitis patients who presented with sheathing noted on clinical examination (p<0.01). Smoking was significantly related to vision loss. Age at presentation below 40 years correlated with therapy beyond oral corticosteroids The heterogeneity of retinal vasculitis should be considered in providing prognostic information. Neovascularisation occurs more commonly in occlusive retinal vasculitis, and ERM is diagnosed more frequently in conjunction with cotton wool spots and intraretinal haemorrhage rather than just vascular sheathing. Cigarette use predicts visual loss and patients who are relatively young often receive treatment beyond oral corticosteroids.


Does performance level affect initial ball flight kinematics in finger and wrist-spin cricket bowlers?
Spin bowling plays a fundamental role within the game of cricket yet little is known about the initial ball kinematics in elite and pathway spin bowlers or their relationship to performance. Therefore, the purpose of this study was to record three-dimensional ball kinematics in a large and truly high level cohort of elite and pathway finger-spin (FS) and wrist-spin (WS) bowlers, identifying potential performance measures that can be subsequently used in future research. A 22-camera Vicon motion analysis system captured retro-reflective markers placed on the seam (static) and ball (dynamic) to quantify ball kinematics in 36 FS (12 elite and 24 pathway) and 20 WS (eight elite and 12 pathway) bowlers. Results indicated that FS bowlers delivered the ball with an increased axis of rotation elevation, while wrist-spin bowlers placed greater amounts of revolutions on the ball. It also highlighted that ball release (BR) velocity, revolutions and velocity/revolution index scores for both groups and seam stability for FS bowlers, and seam azimuth angle and spin axis elevation angle for WS bowlers, were discriminators of playing level. As such these variables could be used as indicators of performance (i.e. performance measures) in future research.


Why do children and adolescents (not) seek and access professional help for their mental health problems? A systematic review of quantitative and qualitative studies.
Mental health disorders in children and adolescents are highly prevalent yet undertreated. A detailed understanding of the reasons for not seeking or accessing help as perceived by young people is crucial to address this gap. We conducted a systematic review (PROSPERO 42018088591) of quantitative and qualitative studies reporting barriers and facilitators to children and adolescents seeking and accessing professional help for mental health problems. We identified 53 eligible studies; 22 provided quantitative data, 30 provided qualitative data, and one provided both. Four main barrier/facilitator themes were identified. Almost all studies (96%) reported barriers related to young people's individual factors, such as limited mental health knowledge and broader perceptions of help-seeking. The second most commonly (92%) reported theme related to social factors, for example, perceived social stigma and embarrassment. The third theme captured young people's perceptions of the therapeutic relationship with professionals (68%) including perceived confidentiality and the ability to trust an unknown person. The fourth theme related to systemic and structural barriers and facilitators (58%), such as financial costs associated with mental health services, logistical barriers, and the availability of professional help. The findings highlight the complex array of internal and external factors that determine whether young people seek and access help for mental health difficulties. In addition to making effective support more available, targeted evidence-based interventions are required to reduce perceived public stigma and improve young people's knowledge of mental health problems and available support, including what to expect from professionals and services.


Musical ability and non-native speech-sound processing are linked through sensitivity to pitch and spectral information.
Is the observed link between musical ability and non-native speech-sound processing due to enhanced sensitivity to acoustic features underlying both musical and linguistic processing? To address this question, native English speakers (N = 118) discriminated Norwegian tonal contrasts and Norwegian vowels. Short tones differing in temporal, pitch, and spectral characteristics were used to measure sensitivity to the various acoustic features implicated in musical and speech processing. Musical ability was measured using Gordon's Advanced Measures of Musical Audiation. Results showed that sensitivity to specific acoustic features played a role in non-native speech-sound processing: Controlling for non-verbal intelligence, prior foreign language-learning experience, and sex, sensitivity to pitch and spectral information partially mediated the link between musical ability and discrimination of non-native vowels and lexical tones. The findings suggest that while sensitivity to certain acoustic features partially mediates the relationship between musical ability and non-native speech-sound processing, complex tests of musical ability also tap into other shared mechanisms.


The impact of midline versus transverse incisions on wound complications and outcome in simultaneous pancreas-kidney transplants: a retrospective analysis.
Intraperitoneal placement of the pancreas allograft, usually through a midline incision, has so far achieved the best results in pancreas transplantation. The usefulness and safety of a transverse incision has not been previously reported. The purpose of this study was to compare midline and transverse incisions, with respect to wound complications and outcome, in simultaneous pancreas-kidney transplant recipients with intraperitoneal placement of the pancreatic graft. The incidence of deep abscess formation, superficial abscess formation, wound leak, and fascial dehiscence, as well as graft survival, were retrospectively compared in 41 bladder-drained simultaneous pancreas-kidney recipients with a midline incision and in 15 with a transverse incision. The overall incidence of wound complications was similar (34% vs 20%, P = NS) in the two groups. Deep abscess formation occurred more frequently in the midline group (27% vs 0%, P = 0.02). Staphylococcus epidermidis and Candida albicans were the most common microbial isolates from deep abscesses. Multivariate logistic regression analysis revealed donor age 40 years or older (P = 0.04), the occurrence of a bladder leak (P = 0.05), and a peak serum amylase in the 1st week of 1000 IU/l or greater (P = 0.02) to be independent risk factors for the development of wound complications. The type of incision, however, was not found to be an independent risk factor. Patient (90% vs 83%, P = NS), pancreas allograft (78% vs 82%, P = NS), and kidney allograft (83% vs 70%, P = NS) survival rates were similar for the midline and transverse groups. We conclude that the transverse incision is a reasonable alternative to the midline incision in simultaneous pancreas-kidney transplantation and it is presently the incision of choice at our institution. It offers excellent exposure and is associated with a similar wound complication rate and outcome when compared to the midline incision.


Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs.
Eight patients had cardiac manifestations that were life-threatening in five while taking psychotropic drugs, either phenothiazines or tricyclic antidepressants. Although most patients were receiving several drugs, Mellaril (thioridazine) appeared to be responsible for five cases of ventricular tachycardia, one of which was fatal in a 35 year old woman. Supraventricular tachycardia developed in one patient receiving Thorazine (chlorpromazine). Aventyl (nortriptyline) and Elavil (amitriptyline) each produced left bundle branch block in a 73 year old woman. Electrocardiographic T and U wave abnormalities were present in most patients. The ventricular arrhythmias responded to intravenous administration of lidocaine and to direct current electric shock; ventricular pacing was required in some instances and intravenous administration of propranolol combined with ventricular pacing in one. The tachyarrhythmias generally subsided within 48 hours after administration of the drugs was stopped. Five of the eight patients were 50 years of age or younger; only one clearly had antecedent heart disease. Major cardiac arrhythmias are a potential hazard in patients without heart disease who are receiving customary therapeutic doses of psychotropic drugs. A prospective clinical trial is suggested to quantify the risk of cardiac complications to patients receiving phenothiazines or tricyclic antidepressant drugs.


Translational frameshifting generates the gamma subunit of DNA polymerase III holoenzyme.
The dnaX gene (previously called dnaZX) of Escherichia coli has only one open reading frame for a 71-kDa polypeptide from which two distinct DNA polymerase III holoenzyme subunits, tau (71 kDa) and gamma (47 kDa), are produced. To determine how the gamma subunit is generated, we examined the influence of mutations in the dnaX gene on the pattern of tau and gamma production in overproducing cells. Important structural elements in dnaX mRNA include a stretch of six adenines (nucleotides 1425-1430), a stable hairpin structure (nucleotides 1437-1466), and a UGA stop codon in a -1 frame (nucleotides 1434-1436) between the stretch of adenines and the hairpin structure. Disruption of this stop codon generates a slightly larger gamma subunit, indicative of the use of a -1 stop codon farther downstream (nucleotides 1470-1472). These results suggest that a -1 frameshift during translation allows the use of this UGA codon to terminate translation of the gamma polypeptide. The amino acid composition, sequence, and mass spectra of a C-terminal peptide from mild digestion of the purified gamma protein with endoproteinase Lys-C confirms that this frameshift occurs at either of the two lysine codons in the region of the adenine stretch. Remarkable features of this frameshifting are its high frequency (i.e., about 80% in an overproducing cell) and the striking structural similarity to the frameshifting signal responsible for expression of the pol and pro genes in many retroviruses.


Efficient feedforward categorization of objects and human postures with address-event image sensors.
This paper proposes an algorithm for feedforward categorization of objects and, in particular, human postures in real-time video sequences from address-event temporal-difference image sensors. The system employs an innovative combination of event based hardware and bio-inspired software architecture. An event-based temporal difference image sensor is used to provide input video sequences, while a software module extracts size and position invariant line features inspired by models of the primate visual cortex. The detected line features are organized into vectorial segments. After feature extraction, a modified line segment Hausdorff distance classifier combined with on-the-fly cluster-based size and position invariant categorization. The system can achieve about 90 percent average success rate in the categorization of human postures, while using only a small number of training samples. Compared to state-of-the-art bio-inspired categorization methods, the proposed algorithm requires less hardware resource, reduces the computation complexity by at least five times, and is an ideal candidate for hardware implementation with event-based circuits.


