Evaluation of a fiber reinforced drillable bone cement for screw augmentation in a sheep model--mechanical testing.
We evaluated the mechanical properties of a novel fiber reinforced calcium phosphate at time zero and after 12 weeks in vivo using a sheep long bone osteotomy model. Time zero data were obtained and compared by pullout testing of 4.5 mm bone screws from bone proper and overdrilled defects of 4.5 and 8 mm diameter. Defects were augmented with: polymethylmethacrylate (PMMA), calcium phosphate, and fiber reinforced calcium phosphate using cadaveric sheep tibiae. Twelve-week data were obtained from explanted tibiae of sheep that underwent unilateral tibial osteotomy surgery repaired with a locking compression plate. The most distal hole was overdrilled to 4.5 or 8 mm diameter, filled with fiber reinforced cement, drilled, tapped and a 4.5 mm screw was placed. Screw holding strength at t= 0 was significantly higher for reinforced when compared to nonreinforced cement, but not different from bone or PMMA in 4.5 mm defects. There was no difference in pullout strength for the 8 mm defect data. After 12 weeks fiber reinforced pullout strength increased by 45% and 8.9% for 4.5 and 8 mm defects, respectively, when compared to t= 0 testing. Fiber reinforced calcium phosphate bone cement can be drilled and tapped to support orthopedic hardware for trauma applications.


Telomere length reprogramming in embryos and stem cells.
Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism's lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg's capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly responsible for restoring telomere DNA, recent studies have elucidated the role of alternative telomeres lengthening mechanisms in the reprogramming of early embryos and stem cells, which we review here.


The association between socioeconomic status and pandemic influenza: Systematic review and meta-analysis.
The objective of this study is to document whether and to what extent there is an association between socioeconomic status (SES) and disease outcomes in the last five influenza pandemics. The review included studies published in English, Danish, Norwegian and Swedish. Records were identified through systematic literature searches in six databases. We summarized results narratively and through meta-analytic strategies. Only studies for the 1918 and 2009 pandemics were identified. Of 14 studies on the 2009 pandemic including data on both medical and social risk factors, after controlling for medical risk factors 8 demonstrated independent impact of SES. In the random effect analysis of 46 estimates from 35 studies we found a pooled mean odds ratio of 1.4 (95% CI: 1.2-1.7, p < 0.001), comparing the lowest to the highest SES, but with substantial effect heterogeneity across studies,-reflecting differences in outcome measures and definitions of case and control samples. Analyses by pandemic period (1918 or 2009) and by level of SES measure (individual or ecological) indicated no differences along these dimensions. Studies using healthy controls tended to document that low SES was associated with worse influenza outcome, and studies using infected controls find low SES associated with more severe outcomes. A few studies compared severe outcomes (ICU or death) to hospital admissions but these did not find significant SES associations in any direction. Studies with more unusual comparisons (e.g., pandemic vs seasonal influenza, seasonal influenza vs other patient groups) reported no or negative non-significant associations. We found that SES was significantly associated with pandemic influenza outcomes with people of lower SES having the highest disease burden in both 1918 and 2009. To prepare for future pandemics, we must consider social vulnerability. The protocol for this study has been registered in PROSPERO (ref. no 87922) and has been published Mamelund et al. (2019).


Markedly enhanced cytolysis by E1B-19kD-deleted oncolytic adenovirus in combination with cisplatin.
Oncolytic adenoviruses are currently being developed as novel antitumor therapeutics. To enhance their therapeutic potential, adenoviruses are being administered in combination with standard chemotherapy. Adenoviral vectors used in these clinical trials, however, can be destructive as they encode intact E1B 19-kDa protein, which can block the apoptotic pathway induced by a variety of chemotherapeutic agents. Previously, we have shown that oncolytic adenovirus Ad-DeltaE1B19/55, deleted for sequence encoding E1B 19-kDa and E1B 55-kDa proteins, exhibits marked enhancement in cytolytic and apoptotic activity [Kim, J., Cho, J.Y., Kim, J.H., Jung, K.C., and Yun, C.O. (2002). Cancer Gene Ther. 9, 725-736]. In the current study, we assess the therapeutic value of Ad- DeltaE1B55 and Ad-DeltaE1B19/55 in combination with cisplatin. A marked increase in cytotoxicity was observed for both Ad-DeltaE1B55 and Ad-DeltaE1B19/55 when combined with cisplatin. Relative to each other in all cell lines examined, the combination of the double-deleted adenovirus, Ad-DeltaE1B19/55, plus cisplatin exhibited a greater cell-killing effect than did the single-deleted adenovirus, Ad-DeltaE1B55, plus cisplatin. Propidium iodide staining and TUNEL analysis also revealed that the combination of cisplatin with Ad-DeltaE1B19/55 caused greater induction of apoptosis than that with Ad-DeltaE1B55. Similarly, in vivo, the combination of Ad-DeltaE1B55 or Ad-DeltaE1B19/55 with cisplatin also induced greater antitumor effect in a human cervical xenograft model. TUNEL staining showed that the apoptotic level was significantly higher in tumor tissue treated with Ad-DeltaE1B19/55 plus cisplatin than with any other treatment. In addition, viral presence was confirmed by immunohistological staining, with increased numbers of adenoviral particles detected in wider areas of tumors treated with Ad-DeltaE1B19/55 oncolytic adenovirus plus cisplatin. Taken together, these findings demonstrate that cisplatin in combination with E1B- 19kD-deleted oncolytic adenovirus may enhance therapeutic efficacy (via active induction of apoptosis), eliciting a greater efficacy profile than that with E1B-19kD-expressing oncolytic adenovirus.


Validation of MALDI-TOF MS Biotyper database optimized for anaerobic bacteria: The ENRIA project.
Within the ENRIA project, several 'expertise laboratories' collaborated in order to optimize the identification of clinical anaerobic isolates by using a widely available platform, the Biotyper Matrix Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS). Main Spectral Profiles (MSPs) of well characterized anaerobic strains were added to one of the latest updates of the Biotyper database db6903; (V6 database) for common use. MSPs of anaerobic strains nominated for addition to the Biotyper database are included in this validation. In this study, we validated the optimized database (db5989 [V5 database] + ENRIA MSPs) using 6309 anaerobic isolates. Using the V5 database 71.1% of the isolates could be identified with high confidence, 16.9% with low confidence and 12.0% could not be identified. Including the MSPs added to the V6 database and all MSPs created within the ENRIA project, the amount of strains identified with high confidence increased to 74.8% and 79.2%, respectively. Strains that could not be identified using MALDI-TOF MS decreased to 10.4% and 7.3%, respectively. The observed increase in high confidence identifications differed per genus. For Bilophila wadsworthia, Prevotella spp., gram-positive anaerobic cocci and other less commonly encountered species more strains were identified with higher confidence. A subset of the non-identified strains (42.1%) were identified using 16S rDNA gene sequencing. The obtained identities demonstrated that strains could not be identified either due to the generation of spectra of insufficient quality or due to the fact that no MSP of the encountered species was present in the database. Undoubtedly, the ENRIA project has successfully increased the number of anaerobic isolates that can be identified with high confidence. We therefore recommend further expansion of the database to include less frequently isolated species as this would also allow us to gain valuable insight into the clinical relevance of these less common anaerobic bacteria.


[Social, demographic, family and economic factors related to adolescent pregnancy in the urban area of Briceño, 2012].
To establish the relationship between the social, demographic, economic and family with pregnancy in adolescents 13 to 19 years in urban areas in the municipality of Briceño, 2012, for the purpose of obtaining information for the formulation of public health policies sexual and reproductive health. Methods: Cross sectional study, conducted in the urban area of Antioquia Briceño, between April and May 2012. A survey was conducted to gather information on factors: social, demographic, economic and family. Implemented a logistic regression model. The adolescents who were 193 survey respondents. Factors associated by multivariate analysis with increased risk of teenage pregnancy were age (OR: 8.33 CI, 1.82 to 38.14), socioeconomic status (OR: 12.52 CI, 1.58 to 98, 91), occupation (OR: 7.60 CI 3.0 to 19.27), living with a partner (OR: 17.47 CI, 3.63 to 83.94), early initiation of sex (OR: 1.95 CI, 0.69 to 5.5), the number of sexual partners (OR: 1.70 CI, 0.74 to 3.86), the father's education level (OR: 3.05 CI 1.01 to 9.22), the fact of having been raped (OR: 3.66 CI, 1.12 to 11.96) and family income (OR: 3.98 CI, 1,45-10, 92). The study found that age, socioeconomic status, occupation, living with the couple, early initiation of sexual intercourse, number of sexual partners, the educational level of the father, having been raped and the family income were associated with teenage pregnancy in the urban area of Briceño.


Fluorescence spectroscopy of UV-MALDI matrices and implications of ionization mechanisms.
Matrix-assisted laser desorption ionization (MALDI) has been widely used in the mass analysis of biomolecules; however, there are a lot of debates about the ionization mechanisms. Previous studies have indicated that S1-S1 annihilation might be a key process in the generation of primary ions. This study investigates S1-S1 annihilation by examining the time-resolved fluorescence spectra of 12 matrices. No S1-S1 annihilation was observed in six of these matrices (3-hydroxy-picolinic acid, 6-aza-2-thiothymine, 2,4-dihydroxy-acetophenone, 2,6-dihydroxy-acetophenone, 2,4,6-trihydroxy-acetophenone, and ferulic acid). We observed two matrix molecules reacting in an electronically excited state (S1) in five of these matrices (2,5-dihydroxybenzoic acid, α-cyano-4-hydroxycinnamic acid, 2,5-dihydroxy-acetophenone, 2,3-dihydroxybenzoic acid, and 2,6-dihydroxybenzoic acid), and S1-S1 annihilation was a possible reaction. Among these five matrices, no S1-S1 annihilation was observed for 2,3-dihydroxybenzoic acid in typical peak power region of nanosecond laser pulses in MALDI, but a very small value of reaction rate constant was observed only in the high peak power region. The excited-state lifetime of sinapinic acid was too short to determine whether the molecules reacted in an electronically excited state. No correlation was observed between the ion generation efficiency of MALDI and S1-S1 annihilation. The results indicate that the proposal of S1-S1 annihilation is unnecessary in MALDI and energy pooling model for MALDI ionization mechanism has to be modified.


