Incorporation of fluorotryptophans into proteins of escherichia coli.
A tryptophan-requiring strain of Escherichia coli can go through two doublings of optical density after L-tryptophan is replaced in the medium by 4-fluorotryptophan, during which the fluoro analog displaces approximately 75% of the L-tryptophan in cell protein. One doubling occurs in the presence of 5- or 6-fluorotryptophan, with 50-60% replacement of L-tryptophan by analog. When beta-galactosidase is induced at the time of addition of analog, it reaches 60% of the control specific activity in the presence of 4-fluorotryptophan, 10% of normal in the presence of 5- or 6-fluorotryptophan. Lactose permease activity is 35% of the control in the presence of 4- and 6-fluorotryptophan, less than 10% in the presence of 5-fluorotryptophan. D-Lactate dehydrogenase shows a specific activity twice that of the control in the presence of 4-fluorotryptophan, one-half with 5- or 6-fluorotryptophan. Thus fluorotryptophan can be incorporated into proteins and affect their activities, although the nature and magnitude of the effect cannot be predicted for any given enzyme. Such substituted proteins should be useful for the study of protein structure and function by 19F nuclear magnetic resonance and other techniques.


Study of Salidroside and Its Inflammation Targeting Emulsion Gel for Wound Repair.
Salidroside has been widely used in anti-tumor, cardiovascular, and cerebrovascular protection. However, there are few reports of its use for wound repair. Herein, salidroside inflammation-targeted emulsion gel and non-targeted emulsion gel were developed for wound repair. The inflammation-targeted emulsion gels showed an overall trend of better transdermal penetration and lower potential than non-targeted emulsion gels (-58.7 mV and -1.6 mV, respectively). The apparent improvement of the trauma surface was significant in each administration group. There was a significant difference in the rate of wound healing of the rats between each administration group and the model group at days 7 and 14. Pathological tissue sections showed that inflammatory cells in the epidermis, dermis, and basal layer were significantly reduced, and the granulation tissue was proliferated in the inflammation-targeted emulsion gel group and the non-targeted emulsion gel group. Regarding the expressions of EGF and bFGF, the expressions of bFGF and EGF in the tissues of the inflammation-targeted group at days 7, 14, or 21 were significantly higher than that of the non-targeted emulsion gel group and the model group, both of which were statistically significant compared with the model group (p < 0.05). These results demonstrated that salidroside has the potential as an alternative drug for wound repair.


Quantitative computerized joint scanning in rheumatoid arthritis: an accurate reproducible method of quantitating synovitis--preliminary report.
Clinical trials in rheumatoid arthritis have been hampered by the highly subjective nature of disease assessment measures and lack of a consistently reliable laboratory test to follow. The authors devised a method of quantitating synovitis by computerized joint scanning and compared it with six conventional parameters in 18 patients entered into two treatment protocols and a control group. The results indicate that quantitative joint scanning probably is at least as reliable as the conventional measures and has the advantage of having no placebo or subjective component.


Identification of benzalkonium chloride in commercial grapefruit seed extracts.
Commercial grapefruit seed extracts (GSE) were extracted with chloroform. The solvent was evaporated, and the resulting solid was subsequently analyzed by high-performance liquid chromatography (HPLC), electrospray ionization mass spectrometry (ESI/MS), tandem mass spectrometry (ESI/MS/MS), and elemental analysis (by proton-induced X-ray emission analysis). Three major constituents were observed by HPLC and were identified as benzyldimethyldodecylammonium chloride, benzyldimethyltetradecylammonium chloride, and benzyldimethylhexadecylammonium chloride. This mixture of homologues is commonly known as benzalkonium chloride, a widely used synthetic antimicrobial ingredient used in cleaning and disinfection agents.


Interpretation of the HJ interval of the normal ballistocardiogram based on the principle of conservation of momentum and aortic ultrasonic Doppler velocity measurements during left ventricular ejection.
The principle of conservation of momentum and the observation that blood acceleration in the ascending aorta is approximately constant during ventricular ejection was applied to develop a new interpretation of the HI and IJ intervals of the normal ballistocardiogram. The results indicate that the acceleration (A), velocity (V), and displacement (D) of the ballistocardiogram in the HI and IJ phases may be expressed by a set of equations which, when evaluated numerically, give theoretical acceleration, velocity, and displacement curves. The theoretical A, V, and D curves corresponded closely to those observed on the normal ballistocardiogram record during the HJ interval.


Contralateral hyperactive caloric response in unilateral labyrinthine weakness.
In a series of 600 patients, 10 showed unilateral hyperactive caloric responses without a trivial explanation such as spontaneous nystagmus or directional preponderance. All 10 had unilateral weakness on the contralateral side, which was accompanied in 9 by cochlear hearing loss. It is assumed that the phenomenon of unilateral hyperreactivity in these cases can be explained by release from commissural inhibition on the basis of temporary vestibular decompensation.


Timing of Estradiol Treatment After Menopause May Determine Benefit or Harm to Insulin Action.
Type 2 diabetes (T2D) is reduced in postmenopausal women randomized to estrogen-based hormone therapy (HT) compared with placebo. Insulin sensitivity is a key determinant of T2D risk and overall cardiometabolic health, and studies indicate that estradiol (E2) directly impacts insulin action. We hypothesized that the timing of E2 administration after menopause is an important determinant of its effect on insulin action. We performed a randomized, crossover, placebo-controlled study. Study participants were early postmenopausal (EPM; ≤ 6 years of final menses; n = 22) and late postmenopausal (LPM; ≥ 10 years since last menses; n = 24) women naive to HT. Study interventions included short-term (1 week) transdermal E2 and placebo. The study's main outcome was insulin-mediated glucose disposal (glucose disposal rate [GDR]) via hyperinsulinemic-euglycemic clamp. Compared to EPM women, LPM women were older (mean ± SD; 63 ± 3 vs 56 ± 4 years, P < .05) and more years past menopause (12 ± 2 vs 3 ± 2 years, P < .05). Body mass index (24 ± 3 vs 25 ± 7 kg/m(2)) and fat mass (25 ± 7 vs 23 ± 6 kg) did not differ between groups, but fat-free mass (FFM) was lower in LPM women compared to EPM women (40 ± 4 vs 43 ± 5 kg, P < .05). Baseline GDR did not differ between groups (11.7 ± 2.8 vs 11.5 ± 2.9 mg/kg FFM/min). In support of our hypothesis, 1 week of E2 decreased GDR in LPM women compared to an increase in EPM women (+0.44 ± 1.7 vs - 0.76 ± 2.1 mg/kg FFM/min, P < .05). There was not an apparent decline in GDR with age or time since menopause per se. However, E2 action on GDR was dependent on time since menopause, such that there was an apparent benefit early (≤ 6 years) compared to harm later (≥ 10 years) in menopause. E2-mediated effects on insulin action may be one mechanism by which HT reduces the incidence of T2D in early postmenopausal women.


ANCA-Associated Vasculitis With Anti-GBM Disease and Two Types of Tumors: A Case Report.
Anti-neutrophil cytoplasm antibody (ANCA)-associated-vasculitis and anti-glomerular basement membrane (GBM) disease are types of autoimmune diseases that are characterized by the presence of circulating autoantibodies. Most patients with these diseases experience sudden onset, rapid progress, and poor prognosis. The purpose of the present article is to report a case of ANCA-associated vasculitis with anti-GBM disease and two types of tumors. A 63-year-old Chinese woman who underwent resection for rectal cancer 6 years before and for lung adenocarcinoma 4 years before, presented with fever and nasal obstruction, for the past 2 months and chondritis of an ear for the past 1 month. The patient failed to respond to an anti-infection treatment at local and higher-level hospitals with the first episode of "recurrent sinusitis and fever." Later, systemic symptoms such as fatigue, numbness of the limbs, and auricular chondritis gradually aggravated, followed by an increase in inconspicuous hematuria, proteinuria, and serum creatinine level. After admission, the GBM antibody, C-ANCA, and PR3 were positive. The renal puncture was diagnosed as anti-glomerular basement membrane antibody disease. After treatment, her serum creatinine decreased to 104 umol/l. In the present report, we introduced the case of a rare double-positive disease in a patient with two types of tumors. Importantly, we noted that colon cancer and lung cancer, PR3, and anti-GBM disease may be related to their pathogenesis and manifestations. Further research is warranted to confirm these hypotheses.


A Case of Peeling Skin Syndrome.
Peeling skin syndrome is a very rare autosomal recessive disease characterized by widespread painless peeling of the skin in superficial sheets. Etiology is still unknown with an autosomal recessive inheritance. Less than 100 cases have been reported in the medical literature. We present a 32-year-old man having asymptomatic peeling of skin since birth. Sheets of skin were peeling from his neck, trunk, and extremities, following friction or rubbing especially if pre-soaked in water but sparing palm and soles. Histologically, there was epidermal separation at the level of stratum corneum, just above the stratum granulosum. This case is being presented due to its rarity.


In vitro schedule-dependent interaction between irinotecan and vinorelbine in NCI H460 non-small cell lung cancer cell line.
Despite recent developments, treatment outcome in advanced non-small cell lung cancer (NSCLC) remains far from satisfactory. Vinorelbine and irinotecan have shown good single-agent activity against NSCLC. These two anticancer agents target different phases of the cell cycle: the cytotoxicity of camptothecin occurs mainly in the S-phase while the cytotoxicity of vinca alkaloids occurs mainly in the M-phase. Thus, it seemed interesting to study the combined activity of these two drugs against human NSCLC cell lines in vitro. In this study, the cytotoxic interaction between vinorelbine and SN 38 (the active metabolite of irinotecan), administered at various schedules, was assessed against a human NSCLC cell line, NCI H460. Cell growth inhibition was determined by the MTT assay. The effects of drug combinations were analysed by the isobologram method. The mean IC50 was 2.06 x 10(-6) mg/ml or vinorelbine, 2.72 x x 10(-3) mg/ml for irinotecan and 2.76 x 10(-6) for SN 38. On simultaneous exposure to these two drugs, additive effects were observed, while antagonistic effects were observed on sequential exposure to vinorelbine followed by SN 38. On sequential exposure to SN 38 first followed by vinorelbine, a slight antagonistic effect was observed at the isoeffect 50%; at the isoeffect 70%, additive effects were observed. These findings suggested that simultaneous exposure to vinorelbine and SN 38 may be the optimum schedule for this combination, while sequential administrations may be less cytotoxic and inadequate. Further preclinical and clinical studies are required to elucidate the relationship between vinorelbine and SN 38 with regard to both anti-tumor activity and toxicity.


