Treatment of bulimia nervosa with fluvoxamine: a randomized controlled trial.
Bulimia nervosa (BN) is one of the most common eating disorders in industrialized societies. It has been suggested that reduced serotonin activity triggers some of the cognitive and mood disturbances associated with BN. For this reason, the pharmacologic treatment of BN consists mainly of selective serotonin reuptake inhibitors (SSRIs), which have been proven effective. At present, the physiologic bases of this disorder are not yet completely understood. We conducted a randomized controlled trial to verify the efficacy of the SSRI fluvoxamine in patients with a diagnosis of BN. Twelve female outpatients aged 21 to 34 years with a diagnosis of BN-binge purging (as defined by the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders [DSM IV]) were randomly assigned to 2 treatment groups: the fluvoxamine 200 mg/day group and the placebo group. The patients underwent weekly clinical assessments for 12 weeks. At the end of the observation period, there was a statistically significant reduction in the number of binge-eating crises and purging episodes in the fluvoxamine group compared with placebo. In no case was treatment interrupted because of emergent side effects. These findings support the hypothesis that fluvoxamine is well tolerated and effective in reducing binge-eating crises and purging episodes in patients with BN.


Orthopaedic surgery for inhibitor patients: a series of 27 procedures (25 patients).
We report on a series of 27 orthopaedic surgical procedures. It includes 20 radiosynoviortheses and seven major orthopaedic procedures, performed on 26 patients. The average age of patients was 36 years (range: 8-53) and the average follow-up time was 2.5 years (range:1-5). There were 23 good results and four fair. In the synoviorthesis group (20 patients, 20 synoviortheses) the average age was 13.5 years (range: 9-26) and the average follow-up was 4.5 years (range: 1-7). There were 19 good results and one fair. All synoviortheses were done with activated prothrombin complex concentrates (FEIBA), all the responses being good except in one case (which had the final fair result). The total dose of FEIBA used was 600 IU kg(-1,) except in a patient that had a haemorrhagic complication. In fact, he required a prolongation of treatment up to a total dose of 2000 IU kg(-1). In the group of major orthopaedic procedures, the average age of the six patients was 30.5 years (range: 11-53) and the average follow-up was 2.5 years (range: 1-5). There were six good results and one fair. Postoperative bleeding complications occurred in one of the seven major orthopaedic procedures performed (arterial pseudoaneurym after a total knee arthroplasty). Despite such complication, which had the final fair result, our study has shown that haemophilic patients with high inhibitor titres requiring orthopaedic surgery can undergo such procedures with a high expectation of success. In other words, orthopaedic surgery is now possible in haemophilia patients with high-titre inhibitors, leading to an improved quality of life for these patients.


RNA and protein metabolism in the oviduct and endometrium of the ewe at pro-oestrus: Regulation by oestradiol and progesterone.
The effects on RNA and protein metabolism in the oviduct and endometrium at pro-oestrus of oestradiol and progesterone secreted during the oestrous cycle were examined, using the ovariectomized, hormone-treated ewe as a model system. Thirty ewes received hormone injections during a period of 13 days, according to schedules designed to simulate endogenous ovarian secretion of oestradiol and progesterone during the oestrous cycle. Hormone effects on RNA:DNA ratios and on rates of synthesis of protein and methylated RNA in vitro, as well as effects on oviducal and uterine weight, were examined. The results obtained suggest that endogenous ovarian hormones have the following effects in the intact ewe. The secretion of oestradiol at pro-oestrus rapidly increases rates of synthesis of protein and methylated RNA, and mean cell content of RNA in both the endometrium and oviduct. Oestradiol secreted during the previous luteal phase of the oestrous cycle markedly increases mean cell content of RNA and amounts of protein and methylated RNA synthesis occurring in both tissues at pro-oestrus. In the endometrium, progesterone secreted during the luteal phase increases the RNA:DNA ratio, and probably also the amounts of protein and methylated RNA synthesized at pro-oestrus, but there are no significant interactions between the effects of oestradiol and progesterone. Progesterone had no effect on either the amounts or rates of synthesis of protein or methylated RNA in the oviduct. The results are discussed in relation to the hormonal regulation of physiological functions of the oviduct and endometrium during the first few days after the onset of oestrus.


An Efficient Sampling-Based Attention Network for Semantic Segmentation.
Self-attention is widely explored to model long-range dependencies in semantic segmentation. However, this operation computes pair-wise relationships between the query point and all other points, leading to prohibitive complexity. In this paper, we propose an efficient Sampling-based Attention Network which combines a novel sample method with an attention mechanism for semantic segmentation. Specifically, we design a Stochastic Sampling-based Attention Module (SSAM) to capture the relationships between the query point and a stochastic sampled representative subset from a global perspective, where the sampled subset is selected by a Stochastic Sampling Module. Compared to self-attention, our SSAM achieves comparable segmentation performance while significantly reducing computational redundancy. In addition, with the observation that not all pixels are interested in the contextual information, we design a Deterministic Sampling-based Attention Module (DSAM) to sample features from a local region for obtaining the detailed information. Extensive experiments demonstrate that our proposed method can compete or perform favorably against the state-of-the-art methods on the Cityscapes, ADE20K, COCO Stuff, and PASCAL Context datasets.


Expression of NOTCH1 in thyroid cancer is mostly restricted to papillary carcinoma.
The NOTCH signaling is an evolutionarily conserved signaling pathway that regulates cell-cell interactions. NOTCH family members play a fundamental role in a variety of processes during development in particular in cell fate decisions. As other crucial factors during embryogenesis, NOTCH signaling is aberrantly reactivated in cancer where it has been linked to context-dependent effects. In thyroid cancer, NOTCH1 expression has been associated to aggressive features even if its in vivo expression within the entire spectrum of thyroid tumors has not definitively established. A series of 106 thyroid specimens including non-neoplastic lesions, benign and malignant tumors of common and rare histotypes, were investigated by immunohistochemistry to assess NOTCH1 expression. Extent of positivity and protein localization were investigated and correlated with clinical and morphological parameters. NOTCH1 positivity was predominantly associated with papillary carcinomas and only occasionally found in follicular carcinomas. Poorly differentiated and undifferentiated thyroid carcinomas showed only a partial positivity. NOTCH1 expression pattern also seemed differently distributed according to histotype. Our data confirm a role of NOTCH1 in thyroid cancer and highlight for the first time the specific involvement of this pathway in papillary carcinomas. Our data also indicate that other thyroid malignancies do not rely on NOTCH1 signaling for development and progression.


Comparison of Buprenorphine and Buprenorphine/naloxone in Detoxification of Opioid-dependent Men.
Buprenorphine sublingual tablets are now available in Iran for opioid detoxification in clinics. Aim of the present study was to compare the efficiency of buprenorphine with buprenorphine/naloxone in short-term detoxification in a group of Iranian male opioid-dependent patients. A double-blind trial was carried out on a group of male opioid dependent patients in a psychiatric hospital in Kerman, Iran, during year 2017. A group of 100 men who met the diagnostic criteria for opiate dependence were included in the study from individuals who had referred for detoxification. They were allocated to the two groups receiving either buprenorphine (n = 51) or buprenorphine/naloxone (n = 49). Severity of withdrawal symptoms and signs were evaluated by Clinical Opiate Withdrawal Scale (COWS) and Adjective Rating Scale for Withdrawal (ARSW). The mean scores of COWS and ARSW in the two groups treated with buprenorphine and buprenorphine/naloxone significantly reduced from the first day to the fifth day of detoxification (P < 0.050). Moreover, there was no significant difference between the two groups in terms of objective and subjective symptom reduction (P > 0.050). Buprenorphine/naloxone is as effective as buprenorphine in controlling opiate withdrawal symptoms.


FMLP actions and its binding sites in isolated human coronary arteries.
The chemoattractant f-Met-Leu-Phe (FMLP) can modulate human coronary arterial tone without the involvement of peripheral leukocytes. We investigated the actions of FMLP and its cellular mechanism in human coronary arteries isolated 2-3 h after death. A single dose of FMLP (0.01-10 microM) produced transient contraction (or, followed by relaxation) responses in most human coronary rings examined. These responses to FMLP were in large part mediated by the generation of cyclooxygenase products, mainly thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). Radiolabeled N-formyl hexapeptide. 125I-f-Nle-Leu-Phe-Nle-Tyr-Lys bound densely to intimal and adventitial sites that accumulated macrophages (CD68-positive) with a Kd of 14-29 nM and, further, weakly to the media with a Kd of 2.4-3.6 microM. Several cell types including macrophages, endothelial cells and smooth muscle cells were positively immunostained for both TXA2 synthase and PGI2 synthase. However, there was no significant relation between the magnitude of the responses to FMLP and dense macrophage accumulation in the intimal plaques or the adventitia. A reverse transcription-polymerase chain reaction showed predominant expression of FMLP receptor homologues, FPRH1 and FPRH2 mRNA, in human coronary medial tissues relative to that in leukocytes. In conclusion. FMLP produced transient tension changes in human coronary arteries, mainly via the generation of TXA2 and PGI2. This effect of FMLP did not appear to be mediated by the activation of densely accumulated intimal and/or adventitial macrophages, but by the activation of unidentified medial tissue cells which might have functional FMLP receptor homologues.


LncRNA-ATB/microRNA-200a/β-catenin regulatory axis involved in the progression of HCV-related hepatic fibrosis.
Long noncoding RNAs (lncRNAs)-activated by transforming growth factor beta (lncRNA-ATB) is known to be involved in the invasion of hepatocellular carcinoma by regulating target genes of miR-200a. However, the role and molecular mechanisms of lncRNA-ATB/miR-200a in HCV-related liver fibrosis remains unclear. In this study, we examined the expression of lncRNA-ATB/miR-200a, and their target gene β-Catenin in liver tissues of HCV patients and hepatic stellate cells (HSCs) to elucidate the possible role of lncRNA-ATB/miR-200a axis in HSC activation and development of liver fibrosis. Liver tissues were obtained by biopsy or surgery from eighteen HCV patients with severe liver fibrosis and six healthy subjects (control). Conditioned media (CM) from cultured HepG2-CORE cells (HepG2 cells stably expressing HCV core protein) were used to treat LX-2 cells. The binding sites between lncRNA-ATB/miR-200a and β-catenin were predicted and then verified by a dual luciferase reporter assay. The effect of lncRNA-ATB/miR-200a/β-catenin on HSC activation was assessed by examining the expression of alpha-smooth muscle actin (α-SMA) and collagen type 1 alpha 1 (Col1A1) in HSCs. Further, the regulatory role of lncRNA-ATB on HSC activation and miR-200a/β-catenin expression was assessed by using siRNA-mediated knockdown of lncRNA-ATB. LncRNA-ATB was up-regulated in fibrotic liver tissues and activated LX-2 cells treated with CM from HepG2-CORE cells. Dual luciferase reporter assays confirmed that lncRNA-ATB contained common binding sites for miR-200a and β-catenin. Decreased expression of miR-200a and increased expression of β-catenin were observed in liver tissues of patients with HCV-related hepatic fibrosis and activated HSCs. Knockdown of lncRNA-ATB could down-regulate β-catenin expression by up-regulating the endogenous miR-200a and suppress the activation of LX-2 cells. LncRNA-ATB/miR-200a/β-catenin regulatory axis likely contributed to the development of liver fibrosis in HCV patients. Knockdown of lncRNA-ATB might be a novel therapeutic target for HCV-related liver fibrosis.