Ellagic acid induces apoptosis through inhibition of nuclear factor kappa B in pancreatic cancer cells.
To determine the effect of ellagic acid on apoptosis and proliferation in pancreatic cancer cells and to determine the mechanism of the pro-survival effects of ellagic acid. The effect of ellagic acid on apoptosis was assessed by measuring phosphatidylserine externalization, caspase activity, mitochondrial membrane potential and DNA fragmentation; and proliferation by measuring DNA thymidine incorporation. Mitochondrial membrane potential was measured in permeabilized cells, and in isolated mitochondria. Nuclear factor kappa B (NF-kappa B) activity was measured by electromobility shift assay (EMSA). We show that ellagic acid, a polyphenolic compound in fruits and berries, at concentrations 10 to 50 mmol/L stimulates apoptosis in human pancreatic adenocarcinoma cells. Further, ellagic acid decreases proliferation by up to 20-fold at 50 mmol/L. Ellagic acid stimulates the mitochondrial pathway of apoptosis associated with mitochondrial depolarization, cytochrome C release, and the downstream caspase activation. Ellagic acid does not directly affect mitochondria. Ellagic acid dose-dependently decreased NF-kappa B binding activity. Furthermore, inhibition of NF-kappa B activity using IkB wild type plasmid prevented the effect of ellagic acid on apoptosis. Our data indicate that ellagic acid stimulates apoptosis through inhibition of the prosurvival transcription factor NF-kappa B.


Spectral watermarking in femtosecond stimulated Raman spectroscopy: resolving the nature of the carotenoid S* state.
A new method for recording femtosecond stimulated Raman spectra was developed that dramatically improves and automatizes baseline problems. Instead of using a narrowband Raman source, the experiment is performed using shaping of a broadband source. This allows locking the signal into carefully crafted watermarks that can be recovered from measured data with high fidelity. The approach uses unique properties of Raman scattering, thus allowing a direct recording of stimulated Raman signals with robust rejection of baselines and fixed-pattern-noise. Low cost technology for generating required pulse-shapes was developed and demonstrated. The methodology is applicable to any Raman experiment but primarily targets Femtosecond Stimulated Raman spectroscopy (FSRS) where a lack of robust methods for parasitic signal rejection has been a major obstacle in the practical development of the field in the last decade. The delivered improvement in FSRS experiments was demonstrated by recording evidence that the so-called S* state of carotenoids in solution corresponds to the optically forbidden S1 state of a sparsely populated carotenoid conformation.


Contrasting behavior of heterochromatic and euchromatic chromosome portions and pericentric genome separation in pre-bouquet spermatocytes of hybrid mice.
The spatial distribution of parental genomes has attracted much interest because intranuclear chromosome distribution can modulate the transcriptome of cells and influence the efficacy of meiotic homologue pairing. Pairing of parental chromosomes is imperative to sexual reproduction as it translates into homologue segregation and genome haploidization to counteract the genome doubling at fertilization. Differential FISH tagging of parental pericentromeric genome portions and specific painting of euchromatic chromosome arms in Mus musculus (MMU) × Mus spretus (MSP) hybrid spermatogenesis disclosed a phase of homotypic non-homologous pericentromere clustering that led to parental pericentric genome separation from the pre-leptoteneup to zygotene stages. Preferential clustering of MMU pericentromeres correlated with particular enrichment of epigenetic marks (H3K9me3), HP1-γ and structural maintenance of chromosomes SMC6 complex proteins at the MMU major satellite DNA repeats. In contrast to the separation of heterochromatic pericentric genome portions, the euchromatic arms of homeologous chromosomes showed considerable presynaptic pairing already during leptotene stage of all mice investigated. Pericentric genome separation was eventually disbanded by telomere clustering that concentrated both parental pericentric genome portions in a limited nuclear sector of the bouquet nucleus. Our data disclose the differential behavior of pericentromeric heterochromatin and the euchromatic portions of the parental genomes during homologue search. Homotypic pericentromere clustering early in prophase I may contribute to the exclusion of large repetitive DNA domains from homology search, while the telomere bouquet congregates and registers spatially separated portions of the genome to fuel synapsis initiation and high levels of homologue pairing, thus contributing to the fidelity of meiosis and reproduction.


Reverse Peroneal Artery Flap for Large Heel and Sole Defects: A Reliable Coverage.
Large soft tissue defects of ankle and foot always have been challenging to reconstruct. Reverse sural flaps, free flaps have been used for this problem with variable success. Reverse peroneal artery flap is an option to use with reliability without microvascular repair. Connections of peroneal artery around talus and ankle joint are deep and reliable with anterior tibial and posterior tibial artery. Arterial inflow and venous drainage improved with including short saphenous vein and reverse sural artery in the flap. Ten patients with large defects around heel underwent reconstruction with (RPAF) reverse peroneal artery flap (pedicled) over a period of 2 years. Final inset given after 18-21 days of primary surgery. The mean age of these patients was 45 years. Of the 10 flaps, all showed complete survival without even marginal necrosis. Two patients had minor donor site problems that settled with conservative management. RPAF is a very reliable flap for the coverage of large soft tissue defects of the heel and sole. Large defects can be reconstructed without microvascular surgery and without compromising major vessel of foot region. If some experience with perforator flaps and free fibula is there then RPAF is easy to execute with reliability.


Illusory memories: a cognitive neuroscience analysis.
Memory illusions and distortions have long been of interest to psychology researchers studying memory, but neuropsychologists and neuroscientists have paid relatively little attention to them. This article attempts to lay the foundation for a cognitive neuroscience analysis of memory illusions and distortions by reviewing relevant evidence from a patient with a right frontal lobe lesion, patients with amnesia produced by damage to the medial temporal lobes, normal aging, and healthy young volunteers studied with functional neuroimaging techniques. Particular attention is paid to the contrasting roles of prefrontal cortex and medial temporal lobe structures in accurate and illusory remembering. Converging evidence suggests that the study of illusory memories can provide a useful tool for delineating the brain processes and systems involved in constructive aspects of remembering.


Lipid-induced insulin resistance is associated with an impaired skeletal muscle protein synthetic response to amino acid ingestion in healthy young men.
The ability to maintain skeletal muscle mass appears to be impaired in insulin-resistant conditions, such as type 2 diabetes, that are characterized by muscle lipid accumulation. The current study investigated the effect of acutely increasing lipid availability on muscle protein synthesis. Seven healthy young male volunteers underwent a 7-h intravenous infusion of l-[ring-(2)H5]phenylalanine on two randomized occasions combined with 0.9% saline or 10% Intralipid at 100 mL/h. After a 4-h "basal" period, a 21-g bolus of amino acids was administered and a 3-h hyperinsulinemic-euglycemic clamp was commenced ("fed" period). Muscle biopsy specimens were obtained from the vastus lateralis at 1.5, 4, and 7 h. Lipid infusion reduced fed whole-body glucose disposal by 20%. Furthermore, whereas the mixed muscle fractional synthetic rate increased from the basal to the fed period during saline infusion by 2.2-fold, no change occurred during lipid infusion, despite similar circulating insulin and leucine concentrations. This "anabolic resistance" to insulin and amino acids with lipid infusion was associated with a complete suppression of muscle 4E-BP1 phosphorylation. We propose that increased muscle lipid availability may contribute to anabolic resistance in insulin-resistant conditions by impairing translation initiation.


Automatic, localized in vivo adjustment of all first- and second-order shim coils.
The implementation of a "fast, automatic shimming technique by mapping along projections" (FASTMAP) on a 2.1-Tesla whole-body system is described. The method provides a localized adjustment of all first- (X, Y, Z) and second-order (Z2, ZX, ZY, X2-Y2, 2XY) coils in 2 min. The time savings are achieved by mapping the magnetic field along six projections rather than from whole-imaging data sets. An analysis of noise error propagation suggests that in 64-ml volumes the residual linewidths obtained with the method are negligible when the signal-to-rms-noise ratio is above 30. The initial application of the method to localized 13C, 31P, and 1H spectroscopy of the human brain resulted in linewidths of approximately 2 Hz for 13C (144-ml volume), approximately 2.5 Hz for 31P (36-ml volume) and approximately 4 Hz for 1H (36-ml volume) with symmetric and reproducible lineshapes.


Factors affecting the heart activity and blood pressure of the swan mussel Anodonta cygnea.
1. The rate of heart beat increased with temperature and was three times as high in the active as in the inactive animal. 2. The rate of shell valve movement rose and the rate of heart beat fell when the foot was extended. 3. The rates of heart beat and shell valve movement decreased when the water was saturated with carbon dioxide. This heart response remained when the visceral ganglion was destroyed. 4. Ventricular contraction occurred simultaneously over the shole chamber. The passage of blood into the posterior aorta could be restricted by the protuberances on its wall. 5. Pericardial cavity pressure rose by about 5 cm H2O at shell valve adduction and 0-25--0-6 cm H2O at ventricular diastole. 6. Pulse pressure changes of 0-25--0-6 cm H2O occurred in the auricle and 1--3 cm H2O in the ventricle and anterior aorta.