Anti-inflammatory and anti-fibrotic profile of fish oil emulsions used in parenteral nutrition-associated liver disease.
Home parenteral nutrition (PN) is associated with many complications including severe hepatobiliary dysfunction. Commercial ω-6 fatty acid-soybean based-lipid emulsions in PN may mediate long term PN associate liver disease (PNALD) whereas ω-3-fish oil parenteral emulsions have shown to reverse PNALD in children. However, its clinical effectiveness in adults has been scarcely reported. In this work, we study the role of soybean and fish oil lipid commercial emulsions on inflammatory and profibrotic liver markers in adults with long term PNALD and in in vitro cellular models. Inflammatory and profibrotic markers were measured in serum of ten adults with long term PNALD and in culture supernatants of monocytes. Liver epithelial to mesenchymal transition (EMT) was induced by transforming growth factor beta 1 (TGFβ1) to evaluate in vitro liver fibrosis. Omegaven®, a 100% fish oil commercial emulsion, was infused during four months in two patients with severe long term PNALD reversing, at the first month, the inflammatory, profibrotic and clinical parameters of PNALD. The effect was maintained during the treatment course but impaired when conventional lipid emulsions were reintroduced. The other patients under chronic soybean oil-based PN showed elevated inflammatory and profibrotic parameters. In vitro human monocytes stimulated with lipopolysaccharide induced a strong inflammatory response that was suppressed by Omegaven®, but increased by soybean emulsions. In other experiments, TGFβ1 induced EMT that was suppressed by Omegaven® and enhanced by soybean oil lipid emulsions. Omegaven® improves clinical, anti-inflammatory and anti-fibrotic parameters in adults with long-term home PNALD.


Long Non-Coding RNA NNT-AS1 Contributes to Cisplatin Resistance via miR-1236-3p/ATG7 Axis in Lung Cancer Cells.
Lung cancer is one of the most prevailing human cancers worldwide. Emerging evidence implies that long non-coding RNA nicotinamide nucleotide transhydrogenase-antisense RNA1 (NNT-AS1) is implicated in the tumorigenesis of lung cancer. Herein, we aimed to expose the impact of NNT-AS1 on the drug resistance of lung cancer. Levels of NNT-AS1, microRNA (miR)-1236-3p and autophagy-related gene 7 (ATG7) were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) assay. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was implemented to detect cell proliferation and the half maximal inhibitory concentration (IC50) of cisplatin (DDP) in vitro. Moreover, flow cytometry was performed to assess cell apoptosis. Cell migration and invasion were examined utilizing transwell assay in lung cancer cells. Besides, levels of ATG7 and cell behavior-related proteins were determined via Western blot. Dual-luciferase reporter assay was administrated to identify the interaction between miR-1236-3p and NNT-AS1 or ATG7. The biological role of NNT-AS1 in DDP resistance of lung cancer was examined by xenograft tumor model in vivo. NNT-AS1 and ATG7 were upregulated, whereas miR-1236-3p was curbed in lung cancer tissues and in with or without DDP-resistant cell lines. NNT-AS1 detection significantly constrained cell growth, metastasis, and the IC50 of DDP in A549/DDP and H522/DDP cells. Interestingly, the influence of miR-1236-3p mimic on DDP resistance was overturned via NNT-AS1 upregulation in vitro. Reintroduction of miR-1236-3p inhibitor relieved the effect of ATG7 silencing on DDP sensitivity in A549/DDP and H522/DDP cells. Importantly, NNT-AS1 was a sponge of miR-1236-3p to separate ATG7. Besides, NNT-AS1 silencing enhanced DDP sensitivity of lung cancer in vivo. NNT-AS1/miR-1236-3p/ATG7 axis regulated DDP resistance in lung cancer cells and might supply a probable target and prognostic marker in lung cancer treatment.


Prevalence of Antiretroviral Drug Resistance in Patients Who Are Not Responding to Protease Inhibitor-Based Treatment: Results From the First National Survey in South Africa.
Limited data exist on human immunodeficiency virus type 1 (HIV-1) resistance in patients who are not responding to protease inhibitor (PI)-based regimens in resource-limited settings. This study assessed resistance profiles in adults across South Africa who were not responding to PI-based regimens. pol sequencing was undertaken and submitted to the Stanford HIV Drug Resistance Database. At least 1 major PI mutation was detected in 16.4% of 350 participants. A total of 53.4% showed intermediate resistance to darunavir/ritonavir, whereas high-level resistance was not observed. Only 5.2% and 32.8% of participants showed high-level and intermediate resistance to etravirine, respectively. Although the prevalence of major PI mutations was within previously reported ranges, most patients will likely experience virological suppression during receipt of currently available South African third-line regimens.


Effect of Number of Players and Maturity on Ball-Drills Training Load in Youth Basketball.
This study aimed to assess the basketball ball-drills workload analyzing: (1) the effect of varying the number of players involved on physiological and technical demands; (2) the temporal changes in players' responses across bouts; and (3) the relationship of players' workload with their maturation status and training age. Twelve young male basketball players (mean ± SD; age 13.9 ± 0.7 years; height 1.76 ± 0.06 m; body mass 65.7 ± 12.5 kg; HRmax 202 ± 8 beat·min-1) completed three bouts of 4 min interspersed by 2 min of passive recovery of two vs. two and four vs. four ball-drills. The mean percentage of HRmax (%HRmax) and ratings of perceived exertion (RPE) were collected. Technical actions (TAs) (dribbles, passes, shots, interceptions, steals, rebounds, and turnovers) were calculated through notational analysis. Players' genitalia development (GD) and pubic hair (PH) growth were assessed using Tanner scale. Results showed a higher %HRmax (p = 0.018), RPE (p = 0.042), dribbles (p = 0.007), shots (p = 0.003), and rebounds (p = 0.006) in two vs. two compared to four vs. four condition. Furthermore, a statistical difference was found for %HRmax (p = 0.005) and number of passes (p = 0.020) between bouts. In addition, no correlation between GD, PH, and training age with %HRmax, RPE, and TAs was found. These findings suggest that variations of the number of players involved affect ball-drills workload and that ball-drills training intensity varies across bouts. Finally, ball-drills elicit an adequate training stimulus, regardless of players' maturation status and training age.


New approach for T-shaped uterus: Metroplasty with resection of lateral fibromuscular tissue using a 15 Fr miniresectoscope. A step-by-step technique.
T-shaped uterus is a congenital uterine malformation (CUM), only recently defined by the ESGE ESHRE classification as Class U1a. The uterus is characterised by a narrow uterine cavity due to thickened lateral walls with a correlation 2/3 uterine corpus and 1/3 cervix. Although the significance of this dysmorphic malformation on reproductive performance has been questioned, recent studies reported significant improvement of life birth rates after surgical correction in patients with failed in-vitro fertilisation (IVF) or recurrent miscarriage. The classical surgical technique to treat a T-shaped uterus is by performing a sidewall incision with the micro scissor or bipolar needle, resulting in a triangular cavity. In this video article, we describe a new surgical technique with a step-by-step method combining three- dimensional ultrasound (3D-US) and hysteroscopic metroplasty in an office setting, using a 15 Fr office resectoscope (Karl Storz, Tuttlingen, Germany), to treat a T-shaped uterus by resecting the lateral fibromuscular tissue of the uterine walls. No complications occurred and the postoperative hysteroscopy showed a triangular and symmetrical uterine cavity without any adhesions.


TNF-alpha-induced self expression in human lung endothelial cells is inhibited by native and oxidized alpha1-antitrypsin.
Endothelial cells are among the main physiological targets of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). In endothelial cells TNF-alpha elicits a broad spectrum of biological effects including differentiation, proliferation and apoptosis. alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteases plays a vital role in protecting host tissue from proteolytic injury at sites of inflammation. Recently, it has been shown that AAT can be internalized by pulmonary endothelial cells, raising speculation that it may modulate endothelial cell function in addition to suppressing protease activity. Using Affymetrix microarray technology, real time PCR and ELISA methods we have investigated the effects of AAT on un-stimulated and TNF-alpha stimulated human primary lung microvascular endothelial cell gene expression and protein secretion. We find that AAT and TNF-alpha generally induced expression of distinct gene families with AAT exhibiting little activity in terms of inflammatory gene expression. Approximately 25% of genes up regulated by TNF-alpha were inhibited by co-administration of AAT including TNF-alpha-induced self expression. Surprisingly, the effects of AAT on TNF-alpha-induced self expression was inhibited equally well by oxidized AAT, a modified form of AAT, which lacks serine protease inhibitor activity. Overall, the pattern of gene expression regulated by native and oxidized AAT was similar with neither inducing pro-inflammatory gene expression. These findings suggest that inhibitory effects of native and oxidized forms of AAT on TNF-alpha stimulated gene expression may play an important role in limiting the uncontrolled endothelial cell activation and vascular injury in inflammatory disease.


Surveying molecular vibrations during the formation of metal-molecule nanocontacts.
Molecular junctions have been characterized to determine the influence of the metal contact formation in the electron transport process through a single molecule. With inelastic electron tunneling spectroscopy and first-principles calculations, the vibration modes of a carbon monoxide molecule have been surveyed as a function of the distance from a copper electrode with unprecedented accuracy. We observe a continuous but nonlinear blue shift of the frustrated rotation mode in tunneling with decreasing distance followed by an abrupt softening upon contact formation. This indicates that the presence of the metal electrode sensibly alters the structural and conductive properties of the junction even without the formation of a strong chemical bond.


[Growth characteristics of haploid and diploid Hansenula polymorpha yeasts on methanol in continuous culture].
The rate of growth and the yield of biomass of a Hunsenula polymorpha homozygous diploid strain ML-3 X ML-3 were nearly identical with those of the parent haploid culture ML-3. The two cultures were eliminated from the fermenter at D = 0.20 to 0.21 h-1. In contrast, a heterozygous diploid strain ML-3 X VKM 1397 could grow at D = 0.23 to 0.25 h-1 and its biomass yield reached 38% while the yields of the haploid and homozygous diploid strains were 35 to 36%. The pH of the medium had the same effect on the three cultures: a change in the pH from 4.0 to 3.5 and then to 3.0 did not influence the yield of biomass; a further pH drop to 2.5 made the cells be eliminated from the fermenter.