Inhibiting host-protein deposition on urinary catheters reduces associated urinary tract infections.
Microbial adhesion to medical devices is common for hospital-acquired infections, particularly for urinary catheters. If not properly treated these infections cause complications and exacerbate antimicrobial resistance. Catheter use elicits bladder inflammation, releasing host serum proteins, including fibrinogen (Fg), into the bladder, which deposit on the urinary catheter. Enterococcus faecalis uses Fg as a scaffold to bind and persist in the bladder despite antibiotic treatments. Inhibition of Fg-pathogen interaction significantly reduces infection. Here, we show deposited Fg is advantageous for uropathogens E. faecalis, Escherichia coli, Pseudomonas aeruginosa, K. pneumoniae, A. baumannii, and C. albicans, suggesting that targeting catheter protein deposition may reduce colonization creating an effective intervention for catheter-associated urinary tract infections (CAUTIs). In a mouse model of CAUTI, host-protein deposition was reduced, using liquid-infused silicone catheters, resulting in decreased colonization on catheters, in bladders, and dissemination in vivo. Furthermore, proteomics revealed a significant decrease in deposition of host-secreted proteins on liquid-infused catheter surfaces. Our findings suggest targeting microbial-binding scaffolds may be an effective antibiotic-sparing intervention for use against CAUTIs and other medical device infections.


[Postoperative infection following craniotomy in adults].
The aim of this study was to determine the risk factors for postoperative infection after craniotomy, a threat for the vital prognosis, in order to define specific prevention measures. An open prospective study was made on all adult patients undergoing craniotomy and followed 30 days postoperatively. The infections were defined according to CDCA criteria. The parameters studied were: age, sex, ASA and Glasgow scores, neurosurgical history, the type, the moment and the surface of shaving, antibioprophylaxis, and the type and duration of surgery as well as its emergency level. One hundred and seventy patients were included. Thirty presented with an infection (17.6%), nine with a skull infection, 13 with meningitis, three with empyema, and two with osteitis. The risk factors identified thanks to a univariate analysis were the emergency level of surgery (P < 0.01), duration of surgery >200 min, and duration of stay in ICU >72 h (P < 0.02).


White noise analysis of pace-maker-response interactions and non-linearities in slowly adapting crayfish stretch receptor.
Input-output relations were investigated in the slowly adapting stretch receptor organ of crayfish using a Gaussian white noise length input with a 0.03-12.5 Hz band width and the resulting action potential output. The noise input was presented to the de-efferented receptor in situ, at three mean elongations and at four different amplitudes. The three mean elongations were set within the normal range in vivo, two at the extremes close to the minimum and maximum physiological lengths and the other in the mid-range. With white noise inputs there is a finite probability that the system will be tested in all possible conditions within the chosen band width because white noise has the advantage that it contains, with a finite probability, all possible stimulus wave forms at random. The analysis indicated similarities between the effects of the input variables, namely white noise amplitude and mean elongation. With low input variables the activity was periodic. With larger inputs, impulse rates were higher and irregular. The average length trajectories leading to a spike (i.e. the average stimulus) were either biphasic with high inputs or multiphasic and periodic with lower input variables. The frequency of periodicity increased with mean elongation. Although for a given length and noise amplitude a variety of individual length trajectories preceded spikes, the final biphasic shortening-lengthening average stimulus sequence before a spike was similar in all cases irrespective of the input variables. The number of possible trajectories decreased with increments in the input variables. The standard deviation of length values for each average stimulus was computed and displayed as a function of time relative to the spike. It was first constant, and decreased gradually to a minimum value at the spike reference. Standard deviation values were lower for higher white noise amplitudes and mean elongation. Simple, short-lasting stimulus wave forms in the white noise were isolated and the corresponding responses were computed. Responses were periodic at low input variables and aperiodic with larger inputs and also asymmetric, being larger and briefer for lengthenings than for shortenings. Asymmetries augmented with input increments. Investigation of the interactions between the pace-maker and the white noise effects showed that lengthenings were more effective when they occurred just after a spike while the effectiveness of shortenings was greater just before a spike.(ABSTRACT TRUNCATED AT 400 WORDS)


Bone Marrow Langerhans Cell Histiocytosis in Association with Kasabach-Merritt Syndrome: The Difficulty of a Differential Diagnosis.
Langerhans cell histiocytosis is a rare haematological disorder with variable clinical findings and a high mortality rate. On the other hand, Kasabach-Merritt syndrome is of rare onset at adult age, requiring the simultaneous presentation of vascular lesion, thrombocytopenia, and consumptive coagulopathy. We present the first reported case of both diseases in a single patient and highlight the difficulties of diagnostic. A 69-year-old woman with immune thrombocytopenic purpura underwent surgery for the removal of giant skin haemangiomas. During post-operative care, intravascular disseminated coagulopathy developed. After weeks of corticosteroids and immunosuppressive therapy with no clinical improvement, pulmonary tuberculosis was diagnosed and appropriate treatment initiated. Despite all the efforts, the patient's clinical condition kept worsening and she eventually died. An autopsy revealed bone marrow Langerhans cell histiocytosis. In this case, the patient's autoimmune background together with tuberculosis and intravascular disseminated coagulopathy masked the presentation and made the diagnosis of a rapidly progressive fatal disease very difficult.


Self-gated cardiac Cine MRI of the rat on a clinical 3 T MRI system.
The ability to perform small animal functional cardiac imaging on clinical MRI scanners may be of particular value in cases in which the availability of a dedicated high field animal MRI scanner is limited. Here, we propose radial MR cardiac imaging in the rat on a whole-body clinical 3 T scanner in combination with interspersed projection navigators for self-gating without any additional external triggering requirements for electrocardiogram (ECG) and respiration. Single navigator readouts were interspersed using the same TR and a high navigator frequency of 54 Hz into a radial golden-angle acquisition. The extracted navigator function was thresholded to exclude data for reconstruction from inhalation phases during the breathing cycle, enabling free breathing acquisition. To minimize flow artifacts in the dynamic cine images a center-out half echo radial acquisition scheme with ramp sampling was used. Navigator functions were derived from the corresponding projection navigator data from which both respiration and cardiac cycles were extracted. Self-gated cine acquisition resulted in high-quality cardiac images which were free of major artifacts with spatial resolution of up to 0.21 × 0.21 × 1.00 mm(3) and a contrast-to-noise ratio (CNR) of 21 ± 3 between the myocardium and left ventricle. Self-gated golden ratio based radial acquisition successfully acquired cine images of the rat heart on a clinical MRI system without the need for dedicated animal ECG equipment.


Crisis Ahead? Why Human-Robot Interaction User Studies May Have Replicability Problems and Directions for Improvement.
There is a confidence crisis in many scientific disciplines, in particular disciplines researching human behavior, as many effects of original experiments have not been replicated successfully in large-scale replication studies. While human-robot interaction (HRI) is an interdisciplinary research field, the study of human behavior, cognition and emotion in HRI plays also a vital part. Are HRI user studies facing the same problems as other fields and if so, what can be done to overcome them? In this article, we first give a short overview of the replicability crisis in behavioral sciences and its causes. In a second step, we estimate the replicability of HRI user studies mainly 1) by structural comparison of HRI research processes and practices with those of other disciplines with replicability issues, 2) by systematically reviewing meta-analyses of HRI user studies to identify parameters that are known to affect replicability, and 3) by summarizing first replication studies in HRI as direct evidence. Our findings suggest that HRI user studies often exhibit the same problems that caused the replicability crisis in many behavioral sciences, such as small sample sizes, lack of theory, or missing information in reported data. In order to improve the stability of future HRI research, we propose some statistical, methodological and social reforms. This article aims to provide a basis for further discussion and a potential outline for improvements in the field.


The impact of cardiopulmonary exercise testing on patients over the age of 80 undergoing elective colorectal cancer surgery.
Advanced age and occult cardiorespiratory disease are associated with increased morbidity and mortality following surgery. Cardiopulmonary exercise testing (CPET) may allow the identification of high-risk patients and facilitate planned postoperative critical care support. The aim of this study was to determine whether preoperative CPET in patients aged over 80 undergoing elective colorectal cancer resection was associated with improved outcome. All patients aged 80 years and above undergoing elective colorectal cancer resection between 1 March 2011 and 1 September 2013 were retrospectively analysed. Referral for CPET testing was at the discretion of the operating surgeon. Postoperative critical care unit (CCU) admission was based upon the CPET results. Ninety-four patients were identified, of whom 48 underwent CPET testing. The CPET group were significantly older than the non-CPET group (85 vs 83 years, P = 0.04) and were more likely to have a planned admission to CCU postoperatively (P < 0.0001). Despite the increased use of CCU resources, the overall CCU length of stay (LOS) in the CPET group did not differ from the non-CPET group, but the non-CPET group had a higher proportion of Level-3 care. There were no differences in the incidence of unplanned CCU admission between the CPET and the non-CPET group (P = 0.23). There were no differences in overall LOS between the two groups (P = 0.42). There was no difference in mortality (P = 0.11), overall complications (P = 0.53) or severe complications (P = 0.3). Preoperative CPET testing in patients aged over 80 undergoing elective colorectal cancer resection allows identification of higher-risk patients and mitigation of risk by preemptive admission to a CCU. This stratification allows equivalent results to be achieved in high- and low-risk elderly patients undergoing colorectal surgery.