Evaluation of an air quality model for the size and composition of source-oriented particle classes.
Air quality model predictions of the size and composition of atmospheric particle classes are evaluated by comparison with aerosol time-of-flight mass spectrometry (ATOFMS) measurements of single-particle size and composition at Long Beach and Riverside, CA, during September 1996. The air quality model tracks the physical diameter, chemical composition, and atmospheric concentration of thousands of representative particles from different emissions classes as they are transported from sources to receptors while undergoing atmospheric chemical reactions. In the model, each representative particle interacts with a common gas phase but otherwise evolves separately from all other particles. The model calculations yield an aerosol population, in which particles of a given size may exhibit different chemical compositions. ATOFMS data are adjusted according to the known particle detection efficiencies of the ATOFMS instruments, and model predictions are modified to simulate the chemical sensitivities and compositional detection limits of the ATOFMS instruments. This permits a direct, semiquantitative comparison between the air quality model predictions and the single-particle ATOFMS measurements to be made. The air quality model accurately predicts the fraction of atmospheric particles containing sodium, ammonium, nitrate, carbon, and mineral dust, across all particle sizes measured by ATOFMS at the Long Beach site, and in the coarse particle size range (Da > or = 1.8 microm) atthe Riverside site. Given thatthis model evaluation is very likely the most stringent test of any aerosol air quality model to date, the model predictions show impressive agreement with the single-particle ATOFMS measurements.


Targeted generation of 16 sequence-tagged sites for bovine chromosome region 5q21-q25 by microdissection.
The cattle chromosome region BTA5q21-q25 is associated with immune defense and is linked with several economically important traits for growth, ovulation, twinning and milk yield. Chromosome microdissection of the region was performed to generate fragment-specific DNA libraries and to provide new bovine-specific DNA sequences as starting material for physical fine-mapping approaches or linkage studies. A first library screening resulted in the identification of 16 region-specific sequence-tagged sites (STS). Fifteen STS represent new unique cattle DNA sequences, of which one identifies a new microsatellite. Homology with the gene CDK2 was found for the remaining STS.


Sensitivity of urethral flow-evoked voiding reflexes decline with age in the rat: insights into age-related underactive bladder.
The prevalence of underactive bladder (UAB) increases with age, suggesting a link between age-related processes and lower urinary tract (LUT) symptoms; however, the underlying mechanisms of age-related UAB are poorly understood. Understanding how aging affects LUT reflexes may help in the development of new treatments by identifying mechanistic targets. In this work, we studied the relationship between age and systems-level function of the LUT and tested the hypothesis that aging is related to weakening of reflexes that control voiding. Three groups of anesthetized female rats, young (4-7 mo old), mature (11-14 mo old), and old (18-24 mo old), were used to quantify the effect of aging on LUT reflexes. A double-lumen catheter enabled us to control the bladder volume and urethral flow rate independently, under quasi-isovolumetric bladder conditions. We systematically investigated the reflex bladder contractions evoked by combinations of rates of urethral infusion and bladder fill volumes as a function of age. Urethral infusion with the same flow rate evoked bladder contractions (via the augmenting reflex) in old animals less often than in younger animals. Furthermore, old animals needed more fluid in their bladders (relative to their bladder capacity) before urethra flow-evoked bladder contractions could be triggered at all, suggesting a delay in the switch of the LUT to "voiding mode." Old rats also showed longer and weaker bladder contractions than young or mature rats. Taken together, this suggests there is an age-related functional weakening and loss of sensitivity in LUT reflexes, which may contribute to age-related UAB symptoms.


Safety and efficacy of salvage surgery for non-small cell lung cancer: a retrospective study of 46 patients from four Keio-affiliated hospitals.
Advances in drug therapy and radiotherapy for non-small cell lung cancer resulted in an increased number of salvage surgeries for initially unresectable tumors. This study aimed to evaluate the safety and efficacy of salvage surgery for non-small cell lung cancer. We defined salvage surgery as (1) surgery for local recurrence/residual tumor after definitive chemoradiotherapy/radiotherapy (salvage surgery in a narrow sense) or (2) conversion surgery after non-surgical treatment. We retrospectively analyzed patients who underwent salvage surgery at four Keio University-affiliated hospitals. Forty-six patients were included. The initial clinical stage was I in 4 patients (9%), III in 19 (41%), and IV in 23 (48%). Initial treatment before salvage surgery was chemoradiotherapy in 10 patients (24%), radiotherapy in 4 (9%), and drug therapy in 32 (67%). Pneumonectomy, lobectomy, segmentectomy, and wedge resection were performed in 2 (4%), 37 (80%), 3 (7%), and 4 (9%) patients, respectively. Complete resection was achieved in 41 patients (89%). Postoperative complications occurred in 11 patients (24%). Initial chemoradiotherapy/radiotherapy was an independent predictor of postoperative complications (odds ratio 10, p = 0.03). The 30- and 90-day mortality rates were 0 and 2%, respectively. The 5-year overall and progression-free survival rates were 66 and 30%, respectively. The safety and efficacy of salvage surgery for non-small cell lung cancer were acceptable. Salvage surgery was a viable treatment option for selected patients with recurrent/residual tumors after non-surgical treatments.


Ogt Demonstrated Conspicuous Clinical Significance in Cancers, from Pan-Cancer to Small-Cell Lung Cancer.
The clinical progression of small-cell lung cancer (SCLC) remains pessimistic. The aim of the present study was to promote the understanding of the clinical significance and mechanism of O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) in SCLC. Wilcoxon tests, standardized mean difference (SMD), and Kruskal-Wallis tests were utilized to compare OGT level differences among the experimental and control groups. The univariate Cox regression analysis, Kaplan-Meier curves, and receiver operating characteristic curves were applied to determine OGT's clinical relevance in cancers. The Spearman correlation analysis and enrichment analysis were utilized to explore the underlying mechanisms of OGT in cancers. For the first time in the field, we provide an overview of OGT in 32 cancers using a large number of samples (n = 21,196), determining distinct OGT expression in 25 cancers and its prognosis effects in 12 cancers. Furthermore, using 950 samples from multiple sources, upregulated OGT was found in both mRNA and protein levels in SCLC (SMD = 0.93, 95% CI [0.24, 1.63]). Higher OGT levels represented a more unfavorable disease-free interval for SCLC patients (p < 0.001). The research also identified OGT expression as a potential marker for SCLC prediction (sensitivity = 0.79, specificity = 0.86, and AUC = 0.88). The high expression of OGT in SCLC may result from the positive regulation of two transcription factors-DEK and XRN2. We primarily investigated the underlying mechanisms of OGT in SCLC. Herein, based on the analyses from pan-cancer to SCLC, OGT demonstrated conspicuous clinical significance. OGT may be an underlying biomarker for the treatment and identification of some cancers, including SCLC.


Seed Selection by the Harvester Ant Pogonomyrmex rugosus (Hymenoptera: Formicidae) in Coastal Sage Scrub: Interactions With Invasive Plant Species.
Harvester ants can be the dominant seed predators on plants by collecting and eating seeds and are known to influence plant communities. Harvester ants are abundant in coastal sage scrub (CSS), and CSS is frequently invaded by several exotic plant species. This study used observations of foraging and cafeteria-style experiments to test for seed species selection by the harvester ant Pogonomyrmex rugosus Emery (Hymenoptera: Formicidae) in CSS. Analysis of foraging behavior showed that P. rugosus carried seeds of exotic Erodium cicutarium (L.) and exotic Brassica tournefortii (Gouan) on 85 and 15% of return trips to the nest (respectively), and only a very few ants carried the native seeds found within the study areas. When compared with the availability of seeds in the field, P. rugosus selected exotic E. cicutarium and avoided both native Encelia farinosa (Torrey & A. Gray) and exotic B. tournefortii. Foraging by P. rugosus had no major effect on the seed bank in the field. Cafeteria-style experiments confirmed that P. rugosus selected E. cicutarium over other available seeds. Native Eriogonum fasciculatum (Bentham) seeds were even less selected than E. farinosa and B. tournefortii.


[Rapamycin affect the apoptosis of splenic CD4+CD25+ regulatory T cells of mouse severe aplastic anemia model].
Objective: To explore the effects and possible mechanism of rapamycin (RAPA) on apoptosis of CD4+CD25+ Tregs from the mouse severe aplastic anemia (SAA) model. Methods: The BALB/c female SAA model mice were induced by interferon-gamma in combination with busulphan. The SAA model mice were intraperitoneal injection with RAPA at daily dose of 0.5 mg/kg for 5 days (the RAPA-treated group, n=15) in the SAA group (n=15) and the un-treated group (n=15) were control. Bone marrow hematopoiesis changes were observed by the patho-morphological examination of femurs. The mononuclear cells of the peripheral blood and spleen were subjected to assess the intracellular Foxp3 expression in CD4+CD25+ Tregs by flow cytometry (FCM). In addition, after being pured by immunomagnetic beads, the splenic CD4+CD25+ Tregs was subjected to assess apoptosis by FCM and the Akt and Stat3 phosphorylation by using of western blot. Results: The patho-morphological examination of femurs showed normal marrow cell proliferation in un-treated group and hypocellularity in both SAA group and RAPA-treat group, with an increase in the number of fat cells. The bone marrow hematopoietic tissue ratio in RAPA-treat group was higher than SAA group [(9.75±1.83)% vs (7.00±2.00)%, Δx=2.15% (95%CI 0.15%-5.35%), P=0.037]. In the SAA group, FCM analysis showed down-expression of Foxp3 in CD4+CD25+ Tregs compared with the un-treated group. However, after treatment with RAPA, the expression of Foxp3 in CD4+CD25+ Tregs was increased (P<0.017). Compared with the un-treated group, increased CD4+CD25+ Tregs apoptosis [(19.84±1.39)% vs (29.85±2.72)%] with increased Akt phosphorylation accompanied by increased Stat3 phosphorylation was found in SAA group (P<0.05, respectively). On the contrary, RAPA-treated group exhibited CD4+ CD25+ Tregs with a reduction in apoptosis rate [(22.39±3.71)%], Akt phosphorylation and Stat3 phosphorylation compared with the SAA group (P<0.05, respectively). Conclusion: These results indicate that RAPA may increase the expression of Foxp3 by down-regulation the levels of Akt and Stat3 phosphorylation and reduce apoptosis in splenic CD4+CD25+ Tregs from the mice model of SAA.