Human renal adipose tissue induces the invasion and progression of renal cell carcinoma.
We evaluated the effects of conditioned media (CMs) of human adipose tissue from renal cell carcinoma located near the tumor (hRATnT) or farther away from the tumor (hRATfT), on proliferation, adhesion and migration of tumor (786-O and ACHN) and non-tumor (HK-2) human renal epithelial cell lines. Human adipose tissues were obtained from patients with renal cell carcinoma (RCC) and CMs from hRATnT and hRATfT incubation. Proliferation, adhesion and migration were quantified in 786-O, ACHN and HK-2 cell lines incubated with hRATnT-, hRATfT- or control-CMs. We evaluated versican, adiponectin and leptin expression in CMs from hRATnT and hRATfT. We evaluated AdipoR1/2, ObR, pERK, pAkt y pPI3K expression on cell lines incubated with CMs. No differences in proliferation of cell lines was found after 24 h of treatment with CMs. All cell lines showed a significant decrease in cell adhesion and increase in cell migration after incubation with hRATnT-CMs vs. hRATfT- or control-CMs. hRATnT-CMs showed increased levels of versican and leptin, compared to hRATfT-CMs. AdipoR2 in 786-O and ACHN cells decreased significantly after incubation with hRATfT- and hRATnT-CMs vs. control-CMs. We observed a decrease in the expression of pAkt in HK-2, 786-O and ACHN incubated with hRATnT-CMs. This result could partially explain the observed changes in migration and cell adhesion. We conclude that hRATnT released factors, such as leptin and versican, could enhance the invasive potential of renal epithelial cell lines and could modulate the progression of the disease.


[Treatment of pruritus and polyneuropathy in patients with chronic renal failure by intermittent plasmapheresis].
Fourteen patients with chronic renal failure treated with hemodialysis received intermittent plasmapheresis with the purpose of treating skin pruritus and polyneuropathy. Skin pruritus and polyneuropathy were completely eliminated in 10 patients, the intensity of pruritus could be considerably reduced in 3 patients, and one patient did not respond to the treatment. About half of the procedures were carried out on an outpatient basis. No serious complications mandating the procedure discontinuation were noted.


Structure and dynamics of Odinarchaeota tubulin and the implications for eukaryotic microtubule evolution.
Tubulins are critical for the internal organization of eukaryotic cells, and understanding their emergence is an important question in eukaryogenesis. Asgard archaea are the closest known prokaryotic relatives to eukaryotes. Here, we elucidated the apo and nucleotide-bound x-ray structures of an Asgard tubulin from hydrothermal living Odinarchaeota (OdinTubulin). The guanosine 5'-triphosphate (GTP)-bound structure resembles a microtubule protofilament, with GTP bound between subunits, coordinating the "+" end subunit through a network of water molecules and unexpectedly by two cations. A water molecule is located suitable for GTP hydrolysis. Time course crystallography and electron microscopy revealed conformational changes on GTP hydrolysis. OdinTubulin forms tubules at high temperatures, with short curved protofilaments coiling around the tubule circumference, more similar to FtsZ, rather than running parallel to its length, as in microtubules. Thus, OdinTubulin represents an evolutionary stage intermediate between prokaryotic FtsZ and eukaryotic microtubule-forming tubulins.


Zonation of the adrenal cortex. I. Isolation of mitochondria from the zona glomerulosa of the bovine adrenal cortex.
Isolation procedures for mitochondria from the zona glomerulosa of the bovine adrenal cortex are described in comparison to those isolated from the zona fasciculo-reticularis. The cristal membranes of mitochondria in the zona glomerulosa in situ are tubular or tubulo-vesicular, whereas those of mitochondria in the zona fasciculo-reticularis in situ are vesicular. When mitochondria are isolated from the former zone, they invariably showed a condensed configuration regardless of isolation media, whereas those isolated from the later zone in a ST medium showed an orthodox configuration. When Ca2+ was added to mitochondria isolated form either zone in an STE medium in the condensed configuration, transition from the condensed to the orthodox configuration took place; the cristel membrane of mitochondria from the zona glomerulosa became tubular or tubulo-vesicular and those of mitochondria from the zona fasciculo-reticularis became vesicular. Purity of mitochondria thus obtained from the zona glomerulosa was examined by electron microscope and marker enzymes. Coupling efficiency of mitochondria was found to be remarkably affected by temperature during the isolation procedures and a choice of substrates.


Interrelationship of Chlamydia trachomatis and other pathogens in the female genital tract.
The isolation of Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and Candida albicans in the female genital tract was studied in 1323 patients attending a venereal disease clinic. Disruption of the cell monolayers use for the isolation of C. trachomatis was significantly associated with the presence of T. vaginalis; this effect was markedly reduced by the addition of vancomycin to gentamicin and amphotericin B in the transport and growth media. The only significant positive association was the more frequent isolation of C. trachomatis in the presence of N. gonorrhoeae. There was a negative association between N. gonorrhoeae and C. albicans and between T. vaginalis and C. albicans, the fungus being isolated significantly less frequently when these microorganisms were present.


EXPERIMENTAL AIR-BORNE INFECTION WITH POLIOMYELITIS VIRUS.
Infection has been obtained in both rhesus and cynomolgus monkeys by inhalation of poliomyelitis virus in the form of droplet nuclei. The olfactory route was excluded in part of the animals successfully infected. The gastrointestinal route is believed to have been excluded in the rhesus monkeys. It seems most probable that the portals of entry were the lower respiratory mucosa in the case of the rhesus monkeys and the oropharyngeal mucosa in the case of the cynomolgus monkeys. Fever and occasional mild symptoms in 8 other rhesus monkeys suggest that an abortive form of poliomyelitis may have resulted from inhalation, but this can not at present be considered as proved. The experiments open up the possibility that human poliomyelitis may, at least sometimes, be an air-borne infection and that the lungs may be a portal of entry. Neither of these aspects of the disease has hitherto, so far as we are aware, been studied experimentally. The presence of virus in the human nasopharynx, which has been repeatedly demonstrated,(7, 8) provides an obvious source of air contamination by patients and carriers; and direct contact has been traced during epidemics in a considerable fraction of cases,(9) amounting to about one third in the report of Top and Vaughan.(10) The relative importance of transmission by air and by ingested material remains to be determined. It would seem probable, however, that both modes of infection must be taken into account.


[The interneuronal functional connections in the sensorimotor cortex of dogs].
Multiunit activity of sensorimotor cortex was recorded from chronically implanted semi-microelectrodes in two dogs. Functional interneuronal connections between neuronal spike trains of 6-8 neurons selected from background multiunit activity were studied by the method of cross-correlation analysis. Bin widths 0.5, 1, 2, 3 and further up to 40 ms by step of 1 ms were used. The cross-interval connections were characterized by complete absence of the shared input (central symmetrical peaks) and signs of inhibitory interrelations. The temporal interrelations between selected neurons were characterized by unilateral and bilateral non-symmetrical excitatory connections--ultra-narrow peaks with short (1-10 ms), middle (10-80 ms) and long (80-2000 ms) delays. The existence of such ultra-narrow peaks contradicts "classical" conceptions on the character of cross-interval connections based on model experiments on simple nervous systems. We suppose that special mechanism of synchronization with high temporal accuracy exists in the cortex.


Experimental Evidence of Solvent-Separated Ion Pairs as Metastable States in Electrostatic Interactions of Biological Macromolecules.
Electrostatic interactions via ion pairs are vital for biological macromolecules. Regarding the free energy of each ion pair as a function of the interionic distance, continuum electrostatic models predict a single energy minimum corresponding to the contact ion-pair (CIP) state, whereas atomically detailed theoretical hydration studies predict multiple energy minima corresponding to the CIP and solvent-separated ion-pair (SIP) states. Through a statistical analysis of high-resolution crystal structures, we present experimental evidence of the SIP as a metastable state. The histogram of interionic distances between protein side-chain NH3+ and DNA phosphate groups clearly shows two major peaks corresponding to the CIP and SIP states. The statistical data are consistent with the probability distribution of the CIP-SIP equilibria previously obtained with molecular dynamics simulations. Spatial distributions of NH3+ ions and water molecules around phosphates reveal preferential sites for CIP and SIP formations and show how the ions compete with water molecules.


A novel ubiquitous protein 'chaperonin' supports the endosymbiotic origin of mitochondrion and plant chloroplast.
The deduced amino acid sequences for a major mitochondrial protein (designated P1, related to the 'chaperonin' family of proteins) from human and Chinese hamster cells show extensive similarity (greater than 60% identity observed over the entire length) with a related protein present in evolutionarily as divergent organisms as Escherichia coli, Coxiella burnetii, Mycobacterium species, cyanobacteria as well as in yeast mitochondria and higher plant chloroplasts. Of the different groups of bacteria for which sequence data is available, maximum similarity of the mammalian/yeast P1 protein is observed with the corresponding protein from purple bacteria (especially C. burnetii) while the protein from plant chloroplasts exhibited highest similarity with the corresponding protein from cyanobacteria. The sequence data for this protein thus support the contention that the endosymbiont that gave rise to mitochondrion was a member of purple bacteria, while plant chloroplast originated from a member of the cyanobacterial lineage.


MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development.
Notch signalling controls the differentiation of haematopoietic progenitor cells (HPCs). Here, we show that loss of membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP14), a cell surface protease expressed in bone marrow stromal cells (BMSCs), increases Notch signalling in HPCs and specifically impairs B-lymphocyte development. When co-cultured with BMSCs in vitro, HPCs differentiation towards B lymphocytes is significantly compromised on MT1-MMP-deficient BMSCs and this defect could be completely rescued by DAPT, a specific Notch signalling inhibitor. The defective B-lymphocyte development could also be largely rescued by DAPT in vivo. MT1-MMP interacts with Notch ligand Delta-like 1 (Dll1) and promotes its cleavage on cell surface in BMSCs. Ectopic MT1-MMP cleaves Dll1 and results in diminished Notch signalling in co-cultured cells. In addition, recombinant MT1-MMP cleaves a synthetic Dll1 peptide at the same site where MT1-MMP cleaves Dll1 on the cell surface. Our data suggest that MT1-MMP directly cleaves Dll1 on BMSCs to negatively regulate Notch signalling to specifically maintain normal B-cell development in bone marrow.


Effects of language of assessment on the measurement of acculturation: measurement equivalence and cultural frame switching.
The present study used a randomized design, with fully bilingual Hispanic participants from the Miami area, to investigate 2 sets of research questions. First, we sought to ascertain the extent to which measures of acculturation (Hispanic and U.S. practices, values, and identifications) satisfied criteria for linguistic measurement equivalence. Second, we sought to examine whether cultural frame switching would emerge--that is, whether latent acculturation mean scores for U.S. acculturation would be higher among participants randomized to complete measures in English and whether latent acculturation mean scores for Hispanic acculturation would be higher among participants randomized to complete measures in Spanish. A sample of 722 Hispanic students from a Hispanic-serving university participated in the study. Participants were first asked to complete translation tasks to verify that they were fully bilingual. Based on ratings from 2 independent coders, 574 participants (79.5% of the sample) qualified as fully bilingual and were randomized to complete the acculturation measures in either English or Spanish. Theoretically relevant criterion measures--self-esteem, depressive symptoms, and personal identity--were also administered in the randomized language. Measurement equivalence analyses indicated that all of the acculturation measures--Hispanic and U.S. practices, values, and identifications-met criteria for configural, weak/metric, strong/scalar, and convergent validity equivalence. These findings indicate that data generated using acculturation measures can, at least under some conditions, be combined or compared across languages of administration. Few latent mean differences emerged. These results are discussed in terms of the measurement of acculturation in linguistically diverse populations.