A novel cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to gemcitabine.
RX-3117 (fluorocyclopentenylcytosine) is a cytidine analog and this class of drugs, including gemcitabine, has been widely used for the treatment of various types of cancers. However, there is no oral formulation of gemcitabine and drug resistance to gemcitabine is common. In this study, the efficacy of orally-administered RX-3117 was examined in 9 different human tumor xenograft models (colon, non-small cell lung, small cell lung, pancreatic, renal and cervical), grown subcutaneously in athymic nude mice. In the Colo 205, H460, H69 and CaSki models, gemcitabine treatment resulted in 28%, 30%, 25% and 0% tumor growth inhibition (TGI), respectively, whereas oral treatment with RX-3117 induced 100%, 78%, 62% and 66% TGI, respectively. This indicates that RX-3117 may have the potential to be used for the treatment of tumors that do not respond to gemcitabine. RX-3117 was also evaluated in a single primary low-passage human pancreatic Tumorgraft™CTG-0298 (TGI 76%), which is relatively resistant to gemcitabine (TGI 38%) and has a favorable RX-3117-activating enzyme profile. These studies demonstrated the therapeutic potential and anticancer efficacy of RX-3117.


Motility induction in hamster spermatozoa from caput epididymidis: effects of forward motility protein (FMP) and calmodulin inhibitor.
The motility characteristics and the behaviour of caput spermatozoa were investigated. After dilution in B2 medium the majority of spermatozoa presented head-to-head agglutination and a twisted flagellum. Only a small population of these spermatozoa developed an anarchic motility pattern. The addition of crude bovine epididymal fluid forward motility protein (FMP) to the incubation medium suppressed flagellar angulation and agglutination. The addition of FMP to caffeine-activated spermatozoa induced a slow-swimming progressive movement in about 10% of the spermatozoa. In order to establish an hypothetical role of FMP in the regulation of calcium transport a calmodulin inhibitor, fluphenazin, was tested. When added to caffeine-activated spermatozoa at a rate of 10(-5) M, it induced about 15% of progressive spermatozoa with flagellar angulations. The trajectories of these spermatozoa were similar to those observed in samples of spermatozoa from the cauda epididymidis. It is concluded that during epididymal maturation a calcium-dependent mechanism might be involved in the transformation of an irregular movement into a progressive movement.


The basics of CAR T design and challenges in immunotherapy of solid tumors - Ovarian cancer as a model.
Chimeric antigen receptor T cells are T cells genetically engineered with CAR constructs which mainly contain scFV and TCR zeta chain. With promising development in blood cancers, CAR T trials are also applied in solid cancers. However, the treatment effect in solid cancers is lower than expected. This review summarizes difference of CAR T applications in solid and blood cancers. Future challenges of CAR T cell treatment in solid cancer are also discussed using ovarian cancer as an example.


Retinol Esterification by DGAT1 Is Essential for Retinoid Homeostasis in Murine Skin.
Retinoic acid (RA) is a potent signaling molecule that is essential for many biological processes, and its levels are tightly regulated by mechanisms that are only partially understood. The synthesis of RA from its precursor retinol (vitamin A) is an important regulatory mechanism. Therefore, the esterification of retinol with fatty acyl moieties to generate retinyl esters, the main storage form of retinol, may also regulate RA levels. Here we show that the neutral lipid synthesis enzyme acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) functions as the major acyl-CoA:retinol acyltransferase (ARAT) in murine skin. When dietary retinol is abundant, DGAT1 deficiency results in elevated levels of RA in skin and cyclical hair loss; both are prevented by dietary retinol deprivation. Further, DGAT1-deficient skin exhibits enhanced sensitivity to topically administered retinol. Deletion of the enzyme specifically in the epidermis causes alopecia, indicating that the regulation of RA homeostasis by DGAT1 is autonomous in the epidermis. These findings show that DGAT1 functions as an ARAT in the skin, where it acts to maintain retinoid homeostasis and prevent retinoid toxicity. Our findings may have implications for human skin or hair disorders treated with agents that modulate RA signaling.


A two-stage cold isostatic pressing and gelling approach for fabricating a therapeutically loaded amorphous calcium polyphosphate local delivery system.
Local delivery systems have taken on a greater clinical focus for osteomyelitis therapy owing to their ability to overcome many disadvantages of systemic delivery. This study reports for the first time the capacity to fabricate strontium- and vancomycin-doped calcium polyphosphate beads using a two-stage cold isostatic pressing and gelling approach. The fabricated beads were of uniform shape and diameter, and upon gelling exhibited reduced porosity. Of greatest significance in the subsequent in vitro study was the improvement of bead long-term structural stability upon vancomycin incorporation; a characteristic that further encourages the extended release of therapeutically relevant levels of antibiotic. Overall, this study provides support for the inclusion of a cold isostatic pressing step in the fabrication of a therapeutically loaded calcium polyphosphate bead-based local delivery system intended for osteomyelitis treatment.


Prolonged Tpeak-Tend interval is associated with ventricular fibrillation during reperfusion in ST-elevation myocardial infarction.
Ventricular fibrillation (VF) during reperfusion in ST-elevation myocardial infarction (STEMI) is associated with increased in-hospital mortality. Dispersion of ventricular repolarization contributes to ventricular vulnerability during ischemia. Tpeak-Tend interval was proposed as a ventricular repolarization dispersion marker, however its value for prediction of reperfusion VF remains uncertain. We aimed to assess whether Tpeak-Tend before PCI in STEMI is associated with reperfusion VF. STEMI patients admitted for primary PCI were retrospectively assessed for VF during reperfusion. Pre-PCI ECGs recorded in 40 patients with reperfusion VF (rVF group; age 65 ± 13 years, 80% male) were compared with 374 consecutive patients without reperfusion arrhythmias (No-rVF group; age 67 ± 12 years; 68% male). Digital ECGs were automatically processed and Tpeak-Tend interval computed on a per-lead basis. The global Tpeak-Tend was calculated between the earliest Tpeak and the latest Tend in any lead, and tested for association with reperfusion VF using logistic regression analysis. The leftward shift of Tpeak toward QRS complex in ischemic leads resulted in Tpeak-Tend prolongation. Global Tpeak-Tend in rVF group was higher than in No-rVF group (142 ± 24 vs 130 ± 27 ms; p = 0.007). Global Tpeak-Tend ≥ 131 ms predicted reperfusion VF (OR = 3.41; 95% CI 1.66-7.04; p = 0.001) and remained a significant predictor of reperfusion VF in multivariable analysis. Tpeak-Tend interval before PCI in STEMI was an independent predictor of reperfusion VF. Our findings warrants further research aimed at prospective validation of Tpeak-Tend as a marker of periprocedural arrhythmic risk.


Asteroid Hyalosis Masquerading as Vitreous Hemorrhage on Point-of-Care Sonography.
Point-of-care ocular sonography is frequently used in the emergency department to evaluate patients with vision disorders. We describe a case series of 3 patients who ultimately had a diagnosis of asteroid hyalosis, a lesser-known condition that on point-of-care sonography may be mistaken for vitreous hemorrhage. Asteroid hyalosis is considered a benign degenerative condition. In contrast, vitreous hemorrhage may be an ocular emergency that warrants an urgent ophthalmologic consultation if there is an underlying retinal tear or detachment. Although similar in appearance on sonography, recognition of the subtle pathognomonic sonographic features along with their clinical presentations can differentiate these diseases, with vastly different management strategies and dispositions.


"Switch-On" Fluorescence Detection of Glucose with High Specificity and Sensitivity Based on Silver Nanoparticles Supported on Porphyrin Metal-Organic Frameworks.
As the energy source of living cells and the intermediate product of metabolism, glucose plays an important role in biological systems. Therefore, it is of great significance to establish a reliable and sensitive method for the detection of glucose, especially in blood. Herein, a "switch-on" fluorescence sensor for rapid, sensitive, and specific detection of glucose was successfully developed. In this strategy, PCN-224 served as the recognition unit, while AgNPs played the roles as both a "quencher", to decrease the fluorescence intensity of PCN-224, and an H2O2 recognizer. After exposure to H2O2 that was produced in situ during GOx-catalyzed oxidation of glucose, AgNPs can be effectively etched into silver ions and released from PCN-224, thereby recovering the fluorescence of PCN-224. The present sensing strategy shows many merits including high sensitivity with a low limit of detection (0.078 μM) and excellent selectivity toward glucose over other saccharides. More importantly, the sensing platform we proposed was further extended to monitoring glucose in human serum samples with satisfactory recoveries, indicating its promising potential for diagnostic purposes.


Pharmacokinetic and phase I trial of intraperitoneal carboplatin and cyclosporine in refractory ovarian cancer patients.
The feasibility and pharmacokinetics of cyclosporine (CsA) delivered intraperitoneally (IP) have not been previously explored. We performed a pharmacokinetic study of IP CsA followed by a phase I dose-escalation trial of the combination of IP CsA and carboplatin in refractory ovarian cancer patients. A pilot study was performed of three patients who received 1, 10, and 20 mg/kg IP CsA alone. Subsequently, a phase I trial of 35 patients was performed between April 1990 and April 1993. Whole-blood and IP fluid CsA concentrations were measured at serial time points. The highest dose delivered IP was 34.6 mg CsA/kg in combination with carboplatin (250 mg/m2 or 300 mg/m2, depending on creatinine clearance), which was not dose-escalated. The area under the concentration-time curve (AUC) for CsA and half-life (T1/2) were calculated. Objective and serologic responses were noted, and toxicity was graded using the National Cancer Institute common toxicity criteria. The feasibility of delivering IP CsA alone was established. We observed a 1,000:1 ratio between IP fluid and blood concentrations at 20 mg CsA/kg. Pharmacokinetic analysis confirmed that at 20 mg CsA/kg, there was an IP fluid-to-blood AUC ratio of 600:1 in favor of peritoneal exposure. At the highest dose delivered, 34.6 mg CsA/kg, the mean IP CsA levels of 1,110 micrograms/ mL were tolerated moderately well and the IP fluid-to-blood ratio of 1,000:1 was maintained. Blood and IP CsA concentrations were analyzed in the presence and absence of IP carboplatin. At 20 mg CsA/kg, there was no difference in either mean blood CsA levels (0.9 microgram/ mL) or mean IP CsA concentrations (1,000 micrograms/mL) obtained in the absence or presence of carboplatin. The most common toxicity in the phase I study was anemia, seen in 66% of patients. Common toxicities at the maximum CsA dose delivered (34.6 mg/kg) were anemia, leukopenia, thrombocytopenia, and hypertension. In this trial, three objective responses (two complete and one partial) were observed for a duration of 3 to 11 months. Control of platinum-resistant ascites was an important feature, noted in five of eight patients. We have established the feasibility of delivering IP CsA up to doses of 34.6 mg/kg in conjunction with carboplatin, and the sustaining of IP fluid to blood ratios of 1,000:1. The IP administration of CsA resulted in a favorable ratio of exposure for the peritoneal cavity compared with systemic exposure, indicating a therapeutic advantage of this approach with a significant decrease in systemic toxicity. We recommend that 34.6 mg/ kg of IP CsA be tested as a phase II dose in combination with carboplatin in refractory ovarian cancer patients. This report provides the groundwork for future studies using IP CsA, both as a chemomodulator of platinum and of multidrug resistance.


Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion.
Erythroid cell commitment and differentiation proceed through activation of a lineage-restricted transcriptional network orchestrated by a group of well characterized genes. However, the minimal set of factors necessary for instructing red blood cell (RBC) development remains undefined. We employed a screen for transcription factors allowing direct lineage reprograming from fibroblasts to induced erythroid progenitors/precursors (iEPs). We show that Gata1, Tal1, Lmo2, and c-Myc (GTLM) can rapidly convert murine and human fibroblasts directly to iEPs. The transcriptional signature of murine iEPs resembled mainly that of primitive erythroid progenitors in the yolk sac, whereas addition of Klf1 or Myb to the GTLM cocktail resulted in iEPs with a more adult-type globin expression pattern. Our results demonstrate that direct lineage conversion is a suitable platform for defining and studying the core factors inducing the different waves of erythroid development.


Management of diabetes mellitus in hospitalized patients: efficiency and effectiveness of sliding-scale insulin therapy.
To determine the efficiency and effectiveness of current prescribing practices relative to short- and intermediate-acting insulins in the prevention or treatment of acute hyperglycemic episodes in hospitalized patients with diabetes mellitus or hyperglycemia, and to identify clinical findings that influence the effectiveness of insulin therapy in these patients. Retrospective observational study. University-affiliated hospital. Ninety consecutive adult inpatients who had orders placed for as-needed subcutaneous regular or lispro sliding-scale insulin. Medical records were reviewed for patients' clinical characteristics and responses to administered insulin that were recorded during each of the first 5 days of hospitalization in which sliding-scale insulin therapy was used. Despite the immediate or bedside availability of both computerized and manual means to record finger-stick blood glucose levels and insulin injections, uncertainties or missing information related to execution, timing, blood glucose levels, or insulin dose were present in approximately 30% of all anticipated points of care involving insulin. Ten episodes of hypoglycemia in six patients were associated with sliding-scale insulin. Appropriately timed, successive glucose measurements documented a decrement in elevated blood glucose values to within the target range of 90-130 mg/dl after 76 (12%) of 621 sliding-scale insulin injections. Glucose levels remained elevated, and insulin effects were therefore subtherapeutic after 523 injections (84%). Despite blood glucose levels that remained persistently elevated, corresponding adjustments in either the timing or the dose of insulin were made infrequently. Sliding-scale insulin regimens were never adjusted in 73 patients (81%). Through 5 days of therapy, the proportion of patients who attained good glycemic control ranged from 2-10% (mean 6%). The mode of overall glycemic control was poor, with 51-68% of patients in this category on any given day. Overall, treated diabetic and hyperglycemic patients were more likely to be poorly controlled than relatively well controlled. Our findings reveal outcomes associated with sliding-scale insulin that are widely variable, often ineffectual, and prone to deficiencies in monitoring, documentation, and prescribing soundness. Efforts to improve glycemic control in hospitalized patients are clearly needed.


The endolymphatic sac and inner ear homeostasis. II: Effect of glycerol on the sensory end organs with or without colchicine pretreatment.
The effects of glycerol and colchicine on the sensory end organs of the inner ear were investigated in mice. Glycerol alone induced a widening of the intercellular spaces lining vestibular dark and transitional cells as well as the marginal cells of the stria vascularis. This was noted within 30 min after the injection of glycerol and was normalized again within 4 h after the injection. Colchicine induced some morphological changes in the inner ear sensory cells, such as dissociation of Golgi complexes etc. These isolated glycerol or colchicine injections did not cause any signs of inner ear functional impairment. Treatment with glycerol following pretreatment with colchicine, however, induced marked inner ear dysfunction with impaired sense of balance and audition. The inner ear morphology revealed a combination of changes as compared with what was observed after isolated treatment with glycerol or colchicine i.e. edema of the stria vascularis, and vestibular dark and transitional cells as well as dissociation of Golgi complexes in the sensory cells. The cochlea showed moderate endolymphatic hydrops. These findings indicate that colchicine affects the inner ear fluid regulating mechanisms which may lead to severe functional derangement after additional glycerol treatment. It is conceivable that the present experiment may serve as a useful model for further studies on inner ear changes related to endolymphatic hydrops and Ménière's disease.


Plasma-gelsolin-binding sites on the actin sequence.
Plasma gelsolin was cross-linked to fluorescently labeled actin in order to identify plasma-gelsolin-binding sites on the primary sequence of actin. Plasma gelsolin can be cross-linked to actin with 1-ethyl-3-[3-(dimethyl-amino)propyl]carbodiimide (EDC), resulting in the formation of 1:1 and 1:2 plasma gelsolin:actin cross-linked complexes with apparent molecular masses of 130 kDa and 180 kDa respectively. The cross-linked complexes were isolated separately, partially digested with cyanogen bromide and subjected to sodium dodecyl sulfate gel electrophoresis to analyze fluorescent fragments. The electrophoretic pattern showed that fluorescent CNBr fragments obtained from a free actin molecule were all found in those obtained from both the complexes. Since the fluorescent probe was attached to an actin molecule through the penultimate cysteine residue (Cys-374), the agreement in the fluorescent patterns indicated that the NH2-terminal CNBr fragments of both the actin molecules were involved in cross-linking with plasma gelsolin. This was also suggested by hydroxylamine cleavage of the two complexes as the cleavage gave the fluorescent 41-kDa fragment which could not be produced unless plasma gelsolin was cross-linked at the NH2-terminal segment comprising 12 amino acids. Since EDC cross-links an amino group with a carboxyl group only when they are direct contact, the characteristic acidic amino acid residues at the NH2 terminus of actin are suggested to participate in binding plasma gelsolin.


Microphase separation and the formation of ion conductivity channels in poly(ionic liquid)s: A coarse-grained molecular dynamics study.
We study generic properties of poly(ionic liquid)s (PILs) via coarse-grained molecular dynamics simulations in bulk solution and under confinement. The influence of different side chain lengths on the spatial properties of the PIL systems and on the ionic transport mechanism is investigated in detail. Our results reveal the formation of apolar and polar nanodomains with increasing side chain length in good agreement with previous results for molecular ionic liquids. The ion transport numbers are unaffected by the occurrence of these domains, and the corresponding values highlight the potential role of PILs as single-ion conductors in electrochemical devices. In contrast to bulk behavior, a pronounced formation of ion conductivity channels in confined systems is initiated in close vicinity to the boundaries. We observe higher ion conductivities in these channels for increasing PIL side chain lengths in comparison with bulk values and provide an explanation for this effect. The appearance of these domains points to an improved application of PILs in modern polymer electrolyte batteries.


[Study on the risk factors regarding deep venous thrombosis in acute pulmonary thromboembolism].
To identify the risk factors of deep venous thrombosis(DVT) in patients with acute pulmonary thromboembolism (PTE). Post hoc analysis on data from a prospective multicenter through a randomized control trial on thrombolysis and anticoagulant among 454 patients with acute symptomatic PTE from June 2002 to December 2004. All patients were confirmed PTE by CT pulmonary angiography (CTPA) and/or ventilation perfusion scan or by magnetic resonance pulmonary angiography. Data of PTE patients with DVT was compared with those without DVT to identify the DVT risk factors. The effect of other variable on DVT was assessed by logistic regression analysis. When comparing the age, sex body weight index and underlying diseases including hypertension, coronary heart disease, chronic obstructive pulmonary disease, cerebral accident and malignant tumor between groups of DVT and no DVT,data showed that there was no statistically significant difference except for diabetes (chi2 = 4.481, P = 0.034) among them.However,results from multi-analysis showed that edema of lower-limb [odd ratio (OR), 2.255; 95% CI, 1.493 to 3.408], phlebitis (OR, 2.380; 95% CI, 1.426 to 3.973) and the entire swollen (calf swelling > or =1 cm) larger than asymptomatic side (OR, 3.834; 95% CI, 2.561 to 5.738) were independent risk factors for DVT. Edema of lower-limb, phlebitis and calf swelling > or =1 cm seemed to be risk factors for DVT.


K114 (trans, trans)-bromo-2,5-bis(4-hydroxystyryl)benzene is an efficient detector of cationic amyloid fibrils.
Cationic amyloid fibrils found in human semen enhance the transmission of the human immunodeficiency virus (HIV) and thus, are named semen-derived enhancer of virus infection (SEVI). The mechanism for the enhancement of transmission is not completely understood but it has been proposed that SEVI neutralizes the repulsion that exists between the negatively charged viral envelope and host cell membrane. Consistent with this view, here we show that the fluorescence of cationic thioflavin T (ThT) in the presence of SEVI is weak, and thus ThT is not an efficient detector of SEVI. On the other hand, K114 ((trans, trans)-bromo-2,5-bis(4-hydroxystyryl)benzene) forms a highly fluorescent, phenolate-like species on the cationic surface of SEVI. This species does not form in the presence of amyloid fibrils from insulin and amyloid-β protein, both of which are efficiently detected by ThT fluorescence. Together, our results show that K114 is an efficient detector of SEVI.


First report of Gyrodactylus spp. (Platyhelminthes: Monogenea) in the western Mediterranean Sea: molecular and morphological descriptions.
The Gyrodactylus spp. fauna on species of gobies, Pomatoschistus, Gobiusculus, and Knipowitschia (Gobiidae: Teleostei), from the western Mediterranean and Adriatic seas is strikingly similar to that found in the Baltic Sea and eastern Atlantic Ocean, both in morphology and in internal transcribed spacer (ITS) rRNA. The fauna consisted of Gyrodactylus branchialis, G. ostendicus, G. gondae, G. rugiensis, G. rugiensoides, and G. arcuatus. No new species have been found. A morphometric comparison between G. branchialis from the Mediterranean and Adriatic seas and its type locality in Ostend (Belgium) showed significant differences in ventral bar and marginal hook features. The morphometric variation was lower in G. rugiensis, whereas no significant differences were found in G. ostendicus. Gyrodactylus branchialis and G. ostendicus collected on P. microps were slightly different in the ITS rDNA (-0.6%) compared with specimens on the closely related P. marmoratus, probably reflecting ongoing speciation. A hybrid zone was identified in the Vaccarès lagoon complex (France) where both host species are sympatric. There was no clear geographic or host-related pattern in the variation found in the ITS2 rDNA in G. arcuatus sampled from P. microps, G. flavescens, Pungitius pungitius, K. panizzae, and its original host Gasterosteus aculeatus (2 polymorphic sites). Of all studied species, only G. arcuatus, G. rugiensis, and G. rugiensoides showed minor intraspecific variation in the ITS rDNA. Hence, the physical separation by a shoreline of more than 10,000 km is hardly reflected in the parasite ITS rDNA.


