Expression of Lysyl Oxidase Predictive of Distant Metastasis of Laryngeal Cancer.
Objective To investigate the prognostic significance of lysyl oxidase (LOX) expression in laryngeal cancer. Study Design Retrospective chart review and histologic analysis. Setting Tertiary referral academic center. Subjects and Methods Patients (N = 100) underwent surgical treatment for laryngeal cancer and had tissue specimens available. Immunohistochemical staining for LOX was performed on laryngeal cancer tissue microarrays, and the proportion and intensity of staining were evaluated. Patients with LOX scores ≤6 were classified into the low LOX group, while those with scores >6 were classified into the high LOX group. We analyzed the correlation between LOX expression and clinical factors as well as prognosis. Results LOX was predominantly expressed in the cytoplasm and nuclei of tumor cells. Kaplan-Meier analysis revealed that the high LOX group had worse overall survival and recurrence-free survival rates than the low LOX group ( P < .05). LOX expression exhibited marginally significant correlation with lymph node metastasis. In the Cox regression analysis, LOX expression and lymph node metastasis were significant factors correlated with overall survival rate (odds ratio [OR] = 3.92, 95% confidence interval [95% CI]: 1.35-11.37, P = .012; OR = 1.96, 95% CI: 0.93-1.43, P = .024, respectively). LOX expression was related to distant metastasis free survival rate (OR = 7.72, 95% CI: 1.02-19.18, P = .048). Conclusion A high expression level of LOX is associated with lymph node and distant metastasis as well as poor prognosis among patients with laryngeal cancer.


A case of lung adenocarcinoma with postoperative recurrence of multiple bone metastases that showed a gradual complete response to combined administration of erlotinib and zoledronic acid.
We describe a case of lung adenocarcinoma with multiple postoperative bone metastases that showed a gradual but complete response to combined administration of erlotinib and zoledronic acid. A 76-year-old man with moderately differentiated adenocarcinoma underwent a radical left upper lobectomy and mediastinal lymph node dissection. Three and a half years after the operation, serum carcinoembryonic antigen (CEA) was elevated and 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) revealed multiple bone metastases. Pretreatment evaluation of EGFR mutations in the resected primary adenocarcinoma specimen showed an L858R mutation in exon 21. Gefitinib was started as first-line treatment. However, evaluation 1 month after administration revealed progressive disease. Erlotinib was started as second-line treatment, and evaluation 1 month after administration revealed that the disease was stable. Administration of zoledronic acid was then begun with continuation of erlotinib. After 2 courses of zoledronic acid, the serum CEA level had not changed but the maximum standardized uptake values of each region uniformly decreased. Furthermore, the uptake of 18FDG completely disappeared after 6 courses. Subsequently, the serum CEA level continued to decrease and the disappearance of 18FDG uptake was confirmed after 10 courses (12 months after initiation of erlotinib administration). Our results suggest that the combined administration of both drugs is effective against bone metastases.We experienced a case of lung adenocarcinoma with postoperative recurrence of multiple bone metastases that showed a gradual but complete response to combined administration of erlotinib and zoledronic acid. Our results suggest that the combined treatment of both drugs is an effective therapy against bone metastases.


Recent advances in the chemistry and biology of anti-inflammatory and specialized pro-resolving mediators biosynthesized from n-3 docosapentaenoic acid.
Several novel oxygenated polyunsaturated lipid mediators biosynthesized from n-3 docosapentaenoic acid were recently isolated from murine inflammatory exudates and human primary cells. These compounds belong to a distinct family of specialized pro-resolving mediators, and display potent in vivo anti-inflammatory and pro-resolution effects. The endogenously formed specialized pro-resolving mediators have attracted a great interest as lead compounds in drug discovery programs towards the development of new classes of drugs that dampen inflammation without interfering with the immune response. Detailed information on the chemical structures, cellular functions and distinct biosynthetic pathways of specialized pro-resolving lipid mediators is a central aspect of these biological actions. Herein, the isolation, structural elucidation, biosynthetic pathways, total synthesis and bioactions of the n-3 docosapentaenoic acid derived mediators PD1n-3 DPA and MaR1n-3 DPA are discussed. In addition, a brief discussion of a novel family of mediators derived from n-3 docosapentaenoic acid, termed 13-series resolvins is included.


Interactive effects of chronic stress and a high-sucrose diet on nonalcoholic fatty liver in young adult male rats.
Glucocorticoids have been implicated in nonalcoholic fatty liver diseases (NAFLD). The influence of a palatable diet on the response to stress is controversial. This study explored whether a high-sucrose diet could protect from hepatic steatosis induced by chronic restraint stress in young adult rats. Male Wistar rats aged 21 days were allocated into four groups (n = 6-8 per group): control, chronic restraint stress, 30% sucrose diet, and 30% sucrose diet plus chronic restraint stress. After being exposed to either tap water or sucrose solution during eight weeks, half of the rats belonging to each group were subject or not to repeated restraint stress (1 h per day, 5 days per week) during four weeks. Triacylglycerol (TAG), oxidative stress, activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1), infiltration of immune cells, and glycogen amount in the liver were quantified. Serum concentrations of corticosterone and testosterone were also measured. The stressed group showed normal serum concentrations of corticosterone and did not have hepatic steatosis. However, this group showed increased glycogen, inflammation, mild fibrosis, oxidative stress, and a high activity of 11β-HSD-1 in the liver. The group exposed to the high-sucrose diet had lower concentrations of corticosterone, hepatic steatosis and moderate fibrosis. The group subject to high-sucrose diet plus chronic restraint stress showed low concentrations of corticosterone, hepatic steatosis, oxidative stress, and high concentrations of testosterone. Thus, restraint stress and a high-sucrose diet each generate different components of nonalcoholic fatty liver in young adult rats. The combination of both the factors could promote a faster development of NAFLD.


Vasorelaxant effect of phosphodiesterase-inhibitor milrinone in the human radial artery used as coronary bypass graft.
The radial artery is a spastic coronary bypass graft. We investigated the effect of the phosphodiesterase III inhibitor milrinone on the human radial artery. Radial artery segments (n = 76) taken from 15 patients were studied in an organ chamber. Concentration-relaxation curves for milrinone were established in the radial artery precontracted with 3 vasoconstrictors (phenylephrine, K(+), and U46619). In radial artery rings incubated with therapeutic plasma concentrations of milrinone (7 and 70 micromol/L) for 10 minutes, concentration-contraction curves for the 3 vasoconstrictors were constructed. Milrinone caused a submaximal relaxation in phenylephrine- (98.6% +/- 1.4%), K(+)- (89.1 +/- 4.5%), or U46619- (74.2 +/- 8.0%) precontracted radial arteries at -4.5 log(10) M. The EC(50) was higher against K(+) (-5.85 +/- 0.24 log(10) M, P =.02) or U46619 (-5. 21 +/- 0.61 log(10) M, P =.03) than phenylephrine (-6.68 +/- 0.11 log(10) M). Pretreatment with milrinone depressed the contraction by phenylephrine from 70.0% +/- 7.9% to 23.5% +/- 9.3% (P =.003) and by K(+) from 138.6% +/- 5.8% to 73.0% +/- 13.9% (P =.006) and shifted the EC(50) 3.8-fold higher (P =.03) for phenylephrine and 2.2-fold higher for K(+) (P =.01). Milrinone reduced the U46619 contraction at low concentration (-8.5 log(10) M) but had little effect on the maximal contraction. Milrinone is a potent vasodilator for the radial artery, with possibly higher potency in alpha-adrenoceptor- and depolarizing agent K(+)-mediated, but less potency in thromboxane A(2)-mediated, contraction. Because it also has a positive inotropic effect, this vasodilator may be particularly indicated for use in patients receiving radial artery grafts in coronary artery bypass grafting.


