A review of the bidirectional relationship between psychiatric disorders and diabetes mellitus.
The prevalence of type 2 diabetes is rising worldwide, including Saudi Arabia. Among patients with diabetes, 30% suffer from mental disorders, such as depression, schizophrenia, delirium, and substance misuse (for example, tobacco smoking). Moreover, these disorders appear to share a bidirectional relationship with diabetes. For example, the incidence of diabetes has been shown to be 2-4 times greater in patients with schizophrenia than in normal individuals; also, there is a known association between depression and diabetes. In this review, we focus specifically on the bidirectional relationship between diabetes and psychiatric disorders, including the effects of antipsychotic drugs.


Pilates and Cognitive Stimulation in Dual Task an Intervention Protocol to Improve Functional Abilities and Minimize the Rate of Age-Related Cognitive Decline in Postmenopausal Women.
It is already known the effectiveness of Pilates training on cognitive and functional abilities. It is also known that dual-task exercise and cognitive stimuli improve cognition and functional capacity. However, no previous report combined cognitive stimuli and Pilates in dual task and measured its effects on the cognitive and physical performances of postmenopausal women. To apply an interventional dual-task (PILATES-COG) protocol and to evaluate its influence on memory, language, and functional physical performances on healthy, community-dwelling postmenopausal older women. 47 women with amenorrhea for at least 12 months participated in this study. Those allocated on the PILATES-COG group underwent a 12-week, twice a week regimen of 50 min sessions of simultaneous mat Pilates exercise program and cognitive tasks. Cognitive and physical functional performance were assessed. Two-way mixed ANOVA was used for data analysis, and Bonferroni post hoc tests were used for within- and between-group comparisons. The PILATES-COG group showed significant improvement after the intervention in semantic verbal fluency (p < 0.001; ηρ² = 0.268), phonological verbal fluency (p < 0.019; ηρ² = 0.143), immediate memory (p < 0.001; ηρ² = 0.258), evocation memory (p < 0.001 ηρ² = 0.282), lower-limb muscle strength (p < 0.001; ηρ² = 0.447), balance (p < 0.001; ηρ² = 0.398), and dual-ask cost (p < 0.05; ηρ² = 0.111) assessments on healthy, community-dwelling postmenopausal older women. This is the first report of a feasible and effective approach using Pilates and cognitive stimulation in dual task for the reduction of age-related cognitive decline and the improvement of physical functional performance in healthy postmenopausal women.


Clinical Significance of Tumor Infiltrating Lymphocytes in Association with Hormone Receptor Expression Patterns in Epithelial Ovarian Cancer.
Hormone receptor expression patterns often correlate with infiltration of specific lymphocytes in tumors. Specifically, the presence of specific tumor-infiltrating lymphocytes (TILs) with particular hormone receptor expression is reportedly associated with breast cancer, however, this has not been revealed in epithelial ovarian cancer (EOC). Therefore, we investigated the association between hormone receptor expression and TILs in EOC. Here we found that ERα, AR, and GR expression increased in EOC, while PR was significantly reduced and ERβ expression showed a reduced trend compared to normal epithelium. Cluster analysis indicated poor disease-free survival (DFS) in AR+/GR+/PR+ subgroup (triple dominant group); while the Cox proportional-hazards model highlighted the triple dominant group as an independent prognostic factor for DFS. In addition, significant upregulation of FoxP3+ TILs, PD-1, and PD-L1 was observed in the triple dominant group compared to other groups. NanoString analyses further suggested that tumor necrosis factor (TNF) and/or NF-κB signaling pathways were activated with significant upregulation of RELA, MAP3K5, TNFAIP3, BCL2L1, RIPK1, TRAF2, PARP1, and AKT1 in the triple dominant EOC group. The triple dominant subgroup correlates with poor prognosis in EOC. Moreover, the TNF and/or NF-κB signaling pathways may be responsible for hormone-mediated inhibition of the immune microenvironment.


Dynamic polarizabilities of polyaromatic hydrocarbons using coupled-cluster linear response theory.
Coupled-cluster theory with single and double excitations is applied to the calculation of optical properties of large polyaromatic hydrocarbons. Dipole polarizabilities are reported for benzene, pyrene, and the oligoacenes sequence n=2-6. Dynamic polarizabilities were calculated on polyacences as large as pentacene for a single frequency and for benzene and pyrene at many frequencies. The basis set effect was studied for benzene using a variety of basis sets in the Pople [Theor. Chim. Acta 28, 213 (1973)] and Dunning [J. Chem. Phys. 90, 1007 (1989)] families up to aug-cc-pVQZ and the Sadlej pVTZ basis [Collect. Czech. Chem. Commun. 53, 1995 (1998)], which was used exclusively for the largest molecules. Geometries were optimized using HF, B3LYP, PBE0, and MP2 and compared to experiment to measure method dependence and the possible role of bond-length alternation. Finally, the polarizability results were compared to four common density functionals (B3LYP, BLYP, PBE0, PBE).


Fabrication and Characterization of Gelatin/Polyvinyl Alcohol Composite Scaffold.
In this study, porous scaffold materials based on polyvinyl alcohol (PVA) and gelatin (Gel) were successfully fabricated and characterized. The mechanism of the reaction, morphology, and crystallinity were investigated by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). In addition, thermogravimetric analysis (TGA) was performed together with differential scanning calorimetry (DSC) for examining the thermostability and phase transformation of the scaffolds. Degradation and swelling studies of PVA/Gel composite scaffold materials were performed in phosphate-buffered saline. Finally, the mechanical performances had been determined. According to the results, the polymer matrix that was formed by the combination of PVA and gelatin had better thermal stability. The synthesized composite scaffold was amorphous in nature. The addition of gelatin did not affect the fishbone-like microstructure of PVA, which ensures the excellent mechanical properties of the PVA scaffold. The denaturation temperature and elastic modulus of the PVA scaffold were improved by the gelatin addition, but the physical and chemical properties of the PVA scaffold were weakened when the gelatin content exceeded 10%. In addition, the PVA-10G sample has suitable degradability. Therefore, the PVA/Gel composite scaffold might potentially be applied in the field of tissue engineering that demands high strength.


Late effect of the cervical irradiation on periodontal status and cariogen flora in hodgkin lymphoma patients.
Cervical radiotherapy may leads to elevated caries risk in Hodgkin-lymphoma (HL) patients. Our aim was to estimate the late effect of cervical irradiation on periodontal status in HL patients. Patients filled out query-form, their clinical data were collected, periodontal status was examined, decayed-missing-filled-teeth and periodontal-indexes were calculated. We examined 68 patients who received, 64 patients who did not received cervical radiotherapy and 51 control person. 23.5% of cervical irradiated, 18.15% of not irradiated patients and 17.64% of controls had subjective xerostomia, but it was not objective by sialometry. Mean decayed-missing-filled-teeth-index was 22.53 among irradiated, 21.54 among not irradiated patients while it was 17.23 in control group. Periodontal index was 2.47, 2.42, and 2.14 in different groups. Difference between decayed-missing-filled-teeth indexes of irradiated patients and controls was significant. We have to emphasize the importance of prevention and closer dental observation of HL patients.


Application of gas-liquid chromatography to the routine identification of nonfermenting gram-negative bacteria in clinical specimens.
A total of 430 strains of glucose-nonfermenting gram-negative bacteria representing 35 species were analyzed for their cellular fatty acid composition by gas-liquid chromatography (GLC). On the basis of qualitative differences in their cellular fatty acid composition, these bacteria could be divided into 19 distinct chromatographic groups. Eight Pseudomonas species, Achromobacter xylosoxidans, group Vd, and Agrobacterium radiobacter were identified from their fatty acid compositions alone. The other glucose-nonfermenting gram-negative bacterial species studied here, classified within nine distinct GLC groups, were easily recognized by using the GLC fatty acid analysis supplemented with a limited number of conventional biochemical tests. The results support the hypothesis that bacterial fatty acid composition is rather specific and that qualitative GLC fatty acid analysis can be adapted in the clinical laboratory either to provide additional criteria for differentiation of closely related groups or to serve as a rapid and highly reproducible method for their routine identification.


Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a devastating illness of unclear etiology affecting motor neurons. It causes unremitting muscle paralysis, atrophy and death usually within 3 - 5 years from diagnosis. The human and economic costs for those affected are sobering. To date, tremendous efforts have failed to find a cure. An extensive literature search was undertaken using Medline and the Cochrane Systematic Review and Clinical Trial databases. Riluzole and investigational ALS drugs are discussed. Riluzole is the only approved disease-modifying therapy despite its modest effect on survival. Recent research has produced promising agents aimed at better disease control if not a cure. This review discusses agents targeting neuronal glutamate excitotoxicity, protein misfolding and accumulation, autophagy, apoptosis, mitochondrial dysfunction, free radical oxidative injury, immunomodulation, mutant mRNA counteraction, muscle physiology, neurotrophic factors and stem cell applications. The challenges in ALS drug development are highlighted. Riluzole should be used for patients with definite, probable, suspected or possible ALS by World Federation of Neurology diagnostic criteria. Systematic monitoring for hepatic dysfunction, neutropenia and other serious adverse effects should be done routinely as outlined. All ALS patients should consider genetic screening and enrollment in ALS trials guided by the data reviewed.


Obsessive compulsive neurosis: treatment of 28 cases by behaviour therapy.
Twenty-eight cases of obsessive compulsive neurosis were treated with a behaviour therapy package and good results were obtained in 15 (53.6%). Relaxation, thought-stopping, implosion, modelling, response prevention, electrical aversion and positive reinforcement wei; the techniques employed. Chronicity, previous treatments, follow-up data, drop-outs and the use of behaviour therapy in our setting are discussed in this paper.


[Sphincter-saving procedure of abdomino-peritoneal amputation? Surgical management of cancer of the lower two third of the rectum].
The authors report their results in surgical treatments of carcinoma localized in the low two thirds of the rectum done between 1980 and 1988. The number of patients was 150. Resectability: 119/150 = 79.33 per cent. Lethality: 4/119 = 3.3 per cent. Seventy three of the patients (61 per cent) had sphincter saving procedures and 46 of them (38.7 per cent) had abdominoperineal excision. Out of the 64 low anterior resection 2 patients (L: 2/64 = 3.1 per cent) and out of the 46 abdominoperineal excision also 2 patients (L: 2/46 = 4.5 per cent) were lost. In the sphincter saving group the distal clearance margin was decreased to below 3 cms at 29 patients without having local recurrence. in many cases of the carcinoma localized in the middle third of the rectum (at 82 per cent of our own patients) the sphincter can be saved without having more local recurrences. Decreasing the distal clearance margin to 2.5 cms does not increase the possibility of local recurrence if we do it cranially the same way as at Miles operation and remove the mesorectum caudally and laterally.