Ornithine decarboxylase is involved in repair of small intestine after ischemia-reperfusion in rats.
To assess whether ornithine decarboxylase (ODC) is involved in mucosal repair after ischemia-reperfusion (I/R), two approaches were used: 1) measurement of mucosal ODC activity at different intervals after I/R, and 2) inhibition of ODC activity with alpha-difluoromethylornithine (DFMO, an irreversible inhibitor). In the first series of experiments, rats were allowed to recover after superior mesenteric arterial occlusion (10 min) before harvesting the intestinal mucosa for measurement of ODC activity. ODC activity increased markedly 6 h after I/R, and greater than 72 h were required for enzyme activity to return to normal. DFMO treatment completely abolished the I/R-induced increase in ODC activity. In another series of experiments, rats with an intestinal lymph fistula were infused intraduodenally at 3 ml/h with vehicle or 2% DFMO in vehicle immediately after I/R. Lipid absorption was measured at 24 and 48 h after I/R. In the DFMO group, lymph radioactive lipid output at 24 h after I/R was significantly lower compared with time-matched sham-operated controls. Lymph lipid output in rats receiving the vehicle was restored to a normal level at 48 h after I/R. However, this restoration of normal lymphatic lipid transport at 48 h I/R was not observed in the DFMO group. These observations indicate that ODC activity plays an important role in the repair process that results in complete restoration of mucosal function 2 days after I/R.


Behavior of Listeria monocytogenes during fabrication and storage of experimentally contaminated smoked salmon.
Experiments were carried out to examine the behavior of Listeria monocytogenes in the course of fabrication and storage of smoked salmon. In three trials, raw salmon fillets were surface inoculated with L. monocytogenes, marinated, smoked at 26 to 30 degrees C, and stored at 4 or 10 degrees C for up to 30 days. At different times during the fabrication and storage, samples were taken and, by means of the three-tube most probable number (MPN) method, quantitatively analyzed for the concentration of L. monocytogenes. The initial Listeria levels in the raw fillets were 10(4) MPN/g in trial 1, 10(1) MPN/g in trial 2, and 10(2) MPN/g in trial 3. During the fabrication, neither an increase nor a decrease of the inoculated quantities was observed. During the storage, however, a significant growth was measured in two of three trials; in trial 1, a 2.5 log10 MPN/g increase and in trial 3, an increase of even 4.5 log10 MPN/g. In the second trial, the Listeria level remained about the same. The results indicate the importance of preventing pre- and postprocessing contamination of L. monocytogenes in raw and smoked salmon. Because a significant increase of L. monocytogenes was measured during storage, there might be an increasing risk of infection for the consumer by storing such fish for a long time.


Fair algorithms for selecting citizens' assemblies.
Globally, there has been a recent surge in 'citizens' assemblies'1, which are a form of civic participation in which a panel of randomly selected constituents contributes to questions of policy. The random process for selecting this panel should satisfy two properties. First, it must produce a panel that is representative of the population. Second, in the spirit of democratic equality, individuals would ideally be selected to serve on this panel with equal probability2,3. However, in practice these desiderata are in tension owing to differential participation rates across subpopulations4,5. Here we apply ideas from fair division to develop selection algorithms that satisfy the two desiderata simultaneously to the greatest possible extent: our selection algorithms choose representative panels while selecting individuals with probabilities as close to equal as mathematically possible, for many metrics of 'closeness to equality'. Our implementation of one such algorithm has already been used to select more than 40 citizens' assemblies around the world. As we demonstrate using data from ten citizens' assemblies, adopting our algorithm over a benchmark representing the previous state of the art leads to substantially fairer selection probabilities. By contributing a fairer, more principled and deployable algorithm, our work puts the practice of sortition on firmer foundations. Moreover, our work establishes citizens' assemblies as a domain in which insights from the field of fair division can lead to high-impact applications.


Effects of feeding guanidinoacetic acid on oxidative status and creatine metabolism in broilers subjected to chronic cyclic heat stress in the finisher phase.
Dietary guanidinoacetic acid (GAA) has been shown to affect creatine (Cr) metabolic pathways resulting in increased cellular Cr and hitherto broiler performances. Yet, the impact of dietary GAA on improving markers of oxidative status remains equivocal. A model of chronic cyclic heat stress, known to inflict oxidative stress, was employed to test the hypothesis that GAA could modify bird's oxidative status. A total of 720-day-old male Ross 308 broilers were allocated to 3 treatments: 0, 0.6 or 1.2 g/kg GAA was added to corn-SBM diets and fed for 39 d, with 12 replicates (20 birds each) per treatment. The chronic cyclic heat stress model (34°C with 50-60% RH for 7 h daily) was applied in the finisher phase (d 25-39). Samples from 1 bird per pen were taken on d 26 (acute heat stress) and d 39 (chronic heat stress). GAA and Cr in plasma were linearly increased by feeding GAA on either sampling day, illustrating efficient absorption and methylation, respectively. Energy metabolism in breast and heart muscle was greatly supported as visible by increased Cr and phosphocreatine: ATP, thus providing higher capacity for rapid ATP generation in cells. Glycogen stores in breast muscle were linearly elevated by incremental GAA, on d 26 only. More Cr seems to be directed to heart muscle as opposed to skeletal muscle during chronic heat stress as tissue Cr was higher in heart but lower in breast muscle on d 39 as opposed to d 26. The lipid peroxidation marker malondialdehyde, and the antioxidant enzymes superoxide dismutase and glutathione peroxidase showed no alterations by dietary GAA in plasma. Opposite to that, superoxide dismutase activity in breast muscle was linearly lowered when feeding GAA (trend on d 26, effect on d 39). Significant correlations between the assessed parameters and GAA inclusion were identified on d 26 and d 39 using principal component analysis. To conclude, beneficial performance in heat-stressed broilers by GAA is associated with enhanced muscle energy metabolism which indirectly may also support tolerance against oxidative stress.


Acute myeloneuropathy: An uncommon presentation of Sjögren's syndrome.
Sjögren's syndrome is associated with central and peripheral nervous system involvement. The peripheral neuropathy is usually a sensory predominant neuropathy or a cranial neuropathy. Myelopathy is usually of focal, subacute, chronic or relapsing type. Acute myeloneuropathy as the predominant manifestation has not been described in the literature. We describe a middle aged woman who presented with an acute onset motor quadriparesis and bladder dysfunction. She had dryness of eyes and mouth for 8 months. Nerve conduction studies revealed motor axonal neuropathy and magnetic resonance imaging of spinal cord showed T2 hyperintensities involving entire cord. Mild perineural fibrosis, focal foamy changes in endoneurium and lymphocytic infiltration were seen in sural nerve biopsy specimen. Patient improved clinically after intravenous methylprednisolone therapy.


The L-shaped combined vertical and transverse abdominal island flap for breast reconstruction.
The occasional patient will present for reconstruction after mastectomy who refuses a foreign-body implant or is desirous of reconstruction by autogenous tissue. An unfavorable midline abdominal scar that extends both below and above the umbilicus will preclude the use of the standard lower or upper transverse abdominal island flaps for such purposes. For these highly select circumstances, we present our experiences with two such patients where a combination of an L-shaped vertical and transverse rectus abdominis myocutaneous flap was employed. In this procedure, the vertical component is planned to provide the external skin cover, while the ipsilateral hemiellipse transverse component is deepithelialized and buried deep to the vertical component to provide the bulk and mound projection.


Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients.
Acute exacerbations of COPD (AECOPD) are common and strongly influence disease severity and relative healthcare costs. Vitamin D deficiency is frequent among COPD patients and its contributory role in disease exacerbations is widely debated. Our aim was to assess the relationship of serum vitamin D levels with COPD severity and AECOPD. Serum vitamin D (25-hydroxyvitamin D) levels were measured in 97 COPD patients and related to lung function, comorbidities, FEV1 decline, AECOPD and hospital admission during the previous year. Most patients (96%) had vitamin D deficiency, which was severe in 35 (36%). No significant relationship was found between vitamin D and FEV1 or annual FEV1 decline. No difference between patients with and without severe vitamin D deficiency was found in age, gender, BMI, smoking history, lung function, and comorbidities, apart from osteoporosis (60.9% in severe deficiency vs 22.7%, p = 0.001). In multiple logistic regression models, severe deficiency was independently associated with AECOPD [adjusted odds ratios (aOR) of 30.5 (95% CI 5.55, 168), p < 0.001] and hospitalization [aOR 3.83 (95% CI 1.29, 11.4), p = 0.02]. The odds ratio of being a frequent exacerbator if having severe vitamin D deficiency was 18.1 (95% CI 4.98, 65.8) (p < 0.001), while that of hospitalization was 4.57 (95% CI 1.83, 11.4) (p = 0.001). In COPD patients severe vitamin D deficiency was related to more frequent disease exacerbations and hospitalization during the year previous to the measurement of vitamin D. This association was independent of patients' characteristics and comorbidities.


Prognostic factors of ovarian granulosa cell tumor: a study of 35 patients and review of the literature.
Ovarian granulosa cell tumors (GCT) are rare tumors with a tendency of late relapse and good prognosis. FIGO stage, tumor size, degree of cellular atypia, and mitotic index have been reported to predict recurrence. The objective of this study is to evaluate treatment practice and prognostic factors of GCT. For this purpose, a detailed review of patient files and histopathologic evaluation of tumor samples, including estimation of growth pattern, presence of Call-Exner bodies, nuclear atypia, mitotic index, and immunohistochemical staining for inhibin and Ki-67 were analyzed. Thirty-five patients had histologically confirmed GCT. Four patients had a simultaneous endometrial adenocarcinoma. Median follow-up time was 135 months (range 19-334 months). Recurrent disease was detected in seven patients. Time from diagnosis to the first recurrence varied from 24 to 141 months. There was no difference in tumor size, nuclear atypia, mitotic index, presence of Call-Exner bodies, or Ki-67 staining between nonrecurred and recurred patients. The only factor associated with risk of recurrence was rupture of the tumor (P < 0.0001), and the only factor associated with overall survival was FIGO stage (P = 0.032). The disease-free and overall survivals were not statistically different between patients treated (N = 18) or not treated (N = 17) with adjuvant therapy. One patient has experienced seven recurrences, has been treated with surgery, radiation therapy, chemotherapy, and hormonal therapy, and is still alive 26 years from diagnosis. FIGO stage and tumor rupture were the only factors associated with the outcome of GCT. Treatment of relapse, even in case of multiple recurrences, is usually worthwhile.