Differential social evaluation of pregnant teens, teen mothers and teen fathers by university students.
Youth may be particularly attuned to social evaluation during the teen years with implications for physical and mental health. Negative attitudes and stereotypes constitute an important type of social evaluative threat. Pregnant and parenting teens not only encounter challenges associated with their early transition to parenthood, but also are confronted with unfavourable attitudes of others. A university sample of 255 men and women responded to surveys targeting their feelings and beliefs about pregnant teens, teen mothers and teen fathers. Teen mothers were generally perceived more positively than pregnant teens who were perceived more positively compared to teen fathers. Social evaluations were generally unrelated to respondents' sex or race, but respondents who had contact with a friend or family member who had experienced a teen pregnancy were selectively more positive, as were freshmen compared to seniors. Risks attributed to early childbearing may be exacerbated by negative social evaluations.


The Broad Habitat Spectrum of the CL500-11 Lineage (Phylum Chloroflexi), a Dominant Bacterioplankton in Oxygenated Hypolimnia of Deep Freshwater Lakes.
CL500-11 (phylum Chloroflexi) is one of the most ubiquitous and abundant bacterioplankton lineages in deep freshwater lakes inhabiting the oxygenated hypolimnion. While metagenomics predicted possible eco-physiological characteristics of this uncultured lineage, no consensus on their ecology has so far been reached, partly because their niche is not clearly understood due to a limited number of quantitative field observations. This study investigated the abundance and distribution of CL500-11 in seven deep perialpine lakes using catalyzed reporter deposition-fluorescence in situ hybridization (CARD-FISH). Samples were taken vertically (5-12 depths in each lake) and temporally (in two lakes) at the deepest point of the lakes located in Switzerland, Italy, and Austria with varying depth, trophic state, mixing regime, and water retention time. The results showed a dominance of CL500-11 in all the lakes; their proportion to total prokaryotes ranged from 4.3% (Mondsee) to 24.3% (Lake Garda) and their abundance ranged from 0.65 × 105 (Mondsee) to 1.77 × 105 (Lake Garda) cells mL-1. By summarizing available information on CL500-11 occurrence to date, we demonstrated their broad habitat spectrum, ranging from ultra-oligotrophic to meso-eutrophic lakes, while low abundances or complete absence was observed in lakes with shallow depth, low pH, and/or short water retention time (<1 year). Together with available metagenomic and geochemical evidences from literatures, here we reviewed potential substrates supporting growth of CL500-11. Overall, the present study further endorsed ubiquity and quantitative significance of CL500-11 in deep freshwater systems and narrowed the focus on their physiological characteristics and ecological importance.


A flexible radical-based approach to TMS-substituted propargyl alcohols and to 2,3-allenols.
The radical reaction of TMS-substituted xanthates with 2,2-dichlorovinyl ethyl sulfone afforded TMS-substituted homodichlorovinyl compounds that can be transformed into TMS-substituted propargyl alcohols. Various 2,3-allenols were efficiently prepared from the reaction of these TMS-substituted propargyl alcohols with TBAF.


Seasonal changes in LH secretion in normal ewes and ewes which grazed oestrogenic clover.
Plasma luteinizing hormone (LH) concentrations were measured in normal (control) Corriedale X Merino (comeback) ewes and in clover-infertile comeback ewes which had grazed oestrogenic Yarloop clover (Trifolium subterraneum L. cv. Yarloop) for more than 4 years. Plasma LH concentrations were measured in samples taken at 20-min intervals for 6 h during the dioestrous stage of the oestrous cycle in the breeding season (BS) and during the anoestrous season (AS). In the control ewes during BS, transitory elevation in plasma LH concentration (pulses) occurred, reflecting secretory episodes, with a frequency of one per 5.2 h. This frequency fell to one per 16.5 h during the anoestrous season. In clover-infertile ewes, LH pulses occurred with a frequency of one per 4.5 h during BS and one per 4.9 h during AS (difference not significant). In the controls, plasma LH levels were higher (P less than 0.05) during BS (mean +/- s.d. = 1.2 +/- 0.4 ng/ml, n = 9) than in AS (0.7 +/- 0.3 ng/ml, n = 5). In the clover-infertile ewes, plasma LH levels in BS (1.3 +/- 0.6 ng/ml, n = 12) were similar to those of controls. During AS, plasma LH levels in the clover-infertile ewes (1.0 +/- 0.6 ng/ml, n = 10) remained similar to their BS levels, being significantly (P less than 0.05) higher than LH levels in the controls at this time. These studies indicate that the higher plasma concentrations of LH which have been reported in clover-infertile ewes arise from more frequent LH pulses. Furthermore, in contrast to normal ewes, average plasma LH, reflecting pulse frequency, is not reduced in AS. This supports the view that ingestion of phytooestrogens affects neural centres involved in regulating LH secretion.


Television news coverage of obesity in China, 1982-2009.
The purpose of this study was to explore how obesity was covered in television news in China, including the trends over time and the characteristics of obesity-related news. The frame analysis was adopted to assess the content of obesity-related news broadcasted in China Central Television (CCTV) from 1982 to 2009. To investigate the characteristics of the news, the obesity-related news was divided into subgroups according to populations concerned, as well as the period in which the news was broadcasted. The differences between subgroups were examined. A total of 1 599 pieces of news reported obesity, in which 1 278 pieces (79.92%) aired in "wealthy" period (2006-2009). More news was concerned with adults (1 134, 70.92%). "Individual behavior" dominated most of the cause frames (389, 24.33%), solution frames (522, 32.65%), and responsibility frames (860, 53.78%). There was more news mentioning individual factors in news aired in "wealthy" period and news concerning children. The coverage of social-structure causes was higher in news concerning children, while the coverage of social-structure solutions was higher in news concerning children and news aired in "wealthy" period. Although the coverage of obesity was modest, it showed an incremental trend as the economy grew. Obesity was mostly depicted as an individual problem in terms of responsibility, causes and solutions.