Circulating clonotypic B cells in multiple myeloma and monoclonal gammopathy of undetermined significance.
The B-cell compartment in which multiple myeloma stem cells reside remains unclear. We investigated the potential presence of mature, surface-membrane immunoglobulin-positive B lymphocytes clonally related to the tumor bone marrow plasma cells among different subsets of peripheral blood B cells from ten patients (7 with multiple myeloma and 3 with monoclonal gammopathies of undetermined significance). The presence of clonotypic immunoglobulin heavy chain gene rearrangements was determined in multiple highly-purified fractions of peripheral blood B-lymphocytes including surface-membrane IgM(+) CD27(-) naïve B-lymphocytes, plus surface-membrane IgG(+), IgA(+) and IgM(+) memory CD27(+) B cells, and normal circulating plasma cells, in addition to (mono)clonal plasma cells, by a highly-specific and sensitive allele-specific oligonucleotide polymerase chain reaction directed to the CDR3 sequence of the rearranged IGH gene of tumor plasma cells from individual patients. Our results showed systematic absence of clonotypic rearrangements in all the different B-cell subsets analyzed, including M-component isotype-matched memory B-lymphocytes, at frequencies <0.03 cells/μL (range: 0.0003-0.08 cells/μL); the only exception were the myeloma plasma cells detected and purified from the peripheral blood of four of the seven myeloma patients. These results indicate that circulating B cells from patients with multiple myeloma and monoclonal gammopathies of undetermined significance are usually devoid of clonotypic B cells while the presence of immunophenotypically aberrant myeloma plasma cells in peripheral blood of myeloma patients is a relatively frequent finding.


An X-ray crystallographic and density functional theory study of (3Z)-4-(5-ethylsulfonyl-2-hydroxyanilino)pent-3-en-2-one and (3Z)-4-(5-tert-butyl-2-hydroxyanilino)pent-3-en-2-one.
The Schiff base enaminones (3Z)-4-(5-ethylsulfonyl-2-hydroxyanilino)pent-3-en-2-one, C13H17NO4S, (I), and (3Z)-4-(5-tert-butyl-2-hydroxyanilino)pent-3-en-2-one, C15H21NO2, (II), were studied by X-ray crystallography and density functional theory (DFT). Although the keto tautomer of these compounds is dominant, the O=C-C=C-N bond lengths are consistent with some electron delocalization and partial enol character. Both (I) and (II) are nonplanar, with the amino-phenol group canted relative to the rest of the molecule; the twist about the N(enamine)-C(aryl) bond leads to dihedral angles of 40.5 (2) and -116.7 (1)° for (I) and (II), respectively. Compound (I) has a bifurcated intramolecular hydrogen bond between the N-H group and the flanking carbonyl and hydroxy O atoms, as well as an intermolecular hydrogen bond, leading to an infinite one-dimensional hydrogen-bonded chain. Compound (II) has one intramolecular hydrogen bond and one intermolecular C=O...H-O hydrogen bond, and consequently also forms a one-dimensional hydrogen-bonded chain. The DFT-calculated structures [in vacuo, B3LYP/6-311G(d,p) level] for the keto tautomers compare favourably with the X-ray crystal structures of (I) and (II), confirming the dominance of the keto tautomer. The simulations indicate that the keto tautomers are 20.55 and 18.86 kJ mol(-1) lower in energy than the enol tautomers for (I) and (II), respectively.


Risk of hematological toxicities in patients with solid tumors treated with ramucirumab: a meta-analysis.
We performed a meta-analysis of the risk of hematological adverse events associated with ramucirumab. Eligible studies included randomized Phase II and III trials of patients with solid tumors on ramucirumab, describing events of anemia, leucopenia, neutropenia, febrile neutropenia and thrombocytopenia. A total of 11 clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade anemia, leucopenia, neutropenia, febrile neutropenia and thrombocytopenia were 0.88 (95% CI: 0.80-0.96; p = 0.007), 1.13 (95% CI: 0.85-1.49; p = 0.41), 1.25 (95% CI: 1.08-1.44; p = 0.002), 1.63 (95% CI: 1.30-2.06; p < 0.0001), 1.91 (95% CI: 1.52-2.42; p < 0.00001), respectively. Our meta-analysis has demonstrated an increased risk of febrile neutropenia, all-grade and high-grade neutropenia and thrombocytopenia with ramucirumab-based treatment compared with control.


Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar.
The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood-brain barrier, and its resultant spare capacity requires substantial blockade to increase the uptake of avid substrates, blunting the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined 2 P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and 2 routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate (11)C-N-desmethyl-loperamide (dLop) while avoiding side effects associated with high doses of tariquidar. Forty-two (11)C-dLop PET scans were obtained from 37 healthy volunteers. PET was performed with (11)C-dLop under the following 5 conditions: injected under baseline conditions without P-gp inhibition, injected 1 h after intravenous tariquidar infusion, injected during intravenous tariquidar infusion, injected after oral tariquidar, and injected after disulfiram. (11)C-dLop uptake was quantified with kinetic modeling using metabolite-corrected arterial input function or by measuring the area under the time-activity curve in the brain from 10 to 30 min. Neither oral tariquidar nor oral disulfiram increased brain uptake of (11)C-dLop. Injecting (11)C-dLop during tariquidar infusion, when plasma tariquidar concentrations reach their peak, resulted in a brain uptake of the radioligand approximately 5-fold greater than baseline. Brain uptake was similar with 2 and 4 mg of intravenous tariquidar per kilogram; however, the lower dose was better tolerated. Injecting (11)C-dLop after tariquidar infusion also increased brain uptake, though higher doses (up to 6 mg/kg) were required. Brain uptake of (11)C-dLop increased fairly linearly with increasing plasma tariquidar concentrations, but we are uncertain whether maximal uptake was achieved. We sought to increase the dynamic range of P-gp function measured after blockade. Performing (11)C-dLop PET during peak plasma concentrations of tariquidar, achieved with concurrent administration of intravenous tariquidar, resulted in greater P-gp inhibition at the human blood-brain barrier than delayed administration and allowed the use of a lower, more tolerable dose of tariquidar. On the basis of prior monkey studies, we suspect that plasma concentrations of tariquidar did not fully block P-gp; however, higher doses of tariquidar would likely be associated with unacceptable side effects.


Vaccination with hatched but non-activated, non-viable oncospheres of Taenia taeniaeformis in rats.
The usefulness of hatched but non-activated oncospheres as a candidate vaccine was evaluated using a Taenia taeniaeformis/rat system, since preparation of these oncospheres in vitro is known to be very simple. The findings were: (1) rats vaccinated with non-viable oncospheres became completely resistant to challenge infection; (2) intra-venous injection was the most effective to induce complete resistance; (3) a single oncosphere was sufficient to induce complete resistance in infected rats, whereas approximately 50 and 500 non-viable oncospheres were required to evoke strong and complete resistance, respectively, in vaccinated rats. The usefulness of non-viable oncospheres without adjuvant is discussed.


Multifunctional Nanocomposites Based on Liposomes and Layered Double Hydroxides Conjugated with Glycylsarcosine for Efficient Topical Drug Delivery to the Posterior Segment of the Eye.
To achieve efficient drug delivery to the posterior segment of the eye via topical instillation, novel multifunctional nanocomposites were prepared by hybridizing dexamethasone disodium phosphate (DEXP)-loaded liposome (LP) glycylsarcosine (GS)-anchored layered double hydroxides (named DEXP-HSPC@LDH-GS) and then fully characterized. The nanocomposites exhibited sustained-release performance as well as prolonged precorneal retention ability. MTT assays showed that the nanocomposites were not cytotoxic to both human corneal epithelial cells (HCEpiC) and human conjunctival epithelial cells (HConEpiC) at an LDH concentration of 100 μg/mL. The DEXP-HSPC@LDH-GS nanocomposites showed superior in vitro permeability on the HConEpiC-cell-based model. In the case of HConEpiC cells, both clathrin-mediated endocytosis and active transport by the peptide transporter-1 (PepT-1) were involved in the internalization of the nanocomposites. Fluorescent images of frozen sections of ocular tissues suggested that the possible route for the delivery of doxorubicin hydrochloride (DOX)-labeled nanocomposites from the ocular surface to the back of the eye was a non-corneal pathway. Furthermore, in rabbit eyes, the hybrid nanocomposites displayed markedly higher drug concentration in choroid-retina tissue than other single nanocarriers, such as LPs and LDH. Besides, the results of the eye irritancy test showed that nanocomposite eye drops can be classified as nonirritant, which are suitable to be used as eye drops. In a word, multifunctional nanocomposites based on LPs and LDH could be used as promising vehicles for efficient noninvasive drug delivery to the posterior segment of the eye.


Female urethral duplication: an unusual condition.
We present the case of a 34-year-old woman who presented with a stone fragment stuck near her distal urethra without obstruction of her urinary flow. During an attempt to explore and remove the fragment, she was discovered to have complete urethral duplication with the stone stuck in one of two distal urethral orifices. This represents an extremely rare variant of a very unusual congenital anomaly, even more so as it occurs usually in male patients. Embryology, etiology, and clinical appearance of this rare anomaly are discussed.


Induction of endoplasmic reticulum stress-mediated apoptosis and non-canonical autophagy by luteolin in NCI-H460 lung carcinoma cells.
In this study, we investigated the anti-cancer effects of luteolin, a member of the flavonoid family, in NCI-H460 human lung carcinoma cells. It was shown that luteolin induces apoptotic cell death through modulating both the extrinsic pathway and intrinsic pathways, which are suppressed by z-VAD-fmk, indicating that luteolin triggers caspase-dependant apoptosis. Furthermore, we found that the α subunit of the eukaryotic initiation factor 2 (eIF2α/C/EBP homologous protein pathway, but not the c-Jun N-terminal kinase pathway, played a critical role in induction of apoptosis by luteolin. The data indicated that luteolin also induces autophagy; evidence for this is the accumulation of microtubule-associated protein light chain-3 (LC3) II protein, the increase of LC3 puncta as well as an enhanced autophagy flux. In addition, inhibiting autophagy by bafilomycin A1 reduced apoptotic cell death, suggesting that luteolin-induced autophagy functions as a cell death mechanism. Notably, the activated caspases that appeared with luteolin treatment cleaved Beclin-1, and the expression of LC3II remained the same even after cells were challenged with Beclin-1 siRNA, demonstrating that luteolin induces Beclin-1-independent autophagy. Taken together, our findings showed that luteolin triggers both endoplasmic reticulum stress-related apoptosis and non-canonical autophagy, which function as a cell death mechanism in NCI-H460 human lung cancer cells.