Optimal foraging in semantic memory.
Do humans search in memory using dynamic local-to-global search strategies similar to those that animals use to forage between patches in space? If so, do their dynamic memory search policies correspond to optimal foraging strategies seen for spatial foraging? Results from a number of fields suggest these possibilities, including the shared structure of the search problems-searching in patchy environments-and recent evidence supporting a domain-general cognitive search process. To investigate these questions directly, we asked participants to recover from memory as many animal names as they could in 3 min. Memory search was modeled over a representation of the semantic search space generated from the BEAGLE memory model of Jones and Mewhort (2007), via a search process similar to models of associative memory search (e.g., Raaijmakers & Shiffrin, 1981). We found evidence for local structure (i.e., patches) in memory search and patch depletion preceding dynamic local-to-global transitions between patches. Dynamic models also significantly outperformed nondynamic models. The timing of dynamic local-to-global transitions was consistent with optimal search policies in space, specifically the marginal value theorem (Charnov, 1976), and participants who were more consistent with this policy recalled more items.


Small-group training as an alternative to individual programs for profoundly retarded persons.
A comparison of group and individualized training methods was made by teaching 12 profoundly retarded men a series of imitative tasks under one of three program conditions. Each of the conditions was allotted 20 hours of training time from staff. The four members of the intact-group program received their 20 hours of instruction on a group basis. The four individual-program members had the training time divided between them and were taught separately. In a third program, the add-in group had the entry times of its membership staggered so that special attention could be given to each new member. The results indicated that the group programs were as effective as individual treatment for increasing imitative skills when staff time was held constant. Advantages of group programming were discussed in terms of increased activity and socialization for clients.


Robotic-assisted laparoscopic radical cystectomy: history, techniques and outcomes.
Robotic-assisted radical cystectomy (RARC) is a less invasive means of performing the radical cystectomy operation, which holds promise for improved patient morbidity. We review the history, technique and current literature pertaining to RARC and place the current results in context with the open procedure. All articles regarding RARC found in PubMed after January 2000 were examined. We selected articles that appeared in high-impact journals, had large patient population size (>80 patients), or were novel in technique or findings. We chose key laparoscopic articles to give reference to the history in transition to robotic radical cystectomy. In addition, we chose classic articles from open radical cystectomy to give reference regarding the newer robotic perioperative outcomes. Studies suggest that a 20-patient learning curve is needed to reach an operative time of 6.5 h, with 30 surgeries performed to reach lymph node counts in excess of 20 (International Robotic Cystectomy Consortium). The only randomized surgical trial comparing open and robotic techniques showed equivalent lymph node yield, which may be surgeon and volume dependent. Literature demonstrates lower estimated blood loss, transfusion rates, early return of bowel function and decreased complications in early small series. RARC and urinary diversion are still early in development and limited to centers with extensive robotic experience and volume, although adoption of the robotic approach is becoming more common. Early studies have shown promise to reduce complications with equivalent oncologic results.


Absence of junctional glutamate receptor clusters in Drosophila mutants lacking spontaneous transmitter release.
Little is known about the functional significance of spontaneous miniature synaptic potentials, which are the result of vesicular exocytosis at nerve terminals. Here, by using Drosophila mutants with specific defects in presynaptic function, we found that glutamate receptors clustered normally at neuromuscular junctions of mutants that retained spontaneous transmitter secretion but had lost the ability to release transmitter in response to action potentials. In contrast, receptor clustering was defective in mutants in which both spontaneous and evoked vesicle exocytosis were absent. Thus, spontaneous vesicle exocytosis appears to be tightly linked to the clustering of glutamate receptors during development.


Cannabidiol Suppresses Angiogenesis and Stemness of Breast Cancer Cells by Downregulation of Hypoxia-Inducible Factors-1α.
To assess the effect of Cannabidiol (CBD) on the angiogenesis and stemness of breast cancer cells as well as proliferation. Methods: mRNA level and the amount of protein of vascular endothelial growth factor (VEGF) were determined by qRT-PCR and ELISA. The angiogenic potential of breast cancer cells under hypoxic conditions was identified by the HUVEC tube formation assay. The degradation of HIF-1α by CBD and the Src/von Hippel-Lindau tumor suppressor protein (VHL) interaction were assessed by a co-immunoprecipitation assay and Western blotting. To identify the stemness of mamospheres, they were evaluated by the sphere-forming assay and flow cytometry. Results: CBD can suppress angiogenesis and stem cell-like properties of breast cancer through Src/VHL/HIF-1α signaling. CBD may potentially be utilized in the treatment of refractory or recurrent breast cancer.


4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion.
In early stage, ERα-positive breast cancer, concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous studies revealed that ZNF423 is a transcription factor for BRCA1 and an intronic single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Here, we identified mitosis-related genes that are regulated by ZNF423 which led us to investigate taxane response in a rs9940645 SNP- and tamoxifen-dependent fashion. The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes correlated with ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene regulation. We used CRISPR/Cas9 to engineer paired ZR-75-1 cells which differ only in ZNF423 rs9940645 SNP genotype to test SNP-dependent phenotypes including cell cycle and cell viability. We validated our findings in an additional two breast cancer cell lines, Hs578T-ERα and HCC1500. Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. ZNF423 knockdown decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown enhanced docetaxel-induced G2/M arrest and cytotoxicity through VRK1 or PBK regulation. Lastly, cells carrying the rs9940645 variant genotype had increased G2/M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM. We identified ZNF423 regulated genes involved in the G2/M phase of the cell cycle. 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen and docetaxel. This would impact a substantial proportion of patients because this SNP has a minor allele frequency of 0.47.


A mHealth-based care model for improving hypertension control in stroke survivors: Pilot RCT.
Hypertension (HTN) is significantly under-treated in stroke survivors. We examined usability and efficacy of a mHealth -based care model for improving post-stroke HTN control (Funding: AHRQ R21HS021794). We used a RCT design. Planned study duration was 90 days. Intervention arm (IA) participants measured their BP daily using a smart phone and wireless BP monitor. This was transmitted automatically to the study database. Investigators (Physician + PharmD) made bi-weekly medication adjustments to achieve the BP goal. Control arm (CA) participants received a digital BP monitor and usual care. We examined Usability (measured with Marshfield System Usability Survey) and HTN control efficacy using an ITT (intent-to-treat) and as-treated (AT) analyses. Fifty participants (IA = 28; CA = 22) completed the study. The Marshfield survey question, "I thought the system was easy to use" mean score was 4.6, (5 = strongly agree). Mean SBP declined significantly between enrollment and study completion in the IA. In ITT, IA SBP declined 9.88 mm, p = 0.005. In AT, IA SBP declined 10.81 mm, p = 0.0036. CA SBP decline was 5-6 mm Hg (not significant). In the ITT, baseline HTN control (SBP < 140 mm Hg) was 50% in IA and CA. At study completion, HTN was controlled in 82% (23/28) of IA and 64% (14/22) of CA (p = 0.14). In the AT, HTN was controlled in 89% (23/26) of IA and 58% (14/24) of CA, (p = 0.015). A mHealth-based HTN care model had excellent usability and provided better HTN control than usual care in stroke survivors. gov: NCT01875094.


Morbihan Disease - An Old and Rare Entity Still Difficult to Treat.
Morbihan disease (MD), also known as Morbihan syndrome, "solid persistent facial edema and erythema", "rosacea lymphedema", and "solid facial edema in acne", is a rare and often unrecognizable entity, that presents with a slow occurrence of persistent lymphoedema of the upper two-thirds of the face (1,2). A 30-year-old woman presented to our Department with persistent, asymptomatic face edema and erythema lasting for 18 months. She was previously treated for rosacea with doxycycline (100 mg/day for four months) without improvement. Dermatological examination revealed erythematous, nonpitting, solid edema located on the mid-forehead, nose, and cheeks with sparse erythematous papules and pustules on the entire face including the chin and comedones, papules, and pustules on the back (Figure 1 and Figure 2). She was otherwise healthy and was not taking any medication. Laboratory tests with immunological tests and Quantiferon test together with MRI of the orbits, chest X-ray, chest high-resolution computed tomography, cranial X-ray, and abdominal ultrasound were all within normal limits. Histopathology revealed dermal edema, perivascular and peri-adnexal lymphohistiocytic infiltrate, and sebaceous gland hyperplasia. Based on the typical clinical picture, histopathological findings, and the exclusion of several differentials the diagnosis of MD was established. The patient was treated with oral isotretinoin (20 mg/day for eight months) without regression of solid edema and erythema on the face but with complete regression of acne on the trunk. She was started on oral corticosteroids (prednisolone, 20 mg/day for two months followed by reduction of the dose over three months), again with only slight short transient improvement and rapid relapse of facial erythema and edema. The patient refused any other suggested treatment. We treated our patient for a total 2 years and followed up for 5 years. The pathogenesis of MD is still unknown. It is considered a clinical variety or a complication of rosacea or acne which does not tend to regress spontaneously. It is believed that chronic inflammation in patients with MD is due to acne or rosacea causing structural damage to blood and lymph vessels (1,3,4). However, cases of MD without previous history of rosacea and acne have been reported supporting the distinct disease theory (3,4). Edema and erythema are localized on the upper half of the face affecting the forehead, glabella, eyelids, nose, and cheeks. Although the symptoms may come and go, MD usually does not improve without treatment (5). Several therapeutic options have been reported, although there is no established standard treatment for MD. Reported therapy includes short-term oral isotretinoin (0.5 mg/kg/day), long-term oral isotretinoin (40-80 mg/day, 10-24 months), long-term doxycycline, combination of systemic corticosteroids and antibiotic (prednisolone 20 mg/day for 2 weeks and doxycycline 200 mg/day for 12 weeks), slow-releasing doxycycline monohydrate (40 mg/day for 6 months), long-term minocycline (50 mg/day for 4 months), and a combination of both oral retinoid and ketotifen (isotretinoin 0.7 mg/kg/day for 4 months, ketotifen 2 mg/day for 4 months) (1,2,6,8). The disease is frequently recalcitrant to therapy, and only several cases of successfully treated patients with MD have been reported (1,2,4, 6-8). We presented a patient with characteristic features of MD, which is a persistent, cosmetically disturbing condition, unfortunately mostly refractory to therapeutic measures.