Dynamic expression of cell-surface antigens probed with Candida albicans-specific monoclonal antibodies.
IgG hybridomas were produced with preferentially reacted with cell-surface antigens of either yeast cells or hyphae of Candida albicans. Four mAbs were used in an immunostaining procedure to follow the expression dynamics of these antigens in media supplemented with glucose or galactose. Yeast cell growth was analysed during the lag phase, the early- and late-exponential phases and the stationary phase, and mycelium formation was analysed between 0.5 and 24 h induction at 37 degrees C. It appears that yeast cell-surface antigens 5C11 and 2E11 are expressed throughout all phases of yeast cell growth as well as on young hyphae after up to 1 h induction. Longer hyphae only faintly react with these two mAbs as they switch to hyphal cell-surface antigens 2G8 and 4E1 after 3 h induction. The reactivity to mAbs 2G8 and 4E1 was induced after a 3 h temperature shift and was confined to the terminal third of growing mycelia. Growth and hyphae induction in galactose prolonged the reactivity of young hyphae with the two anti-yeast-cell mAbs, whereas the expression of surface antigens 2G8 and 2E11 appeared delayed and desynchronized on hyphae. Whereas a similar reactivity was found with ten ATCC strains of C. albicans, four clinical isolates had a unique pattern of reactivity. Immunoblot analyses of DTT extracts of cell-surface constituents indicated that the antigens were proteinaceous in nature and showed that yeast-cell antigens 5C11 and 2E11 are detected in four bands between 68 and 104 kDa, whereas mycelial antigens 4E1 and 2G8 are detected in 117 kDa and 104 kDa bands found in mycelial but not in yeast-cell extracts. Present data support the concept of a dynamic balance in the expression of phase-specific antigens in C. albicans.


Psychiatric and somatic co-morbidities in patients with Parkinson's disease: A STROBE-compliant national multi-center, cross-sectional, observational study COSMOS in Slovakia.
Co-morbidities in any disorder can complicate its diagnostic process, they require more complex clinical management and lead to worse health outcomes and increased healthcare costs. There are regional differences in the prevalence of specific co-morbidities in Parkinson's disease (PD), and data from middle Europe are lacking. The project COSMOS aimed to disclose the prevalence of co-morbidities among patients with PD in Slovakia. In a national, multi-center, cross-sectional, observational study, neurologists gathered relevant demographical and clinical data aimed at all psychiatric and somatic co-morbidities. From overall 737 patients, 51.00 % had at least one psychiatric co-morbidity, the most prevalent were depressive episode/recurrent depressive disorder (26.05%), sleep disorders (23.20%), dementia (13.16%), and neurotic, stress-related, and somatoform disorders (11.53%). In addition, 92.9 % had at least one somatic co-morbidity, the most prevalent were hypertensive diseases (67.71%), ischemic heart diseases (42.74%), diseases of the musculoskeletal system, and connective tissue (39.21), and disorders of lipoprotein metabolism (33.24%). The number of psychiatric co-morbidities increased with PD progression; the prevalence of somatic comorbidities increased also with the age (p<0.001 in all cases). This study with a large cohort of PD patients confirmed a high prevalence of depression, dementia, sleep problems, and anxiety disorders, together with cardiovascular disorders, diseases of the musculoskeletal system, and metabolic syndrome. With PD progression, the number of both psychiatric and somatic co-morbidities is on the increase. If not treated properly, they lead to more complicated management. That's why it's essential to search for any co-morbidity to provide patients with early and adequate therapy to avoid further worsening of quality of life.


Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study.
The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell-replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/μL, CD8 < 50 cells/μL, CD45RA < 10%, or a restricted Vβ T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.


Percutaneous absorption of salicylic acid.
The potential hazards of repeated topical application of salicylic acid under occlusion to large areas of the body was evaluated by measuring the percutaneous absorption and serum salicylate concentrations in four patients with active psoriasis. Serum salicylate concentrations never exceeded 5 mg/100 ml in any of the patients, and although greater than 60 percent of the salicylic acid applied was absorbed, no evidence of accumulation or toxicity was observed. This form of treatment appears to present little potential hazard even in patients with extensive skin disease. Therapy could be hazardous for patients with impaired hepatic or renal function or for smaller children. The urinary excretory products of salicylate metabolism were compared following topical and intravenous salicylate administration to determine if the skin plays any part in the biotransformation of salicylate during percutaneous absorption. Our data are too limited and inconclusive to answer this question.


Targeting ERBB receptors to inhibit metastasis: old hopes and new certainties.
The very early intuition of Paget about the molecular feature of metastasis has come in the field of therapeutic opportunities only in the last few years with the development of targeted therapy. However, to date the diagnosis of metastases is associated in the majority of cases with the loss of any therapeutic hope. According to present knowledge, metastatic spreading is considered as part of a long process in which tumor cells gain new properties in their cellular function, including invasion and adaptive survival. This gain of function is based on the expression of new molecular markers that may be potential therapeutic targets in blocking tumor dissemination. The epidermal growth factor receptor family comprises four members (ERBB) that are frequently upregulated in advanced tumor stages and have been associated with the metastatic potential of several tumors. ERBB receptor inhibitors are very effective against specific primary tumors and their use is frequently accompanied by toxicity problems, drug resistance and molecular desensitization. However, new studies indicate that ERBB inhibitors may provide a much-needed therapeutic option mainly for patients with metastases. In order to illustrate the potential of ERBB family members as therapeutic targets in blocking metastases we summarize the new molecular evidence and the observations from clinical trials.


Indications for lung transplant referral and listing.
Lung transplantation is a valuable therapeutic option for many patients with severe lung disease who have exhausted other medical or surgical therapies. However, since lungs are not a manufacturable organ like artificial heart valves or left ventricular assist devices, and since they are a limited resource compared to number of patients requiring the organs, the Department of Health and Human Services set the Final Rule of organ allocation in 1998. This led to development and implementation of Lung Allocation Score (LAS) in 2005. The score broadly divides lung diseases into 4 diagnostic criteria with a coefficient factor given to each category. The score is based on the prognostic factors of each patient to determine the risk of mortality without a transplant combined with the probability of patient survival post-transplant. Most of the guidelines for "Indications for referral and listing in lung transplant" is based on consensus opinion as there is limited amount of robust data and trials about this topic. The International Society for Heart and Lung Transplant (ISHLT) has published three editions for candidate selection and listing. In this article, we have attempted to highlight the guidelines and incorporated other disease specific prognostic factors that are not captured in the LAS. Ultimately, there are other factors like geographic location, height, blood group, preformed antibodies, transplant center experience, past wait times and transplant rate, availability of organs, etc., which also play a role especially when considering listing a patient for lung transplant. We also highlighted a representative disease in each category and most criteria for that disease will apply to other diseases in that category. Finally, this article does not delve into the history and reasoning behind each guideline but is meant to provide a general overview of indications and contraindications applicable in the field of adult lung transplantation.


Evaluation of perinatal and intrafamilial hepatitis B prevention programmes in a well child clinic: 9-year follow-up study in Turkey.
Evaluating the performance of well child clinics on adherence to recommended perinatal hepatitis B prevention programmes as well as assessing the outcome of infants living with hepatitis B surface antigen (HBsAg)-positive parents is important. A retrospective study was performed of 336 babies who had at least one HBsAg-positive parent and were followed-up in the well child clinic of Gazi University Hospital (Ankara, Turkey) between 2001 and 2009. Rates of passive immunisation in 109 babies with HBsAg-positive mothers and initiation of hepatitis B vaccination of all 336 babies with HBsAg-positive parents were 98.8% and 100% respectively. Ninety-two babies (27.4%) were lost to follow-up before completing primary immunisation. The recommended perinatal hepatitis B prevention programme was performed successfully in 194 of the 306 infants who were old enough for post-vaccination serotesting (63.4%). One baby became HBsAg-positive, and 88.1% of babies were seroprotected. Hepatitis B surface antibody (anti-HBs) levels were found to be increased if the HBsAg-positive parent was the father. There was a negative correlation between serotesting time and anti-HBs titres. The study infants had a total of 187 siblings and 123 (65.8%) were serotested after completing primary immunisation with 108 found to be seropositive. Although the vaccination rate in the perinatal hepatitis B prevention programme is satisfactory, post-vaccination serotesting and evaluation of infants and their siblings are still deficient.