Overexpression of carbonic anhydrase IX (CAIX) is an independent unfavorable prognostic marker in endometrioid ovarian cancer.
Carbonic anhydrase IX (CAIX) is a strictly membranous expressed metalloenzyme involved in cell adhesion, pH homeostasis, and cancer progression. This study was designed to assess the role of CAIX in primary ovarian cancer. Two hundred five well-characterized primary ovarian carcinomas were analyzed on a tissue microarray. CAIX expression was determined by immunohistochemistry using a four-step scoring system. Moderate and strong membranous CAIX expression was found in 37 out of 205 (18%) of all assessable ovarian cancer specimens. High levels of CAIX expression were related to mucinous and endometrioid phenotype of ovarian carcinomas (p < 0.05). There was no association between CAIX overexpression and tumor stage, grading, and mitotic count of ovarian carcinomas (p > 0.05). In univariate Cox regression analysis, advanced tumor stage (p < 0.01), high tumor grade (p = 0.017), high mitotic count (p = 0.025), and high CAIX expression levels (p = 0.031) were correlated to shorter overall patient survival. High pT stage (p = 0.036) and CAIX overexpression were connected to poor clinical outcome in endometrioid ovarian carcinomas. Multivariate Cox regression hazard analysis comprising tumor stage, tumor grade, mitotic count, and CAIX expression revealed pT2/3 stage and CAIX overexpression (scores 2 and 3) as independent prognostic markers in ovarian cancer (p < 0.01, each) as well as in the subgroup of endometrioid carcinomas (p < 0.05, each). In conclusion, CAIX is overexpressed in a substantial proportion of mucinous and endometrioid ovarian carcinomas and connected to poor patient outcome. Our data support the potential therapeutic benefit of newly developed targeting antibodies in advanced ovarian cancer.


Cannabinoids: Potential Role in Inflammatory and Neoplastic Skin Diseases.
The endocannabinoid system is a complex and nearly ubiquitous network of endogenous ligands, enzymes, and receptors that can also be stimulated by exogenous compounds such as those derived from the marijuana plant, Cannabis sativa. Recent data have shown that the endocannabinoid system is fully functional in the skin and is responsible for maintaining many aspects of skin homeostasis, such as proliferation, differentiation, and release of inflammatory mediators. Because of its role in regulating these key processes, the endocannabinoid system has been studied for its modulating effects on both inflammatory disorders of the skin and skin cancer. Although legal restrictions on marijuana as a Schedule I drug in the USA have made studying cannabinoid compounds unfavorable, an increasing number of studies and clinical trials have focused on the therapeutic uses of cannabinoids. This review seeks to summarize the current, and rapidly expanding field of research on the broad potential uses of cannabinoids in inflammatory and neoplastic diseases of the skin.


The Role of Planned and On-Demand Relaparotomy in the Developing World.
This study compares planned repeat laparotomy (PR) with on-demand repeat laparotomy (OD) in a developing world setting. This study was conducted over a 30-month study period (December 2012-May 2015) at Greys Hospital, Pietermaritzburg, South Africa. All trauma and general surgery adult patients requiring a single relaparotomy were included in this study. Prospectively gathered data entered into an established electronic registry were retrospectively analysed. Full ethical approval for the registry and this study was granted by the University of KwaZulu-Natal Biomedical Ethics Committee. A total of 162 patients were included, with an average age of 36 years (standard deviation 17) and 69 % male predominance. Appendicitis and stab abdomen were the most common underlying diagnoses. PR strategy was used in 46 % and an OD approach in 54 %. Patients selected for the PR strategy had higher admission pulse rates, higher Modified Early Warning System (MEWS) scores and significantly higher rates of diffuse intra-abdominal sepsis at initial laparotomy. However, findings at relaparotomy were similar in both groups. The PR group had a much shorter time between operations, but much higher need for intensive care unit (ICU) admission. There was no difference between the groups in terms of open abdomen at discharge, length of hospital stay, morbidity or mortality. In our environment, a planned approach to relaparotomy shows no major outcome advantages over an on-demand approach. There is however increased need for ICU admission with the PR approach. This is in keeping with international literature. Of concern is the much longer time delay between index procedure and repeat operation in the OD group. Improved post-operative decision making may help address this.


Common Terminology and Acoustic Measures for Human Voice and Birdsong.
Purpose The zebra finch is used as a model to study the neural circuitry of auditory-guided human vocal production. The terminology of birdsong production and acoustic analysis, however, differs from human voice production, making it difficult for voice researchers of either species to navigate the literature from the other. The purpose of this research note is to identify common terminology and measures to better compare information across species. Method Terminology used in the birdsong literature will be mapped onto terminology used in the human voice production literature. Measures typically used to quantify the percepts of pitch, loudness, and quality will be described. Measures common to the literature in both species will be made from the songs of 3 middle-age birds using Praat and Song Analysis Pro. Two measures, cepstral peak prominence (CPP) and Wiener entropy (WE), will be compared to determine if they provide similar information. Results Similarities and differences in terminology and acoustic analyses are presented. A core set of measures including frequency, frequency variability within a syllable, intensity, CPP, and WE are proposed for future studies. CPP and WE are related yet provide unique information about the syllable structure. Conclusions Using a core set of measures familiar to both human voice and birdsong researchers, along with both CPP and WE, will allow characterization of similarities and differences among birds. Standard terminology and measures will improve accessibility of the birdsong literature to human voice researchers and vice versa. Supplemental Material https://doi.org/10.23641/asha.7438964.


Immunogenicity and protective efficacy of a Vero cell culture-derived whole-virus H7N9 vaccine in mice and guinea pigs.
A novel avian H7N9 virus with a high case fatality rate in humans emerged in China in 2013. We evaluated the immunogenicity and protective efficacy of a candidate Vero cell culture-derived whole-virus H7N9 vaccine in small animal models. Antibody responses induced in immunized DBA/2J mice and guinea pigs were evaluated by hemagglutination inhibition (HI), microneutralization (MN), and neuraminidase inhibition (NAi) assays. T-helper cell responses and IgG subclass responses in mice were analyzed by ELISPOT and ELISA, respectively. Vaccine efficacy against lethal challenge with wild-type H7N9 virus was evaluated in immunized mice. H7N9-specific antibody responses induced in mice and guinea pigs were compared to those induced by a licensed whole-virus pandemic H1N1 (H1N1pdm09) vaccine. The whole-virus H7N9 vaccine induced dose-dependent H7N9-specific HI, MN and NAi antibodies in mice and guinea pigs. Evaluation of T-helper cell responses and IgG subclasses indicated the induction of a balanced Th1/Th2 response. Immunized mice were protected against lethal H7N9 challenge in a dose-dependent manner. H7N9 and H1N1pdm09 vaccines were similarly immunogenic. The induction of H7N9-specific antibody and T cell responses and protection against lethal challenge suggest that the Vero cell culture-derived whole-virus vaccine would provide an effective intervention against the H7N9 virus.


GEMS: a web server for biclustering analysis of expression data.
The advent of microarray technology has revolutionized the search for genes that are differentially expressed across a range of cell types or experimental conditions. Traditional clustering methods, such as hierarchical clustering, are often difficult to deploy effectively since genes rarely exhibit similar expression pattern across a wide range of conditions. Biclustering of gene expression data (also called co-clustering or two-way clustering) is a non-trivial but promising methodology for the identification of gene groups that show a coherent expression profile across a subset of conditions. Thus, biclustering is a natural methodology as a screen for genes that are functionally related, participate in the same pathways, affected by the same drug or pathological condition, or genes that form modules that are potentially co-regulated by a small group of transcription factors. We have developed a web-enabled service called GEMS (Gene Expression Mining Server) for biclustering microarray data. Users may upload expression data and specify a set of criteria. GEMS then performs bicluster mining based on a Gibbs sampling paradigm. The web server provides a flexible and an useful platform for the discovery of co-expressed and potentially co-regulated gene modules. GEMS is an open source software and is available at http://genomics10.bu.edu/terrence/gems/.