Review of Testim gel.
Hypogonadism is a medical condition characterised by testosterone deficiency in males, accompanied by numerous clinical symptoms, which can negatively affect quality of life and multiple organ systems. Late-onset hypogonadism describes testosterone deficiency or reduced effect seen in ageing men. The conditions are generally managed using testosterone supplementation. Many formulations of testosterone are available, including deep-muscle injections, buccal formulations, transdermal patches and topical gels. Testim gel 1% testosterone gel (Auxilium Pharmaceuticals, Inc. and Ipsen) has been shown to restore serum testosterone concentrations to within the normal range in men with hypogonadism. Two randomised, controlled studies showed that Testim gel significantly improved sexual motivation, desire, performance and function, as well as positive and negative mood scores and body composition after 90 days, compared with baseline. The magnitude of improvement seen with Testim gel was similar to that achieved with testosterone patches, but with fewer application-site reactions. In another study, improvements in mood and sexual function were seen within the first 2 weeks of treatment. Long-term, open-label extension studies of Testim gel suggest that clinical benefits are maintained for < or = 12 months without an additional increase in side effects. Notably, Testim gel treatment for 12 months was associated with a gradual increase in bone mineral density, suggesting that Testim gel may help to prevent osteoporosis. The most common adverse events associated with Testim gel were application-site reactions, increased haematological parameters, and moderately increased prostate-specific antigen levels that remained within the normal range in 96% of subjects. Men on any testosterone therapy will require careful monitoring, including serial digital rectal examination and prostate-specific antigen testing. Overall, the clinical evidence so far indicates that Testim gel is a safe and effective treatment option for daily use in the management of male hypogonadism.


Single agents with designed combination chemotherapy potential: synthesis and evaluation of substituted pyrimido[4,5-b]indoles as receptor tyrosine kinase and thymidylate synthase inhibitors and as antitumor agents.
Combinations of antiangiogenic agents (AAs) with cytotoxic agents have shown significant promise in cancer treatment, and several such clinical trials are currently underway. We have designed, synthesized, and evaluated two compounds that each inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor-beta (PDGFR-beta) for antiangiogenic effects and also inhibit human thymidylate synthase (hTS) for cytotoxic effects in single agents. The synthesis of these compounds involved the nucleophilic displacement of the common intermediate 5-chloro-9H-pyrimido[4,5-b]indole-2,4-diamine with appropriate benzenethiols. The inhibitory potency of both these single agents against VEGFR-2, PDGFR-beta, and hTS is better than or close to standards. In a COLO-205 xenograft mouse model, one of the analogs significantly decreased tumor growth (tumor growth inhibition (TGI) = 76% at 35 mg/kg), liver metastases, and tumor blood vessels compared with a standard drug and with control and thus demonstrated potent tumor growth inhibition, inhibition of metastasis, and antiangiogenic effects in vivo. These compounds afford combination chemotherapeutic potential in single agents.


The posterior tibial artery perforator flap: an alternative to free-flap closure in the comorbid patient.
Wounds of the distal third of the leg with exposed bone traditionally require free flaps for coverage. Although this often provides good results, patients with multiple comorbidities cannot undergo the long operating times and multiple surgical sites required for these complex procedures. We reviewed the use of posterior tibial (PT) perforator flaps as an alternative to free flaps for distal leg wound coverage in ill patients. Six patients (mean age, 53 years) with multiple comorbidities that precluded free-flap closures were treated with PT perforator flaps to cover complex distal leg wounds. The most common comorbidity was cardiac disease. Five patients had Gustilo grade IIIB open tibial fractures and one had a chronic wound. Mean flap size was 8x5.5 cm with a mean of one perforator per flap. Mean operating room time was 103 minutes. Four flaps were done without general anesthesia. There were no perioperative cardiopulmonary events. With a mean follow-up of 15 months, all flaps survived and all patients were ambulatory. There were no cases of malunion, nonunion, infection, wound breakdown, or partial flap loss. The PT perforator flap is a reliable choice for patients with open leg wounds and comorbidities precluding free-flap closure.


Ricin detection by biological signal amplification in a well-in-a-well device.
This paper presents a ricin detection method based on ricin's inhibitory effects on protein synthesis. Biological synthesis (expression) of a protein includes the steps of gene transcription (DNA --> RNA) and protein translation (RNA --> proteins); these reactions can be coupled into a one-step operation and carried out in a cell-free medium. Ricin is known to inhibit protein synthesis by interacting with 28S ribosome RNA; the inhibitory effect is exploited as the sensing mechanism in this work. For each copy of DNA, thousands of copies of proteins can be produced. As a result, the inhibitory effects of ricin are amplified, leading to a significantly enhanced detection signal (the difference between the positive control and samples). An array of protein expression units is developed to accommodate positive/negative controls and multiple samples. The array device contains a solution without any reagent captured on a solid surface, offering flexibility without comprising the activities of biomolecules. The miniaturized well-in-a-well design possesses a mechanism to supply nutrients continuously and remove byproducts, leading to higher protein expression yields and thus larger detection signals (lower detection limit) when ricin is present. We demonstrate the production of green fluorescent protein and luciferase in the device. A calibration curve has been obtained between the luciferase expression yield and the ricin concentration, showing a detection limit of 0.01 nM (0.3 ng/mL) ricin. The nested-well device is also used for measuring the toxicity level of ricin after physical or chemical treatment.


Liver morphology in southern African blacks with hepatocellular carcinoma: a study within the urban environment.
Hepatocellular carcinoma has a lower prevalence and presents at a later age in urban Blacks than in rural Blacks. These differences have previously been shown not to be attributable to differences in serum hepatitis B virus markers. In the present study, the average age of patients with hepatocellular carcinoma in a developing urban Black population is shown to have risen from 38.9 to 56.5 years (p less than 0.0001) over a 20-year interval, while the prevalence of co-existing cirrhosis has declined from 66 to 44% (p less than 0.05) and tissue HBsAg positivity has fallen from 44 to 17.7% (p = 0.002). The lower prevalence of tissue HBsAg in the recent patients may be explained by their older age. Macronodular cirrhosis was present in 56% of cases in the earlier period but declined to 18.9% in the later period, with micronodular cirrhosis becoming the dominant nontumor pathology (p = 0.002). Liver damage attributable to the abuse of alcohol is now found in more than half of the cases (48/90) of hepatocellular carcinoma occurring in this population. The remainder show no changes (12 cases) or show macronodular or incomplete septal cirrhosis (30 cases), presumed to be of viral origin. The latter cases are more likely to have serum markers of current hepatitis B virus infection than those with evidence of alcohol abuse. We conclude that alcohol is increasing in importance as an etiologic association of hepatocellular carcinoma in urban South African Blacks. At the same time, the prevalence of macronodular cirrhosis (and of cirrhosis as a whole) in urban patients with this tumor has declined. The reason for this decline is not known.


IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na+/HCO3- cotransporter 1 (pNBC1).
Inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs) are IP(3)-gated Ca(2+) channels that are located on intracellular Ca(2+) stores. We previously identified an IP(3)R binding protein, termed IP(3)R binding protein released with IP(3) (IRBIT). Because IRBIT is released from IP(3)R by physiological concentrations of IP(3), we hypothesized that IRBIT is a signaling molecule that is released from IP(3)R and regulates downstream target molecules in response to the production of IP(3). Therefore, in this study, we attempted to identify the target molecules of IRBIT, and we succeeded in identifying Na(+)/HCO(3)(-) cotransporter 1 (NBC1) as an IRBIT binding protein. Of the two major splicing variants of NBC1, pancreas-type NBC1 (pNBC1) and kidney-type NBC1 (kNBC1), IRBIT was found to bind specifically to pNBC1 and not to bind to kNBC1. IRBIT binds to the N-terminal pNBC1-specific domain, and its binding depends on the phosphorylation of multiple serine residues of IRBIT. Also, an electrophysiological analysis in Xenopus oocytes revealed that pNBC1 requires coexpression of IRBIT to manifest substantial activity comparable with that of kNBC1, which displays substantial activity independently of IRBIT. These results strongly suggest that pNBC1 is the target molecule of IRBIT and that IRBIT has an important role in pH regulation through pNBC1. Also, our findings raise the possibility that the regulation through IRBIT enables NBC1 variants to have different physiological roles.


Removing the cardiac field artifact from the EEG using neural network regression.
When EEG recordings are used to reveal interactions between central-nervous and cardiovascular processes, the cardiac field artifact (CFA) poses a major challenge. Because the electric field generated by cardiac activity is also captured by scalp electrodes, the CFA arises as a heavy contaminant whenever EEG data are analyzed time-locked to cardio-electric events. A typical example is measuring stimulus-evoked potentials elicited at different phases of the cardiac cycle. Here, we present a nonlinear regression method deploying neural networks that allows to remove the CFA from the EEG signal in such scenarios. We train neural network models to predict R-peak centered EEG episodes based on the ECG and additional CFA-related information. In a second step, these trained models are used to predict and consequently remove the CFA in EEG episodes containing visual stimulation occurring time-locked to the ECG. We show that removing these predictions from the signal effectively removes the CFA without affecting the intertrial phase coherence of stimulus-evoked activity. In addition, we provide the results of an extensive grid search suggesting a set of appropriate model hyperparameters. The proposed method offers a replicable way of removing the CFA on the single-trial level, without affecting stimulus-related variance occurring time-locked to cardiac events. Disentangling the cardiac field artifact (CFA) from the EEG signal is a major challenge when investigating the neurocognitive impact of cardioafferent traffic by means of the EEG. When stimuli are presented time-locked to the cardiac cycle, both sources of variance are systematically confounded. Here, we propose a regression-based approach deploying neural network models to remove the CFA from the EEG. This approach effectively removes the CFA on a single-trial level and is purely data-driven, providing replicable results.