[Study on HPCE fingerprints of Poecilobdella manillensis from Guangxi province].
To establish fingerprints for Poecilobdella manillensis from Guangxi province using the high performance capillary electrophoresis (HPCE) method. Electrophoresis was performed on a fused silica capillary column (75 microm x 56 cm), with 25 mmol x L(-1) Na2HPO4-120 mmol x L(-1) Tris-16 mmol x L(-1) SDS (adjusted to pH 12.0 with 1 mol x L(-1) NaOH ) as the running buffer. The applied voltage was 17 kV, the temperature was 25 degrees C and the detection wavelength was 254 nm. The sample's hydrodynamic injection was 3.4 kPa x 6s and the duration was 27 min. HPCE fingerprint was established with 13 common peaks. The similarity between fingerprints of P. manillensis in 10 batches and control fingerprints was more than 0.98. The method is so precise, reproducible and stable that it could be used as a new means for the quality control of P. manillensis.


Effect of dietary fat on X-ray-induced mammary cancer in Sprague-Dawley rats.
We studied the effect of dietary fat levels on the induction of mammary cancer by 350 rads total-body X-radiation given to noninbred albino Sprague-Dawley rats at 50 days of age. Compared to rats on a low-fat (LF) diet (5% lard), rats on a high-fat (HF) diet (20% lard) from 30 days of age had more tumors, with a higher multiplicity of carcinomas per rat. LF-fed groups exhibited a longer median tumor latency period thatn did HF-fed groups. A similar trend toward more tumors with an earlier time of death was seen in rats given single iv doses of 50 mg 1-methyl-1-nitrosourea/kg and fed an HF diet as compared to an LF diet.


Evaluation of a novel median power spectrogram for seizure detection by non-neurophysiologists.
(1) To evaluate how well resident physicians use a novel EEG spectral analysis tool (the median power spectrogram; MPS) to detect seizures. (2) To assess the capability of the MPS to identify different seizure types. 120 EEG records from children with intractable seizures were converted to MPS by taking the median power across leads and using multi-taper spectral estimation. Twelve blinded neurology residents were trained to interpret the spectrogram with a five-minute video tutorial and post-test. Two residents independently assessed each set for presence of seizures. Their performance was compared to seizures identified using conventional EEG. Two blinded neurologists separately reviewed the EEGs and spectrograms to independently categorize the seizures. Their results were used to determine the spectrogram's capability to reveal seizures and visualize different seizure types for the user. Three key MPS features distinguished seizures from inter-ictal background: power difference relative to background, down-sloping resonance bands, and power in high frequencies. Using these features, residents identified seizures with 77% sensitivity and 72% specificity. 86% (51/59) of focal seizures and 81% (22/27) of generalized seizures were detected by at least one resident. Missed seizures included brief (<60s) seizures, tonic seizures, seizures with predominant delta (0-4Hz) activity, and seizures evident primarily in supplementary low temporal leads. The MPS is a novel qEEG modality that requires minimal training to interpret. It enables physicians without extensive neurophysiology training to identify seizures with sensitivity and specificity comparable to more complex multi-modal qEEG displays.


Cutaneous head and neck squamous cell carcinoma metastatic to cervical lymph nodes (nonparotid): a better outcome with surgery and adjuvant radiotherapy.
The aim of this study is to report on the experience of treating cutaneous squamous cell carcinoma (SCC) metastatic to cervical (nonparotid) lymph nodes at the Head and Neck Unit, Westmead Hospital, Sydney, Australia. Retrospective chart review. Patients diagnosed with previously untreated metastatic cutaneous SCC to cervical lymph nodes (levels I-V) and treated with radiotherapy, surgery, or surgery and adjuvant radiotherapy were identified. Relapse and outcome was analyzed using Cox regression analysis. Between 1980 and 2000, 74 patients were treated with curative intent. There were 59 males and 15 females, with a median age of 66 (range 37-93) years. Median duration of follow up was 48 (range 12-187) months. Fifty-two were treated with neck dissection and radiotherapy, 13 with neck dissection alone, and 9 with only radiotherapy. Most patients (85%) had an identifiable index lesion. Level I (38%) and II (36%) lymph nodes were the most often involved. In total, 25 (34%) patients developed recurrent disease, predominantly locoregional (22 of 25). Median time to recurrence was 5.2 (2-34.3) months. Increasing nodal size (> or =3 cm) (P =.01), metastatic spread to multiple nodes (P =.05), and the presence of extranodal spread (P =.01) all predicted for worse survival. Patients undergoing combined modality treatment had a lower relapse rate (15%) and a significantly better disease free survival (P =.001) compared with single modality treatment. Metastatic cutaneous SCC is uncommon but potentially lethal. Surgery and adjuvant radiotherapy remain the best practice and provide the best chance of achieving locoregional control.


CuTira brachytherapy: a new combination of radioactive copper isotopes and the hypoxic cytotoxin, tirapazamine, for targeted tumor therapy.
We previously showed a significant enhancement of tirapazamine-induced cytotoxicity and DNA damage after binding with copper. This result suggests that conjugates of tirapazamine with radioactive copper, i.e., 64Cu and 67Cu, may offer potential for targeted therapy of a wide range of advanced stage tumors including a possible treatment for patients with solitary hepatocellular carcinoma by intrahepatic arterial infusion. Major supporting considerations include: (a) tirapazamine having a high selective toxicity against hypoxic cells; (b) the nature of radioactive decay of these copper isotopes and obtainable high specific activity; and (c) simple procedure for the production of copper-tirapazamine complex.


Microbial transformation of ambrisentan to its glycosides by Cunninghamella elegans.
The purpose of this paper is to describe the glycosylation of ambrisentan (AMB) by cultures of Cunninghamella elegans ATCC 9245. AMB is an endothelin receptor antagonist, which is used to treat pulmonary arterial hypertension. Filamentous fungi are morphologically complex and may exhibit different forms depending on the species and the nature of the culture medium. A biotransformation study was conducted to investigate the ability of C. elegans to metabolize AMB. Parameters were optimized by testing on different culture media and concentrations, pH, drug concentration, static and shaking conditions. Ambrisentan's metabolite, obtained after 240 h of incubation as a result of glycosylation pathway, was separated by HPLC and determined by high-resolution mass spectrometry. The method showed linearity over 300-1000 μg mL-1 (r = 0.998). Accuracy, precision, robustness and stability studies agree with international guidelines. Results are consistent in accordance with the principles of green chemistry as the experimental conditions had a low environmental impact, and used little solvent.


Stability of aminoglycoside resistance in vitro in gentamicin-resistant Staphylococcus aureus.
Stability of aminoglycoside resistance has been investigated in 20 strains of Staphylococcus aureus resistant to gentamicin (16 strains were also resistant to methicillin). In view of previous reports that incubation at elevated temperatures can hasten the loss of unstable antibiotic resistance, we passaged strains daily in a liquid medium for 24 days at 43 degrees C. The nine strains which were resistant to neomycin kept their aminoglycoside resistance virtually intact, whereas most of the other 11 strains (sensitive to neomycin) lost almost all their resistance to gentamicin and kanamycin after 5 days. It thus appears that the stability of aminoglycoside resistances in Staph. aureus is closely linked to the resistance of the strains to neomycin. This finding has important possible consequences in terms of the advisability of the clinical usage of preparations containing neomycin or framycetin for topical application and bowel sterilization.


The sac shrinking process after EAR does not start immediately in most patients.
the aim of this study was to determine the pattern of shrinkage after endovascular aneurysm repair (EAR) using logarithmic, exponential and linear models and to calculate a lag time is present. patients with a complete CTA follow-up of 2 years and a primary shrinking aneurysm were included, resulting in a study group of 29 patients. Six functions, logarithmic, exponential and linear, all with and without lag time, were fitted to the thrombus volume obtained from measurements postoperative and after 6, 12 and 24 months. The correlation coefficient was used to determine the association between the calculated and measured values. A correlation coefficient >0.95 was considered a good fit. a logarithmic model produced the best fits. From the 29 patients, two patients could not be described by any model. The remaining 27 patients could be fitted using a logarithmic function with a correlation coefficient of >0.95 (median 0.99, range 0.95-1.00). Twenty-two of these patients had a lag time (median 63.4 days, range 5.8-252.3). Only five of the initial 44 patients (11%) showed immediate sac shrinkage. almost all shrinkage processes could be described by a logarithmic function. In over 75% of patients a lag time to shrinkage could be calculated. In only a small proportion did the shrinking process start immediately after EAR.


Evoked cavernous activity: measuring penile autonomic innervation following pelvic surgery.
To assess cavernous nerve integrity, we measured evoked cavernous activity (ECA) in 16 men who underwent nerve sparing radical prostatectomy (NS group) and 11 men who underwent non-nerve-sparing surgery (non-NS group). The right median nerve was electrically stimulated and ECA was recorded with two concentric electromyography needles placed into the right and left cavernous bodies. We simultaneously recorded hand and foot sympathetic skin responses (SSRs) as controls. All subjects had recordable SSR, and all subjects following nerve-sparing radical prostatectomy had reproducible ECA. Of the 11 non-NS subjects, eight had no response, indicating interrupted corporal innervation. Three subjects had reproducible ECA, one of whom had a very late latency, suggesting residual innervation was present. The mean latencies of ECA were similar to foot SSR mean latencies (P>0.05), but not to hand SSR latencies. The non-NS group was significantly different from the NS group for the presence of ECA (P<0.001). ECA is a viable method of evaluating the autonomic innervation of the penis.


Thermodynamics of lattice heteropolymers.
We calculate thermodynamic quantities of hydrophobic-polar (HP) lattice proteins by means of a multicanonical chain-growth algorithm that connects the new variants of the Pruned-Enriched Rosenbluth Method and flat histogram sampling of the entire energy space. Since our method directly simulates the density of states, we obtain results for thermodynamic quantities of the system for all temperatures. In particular, this algorithm enables us to accurately simulate the usually difficult accessible low-temperature region. Therefore, it becomes possible to perform detailed analyses of the low-temperature transition between ground states and compact globules.


Perceptions and Behaviors of Patients with Inflammatory Bowel Disease during the COVID-19 Crisis.
This study aimed to investigate the perceptions and behaviors of patients with inflammatory bowel disease (IBD) during the early coronavirus disease 2019 (COVID-19) pandemic in the major epidemic area in Korea. Between April and May 2020, a cross-sectional survey was performed at two tertiary hospitals in Daegu, South Korea, on patients' experiences, coping strategies and perceptions. Most of the 544 patients participating in the survey strictly adhered to personal protection guidance against COVID-19. In the early COVID-19 crisis, many patients canceled or postponed hospital visits (57.5%) and rescheduled biologics administrations (26.4%). Although 13.6% utilized telemedicine, the frequency of individuals leaving their homes remained unchanged. Although 50.4% were concerned about their susceptibility to COVID-19, 72.2% adhered to their treatment for IBD. In patients taking biologics or Janus kinase inhibitors, 86.8% disagreed that they should discontinue their medication as a preventative measure against COVID-19, but 21.9% actually discontinued their medications. Of those with discordance between the perception of IBD drug adherence and active behaviors, 5.4% of all and 39.4% of biologics or Janus kinase inhibitors withheld drugs specifically due to fear of COVID-19. Only 7% of all patients discussed drug safety with their physicians. The level of concern for COVID-19 depended on the type of drug used. Patients with IBD showed concerns about the increased risk of COVID-19 due to IBD or their medications, and a considerable number of patients withheld their medications without consulting medical staff. Enhanced active communications with patients with IBD and appropriate health-related education should be provided.