Zwitterionic nanocomposite hydrogels as effective wound dressings.
In this study, zwitterionic poly(sulfobetaine acrylamide) (pSBAA) nanocomposite hydrogels were synthesized and implemented as effective chronic wound dressings. The hydrogels exhibited reinforced mechanical properties from added hectorite nanoclay as a physical crosslinker in the polymer chains. Due to the strong interaction with water molecules via ionic solvation, the hydration of the zwitterionic nanocomposite hydrogels was superior to the non-ionic 2-hydroxyethyl methacrylate (pHEMA) hydrogels, which interacts with water molecules via hydrogen bonding. The pSBAA nanocomposite hydrogels cytotoxicity was accessed with NIH-3T3 fibroblast by the MTT assay, the results indicated negligible cytotoxicity after incubation for three days. In addition, the zwitterionic hydrogels displayed evident resistance to adsorption of bovine serum albumin (BSA), NIH-3T3 fibroblast, and bacteria of gram positive S. epidermidis and gram negative P. aeruginosa. The need for antifouling properties in a wound dressing is because commercial dressings removal typically damaging newly formed tissues and colonization of microorganisms occurs on the dressings. For clinical applications as wound dressings, we created normal and diabetic wounds on mice and compared newly developed pSBAA nanocomposite hydrogels with commercial available products. We demonstrated that non-adhesive pSBAA nanocomposite hydrogels enabled ready wound surface removal. Moreover, the wound recovery was conducted with normal and diabetic wounds on rat dorsal by visual observation and showed a complete heal after 10 and 12 days, respectively. Moreover, the histological examination of mice skin confirmed that the zwitterionic hydrogels exhibited thorough re-epithelialization and total formation of new connective tissues in the normal and diabetic wounds after 10 and 12 days, respectively, which was faster than commercial dressings. Consequently, we demonstrated that the pSBAA nanocomposite can serve as an effective dressing for wound management.


Medical management of autism.
The primary care physician should be knowledgeable about the medical issues that children with ASD encounter and also be aware of available treatment options. Included among these are: identification of seizures, treatment of sleep problems, aggressive management of chronic constipation and GERD as well as timely referral for preventive dental care. Due to the scarcity of sub-specialists (Pediatric Neurologist, Developmental Pediatrician, Child Psychiatrist/ Psychologist) managing children with ASD, the primary care physician should likewise be familiar with medication options for challenging behaviors. More importantly, there needs to be a close collaboration and communication between the family, the sub-specialist and the child's primary care physician.


A new boronic acid-based fluorescent sensor for L-dihydroxyphenylalanine.
Catecholamines, such as dopamine and L-dihydroxyphenylalanine (L-DOPA), are associated with different physiological functions and diseases. In our recent studies, a novel water-soluble boronic acid compound 3c was identified as a selective fluorescent sensor for L-DOPA. This compound not only has the ability to interact with dopamine and catechol, but also has no fluorescence intensity change for L-DOPA precursors in vivo, such as L-tyrosine.


Nanocarriers for DNA Vaccines: Co-Delivery of TLR-9 and NLR-2 Ligands Leads to Synergistic Enhancement of Proinflammatory Cytokine Release.
Adjuvants enhance immunogenicity of vaccines through either targeted antigen delivery or stimulation of immune receptors. Three cationic nanoparticle formulations were evaluated for their potential as carriers for a DNA vaccine, and muramyl dipeptide (MDP) as immunostimulatory agent, to induce and increase immunogenicity of Mycobacterium tuberculosis antigen encoding plasmid DNA (pDNA). The formulations included (1) trimethyl chitosan (TMC) nanoparticles, (2) a squalene-in-water nanoemulsion, and (3) a mineral oil-in-water nanoemulsion. The adjuvant effect of the pDNA-nanocomplexes was evaluated by serum antibody analysis in immunized mice. All three carriers display a strong adjuvant effect, however, only TMC nanoparticles were capable to bias immune responses towards Th1. pDNA naturally contains immunostimulatory unmethylated CpG motifs that are recognized by Toll-like receptor 9 (TLR-9). In mechanistic in vitro studies, activation of TLR-9 and the ability to enhance immunogenicity by simultaneously targeting TLR-9 and NOD-like receptor 2 (NLR-2) was determined by proinflammatory cytokine release in RAW264.7 macrophages. pDNA in combination with MDP was shown to significantly increase proinflammatory cytokine release in a synergistic manner, dependent on NLR-2 activation. In summary, novel pDNA-Ag85A loaded nanoparticle formulations, which induce antigen specific immune responses in mice were developed, taking advantage of the synergistic combinations of TLR and NLR agonists to increase the adjuvanticity of the carriers used.


One-stage surgical excision of a huge bilateral multiple osteochondroma of the hip: a case report.
Osteochondroma or hereditary multiple exostoses is the most common benign bone tumor and is usually found in young patients. Osteochondromata of the proximal femur or hip have been reported in 30% to 90% of patients with hereditary multiple exostoses. This article presents a 25-year-old-male referred to our orthopedic clinic with a complaint of pain in both groins for the last four years which has deteriorated in the past 6 months by limitation of range of motion. Radiographic findings were consistent with huge hip osteochondroma and a histopathological report confirmed the diagnosis. This was a case of a huge bilateral osteochondroma of the hip originating from the posterior of the hips to the neck of the femur and hip joints and part of proximal of femur, that underwent one-stage surgical excision of the tumor with posterior approach and tumor resection. As we know, this case of bilateral huge hip osteochondromas has rarely been presented previously by someone who has undergone one-stage surgery treatment of a tumor this size. Bilateral hip osteochondroma is a rare condition and we showed that one-stage excision can be performed successfully.