Electrical stimulation for propelling endoscopes.
Methods are needed for propulsion of endoscopes and wireless video capsules along the small intestine. This work aims to test the hypothesis that electrical stimulation could propel an endoscope by stimulating muscular contraction. Prototype acrylic ovoid-shaped devices were constructed with 2 stainless steel electrodes mounted on the tapered section. Five devices 15 to 23 mm diameter with a taper of 28 degrees to 40 degrees (included angle) were tested. When these devices were in contact with the bowel wall, electrostimulation was applied causing circular muscle contraction, which when applied to the taper of the ovoid resulted in forward propulsion of the device. The method does not induce peristalsis but works by stimulating local contraction. The device was tested in the small intestine and esophagus of anesthetized pigs. Electrostimulation caused the ovoid to advance rapidly (6 mm/sec) up and down the esophagus by inducing circular esophageal muscle contraction. When stimulated at 15 Hz with 30-ms pulses, the threshold for movement in the small intestine was 12 mA; at 20 mA the device moved reliably in either direction in the small intestine at speeds of up to 4.5 mm/sec and negotiated tight curves. Electrostimulation can move endoscopes in the small intestine.


Investigating a sexual network of black men who have sex with men: implications for transmission and prevention of HIV infection in the United States.
HIV infections increased 48% among young Black men who have sex with men (MSM) in the United States between 2006 and 2009. Incomplete understanding of this trend undermines prevention strategy development. We investigated a sexual network to characterize the risk environment in which young Black MSM acquire HIV. Persons reported to the state after diagnosis of HIV or syphilis were included, along with sexual partners. We used network mapping alongside descriptive and bivariate statistics to characterize network connections. Generalized linear models assessed predictors of having untraceable sex partners. The network included 398 individuals and 419 sexual relationships. Three-quarters were Black (n = 299); 92% were MSM. Median age at first network appearance was 26 years and decreased over time (P < 0.001). HIV prevalence was at least 29% (n = 117); serostatus was unknown for 47% of the network, either because they were untraceable (n = 150) or refused HIV testing (n = 39). One in 5 network members diagnosed with HIV had a subsequent incident sexually transmitted infection. In multivariable models, one-time encounters increased the risk of having an untraceable partner (risk ratio = 4.51, 95% CI: 2.27 to 8.97), whereas being acutely HIV infected at diagnosis reduced it (risk ratio = 0.27, 95% CI: 0.08 to 0.89). HIV prevalence in this sexual network of young Black MSM rivals that of sub-Saharan Africa, reflecting dramatically increased risk of acquiring HIV from the moment one entered the network. Prevention efforts for this population must consider the effect of sexual networks on HIV risk and find ways of leveraging network structure to reduce transmission.


Antioxidant, antiapoptotic and amino acid balance regulating activities of 1,7-dihydroxy-3,4,8-trimethoxyxanthone against dimethylnitrosamine-induced liver fibrosis.
Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury which could be caused by viral, autoimmune, drugs, and so on. Unfortunately, there was no effective therapy available for liver fibrosis in clinic. In this study, we identified the anti-fibrotic effects of 1,7-dihydroxy-3,4,8-trimethoxyxanthone (ZYC-1) on the dimethylnitrosamine (DMN)-induced rat model. ZYC-1 was isolated from Swertia punicea Hemsl and was administrated to DMN-induced rat model. ZYC decreased the hyaluronic acid (HA), type IV collagen (CIV) and hydroxyproline (Hyp) levels and inhibited the expression of α smooth muscle actin (α-SMA) and transforming growth factor beta 1 (TGF-1β). The anti-fibrotic effect of ZYC-1 was also confirmed by Sirius Red staining. Finally, we identified 42 differentially expressed proteins by using proteomics analysis after ZYC-1 treatment, of which 17 were up-regulated and 25 were down-regulated. These Most of the 42 proteins are involved in the oxidative stress pathway, the mitochondrial-mediated apoptotic pathway and the amino acid metabolism pathway. Our study presented the first elucidated mechanisms of xanthone on liver fibrosis in vivo. This study pointed out that ZYC-1 may be used as a lead compound for hepatofibrosis treatment.


Real world experience on treatment, outcome and toxicity of crizotinib in patients with anaplastic lymphoma kinase positive advanced non-small cell lung cancer.
Crizotinib has been the standard treatment for patients with anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC). It demonstrated superior progression-free survival (PFS) and higher objective response rates (ORRs) vs. chemotherapy in previously treated and untreated patients with ALK-positive advanced NSCLC. This retrospective analysis reports real-world experience in treatment outcome and toxicity of crizotinib in this group of patients, with a focus on the cardiac toxicity and its management. Twenty-two patients diagnosed with ALK-positive NSCLC, either by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), treated at Johns Hopkins Singapore International Medical Centre (JHSIMC) and Tan Tock Seng Hospital (TTSH) in Singapore, were identified and followed for a median of 18 months. Data were collected and analyzed for baseline demographics, PFS, ORR, duration of response, toxicity and overall survival (OS). Clinical profile of patients included in the study was similar with clinical trials on crizotinib. Most patients were young of mean age 42, non-smokers and with good performance status. Fifty-nine percent had prior chemotherapy. Fifty percent of patients had brain metastases (BM), either de novo or on progression. ORR of crizotinib was 64% with median total duration of treatment of 8.5 months (range, 2-73+ months). Median PFS for patients treated with first-line crizotinib was 15 months. Most patients with BM had brain radiation. Median time for intracranial progression from the start of crizotinib was 11 months. Those with stable or responding extracranial disease continued crizotinib after radiotherapy to the brain. Median duration of response in this group of patients was 14 months (range, 2-31 months). Median OS among patients treated with upfront crizotinib was not reached, with 7 out of 11 patients still alive at the time of data analysis (n=11, range, 1-73+). Toxicity was manageable with moderate rate of grade 3 or worse toxicity (n=7, 31.8%). Three patients had grade 3-4 neutropenia. Eighteen percent (n=4) of patients developed cardiotoxicities such as bradycardia, prolonged QTc interval and complete heart block. One patient who developed complete heart block required pacemaker insertion. Two patients are long term responders who have been on crizotinib for 68+ and 73+ months. This retrospective analysis of a real-world experience confirms the therapeutic benefit of crizotinib in advanced ALK-positive NSCLC. Our data showed crizotinib is tolerable and effective, comparable with literature report. Occasional serious cardiac toxicity requires attention.


Correlation of blood-spot 17-hydroxyprogesterone daily profiles and urinary steroid profiles in congenital adrenal hyperplasia.
To compare the value of blood-spot 17-hydroxyprogesterone (17-OHP) daily profiles and urinary steroid excretion in untreated and treated patients with congenital adrenal hyperplasia (CAH). Ten patients with CAH were investigated during steroid replacement therapy (Group 1), and 11 patients were investigated without treatment (Group 2). Capillary blood samples were collected for measurement of blood-spot 17-OHP values by non-chromatographic radioimmunoassay. Steroid profiles of 24-h urine samples were analyzed by gas chromatography. There was a close correlation between the individual daily means of blood-spot 17-OHP measurements and the pregnanetriol/ tetrahydrocortisone ratio in both groups of patients (Group 2: r=0.839, p<0.001; Group 1: r=0.686, p<0.001). Almost the same correlation was found between the blood-spot 17-OHP value and the sum of three 17-hydroxyprogesterone metabolites/the sum of three cortisol/cortisone metabolites ratio (Group 2: r=0.918, p<0.001; Group 1: r=0.741, p<0.001). Blood-spot 17-OHP measurements and 24-h urinary steroid profile have the same impact in identification and monitoring therapy of children with CAH.


Laser ionization orthogonal time-of-flight mass spectrometry for simultaneous determination of nonmetallic elements in solids.
The simultaneous determination of nonmetallic elements in solid samples is difficult owing to their discrepant physical and chemical properties. We developed a high-irradiance laser ionization orthogonal time-of-flight mass spectrometry (LI-O-TOFMS) system and applied it for the determination of nonmetallic elements in solids. Helium was used as the buffer gas at 250 Pa in the source chamber; the laser irradiance was about 7 x 10(10) W/cm(2). A series of artificial standards containing B, C, N, O, F, Si, P, S, Cl, As, Br, Se, I, and Te were used. Explicit spectra were obtained with only a little interference from gas species and doubly charged matrix ions. Standardless semiquantitative analysis could be accomplished with a novel sampling methodology to obtain near-uniform sensitivity coefficients for different elements. Limits of detection (LOD) at microgram per gram level and a dynamic range of 6 orders of magnitude were achieved for most nonmetallic elements.


Benzophenone Rhamnosides and Chromones from Hypericum seniawinii Maxim.
Two new benzophenone glycosides, hypersens A and B, along with four known compounds, (S)-(+)-5,7-dihydroxy-2-(1-methylpropyl) chromone (3), 5,7-dihydroxy-2-isopropylchromone (4), urachromone B (5), and 3-8'' bisapigenin (6), were isolated from Hypericum seniawinii. The structures of new compounds (1 and 2) were elucidated according to comprehensive spectroscopic data analyses. The absolute configurations of 1 and 2 were determined by electronic circular dichroism (ECD) calculations. All isolated compounds were evaluated for their neuroprotective effect using corticosterone-induced PC12 cell injury. In addition, compounds 1-6 were evaluated for their anti-inflammatory activity in lipopolysaccharide-induced RAW 264.7 cells. Compound 6 was a biflavonoid and significantly inhibited the production of nitric oxide with an IC50 value of 11.48 ± 1.23 μM.


Characterization of Chimeric Antigen Receptor Modified T Cells Expressing scFv-IL-13Rα2 after Radiolabeling with 89Zirconium Oxine for PET Imaging.
Background Chimeric antigen receptor (CAR) T cell therapy is an exciting cell-based cancer immunotherapy. Unfortunately, CAR-T cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and neurotoxicity. The mechanism of these serious adverse events (SAEs) and how homing, distribution and retention of CAR-T cells contribute to toxicities is not fully understood. Methods To determine if radiolabelling of CAR-T cells could support positron emission tomography (PET)-based biodistribution studies, we labeled IL-13Rα2 targeting scFv-IL-13Rα2-CAR-T cells (CAR-T cells) with 89 Zirconium-oxine ( 89 Zr-oxine), and characterized and compared their product attributes with non-labeled CAR-T cells. The 89 Zr-oxine labeling conditions were optimized for incubation time, temperature, and use of serum for labeling. In addition, product attributes of radiolabeled CAR-T cells were studied to assess their overall quality including cell viability, proliferation, phenotype markers of T-cell activation and exhaustion, cytolytic activity and release of interferon-γ upon co-culture with IL-13Rα2 expressing glioma cells. Results We observed that radiolabeling of CAR-T cells with 89 Zr-oxine is quick, efficient, and radioactivity is retained in the cells for at least 8 days with minimal loss. Also, viability of radiolabeled CAR-T cells was similar to that of unlabeled cells as determined by TUNEL assay and caspase 3/7 enzyme activity assay. Moreover, there were no significant changes in T cell activation (CD24, CD44, CD69 and IFN-γ) or T cell exhaustion(PD-1, LAG-3 and TIM3) markers expression between radiolabeled and unlabeled CAR-T cells. In chemotaxis assays, migratory capability of radiolabeled CAR-T cells to IL-13Rα2Fc was similar to that of non-labeled cells. Conclusions Importantly, radiolabeling has minimal impact on biological product attributes including potency of CAR-T cells towards IL-13Rα2 positive tumor cells but not IL-13Rα2 negative cells as measured by cytolytic activity and release of IFN-γ. Thus, IL-13Rα2 targeting CAR-T cells radiolabeled with 89 Zr-oxine retain critical product attributes and suggest 89 Zr-oxine radiolabeling of CAR-T cells may facilitate biodistribution and tissue trafficking studies in vivo using PET.