Increasing the use of an existing medical emergency team in a teaching hospital.
Cultural barriers in hospital ward staff may limit the use of a Medical Emergency Team (MET) service. In December 2000 the role of the existing Code Blue team in our hospital was expanded to incorporate review of patients fulfilling commonly employed MET criteria. Between January 2001 and June 2003, the average call rate was only 9.8 calls/ 1000 admissions. Anecdotal feedback and a group-administered questionnaire conducted in July 2003 demonstrated a number of obstacles to initiating calls and the system was modified in October 2004. Specifically, emergency response calls were separated into Code Blue calls (for cardiorespiratory arrests) and MET calls (with physiological and worried criteria). Further loud overhead chimes as well as anaesthetist and cardiologist attendance were used only in the case of Code Blue calls (suspected arrests). Finally, the heart rate and respiratory rate criteria for MET service activation were modified. In the 12 months before the intervention (October 2003 to September 2004) there were 817 emergency response calls and 51,963 admissions (15.7 calls/1000 admissions). In the 12 months after the intervention there were 1349 emergency response calls (Code Blue plus MET calls) and 54,593 admissions (24.7 calls/1000 admissions [OR 1.59; 95% CI=1.45-1.73; P<0.0001]). Our findings suggest that increasing the use of an existing service to review patients fulfilling MET criteria requires repeated education and a periodic assessment of site-specific obstacles to utilization.


Longitudinal association between poor parental supervision and risk-taking behavior: The role of self-control and school climate.
Although poor parental supervision has been associated with an increased adolescents' propensity for risk-taking behavior, few researchers have investigated nuanced mechanisms of how and for whom from the perspective of "family × school." Inspired by ecological system theory and self-control theory, this study aimed to investigate the mediating role of self-control and the moderating role of school climate between the link between poor parental supervision and risk-taking behavior. Four hundred and ninety-one Chinese adolescents (231 females, Mage = 15.39 ± 1.36) were recruited to participate in a three-wave longitudinal study (3 months apart) and complete questionnaires regarding poor parental supervision (W1), school climate (W1), self-control (W2), and risk-taking behavior (W1/W3). After controlling for W1 risk-taking behavior, our moderated mediation model indicated that W1 poor parental supervision was positively related to W3 risk-taking behavior by restraining the development of W2 self-control. Additionally, a high level of school climate as a protective factor buffered the negative impact of poor parental supervision on adolescents' self-control, further reducing risk-taking behavior. Our findings shed light on the processing mechanisms between poor parental supervision and risk-taking behavior among Chinese adolescents and underscore the importance of effective preventions and interventions to facilitate adolescents' healthy development.


St Gallen molecular subtypes in feline mammary carcinoma and paired metastases-disease progression and clinical implications from a 3-year follow-up study.
Considering that scarce data are available on disease progression of feline mammary carcinoma (FMC), this study aimed to analyze the clinical, pathological, and immunophenotypic features collected from 61 queens with FMC and to compare the concordance ratios of the expression levels of five molecular markers (ER, PR, fHER2, CK5/6, and Ki-67) between primary tumors (PT) and metastatic lesions. The results showed that cats with luminal A mammary carcinomas (MC) had higher overall survival (924.6 days, p = 0.001) and longer disease-free period (385.4 days, p = 0.005) compared to the ones with other MC subtypes. In fact, queens with triple negative/basal-like MC showed the lowest survival (mean 156.2 days) and the shortest disease-free survival (mean 28 days) among the molecular subtypes of MC. The lung was the organ most frequently affected by metastases, and animals with lung and/or pleural metastases were more likely to display metastases at three or more locations (p = 0.039). A large heterogeneity in protein expression levels was found between PT and paired metastases, with both estrogen and progesterone receptors more likely to be downregulated in metastases. Paired metastases frequently had higher Ki-67 index than PT, whereas fHER2 overexpression was seen in 46 samples (30 %) and CK5/6 expression was found in 50.7 % of metastases (36/71). Results also revealed that disease progression leads to a high percentage of triple negative/basal-like metastases (9/23; 39.1 %) associated with the absence of luminal A subtype in distant metastases (0/23). This study highlights the prognostic importance of immunophenotyping of MC in cats, although the modified protein expression identified in metastases contributes to justify why possible targeted therapies may fail in some animals with metastatic disease. Altogether, the results obtained also demonstrate that FMC can be used as a model to study human breast cancer.


Detection of Porcine Bocavirus From a Child With Acute Respiratory Tract Infection.
Porcine bocavirus is a recently discovered virus classified within the Bocavirus genus. We present a case of upper respiratory tract infection associated with porcine bocavirus in a 3-year-old child who was in close contact with hogs in northeastern Iran. To the best of our knowledge, this is the first report on the human porcine bocavirus infection.


A review of multiomics platforms in pituitary adenoma pathogenesis.
Pituitary adenomas (PA), or pituitary neuroendocrine tumors (PitNETs), represent 15% of all central nervous system tumors. Classic description of PitNETs solely by hormonal classification has given way to key transcription factors that play a role in the pathology of PitNETs including steroidogenic factor-1 (SF-1), t-box pituitary transcription factor (TPIT), and pituitary transcription factor 1 (PIT-1). Germline mutations in various familial PitNETs are discussed including those in familial isolated pituitary adenoma (FIPA), multiple endocrine neoplasia (MEN), neurofibromatosis 1 (NF1), and Carney complex. Recent advances in next generation sequencing have improved insight into the pathogenesis of PitNETs. A review of key studies in evaluating the genomic analysis of PitNETs was performed. Chromosomal mutations, whole exome sequencing, microRNA genomics, methylomics and transcriptomics were analyzed. Moreover, the multiomic analysis of various genomic panels has helped to better understand PA classification.


The effect of tetrodotoxin on the sodium gating current in the squid giant axon.
The effect of tetrodotoxin (TTX) on the sodium gating current in the squid giant axon was examined by recording the current that flowed at the pulse potential at which the ionic current fell to zero, first in the absence and then in the presence of TTX. The addition of 1 microM TTX to the bathing solution had no consistent effect on the size of the initial peak of the gating current, but resulted in small changes in the timecourse of its subsequent relaxation which were mainly caused by a reduction of about one quarter in the component that has a delayed onset and may possibly arise from changes in the state of ionization of groups in the channel wall when the lumen fills with water. Our findings suggest that the binding of TTX at the outer face of the sodium channel does not interfere with the mechanisms of activation and inactivation by the voltage sensors, but has an allosteric effect on the access of internal cations to the inside of the channel.


Limited proteolysis of tubulin and the localization of the binding site for colchicine.
Limited proteolysis of porcine brain tubulin with trypsin resulted in a gradual loss of its colchicine binding activity as well as its ability of assembly into microtubules. The analysis of the tryptic degradation products showed a preferential proteolysis of alpha-tubulin subunit. This enzymatic proteolysis cleaved tubulin in one major site producing fragments of 36,000 and 16,000 daltons, the smaller polypeptides containing the carboxyl-terminal residue as shown by 14C tyrosination . However, proteolysis after incubation with 1 X 10(-3) M colchicine resulted in formation of the indicated fragments plus a 41,000-dalton fragment and smaller size peptides indicating the drug induces a second cleavage site closer to the carboxyl-terminal alpha-tubulin. Preincubation of tubulin with [3H]colchicine followed by proteolysis and separation of the fragments by Sephadex G-75 chromatography showed radioactive colchicine associated with the 16,000-dalton fragment and to the smaller size peptides resulting from digestion in the presence of the drug. The data indicate a localization of the colchicine-binding site in the 16,000-dalton segment containing the COOH-terminal region of alpha-tubulin subunit.


Health related quality of life in elderly people living in Bandar Abbas, Iran: a population-based study.
Measuring health related quality of life of old people has become an important public health issue with the aging of population in developing countries. The aim of this study was to examine the health related quality of life of old people living in Bandar Abbas, Iran. This was a population-based study in which a random sample of 1000 individuals of the community aged over 60 years were interviewed using SF-36 questionnaire. Overall health related quality of life and relative differences between men and women and also between different age groups (60-75 years vs. >75 years) was assessed in this study. A total of 1000 elderly individuals completed the SF-36 questionnaire. Of all participants 499 (49.9%) were men, 501 (50.01%) women, 789 (78.9%) aged 60-75 years, and 211 (21.1) aged over 75 years. The logistic regression analysis showed the age over 75 years could increase the risk of lower score of physical [OR: 2.69, CI; (1.96-3.73] and mental [OR: 1.58, CI (1.16-2.15)] component summaries of SF-36 regardless other factors. Additionally, suffering from chronic diseases could decrease physical and mental scores of health related quality of life separately [OR: 8.6, CI; (4.37-16.94) and OR: 1.8, CI (1.1-2.99) respectively]. Women compared to men and illiterate old people compared to literate ones are more likely to perceive worse health related quality of life especially in physical component [OR: 1.35, CI; (1.01-1.81) and OR: 1.59, CI (1.12-2.24) respectively]. The findings of this study suggest that health related quality of life in old people is not only decreased by aging, but each of other factors such as female gender, illiteracy, and chronic diseases could decrease health related quality of life of old people.


Effect of hyperthermia on expression of histocompatibility antigens and heat-shock protein molecules on three human ocular melanoma cell lines.
Hyperthermia is used as a new treatment modality for ocular melanoma. We wondered whether this treatment would affect the antigenicity of melanoma cells and studied the effect of hyperthermia on the expression of histocompatibility antigens (HLA), beta 2-microglobulin, as well as heat-shock proteins (HSP-60 and HSP-70) on choroidal melanoma cells. Uveal melanoma cell lines were exposed to different temperatures (39-45 degrees C) in a waterbath. Antigen expression was determined with fluorescence-activated cell sorting analysis, using monoclonal antibodies against HLA and HSP. In a 51Cr-release cytotoxicity assay we studied the effect of heat on natural killer (NK) cell susceptibility. Exposure to 45 degrees C for 30 min reduced expression of HLA class I antigens and beta 2-microglobulin. A greater reduction was observed after longer exposure times. Expression of HSP-70 was increased after exposure to 45 degrees C at all time intervals, while expression of HSP-60 was not induced by heat treatment. We did not find a significant difference in the NK cell susceptibility between heated and unheated cells. Hyperthermia has a time- and temperature-dependent effect on expression of HLA class I and HSP-70 molecules on the cell surface of uveal melanoma cells. Hyperthermia did not alter the susceptibility to NK cell lysis.