Time-frequency and complexity analyses for differentiation of physiologic murmurs from heart murmurs caused by aortic stenosis in Boxers.
To investigate whether time-frequency and complexity analyses of heart murmurs can be used to differentiate physiologic murmurs from murmurs caused by aortic stenosis (AS) in Boxers. 27 Boxers with murmurs. Dogs were evaluated via auscultation and echocardiography. Analyses of time-frequency properties (TFPs; ie, maximal murmur frequency and duration of murmur frequency > 200 Hz) and correlation dimension (T(2)) of murmurs were performed on phonocardiographic sound data. Time-frequency property and T(2) analyses of low-intensity murmurs in 16 dogs without AS were performed at 7 weeks and 12 months of age. Additionally, TFP and T(2) analyses were performed on data obtained from 11 adult AS-affected dogs with murmurs. In dogs with low-intensity murmurs, TFP or T(2) values at 7 weeks and 12 months did not differ significantly. For differentiation of physiologic murmurs from murmurs caused by mild AS, duration of murmur frequency > 200 Hz was useful and the combination assessment of duration of frequency > 200 Hz and T(2) of the murmur had a sensitivity of 94% and a specificity of 82%. Maximal murmur frequency did not differentiate dogs with AS from those without AS. Results suggested that assessment of the duration of murmur frequency > 200 Hz can be used to distinguish physiologic heart murmurs from murmurs caused by mild AS in Boxers. Combination of this analysis with T(2) analysis may be a useful complementary method for diagnostic assessment of cardiovascular function in dogs.


High resolution mapping of development in the wildland-urban interface using object based image extraction.
The wildland-urban interface (WUI), the area where human development encroaches on undeveloped land, is expanding throughout the western United States resulting in increased wildfire risk to homes and communities. Although census based mapping efforts have provided insights into the pattern of development and expansion of the WUI at regional and national scales, these approaches do not provide sufficient detail for fine-scale fire and emergency management planning, which requires maps of individual building locations. Although fine-scale maps of the WUI have been developed, they are often limited in their spatial extent, have unknown accuracies and biases, and are costly to update over time. In this paper we assess a semi-automated Object Based Image Analysis (OBIA) approach that utilizes 4-band multispectral National Aerial Image Program (NAIP) imagery for the detection of individual buildings within the WUI. We evaluate this approach by comparing the accuracy and overall quality of extracted buildings to a building footprint control dataset. In addition, we assessed the effects of buffer distance, topographic conditions, and building characteristics on the accuracy and quality of building extraction. The overall accuracy and quality of our approach was positively related to buffer distance, with accuracies ranging from 50 to 95% for buffer distances from 0 to 100 m. Our results also indicate that building detection was sensitive to building size, with smaller outbuildings (footprints less than 75 m2) having detection rates below 80% and larger residential buildings having detection rates above 90%. These findings demonstrate that this approach can successfully identify buildings in the WUI in diverse landscapes while achieving high accuracies at buffer distances appropriate for most fire management applications while overcoming cost and time constraints associated with traditional approaches. This study is unique in that it evaluates the ability of an OBIA approach to extract highly detailed data on building locations in a WUI setting.


Risk factor assessment tools for the prevention of periodontitis progression a systematic review.
(i) To identify characteristics of currently published patient-based tools used to assess levels of risk for periodontitis progression and (ii) systematically review the evidence documenting the use of patient-based risk assessment tools for predicting periodontitis progression. A systematic review was prepared on the basis of an electronic search of the literature supplemented with manually searching the relevant journals of the latest 5 years. Prospective and retrospective cohort studies were included as no randomized controlled clinical trials were available. The search identified 336 titles, and 19 articles were included in this systematic review. The search identified five different risk assessment tools. Results of nine of 10 cohort studies reporting outcomes of 2110 patients indicate that risk assessment tools are able to identify subjects with different probability of periodontitis progression and/or tooth loss. Subjects with higher risk scores showed more progression of periodontitis and tooth loss. In treated populations, results of patient-based risk assessments, for example periodontal risk calculator (PRC) and periodontal risk assessment (PRA), predicted periodontitis progression and tooth loss in various populations. Additional research on the utility of risk assessment and results in improving patient management are needed.


Informing the scale-up of Kenya's nursing workforce: a mixed methods study of factors affecting pre-service training capacity and production.
Given the global nursing shortage and investments to scale-up the workforce, this study evaluated trends in annual student nurse enrolment, pre-service attrition between enrolment and registration, and factors that influence nurse production in Kenya. This study used a mixed methods approach with data from the Regulatory Human Resources Information System (tracks initial student enrolment through registration) and the Kenya Health Workforce Information System (tracks deployment and demographic information on licensed nurses) for the quantitative analyses and qualitative data from key informant interviews with nurse training institution educators and/or administrators. Trends in annual student nurse enrolment from 1999 to 2010 were analyzed using regulatory and demographic data. To assess pre-service attrition between training enrolment and registration with the nursing council, data for a cohort that enrolled in training from 1999 to 2004 and completed training by 2010 was analyzed. Multivariate logistic regression was used to test for factors that significantly affected attrition. To assess the capacity of nurse training institutions for scale-up, qualitative data was obtained through key informant interviews. From 1999 to 2010, 23,350 students enrolled in nurse training in Kenya. While annual new student enrolment doubled between 1999 (1,493) and 2010 (3,030), training institutions reported challenges in their capacity to accommodate the increased numbers. Key factors identified by the nursing faculty included congestion at clinical placement sites, limited clinical mentorship by qualified nurses, challenges with faculty recruitment and retention, and inadequate student housing, transportation and classroom space. Pre-service attrition among the cohort that enrolled between 1999 and 2004 and completed training by 2010 was found to be low (6%). To scale-up the nursing workforce in Kenya, concurrent investments in expanding the number of student nurse clinical placement sites, utilizing alternate forms of skills training, hiring more faculty and clinical instructors, and expanding the dormitory and classroom space to accommodate new students are needed to ensure that increases in student enrolment are not at the cost of quality nursing education. Student attrition does not appear to be a concern in Kenya compared to other African countries (10 to 40%).


Prophylaxis against deep vein thrombosis in critically ill patients with severe renal insufficiency with the low-molecular-weight heparin dalteparin: an assessment of safety and pharmacodynamics: the DIRECT study.
Use of low-molecular-weight heparins is avoided in patients with renal insufficiency because of concerns about an excessive anticoagulant effect and increased bleeding risk. To challenge this premise, we evaluated if deep vein thrombosis (DVT) prophylaxis with dalteparin sodium confers an excessive anticoagulant effect in critically ill patients with severe renal insufficiency. We conducted a multicenter, single-arm clinical trial of DVT prophylaxis with dalteparin sodium, 5000 IU once daily in critically ill patients with a creatinine clearance lower than 30 mL/min (to convert to milliliters per second, multiply by 0.0167). Bioaccumulation was defined by a trough anti-Xa level higher than 0.40 IU/mL, measured twice weekly. The pharmacodynamic properties of dalteparin were assessed by serial anti-Xa levels measured on days 3, 10, and 17. We enrolled 156 patients with a mean (SD) creatinine clearance of 18.9 (6.5) mL/min; 18 were excluded because they died or were discharged before testing (n = 3) or had prevalent DVT (n = 15). Of 138 patients included, the median (interquartile range [IQR]) duration of dalteparin exposure was 7 (4-12) days. In 120 patients who had at least 1 trough anti-Xa level (427 total measurements), no patient had bioaccumulation (0%; 95% confidence interval [CI]: 0%-3.0%); the median (IQR) trough anti-Xa level was undetectable (<0.10 IU/mL [<0.10 to <0.10 IU/mL]). Based on serial measurements, peak anti-Xa levels were 0.29 to 0.34 IU/mL and trough levels were lower than 0.06 IU/mL. Deep vein thrombosis occurred in 7 of 138 patients (5.1%; 95% CI, 2.5%-10.1%); major bleeding occurred in 10 patients (7.2%; 95% CI, 4.0%-12.8%), all with trough anti-Xa levels of 0.18 IU/mL or lower. In critically ill patients with severe renal insufficiency, DVT prophylaxis with dalteparin sodium, 5000 IU once daily, is not associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding. clinicaltrials.gov Identifier: NCT00138099.


Effect of genetic variants of bilirubin metabolism on the degree of hyperbilirubinemia in African-American newborns.
The objective of our study was to measure the effect of genetic variants of these two enzymes, UGT1A1 and SLCO1B1, in the bilirubin metabolic pathway on the degree of hyperbilirubinemia in a cohort of African-American (AA) infants from our well-baby nursery. In addition, a second objective was to document the types and frequencies of genetic variations of these enzymes in our cohort. A prospective study of 180 AA infants from the Well Baby Nursery of an inner city community hospital, all of whose mothers were type O pos. Sixty infants were ABO-incompatible direct antiglobulin test (DAT) pos, 60 were ABO-incompatible DAT neg and 60 were type O+. Blood for carboxyhemoglobin (COHb) and variants of the enzymes uridine diphosphoglucuronosyltransferase 1A1 and hepatic solute carrier organic anion transporter 1B1 (SLCO1B1) was drawn at the time of the infants' initial bilirubin, and the infants' precise percentile on the Bhutani nomogram was calculated. Variants in the two enzymes studied were quite common. In total, 21.1% were positive for a Gilbert phenotype, whereas an additional 42.4% were heterozygous for the *28 or *37 variant of UGT1A1. In total, 67.2% were homozygous for the *60 variant of the phenobarbital responsive enhancer module. In total, 41.1% were homozygous for the *1b variant of SLCO1B1, whereas an additional 12.7% were positive for the *4 variant of this gene. In total, 20.6% of infants had variations in both genes. Using logistic regression when COHbc was assessed with each of the different variants, only COHbc (P<0.0001 to 0.0004) was significantly associated with the level of hyperbilirubinemia as defined by the Bhutani nomogram. Although we have found quite a large number of genetic variants of the UGT1A1 and SLCO1B1 genes in the AA population, it does not appear that they have a significant impact on the incidence of hyperbilirubinemia among this group of infants.