Dyspnea self-management in patients with chronic obstructive pulmonary disease: moderating effects of depressed mood.
The effects of three versions of a dyspnea self-management program on depressed mood and the moderating effects of baseline depression risk on improvements in dyspnea severity, exercise performance, and physical and social functioning were examined over a 2-month period in 100 patients with moderate to severe chronic obstructive pulmonary disease (COPD). All three versions of the dyspnea self-management programs, which differed in the amount of supervised exercise (no sessions or four or 24 sessions), equally and significantly improved depressed mood. Subjects at high risk for depression at study entry who received 24 sessions had greater reduction in dyspnea than those who received four sessions or no sessions. Patients with COPD at high risk for depression are likely to achieve greater relief of dyspnea with self-management programs that include more intensive supervised exercise.


Drosophila hemocyte migration: an in vivo assay for directional cell migration.
This protocol describes an in vivo assay for random and directed hemocyte migration in Drosophila. Drosophila is becoming an increasingly powerful model system for in vivo cell migration analysis, combining unique genetic tools with translucency of the embryo and pupa, which allows direct imaging and traceability of different cell types. In the assay we present here, we make use of the hemocyte response to epithelium wounding to experimentally induce a transition from random to directed migration. Time-lapse confocal microscopy of hemocyte migration in untreated conditions provides a random cell migration assay that allows identification of molecular mechanisms involved in this complex process. Upon laser-induced wounding of the thorax epithelium, a rapid chemotactic response changes hemocyte migratory behavior into a directed migration toward the wound site. This protocol provides a direct comparison of cells during both types of migration in vivo, and combined with recently developed resources such as transgenic RNAi, is ideal for forward genetic screens.


Preliminary studies of new proteasome inhibitors in the tumor targeting approach: synthesis and in vitro cytotoxicity.
The proteasome is a multicatalytic protease that plays a critical role in the cell. The control of proteasomes could, thus, provide a weapon for the treatment of cancer. Therefore, we have synthesized six new peptide aldehyde inhibitors of the proteasome linked to the N-(2-diethylaminoethyl)benzamide (BZA-CO) structure, in order to target the cytotoxic activity to malignant melanoma cells. Biological studies demonstrated the influence of length and composition of the amino acid chain on the cytotoxicity of our compounds. Among them, compound 19 presents the highest cytotoxicity (IC50 = 0.64 +/- 0.07 micromol): this cytotoxicity was maintained in the presence of BZA-CO but decreased 8-fold compared to the control MG132. Fluorescence activated cell sorter (FACS) and cytotoxic activity analysis demonstrated the selectivity of compound 19 for melanoma cells. Finally, western blottings of ubiquitinated proteins in IPC227F cells as well as proteasome assays confirmed that the cytotoxicity was linked to an inhibition of the proteasome activity.


Factors associated with the use of protective measures against vector-borne diseases among troops deployed to Iraq and Afghanistan.
Vector-borne diseases are known threats to deployed troops. We performed a cross-sectional study of troops deployed to Southwest Asia between January 2005 and February 2007 to evaluate practices of personal protective measures and their relationship to self-report of Old World cutaneous leishmaniasis (CL), a marker of vector-borne disease threat. Regular or always N, N-diethyl-m-toluamide (DEET) use was low (2-5%). Associations for DEET use were command emphasis, branch of service, uniform treatment with permethrin, and duty station. Uniform treatment with permethrin was associated with branch of service, command emphasis, and use of DEET. We identified 22 cases of CL (incidence density of 1.8-3.7 per 100 person-years) with increased risk among Reserve/National Guard components, Air Force and Marine personnel. Commanders can influence the use of the military insect repellent system. Unit-based treatment of uniforms improves prevalence. CL incidence may be higher than previously reported.


Influence of architecture on the interaction of negatively charged multisensitive poly(N-isopropylacrylamide)-co-methacrylic acid microgels with oppositely charged polyelectrolyte: absorption vs adsorption.
Two sets of core-shell microgels composed of temperature-sensitive poly(N-isopropylacrylamide) (PNiPAM) with different spatial distribution of pH-sensitive methacrylic acid (MAA) groups were prepared. The cores consist of either PNiPAM (neutral core; nc) or PNiPAM-co-MAA (charged core; cc). A charged shell existing of PNiPAM-co-MAA was added to the neutral core (yielding neutral core-charged shell; nccs), on the charged core, on the other hand, a neutral shell of PNiPAM was added (charged core-neutral shell; ccns). Complexes of these microgels with positively charged poly(diallyldimethylammonium chloride) (PDADMAC) of different molar masses were prepared. The amount of bound polyelectrolyte was quantified, and the microgel-polyelectrolyte complexes were characterized with respect to electrophoretic mobility and hydrodynamic radius. The penetration of polyelectrolyte into the microgel was also monitored by means of lifetime analysis of a fluorescent dye covalently bound to poly(L-lysine) providing information on the probe's local environment. The architecture of the microgel has a significant influence on the interaction with oppositely charged polyelectrolyte. Complexes with microgel with the charged shell tend to flocculate at charge ratios of 1 and are thus similar to polyelectrolyte complexes with rigid colloidal particles. Complexes with microgels that consist of a charged core and a neutral shell show very different properties: They are still temperature sensitive and reveal an influence of the polyelectrolyte's chain length. Low molecular weight PDADMAC can penetrate through the neutral shell into the charged core, and thus nearly no charge reversal occurs. The high-MW polyelectrolyte does not penetrate fully and leads to charge reversal. The results demonstrate that microgels are able to absorb or adsorb polyelectrolytes depending on the polyelectrolyte's chain length and the microgels architecture. Complexes with different surface properties and different colloidal stability can be prepared, and polyelectrolytes can be encapsulated in the microgel core. Thus, multisensitive core-shell microgels combine permeability and compartmentalization on a nanometer length scale and provide unique opportunities for applications in controlled uptake and release.


Molecular cloning and functional expression of cDNAs encoding oxidosqualene cyclases from Costus speciosus.
Costus speciosus produces a large quantity of steroidal glycosides derived from the sole aglycone, diosgenin. Cycloartenol, a product of oxidosqualene cyclase (OSC), is postulated to be a common intermediate for phytosterols of primary metabolism and diosgenin of secondary metabolism, possibly providing a metabolic branch point. Two cDNAs, CSOSC1 and CSOSC2, were cloned from C. speciosus by RT-PCR and cDNA library screening. Both cDNAs encode 759 amino acids with high mutual identity (74%), resembling (>55% identity) the known OSCs. Phylogenetic tree analysis indicated that the gene products occupy distinct positions from those of cycloartenol synthases (CASs) and triterpene synthases from dicotyledonous plants. By functional expression in yeast, CSOSC1 and CSOSC2 were proved to encode a CAS and a multifunctional triterpene synthase, respectively. The present result is the first demonstration of the functional expression of OSCs from monocotyledonous plants.


Force degradation of orthodontic latex elastics: An in-vivo study.
Our objectives were to assess the force degradation of orthodontic latex elastics over 48 hours in vivo and to study the relationship between the amount of mouth opening and the degree of force decay. Fifty-two orthodontic patients wearing fixed appliances using Class II elastics were asked to wear premeasured-force 3/16-in heavy and medium intermaxillary elastics. The force amounts were measured and compared at different time intervals. Fifty percent of the force was lost after 3.9 hours for the medium elastics and after 4.9 hours for the heavy elastics. A continuous significant force drop in all elastics was seen at all time intervals (P <0.05, P <0.001). There was greater force loss in the heavy elastics compared with the medium elastics in vivo at all time intervals (P <0.001); the rates of force loss, however, were similar. Fifty percent of force degradation occurred in the first 4 to 5 hours. Because of breakage and for oral hygiene purposes, orthodontic elastics should be changed daily; otherwise, elastics can be used for 48 hours. Force decay of the elastics was correlated to the lateral distance between the maxillary canine and the mandibular first molar in occlusion.


Comparison of three serological assays to determine the cross-reactivity of antibodies from eight genetically diverse U.S. swine influenza viruses.
Swine influenza virus is an economically important pathogen to the U.S. swine industry. New influenza subtypes and isolates within subtypes with different genetic and antigenic makeup have recently emerged in U.S. swineherds. As a result of the emergence of these new viruses, diagnosticians' ability to accurately diagnose influenza infection in pigs and develop appropriate vaccine strategies has become increasingly difficult. The current study compares the ability of subtype-specific commercial enzyme-linked immunosorbent assays (ELISA), hemagglutination inhibition (HI), and serum neutralization (SN) assays to detect antibodies elicited by multiple isolates within different subtypes of influenza virus. Pigs were infected with genetically and antigenically different isolates of the 3 major circulating subtypes within populations of swine (H1N1, H1N2, and H3N2). Serum was collected when all pigs within a group collectively reached HI reciprocal titers >or=160 against that group's homologous challenge virus. The antibody cross-reactivity of the sera between isolates was determined using ELISA, HI, and SN assays. In addition, the correlation between the 3 assays was determined. The assays differed in their ability to detect antibodies produced by the viruses used in the study. The results provide important information to diagnostic laboratories, veterinarians, and swine producers on the ability of 3 common serological assays used in identifying infection with influenza in pigs.


C5 palsy after laminectomy and posterior cervical fixation for ossification of posterior longitudinal ligament.
To investigate the imaging findings correlated with C5 root palsies in the patients undergoing laminectomy and lateral mass screw fixation for ossification of posterior longitudinal ligament (OPLL), and clarify its pathogenic mechanism. The series included 49 patients with OPLL. Characteristics of preoperative and postoperative x-ray, computed tomography, and magnetic resonance images were compared between the patients with and those without C5 root palsies. Postoperative C5 root palsies occurred in 9 patients 6 to 64 hours postoperatively. They tended to have increased cervical lordosis and severe OPLL. However, there was no significant positive correlation with an increase in T2-weighted hyperintense foci on magnetic resonance studies. The tethering effect on the root seemed to be the main pathogenic mechanism of C5 root palsies in this study.