Newly Identified AhR-Active Compounds in the Sediments of an Industrial Area Using Effect-Directed Analysis.
Effect-directed analysis was used to identify previously unidentified aryl hydrocarbon receptor (AhR) agonists in sediments collected from a highly industrialized area of Ulsan Bay, Korea. The specific objectives were to (i) investigate potent fractions of sediment extracts using the H4IIE-luc bioassay, (ii) determine the concentrations of known AhR agonists (polycyclic aromatic hydrocarbons (PAHs) and styrene oligomers (SOs)), (iii) identify previously unreported AhR agonists in fractions by use of GC-QTOFMS, and (iv) evaluate contributions of individual compounds to overall AhR-mediated potencies, found primarily in fractions containing aromatics with log Kow 5-8. Greater concentrations of PAHs and SOs were also found in those fractions. On the basis of GC-QTOFMS and GC-MSD analyses, 16 candidates for AhR agonists were identified in extracts of sediments. Of these, seven compounds, including 1-methylchrysene, benzo[j]fluoranthene, 3-methylchrysene, 5-methylbenz[a]anthracene, 11H-benzo[b]fluorene, benzo[b]naphtho[2,3-d]furan, and benzo[b]naphtho[2,1-d]thiophene, exhibited significant AhR activity. Relative potency values of newly identified AhR agonists were found to be greater than or comparable to that of benzo[a]pyrene (BaP). The potency balance analysis showed that newly identified AhR agonists explained 0.07-16% of bioassay-derived BaP-EQs. These chemicals were widely distributed in industrial sediments; thus, it is of immediate importance to conduct studies on sources and potential effects of those chemicals.


The use of serotonin reuptake inhibitors for the treatment of recurrent syncope due to carotid sinus hypersensitivity unresponsive to dual chamber cardiac pacing.
Carotid sinus hypersensitivity can be a cause of recurrent unexplained syncope in the older patient. Dual chamber cardiac pacing may relieve the bradycardia, but may not affect the vasodilatory component of this disorder. We report on two patients with carotid sinus hypersensitivity with a predominant vasodilatory component who experienced recurrent syncope following permanent pacemaker implantation. Both patients were treated with serotonin reuptake inhibitors and after 4-6 weeks of therapy had complete resolution of symptoms. We conclude that serotonin reuptake inhibitors may be useful in the treatment of recurrent syncope due to carotid sinus hypersensitivity resistant to dual chamber cardiac pacing.


Estimation of joint forces and moments for the in-run and take-off in ski jumping based on measurements with wearable inertial sensors.
This study uses inertial sensors to measure ski jumper kinematics and joint dynamics, which was until now only a part of simulation studies. For subsequent calculation of dynamics in the joints, a link-segment model was developed. The model relies on the recursive Newton-Euler inverse dynamics. This approach allowed the calculation of the ground reaction force at take-off. For the model validation, four ski jumpers from the National Nordic center performed a simulated jump in a laboratory environment on a force platform; in total, 20 jumps were recorded. The results fit well to the reference system, presenting small errors in the mean and standard deviation and small root-mean-square errors. The error is under 12% of the reference value. For field tests, six jumpers participated in the study; in total, 28 jumps were recorded. All of the measured forces and moments were within the range of prior simulated studies. The proposed system was able to indirectly provide the values of forces and moments in the joints of the ski-jumpers' body segments, as well as the ground reaction force during the in-run and take-off phases in comparison to the force platform installed on the table. Kinematics assessment and estimation of dynamics parameters can be applied to jumps from any ski jumping hill.


Psychological and financial impacts of COVID-19-related travel measures: An international cross-sectional study.
The impact of COVID-19 international travel restrictions has to date, not been fully explored, and with the ongoing threat that new variants could potentially restrict movement further, it is important to consider the impacts that travel restrictions have on community members. This study aimed to evaluate the psychological and financial impact of COVID-19 travel restrictions on those separated from their partners or immediate families, as well as temporary visa holders who were unable to migrate. Between 4 November 2021 to 1 December 2021, we executed a cross-sectional online survey targeting three specific groups; (1) those stranded from their partners; (2) those stranded from immediate families; and (3) temporary visa holders unable to migrate or cross international borders. We collected data on respondents' demographic profile; the nature of COVID-19-related travel impacts; depression, anxiety, and stress levels (using the validated DASS-21); and finally, data on respondents financial, employment and accommodation situation. 1363 respondents located globally completed the survey. 71.2% reported financial stress, 76.8% ([Formula: see text], SD = 5.94) reported moderate-to-extremely severe depression, 51.6% ([Formula: see text], SD = 5.49) moderate-to-extremely severe anxiety, and 62.6% ([Formula: see text], SD = 5.55) moderate-to-extremely severe stress levels. Statistically significant factors associated with moderate-to-extremely severe depression, anxiety, and stress included being female, chronic illness, and experiencing financial stress. Employment during COVID-19 -specifically essential services workers or unemployed-was associated with higher levels of anxiety and stress, with only essential workers being a predictor of higher stress severity. Factors that provided psychological protection included being older and having children. This study is one of the first to explore the impact COVID-19-related international travel restrictions have had on the financial status and psychological health of affected individuals. It highlights the significant human cost associated with the restrictions and identifies psychologically vulnerable populations. These results will help the design of targeted health and social policy responses.


High intensity focused ultrasound for the treatment of tumors.
High intensity focused ultrasound (HIFU) is a technique that was first investigated in the 1940s as a potential method of destroying selective regions within the brain to aid neurobehavioral studies. A beam of ultrasound can be brought to a tight focus at a distance from its source, and if sufficient energy is concentrated within the focus, the cells lying within this focal volume are killed, whereas those lying elsewhere are spared. This is, therefore, a noninvasive method of producing selective and "trackless" tissue destruction in deep-seated targets in the body without damage to overlying tissues. This technique is being investigated in a number of medical fields, including urology, ophthalmology, and oncology. The mechanism for cell killing is mainly thermal in origin. Renewal of interest in this technique is due to the availability of sophisticated medical imaging, which now allows the focal volume to be accurately targeted and also allows the tissue destruction to be monitored during treatment. The burgeoning field of HIFU focused ultrasound surgery (FUS) are reviewed in this article.


PET imaging of tenascin-C with a radiolabeled single-stranded DNA aptamer.
Tenascin-C is an extracellular matrix glycoprotein that is expressed by injured tissues and by various cancers. Recent publications showed that tenascin-C expression by cancer lesions predicts tumor growth, metastasis, and angiogenesis, suggesting tenascin-C as a potential therapeutic target. Currently there is no noninvasive method to determine tumoral tenascin-C expression in vivo. To address the need for an agent to image and quantify tenascin-C, we report the development of a radioactive PET tracer based on a tenascin-C-specific single-stranded DNA aptamer (tenascin-C aptamer). Tenascin-C aptamer was radiolabeled with (18)F and (64)Cu. PET imaging studies for the evaluation of tumor uptake and pharmacokinetics of tenascin-C aptamer were performed in comparison to a nonspecific scrambled aptamer (Sc aptamer). The labeled tenascin-C aptamer provided clear visualization of tenascin-C-positive but not tenascin-C-negative tumors. The uptake of tenascin-C aptamer was significantly higher than that of Sc aptamer in tenascin-C-positive tumors. The labeled tenascin-C aptamer had fast clearance from the blood and other nonspecific organs through the kidneys, resulting in high tumor contrast. Our data suggest that suitably labeled tenascin-C aptamer can be used as a PET tracer to image tumor expression of tenascin-C with a high tumor-to-background ratio and might provide insightful and personalized medical data that will help determine appropriate treatment and monitoring.


Delta Infection After Vaccination Elicits Potent Neutralizing Immunity Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant extensively escape neutralizing antibodies by vaccines or infection. We assessed serum neutralizing activity in sera from Delta infection after vaccination and Delta infection only against SARS-CoV-2 Wuhan-Hu-1 (WA1), Beta, Delta, and Omicron. Sera from Delta infection only could neutralize WA1 and Delta but almost completely lost capacity to neutralize Beta and Omicron. However, Delta infection after vaccination resulted in a significant increase of serum neutralizing activity against WA1, Beta, and Omicron. This study demonstrates that breakthrough infection of Delta substantially induced high potency humoral immune response against the Omicron variant and other emerged variants.


Incorporating individual historical controls and aggregate treatment effect estimates into a Bayesian survival trial: a simulation study.
Performing well-powered randomised controlled trials (RCTs) of new treatments for rare diseases is often infeasible. However, with the increasing availability of historical data, incorporating existing information into trials with small sample sizes is appealing in order to increase the power. Bayesian approaches enable one to incorporate historical data into a trial's analysis through a prior distribution. Motivated by a RCT intended to evaluate the impact on event-free survival of mifamurtide in patients with osteosarcoma, we performed a simulation study to evaluate the impact on trial operating characteristics of incorporating historical individual control data and aggregate treatment effect estimates. We used power priors derived from historical individual control data for baseline parameters of Weibull and piecewise exponential models, while we used a mixture prior to summarise aggregate information obtained on the relative treatment effect. The impact of prior-data conflicts, both with respect to the parameters and survival models, was evaluated for a set of pre-specified weights assigned to the historical information in the prior distributions. The operating characteristics varied according to the weights assigned to each source of historical information, the variance of the informative and vague component of the mixture prior and the level of commensurability between the historical and new data. When historical and new controls follow different survival distributions, we did not observe any advantage of choosing a piecewise exponential model compared to a Weibull model for the new trial analysis. However, we think that it remains appealing given the uncertainty that will often surround the shape of the survival distribution of the new data. In the setting of Sarcome-13 trial, and other similar studies in rare diseases, the gains in power and accuracy made possible by incorporating different types of historical information commensurate with the new trial data have to be balanced against the risk of biased estimates and a possible loss in power if data are not commensurate. The weights allocated to the historical data have to be carefully chosen based on this trade-off. Further simulation studies investigating methods for incorporating historical data are required to generalise the findings.