Chronic pain, depression symptoms and daily living independency level among geriatrics in nursing home.
The aim of this study was to investigate pain, depression and independence in activities of daily living in geriatric residents of nursing homes, as well as to evaluate the relationship between these parameters. 186 nursing home residents, aged 65 to 90 years, were enrolled in the study. Their socio-demographic features, depression levels, pain levels and independence in activities of daily living were evaluated using a socio-demographic assessment form, the Geriatric Depression Scale (GDS), the Visual Analogue Scale (VAS) and the Nottingham Extended Activities of Daily Living Index (NEADL), respectively. For statistical analyses, participants were divided into groups with and without chronic pain. The main finding of this study was that 55.9% of the participants reported chronic pain, and these participants had significantly higher GDS (p=0.001) and lower NEADL scores (p=0.01) than those who reported no chronic pain. We found a significant correlation between VAS and GDS (r=0.47, p=0.001), VAS and NEADL (r=-0.30, p=0.001), and GDS and NEADL scores (r=-0.50, p=0.001). Female gender (p=0.001), number of children (p=0.005), number of chronic diseases (p=0.009), and GDS score (p=0.001) were found to affect chronic pain in multivariate model. Investigation of pain, presence of depression, and independence in activities of daily living is important in determining the necessary measures to be adopted for promoting the health and well-being of the geriatric population.


Comparison of metabolic control in a cross-sectional study of 2,873 children and adolescents with IDDM from 18 countries. The Hvidøre Study Group on Childhood Diabetes.
To obtain an estimate of the current level of metabolic control in children and adolescents with IDDM, the Hvidøre Study Group on Childhood Diabetes decided to establish a formal collaboration among countries to gather and exchange data for comparative purposes. This cross-sectional non-population-based survey involved 22 pediatric departments from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from March through August 1995 on 2,873 children who were born in 1977 or later and seen in the outpatient clinics. HbA1c levels were determined once and analyzed centrally (normal range, 4.4-6.3%; mean, 5.4%). Year of birth, sex, duration of diabetes, height, body weight, insulin regimen, and number of episodes of severe hypoglycemia during the past 3 months were recorded. Average HbA1c was 8.6 +/- 1.7%, but varied significantly (P < 0.0001) between centers. Hypoglycemia resulting in unconsciousness and/or seizures was related to younger age (0-8 years) and lower HbA1c level. The incidence, based on the 3-month period, was 22 per 100 patient-years. Sixty percent of the children (n = 1,707) had two injections daily, while 37% (n = 1,071) were on three or more. HbA1c increased during maturation for both sexes. No difference in glycemic control was found among adolescents treated with two, three, and four or more daily injections. Adolescents on four or more injections received significantly (P < 0.001) more insulin. Girls on four or more injections had significantly (P < 0.01) higher BMI than girls on twice-daily insulin. In the participating centers with a multidisciplinary team, only one third of the patients had an HbA1c level of < 8%.


Untying the anchor for the lipopolysaccharide: lipid A structural modification systems offer diagnostic and therapeutic options to tackle polymyxin resistance.
Polymyxin antibiotics are the last resort for treating patients in intensive care units infected with multiple-resistant Gram-negative bacteria. Due to their polycationic structure, their mode of action is based on an ionic interaction with the negatively charged lipid A portion of the lipopolysaccharide (LPS). The most prevalent polymyxin resistance mechanisms involve covalent modifications of lipid A: addition of the cationic sugar 4-amino-L-arabinose (L-Ara4N) and/or phosphoethanolamine (pEtN). The modified structure of lipid A has a lower net negative charge, leading to the repulsion of polymyxins and bacterial resistance to membrane disruption. Genes encoding the enzymatic systems involved in these modifications can be transferred either through chromosomes or mobile genetic elements. Therefore, new approaches to resistance diagnostics have been developed. On another note, interfering with these enzymatic systems might offer new therapeutic targets for drug discovery. This literature review focuses on diagnostic approaches based on structural changes in lipid A and on the therapeutic potential of molecules interfering with these changes.


Management of pregnancy at and beyond 41 completed weeks of gestation in low-risk women: a secondary analysis of two WHO multi-country surveys on maternal and newborn health.
The World Health Organization (WHO) recommends induction of labour (IOL) for women who have reached 41 completed weeks of pregnancy without spontaneous onset of labour. Many women with prolonged pregnancy and/or their clinicians elect not to induce, and chose either elective caesarean section (ECS) or expectant management (EM). This study intended to assess pregnancy outcomes of IOL, ECS and EM at and beyond 41 completed weeks. This study is a secondary analysis of the WHO Global Survey (WHOGS) and the WHO Multi-country Survey (WHOMCS) conducted in Africa, Asia, Latin America and the Middle East. There were 33,003 women with low risk singleton pregnancies at ≥41 completed weeks from 292 facilities in 21 countries. Multilevel logistic regression model was used to assess associations of different management groups with each pregnancy outcome accounted for hierarchical survey design. The results were presented by adjusted odds ratios (aORs) with 95% confidence intervals (CIs) after adjusting for age, education, marital status, parity, previous caesarean section (CS), birth weight, and facility capacity index score. The prevalence of prolonged pregnancy at facility setting in WHOGS, WHOMCS and combined databases were 7.9%, 7.5% and 7.7% respectively. Regarding to maternal adverse outcomes, EM was significantly associated with decreased risk of CS rate consistently in both databases i.e. (aOR0.76; 95% CI: 0.66-0.87) in WHOGS, (aOR0.67; 95% CI: 0.59-0.76) in WHOMCS and (aOR0.70; 95% CI: 0.64-0.77) in combined database, compared to IOL. Regarding the adverse perinatal outcomes, ECS was significantly associated with increased risks of neonatal intensive care unit admission (aOR1.76; 95% CI: 1.28-2.42) in WHOMCS and (aOR1.51; 95% CI: 1.19-1.92) in combined database compared to IOL but not significant in WHOGS database. Compared to IOL, ECS significantly increased risk of NICU admission while EM was significantly associated with decreased risk of CS. ECS should not be recommended for women at 41 completed weeks of pregnancy. However, the choice between IOL and EM should be cautiously considered since the available evidences are still quite limited.


Sol-gel encapsulation of biomolecules and cells for medicinal applications.
The sol-gel process provides a robust and versatile technology for the immobilization of biologicals. A wide range of inorganic, composites and hybrid materials can be prepared to encapsulate molecular drugs, proteins, antibodies/antigens, enzymes, nucleic acids, prokaryotic and eukaryotic cells into bulk gels, particles and films. This review describes the applications of sol-gel encapsulation relevant to medicinal chemistry focusing on the recent development of biosensors as well as systems for production, screening and delivery of bioactive compounds and biomaterials.


Epidemiology of two orbiviruses in California's native wild ruminants: preliminary report.
Between 1978 and 1983 we collected more than 1,500 serum samples from California's native black-tailed deer (Odocoileus hemionus columbianus), 4 races of mule deer (O. h. sp.), tule elk (Cervus elaphus nannodes), Roosevelt elk (C. e. roosevelti), pronghorn antelope (Antilocapra americana), California bighorn sheep (Ovis canadensis californiana), Peninsular bighorn sheep (O. c. cremnobates) and desert bighorn sheep (O. c. nelsoni) and analyzed them for agar gel precipitating (AGP) antibodies to bluetongue (BT) virus (BTV). Various serologic tests for antibodies to a closely-related Orbivirus, epizootic hemorrhagic disease (EHD) virus (EHDV) of deer, were conducted on many herds in most years. Parallel attempts at virus isolation yielded 4 BT serotypes: 10, 11, 13 and 17. EHDV was isolated only twice. The herds sampled were representative of those found in various habitats under various management stages in California. Sampling schemes varied as attempts were made to pinpoint temporal, locational, weather, temperature--related and livestock grazing pressure factors influencing rates of infection. Some disease syndromes associated with isolated BTV and BT antibodies are discussed. This work is the 1st attempt to quantitate the level of Orbivirus infection in wildlife in California.


Co-occurrence of eating disorders and alcohol use disorders in women: a meta analysis.
This meta analysis involved 41 studies published between January of 1985 and May of 2006, which examined the co-occurrence of eating disorders (ED) and alcohol use disorders (AUD) in women. Studies were reviewed and a quantitative synthesis of their results was carried out via the calculation of standardised effect sizes. Direction and strength of the relationships between AUD and specific disordered eating patterns were examined. Heterogeneity of reported results was also assessed and examined. Only 4 out of 41 studies reported negative associations between ED and AUD. The magnitude of the associations between eating-disordered patterns and AUD ranged from small to medium size and were statistically significant for any ED, bulimia nervosa (BN)/bulimic behavior, purging, binge eating disorder (BED) and eating disorders not otherwise specified (EDNOS). No association was found between anorexia nervosa (AN) and AUD. The magnitude of the association between BN and AUD was the most divergent across studies and those between each of BED and dietary restriction and AUD were the most consistent across studies. Reported associations of different patterns of disordered eating and AUD were generally weakest and most divergent when participants were recruited from clinical settings and strongest and most homogeneous when participants were recruited from student populations.


Primary central nervous system extranodal NK/T cell lymphoma, nasal type, with antecedent hemophagocytic syndrome in a child.
Primary central nervous system (CNS) extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is an exceedingly uncommon entity. Here, we present a case of CNS NKTCL that manifested initially as hemophagocytic syndrome 4 months earlier in a 13-year-old girl. Histological examination revealed the cerebellum mass was composed of large-sized and atypical tumor cells, with an angiocentric and angiodestructive growth pattern and prominent necrosis. The tumor cells exhibited marked pleomorphism with conspicuous nucleoli and prominent mitotic activity. Immunohistochemical staining showed the tumor cells were positive for CD45, CD2, CD3ε, CD30, CD43, CD56, and granzyme B. Epstein-Barr virus--encoded ribonucleic acid was expressed in almost all of the nuclei of the lymphoma cells. The T-cell receptor γ chain gene rearrangement study showed no evidence of a clonal rearrangement. The patient was treated with etoposide and dexamethasone and died a few days after the operation. As far as we know, this case is the 1st pediatric and female patient of primary CNS NKTCL with antecedent hemophagocytic syndrome, which highlights the clinical data and is helpful for the diagnosis of this tumor.