SH3 domain-mediated interaction of dystroglycan and Grb2.
Dystroglycan is a novel laminin receptor that links the extracellular matrix and sarcolemma in skeletal muscle. The dystroglycan complex containing alpha- and beta-dystroglycan also serves as an agrin receptor in muscle, where it may regulate agrin-induced acetylcholine receptor clustering at the neuromuscular junction. beta-Dystroglycan has now been expressed in vitro and shown to directly interact with Grb2, an adapter protein involved in signal transduction and cytoskeletal organization. Protein binding assays with two Grb2 mutants, Grb2/P49L and Grb2/G203R, which correspond to the loss-of-function mutants in the Caenorhabditis elegans sem-5, demonstrated that the dystroglycan-Grb2 association is through beta-dystroglycan C-terminal proline-rich domains and Grb2 Src homology 3 domains. Affinity chromatography has also shown endogenous skeletal muscle Grb2 interacts with beta-dystroglycan. Immunoprecipitation experiments have demonstrated that Grb2 associates with alpha/beta-dystroglycan in vivo in both skeletal muscle and brain. The specific dystroglycan-Grb2 interaction may play an important role in extracellular matrix-mediated signal transduction and/or cytoskeleton organization in skeletal muscle that may be essential for muscle cell viability.


Assessment of Trace Metals Contamination, Species Distribution and Mobility in River Sediments Using EDTA Extraction.
The impact of the ethylenediaminetetraacetic acid (EDTA) on speciation image of selected trace metals (Zn, Cd, Cu, Pb) in bottom sediments was determined. The influence on the effectiveness of metal removal of extraction multiplicity, type of metal, extraction time and concentration of EDTA were analyzed. With the increase of extraction multiplicity, the concentration of EDTA and contact time, the efficiency of trace metals leaching increased. The speciation analysis revealed that EDTA not only leached metals from bioavailable fractions, but also caused the transition of the metals between the fractions. The biggest amounts of bioavailable forms were found for Cd, less for Zn. The amount of bioavailable fraction was the lowest for Cu and Pb. The two first-order kinetic models fitted well the kinetics of metals extraction with EDTA, allowing the metals fractionation into "labile" (Q1), "moderately labile" (Q2) and "not extractable" fractions (Q3).


[First trimester fasting glycemia and risk factors of pregnant women diagnosed with gestational diabetes mellitus].
To evaluate the incidence of maternal and fetal repercussions and glycemic control in women with Gestational Diabetes Mellitus (GDM) using a fasting glucose of 85 mg/dL in the first trimester as a cut-off point and to correlate it with risk factors. The medical records of pregnant women followed in the outpatient antenatal high-risk service (PNAR) of HRAN from January 2011 to March 2012 were reviewed and those women diagnosed with GDM were selected for contact and for prenatal card verification. We collected data of age, parity, fasting glucose during the first quarter, the value of the Oral Glucose Tolerance Test (OGTT), Body Mass Index (BMI), mode of delivery, form of control, effects and fetal risk factors for GDM. Statistical analysis was performed using the PSPP 0.6.2 software and consisted of descriptive analysis of frequencies, χ2 test for categorical variables, Student's t-test for independent samples, and Pearson test for correlations, with the level of significance set at 5%. From 408 pregnant women enrolled, 105 were diagnosed with GDM and 71 had complete records or answered to the contact in order to provide the missing information. The GDM-fasting <85 (fasting glucose <85 mg/dL at the first prenatal visit, in the first trimester) group consisted of 29 (40.8%) women and the GDM-fasting >85 (fasting glucose >85 mg/dL at the first prenatal visit, in the first trimester) consisted of 42 (59.1%) women. It was observed that few patients (five in the GDM-fasting <85 group and three in the GDM-fasting >85 group) had no risk factors for GDM. There was a major need for control with insulin in patients of the GDM-fasting >85 group. There was no significant difference related to fetal impact or mode of delivery between the groups. The first trimester fasting glycemia, with a cut-off value of 85 mg/dL alone or associated with risk factors, does not seem to be a good single predictor of the maternal-fetal effects of GDM.


Vasoconstriction by electrical stimulation: new approach to control of non-compressible hemorrhage.
Non-compressible hemorrhage is the most common preventable cause of death on battlefield and in civilian traumatic injuries. We report the use of microsecond pulses of electric current to induce rapid constriction in femoral and mesenteric arteries and veins in rats. Electrically-induced vasoconstriction could be induced in seconds while blood vessels dilated back to their original size within minutes after stimulation. At higher settings, a blood clotting formed, leading to complete and permanent occlusion of the vessels. The latter regime dramatically decreased the bleeding rate in the injured femoral and mesenteric arteries, with a complete hemorrhage arrest achieved within seconds. The average blood loss from the treated femoral artery during the first minute after injury was about 7 times less than that of a non-treated control. This new treatment modality offers a promising approach to non-damaging control of bleeding during surgery, and to efficient hemorrhage arrest in trauma patients.


Design, set-up and utility of the UK facioscapulohumeral muscular dystrophy patient registry.
Facioscapulohumeral dystrophy (FSHD) is a rare inherited neuromuscular disease estimated to affect 1/15,000 people. Through basic research, remarkable progress has been made towards the development of targeted therapies. Patient identification, through registries or other means is essential for trial-readiness. The UK FSHD Patient Registry is a patient initiated registry that collects standardised and internationally agreed dataset of self-reported clinical details combined with professionally verified genetic information. It includes four additional questionnaires to capture patient reported outcomes related to pain, quality of life and scapular fixation. Between 2013 and 2015, 518 patients registered 243 males, 241 females with a mean age of 47.8 years. Most of the patients have FSHD type 1 (91.7 %), and weakness of the facial (59.2 %) was the most prevalent symptom at onset, followed by shoulder-girdle muscles (53.3 %) and distal (22.45 %) or proximal lower limb weakness (14.8 %). 85.57 % patients were ambulant or ambulant with assistance at the time of registration, 7.9 % report respiratory insufficiency. The registry has demonstrated utility with the recruitment of patients for a natural history study of infantile onset FSHD, and the longitudinal analysis of patient-related outcomes will provide much-needed baseline information to power future trials. The internationally agreed core dataset enables national registries to participate in a "Global FSHD registry". We suggest that the registry's ability to interoperate with other large datasets will be instrumental for sharing and exploiting data globally.


Design of glass filter combinations for photometers.
Two nonlinear curve-fitting computer programs have been developed for designing subtractive glass filter combinations for use in hotoelectric photometers. One program adjusts the filter thicknesses to minimize the sum of squares of errors at each wavelength and is thus useful in designing a general purpose instrument. The second program minimizes the errors in the photometric measurements of preselected light sources. Filters for correcting various photoelectric detectors to the CIE luminous efficiency function are specified. Several spectral response functions have been utilized including S-4, S-10, S-11, S-20 types, and those of typical silicon diodes, and selenium cells. Practical photometer designs with predicted measurement errors of less than 0.1% are presented.


The nature and impact of chronic stressors on refugee children in Ban Mai Nai Soi camp, Thailand.
Refugee camps are replete with risk factors for mental health problems among children, including poverty, disruption of family structure, family violence and food insecurity. This study, focused on refugee children from Burma, in Ban Mai Nai Soi camp in Thailand, sought to identify the particular risks children are exposed to in this context, and the impacts on their mental health and psychosocial well-being. This study employed two qualitative methods--free list interviews and key informant interviews--to identify the main problems impacting children in Ban Mai Nai Soi camp and to explore the causes of these problems and their impact on children's well-being. Respondents in free list interviews identified a number of problems that impact children in this context, including fighting between adults, alcohol use by adults and children, and child abuse and neglect. Across the issues, the causes included economic and social conditions associated with living in the camp and changes in family structures. Children are chronically exposed to stressors during their growth and development in the camp environment. Policies and interventions in areas of protracted displacement in camp-based settings should work to address these stressors and their impacts at community, household and individual levels.