Circulating Tumor Cells: From Theory to Nanotechnology-Based Detection.
Cancer stem cells with stem-cell properties are regarded as tumor initiating cells. Sharing stem-cell properties, circulating tumor cells (CTCs) are responsible for the development of metastasis, which significant affects CTC analysis in clinical practice. Due to their extremely low occurrence in blood, however, it is challenging to enumerate and analyze CTCs. Nanotechnology is able to address the problems of insufficient capture efficiency and low purity of CTCs owing to the unique structural and functional properties of nanomaterials, showing strong promise for CTC isolation and detection. In this review, we discuss the role of stem-like CTCs in metastases, provide insight into recent progress in CTC isolation and detection approaches using various nanoplatforms, and highlight the role of nanotechnology in the advancement of CTC research.


Selenomethionine inhibits growth and suppresses cyclooxygenase-2 (COX-2) protein expression in human colon cancer cell lines.
Currently, selenium (in the form of high selenium containing yeast or selenomethionine) is being evaluated for anticancer effects against both human colon polyp recurrence and human prostate cancer, respectively. Chemical speciation analysis of the high selenium containing yeast indicates that selenomethionine (SeMet) is a major constituent of selenized yeast. We tested the hypothesis that SeMet might affect colon cancer cell growth by mechanisms involving cyclooxygenases (COX). The growth of all four-colon cancer cell lines tested was inhibited by selenomethionine. Furthermore, selenomethionine decreased COX-2 protein and PGE2 levels in HCA-7 cells. Selenomethionine suppressed COX-2 RNA levels in HCA-7 cells which could account for decreased COX-2 protein levels. Finally, the addition of PGE2 protected cells from the antiproliferative effects of selenomethionine in a concentration dependent manner. Selenomethionine might regulate COX-2 at the transcriptional level. These data suggests that Se-Met-induced cell growth inhibition may be, in part, mediated by COX-2 dependent mechanisms. The results of this study support the use of selenium agents in colon cancer chemoprevention trials.


Measurement of anal sphincter muscles: endoanal US, endoanal MR imaging, or phased-array MR imaging? A study with healthy volunteers.
To compare endoanal ultrasonography (US), endoanal magnetic resonance (MR) imaging, and phased-array MR imaging for anal sphincter muscle measurement. Sixty healthy volunteers underwent 1.5-T phased-array MR, endoanal MR, and endoanal US examinations. Sphincter muscle thicknesses were measured. Measurement reliability was analyzed, and correlations among the imaging methods were calculated. Multivariate analysis was performed to assess the influence of age, weight, height, sex, parity, and obstetric trauma on sphincter dimensions. Both MR methods had good reliability for measurements of all sphincter components, whereas endoanal US was reliable for internal sphincter measurement only. There was little correlation between the techniques, except between the two MR techniques, with a strong correlation for total sphincter and perineal body thickness. The internal sphincter thickened significantly (P =.002) with age at endoanal US and endoanal MR imaging but not at phased-array MR imaging. There were small sex-based differences in sphincter muscle measurements at phased-array MR imaging only. Endoanal US enables reliable measurement of only internal sphincter thickness, whereas both MR imaging methods enable reliable measurement of all sphincter components. Sphincter measurement with phased-array MR imaging is as reliable as that with endoanal MR imaging.


Meat and meat-related compounds and risk of prostate cancer in a large prospective cohort study in the United States.
The authors examined associations between meat consumption (type, cooking method, and related mutagens), heme iron, nitrite/nitrate, and prostate cancer in a cohort of 175,343 US men aged 50-71 years. During 9 years of follow-up (1995-2003), they ascertained 10,313 prostate cancer cases (1,102 advanced) and 419 fatal cases. Hazard ratios comparing the fifth intake quintile with the first revealed elevated risks associated with red and processed meat for total (red meat: hazard ratio (HR) = 1.12, 95% confidence interval (CI): 1.04, 1.21; processed meat: HR = 1.07, 95% CI: 1.00, 1.14) and advanced (red meat: HR = 1.31, 95% CI: 1.05, 1.65; processed meat: HR = 1.32, 95% CI: 1.08, 1.61) prostate cancer. Heme iron, barbecued/grilled meat, and benzo[a]pyrene were all positively associated with total (HR = 1.09 (95% CI: 1.02, 1.17), HR = 1.11 (95% CI: 1.03, 1.19), and HR = 1.09 (95% CI: 1.00, 1.18), respectively) and advanced (HR = 1.28 (95% CI: 1.03, 1.58), HR = 1.36 (95% CI: 1.10, 1.69), and HR = 1.28 (95% CI: 1.00, 1.65), respectively) disease. Nitrite (HR = 1.24, 95% CI: 1.02, 1.51) and nitrate (HR = 1.31, 95% CI: 1.07, 1.61) intakes were associated with advanced prostate cancer. There were no clear associations for fatal prostate cancer. Red and processed meat may be positively associated with prostate cancer via mechanisms involving heme iron, nitrite/nitrate, grilling/barbecuing, and benzo[a]pyrene.


Positively essential: traditional birth attendants in Malawi.
One of the biggest challenges for healthcare professionals working in developing countries is the lack of trained personnel to carry out much needed health care provision. Shirley Stronge worked as a nurse/midwife tutor in a rural area in the north of Malawi. Millennium Development Goals four and five have focused our attention on the care required by mothers and newborns. Shirley has chosen to reflect on the role of Traditional Birth Attendants in the north of Malawi and their positive impact on maternity services in this area.


Carbohydrate variant of the recombinant beta-subunit of human choriogonadotropin expressed in baculovirus expression system.
The beta-subunit of human choriogonadotropin (hCG) has two complex type N-linked and four O-linked carbohydrate chains. To further evaluate the specificity of the carbohydrate moiety on the hCG function, we have expressed hCG beta subunit in the baculovirus insect cell system to modify its carbohydrate structures. The recombinant hCG beta (rhCG beta) was efficiently secreted in the medium and was purified to homogeneity by immunoaffinity chromatography using a highly specific monoclonal antibody against hCG beta. The homogeneity of the recombinant subunit was established by sodium dodecyl sulfate-polyacrylamide gel electrophoresis performed under reducing and nonreducing conditions and reverse phase high performance liquid chromatography. rhCG beta had molecular weights of 22,500 and 33,000 under reducing and nonreducing conditions, respectively. Digestion with N-glycanase cleaved the Mr = 22,500 protein to 18,000, while digestion with Endo H or Endo F yielded an additional protein band of 20,500 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The carbohydrate analysis by pulse amperometry yielded the relative number of 2.5, 2.4, 3.7, and 11.3 residues of fucose, N-acetylgalactosamine, galactose, and mannose, respectively, based on a value of 4 residues for N-acetylglucosamine. Lectin binding studies showed rhCG beta to bind with concanavalin A with a high affinity and not with wheat germ agglutinin. In the studies with endoglycosidases together with the carbohydrate analysis and lectin binding properties, rhCG beta appears to have two high mannose-type N-linked and three to four O-linked carbohydrate simple disaccharide chains. The carbohydrate modification of the beta-subunit did not alter its immunopotency and its ability to combine with hCG alpha. The reconstituted hormone made up of rhCG beta and hCG alpha was found to be similar to hCG in biological properties such as receptor binding and in its ability to stimulate cAMP and steroidogenesis.


Developmental enhancers are marked independently of zygotic Nodal signals in Xenopus.
To determine the hierarchy of transcriptional regulation within the in vivo vertebrate embryo, we examined whether developmental enhancers were influenced by Nodal signaling during early embryogenesis in Xenopus tropicalis. We find that developmental enhancers, defined by the active enhancer chromatin marks H3K4me1 and H3K27ac, are established as early as blastula stage and that Smad2/3 only strongly associates with these regions at gastrula stages. Significantly, when we perturb Nodal signaling using the drug SB431542, most enhancers remain marked, including at genes known to be sensitive to Nodal signaling. Overall, as enhancers are in an active conformation prior to Nodal signaling and are established independently of Nodal signaling, we suggest that many developmental enhancers are marked maternally, prior to exposure to extrinsic signals.


[Standardization of larval development of the sea urchin, Paracentrotus lividus, as tool for the assessment sea water quality].
All stages of development of the sea urchin are of interest in ecotoxicology; the largest number of prior works concerns studies on gametes. Previous studies indicated that the use of sea urchin larvae was difficult because of the need to obtain the parent generations and good quality gametes. Progress in sea urchin culture has allowed one to standardize the method. The proposed technique is based on an evaluation of the number of non-developing fertilized eggs, on the frequency of malformations, and on the length of the larvae at 96 hours, using parents raised under well-controlled conditions. Temperature (18-22 degrees C), salinity (28-34 ppt) and pH (8-8.4) have been fixed to standardize the proposed biological test. Thirty micrograms per litre of copper reduce significantly the length of the larvae and could be used as a positive control. On the other hand, reconstituted sea water permits an optimal development of the larvae and may be used as negative control. A seasonal follow-up of water quality has been achieved to validate the use of this technique in a surveillance network of water quality. The method may be used whatever the salinity, including fresh and brackish waters.


Highly thymine-dependent formation of fluorescent copper nanoparticles templated by ss-DNA.
Double-stranded DNAs (ds-DNAs) have been identified as efficient templates favoring the formation of fluorescent copper nanoparticles (Cu NPs). Herein, we have tried to synthesize fluorescent Cu NPs using single-stranded DNAs (ss-DNAs) as templates and to identify the critical DNA sequences. By comparing the results using homopolymer DNAs, hairpin DNAs, and pristine ss-DNAs as templates, we found that DNA thymine base plays a dominant role in producing red-emissive fluorescent Cu NPs on ss-DNA templates. The thymine-dependent growth of the fluorescent Cu NPs is confirmed by Hg2+ mediated T–T base pair in comparison with the other non-specific metal ions, which could be developed into a practical sensor for turn-on fluorescence detection of Hg2+ with a high selectivity. The mechanism is briefly discussed according the DNA sequence-dependent formation of fluorescent Cu NPs. This work demonstrates the sequence role in producing fluorescent Cu NPs that could serve as promising fluorescent nanoprobes in biosensing and DNA-hosted Cu nanomaterials.