Blood glucose self-monitoring with a long-term subconjunctival glucose sensor.
To evaluate the feasibility of an implantable subconjunctival glucose monitoring system (SGMS) for long-term glucose monitoring, we investigated the in vivo performance of the system. The SGMS consists of an implantable ocular mini implant (OMI) and a handheld fluorescence photometer. A clinical study was performed on 47 diabetes patients split into two cohorts. Two different types of OMI were used, with and without a biocompatible surface coating. Duration of the study was 1 year. Correlation between capillary blood glucose and SGMS-derived interstitial fluid glucose was investigated during the first 6 months of the study. Both OMI types were tolerated well in the eyes of the patients. At the beginning of the study, the SGMS of both cohorts revealed a high accuracy with mean absolute relative difference (MARD) values of 7-12%. The performance of the uncoated OMIs deteriorated within 3 months of wearing time, exhibiting a MARD value of 20%. The performance of the surface-coated OMIs was preserved longer. Glucose correlation measurement with reasonable results (MARD of 14%) could be performed for up to 6 months of wear. The biocompatible surface coating on the OMIs enabled a longer duration of action of up to 6 months compared with 3 months for uncoated implants in a clinical trial.


Metallothionein expression in normal, hyperplastic, and neoplastic thyroid follicular and parafollicular C cells using monoclonal antimetallothionein antibody E9.
Metallothioneins (MTs) are a set of ubiquitous low molecular proteins with a high affinity for metal ions, such as zinc, copper, and cadmium. MT overexpression can be induced by these metal ions as well as by other endogenous and exogenous factors. In this study, normal, hyperplastic, and neoplastic thyroid tissues of both follicular and C-cell origin were immuno-histochemically investigated with a monoclonal antibody against I- and II-isoforms of MTs. MT immunoreactivity was demonstrated in the follicular epithelium of 19 normal thyroid glands and in all 32 cases of Graves' disease investigated; 26 of 30 follicular adenomas and 25 of 28 follicular carcinomas showed MT immunoreactivity, whereas only 7 of 20 papillary carcinomas were MT-positive (p < 0.0001 ). In 3 of the 7 positive samples, positivity was restricted to follicular areas of differentation. No MT could be immunolocalized in normal and hyperplastic C cells and medullary thyroid carcinomas (n = 20). In mixed medullary-follicular carcinomas (n = 4), MT staining patterns resembled those seen for thyroglobulin. In anaplastic carcinomas, MTs were mainly immunolocalized in nonspindle cell areas. MT expression in thyroid tumors may reflect the different biological behavior of follicular and papillary carcinomas. Antibodies to MTs may also serve as fairly specific immunohistochemical markers of follicular cell differentiation in thyroid neoplasia.


Insulin and growth hormone responses to glucose infusion in mature and first-lactation dairy cows.
Five mature Holstein cows and 6 first-lactation Holstein cows were administered 100 mg of glucose/kg of body weight, IV, over a 20-minute period on postpartum day 30. A series (preinfusion, glucose infusion, and postinfusion) of blood samples was collected at -15, -10, -5, 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, and 120 minutes from the start of the infusion. Serum was obtained and was assayed for glucose, immunoreactive insulin (IRI), growth hormone (GH), and free fatty acid concentrations. Baseline glucose and free fatty acid concentrations were similar in cattle of both groups throughout the sample collection period. Both groups of cattle disposed of the infused glucose in a similar manner. The first-lactation cows secreted significantly (P less than 0.0001) more IRI to utilize the glucose load than did the mature cows, 71 +/- 13 microU/ml vs 38 +/- 7 microU/ml, respectively (mean +/- SEM). Preinfusion and glucose infusion GH concentrations were similar in cattle of both groups. In the postinfusion period, GH values were significantly (P less than 0.0002) higher in the first-lactation cows (8.7 +/- 1.8 ng/ml) than in the mature cows (5.8 +/- 1.6 ng/ml). Compared with that in the mature cows, the higher IRI concentration required by the first-lactation cows to utilize approximately the same glucose load suggested that first-lactation cows were insulin resistant. The increased insulin response to increased glucose concentration may be one reason first-lactation cows produce less milk than do mature cows. Other factors, such as variation in the ability of the mammary gland to synthesize milk cannot be excluded.


Impact loading of the lumbar spine during football blocking.
The purpose of our study was to determine the impact force to the lumbar spine when football players hit a blocking sled. We quantified the loads at the L4-5 motion segment throughout the blocking sequence. Five Division I-A college football linemen were subjects for our study. Kinematic data were obtained while the subjects hit a blocking sled instrumented with a force plate. Three plane forces were then calculated from these data. The average impact force measured at the blocking sled was 3013 +/- 598 N. The average peak compression force at the L4-5 motion segment was 8679 +/- 1965 N. The average peak anteroposterior shear force was 3304 +/- 1116 N, and the average peak lateral shear force was 1709 +/- 411 N. The magnitude of the loads on the L4-5 motion segment during football blocking exceed those determined during fatigue studies to cause pathologic changes in both the lumbar disk and the pars interarticularis. These data suggest that the mechanics of repetitive blocking may be responsible for the increased incidence of lumbar spine injury incurred by football linemen.


The Unique Molecular Choreography of Giant Pore Formation by the Cholesterol-Dependent Cytolysins of Gram-Positive Bacteria.
The mechanism by which the cholesterol-dependent cytolysins (CDCs) assemble their giant β-barrel pore in cholesterol-rich membranes has been the subject of intense study in the past two decades. A combination of structural, biophysical, and biochemical analyses has revealed deep insights into the series of complex and highly choreographed secondary and tertiary structural transitions that the CDCs undergo to assemble their β-barrel pore in eukaryotic membranes. Our knowledge of the molecular details of these dramatic structural changes in CDCs has transformed our understanding of how giant pore complexes are assembled and has been critical to our understanding of the mechanisms of other important classes of pore-forming toxins and proteins across the kingdoms of life. Finally, there are tantalizing hints that the CDC pore-forming mechanism is more sophisticated than previously imagined and that some CDCs are employed in pore-independent processes.


Parameterized level-set based pharmacokinetic fluorescence optical tomography using the regularized Gauss-Newton filter.
Pharmacokinetic tomography is emerging as an important methodology for detecting abnormalities in tissue based upon spatially varying estimation of the pharmacokinetic rates governing the leakage of an injected fluorophore between blood plasma and tissue. We present a shape-based reconstruction framework of a compartment-model based formulation of this dynamic fluorescent optical tomography problem to solve for the pharmacokinetic rates and concentrations of the fluorophore from time-varying log intensity measurements of the optical signal. The compartment-model based state variable model is set up in a radial basis function parameterized level set setting. The state (concentrations) and (pharmacokinetic) parameter estimation problem is solved with an iteratively regularized Gauss-Newton filter in a trust-region framework. Reconstructions obtained using this scheme for noisy data obtained from cancer mimicking numerical phantoms of near/sub-cm sizes show a good localization of the affected regions and reasonable estimates of the pharmacokinetic rates and concentration curves.


Supplementing transcranial direct current stimulation to local infiltration series for refractory neuropathic craniocephalic pain: A randomized controlled pilot trial.
Some patients with neuralgia of cranial nerves with otherwise therapy-refractory pain respond to invasive therapy with local anesthetics. Unfortunately, pain regularly relapses despite multimodal pain management. Transcranial direct current stimulation (tDCS) may prolong pain response due to neuro-modulatory effects. This controlled clinical pilot trial randomized patients to receive anodal, cathodal or sham-tDCS stimulation prior to local anesthetic infiltration. Pain attenuation, quality-of-life and side effects were assessed and compared with historic controls to estimate effects of tDCS stimulation setting. Altogether, 17 patients were randomized into three groups with different stimulation protocols. Relative reduction of pain intensity in per protocol treated patients were median 73%, 50% and 69% in anodal, cathodal and sham group, respectively (p = 0.726). Compared with a historic control group, a lower rate of responders with 50% reduction of pain intensity indicates probable placebo effects (OR 3.41 stimulation vs. non-stimulation setting, NNT 3.63). 76.9% (n = 10) of tDCS patients reported mild side-effects. Of all initially included 17 patients, 23.5% (n = 4) withdrew their study participation with highest proportion in the cathodal group (n = 3). A sample size calculation for a confirmatory trial revealed 120 patients using conservative estimations. This pilot trial does not support series of anodal tDCS as neuro-modulatory treatment to enhance pain alleviation of local anesthetic infiltration series. Notably, results may indicate placebo effects of tDCS settings. Feasibility of studies in this population was limited due to relevant drop-out rates. Anodal tDCS warrants further confirmation as neuro-modulatory pain treatment option.


Charophytes collapse beyond a critical warming and brownification threshold in shallow lake systems.
Charophytes play a critical role for the functioning of shallow lake ecosystems. Although growth of charophytes can be limited by many factors, such as temperature, nutrients and light availability, our understanding about concomitant effects of climate warming and other large-scale environmental perturbations, e.g. increases in humic matter content ('brownification') is still limited. Here we conducted an outdoor mesocosm experiment during 71days with a common charophyte species, Chara vulgaris, along an increasing gradient of temperature and brownification. We hypothesized the growth of C. vulgaris to increase with temperature, but to level off along the combined temperature and brownification gradient when reaching a critical threshold for light limitation via brownification. We show that C. vulgaris increases the relative growth rate (RGR), main and total shoot elongation, as well as number of lateral shoots when temperature and brownification increased by +2°C and+100%, respectively above today's levels. However, the RGR, shoot elongation and number of lateral shoots declined at further increment of temperature and brownification. Macrophyte weight-length ratio decreased with increased temperature and brownification, indicating that C. vulgaris allocate more resources or energy for shoot elongation instead of biomass increase at warmer temperatures and higher brownification. Our study shows that C. vulgaris will initially benefit from warming and brownification but will then decline as a future scenario of increased warming and brownification reaches a certain threshold level, in case of our experiment at +4°C and a 2-fold increase in brownification above today's levels.