Frame-Based Stereotactic Biopsy of Canine Brain Masses: Technique and Clinical Results in 26 Cases.
This report describes the methodology, diagnostic yield, and adverse events (AE) associated with frame-based stereotactic brain biopsies (FBSB) obtained from 26 dogs with solitary forebrain lesions. Medical records were reviewed from dogs that underwent FBSB using two stereotactic headframes designed for use in small animals and compatible with computed tomographic (CT) and magnetic resonance (MR) imaging. Stereotactic plans were generated from MR and CT images using commercial software, and FBSB performed both with (14/26) and without intraoperative image guidance. Records were reviewed for diagnostic yield, defined as the proportion of biopsies producing a specific neuropathological diagnosis, AE associated with FBSB, and risk factors for the development of AE. Postprocedural AE were evaluated in 19/26 dogs that did not proceed to a therapeutic intervention immediately following biopsy. Biopsy targets included intra-axial telencephalic masses (24/26), one intra-axial diencephalic mass, and one extra-axial parasellar mass. The median target volume was 1.99 cm(3). No differences in patient, lesion, or outcome variables were observed between the two headframe systems used or between FBSB performed with or without intraoperative CT guidance. The diagnostic yield of FBSB was 94.6%. Needle placement error was a significant risk factor associated with procurement of non-diagnostic biopsy specimens. Gliomas were diagnosed in 24/26 dogs, and meningioma and granulomatous meningoencephalitis in 1 dog each. AE directly related to FBSB were observed in a total of 7/26 (27%) of dogs. Biopsy-associated clinical morbidity, manifesting as seizures and transient neurological deterioration, occurred in 3/19 (16%) of dogs. The case fatality rate was 5.2% (1/19 dogs), with death attributable to intracranial hemorrhage. FBSB using the described apparatus was relatively safe and effective at providing neuropathological diagnoses in dogs with focal forebrain lesions.


Development of Microvascular Complications and Effect of Concurrent Risk Factors in Type 1 Diabetes: A Multistate Model From an Observational Clinical Cohort Study.
Type 1 diabetes is a complex disease, and development of multiple complications over time can be analyzed only with advanced statistical methods. This study describes the development of microvascular complications and explores the effect of complication burden and important concurrent risk factors by applying a multistate model. We used a clinical cohort at the Steno Diabetes Center Copenhagen to study the development of diabetic kidney disease, retinopathy, and neuropathy. We extracted information from electronic patient records and estimated incidence rates of complications by concurrent complication burden. We explored the extent to which concurrent complications modify the effect of selected risk factors on the development of microvascular complications. We included 3,586 individuals. Incidence rate ratios in individuals with two previous complications were 3.2 (95% CI 2.3-4.5) for diabetic kidney disease, 2.1 (1.5-3.1) for retinopathy, and 1.7 (1.2-2.4) for neuropathy compared with individuals without complications. The models included diabetes duration; calendar time and age as timescales; and sex, HbA1c, lipid-lowering and antihypertensive treatment, systolic blood pressure, BMI, estimated glomerular filtration rate (eGFR), cardiovascular disease (CVD), LDL cholesterol, insulin dose (units/kg/day), and smoking status as covariates. Effects of HbA1c, diabetes duration, systolic blood pressure, BMI, eGFR, and LDL cholesterol where not modified by concurrent complication burden, whereas the effect of sex and CVD were. The risk of microvascular complications highly depends on the concurrent complication burden and risk factor profile in individuals with type 1 diabetes. The results emphasize attention to risk factors, regardless of existing number of complications, to prevent development of further microvascular complications.


Heat Shock Proteins: Therapeutic Perspectives in Inflammatory Disorders.
Heat shock proteins (HSPs) are highly conserved proteins present in all kingdoms of organisms. These are expressed under stress conditions in order to protect the cells from injuries. The stress induced protein denaturation is rectified by refolding and remodelling. These are intracellular proteins but can be present in extracellular fluid like serum of the patients suffering from trauma, autoimmune and inflammatory disorders. Virtually in most inflammatory diseases, immune response towards HSPs is developed. The present review expedites the role of HSPs in inflammatory process and associated disorders, mainly in context to HSP70 and HSP90. Commencing a thorough survey of the literature and patents available on HSPs and their role in the process of inflammation, from the authentic published resources available on Medline, Pubmed, Pubmed Central, Science Direct and other scientific databases; the information retrieved has been compiled and analyzed. HSPs modulate the process of inflammation by producing anti-inflammatory cytokines in chronic inflammatory disease. HSPs mediated expression of IL10 contributes in anti-inflammatory role via TLR2 and TLR4-dependent mechanisms. Necroptosis, a caspase independent programmed apoptosis plays an important role in progression of several inflammatory disorders and its major components MLKL and RIPK-1 are the clients of HSP. Necroptosis is also involved in exposure of several damageassociated molecular patterns (DAMPs) including HSPs in extracellular environment leading to inflammation. Endocytosed or intracellular HSP70, is presented by MHC-II molecules and in absence of proper co stimulation, it lead to expansion of tolerogenic or regulatory T cells (Tregs) responses, which have inflammation suppressive activity by virtue of production of anti-inflammatory cytokines, suppression or killing of effector T cells or bringing the APC into tolerogenic state. HSP induced Tregs play an important role in combating autoimmunity and inflammation. Present review gives an insight towards the cause of inflammation and an account of different HSPs contributing various inflammatory disorders viz. inflammatory bowel disease (IBD), intestinal inflammation, atherosclerosis, rheumatoid arthritis (RA), multiple sclerosis etc. The importance of HSPs in handling inflammatory disorders has been depicted in recent patents also.


Cancer screening: a mathematical model relating secreted blood biomarker levels to tumor sizes.
Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden. Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm(3) and 3,610.14 mm(3) for CA125 and between 0.21 mm(3) and 131.51 mm(3) for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm(3) and 1.52 x 10(6) mm(3) for CA125 and between 27 mm(3) and 3.45 x 10(5) mm(3) for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment. This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.


Bile duct injury following laparoscopic cholecystectomy: a cause for continued concern.
Previous reports suggest that bile duct injuries sustained during laparoscopic cholecystectomy (lap chole) are frequently severe and related to cautery and high clip ligation. We performed a review of patients who sustained bile duct injury from lap chole since 1990 and assessed time to injury recognition, time to referral, Bismuth classification, initial and subsequent repairs, rate of recurrence, and length of follow-up. Seventy-four patients [median age 44 years, 58 of 74 female (78%)] were referred with a bile duct injury after lap chole. The level of injury was evenly divided between the bile duct bifurcation and the common hepatic duct: Bismuth III, IV, and V (40 of 74, 54%) versus Bismuth I and II (34 of 74, 46%). Concomitant hepatic arterial injury was identified in nine (12%) patients. Patients referred early after bile duct injury and requiring operative intervention underwent hepaticojejunostomy at a median of 2 days after referral. After surgical reconstruction at our center there has been an overall success rate of 89 per cent with no need for reintervention. Six (10%) of these patients have required one additional balloon dilatation at a mean follow-up of >24 months. One (2%) patient underwent biliary-enteric revision in follow-up. In patients with bile duct injury, stricture repair without delay was successful in the majority of patients treated in this series. Only one of 64 patients reconstructed at our center has required reoperation; six others have required a single balloon dilatation with subsequent good or excellent results. The majority of patients treated with operative repair at an experienced center can expect good long-term results with rare need for reintervention.


Slit: a roadblock for chemotaxis.
The immune system and nervous system display striking similarities. Fernandis and Ganju discuss yet another example where a protein (Slit) originally identified for its role in modulating axon pathfinding is able to regulate immune cell migration. Slit isoforms expressed in the nervous system interact with members of the Robo receptor family to modify movement stimulated by the secreted attractants netrins and their receptors. In leukocytes, Slit 2 interacting with Robo receptors inhibits movement stimulated by the chemokine receptor (CXCR4). Fernandis and Ganju discuss the therapeutic potential of Slit as an antiviral agent and in the treatment of inflammatory diseases, autoimmune disorders, and cancer.


Modulator effects of L-carnitine and selenium on wireless devices (2.45 GHz)-induced oxidative stress and electroencephalography records in brain of rat.
Electromagnetic radiation (EMR) from wireless devices may affect biological systems by increasing free radicals. The present study was designed to determine the effects of 2.45 GHz EMR on the brain antioxidant redox system and electroencephalography (EEG) records in rat. The possible protective effects of selenium and L-carnitine were also tested and compared to untreated controls. Thirty rats were equally divided into five different groups, namely Group A(1): Cage control, Group A(2): Sham control, group B: 2.45 GHz EMR, group C: 2.45 GHz EMR + selenium, group D: 2.45 GHz EMR + L-carnitine. Groups B, C and D were exposed to 2.45 GHz EMR during 60 min/day for 28 days. End of the experiments, EEG records and the brain cortex samples were taken. The cortex brain vitamin A (p < 0.05), vitamin C (p < 0.01) and vitamin E (p < 0.05) concentrations values were lower in group B than in group A1 and A2 although their concentrations were increased by selenium and L-carnitine supplementation. Lipid peroxidation, levels were lower in group C (p < 0.05) and D (p < 0.01) than in group B where as reduced glutathione levels were higher in group C (p < 0.05) than in group A1, A2 and B. However, B-carotene levels did not change in the five groups. L-carnitine and selenium seem to have protective effects on the 2.45 GHz-induced decrease of the vitamins by supporting antioxidant redox system. L-carnitine on the vitamin concentrations seems to more protective affect than in selenium.