Hospital workplace experiences of registered nurses that have contributed to their resignation in the Durban metropolitan area.
Hospital workplace experiences of registered nurses that have contributed to their resignation in the Durban Metropolitan Area. The purpose of this research was to explore and describe the hospital workplace experiences that had contributed to the resignations of Registered Nurses in the Durban Metropolitan Area. The broad perspective governing this research is qualitative in nature. The researcher employed a phenomenological approach specifically because the researcher was interested in identifying, describing and understanding the subjective experiences of individual nurses at the two Private and two Provincial health care institutions selected to participate in the study - in respect of their decision (s) to resign from their employment, and/or to leave the nursing profession. Two semistructured interviews were conducted with each participant by the researcher. The researcher applied the principle of theoretical saturation and a total of fifteen participants were interviewed and thirty interviews were conducted. Experiential themes and subthemes in the data were identified by a process of meaning condensation, and the data were managed by means of a qualitative software package - NVIVO (QSR - NUD*IST). The resignations of registered nurses in the Durban Metropolitan Area were found to be linked to their respective hospital workplace experiences. These experiences related to their physical working conditions and environment and included the following: unsupportive management structures, autocratic and dehumanizing management styles, negative stereotypy of nurses and the nursing profession, lack of autonomy in the workplace, professional jealousies and fractures within the profession, sub-optimal physical working conditions and shortage of staff, equipment and lack of appropriate surgical supplies, concerns regarding occupational safety e.g. the increasing exposure of health care personnel to HIV and AIDS; lack of opportunities for promotion or continuing one's professional education, the experience of workplace violence--predominantly in the form of verbal and psychological abuse, inaccurate systems of performance assessment (Joint Performance Management, Reports, Personal Profile systems)--compounded by favouritism and racism; and inadequate remuneration. In terms of the findings of this study, the participants' lived experiences in terms of their respective hospital workplace experiences indicated that neither the maintenance factors nor the motivator factors were optimally represented, experienced or enjoyed in their respective workplaces. In terms of Herzberg's Motivator-Maintenance theory, the registered nurses who participated in this study may be described as being 'not satisfied' and 'dissatisfied' with their hospital workplace experiences, physical conditions and environment. A number of recommendations pertaining to strategies for the retention of registered nurses were made for the consideration of both Provincial and Private health care authorities, hospital management structures and the nursing profession respectively. Recommendations for further nursing research were also made.


The effect of Medicaid eligibility on coverage, utilization, and children's health.
I estimate the causal impact of Medicaid eligibility on take up, private health insurance coverage, healthcare utilization, and children's health by using a regression discontinuity design. In contrast to a standard regression discontinuity design, identification exploits multiple thresholds that arise from variation across states in income eligibility rules. Using data from the Panel Study of Income Dynamics and its Child Development Study supplement, I find that Medicaid eligibility increases take up by 10-13 percentage points on average, rising to 24-29 percentage points at lower income eligibility thresholds. There are significant crowding out effects of the same magnitude as those on take up rates. Medicaid eligibility increases the use of preventive health care by 11-14 percentage points but only at low income thresholds. Finally, I find that Medicaid eligibility has no significant effects on health outcomes in the short and medium run.


Management of Parkinson's Disease 20 Years from Now: Towards Digital Health Pathways.
Current best medical treatment for patients with Parkinson's disease (PD) involves a medical professional who applies state-of-the-art knowledge of diagnostics and treatment- as derived from cohort studies and clinical trials- to the healthcare process of individual patients. Thus, the much-needed personalization of medicine depends on the abilities, experience and intuition of medical professionals to adjust group-based knowledge to individual decision making. Within 20 years from now, such personal clinical decisions will be largely supported by digital means, also defining a new ecosystem of healthcare often referred to as "digital medicine". We expect that the next phase of digitalization will include new "digital health pathways": data-driven personalized decision support that is based on a combination of multimodal data sources, including evidence-based medical knowledge (e.g., clinical guidelines), personal disease profiles (including genetic determinants of disease progression and treatment response), insights into individual disease trajectories (thereby defining subgroups of patients) and individual patients' needs. Here, we illustrate the potential of this development by sketching the contours of a digitally supported care pathway for gait disability and falls. Such digital health pathways will support the introduction of personalized medicine for PD patients, allowing patients to benefit optimally from individually tailored treatments. This should result in a better quality of life for patients and lower costs for society.


Fractional Flow Reserve Derived from Coronary Computed Tomography Angiography Safely Defers Invasive Coronary Angiography in Patients with Stable Coronary Artery Disease.
In the United States, the real-world feasibility and outcome of using fractional flow reserve from coronary computed tomography angiography (FFRCT) is unknown. We sought to determine whether a strategy that combined coronary computed tomography angiography (CTA) and FFRCT could safely reduce the need for invasive coronary angiography (ICA), as compared to coronary CTA alone. The study included 387 consecutive patients with suspected CAD referred for coronary CTA with selective FFRCT and 44 control patients who underwent CTA alone. Lesions with 30-90% diameter stenoses were considered of indeterminate hemodynamic significance and underwent FFRCT. Nadir FFRCT ≤ 0.80 was positive. The rate of patients having ICA, revascularization and major adverse cardiac events were recorded. Using coronary CTA and selective FFRCT, 121 patients (32%) had at least one vessel with ≥50% diameter stenosis; 67/121 (55%) patients had at least one vessel with FFRCT ≤ 0.80; 55/121 (45%) underwent ICA; and 34 were revascularized. The proportion of ICA patients undergoing revascularization was 62% (34 of 55). The number of patients with vessels with 30-50% diameter of stenosis was 90 (23%); 28/90 (31%) patients had at least one vessel with FFRCT ≤ 0.80; 8/90 (9%) underwent ICA; and five were revascularized. In our institutional practice, compared to coronary CTA alone, coronary CTA with selective FFRCT reduced the rates of ICA (45% vs. 80%) for those with obstructive CAD. Using coronary CTA with selective FFRCT, no major adverse cardiac events occurred over a mean follow-up of 440 days. FFRCT safely deferred ICA in patients with CAD of indeterminate hemodynamic significance. A high proportion of those who underwent ICA were revascularized.


Serum concentrations of fluoxetine in the clinical treatment setting.
This article discusses fluoxetine serum concentrations as displayed in a clinical setting. A racemic serum fluoxetine and norfluoxetine high-performance liquid chromatography method, including ultraviolet light detection, was used for routine therapeutic drug monitoring (TDM) purposes. In all, 508 samples were analyzed. For the scientific investigation, predefined inclusion and exclusion criteria were applied and 150 samples representative of trough values in steady-state conditions with essential clinical information provided on the assay request forms were evaluated. Fluoxetine plus norfluoxetine concentration-to-dose (C/D) ratio showed Gaussian distribution. Interindividual coefficients of variation of fluoxetine and norfluoxetine serum concentrations after different doses were found to be 40-63%. Intraindividual fluoxetine TDM variability was low. The Spearman rank correlation coefficient for fluoxetine and norfluoxetine C/D ratios in first and second samples was 0.68. Minor increases in norfluoxetine C/D and fluoxetine plus norfluoxetine C/D ratios were found in elderly patients compared with younger adult patients. A higher body-mass index was associated with minor decreases in fluoxetine and fluoxetine plus norfluoxetine C/D ratios. New fluoxetine pharmacokinetic data are added to the results from earlier phases of drug development. Moreover, the results of this study support the usefulness of a fluoxetine TDM procedure for individual dose optimization, detection of drug interactions, and assessments of patient compliance.


E2F transcription factor 8 promotes cell proliferation via CCND1/p21 in esophageal squamous cell carcinoma.
E2F transcription factor 8 (E2F8) is a novel member of the E2F family, but its function in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to research the function of E2F8 in ESCC. We used quantitative real-time PCR and Western blot analyses to detect the expression pattern of E2F8 in ESCC. The effects of E2F8 on proliferation were investigated by Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, and colony formation assays. We also confirmed the function of E2F8 in vivo. E2F8 expression was upregulated in ESCC, and promoted cell proliferation and influenced the expression of CCND1/p21. Downregulation of E2F8 expression inhibited cell proliferation in vivo. E2F8 was identified as a new potential oncogene in ESCC.