Membrane Potential Is Required for MurJ Function.
MurJ, the flippase that exports the bacterial cell wall monomer Lipid II to the periplasm, is a target for new antibiotics, which are desperately needed to treat Gram-negative infections. Quantitative methods to monitor MurJ activity are required to characterize inhibitors but are challenging to develop because the lipid-linked substrate is not chemically altered in a flippase reaction. Here we show that MurJ inhibition can be quantified by measuring the accumulation of intracellular Lipid II using a biotin-tagging strategy. We have exploited this assay to show that MurJ is inhibited in the presence of a compound that dissipates the membrane potential. By probing cysteine accessibility we have found that under this condition MurJ relaxes into an inactive, outward-facing conformation reminiscent of that targeted by the peptide antibiotic LysM. We conclude that membrane potential is required for MurJ function in E. coli, and we anticipate that the ability to accumulate this inactive conformation will lead to structures useful for inhibitor design.


Morphology memory but reconstructing crystal structure: porous hexagonal GeO2 nanorods for rechargeable lithium-ion batteries.
Hexagonal GeO2, with high theoretical reversible capacity and low operating voltage, is regarded as a promising anode material for Li ion batteries. Being similar to other alloy type anode materials, the practical application of GeO2 is confronted with large volume change and fast capacity fading during lithiation/delithiation cycles. Constructing unique GeO2 nanostructures is proposed as an effective strategy to address this issue of fast capacity degradation. However, the controllable synthesis of GeO2 nanomaterials is challenged due to the fast hydrolysis of Ge precursors in aqueous solution. In this work, we report a simple strategy to synthesize GeO2 nanorods by using orthorhombic Ca2Ge7O16 nanorods as the sacrificial template with HNO3 as the etching agent. With the morphology memory of orthorhombic Ca2Ge7O16 nanorods, the as-prepared porous hexagonal GeO2 nanorods exhibit excellent electrochemical performance with a high capacity of 747 mA h g-1 after 50 cycles, which should be attributed to the porous and one dimensional nanostructure of GeO2 nanorods. This facile 'morphology memory but restructuring crystal structure' method could be extended to the controllable preparation of other GeO2 nanostructures, and achieve more efficient anode materials.


Explainable Multilayer Graph Neural Network for cancer gene prediction.
The identification of cancer genes is a critical yet challenging problem in cancer genomics research. Existing computational methods, including deep graph neural networks, fail to exploit the multilayered gene-gene interactions or provide limited explanations for their predictions. These methods are restricted to a single biological network, which cannot capture the full complexity of tumorigenesis. Models trained on different biological networks often yield different and even opposite cancer gene predictions, hindering their trustworthy adaptation. Here, we introduce an Explainable Multilayer Graph Neural Network (EMGNN) approach to identify cancer genes by leveraging multiple gene-gene interaction networks and pan-cancer multi-omics data. Unlike conventional graph learning on a single biological network, EMGNN uses a multilayered graph neural network to learn from multiple biological networks for accurate cancer gene prediction. Our method consistently outperforms all existing methods, with an average 7.15% improvement in area under the precision-recall curve over the current state-of-the-art method. Importantly, EMGNN integrated multiple graphs to prioritize newly predicted cancer genes with conflicting predictions from single biological networks. For each prediction, EMGNN provided valuable biological insights via both model-level feature importance explanations and molecular-level gene set enrichment analysis. Overall, EMGNN offers a powerful new paradigm of graph learning through modeling the multilayered topological gene relationships and provides a valuable tool for cancer genomics research. Our code is publicly available at https://github.com/zhanglab-aim/EMGNN.


Dipyridamole scintigraphy and intravascular ultrasound after successful coronary intervention.
Despite angiographically successful interventions, perfusion defects are not uncommonly observed in postinterventional perfusion scintigrams. The aim of this study was to test the hypothesis that perfusion defects after coronary intervention are associated with a significant residual stenosis in the treated vessel segment detectable by intravascular ultrasound but not by angiography. Forty consecutive patients with angiographically successful coronary interventions were prospectively studied by intravascular ultrasound immediately after the intervention. Within 48 hr after the intervention all patients had myocardial scintigraphy using 99mTc-methoxyisobutyl-isonitrile SPECT after dipyridamole stress. Myocardial perfusion defects in the scintigram were assigned to a segmental left ventricular model and compared to the perfusion territory of the treated vessel estimated from the coronary angiogram. Twenty of 40 patients had reversible myocardial perfusion defects. Mean ultrasound area stenosis was 50% in these patients and 33% in patients without perfusion defects (p < 0.002); ultrasound percent plaque area was 75% versus 63% (p < 0.0001), respectively. The best concordance between residual area stenosis and perfusion defects was found for an ultrasound area stenosis > or = 40%. Patients with stress-induced myocardial perfusion defects immediately after successful coronary intervention show high-grade residual stenoses that are more pronounced in patients with perfusion defects than in patients with normal postinterventional scintigrams. In addition, vessels serving myocardial regions with perfusion defects showed a significantly higher plaque burden indicating diffuse atherosclerotic changes in the vessel. The evaluation of the postprocedural result by intravascular ultrasound contributes to a better understanding of the discrepancy between the angiographic finding of a widely patent vessel but scintigraphic evidence of impaired perfusion.


NLX-112, a highly selective 5-HT1A receptor agonist, mediates analgesia and antidepressant-like activity in rats via spinal cord and prefrontal cortex 5-HT1A receptors, respectively.
NLX-112 (a.k.a. F13640 or befiradol) possesses marked activity in a variety of animal models of pain and of neuropsychiatric disorders; it exhibits nanomolar affinity, exceptional selectivity and high agonist efficacy at 5-hydroxytryptamine1A (5-HT1A) receptors. Although NLX-112 has been shown to activate 5-HT1A postsynaptic heteroreceptors in the prefrontal cortex (PFC), a brain region involved in the control of depressive states, the influence of NLX-112 on spinal cord 5-HT1A receptors (implicated in the control of pain) has not been described. Here we report on the ability, in rats, of NLX-112 to elicit analgesia in the intraplantar formalin model of nociceptive pain following intrathecal (i.t.) administration, and its ability to produce antidepressant-like activity in the forced swim test (FST) following in situ PFC microinjection. NLX-112, injected i.t. (L5-L6 region) induced analgesic effects in the formalin model of tonic nociceptive pain. At 20 µg, it almost abolished the effect of formalin on both the paw licking and paw elevation measures, and in both the early (0-5 min after formalin administration, reflecting acute pain) and the late (22.5-27.5 min, reflecting inflammatory pain) phases. The effects of NLX-112 (20 µg i.t.) were reversed by co-administration of 20 µg i.t. of the 5-HT1A receptor antagonist, WAY100635. Furthermore, the analgesic effects of systemically administered NLX-112 (0.63 mg/kg i.p.) were reversed by i.t. administration of WAY100635 (20 µg), most notably on paw licking. Finally, microinjection of NLX-112, bilaterally in the PFC, dose-dependently (MED 4 µg) and markedly reduced immobility in the FST (circa 90% reduction at 32 µg). In conclusion, the present data demonstrate that activation of spinal cord-located 5-HT1A receptors is sufficient for NLX-112 to mediate its analgesic effects in a rat model of tonic nociceptive pain. The data also highlight the involvement of PFC 5-HT1A receptors in the antidepressant-like activity of NLX-112 in the FST. Overall, the study suggests that highly selective and high efficacy 5-HT1A receptors agonists, such as NLX-112, could be useful to treat painful conditions associated with depressive states, through activation of different sub-populations of 5-HT1A receptors.


Efficient Monte Carlo algorithm for restricted maximum likelihood estimation of genetic parameters.
Monte Carlo (MC) methods have been found useful in estimation of variance parameters for large data and complex models with many variance components (VC), with respect to both computer memory and computing time. A disadvantage has been a fluctuation in round-to-round values of estimates that makes the estimation of convergence challenging. Furthermore, with Newton-type algorithms, the approximate Hessian matrix might have sufficient accuracy, but the inaccuracy in the gradient vector exaggerates the round-to-round fluctuation to intolerable. In this study, the reuse of the same random numbers within each MC sample was used to remove the MC fluctuation. Simulated data with six VC parameters were analysed by four different MC REML methods: expectation-maximization (EM), Newton-Raphson (NR), average information (AI) and Broyden's method (BM). In addition, field data with 96 VC parameters were analysed by MC EM REML. In all the analyses with reused samples, the MC fluctuations disappeared, but the final estimates by the MC REML methods differed from the analytically calculated values more than expected especially when the number of MC samples was small. The difference depended on the random numbers generated, and based on repeated MC AI REML analyses, the VC estimates were on average non-biased. The advantage of reusing MC samples is more apparent in the NR-type algorithms. Smooth convergence opens the possibility to use the fast converging Newton-type algorithms. However, a disadvantage from reusing MC samples is a possible "bias" in the estimates. To attain acceptable accuracy, sufficient number of MC samples need to be generated.


The immune system and hormones: review and relevance to pregnancy and contraception in women with MS.
Two-thirds of multiple sclerosis (MS) patients are women, and the average age of onset overlaps the childbearing years. Clinicians are frequently asked, therefore, about the most appropriate form of contraception and the risk of an MS relapse/exacerbation during pregnancy and the post-partum period. This paper reviews the literature on the immune system and the effects of pregnancy, oral contraceptives and hormone replacement therapy on MS.


Determining Ribosome Translational Status by Ribo-ELISA.
The Ribo-ELISA was originally developed to elucidate the basis for the ribopuromycylation method (RPM)-based detection of ribosome bound nascent chains. The Ribo-ELISA enables characterization of the translational status of ribosomes, and can be applied to the discovery of super-ribosomal complexes with novel ribosome associated macromolecules that are isolated by physical fractionation in sucrose gradients or other methods.


Perceived discrimination and psychological distress in Sweden.
There is lack of evidence on the health effects of perceived discrimination. We analysed the association between perceived discrimination and psychological distress, and whether socio-economic disadvantage explains this association in 15,406 men and 17,922 women in Sweden during 2004. After adjustment for age and long-term illness, frequent experiences of discrimination were associated with increased likelihood of psychological distress. Socio-economic disadvantage explained about 25% of this association.