Comparative Evaluation of Accuracy of Ipex, Root Zx Mini, and Epex Pro Apex Locators in Teeth with Artificially Created Root Perforations in Presence of Various Intracanal Irrigants.
The study aimed to compare and evaluate the accuracy of iPex, Root ZX mini, and Epex Pro Electronic apex locators (EALs) in diagnosing root perforations in both dry and in different wet conditions: 5% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX), and 17% Ethylenediaminetetraacetic acid (EDTA). Thirty extracted, human single rooted mandibular premolars were artificially perforated with a diameter of 1.5 mm in middle third of root. Actual canal lengths (ALs) in millimetre (mm) were evaluated for all teeth up to perforation location, and alginate mould were used to embed the teeth. After this, the electronic measurements were calculated by all EALs up to perforation site using a 20 K-file in both dry and wet canal conditions. Up to the perforation sites, the ALs were subtracted from the electronic length. Statistical analyses were done using One-way ANOVA with post hoc tukey's test for pairwise comparison and the level of significance was set at 0.05. All three EAL's detected canal perforations which were clinically acceptable. There was significant difference for dry and wet conditions. Most accurate measurement were seen in dry canals for all three EALs. Root ZX mini in dry condition showed most accurate reading and there was a significant difference when compared with other groups. No significance difference was observed in iPex and Epex Pro Apex locator, and between NaOCl and CHX, CHX and EDTA. Perforations were determined within a clinical acceptable range of 0.03-0.05 mm by all three EALs. Root ZX mini in dry canals gave most accurate measurement. The presence of irrigating solution influenced the accuracy of all the apex locators.


Clinical and pathological findings in dogs following supralethal total body irradiation with and without infusion of autologous long-term marrow culture cells.
We developed a canine model for autologous bone marrow transplantation (AuBMT) with long-term marrow culture (LTMC) cells. Marrow was harvested from nine normal dogs. Harvests from dogs 2-7 were placed into 21 day LTMC. Cells in LTMC from dogs 4-7 were labelled with the neomycin phosphotransferase gene neo. Dogs were given 60Co total body irradiation (TBI) and then infused with LTMC cells: dog 1 received 500 cGy TBI and 2.08 x 10(8)/kg uncultured marrow cells. Dogs 2-7 received 600-800 cGy TBI and 0.07-0.45 x 10(8)/kg LTMC cells. Dogs 8 and 9 received 600 and 800 cGy TBI, respectively, but no infusion of marrow or LTMC cells. For all dogs, profound myelosuppression developed during week 1 and pyrexia developed during week 2. Enrofloxacin was given from one day before TBI until a peripheral neutrophil count > 1.0 x 10(9)/L was achieved, which eliminated Escherichia coli from feces. Dogs 1, 2 and 5-9 also received gentamicin and/or combination beta-lactam antibiotics. Numerous platelet transfusions were needed to control hemorrhages in all dogs except dog 1. Dog 1 achieved neutrophils > 1.0 x 10(9)/L on day 15, while dogs 2 and 5-9 achieved this count on days 33-48. Dogs 3 and 4 died on days 17 and 18, respectively, of beta-hemolytic streptococcal sepsis and hemorrhage, with no evidence of hematopoiesis at necropsy. The marker gene, neo, was documented in lymphoid and myeloid cells of dogs 5-7 up to 21 months post-AuBMT. Our studies indicate that dogs can recover following supralethal TBI and can survive the delayed engraftment associated with AuBMT using LTMC cells, if they receive intensive platelet and antimicrobial therapy. Used prophylactically for such therapy, enrofloxacin achieved selective intestinal decontamination, but did not prevent sepsis when used as the sole antimicrobial agent during myelosuppression. Furthermore, our studies indicate that infused LTMC cells, at the above doses, can contribute to hematopoietic recovery, but are not essential for recovery following TBI, and do not shorten the period of prolonged profound myelosuppression induced by TBI.


A Prospective Observational Study of Hypogammaglobulinemia in the First Year After Lung Transplantation.
Immunosuppressive therapies have led to improved survival for lung transplant (LT) recipients but these therapies can lead to hypogammaglobulinemia (HGG) and potentially an increased risk of infection. Large prospective studies have not been performed to evaluate the impact of HGG on outcomes for LT recipients. This is a single-center prospective observational study of LT recipients. Pretransplant and posttransplant IgG levels were measured and related to infection, rejection, antibiotic use, and immunosuppression use. One hundred thirty-three LT recipients were prospectively evaluated. Pretransplant IgG values were higher than IgG values at the time of transplant or any time thereafter (all P < 0.0001). Severe HGG (IgG < 400 mg/dL) was highest at the time of transplant (32.4%) while at 3, 6, 9, and 12 months posttransplant the prevalence of severe HGG was 7.4%, 7.5%, 8.9%, and 6.3%, respectively. Severe HGG was associated with 2 or more pneumonias (P = 0.0006) and increased number of antibiotic courses (P = 0.003) compared with the subjects without severe HGG. Pretransplant IgG level and less than 30% of pretransplant protective pneumococcal antibody levels were identified as pretransplant risk factors for severe HGG. In multivariate analysis, chronic obstructive pulmonary disease as the underlying disease and the use of basiliximab as the induction agent in conjunction with higher prednisone and mycophenolate dosing were most predictive of severe HGG (P = 0.005), whereas the combination of age, severe HGG and number of acute steroid courses were most predictive of total days of pneumonia (P = 0.0001). Our large prospective study identifies risk factors for severe HGG after LT and demonstrates that LT recipients with severe HGG are at increased risk for recurrent pneumonias and more antibiotic courses.


GABAergic neuron distribution in the pedunculopontine nucleus defines functional subterritories.
gamma-Aminobutyric acid (GABA)ergic neurons are widely distributed in brainstem structures involved in the regulation of the sleep-wake cycle, locomotion, and attention. These brainstem structures include the pedunculopontine nucleus (PPN), which is traditionally characterized by its population of cholinergic neurons that have local and wide-ranging connections. The functional heterogeneity of the PPN is partially explained by the topographic distribution of cholinergic neurons, but such heterogeneity might also arise from the organization of other neuronal populations within the PPN. To understand whether a topographical organization is also maintained by GABAergic neurons, we labeled these neurons by in situ hybridization for glutamic acid decarboxylase mRNA combined with immunohistochemistry for choline acetyltransferase to reveal cholinergic neurons. We analyzed their distribution within the PPN by using a method to quantify regional differences based on stereological cell counts. We show that GABAergic neurons of the rat PPN have a rostrocaudal gradient that is opposite to that of cholinergic neurons. Indeed, GABAergic neurons are predominantly concentrated in the rostral PPN; in addition, they form, along with cholinergic neurons, a small, high-density cluster in the most caudal portion of the nucleus. Thus, we provide evidence of heterogeneity in the distribution of different neuronal populations in the PPN and show that GABAergic and cholinergic neurons define neurochemically distinct areas. Our data suggest that the PPN is neurochemically segregated, and such differences define functional territories.


Uncertainty and variability in human exposure limits - a chemical-specific approach for ciprofloxacin and methotrexate.
Human exposure limits (HELs) for chemicals with a toxicological threshold are traditionally derived using default assessment factors that account for variations in exposure duration, species sensitivity and individual sensitivity. The present paper elaborates a probabilistic approach for human hazard characterization and the derivation of HELs. It extends the framework for evaluating and expressing uncertainty in hazard characterization recently proposed by WHO-IPCS, i.e. by the incorporation of chemical-specific data on human variability in toxicokinetics. The incorporation of human variability in toxicodynamics was based on the variation between adverse outcome pathways (AOPs). Furthermore, sources of interindividual variability and uncertainty are propagated separately throughout the derivation process. The outcome is a two-dimensional human dose distribution that quantifies the population fraction exceeding a pre-selected critical effect level with an estimate of the associated uncertainty. This enables policy makers to set separate standards for the fraction of the population to be protected and the confidence level of the assessment. The main sources of uncertainty in the human dose distribution can be identified in order to plan new research for reducing uncertainty. Additionally, the approach enables quantification of the relative risk for specific subpopulations. The approach is demonstrated for two pharmaceuticals, i.e. the antibiotic ciprofloxacin and the antineoplastic methotrexate. For both substances, the probabilistic HEL is mainly influenced by uncertainty originating from: (1) the point of departure (PoD), (2) extrapolation from sub-acute to chronic toxicity and (3) interspecies extrapolation. However, when assessing the tails of the two-dimensional human dose distributions, i.e. the section relevant for the derivation of human exposure limits, interindividual variability in toxicodynamics also becomes important.