Novel sesquiterpenoids from the fermentation of Xylaria persicaria are selective ligands for the NPY Y5 receptor.
Neuropeptide Y (NPY) is a polypeptide found in the peripheral and central nervous system and is involved in the regulation of feeding. Antagonists of NPY receptor activation could therefore have potential for development as antiobesity drugs. Fermentation of an isolate of Xylaria persicaria yielded two novel eremophilane sesquiterpenoids xylarenals A (1) and B (2). These compounds are selective for the NPY Y5 receptor but have only modest affinity. The isolation, structure elucidation, and biological activities of these compounds are described.


Cocaine increases natural killer cell activity.
The administration of epinephrine to humans increases natural killer (NK) cell activity and numbers. If endogenous catecholamines regulate NK cells, then their activity should be increased by cocaine, an agent that potentiates endogenous catecholamines. We investigated the in vivo effect of cocaine on NK cell activity and on the distribution of lymphocyte subsets, including NK cells. Intravenous cocaine (0.6 mg/kg) produced a three- to fourfold increase in NK cell activity in peripheral blood. The increase was accompanied by a marked and selective increase in circulating NK cells, as identified by the Fc receptor (Leu-11). Normal saline and benzoylecgonine, a major metabolite of cocaine, had little effect on NK cell activity or on levels of Leu-11+ cells. Other lymphocyte subpopulations were not increased by cocaine. The time course of the alterations in NK cell numbers and activity paralleled plasma levels of cocaine. In vitro cocaine did not increase NK cell activity. Our results indicate that cocaine selectively alters the activity and distribution of the NK lymphocyte subset. Because cocaine increases the activity of endogenous catecholamines, these findings suggest that human NK cells are selectively regulated by the sympathetic nervous system.


Light-regulated collective contractility in a multicellular choanoflagellate.
Collective cell contractions that generate global tissue deformations are a signature feature of animal movement and morphogenesis. However, the origin of collective contractility in animals remains unclear. While surveying the Caribbean island of Curaçao for choanoflagellates, the closest living relatives of animals, we isolated a previously undescribed species (here named Choanoeca flexa sp. nov.) that forms multicellular cup-shaped colonies. The colonies rapidly invert their curvature in response to changing light levels, which they detect through a rhodopsin-cyclic guanosine monophosphate pathway. Inversion requires actomyosin-mediated apical contractility and allows alternation between feeding and swimming behavior. C. flexa thus rapidly converts sensory inputs directly into multicellular contractions. These findings may inform reconstructions of hypothesized animal ancestors that existed before the evolution of specialized sensory and contractile cells.


Peroneal tendon abnormalities. A review of 40 surgical cases.
The authors reviewed data from 40 peroneal tendon surgeries performed on 39 patients (25 males and 14 females) between 1991 and 1999. Patients underwent tendon repair, subluxation repair, and/or accessory ossicle and muscle excisions. Some patients underwent more than one procedure, including eight undergoing ankle stabilizations. Preoperatively and postoperatively, the American Orthopaedic Foot and Ankle Society ankle-hindfoot score was assessed. Average preoperative and postoperative ankle-hindfoot scores were 61.6 (range, 19 to 72) and 91.4 (range, 63 to 100), respectively. Mean group return-to-activity time, defined as initiation of regular activity, including sports, was 3.2 months (range, 1 to 6 months). There were 17 athletes and 22 active patients; no patients were sedentary. Magnetic resonance imaging was used to evaluate peroneal tendon pathology in 29 patients. Sensitivity was 82.7%; specificity, 50%; and positive predictive value, 100%. Overall results were excellent in 25 cases, good in 12, fair in 1, and poor in 2. A paired t-test showed that patients with previous steroid injections had statistically poorer results. Patients with symptoms for more than 12 months also had poorer outcomes.


Metabolic Activity of Micromycetes Affecting Urban Concrete Constructions.
Concrete resistance to the destructive action of microorganisms is considered as a measure of its durability and is increasingly being raised as an important issue. We focused our study on the biodeterioration of concrete specimens widely used as a building material of urban houses by micromycetes isolated from the inner wall surface of the former military hospital in Kazan city, Tatarstan, Russia. Fungal community consists of 9 Penicillium isolates, 6 Aspergillus, 2 Trichoderma, and 1 isolate of Alternaria. First, we have identified two dominant isolates, Aspergillus fumigatus and Penicillium brevicompactum, and characterized their destructive properties according to the radial growth rate, antagonistic activity towards bacterial habitants of concrete, and production of organic acids. Then, we have demonstrated that five tested brands of high-strength concrete differ in bioreceptivity. The alterations in concrete resistances to compression and flexure after fungal attack were recorded at the trend level, mainly due to a short exposure time of concrete to fungal destructors in tests recommended by national Russian standard. Finally, using scanning electron microscopy we have shown that colonization of concrete by the dominant fungi includes their penetration into the thickness of concrete and germination in cracks. Elementary analysis revealed the decrease of calcium content on about 41% after fungal growth on the concrete in liquid phase and on 32% by superficial growth in comparison with the samples without fungal treatment.


Cardiac Outcomes After Perinatal Sertraline Exposure in Mice.
Selective serotonin reuptake inhibitors are prescribed to 6%-10% of pregnant women in the United States. Using an intrauterine plus neonatal exposure model to represent exposure throughout human pregnancy, we hypothesized sertraline exposure would impact intracardiac serotonin signaling and lead to small left heart syndrome in the absence of maternal psychopathology. C57BL/6 adult female mice received sertraline (5 mg·kg·d IP) or saline throughout pregnancy to time of delivery. Pups maintained exposure on postnatal days 1-14 to encompass the developmental window analogous to human gestation. Sertraline-exposed mice had increased cardiac hydroxyproline content, decreased 5-HT2B receptor mRNA levels, and increased 5-HT2A receptor and serotonin transporter mRNA levels on postnatal day 21 (P < 0.05). These changes were associated with diminished exercise capacity at 6 weeks (P < 0.05) and decreased adult shortening fraction and stroke volume at 5 months. Isolated cardiomyocytes from neonatal sertraline-exposed mice had significantly decreased proliferation, cross-sectional area, and phosphorylation of Akt (P < 0.05 vs. neonatal control mice). Perinatal sertraline exposure alters neonatal cardiac development and produces long-standing changes in adult cardiac function and exercise capacity. Further studies are needed to assess whether similar findings are present in the growing population that has been exposed to selective serotonin reuptake inhibitors during development.


High thoracic epidural decreases perioperative myocardial ischemia and improves left ventricle function in aortic valve replacement alone or in addition to cabg surgery even with increased left ventricle mass index.
High thoracic epidural (HTE) may reduce perioperative tachyarrhythmias, respiratory complications and myocardial ischemia (MI) and it may increase coronary perfusion and myocardial oxygen balance through sympatholysis and pain control. The aim of this study is to investigate the benefit of HTE in patients undergoing aortic valve replacement (AVR) alone or in addition to coronary artery bypass graft (CABG). This prospective randomized controlled study was conducted on 80 patients (40 with increased left ventricular mass index (LVMI) and 40 with normal LVMI) who were equally randomised (n = 40) to receive either GA with HTE (HTE group) or GA alone (GA group). Heart rate (HR), mean arterial blood pressure (MAP) and the incidence of ischemic ECG changes were recorded. LV functions (preoperative and postoperative by transthoracic echocardiography and intraoperative by transoesophageal echocardiography) were measured preoperative, intraoperative and till 48 H postoperative. There was no significant difference in the baseline values of all measurements. HR and MAP were lower, and LV functions were improved in HTE group intraoperatively and postoperatively. Ischemic ECG changes were significantly lower in HTE group; with 42.9% intraoperative risk reduction (95% CI: 0.195-0.943) and 46.6% postoperative risk reduction (95% CI 0.227-0.952) as compared to GA group. The risk of ischemia was significantly higher in patients with increased LVMI in GA group (2.25 times compared to normal LVMI patients with 95% CI: 1.195-4.236), but it wasn't increased in HTE group. LV functions were significantly improved from the induction to 48 H postoperative in HTE group as compared to GA group. HTE reduced the incidence of MI and improved the LV function, even with increased LVM, in patients undergoing AVR alone or in addition to CABG.