N-Methyl-D-aspartate attenuates opioid receptor-mediated G protein activation and this process involves protein kinase C.
The effects of N-methyl-D-aspartate (NMDA) on opioid receptor-mediated G protein activation were explored in neuroblastoma X glioma hybrid (NG108-15) cells. Treatment of the cells with NMDA resulted in a remarkable attenuation of [35S]guanosine-5'-O-(3-thio)triphosphate binding stimulated by [D-Pen2,D-Pen5]-enkephalin (DPDPE), a delta-opioid receptor agonist. The effects of NMDA were dose and time dependent with an IC50 value of 5 nM and could be blocked by NMDA receptor antagonists. After NMDA treatment, the DPDPE dose-response curve shifted to the right (EC50 value increased approximately 7-fold, from 6 to 40 nM), and the maximal response induced by DPDPE was reduced by approximately 60%. The effects of NMDA were reversible, and the DPDPE response could recover within 60 min. The functional responses of delta-, mu-, and kappa-opioid receptors in primarily cultured neurons also were attenuated significantly by NMDA treatment. The inhibitory effects of NMDA on opioid receptor-mediated G protein activation could be blocked by coadministration of the protein kinase C (PKC) inhibitors or by elimination of the extracellular Ca2+. Correspondingly, NMDA treatment of NG108 cells significantly elevated cellular PKC activity and stimulated Gialpha2 phosphorylation. Transient transfection into NG108-15 cells of the wild-type Gialpha2 and a mutated Gialpha2 (Ser144Ala) resulted in a 2-fold increase in DPDPE-stimulated G protein activation. The DPDPE responses were greatly inhibited by NMDA treatment in the wild-type Gialpha2-transfected cells but much less affected in the mutant Gialpha2-transfected cells. In summary, NMDA attenuates opioid receptor/G protein coupling, and this process requires activation of PKC.


The influence of yeast on thermophilic composting of food waste.
The microbial changes during thermophilic composting of food waste were investigated at 50 degrees C using a laboratory-scale composter. The results showed that an early increase in the growth of yeast was followed by the growth of thermophilic bacteria, and that subsequently, the yeast declined rapidly. The growth interactions of selected strains of yeast and bacteria were studied in culture media containing organic acids. The results demonstrated that the acidity of the media was reduced during the growth of the yeast. Therefore, it is concluded that in the early stages of composting, the growth thermophilic bacteria is inhibited by organic acids, and that the growth of yeast enables subsequent bacterial growth by removing organic acids from food waste.


Fatal hepatic failure caused by miliary tuberculosis in a hemodialysis patient: case report.
A 57 year-old male dialysis patient died soon after the onset of high fever, hypoglycemia, and disturbance of consciousness. Autopsy revealed granulomatous lesions associated with caseous necrosis mainly found in the liver, despite the absence of pulmonary changes on chest radiographs performed during the patients illness. It appears that tubercle bacilli were hematogenously disseminated mainly to the liver causing miliary tuberculosis without producing typical diffuse lesions in the lungs. Since tuberculosis is a common complication in hemodialysis patients, the potential development of atypical miliary tuberculosis should always be borne in mind.


Focal and Ambient Processing of Built Environments: Intellectual and Atmospheric Experiences of Architecture.
Neuroscience has well established that human vision divides into the central and peripheral fields of view. Central vision extends from the point of gaze (where we are looking) out to about 5° of visual angle (the width of one's fist at arm's length), while peripheral vision is the vast remainder of the visual field. These visual fields project to the parvo and magno ganglion cells, which process distinctly different types of information from the world around us and project that information to the ventral and dorsal visual streams, respectively. Building on the dorsal/ventral stream dichotomy, we can further distinguish between focal processing of central vision, and ambient processing of peripheral vision. Thus, our visual processing of and attention to objects and scenes depends on how and where these stimuli fall on the retina. The built environment is no exception to these dependencies, specifically in terms of how focal object perception and ambient spatial perception create different types of experiences we have with built environments. We argue that these foundational mechanisms of the eye and the visual stream are limiting parameters of architectural experience. We hypothesize that people experience architecture in two basic ways based on these visual limitations; by intellectually assessing architecture consciously through focal object processing and assessing architecture in terms of atmosphere through pre-conscious ambient spatial processing. Furthermore, these separate ways of processing architectural stimuli operate in parallel throughout the visual perceptual system. Thus, a more comprehensive understanding of architecture must take into account that built environments are stimuli that are treated differently by focal and ambient vision, which enable intellectual analysis of architectural experience versus the experience of architectural atmosphere, respectively. We offer this theoretical model to help advance a more precise understanding of the experience of architecture, which can be tested through future experimentation. (298 words).


Markers of oxidative stress and aging in Duchene muscular dystrophy patients and the possible ameliorating effect of He:Ne laser.
Replicative aging and oxidative stress are two plausible theories explaining the etiology of muscular dystrophy. The first theory indicates that replicative aging of myogenic cells (satellite cells), owing to enhanced myofiber turnover, is a plausible explanation of the progression of Duchenne muscular dystrophy (DMD). The oxidative stress theory indicates that failure of muscle regeneration to keep up with the ongoing apoptosis and necrosis following oxidative stress, that normally associates muscular exercise, leads to muscle atrophy in DMD. To test for these two theories, markers of replicative aging and oxidative stress were assessed in the blood of 30 DMD patients vs. 20 normal healthy age matching controls. Markers of replicative aging showed significantly lower telomerase activity, significantly increased expression of receptors for advanced glycation end products (RAGEs) mRNA and Bax mRNA (an apoptotic gene) in DMD compared to controls. There was a significant increase in markers of oxidative stress among DMD patients compared to controls, measured in terms of increased apoptotic percentage in circulating mononuclear cells, increased lipid peroxidation measured in terms of plasma malondialdehyde (MDA) and increased protein carbonyls. Levels of plasma nitric oxide (NO), which neutralizes oxygen radicals, and expression of inducible nitric oxide synthase (iNOS) mRNA in neutrophils was significantly lower among DMD compared to controls. Biostimulation of WBC by helium neon (He:Ne) laser irradiation induced a significant increase in the expression of iNOS mRNA and plasma NO levels, but still at a lower level compared to controls. He:Ne laser irradiation induced a marked decrease in markers of oxidative stress among DMD patients compared to their level before irradiation, measured in terms of decreased plasma protein carbonyls, decreased plasma MDA, and decreased apoptosis percentage. This study points to that oxidative stress is the prime cause for muscle degeneration in DMD and points out to the possible ameliorative effect of He:Ne laser on this


Use of a self-etching primer in combination with a resin-modified glass ionomer: effect of water and saliva contamination on shear bond strength.
The purpose of this study was to evaluate the effects of 3 different enamel conditioners (10% polyacrylic acid, 37% phosphoric acid, and self-etching primer) on the shear bond strength and site of bond failure of a resin-modified glass ionomer (Fuji Ortho LC, GC Europe, Leuven, Belgium) bonded onto dry, water-moistened, and saliva-moistened enamel. One hundred eighty bovine permanent mandibular incisors were randomly divided into 12 groups; each group consisted of 15 specimens. Three different enamel surface conditions were studied: dry, soaked with water, soaked with saliva. One hundred eighty stainless steel brackets were bonded with the resin-modified glass ionomer. After bonding, all samples were stored in distilled water for 24 hours and then tested in a shear mode on a testing machine. After self-etching primer application, Fuji Ortho LC produced the highest shear bond strengths under all the different enamel surface conditions; these values were significantly higher than those achieved in the remaining groups, except when Fuji Ortho LC was used in combination with 37% phosphoric acid on dry enamel. Fuji Ortho LC bonded without enamel conditioning produced the lowest shear bond strengths. The bond strength of the groups conditioned with 10% polyacrylic acid was significantly lower than that of the groups etched with 37% phosphoric acid, except when both conditioners were used on enamel soaked with water.


Fruit and vegetable preferences and intake among children in Alberta.
The association between preference for and intake of fruits and vegetables was examined among Albertan children. Data used were collected as part of a provincial population-based survey among grade 5 children in Alberta. Intake of two fruits and five vegetables was assessed using the Harvard food frequency questionnaire, and preference for individual fruit and vegetable items was rated using a three-point Likert-type scale. Random effects models with children nested within schools were used to test for associations between fruit and vegetable preference and intake. A total of 3398 children aged 10 to 11 years returned completed surveys. Children who reported a greater liking for fruits and vegetables also reported significantly (p<0.001) higher intake. On average, children who liked a food a lot ate 0.5 to 2.7 more weekly servings of the food than did children who did not like the food. These findings suggest that focusing on interventions designed to increase taste preference may lead to increased fruit and vegetable intake among children. Introducing children to unfamiliar fruits and vegetables through taste testing may be an effective and practical health promotion approach for improving dietary habits.


Prediction of outcome in schizophrenia.
Prediction of 5-8 year outcome from presenting symptoms and background data was attempted in a sample of 110 first-admitted schizophrenics. Correlations between outcome criteria and single predictors as well as factor analytically derived clusters of predictors were studied. A rather consistent pattern of symptom variables as well as personality and social variables was found to be predictive of outcome. 'Atypical' symptoms were associated with good prognosis while longitudinal variables indicative of 'high-risk personality', or duration and severity of illness, were related to bad prognosis. Overt psychotic symptoms usually gave no correlations with outcome. A discriminant analytical approach was also used to predict outcome from combinations of predictor variables. When all variables were used to predict a combined outcome score, a high accuracy was achieved.


Fish DNA barcoding around large marine infrastructure for improved biodiversity assessment and monitoring.
Accurate species-level identification is pivotal for environmental assessments and monitoring. The PERU LNG terminal is composed of large marine infrastructure located on the central coast of Peru. Since construction, taxonomically challenging species such as drum fishes (Sciaenidae) have been attracted to the new hard-bottom habitat. We conducted a DNA barcoding study to investigate fish diversity and constructed a DNA barcode reference library. We examined 56 vouchered specimens and identified 24 unique species. Intra- and interspecific divergence estimates ranged between 0 and 0.64% and 11 and 35.5%, respectively. We assessed the efficiency of the reference library to identify 29 non-vouchered specimens. We had 82.5% efficiency by using both our reference library (n = 17) and GenBank (n = 24). We highlight the importance of implementing molecular barcoding for complementing biodiversity assessments in marine environments. This study represents a first step towards generating a comprehensive DNA barcode reference library for marine fishes in Peru.