Participation of the endocannabinoid system in the effect of TNF-alpha on hypothalamic release of gonadotropin-releasing hormone.
It is known that Delta(9)-tetrahydrocannabinol (THC), the major active ingredient of marijuana, can suppress reproductive function. Also, we reported previously that the endocannabinoid, anandamide (AEA), inhibited gonadotropin-releasing hormone (LHRH) release from medial basal hypothalamus (MBH) of male rats incubated in vitro as well as reduced plasma LH levels after i.c.v. AEA injections into the cerebral lateral ventricle. On the other hand, it is known that during endotoxemia the hypothalamic gonadotropin axis is inhibited. Therefore, the aim of the present study was to determine whether the effect of TNF-alpha, a proinflammatory cytokine induced by lipopolysaccharide (LPS) that inhibits LHRH release, is mediated by the activation of the endocannabinoid system. The intraperitoneal injection of LPS (5 mg/kg) as well as the i.c.v. injection of tumor necrosis factor-alpha (TNF-alpha) (100 ng/rat) increased significantly the AEA synthesis measured ex vivo in MBHs removed 3 h after the treatments. To examine the possibility that TNF-alpha also acted by increasing the synthesis of AEA that was released and activated the CB1-r followed by inhibition of LHRH release, we measured the effect of TNF-alpha on the AEA synthase activity in MBHs incubated in vitro. As expected, we found that TNF-alpha (2.9 x 10(-9) M) increased the AEA synthesis. Second, we showed that TNF-alpha reduced significantly the forskolin-stimulated LHRH release and that the CB1-r antagonist AM251 (10(-5) M) blocked that inhibition, supporting the hypothesis that TNF-alpha inhibits LHRH release, acting at least in part by activating the endocannabinoid system. Therefore, our data demonstrate a key role for the endocannabinoid system in the response of the reproductive system to inflammatory signals.


Epithelial neutral amino acid transporters: lessons from mouse models.
Epithelial neutral amino acid transporters have been identified at the molecular level in recent years. Mouse models have now established the crucial role of these transporters for systemic amino acid homeostasis. This review summarizes recent progress in this field. Epithelial neutral amino acid transporters play an important role in the homeostasis of neutral amino acid levels in the body. They are important for the maintenance of body weight and muscle mass and serve as fuels. They also serve a role in providing nutrients to epithelial cells. Changes of plasma amino acid levels are not necessarily correlated to the amino acids appearing in the urine; changes in organ amino acid metabolism need to be taken into account. Genetic deletion of neutral amino acid transporters provides insight into their role in protein nutrition and homeostasis.


Are titin properties reflected in single myofibrils?
Titin is a structural protein in muscle that spans the half sarcomere from Z-band to M-line. Although there are selected studies on titin's mechanical properties from tests on isolated molecules or titin fragments, little is known about its behavior within the structural confines of a sarcomere. Here, we tested the hypothesis that titin properties might be reflected well in single myofibrils. Single myofibrils from rabbit psoas were prepared for measurement of passive stretch-shortening cycles at lengths where passive titin forces occur. Three repeat stretch-shortening cycles with magnitudes between 1.0 and 3.0μm/sarcomere were performed at a speed of 0.1μm/s·sarcomere and repeated after a ten minute rest at zero force. These tests were performed in a relaxation solution (passive) and an activation solution (active) where cross-bridge attachment was inhibited with 2,3 butanedionemonoxime. Myofibrils behaved viscoelastically producing an increased efficiency with repeat stretch-shortening cycles, but a decreased efficiency with increasing stretch magnitudes. Furthermore, we observed a first distinct inflection point in the force-elongation curve at an average sarcomere length of 3.5μm that was associated with an average force of 68±5nN/mm. This inflection point was thought to reflect the onset of Ig domain unfolding and was missing after a ten minute rest at zero force, suggesting a lack of spontaneous Ig domain refolding. These passive myofibrillar properties observed here are consistent with those observed in isolated titin molecules, suggesting that the mechanics of titin are well preserved in isolated myofibrils, and thus, can be studied readily in myofibrils, rather than in the extremely difficult and labile single titin preparations.


Dynamical and Biological Panspermia Constraints Within Multi-planet Exosystems.
As discoveries of multiple planets in the habitable zone of their parent star mount, developing analytical techniques to quantify extrasolar intra-system panspermia will become increasingly important. Here, we provide user-friendly prescriptions that describe the asteroid impact characteristics which would be necessary to transport life both inwards and outwards within these systems within a single framework. Our focus is on projectile generation and delivery and our expressions are algebraic, eliminating the need for the solution of differential equations. We derive a probability distribution function for life-bearing debris to reach a planetary orbit, and describe the survival of micro-organisms during planetary ejection, their journey through interplanetary space, and atmospheric entry.


Crystal Structures of Metallo-β-Lactamase (IMP-1) and Its D120E Mutant in Complexes with Citrate and the Inhibitory Effect of the Benzyl Group in Citrate Monobenzyl Ester.
The emergence and rapid spread of carbapenem-resistant pathogens producing metallo-β-lactamases such as IMP-1 and NDM-1 have been of great concern in the global clinical setting. The X-ray crystal structures of IMP-1 from Serratia marcescens and its single mutant, D120E, in complexes with citrate were determined at resolutions of 2.00 and 1.85 Å, respectively. Two crystal structures indicate that a single mutation at position 120 caused a structural change around Zn1, where the geometry changes from a tetrahedron in the native IMP-1 to a square pyramid in D120E. Based on these two complex structures, the authors synthesized citrate monobenzyl ester 1 to evaluate the structural requirement for the inhibitory activity against IMP-1 and compared the inhibitory activities with nonsubstituted citrate. The introduction of a benzyl group into citrate enhanced the inhibitory activity in comparison to citrate (IC50 > 5 mM).


Neutralizing Anti-IL-17A Antibody Demonstrates Preclinical Activity Enhanced by Vinblastine in Langerhans Cell Histiocytosis.
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterised by the accumulation into granulomas of apoptosis-resistant pathological dendritic cells (LCH-DCs). LCH outcome ranges from self-resolving to fatal. Having previously shown that, (i) monocyte-derived DCs (Mo-DCs) from LCH patients differentiate into abnormal and pro-inflammatory IL-17A-producing DCs, and (ii) recombinant IL-17A induces survival and chemoresistance of healthy Mo-DCs, we investigated the link between IL-17A and resistance to apoptosis of LCH-DCs. In LCH granulomas, we uncovered the strong expression of BCL2A1 (alias BFL1), an anti-apoptotic BCL2 family member. In vitro, intracellular IL-17A expression was correlated with BCL2A1 expression and survival of Mo-DCs from LCH patients. Based on the chemotherapeutic drugs routinely used as first or second line LCH therapy, we treated these cells with vinblastine, or cytarabine and cladribine. Our preclinical results indicate that high doses of these drugs decreased the expression of Mcl-1, the main anti-apoptotic BCL2 family member for myeloid cells, and killed Mo-DCs from LCH patients ex vivo, without affecting BCL2A1 expression. Conversely, neutralizing anti-IL-17A antibodies decreased BCL2A1 expression, the downregulation of which lowered the survival rate of Mo-DCs from LCH patients. Interestingly, the in vitro combination of low-dose vinblastine with neutralizing anti-IL-17A antibodies killed Mo-DCs from LCH patients. In conclusion, we show that BCL2A1 expression induced by IL-17A links the inflammatory environment to the unusual pro-survival gene activation in LCH-DCs. Finally, these preclinical data support that targeting both Mcl-1 and BCL2A1 with low-dose vinblastine and anti-IL-17A biotherapy may represent a synergistic combination for managing recurrent or severe forms of LCH.


Identification and characterization of a short 2'-3' bond-forming ribozyme.
A large number of natural and artificial ribozymes have been isolated since the demonstration of the catalytic potential of RNA, with the majority of these catalyzing phosphate hydrolysis or transesterification reactions. Here, we describe and characterize an extremely short ribozyme that catalyzes the positionally specific transesterification that produces a 2'-3' phosphodiester bond between itself and a branch substrate provided in trans, cleaving itself internally in the process. Although this ribozyme was originally derived from constructs based on snRNAs, its minimal catalytic motif contains essentially no snRNA sequence and the reaction it catalyzes is not directly related to either step of pre-mRNA splicing. Our data have implications for the intrinsic reactivity of the large amount of RNA sequence space known to be transcribed in nature and for the validity and utility of the use of protein-free systems to study pre-mRNA splicing.


Non heart beating organ donor: new experimental model in pigs.
To describe technical aspects of a new experimental model that simulates a non heart beating organ donor. Landrace pigs were operated on and cardiac arrest was obtained by means of myocardial infarction and interruption of ventilator support. Mean cardiac frequency, systolic and diastolic blood pressure levels, central venous pressure, oxygen saturation and concentration of expired CO(2) dropout occurred at seven minutes after cardiac arrest. The procedure was easily reproduced and a homogeneous circulatory failure could de obtained by the end of seven minutes. The model is suitable for further studies regarding abdominal organ transplantation.


[Surgical Outcome of Acute and Subacute Subdural Hematoma with Endoscopic Surgery].
Acute subdural hematoma (ASDH) and subacute subdural hematoma(SASDH)evacuations are commonly performed through a large craniotomy or with external decompression surgery to avoid secondary brain injury. In the field of head trauma, minimally invasive surgeries performed with neuroendoscopy were recently reported. We report 12 patients with ASDH( n=9) and SASDH (n=3)w ho underwent endoscopic hematoma evacuation via a small craniotomy between November 2013 and May 2015. All patients were over 65 years of age(mean age, 78.8 years[range, 65-91 years]) and had subdural hematomas without extensive contusion. The mean preoperative Glasgow Coma Scale(GCS)score was 8.75 (range, 4-13). In three patients, we observed the bleeding point and substantially coagulated it. Decompression in all patients was adequate after surgery. Patients with a preoperative GCS score of 4-6 showed poor outcomes, whereas those with a score >9 showed relatively good outcomes. We performed the operations safely in patients who were on antithrombotic therapy or had a systemic bleeding tendency pre-injury. Endoscopic hematoma evacuation via a small craniotomy is a safe and minimally invasive procedure in patients older than 65 years with comorbidities.


Isolation of a pea (Pisum sativum) seed lipoxygenase promoter by inverse polymerase chain reaction and characterization of its expression in transgenic tobacco.
Part of the 5'-flanking sequence of a pea (Pisum sativum) lipoxygenase (LOX) gene was cloned, after amplification from genomic DNA by inverse polymerase chain reaction. Translational and transcriptional fusions of 818 bp of the 5'-flanking region and its deletion derivatives (-513 and -356) were made to a beta-glucuronidase (GUS)-coding sequence and introduced into tobacco. Analysis of T1 transformants showed that the 818 bp 5'-flanking sequence drove GUS expression in seeds that was temporally regulated in a fashion similar to the accumulation of LOX mRNA in developing pea seeds. Contrary to expectations, however, expression of the 818 bp promoter-GUS fusion was not seed-specific; GUS activity was highest in leaves and also present in stems and, to a lesser extent, roots. Deletion analyses identified the region between -818 and -513 as essential for high-level, temporally regulated expression in seeds and also indicated that the sequence between -513 and -356 plays a negative role in leaf/stem, but not seed, expression. Comparison of translational and transcriptional fusions indicated that the LOX initiation codon was used more efficiently than the GUS initiation codon by the tobacco leaf translational apparatus.