The Economic Implications of Introducing Single-Patient ECG Systems for Cardiac Surgery in Australia.
Sternal wound infections (SWIs) are severe adverse events of cardiac surgery. This study aimed to estimate the economic burden of SWIs following coronary artery bypass grafts (CABG) in Australia. It also aimed to estimate the national and hospital cost-benefit of adopting single-patient electrocardiograph (spECG) systems for CABG monitoring, a measure that reduces the rate of surgical site infections (SSIs). A literature review, which focused on CABG-related SSIs, was conducted to identify data which were then used to adapt a published Markov cost-effectiveness model. The model adopted an Australian hospital perspective. The average SWI-related cost of care increase per patient was estimated at 1022 Australian dollars (AUD), and the annual burden to the Australian health care system at AUD 9.2 million. SWI burden comprised 360 additional intensive care unit (ICU) days; 1979 additional general ward (GW) days; and 186 readmissions. Implementing spECG resulted in 103 fewer ICU days, 565 fewer GW days, 48 avoided readmissions, and a total national cost saving of AUD 2.5 million, annually. A hospital performing 200 yearly CABGs was estimated to save AUD 54,830. SWIs cause substantial costs to the Australian health care system. Implementing new technologies shown to reduce the SWI rate is likely to benefit patients and reduce costs.


Ability of Candida albicans mutants to induce Staphylococcus aureus vancomycin resistance during polymicrobial biofilm formation.
Candida albicans and Staphylococcus aureus form vigorous polymicrobial biofilms in serum, which may serve as the source of coinfection in patients. More importantly, S. aureus is highly resistant to vancomycin during polymicrobial biofilm formation, with no decreases in bacterial viability observed with up to 1,600 microg/ml drug. In these mixed-species biofilms, S. aureus preferentially associates with C. albicans hyphae, which express a variety of unique adhesins. We tested C. albicans mutants deficient in transcriptional regulators of morphogenesis (CPH1 and EFG1) and biofilm formation (BCR1) to investigate the role of hyphae in mediating polymicrobial biofilm formation. These mutants also have reduced expression of hypha-specific adhesins. The ability to form polymicrobial biofilms correlated with the ability to form hyphae in these mutants. However, only mutants that could adhere to the abiotic surface could induce S. aureus vancomycin resistance, regardless of the presence of hyphae. In examining factors that may mediate interspecies adhesion, we found that the C. albicans ALS family of adhesins (Als1 to Als7 and Als9) was not involved, and neither was the hypha-specific adhesin Hwp1. Therefore, polymicrobial biofilm formation and subsequent antibiotic resistance is a multifactorial process that may require a unique combination of fungal and/or bacterial adhesins.


ROBITT: A tool for assessing the risk-of-bias in studies of temporal trends in ecology.
Aggregated species occurrence and abundance data from disparate sources are increasingly accessible to ecologists for the analysis of temporal trends in biodiversity. However, sampling biases relevant to any given research question are often poorly explored and infrequently reported; this can undermine statistical inference. In other disciplines, it is common for researchers to complete 'risk-of-bias' assessments to expose and document the potential for biases to undermine conclusions. The huge growth in available data, and recent controversies surrounding their use to infer temporal trends, indicate that similar assessments are urgently needed in ecology.We introduce ROBITT, a structured tool for assessing the 'Risk-Of-Bias In studies of Temporal Trends in ecology'. ROBITT has a similar format to its counterparts in other disciplines: it comprises signalling questions designed to elicit information on the potential for bias in key study domains. In answering these, users will define study inferential goal(s) and relevant statistical target populations. This information is used to assess potential sampling biases across domains relevant to the research question (e.g. geography, taxonomy, environment), and how these vary through time. If assessments indicate biases, then users must clearly describe them and/or explain what mitigating action will be taken.Everything that users need to complete a ROBITT assessment is provided: the tool, a guidance document and a worked example. Following other disciplines, the tool and guidance document were developed through a consensus-forming process across experts working in relevant areas of ecology and evidence synthesis.We propose that researchers should be strongly encouraged to include a ROBITT assessment when publishing studies of biodiversity trends, especially when using aggregated data. This will help researchers to structure their thinking, clearly acknowledge potential sampling issues, highlight where expert consultation is required and provide an opportunity to describe data checks that might go unreported. ROBITT will also enable reviewers, editors and readers to establish how well research conclusions are supported given a dataset combined with some analytical approach. In turn, it should strengthen evidence-based policy and practice, reduce differing interpretations of data and provide a clearer picture of the uncertainties associated with our understanding of reality.


Neutral iridium(iii) complexes bearing BODIPY-substituted N-heterocyclic carbene (NHC) ligands: synthesis, photophysics, in vitro theranostic photodynamic therapy, and antimicrobial activity.
The synthesis, photophysics, and photobiological activities of a series of novel neutral heteroleptic cyclometalated iridium(iii) complexes incorporating boron dipyrromethene (BODIPY) substituted N-heterocyclic carbene (NHC) ligands (Ir1-Ir5) are reported. The effect of the substitution position of BODIPY on the NHC ligands, either on C4 of the phenyl ring (Ir1-Ir3) or C5 of the benzimidazole unit (Ir4 and Ir5), and its linker type (single or triple bond) on the photophysical properties was studied. Ir1-Ir5 exhibited BODIPY-localized intense 1IL (intraligand transition)/1MLCT (metal-to-ligand charge transfer) absorption at 530-543 nm and 1,3IL/1,3CT (charge transfer) emission at 582-610 nm. The nanosecond transient absorption results revealed that the lowest triplet excited states of these complexes were the BODIPY-localized 3π,π* states. Complexes Ir4 and Ir5 exhibited blue-shifted 1IL absorption and 1,3IL/1,3CT emission bands compared to the corresponding absorption and emission bands in complexes Ir1 and Ir3. However, replacing the methyl substituents on N3 of benzimidazole in complexes Ir1 and Ir4 with oligoether substituents in Ir3 and Ir5, respectively, did not impact the energies of the low-energy absorption and emission bands in the corresponding complexes. Water-soluble complexes Ir3 and Ir5 have been explored as photosensitizers for in vitro photodynamic therapy (PDT) effects toward human SKMEL28 melanoma cells. Ir3 showed no dark cytotoxicity (EC50 > 300 μM) but good photocytotoxic activity (9.66 ± 0.28 μM), whereas Ir5 exhibited a higher dark cytotoxicity (20.2 ± 1.26 μM) and excellent photocytotoxicity (0.15 ± 0.01 μM). The phototherapeutic indices with visible light (400-700 nm) activation were >31 for Ir3 and 135 for Ir5. Ir3 and Ir5 displayed 1O2 quantum yields of 38% and 22% in CH3CN, respectively, upon 450 nm excitation. Ir5 was more effective at generating reactive oxygen species (ROS) in vitro. Ir5 was also active against Staphylococcus aureus upon visible light activation, with a phototherapeutic index of >15 and EC50 value of 6.67 μM. These photobiological activities demonstrated that these neutral Ir(iii) complexes are promising in vitro PDT reagents, and substitution at C5 on the benzimidazole group of the NHC ligand was superior to C4 substitution on the phenyl ring.