Codelivery of doxorubicin-containing thermosensitive hydrogels incorporated with docetaxel-loaded mixed micelles enhances local cancer therapy.
Doxorubicin (DOX) thermosensitive hydrogels (TSHs) incorporated with docetaxel (DOC)-loaded mixed micelles were developed to co-deliver these two drugs through a TSH system, DH700kMF-13.5/M-DocLF, to improve local cancer therapy and reduce side effects. First, Pluronics-based DOC-loaded mixed micelles were developed and optimized. The optimal formulation designated as M-DocLF was composed of 1mg/g docetaxel, 15mg/g Pluronic F127 (PF127), and 45mg/g Pluronic L121 (PL121). Rheological tests showed that DH700kMF-13.5/M-DocLF was an injectable flowing solution, which formed a nonflowing gel at body temperature. After intratumoral (IT) or peritumoral (PT) administration, DH700kMF-13.5/M-DocLF demonstrated efficient growth inhibition of CT-26 tumors in a Balb/c mice model. The tumor inhibitory rate after IT administration of DH700kMF-13.5/M-DocLF was 92.4%, followed by 85.8%, 75.6%, 62.9%, 50.6%, and 49.5% for DH700kMF-15, free DOX, F-13.5/M-DocLF, Tynen (DOC solution), and M-DocLF, respectively. Furthermore, PT administration of DH700kMF-13.5/M-DocLF resulted in similar efficacies. Pharmacokinetic and biodistribution studies showed that after subcutaneous (SC) and IT administration of the designated formulations, smaller amounts of DOX and DOC were absorbed from the local SC or tumor sites into systemic circulation, probably reducing their systemic toxicity. Tumor retention of DOX and DOC in biodistribution studies further revealed that co-delivery of these two drugs in DH700KMF-13.5/M-DocLF potentially enhanced the efficacy of tumor inhibition. In conclusion, our in situ injectable DOX and DOC TSH is a potential dual drug delivery system, which can enhance the efficacy of cancer chemotherapy with minimal side effects and reduced chemoresistance.


Isolation and characterization of an avian A1 adenosine receptor gene and a related cDNA clone.
We have isolated the gene for a chick A1 adenosine receptor along with a cDNA that codes for the same adenosine receptor. The cDNA clone was isolated from both adipose tissue and heart cDNA libraries and encodes a 324-amino acid protein with 80% identity with mammalian A1 adenosine receptors. Transient expression of the cDNA in human embryonic kidney (HEK) 293 cells shows that it encodes a protein that binds [3H]CCPA (2-chloro-N6-[cyclopentyl-2,3,4,5-3H]cyclopentyladenosine, a specific agonist radioligand, with a KD of 5.6 +/- 2.4 nM. Cyclic AMP measurements in HEK 293 cells co-transfected with the chick cDNA and a cDNA for a luteinizing hormone/choriogonadotropin receptor shows that A1 adenosine receptor agonists antagonize the cyclic AMP-elevating effect of bovine luteinizing hormone. Two partial genomic clones were isolated. The first contains 5'-untranslated sequence including a putative promoter region which does not contain a TATA box, an intron and the first third of the coding sequence of the A1 adenosine receptor cDNA. The coding sequence of this partial genomic clone terminates at a second intron. The second partial genomic clone contains the rest of the coding sequence and the 3'-untranslated elements in a single exon. Thus the chick A1 adenosine receptor gene contains one intron in the 5'-untranslated region and a minimum of one intron in the coding sequence.


Fetal Renal DNA Methylation and Developmental Programming of Stress-Induced Hypertension in Growth-Restricted Male Mice.
Fetal growth restriction (FGR) is associated with developmental programming of adult onset hypertension, which may be related to differences in nephron development. Prior studies showed that maternal nutrient restriction is associated with reduced nephrogenesis in rodents, especially in male progeny. We hypothesized that maternal genetic risk for FGR may similarly affect fetal kidney development, leading to adult onset hypertension. We employed an angiotensinogen (AGT) gene titration transgenic (TG) construct with 3 copies of the mouse AGT gene that mimics a common human genotype (AGT A[-6]G) associated with FGR. We investigated whether FGR in 2-copy (wild type, [WT]) progeny from 3-copy TG dams leads to developmental programming differences in kidney development and adult blood pressure compared with age- and sex-matched controls. Progeny were tested in the late fetal period (e17.5), neonatal period (2 weeks of age), and as young adults (12 weeks). We measured weights, tested for renal oxidative stress, compared renal DNA methylation profiles, counted the number of glomeruli, and measured adult blood pressure ± stress. Progeny from TG dams were growth restricted with evidence of renal oxidative stress, males showed fetal renal DNA hypermethylation, they had fewer glomeruli, and they developed stress-induced hypertension as adults. Their female siblings did not share this pathology and instead resembled progeny from WT dams. Surprisingly, glomerular counts in the neonatal period were not different between sexes or maternal genotypes. In turn, we suspect that differences in fetal renal DNA methylation may affect the long-term viability of glomeruli, rather than reducing nephrogenesis.


Cineholomicroscopy of small animal microcirculation.
A holomicrographic system capable of recording the dynamic microscopic events occurring in a living tissue has been developed. This paper discusses the system parameters, the basic configuration, and initial test results. The reconstructed real image from the hologram can be studied with a conventional microscope. The holographic system uses a collecting lens both in recording and in reconstructing. Test results reported include the dissolving of a gas bubble under increased pressure and the movement of polystyrene balls when ejected from a needle. Present resolution is greater than 3 micro, and object velocities greater than 25 mm sec(-1) can be recorded.


Polymorphism of NLRP3 Gene and Association with Susceptibility to Digestive Disorders in Rabbit.
NLR family pyrin domain containing 3 (NLRP3) is a key component of the inflammasome, whose assembly is a crucial part of the innate immune response. The aim of the present study was to evaluate the association between exon 3 polymorphisms of NLRP3 and the susceptibility to digestive disorders in rabbits. In total, five coding single-nucleotide polymorphisms (cSNPs) were identified; all of which are synonymous. Among them, c.456 C> and c.594 G> were further genotyped for association analysis based on case-control design (n =162 vs n =102). Meanwhile, growing rabbits were experimentally induced to digestive disorders by feeding a fiber-deficient diet, subsequently they were subjected to mRNA expression analysis. Association analysis revealed that haplotype H1 (the two cSNPs: GT) played a potential protective role against digestive disorders (p<0.001). The expression of NLRP3 in the group H1HX1 (H1HX1 is composed of H1H1, H1H3 and H1H4) was the lowest among four groups which were classified by different types of diplotypes. Those results suggested that the NLRP3 gene was significantly associated with susceptibility to digestive disorders in rabbit.


Hyperbolic geometry of the olfactory space.
In the natural environment, the sense of smell, or olfaction, serves to detect toxins and judge nutritional content by taking advantage of the associations between compounds as they are created in biochemical reactions. This suggests that the nervous system can classify odors based on statistics of their co-occurrence within natural mixtures rather than from the chemical structures of the ligands themselves. We show that this statistical perspective makes it possible to map odors to points in a hyperbolic space. Hyperbolic coordinates have a long but often underappreciated history of relevance to biology. For example, these coordinates approximate the distance between species computed along dendrograms and, more generally, between points within hierarchical tree-like networks. We find that both natural odors and human perceptual descriptions of smells can be described using a three-dimensional hyperbolic space. This match in geometries can avoid distortions that would otherwise arise when mapping odors to perception.


Measuring and Promoting SARS-CoV-2 Vaccine Equity: Development of a COVID-19 Vaccine Equity Index.
Purpose: The coronavirus pandemic has created the greatest public health crisis in a century, causing >500,000 deaths in the United States alone. Minoritized and socioeconomically disadvantaged groups have borne a disproportionate burden of severe illness, hospitalization, and death from COVID-19. Recently developed FDA-approved vaccines have been shown to significantly reduce severe COVID-19-related outcomes. Vaccination campaigns have the potential to advance health equity by prioritizing allocation to those at highest risk while striving for herd immunity. Large integrated health systems have been faced with the daunting task of meeting the rapidly evolving needs of diverse patient populations for the provision of population-based testing, treatment, education, and now vaccine distribution. We have designed a COVID-19 vaccine equity index (CVEI) to guide health system vaccination strategy. Methods: We considered proportion unvaccinated within a health care system. We then used real-time readily available electronic health record (EHR) COVID-19 testing positivity and proportion hospitalized to measure burden of illness by race/ethnicity. We used conditional probability and statistical theory to measure equity for unvaccinated individuals and to derive an index to highlight these inequities for specific subgroups. Results: We present an illustrative hypothetical example using simulated data for which we calculated the CVEI for non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic patients. In the example, non-Hispanic Black and Hispanic patients had inequitable outcomes. Conclusion: The index can be widely implemented to promote more equitable outcomes among racial/ethnic groups, reducing morbidity and mortality within the overall population as we pursue the collective goal of herd immunity through mass vaccination.