Removal of polysialic acid-neural cell adhesion molecule induces aberrant mossy fiber innervation and ectopic synaptogenesis in the hippocampus.
The mossy fiber axons of both the developing and adult dentate gyrus express the highly polysialylated form of neural cell adhesion molecule (NCAM) as they innervate the proximal apical dendrites of pyramidal cells in the CA3 region of the hippocampus. The present study used polysialic acid (PSA)-deficient and NCAM mutant mice to evaluate the role of PSA in mossy fiber development. The results indicate that removal of PSA by either specific enzymatic degradation or mutation of the NCAM-180 isoform that carries PSA in the brain causes an aberrant and persistent innervation of the pyramidal cell layer by mossy fibers, including excessive collateral sprouting and/or defasciculation of these processes, as well as formation of ectopic mossy fiber synaptic boutons. These results are considered in terms of two possible effects of PSA removal: an increase in the number of mossy fibers that can grow into the pyramidal cell layer and an inhibition of process retraction by formation of stable junctions including synapses. As these defects on granule cells in the adult animal and PSA-positive granule cells continue to be produced in the mature brain, the present findings may be relevant to previous studies suggesting that PSA-NCAM function is required for long-term potentiation, long-term depression, and learning behaviors associated with hippocampus.


A role for diacylglycerol acyltransferase during leaf senescence.
Lipid analysis of rosette leaves from Arabidopsis has revealed an accumulation of triacylglycerol (TAG) with advancing leaf senescence coincident with an increase in the abundance and size of plastoglobuli. The terminal step in the biosynthesis of TAG in Arabidopsis is catalyzed by diacylglycerol acyltransferase 1 (DGAT1; EC 18.104.22.168). When gel blots of RNA isolated from rosette leaves at various stages of development were probed with the Arabidopsis expressed sequence tag clone, E6B2T7, which has been annotated as DGAT1, a steep increase in DGAT1 transcript levels was evident in the senescing leaves coincident with the accumulation of TAG. The increase in DGAT1 transcript correlated temporally with enhanced levels of DGAT1 protein detected immunologically. Two lines of evidence indicated that the TAG of senescing leaves is synthesized in chloroplasts and sequesters fatty acids released from the catabolism of thylakoid galactolipids. First, TAG isolated from senescing leaves proved to be enriched in hexadecatrienoic acid (16:3) and linolenic acid (18:3), which are normally present in thylakoid galactolipids. Second, DGAT1 protein in senescing leaves was found to be associated with chloroplast membranes. These findings collectively indicate that diacylglycerol acyltransferase plays a role in senescence by sequestering fatty acids de-esterified from galactolipids into TAG. This would appear to be an intermediate step in the conversion of thylakoid fatty acids to phloem-mobile sucrose during leaf senescence.


Possible role of imatinib in clinical pulmonary veno-occlusive disease.
The platelet-derived growth factor receptor inhibitor imatinib has demonstrated clinical and haemodynamical improvement in both animal models of pulmonary hypertension (PH) and patients with PH. It has been suggested that anti-proliferative effects on pulmonary vascular smooth muscle cells are responsible for these beneficial effects. The current study describes a patient with pulmonary arterial hypertension associated with a suspected pulmonary veno-occlusive disease. Treatment with imatinib resulted in rapid clinical improvement and decrease of ground-glass opacities and lobular septal thickening on high-resolution computed tomography. Based on these findings and on in vitro effects of imatinib on permeability of the endothelium, the authors hypothesise that the rapid clinical outcome is partly due to effects of imatinib on vascular integrity.


Modular protein supplements and their application to long-term care.
Modular protein supplements are added to either the diet or enteral formula to increase the protein or amino acid intakes of people who are nutritionally compromised. Protein supplements are aggressively marketed to long-term care clinicians because protein energy malnutrition and wounds are a common problem in this care setting. It can be challenging for clinicians to distinguish one product from another and to determine the best product for a specific application or nutrition care goal. Modular protein products can be sorted into 4 categories: (1) protein concentrates derived from a complete protein such as milk, soy, or eggs; (2) protein concentrates derived from collagen, either alone or in combination with a complete protein; (3) doses of 1 or more dispensable (nonessential) amino acids; and (4) hybrids of the complete or collagen-based proteins and amino acid dose. Modular protein supplements are generally provided either as a substrate for protein synthesis or as a source of 1 or more amino acids that may be conditionally indispensable (conditionally essential) under certain disease conditions. This review provides guidelines for the use of modular protein supplements according to their intended physiologic function and the assessment and nutrition care goals of the long-term care resident.


A survey of senior dental students' experiences with young dental patients in Pennsylvania.
The purpose of this study was to determine graduating dental students' perceptions about their training and experience in examination and treatment of infants and their plans to examine infants upon graduation. A survey was distributed to dental students graduating from Pennsylvania dental schools in 2007 and 2008. Of the returned surveys, 47.9 percent correctly identified 12 months as the recommended age for the first dental exam. Sixty-five percent of responders felt they would be comfortable performing exams on young children. This study's primary objective was to test the association between performance of a clinical exam in a young child, enjoyment of clinical and didactic pediatric dental experience, plans for additional training in pediatric dentistry and willingness to see children younger than two years old in practice. Performing a clinical exam on a young child was associated to willingness to see children younger than two years of age in practice. Early exposure (lecture or clinical) to young pediatric patients while in dental school was significantly associated to perceived comfort with oral exam of young patients but not to reported willingness to see them in practice.


[Analysis of mortality caused by tuberculosis in Medellín, Colombia, 2012].
Tuberculosis is a relevant global public health problem. Although reports of the World Health Organization show decrease in overall mortality rates, Colombia and Medellin show no significant decline. To describe the sociodemographic, clinical, diagnosis, and treatment characteristics of patients who died due to tuberculosis in Medellin, Colombia, during 2012. A descriptive study of tuberculosis deaths reported in the city. 93 deaths were identified, of which 32 were confirmed as directly caused by tuberculosis (34.4%); in 23 deaths (24.7%) tuberculosis was an associated cause. Co-morbidities were found in 34 patients (61.7%), HIV being the most common with 18 cases important(32.7%). Social risk factors such as being homeless, drug addiction or having no fixed address were found in 32 cases (58.1%); and there were deficiencies in the healthcare system in 26 cases (47.2%). No meaningful delay in the onset of anti-tuberculosis treatment was found after the microbiological diagnosis; however, 64% of patients did not adhere to treatment. Mortality caused by tuberculosis in Medellin is a relevant problem associated with delays in diagnosis of the disease and lack of adherence to treatment.


Impact of an antimicrobial stewardship program on critical haematological patients.
Antimicrobial Stewardship Programs (ASPs) have appeared as very useful tools in order to improve the use of antimicrobial agents. The objective of this study is to assess the impact of an ASP on haematological patients hospitalized in an Intensive Care Unit (ICU). A quasi-experimental pre-post intervention study, which included haematological patients admitted to an ICU and assessed by the ASP program during 3 years. The impact of the program on patient evolution was assessed by comparison between the previous period and the intervention period in terms of mortality, mean stay, number of re-hospitalizations, and duration of mechanical ventilation for intubated patients. The ASP team assessed 324 antimicrobial agents in 169 patients; they recommended 121 modifications, including 55 treatment discontinuations. Compared with the pre-intervention period, there were no significant differences in the variables assessed. No variation was observed in colonization by multi-resistant bacteria. The implementation of an APS on critical haematological patients will lead to a relevant number of treatment modifications, without any impact on the clinical evolution of patients.


Plasmablastic lymphoma presenting as a brachial artery aneurysm associated with haemodialysis arteriovenous access ligation in a renal transplant patient.
Plasmablastic lymphoma is a rare and aggressive neoplasm, generally associated with immunodeficiencies and related to latent Epstein-Barr virus infection. This case is the first reported case of plasmablastic lymphoma relapse in aneurysmatic brachial artery wall. We describe the case of male patient who underwent cadaveric donor kidney transplant when he was 61 years old and radio-cephalic distal arteriovenous fistula ligation 8 months later. After 8 years, he developed gingival plasmablastic lymphoma treated with cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone regimen with subsequent remission. During follow-up, a mid-forearm vascular access was created because of the worsening of renal function. Twenty-two months later, the patient showed a symptomatic 20 mm brachial artery aneurysm with radiological signs of imminent rupture, for which he was surgically treated. The histological evaluation of the brachial artery specimen revealed a relapse of plasmablastic lymphoma in the arterial wall and in an adjacent lymph node. Brachial artery aneurysms are a rare complication in kidney transplant recipients after ligation of arteriovenous access for haemodialysis. Here, we report a case in which this condition is associated with an even rarer plasmablastic lymphoma. A common aetiology, due to immunosuppressive therapy, is postulated for the two coexisting diseases.


Faecal bile acid profiles in patients with large bowel cancer in Japan.
To study the possible role of bile acids in carcinogenesis of the large bowel faecal bile acid profiles were analysed in detail in 14 patients with large bowel cancer and compared with 14 matched healthy subjects. The total faecal bile acid excretion was lower in the patients (297.3 +/- 402.8 mumol/day) than in the healthy subjects (470.6 +/- 231.1 mumol/day) (p less than 0.01), although the difference became insignificant when these data were expressed as mumol per wet or dry faecal weight. The faecal profiles of individual bile acids and their conjugates were similar in both groups except that 5 beta-chol-3-en-24-oic acid, a bacterial metabolite of sulpholithocholic acid, was found in nine cancer patients (64%) compared with only two healthy subjects (14%) (p less than 0.01). The significance of 5 beta-chol-3-en-24-oic acid in carcinogenesis needs further prospective and experimental studies.


Calcific tendinitis of biceps femoris: an unusual site and cause for lateral knee pain.
A 37-year-old man presented to the acute knee and sports medicine clinic with atraumatic lateral knee pain. He had point tenderness over the lateral aspect of his knee which had not settled with anti-inflammatory medications. Imaging revealed a large opaque lesion lateral to the knee and although there was no clear mechanism, injury to the posterolateral corner was considered. An MRI subsequently revealed a rare case of calcific tendinitis to the biceps femoris tendon insertion. This condition was self-limiting and did not require interventions such as steroid injections. This is the first reported case of calcific tendinitis of biceps femoris as a cause of acute knee pain.