[Synthesis of flavor esters catalyzed by CALB-displaying Pichia pastoris whole-cells in non-aqueous phase].
An enzyme-displaying yeast as a whole-cell biocatalyst seemed an alternative to immobilized enzyme, due to its low-cost preparation and simple recycle course. Here, we tried to use a recombinant Pichia pastoris displaying Candida antarctica lipase B (CALB) to catalyze the synthesis of short chain flavor esters in n-heptane. We studied some major influential factors of esterification reactions, such as carbon chain length of the substrates, alcohol structure, enzyme concentration, substrates concentration, molar ratio of the substrates. The acid conversions were determined by titration and gas chromatography analysis. About ten kinds of esters were synthesized successfully, and the acid conversions of eight esters reached as high as 90% after reaction for 6 h. The result also indicated that ethanol and hexanoic acid were the most suitable substrates for this whole-cell catalyst. Under the optimal reaction conditions (the amount of lipase 20 g/L (306.0 U/g-dry cell), hexanoic acid concentration 0.8 mol/L, the molar ratio of hexanoic acid to ethanol 1:1.1), hexanoic acid conversion reached 97.3% after reaction for 1.5 h. To our knowledge, the CALB-displaying P. pastoris whole-cell biocatalyst showed good tolerance for high substrates concentration and exhibited high reaction rate on esterification of short chain flavor esters among the present enzyme/cell reported. Thus, CALB-displaying P pastoris whole-cell biocatalyst was promising in commercial application for flavor esters synthesis in non-aqueous phase.


Enteral nutrition regimen for neonates with short bowel syndrome.
Short bowel syndrome is characterized as a state of malabsorption after massive resection of the small intestine. It has a wide spectrum of clinical presentations, from mild to severe depending predominantly on the length of intestine remnant. Management is challenging and requires vigorous attention to every detail. Enteral nutrition is the key to intestinal adaptation and reduction of dependency on parenteral nutrition. Therefore, creative ways are essential to maximize enteral nutrition despite obstacles to its use.


A new and rare form of Williams' syndrome.
A 7 year old girl and her mother have typical phenotypic features of the Williams' (elfin facies) syndrome, and both have only mild mitral regurgitation with mitral valve prolapse (MVP). Mitral valve prolapse has been reported in only three cases but pure mitral insufficiency has not been reported alone. In this paper two cases of a new rare form of Williams' syndrome with MVP are presented and this rare disorder is discussed.


Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size.
Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain. Here, we provide an overview of the different types of PMs, i.e., isolated PMs with or without malformations of cortical development and PMs associated with short stature (microcephalic dwarfism) or sensorineural disorders. We present an overview of the genetic, developmental, neurological, and cognitive aspects characterizing the most representative PMs. The analysis of phenotypic similarities and differences among patients has led scientists to elucidate the roles of these PM proteins in humans. Phenotypic similarities indicate possible redundant functions of a few of these proteins, such as ASPM and WDR62, which play roles only in determining brain size and structure. However, the protein pericentrin (PCNT) is equally required for determining brain and body size. Other PM proteins perform both functions, albeit to different degrees. Finally, by comparing phenotypes, we considered the interrelationships among these proteins.


Mid-term results of the BIOLOX delta ceramic-on-ceramic total hip arthroplasty.
We conducted a prospective study of a delta ceramic total hip arthroplasty (THA) to determine the rate of ceramic fracture, to characterise post-operative noise, and to evaluate the mid-term results and survivorship. Between March 2009 and March 2011, 274 patients (310 hips) underwent cementless THA using a delta ceramic femoral head and liner. At each follow-up, clinical and radiological outcomes were recorded. A Kaplan-Meier analysis was undertaken to estimate survival. Four patients (four hips) died and 18 patients (20 hips) were lost to follow-up within five years. The remaining 252 patients (286 hips) were followed for a mean of 66.5 months (60 to 84). There were 144 men (166 hips) and 108 women (120 hips) with a mean age of 49.7 years (16 to 83) at surgery. The mean pre-operative Harris Hip Score of 47.1 points improved to 93.8 points at final follow-up. Six patients reported squeaking in seven hips; however, none were audible. Radiolucent lines involving Gruen zones one and/or seven were seen in 52 hips (18.2%). No hip had detectable wear, focal osteolysis or signs of loosening. One hip was revised because of fracture of the ceramic liner, which occurred due to an undetected malseating of the ceramic liner at the time of surgery. One hip was revised for a periprosthetic fracture of the femur, and one hip was treated for periprosthetic joint infection. The six-year survivorship with re-operation for any reason as the endpoint was 99.0% (95% confidence interval 97.8% to 100%). The rate of delta ceramic fracture was 0.3% (one of 286). While ceramic head fracture was dominant in previous ceramic-on-ceramic THA, fracture of the delta ceramic liner due to malseating is a concern. Cite this article: Bone Joint J 2017;99-B:741-8.


ALTHEA Gold Libraries™: antibody libraries for therapeutic antibody discovery.
We describe here the design, construction and validation of ALTHEA Gold Libraries™. These single-chain variable fragment (scFv), semisynthetic libraries are built on synthetic human well-known IGHV and IGKV germline genes combined with natural human complementarity-determining region (CDR)-H3/JH (H3J) fragments. One IGHV gene provided a universal VH scaffold and was paired with two IGKV scaffolds to furnish different topographies for binding distinct epitopes. The scaffolds were diversified at positions identified as in contact with antigens in the known antigen-antibody complex structures. The diversification regime consisted of high-usage amino acids found at those positions in human antibody sequences. Functionality, stability and diversity of the libraries were improved throughout a three-step construction process. In a first step, fully synthetic primary libraries were generated by combining the diversified scaffolds with a set of synthetic neutral H3J germline gene fragments. The second step consisted of selecting the primary libraries for enhanced thermostability based on the natural capacity of Protein A to bind the universal VH scaffold. In the third and final step, the resultant stable synthetic antibody fragments were combined with natural H3J fragments obtained from peripheral blood mononuclear cells of a large pool of 200 donors. Validation of ALTHEA Gold Libraries™ with seven targets yielded specific antibodies in all the cases. Further characterization of the isolated antibodies indicated KD values as human IgG1 molecules in the single-digit and sub-nM range. The thermal stability (Tm) of all the antigen-binding fragments was 75°C-80°C, demonstrating that ALTHEA Gold Libraries™ are a valuable source of specific, high affinity and highly stable antibodies.


Targeted antibodies in the treatment of lymphomas.
Monoclonal antibodies coupled to drugs and toxic agents (immunotoxins) or radionuclides (radioimmunoconjugates) represent new tools for immunotherapy of haematological malignancies. Immunotoxins constructed with toxins of either plant or bacterial origin have shown a powerful antitumor activity both in vitro and in mice with severe combined immunodeficiency bearing various kinds of leukaemias and lymphomas. Preliminary clinical trials have shown an activity of these compounds at least in a proportion of patients. However, tumour responses have generally been partial and transient. The main problems with immunotoxin therapy remain the inability of immunotoxins to target tumour cells in the presence of a high burden of disease, the host immune response against both the antibody and the toxin moieties, which precludes repeated administration of immunotoxins, and the vascular leak syndrome. Targeting of tumour cells with specific antibodies armed with radionuclides (usually iodine-131 or yttrium-90) appears to be an even more attractive approach. Preliminary clinical studies have clearly demonstrated the ability of radioimmunoconjugates, especially when administered at high dose followed by bone marrow rescue, to induce durable complete remission in patients with non-Hodgkin's lymphomas refractory to conventional therapies. Radioimmunotherapy also overcomes the antigenic heterogeneity of the tumour cell population, since antigen negative tumour cells will be irradiated by the nearby targeted antigen-positive cells. Efforts should now be focused on defining more precisely the optimal clinical setting for administration of immunotoxin and radioimmunoconjugates (e.g. minimal residual disease), to reduce the immunogenicity of these compounds and solve the problem of vascular leak syndrome.


First isolation of eclipsed vic-disulfoxide: 7,8-dithiabicyclo[4.2.1]nona-2,4-diene 7-exo,8-exo-dioxide.
[reaction: see text] The oxidation of 7,8-dithiabicyclo[4.2.1]nona-2,4-diene 7-exo-oxide with dimethyldioxirane (DMD) provided the 7-exo-8-exo-dioxide, the structure of which was determined by X-ray crystallography [S-S 2.341(2) A and 90 degree angle O-S-S-O 4.1(3) degrees ]. The exo attack of DMD to give the exo,exo-dioxide was kinetically more favorable than the endo attack to give the endo,exo-dioxide. DFT calculations showed that the exo,exo-dioxide is thermodynamically more stable than the other stereoisomers.


True colour classification of natural waters with medium-spectral resolution satellites: SeaWiFS, MODIS, MERIS and OLCI.
The colours from natural waters differ markedly over the globe, depending on the water composition and illumination conditions. The space-borne "ocean colour" instruments are operational instruments designed to retrieve important water-quality indicators, based on the measurement of water leaving radiance in a limited number (5 to 10) of narrow (≈10 nm) bands. Surprisingly, the analysis of the satellite data has not yet paid attention to colour as an integral optical property that can also be retrieved from multispectral satellite data. In this paper we re-introduce colour as a valuable parameter that can be expressed mainly by the hue angle (α). Based on a set of 500 synthetic spectra covering a broad range of natural waters a simple algorithm is developed to derive the hue angle from SeaWiFS, MODIS, MERIS and OLCI data. The algorithm consists of a weighted linear sum of the remote sensing reflectance in all visual bands plus a correction term for the specific band-setting of each instrument. The algorithm is validated by a set of 603 hyperspectral measurements from inland-, coastal- and near-ocean waters. We conclude that the hue angle is a simple objective parameter of natural waters that can be retrieved uniformly for all space-borne ocean colour instruments.


Diabetes mellitus in pregnancy.
Physiologic changes that occur during pregnancy are diabetogenic. If diabetes does not exist before pregnancy, it may become evident, and if diabetes pre-exists, it becomes aggravated. The changing insulin requirements and propensity for ketoacidosis require weekly visits and careful urine testing on a daily basis by the mother. In addition, microvascular complications of diabetes must be carefully monitored. Delivery is planned progressively early in the pregnancy according to diabetic class. Hospitalization is necessary one week before anticipated delivery. Urinary estriol tests, OCT, amniocentesis, and ultrasound are all helpful in managing the pregnancy. Delivery of the fetus and placenta results in a profound fall in the insulin requirement. The neonate should be carefully observed during the first few days of life because of the increased frequency of complications.