Plasma and liver lipid profiles in rats exposed to chronic hypobaric hypoxia: changes in metabolic pathways.
Lipid metabolism under chronic hypoxia (CH) has not received equal attention as intermittent hypoxia (IH). To determine the CH-induced changes in plasma and liver, as well as the mRNA and protein expression of two key enzymes in the triglyceride and cholesterol biosynthesis pathways, SREBP-1 (HMG-CoA reductase) and SREBP-2 (SCD-1), we exposed adult male Wistar rats to CH (4600 m; n=15) for 30 days compared to normoxic rats (n=15). The CH rats exhibited weight loss (p<0.001), higher hematocrit (%), and higher hemoglobin (g/dL) (p<0.01). In the plasma of CH rats, total cholesterol and LDL-cholesterol increased at day 15. VLDL-cholesterol and triglycerides (p<0.01) greatly increased (35%), while HDL-cholesterol decreased (p<0.01). Triglycerides and VLDL-cholesterol remained elevated by 28% at day 30 (p<0.01). Hepatic triglycerides increased two-fold, while total cholesterol increased by 51% (p<0.001; p<0.05). Upregulation of SCD-1 mRNA and protein was observed in the CH rats (p<0.01); however, no differences were observed in HMG-CoA reductase mRNA or protein expression in both groups. In conclusion, CH, like IH, alters lipid profiles by increasing triglycerides in the plasma and liver and upregulating triglyceride biosynthesis without affecting the cholesterol biosynthetic pathway. Additional involved mechanisms require further study because of the importance of lipids in cardiovascular risk.


Does the presence of a urinary catheter predict severe sepsis in a bacteraemic cohort?
Sepsis is a major cause of mortality with an estimated 37,000 deaths in the UK each year. This study aimed to determine host factors that can predict severe sepsis in a bacteraemic cohort. From December 2012 to November 2013, demographic, clinical and microbiological data were collected on consecutive patients with bacteraemia at a London teaching hospital. These data were used to categorize patients as having severe or non-severe sepsis. Multi-variate logistic regression was used to determine the association between host factors and severe sepsis. Five hundred and ninety-four bacteraemic episodes occurred in 500 patients. The majority of cases were in patients aged >50 years (382/594, 64.3%) and in males (346/594, 58.2%). The most common isolates were Escherichia coli (207/594, 34.8%) and meticillin-susceptible Staphylococcus aureus (57/594, 9.6%). In logistic regression multi-variable analysis, site of infection was significantly associated with severe sepsis. For catheter-associated urinary tract infections, the association was significant after adjustment for age, sex, Charlson comorbidity index and where infection was acquired (odds ratio 3.94, 95% confidence interval 1.70-9.11). Urinary catheters increase the risk of severe sepsis. They should only be used if clinically indicated. If inserted, a care bundle approach should be used and the anticipated removal date should be recorded unless a long-term catheter is required. In the context of sepsis, the presence of a urinary catheter should prompt immediate implementation of 'Sepsis Six' and consideration of transfer to a critical care unit.


LH-RH agonist, Zoladex (Goserelin), depot formulation in the treatment of prostatic cancer. Randomized dose-finding trial in Japan.
Ninety patients with advanced prostatic cancer (15 with stage B, 23 with stage C, and 52 with stage D) were randomized to receive 0.9, 1.8, or 3.6 mg, respectively, of Zoladex depot subcutaneous injection every 28 days for 12 weeks. The serum levels of LH, FSH, and testosterone were elevated after the first injection, and followed by a significant decrease. The suppression of testosterone levels in the blood to castrate levels was observed in all patients except two treated with 0.9 mg. Objective response (CR and PR) was seen in 63.6% (0.9 mg), 47.8% (1.8 mg), and 68% (3.6 mg) of patients according to the Japanese Prostatic Group Criteria. Subjective improvement (performance status, analgesic consumption) was also observed in 75-88% of patients but without a statistically significant difference between each dose group. Only minor adverse effects were found during the treatments. The drug was detected dose dependently in the blood by radioimmunoassay. These results suggest that endocrine therapy with Zoladex depot in doses of 3.6 mg subcutaneously every 4 weeks is a useful alternative to surgical castration in patients with prostatic cancer.


Communicate and Fuse: How Filamentous Fungi Establish and Maintain an Interconnected Mycelial Network.
Cell-to-cell communication and cell fusion are fundamental biological processes across the tree of life. Survival is often dependent upon being able to identify nearby individuals and respond appropriately. Communication between genetically different individuals allows for the identification of potential mating partners, symbionts, prey, or predators. In contrast, communication between genetically similar (or identical) individuals is important for mediating the development of multicellular organisms or for coordinating density-dependent behaviors (i.e., quorum sensing). This review describes the molecular and genetic mechanisms that mediate cell-to-cell communication and cell fusion between cells of Ascomycete filamentous fungi, with a focus on Neurospora crassa. Filamentous fungi exist as a multicellular, multinuclear network of hyphae, and communication-mediated cell fusion is an important aspect of colony development at each stage of the life cycle. Asexual spore germination occurs in a density-dependent manner. Germinated spores (germlings) avoid cells that are genetically different at specific loci, while chemotropically engaging with cells that share identity at these recognition loci. Germlings with genetic identity at recognition loci undergo cell fusion when in close proximity, a fitness attribute that contributes to more rapid colony establishment. Communication and cell fusion also occur between hyphae in a colony, which are important for reinforcing colony architecture and supporting the development of complex structures such as aerial hyphae and sexual reproductive structures. Over 70 genes have been identified in filamentous fungi (primarily N. crassa) that are involved in kind recognition, chemotropic interactions, and cell fusion. While the hypothetical signal(s) and receptor(s) remain to be described, a dynamic molecular signaling network that regulates cell-cell interactions has been revealed, including two conserved MAP-Kinase cascades, a conserved STRIPAK complex, transcription factors, a NOX complex involved in the generation of reactive oxygen species, cell-integrity sensors, actin, components of the secretory pathway, and several other proteins. Together these pathways facilitate the integration of extracellular signals, direct polarized growth, and initiate a transcriptional program that reinforces signaling and prepares cells for downstream processes, such as membrane merger, cell fusion and adaptation to heterokaryon formation.


Hepatocellular carcinoma that relapsed 54 months after living donor liver transplantation.
We report the case of a 41-year-old woman with hepatocellular carcinoma (HCC). She received living donor liver transplantation (LDLT) from her husband for HCC at 36 years of age. She had few risk factors for HCC recurrence, such as elevated alpha-fetoprotein (AFP), protein induced by vitamin K absence (PIVKA) II, vascular invasion, and number, size of tumors. However, recurrent tumors were found in the graft at 54 months after LDLT. Although we examined the sex chromosomes of the HCC by fluorescence in situ hybridization (FISH) methods, the origin of the HCC was unclear. This is a very rare case of recurrent HCC appearing more than 4 years after LDLT in the absence of risk factors for recurrence.


Functional health pattern assessment: a seasonal migrant farmworker community.
A broad-based needs assessment of a migrant farmworker community was conducted using the community functional health pattern tool (Gikow & Kucharski, 1987) and Porter's (1987) factor-isolating theory of population group diagnosis. Data analysis revealed numerous health needs in all 10 functional health patterns and an urgent need for accessible primary prevention programs. A mobile outreach program to the migrant camps was seen as the most effective way to provide education, screening, and health care.


The role of nuclear medicine in monitoring treatment in skeletal malignancy.
The nuclear medicine bone scan has historically been one of the most common investigations to stage and monitor skeletal malignancy. Current guidelines for using radiographs to assess the response of skeletal metastases to systemic therapy are limited in their ability to give a timely result. Despite some minor limitations caused by the flare phenomenon, skeletal scintigraphy remains widely used for this purpose, both clinically and in trials of new cancer treatments. Nuclear medicine has also played an important role in the posttherapy evaluation of primary bone tumors, both with bone agents and nonspecific tumor agents, such as 201Tl. In the future, it is possible that positron emission tomography radiopharmaceuticals such as 18F-fluorodeoxyglucose may prove to be superior in predicting and measuring treatment response in primary and metastatic bone and bone marrow disease, but further work is required in this area.


Photochemical production and consumption mechanisms of nitric oxide in seawater.
Nitric oxide (NO•) is an active odd-nitrogen species that plays a critical role in determining the levels of ozone (O₃) and other nitrogen species in the troposphere. Here, we provide experimental evidence for photochemical formation of NO• in seawater. Photoproduction rates and overall scavenging rate constants were measured by irradiation of surface seawater samples collected from the Seto Inland Sea, Japan. Photoproduction rates of NO• ranged from 8.7 × 10⁻¹² M s⁻¹ to 38.8 × 10⁻¹² M s⁻¹ and scavenging rate constants were 0.05-0.33 s⁻¹. The steady state concentrations of NO• in seawater, which were calculated from the photoproduction rates and scavenging rate constants were in the range 2.4-32 × 10⁻¹¹ M. Estimation from the scavenging rate constant showed that the NO• lifetime in seawater was a few seconds. Our results indicate that nitrite photolysis plays a crucial role in the formation of NO•, even though we cannot exclude minor contributions from other sources. Analysis of filtered and unfiltered seawater samples showed no significant difference in NO• photoformation rates, which suggests a negligible contribution of NO• produced by photobiological processes. Using an estimated value of the Henry's law constant (kH ≈ 0.0019 M atm⁻¹), a supersaturation of surface seawater of 2 to 3 orders of magnitude was estimated. On the basis of the average values of the surface seawater concentration and the atmospheric NO• concentration, a sea-to-air NO• flux was estimated.