Determination of calcium-binding sites in rat brain calbindin D28K by electrospray ionization mass spectrometry.
Calbindin D28K, a member of the troponin-C superfamily of calcium-binding proteins, contains six putative EF-hand domains. Calcium-binding studies of the protein by different groups of investigators have yielded discordant results with respect to the stoichiometry of calcium-binding. It has been suggested that the protein binds anywhere from 3-6 mol of calcium/mol of protein. We used negative ion electrospray ionization mass spectrometry in order to definitively determine the exact calcium-binding stoichiometry of calbindin D28K and two mutant forms of the protein, one lacking EF-hand 2 (delta2) and the other lacking EF-hands 2 and 6 (delta2,6). The full-length protein bound 4 mol of calcium/mol of protein, while both of the deletion mutants bound 3 mol of calcium. Since terbium has been used extensively as a probe for the determination of the calcium-binding stoichiometries of calcium-binding proteins, we also examined the binding of terbium to the three proteins under the same conditions. Full-length calbindin D28K bound 4 mol of terbium/mol of protein, while calbindin delta2 and delta2,6 each bound 3 mol. These results clearly show that calbindin D28K binds 4 mol of calcium/mol of protein and that terbium-binding stoichiometry is similar to that of calcium.


Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis.
In most patients with multiple sclerosis, the disease initiates with a first attack or clinically isolated syndrome. At this phase, magnetic resonance imaging is an important predictor of conversion to multiple sclerosis. With the exception of oligoclonal bands, the role of other biomarkers in patients with clinically isolated syndrome is controversial. In the present study, we aimed to identify proteins associated with conversion to multiple sclerosis in patients with clinically isolated syndrome. We applied a mass spectrometry-based proteomic approach (isobaric labelling) to previously collected pooled cerebrospinal fluid samples from patients with clinically isolated syndrome, who subsequently converted to clinically definite multiple sclerosis (n=30) and patients who remained as having clinically isolated syndrome (n=30). Next, three of the most represented differentially expressed proteins, i.e. ceruloplasmin, vitamin D-binding protein and chitinase 3-like 1 were selected for validation in individual cerebrospinal fluid samples by enzyme-linked immunosorbent assay. Only chitinase 3-like 1 was validated and cerebrospinal fluid levels were increased in patients who converted to clinically definite multiple sclerosis compared with patients who continued as clinically isolated syndrome (P=0.00002) and controls (P=0.012). High cerebrospinal fluid levels of chitinase 3-like 1 significantly correlated with the number of gadolinium enhancing lesions and the number of T2 lesions observed in brain magnetic resonance imaging scans performed at baseline, and were associated with disability progression during follow-up and shorter time to clinically definite multiple sclerosis (log-rank P-value=0.003). Cerebrospinal fluid chitinase 3-like 1 levels were also measured in a second validation clinically isolated syndrome cohort and found to be increased in patients who converted to multiple sclerosis compared with patients who remained as having clinically isolated syndrome (P=0.018). Our results indicate that patients who will convert to clinically definite multiple sclerosis could be distinguished from those patients who will remain as clinically isolated syndrome by proteomic analysis of cerebrospinal fluid samples. Although protein levels are also increased in other disorders characterized by chronic inflammation, chitinase 3-like 1 may serve as a prognostic biomarker for conversion to multiple sclerosis and development of disability which may help to improve the understanding of the aetiopathogenesis in the early stages of multiple sclerosis.


Work through the valley: evaluate.
While all stages of a community-partnered participatory research (CPPR) initiative involve evaluation, the main focus is the evaluation of the action plans, which often involves the most rigorous evaluation activities of the project, from both a community-engagement and scientific perspective. This article reviews evaluation principles for a community-based project, and describes the goals and functions of the Council's research and evaluation committee. It outlines 10 steps to partnered evaluation, and concludes by emphasizing the importance of asset-based evaluation that builds capacity for the community and the partnership.


Outlier exclusion procedures must be blind to the researcher's hypothesis.
When researchers choose to identify and exclude outliers from their data, should they do so across all the data, or within experimental conditions? A survey of recent papers published in the Journal of Experimental Psychology: General shows that both methods are widely used, and common data visualization techniques suggest that outliers should be excluded at the condition-level. However, I highlight in the present paper that removing outliers by condition runs against the logic of hypothesis testing, and that this practice leads to unacceptable increases in false-positive rates. I demonstrate that this conclusion holds true across a variety of statistical tests, exclusion criterion and cutoffs, sample sizes, and data types, and shows in simulated experiments and in a reanalysis of existing data that by-condition exclusions can result in false-positive rates as high as 43%. I finally demonstrate that by-condition exclusions are a specific case of a more general issue: Any outlier exclusion procedure that is not blind to the hypothesis that researchers want to test may result in inflated Type I errors. I conclude by offering best practices and recommendations for excluding outliers. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Virus-mediated release of endosomal content in vitro: different behavior of adenovirus and rhinovirus serotype 2.
Endosomal penetration by nonenveloped viruses might be accomplished by either local breakdown of the endosomal membrane (e.g., adenovirus) or formation of a membrane-spanning pore by capsid proteins. Uncoating of the nonenveloped virus human rhinovirus serotype 2 (HRV2) has been shown to occur from late endosomes and to be entirely dependent on the acidic pH in this compartment (Prchla, E., E. Kuechler, D. Blaas, and R. Fuchs. 1994. J. Virol. 68: 3713-3723). To investigate further the mechanism of uncoating of HRV2, an in vitro assay was established to test viruses or virus-derived peptides for their capacity to release cointernalized biotin-dextran of different molecular mass (10 and 70 kD) from isolated endosomes. The suitability of the assay was demonstrated by use of a fusogenic peptide derived from influenza virus hemagglutinin (GALA-INF3). Whereas adenovirus induced a low pH-dependent release of up to 46% of the internalized biotin-dextran and did not show any significant size selectivity (as expected for endosome disruption), HRV2 mediated release of 27% of the 10 kD dextran and only traces of the 70-kD dextran. Similarly, GALA-INF3-induced release of biotin-dextran was also size dependent. The potential role of the capsid protein VP1 in HRV2 uncoating in vivo was also substantiated in our in vitro system using an amphipathic, NH2-terminal peptide of VP1. Taken together, these data favor the model of a specific pore-forming mechanism for HRV2 uncoating which is in contrast to the membrane-disrupting mechanism of adenovirus.


[Anti-arthritic and anti-oxidative effect of ethyl acetate fraction of Blumea balsamlfera residues in rat adjuvant-induced arthritis].
To study the effect of ethyl acetate fraction of Blumea balsamifera (BBE) residue on treating rats of adjuvant arthritis (AA) and its mechanism. The rats were immunized with the Freund's complete adjuvant (FCA). After modeling, 28 days' treatment with BBE was performed. During the experimental process, rat mass, toe girth, arthritic index (AI), proliferation of immune organs and pathological section were measured. After treatment, blood samples were collected through fossa orbitalis vein for detection of serum SOD, MDA, GSH, NO, OH*, ALP, AST, ALT, NAG and SA content using colorimetric method and IL-1, IL-6, TNF-α content using ELISA method. Administration with BBE (high dose) could significantly ameliorate joint swelling and arthritis index, effectively inhibit synovial hyperplasia, down-regulate the levels of MDA, NO, OH*, ALP, AST, ALT, NAG, SA, IL-1, IL-6, TNF-α and up-regulate the SOD and GSH levels in serum. The results suggested BBE possesses substantial anti-arthritis and antioxidant activities.


Reliability of coded data to identify earliest indications of cognitive decline, cognitive evaluation and Alzheimer's disease diagnosis: a pilot study in England.
Evaluate the reliability of using diagnosis codes and prescription data to identify the timing of symptomatic onset, cognitive assessment and diagnosis of Alzheimer's disease (AD) among patients diagnosed with AD. This was a retrospective cohort study using the UK Clinical Practice Research Datalink (CPRD). The study cohort consisted of a random sample of 50 patients with first AD diagnosis in 2010-2013. Additionally, patients were required to have a valid text-field code and a hospital episode or a referral in the 3 years before the first AD diagnosis. The earliest indications of cognitive impairment, cognitive assessment and AD diagnosis were identified using two approaches: (1) using an algorithm based on diagnostic codes and prescription drug information and (2) using information compiled from manual review of both text-based and coded data. The reliability of the code-based algorithm for identifying the earliest dates of the three measures described earlier was evaluated relative to the comprehensive second approach. Additionally, common cognitive assessments (with and without results) were described for both approaches. The two approaches identified the same first dates of cognitive symptoms in 33 (66%) of the 50 patients, first cognitive assessment in 29 (58%) patients and first AD diagnosis in 43 (86%) patients. Allowing for the dates from the two approaches to be within 30 days, the code-based algorithm's success rates increased to 74%, 70% and 94%, respectively. Mini-Mental State Examination was the most commonly observed cognitive assessment in both approaches; however, of the 53 tests performed, only 19 results were observed in the coded data. The code-based algorithm shows promise for identifying the first AD diagnosis. However, the reliability of using coded data to identify earliest indications of cognitive impairment and cognitive assessments is questionable. Additionally, CPRD is not a recommended data source to identify results of cognitive assessments.


The epidemiology of ventilator-associated pneumonia in a network of community hospitals: a prospective multicenter study.
To describe the epidemiology of ventilator-associated pneumonia (VAP) in community hospitals. Prospective study in 31 community hospitals from 2007 to 2011. VAP surveillance was performed by infection preventionists using the National Healthcare Safety Network protocol. VAP incidence was reported as number of events per 1,000 ventilator-days. We categorized hospitals into small (<30,000 patient-days/year), medium (30,000-60,000 patient-days/year), and large (>60,000 patient-days/year) groups and compared VAP incidence by hospital size. he median VAP incidence was 1.4 (interquartile range, 0.4-2.4), and ventilator utilization ratio (VUR) was 0.33 (0.25-0.47). VAP incidence was higher in small hospitals (2.1) than medium (0.85) or large (0.69) hospitals ([Formula: see text]) despite a lower VUR in small hospitals (0.29 vs 0.31 vs 0.44, respectively; [Formula: see text]). The median age of 247 VAP cases was 64 (53-73); 136 (55.1%) were female; 142 (57.5%) were Caucasian; 170 (68.8%) were admitted from home. The length of stay and duration of ventilation were 26 (14-42) and 12 (4-21) days, respectively. The pre- and postinfection hospital stays were 8 (3-13) days and 14 (8-30) days, respectively. Data on outcomes were available in 214 cases (86.6%), and 75 (35.0%) cases died during hospitalization. The top 3 pathogens were methicillin-resistant Staphylococcus aureus (MRSA; [Formula: see text], 27.9%), Pseudomonas species ([Formula: see text], 16.3%), and Klebsiella species ([Formula: see text], 13.3%). VAP incidence was inversely associated with size of hospital. VAP in community hospitals was frequently caused by MRSA. Importantly, predictors of VAP incidence in tertiary care hospitals such as VUR may not be predictive in community hospitals with few ventilated patients.