Identification of transforming growth factor-beta-regulated microRNAs and the microRNA-targetomes in primary lung fibroblasts.
Lung fibroblasts are involved in extracellular matrix homeostasis, which is mainly regulated by transforming growth factor-beta (TGF-β), and are therefore crucial in lung tissue repair and remodeling. Abnormal repair and remodeling has been observed in lung diseases like COPD. As miRNA levels can be influenced by TGF-β, we hypothesized that TGF-β influences miRNA expression in lung fibroblasts, thereby affecting their function. We investigated TGF-β1-induced miRNA expression changes in 9 control primary parenchymal lung fibroblasts using miRNA arrays. TGF-β1-induced miRNA expression changes were validated and replicated in an independent set of lung fibroblasts composted of 10 controls and 15 COPD patients using qRT-PCR. Ago2-immunoprecipitation followed by mRNA expression profiling was used to identify the miRNA-targetomes of unstimulated and TGF-β1-stimulated primary lung fibroblasts (n = 2). The genes affected by TGF-β1-modulated miRNAs were identified by comparing the miRNA targetomes of unstimulated and TGF-β1-stimulated fibroblasts. Twenty-nine miRNAs were significantly differentially expressed after TGF-β1 stimulation (FDR<0.05). The TGF-β1-induced miR-455-3p and miR-21-3p expression changes were validated and replicated, with in addition, lower miR-455-3p levels in COPD (p<0.05). We identified 964 and 945 genes in the miRNA-targetomes of unstimulated and TGF-β1-stimulated lung fibroblasts, respectively. The TGF-β and Wnt pathways were significantly enriched among the Ago2-IP enriched and predicted targets of miR-455-3p and miR-21-3p. The miR-455-3p target genes HN1, NGF, STRADB, DLD and ANO3 and the miR-21-3p target genes HHEX, CHORDC1 and ZBTB49 were consistently more enriched after TGF-β1 stimulation. Two miRNAs, miR-455-3p and miR-21-3p, were induced by TGF-β1 in lung fibroblasts. The significant Ago2-IP enrichment of targets of these miRNAs related to the TGF-β and/or Wnt pathways (NGF, DLD, HHEX) in TGF-β1-stimulated fibroblasts suggest a role for these miRNAs in lung diseases by affecting lung fibroblast function.


Techno pearls for digital image management.
The past decade has provided a paradigm shift in image management. Technological advances have enabled affordable, high-quality digital clinical photography. In addition, this technology has enabled doctors to easily compose and present multimedia lectures with programs such as Microsoft PowerPoint. Since most practitioners already possess large numbers of conventional slides and photographs, digitization is required to convert these to a usable format. Depending on the type of image and resolution, it can take anywhere from 30 seconds to several minutes to scan each slide. This drawback delays or prevents many practitioners from switching to digital technology. Using a digital camera and the XP version of Windows, some common tasks associated with digital images and PowerPoint presentations may be simplified and facilitated. Using common digital cameras and computer image editing software, slides, photographs, radiographs, and textbook images may be digitized in seconds with adequate quality for most common clinical and educational applications. In addition, the use of new dual monitor functionality is discussed. This new technology comes standard with Windows XP and allows the use of two monitors simultaneously, allowing the user to view thumbnail images on one monitor and the PowerPoint presentation on the other monitor. Images may be dragged and dropped into the presentation, thereby avoiding repetitive menu commands. The author shows several techniques and shortcuts to assist the clinical practitioner in digitizing slides and facilitating the management of these images in PowerPoint presentations. A digital camera can be used to adequately digitize most slide pictures, and these images can be managed in a more simple and direct manner utilizing the Windows XP operating system that is shipping with most new computers.


Template-free hydrothermal synthesis of mesoporous MgO nanostructures and their applications in water treatment.
The controlled synthesis of Mg(OH)(2) nanowires and microflowers composed of nanoplates was successfully achieved by a template-free hydrothermal synthetic method. It was found that the reaction medium played a crucial role in the morphological control of the precursor nanostructures. The high polarity of water molecules favored the polar growth of the precursor, resulting in the formation of nanowires with a diameter of 80 nm, whereas a mixed water/ethanol medium with a lower degree of polarity led to the formation of microflowers. Moreover, mesoporous MgO nanostructures could be obtained by further annealing these as-prepared precursors in air at 500 °C for 2 h. During thermal treatment, the wire- and flower-like morphologies were retained. Porosity formation was due to thermal decomposition of Mg(OH)(2) and release of H(2)O. Both the mesoporous MgO nanowires and microflowers showed superior ability of adsorbing the organic dye methyl orange, and thus they are promising candidates for polluted water treatment.


Four central questions about prediction in language processing.
The notion that prediction is a fundamental principle of human information processing has been en vogue over recent years. The investigation of language processing may be particularly illuminating for testing this claim. Linguists traditionally have argued prediction plays only a minor role during language understanding because of the vast possibilities available to the language user as each word is encountered. In the present review I consider four central questions of anticipatory language processing: Why (i.e. what is the function of prediction in language processing)? What (i.e. what are the cues used to predict up-coming linguistic information and what type of representations are predicted)? How (what mechanisms are involved in predictive language processing and what is the role of possible mediating factors such as working memory)? When (i.e. do individuals always predict up-coming input during language processing)? I propose that prediction occurs via a set of diverse PACS (production-, association-, combinatorial-, and simulation-based prediction) mechanisms which are minimally required for a comprehensive account of predictive language processing. Models of anticipatory language processing must be revised to take multiple mechanisms, mediating factors, and situational context into account. Finally, I conjecture that the evidence considered here is consistent with the notion that prediction is an important aspect but not a fundamental principle of language processing. This article is part of a Special Issue entitled SI: Prediction and Attention.


Cytogenetic characterization of head and neck squamous cell carcinoma cell lines as model systems for the functional analyses of tumor-associated genes.
Head and neck squamous cell carcinoma (HNSCC) is a solid malignant neoplasm exhibiting aggressive phenotypes and high recurrence rates. To improve its clinical management, understanding the molecular basis of HNSCC development is of critical importance. For the investigation of tumor-associated genes, functional analyses in well-characterized tumor cell systems are required. To establish an experimental platform, a set of 20 HNSCC cell lines was screened for genetic imbalances by chromosomal comparative genomic hybridization (cCGH). Frequent DNA copy number gains were detected on 3q26.3-qter, 5p, 7p11-p13, 8q23-qter, 9p11-p13, 9q31-qter, 11q13 and 20q13.1, whereas copy number losses were found on 3p, 4p, 4q32.1-qter, 8p11-p12 and 18q22 in agreement with previous observations on genetic aberrations detected in primary HNSCC specimens. Subsequent mRNA expression analysis of 11q13 candidate genes CCND1 and CTTN revealed that HNSCC cell lines exhibiting a DNA copy number gain on 11q13 had a higher transcript level of CCND1 and CTTN compared with HNSCC cell lines without 11q13 copy number gain (P = 0.014 and P = 0.009, respectively). Furthermore, CCND1 and CTTN amplification as detected by fluorescence in situ hybridization correlated with protein expression as assessed by immunocytochemistry. In summary, the cytogenetic characterization illustrates that this set of HNSCC cell lines is representative for the HNSCC genome and provides tumor model systems for detailed analysis of genes with a possible role in the pathomechanism of head and neck tumors.


Component crystallization and physical collapse during freeze-drying of L-arginine-citric acid mixtures.
Component crystallization and physical collapse during freeze-drying of aqueous solutions containing protein-stabilizing L-arginine and citric acid mixtures were studied. Freeze-drying microscopy (FDM) and thermal analysis of the solute-mixture frozen solutions showed collapse onset at temperatures (T(c)) approximately 10°C higher than their T(g)'s (glass transition temperatures of the maximally freeze-concentrated solute phase). Experimental freeze-drying of these solutions at a low chamber pressure showed the occurrence of physical collapse at shelf temperatures close to or slightly higher than the T(c). Slower ice sublimation at higher chamber pressures induced the physical collapse from lower shelf temperatures. The large effect of chamber pressures on the collapse-inducing shelf temperatures confirmed significance of the sublimation-related heat loss on the sublimation interface temperature during the primary drying. Drying of the single-solute L-arginine solution resulted in cake-structure solids composed of its anhydrous crystal. Thermal and powder X-ray diffraction (PXRD) analysis suggested slow crystal nucleation of L-arginine dihydrate in the frozen solutions. Characterization of the frozen solutions and freeze-dried solids should enable rational formulation design and process control of amino acid-containing lyophilized pharmaceuticals.


Disseminated intravascular coagulation in a cohort of adult acute leukemia patients: a single center experience.
We aimed to detect the incidence of disseminated intravascular coagulation (DIC) in patients with acute leukemia (AL) and find out its association with types of AL and patients' clinical and pathological parameters. In this prospective study, 59 newly diagnosed adults with AL were clinically examined and screened for DIC presentation time. Coagulation tests, including prothrombin time, activated partial thromboplastin time, fibrinogen level, D-dimer, antithrombin, and protein C and protein S levels were all assessed. The International Society for Thrombosis and Hemostasis scoring system was adopted to diagnose overt DIC. The age of the studied patients ranged from 15 to 81 years with a median of 41 years; male to female ratio was 1.1:1. acute myeloid leukemia (AML) constituted 64.4% of the total cases (38 patients). DIC was detected in 28 patients (47.5%); its incidence was higher in AML than in acute lymphoblastic leukemia (ALL) (52.6% vs. 38.1%). Overt DIC was significantly associated with bleeding manifestations, duration of symptoms, and leukocytosis ( P -values = 0.050, 0.044, and 0.003, respectively). Bleeding events were encountered in 50.8% of patients (25 AML and 5 ALL patients). Bleeding was associated significantly with leukocytosis, thrombocytopenia, and low fibrinogen level. Thrombosis was found in two patients (3.4%) at presentation. Overt DIC was common in patients with AL at presentation, mostly in AML. Routine testing for coagulopathy in newly diagnosed AL patients will possibly aid in improving the overall patients' survival.


Birth and early life influences on the timing of puberty onset: results from the DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) Study.
Early age at puberty onset may predispose an individual to many currently prevalent diseases, including cancer and adiposity. The objective was to investigate whether early life exposures influence the timing of puberty, as defined by both early and late markers, in healthy German girls and boys. Term participants (n = 215; 49.8% female) of the DONALD (DOrtmund Nutritional and Anthropometric Longitudinally Designed) Study, with sufficient repeated anthropometric measurements between 6 and 13 y to allow estimation of age at take-off of the pubertal growth spurt (ATO) and information on a variety of early life exposures, including birth weight, breastfeeding status, velocity of weight gain, and parental characteristics, were studied. Age at peak height velocity (APHV) and menarche were also considered. Children who weighed between 2500 and <3000 g at birth were approximately 7 mo younger at ATO than were the other children (beta +/- SE: -0.56 +/- 0.20 y; P = 0.006). Children who had gained weight rapidly between birth and 24 mo (increase in weight SD score >0.67) experienced ATO 4 mo earlier than those who had gained weight normally (-0.34 +/- 0.15 y; P = 0.02). Rapid weight gain was also associated with an earlier APHV (P = 0.0006) and, in girls, with an earlier menarche (P = 0.002). Adjustment for body mass index SD score or body fat percentage 1, 2, or 3 y before ATO did not account for these effects. In both boys and girls, intrauterine and early postnatal growth factors appear to influence both early and later markers of puberty onset independently of prepubertal body composition.


Soft contact lens biomaterials from bioinspired phospholipid polymers.
Soft contact lens (SCL) biomaterials originated from the discovery of a poly(2-hydroxyethyl methacrylate) (poly[HEMA])-based hydrogel in 1960. Incorporation of hydrophilic polymers into poly(HEMA) hydrogels was performed in the 1970-1980s, which brought an increase in the equilibrium water content, leading to an enhancement of the oxygen permeability. Nowadays, the poly(HEMA)-based hydrogels have been applied in disposable SCL. At the same time, high oxygen-permeable silicone hydrogels were produced, which made it possible to continually wear SCL. Recently, numerous trials for improving the water wettability of silicone hydrogels have been performed. However, little attention has been paid to improving their anti-biofouling properties and biocompatibility. Since biomimetic phospholipid polymers possess excellent anti-biofouling properties and biocompatibility they have the potential to play a valuable role in the surface modification of the silicone hydrogel. The representative phospholipid polymers containing a 2-methacryloyloxyethyl phosphorylcholine (MPC) unit suppressed nonspecific protein adsorption, increased cell compatibility and contributed to blood compatible biomaterials. The MPC polymer coating on the silicone hydrogel improved its water wettability and biocompatibility, while maintaining high oxygen permeability compared with the original silicone hydrogel. Furthermore, the newly prepared phospholipid-type intermolecular crosslinker made it possible to synthesize a 100% phospholipid polymer hydrogel that can enhance the anti-biofouling properties and biocompatibility. In this review, the authors discuss how polymer hydrogels should be designed in order to obtain a biocompatible SCL and future perspectives.


The effect of hydroxy citric acid supplementation with calorie-restricted diet on metabolic, atherogenic and inflammatory biomarkers in women with non-alcoholic fatty liver disease: a randomized controlled clinical trial.
The objective of the present study was to examine the effects of hydroxy citric acid (HCA) extracts from Garcinia cambogia on metabolic, atherogenic and inflammatory biomarkers in obese women with non-alcoholic fatty liver disease (NAFLD). The present clinical trial was carried out on 40 overweight/obese women with NAFLD. The patients were randomly allocated into either the "HCA group" (receiving calorie-restricted diet (-700 kcal d-1) accompanied by HCA tablets) and the "control group" (receiving only calorie-restricted diet) for eight weeks. Weight, height, body mass index (BMI), and waist circumference (WC) were measured. Fasting blood sugar (FBS), lipid profile, liver enzymes, as well as inflammatory biomarkers were determined at baseline and after the intervention. Dietary intake was assessed at baseline and at the end of the trial and food intake data were analyzed by the Nutritionist IV software. Results showed a decrease in energy and macronutrient intake in both groups (p < 0.05). Weight, BMI, WC, and hip circumference as well as FBS, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) decreased and high-density lipoprotein cholesterol (HDL-C) increased significantly in the HCA group (p < 0.05). There were also significant reductions in WC, FBS, TG, total cholesterol, LDL-C in the control group while inter-group changes in FBS, TG, LDL-C and HDL-C were statistically significant. Although atherogenic indices reduced significantly in both groups, inter-group comparison revealed that the HCA group showed greater decrease in the TG/HDL-C ratio than the control group (p = 0.004). Other atherogenic indices including TC/HDL-C and non-HDL-C/HDL-C ratio showed greater reduction in the control versus HCA group (p < 0.01). Some inflammatory factors were reduced in the HCA group; however, no significant within- or between-group differences were revealed post-intervention. Our results indicated that HCA supplementation plus calorie-restricted diet could improve some metabolic factors without any significant effect on inflammation in patients with NAFLD.


[The current revision of Directive 86/609/EWG from the perspective of animal welfare legislation].
The necessity to revise Directive 86/609/EWG has been discussed since 1993, growing more urgent since the Protocol to the Treaty of Amsterdam (1997) and the Treaty establishing a Constitution for the European Union (2004), both of which recognise the welfare of animals as sentient beings; a revision also proves necessary because of various changes within the framework of animal experimentation. Within an expert questionnaire launched in the summer of 2006 several shortcomings of Directive 86/609/EWG are pointed out; proposals for revision mainly concern the scope of the directive, authorisation of animal experiments by national bodies, controls on institutional level, minimal requirements for housing and care of laboratory animals as well as for qualification of staff, and instruments for reducing duplication of animal experiments. The introduction of an obligatory ethical review as part of a standardised and project-related authorisation procedure, the up-grading of housing and care standards and the implementation of mechanisms for reducing duplication of animal experiments may enhance full exploitation of the 3R and are therefore crucially important for a directive complying with the requirements of the Treaty of Amsterdam.


Crossreactivity of human anti-dsDNA antibodies to phosphorylcholine: clues to their origin.
The presence of anti-double stranded DNA (dsDNA) antibodies is a serological diagnostic feature of systemic lupus erythematosus (SLE), an autoimmune rheumatic disorder. Studies by several investigators have suggested that a response to a microbial antigen can lead to the induction of SLE-like autoimmunity, in both humans and mice, since anti-dsDNA antibodies have been shown to crossreact with foreign antigens. In particular, anti-DNA antibodies have been shown to crossreact with phosphorylcholine (PC), a dominant epitope on pneumococcal cell wall polysaccharide. We have investigated the binding characteristics of human polyclonal anti-DNA antibodies from the sera of SLE patients. In this study we show that the DNA binding of polyclonal serum derived antibodies can be partially inhibited by phosphorylcholine (PC). The binding of affinity-purified anti-DNA antibodies from the sera of patients with SLE was also found to be inhibited by PC. We further demonstrated that the serum IgG1 (T dependent) anti-DNA response was more likely to crossreact with PC than the IgG2 (T independent) response to DNA. The studies suggest there may be a T dependent and T independent response to DNA with the T dependent response displaying more crossreactivity with microbial antigen.


Surface analysis of ProFile instruments by scanning electron microscopy and X-ray energy-dispersive spectroscopy: a preliminary study.
The purpose of this preliminary study was to analyze surface irregularities on ProFile nickel-titanium (NiTi) rotary instruments before use, after sterilization by two different methods and after instrumentation of molar root canals. Five new ProFile NiTi rotary instruments with 0.04 taper, size 20, five instruments with 0.04 taper, size 25 and five with 0.06 taper, size 20 were analyzed by scanning electron microscopy (SEM) and X-ray energy-dispersive spectroscopy (EDS). The instruments were then divided into two groups: three of each taper and size were sterilized in a dry heat sterilizer, whilst two of each taper and size were sterilized in an autoclave. After inspection by the same techniques, the files were used to instrument six molar root canals, and again analyzed by SEM/EDS. Together with the usual machining defects, a variable amount of material containing mainly carbon and sulphur was found on the surface of new instruments. This material was not removed by standard cleaning and sterilization procedures. The use of the files for instrumentation of root canals eliminated a considerable amount of the adhered substance, but deposits rich in calcium and phosphorus accumulated on the remaining impurities. The adherence of dentine on surface deposits found on new ProFile instruments requires special cleaning, prior to sterilization.


Preparation of Ultrasmall AIE Nanoparticles with Tunable Molecular Packing via Freeze Assembly.
Advances in the development of aggregation-induced emission luminogens (AIEgens) depend on understanding how the molecular packing affects their luminescent properties and on making nanoparticles (NPs) with desired sizes. Although reported strategies have advanced the field, rational control of molecular packing and efficient fabrication of AIEgen NPs sub-5.5 nm in diameter remain pressing issues. Here we report a "freeze assembly" strategy, in which the diameter of AIEgen NPs can be precisely tuned from ∼3 nm to hundreds of nanometers, and a molecular packing in kinetically trapped states that are not easily captured by conventional assembly methods can be obtained, leading to tunable fluorescence emissions. Therefore, this study provides a significant tool to fabricate organic luminescent nanomaterials with diameters smaller than 5 nm, which is of critical importance for biomedical applications; meanwhile, tuning molecular packing in nanoparticles displaying different fluorescence may help to shed new light on the mechanism of AIEgens.


Acute intermittent hypoxia activates myocardial cell survival signaling.
Intermittent hypoxia (IH) with repeated episodes of hypoxia-normoxia cycle has been shown to exert preconditioning-like cardioprotective effects. To understand the mechanism of these events, we investigated the changes in cardiac gene expression in response to acute IH. Mice were subjected to five cycles of 2 min of 10% O(2) plus 2 min of 21% O(2). RNA was isolated, and gene array analysis was performed. Results show that the expression of antiapoptotic genes, such as Bcl-2 and Bcl-x(L), were increased after acute IH. GATA-4 regulates transcription of these genes, and, consistently, GATA-4 activity was increased by acute IH. Although the phosphorylation of GATA-4 has been shown to regulate its activity, no changes in GATA-4 phosphorylation status by acute IH were noted. Gene transcription of gata4 was increased by acute IH, and this might be responsible for the enhanced GATA activity. To understand the mechanism of acute IH activation of gata4 gene transcription, we identified a promoter region of the mouse gata4 gene that is 1,000 bp immediately upstream from the transcriptional start site. In cardiac muscle cells, truncation of 1,000 to 250 bp did not alter the transcriptional activity, suggesting that the proximal 250-bp region contains important transcriptional regulatory sites. We further found that acute IH activates factors which bind to the proximal 100-bp region. Thus acute IH activates not yet identified factors that bind to the proximal 100-bp region of the gata4 promoter and, in turn, increases gata4 gene transcription, leading to enhanced expression of Bcl-2 and Bcl-x(L).


Goldenhar syndrome - a case report.
Goldenhar syndrome is a developmental abnormality of 1st & 2nd branchial arch involving the craniofacial microsomia with ocular & vertebral abnormality. Though most of the cases are sporadic, some familial association is also found in autosomal dominant or recessive manner. Teratogenic effect of some toxic substances may lead to the condition. Ocular abnormalities are epibulbar dermoid, lipodermoid & coloboma. Otic defects are preauricular tags, microtia, anotia & conductive hearing loss. Cardio-pulmonary & genitourinary abnormalities are common associations. Here we have described the case of a 10 years old girl had ocular, auricular & vertebral changes consistent with Goldenhar syndrome, she was managed with multidisciplinary approach and she was symptomatically improved but corrective surgery was planned as schedule of respective department.