Human Infection with Fusobacterium necrophorum without Jugular Venous Thrombosis: A Varied Presentation of Lemierre's Syndrome.
Lemierre's syndrome is also known as postangina septicemia, which is commonly caused by Fusobacterium necrophorum also known as Necrobacillus and also by other microorganisms like Staphylococcus, Streptococcus, Peptostreptococcus, and Bacteroides. Though the disease starts as an upper respiratory tract infection, it may spread and cause thrombophlebitis of the internal jugular vein. It may present itself through cranial nerve palsy or sepsis involving distant organs like the lungs or bones. It is also known as forgotten disease because of its rarity. Fusobacterium necrophorum usually causes infection in animals and rarely affects humans. We hereby present a case of Necrobacillus infection which did not cause any thrombophlebitis but resulted in severe pneumonia and acute kidney injury, leading to respiratory failure and requiring mechanical ventilation.


Pharmacokinetic analysis of new synthetic antimalarial N-251.
With the emergence and growing number of drug-resistant Plasmodium falciparum, a new drug for malaria control must be urgently developed. The new antimalarial synthetic compound N-251 was recently discovered. As an endoperoxide structure in the body, the compound shows high antimalarial activity and curative effects. We performed a pharmacokinetic (PK) analysis of N-251 under various conditions using mice to understand the inhibitory effect of N-251 in parasite-infected mice. PK study of N-251 after intravenous and oral administration in mice showed plasma concentration of N-251 was decreased drastically by intravenous route. C max was reached in 2 h after oral administration of N-251, and the level decreased to a level similar to that obtained after intravenous administration. The area under the curves (AUCs) of the plasma concentration of N-251 increased dose-proportionally in both administrations, and bioavailability (F) was approximately 23%. Additionally, T max, C max, AUC, and F increased in fasted mice compared to normal-fed mice after the administration of N-251, indicating the influence of diet on the absorption kinetics of N-251. Furthermore, in parasite-infected fasted mice, the plasma concentration-time profile of N-251 was similar to that in normal-fasted mice. Based on the PK parameters of single oral administration of N-251, we investigated the effect of multiple oral doses of N-251 (68 mg/kg three times per day for 2 days) in normal-fed mice. The plasma concentration of N-251 was between 10 and 1000 ng/mL. The simulation curve calculated based on the PK parameters obtained from the single-dose study well described the plasma concentrations after multiple oral dosing, indicating that N-251 did not accumulate in the mice. Multiple oral administrations of N-251 in mice were required to completely eliminate parasites without accumulation of N-251. N-251 has been selected as a potent antimalarial candidate. We found that N-251 showed short half-life in plasma, and AUCs increased proportionally to dose. With multiple doses of N-251, the plasma level of N-251 was greater than 10 ng/mL in normal-fed mice, and accumulation of N-251 was not observed; however, multiple treatments with N-251 are required for the complete cure of parasite-infected mice. Determining the appropriate dosage was an important step in the clinical applications of N-251.


Consistency in attitudes across cancer screenings in medically underserved minority populations.
While a wide range of behavioral and psychosocial literature explores attitudes and beliefs towards cancer screenings, fewer studies examine attitudes across cancer screening types. We draw on quantitative and qualitative findings from a 4-year prospective study based at a community health center serving diverse, low-income patients. Methods included self-report surveys (n = 297), medical chart abstraction, and several qualitative methods with a subsample of participants. Participants included white, African-American, Vietnamese, and Latino patients who were diagnosed with diabetes, hypertension, or both. Patients' attitudes (both positive and negative) towards cancer screening types were remarkably consistent across cancer screening types. These effects were stronger among men than women. Never having had a cancer screening was generally associated with more unfavorable attitudes towards all screenings. Qualitative interviews indicate the importance of information circulated through social networks in shaping attitudes towards cancer screenings. In a multi-method study of attitudes towards cancer screening among medically underserved patients in a primary care setting, we found that attitudes (both positive and negative) were remarkably consistent across cancer screening types.


Resistance to fracture of endodontically treated teeth: Influence of the post systems and cements.
Endodontically treated teeth with extensive structural damage present higher fragility due to the low amount and worse quality of the reminiscent tissues of the crown. The present in vitro study evaluated the effect of different intraradicular retainers and cementation agents on the fracture resistance of devitalized teeth. Incisive teeth (n = 40) of bovine mandibles were used. After preparation of the root canals, they were immersed in polyether, in a polyvinyl chloride cylinder containing acrylic resin, to simulate the periodontal ligament. The specimens were randomly divided into four groups (n = 10), according to the type of retainer (anatomical or main with accessory posts) and resin cement used (conventional resin cement - RelyX ARC or self-adhesive resin cement - RelyX U200). The specimens were stored in distilled water at 37°C and submitted to fracture resistance testing. ANOVA and Tukey's test were applied for data analysis, with significance level set at 5%. There was no interaction between cement type and intraradicular retainers (P = 0.56) or even between the types of cement used (P = 0.65). However, in the variation of the types of retainers, the group using main with accessory posts presented greater resistance to the fracture than the anatomical post (P = 0.04). Different cementing agents have no effect on the fracture strength of devitalized teeth, unlike the use of posts, in which the use of accessory post proved more resistant when compared to the anatomical post.


Keratinocyte growth factor is an important endogenous mediator of hair follicle growth, development, and differentiation. Normalization of the nu/nu follicular differentiation defect and amelioration of chemotherapy-induced alopecia.
The growth and development of hair follicles is influenced by a number of different growth factors and cytokines, particularly members of the fibroblast growth factor (FGF) family. Keratinocyte growth factor (KGF or FGF-7) is a recently identified 28-kd member of the FGF family that induces proliferation of a wide variety of epithelial cells, including keratinocytes within the epidermis and dermal adnexa. Because KGF induces marked proliferation of keratinocytes, and both KGF and KGF receptor (KGFR) mRNA are expressed at high levels in skin, we sought to localize KGF and KGFR in skin by in situ hybridization. KGFR mRNA was relatively strongly expressed by keratinocytes in the basilar epidermis as well as throughout developing hair follicles of rat embryos and neonates. KGF mRNA was expressed at lower levels than was KGFR but could be localized to follicular dermal papillae in rat embryos and neonates. These results prompted us to investigate the effects of KGF on hair follicles in two distinct murine models of alopecia. In the first model, recombinant KGF (rKGF) induced dose-dependent hair growth over most of the body in nu/nu athymic nude mice when administered intraperitoneally or subcutaneously over 17 to 18 days. When administered subcutaneously, rKGF induced the most extensive hair growth at the sites of injection. Histologically, rKGF induced marked follicular and sebaceous gland hypertrophy, a normalization of the nu/nu follicular keratinization defect, and an increase in follicular keratinocyte proliferation as assessed by bromodeoxyuridine labeling. In the second model, a neonatal rat model of cytosine arabinoside chemotherapy-induced alopecia in which interleukin-1, epidermal growth factor, and acidic FGF have all demonstrated some degree of alopecia cytoprotection, rKGF induced a dose-dependent cytoprotective effect, abrogating as much as 50% of the alopecia in this model when administered beginning 1 day before the onset of chemotherapy. Taken together, these data suggest that KGF is an important endogenous mediator of normal hair follicle growth, development, and differentiation.


Initiation of oogenesis and meiosis in the fetal ovary depends on Dennd1a-mediated production of Wnt5a and retinoic acid from the somatic niches.
The DENN (differentially expressed in neoplastic versus normal cells) domain containing 1A (Dennd1a), a guanine nucleotide exchange factor (GEF) for the small GTPase Rab35, is essential for mouse embryogenesis. Disruption of Dennd1a impairs the migration and differentiation of fetal germ cells. In the present study, we further elucidated the role of Dennd1a in oogenesis and meiosis in the fetal ovary. Ablation of Dennd1a disrupted the mRNA expression of Sohlh2, Figla, Stra8, and Rec8 in the ovary of Dennd1a-/- mutants at E13.5. Using ex vivo culture of E12.5 female gonads and adenoviral Dennd1a shRNA infection, we demonstrated that transcription of Sohlh2, Figla, Stra8 and Rec8 were not activated in the fetal ovary lacking Dennd1a. Dennd1a in the somatic cells might stimulate Sohlh2 expression at early stage of oocyte differentiation via regulating Wnt5a synthesis. On the other hand, meiotic initiation of the fetal germ cells required Dennd1a-mediated RA production from the somatic cells, which induced the expression of Stra8 and Rec8. Dennd1a could be involved in multiple signal pathways in the somatic cells that are critical for various processes of oogenesis and meiosis in the fetal ovary.


Palladium-catalyzed cross-coupling reactions in total synthesis.
In studying the evolution of organic chemistry and grasping its essence, one comes quickly to the conclusion that no other type of reaction plays as large a role in shaping this domain of science than carbon-carbon bond-forming reactions. The Grignard, Diels-Alder, and Wittig reactions are but three prominent examples of such processes, and are among those which have undeniably exercised decisive roles in the last century in the emergence of chemical synthesis as we know it today. In the last quarter of the 20th century, a new family of carbon-carbon bond-forming reactions based on transition-metal catalysts evolved as powerful tools in synthesis. Among them, the palladium-catalyzed cross-coupling reactions are the most prominent. In this Review, highlights of a number of selected syntheses are discussed. The examples chosen demonstrate the enormous power of these processes in the art of total synthesis and underscore their future potential in chemical synthesis.


Diversity in structures and properties of 3d-incorporating polyoxotungstates.
This critical review surveys the 3d substituted magnetic polyoxotungstate (POT) molecular compounds reported these last ten years, illustrating the huge variety of topologies that these systems can adopt. Both purely inorganic and organic/inorganic species have been considered, and the cited compounds have been classified according to their nuclearity, i.e., the number of magnetic 3d centres embedded in the POT matrix, which can be as high as 48. This review highlights the synthetic conditions, the solubility and the stability in solution of these species. The magnetic, catalytic and electrocatalytic properties of these complexes are also summarized.