Cell intrinsic alterations underlie hematopoietic stem cell aging.
Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.


Antituberculosis activity of polyphenols of Areca catechu.
Polyphenols have been studied for their potential involvement in the prevention of various chronic diseases as well as for their antimicrobial potential. The crude extracts of arecanut have been reported to have antiinfective properties. We aimed to explore the endosperm of Areca catechu (arecanut) for the extraction of polyphenol components and to study the antituberculosis activity of these polyphenol against Mycobacterium tuberculosis H37Rv. A comparative extraction was performed using microwave and Soxlet apparatus. High performance liquid chromatography (HPLC) technique was used for the estimation of the extracted polyphenols. The minimum inhibitory concentration (MIC) values against M.tuberculosis H37Rv stain, Staphylococcus aureus and Escherichia coli were estimated by resazurin microtiter assay. There was a 11-fold increase in the total phenolic content by microwave assisted extraction compared to the Soxhlet extraction. The powdered extract was found to be active with MIC value of 0.975 ± 0.02 μg/mL. Fractionation and HPLC-based estimation of the extract revealed catechin, epicatechin, and epigallocatechin gallate to be the polyphenol components in the ethanol fraction. The bioactivity of these polyphenols confirmed their presence and complementary effect in the extract form. Because the toxic alkaloid arecoline, known to be present in arecanut, did not show any activity individually, the bioactivity of the extract was attributed to the nontoxic polyphenols present. This extract also showed selective inhibition of M. tuberculosis over other gram positive and gram-negative bacteria, thereby establishing that arecanut is an exploitable selective source of polyphenols acting against M. tuberculosis.


Perfluorooctane sulfonate disturbs Nanog expression through miR-490-3p in mouse embryonic stem cells.
Perfluorooctane sulfonate (PFOS) poses potential risks to reproduction and development. Mouse embryonic stem cells (mESCs) are ideal models for developmental toxicity testing of environmental contaminants in vitro. However, the mechanism by which PFOS affects early embryonic development is still unclear. In this study, mESCs were exposed to PFOS for 24 h, and then general cytotoxicity and pluripotency were evaluated. MTT assay showed that neither PFOS (0.2 µM, 2 µM, 20 µM, and 200 µM) nor control medium (0.1% DMSO) treatments affected cell viability. Furthermore, there were no significant differences in cell cycle and apoptosis between the PFOS treatment and control groups. However, we found that the mRNA and protein levels of pluripotency markers (Sox2, Nanog) in mESCs were significantly decreased following exposure to PFOS for 24 h, while there were no significant changes in the mRNA and protein levels of Oct4. Accordingly, the expression levels of miR-145 and miR-490-3p, which can regulate Sox2 and Nanog expressions were significantly increased. Chrm2, the host gene of miR-490-3p, was positively associated with miR-490-3p expression after PFOS exposure. Dual luciferase reporter assay suggests that miR-490-3p directly targets Nanog. These results suggest that PFOS can disturb the expression of pluripotency factors in mESCs, while miR-145 and miR-490-3p play key roles in modulating this effect.


Addition of Cleaved Tail Fragments during Lipid Oxidation Stabilizes Membrane Permeability Behavior.
Lipid oxidation has been linked to plasma membrane damage leading to cell death. In previous work, we examined the effect of oxidation on bilayer permeability by replacing defined amounts of an unsaturated lipid species with the corresponding phospholipid product that would result from oxidative tail scission of that species. This study adds the cleaved tail fragment, better mimicking the chemical results of oxidation. Permeability of PEG12-NBD, a small, uncharged molecule, was measured for vesicles with oxidation concentration corresponding to between 0 and 18 mol % of total lipid content. Permeability was measured using a microfluidic trap to capture the vesicles and spinning disk confocal microscopy (SDCM) to measure the transport of fluorescent PEG12-NBD at the equatorial plane. The thicknesses of lipid bilayers containing oxidized species were estimated by measuring capacitance of a black lipid membrane while simultaneously measuring bilayer area. We found that relative to chemically modeled oxidized bilayers without tail fragments, bilayers containing cleaved tail groups were less permeable for the same degree of oxidation. Curiously, membrane capacitance measurements indicated that the addition of tail fragments to chemically modeled oxidized bilayers also thinned these bilayers relative to samples with no tail fragments; in other words, the more permeable membranes were thicker. Above 12.5% chemically modeled oxidation, compositions both with and without the cleaved tail groups showed pore formation. This work highlights the complexity of the relationship between chemically modeled lipid bilayer oxidation and cell membrane properties.


Confocal laser scanning microscopy for detection of Schistosoma mansoni eggs in the gut of mice.
The gold standard for diagnosing Schistosoma mansoni infections is the detection of eggs from stool or biopsy specimens. The viability of collected eggs can be tested by the miracidium hatching procedure. Direct detection methods are often limited in patients with light or early infections, whereas serological tests and PCR methods fail to differentiate between an inactive and persistent infection and between schistosomal species. Recently, confocal laser scanning microscopy (CLSM) has been introduced as a diagnostic tool in several fields of medicine. In this study we evaluated CLSM for the detection of viable eggs of S. mansoni directly within the gut of infected mice. The confocal laser scanning microscope used in this study is based on the Heidelberg Retina Tomograph II scanning laser system in combination with the Rostock Cornea Module (image modality 1) or a rigid endoscope (image modality 2). Colon sections of five infected mice were examined with image modalities 1 and 2 for schistosomal eggs. Afterwards a biopsy specimen was taken from each colon section and examined by bright-field microscopy. Visualised eggs were counted and classified in terms of viability status. We were able to show that CLSM visualises eggs directly within the gut and permits discrimination of schistosomal species and determination of egg viability. Thus, CLSM may be a suitable non-invasive tool for the diagnosis of schistosomiasis in humans.


Constant infusion transpulmonary thermodilution for the assessment of cardiac output in exercising humans.
To determine the accuracy and precision of constant infusion transpulmonary thermodilution cardiac output (CITT-Q) assessment during exercise in humans, using indocyanine green (ICG) dilution and bolus transpulmonary thermodilution (BTD) as reference methods, cardiac output (Q) was determined at rest and during incremental one- and two-legged pedaling on a cycle ergometer, and combined arm cranking with leg pedaling to exhaustion in 15 healthy men. Continuous infusions of iced saline in the femoral vein (n = 41) or simultaneously in the femoral and axillary (n = 66) veins with determination of temperature in the femoral artery were used for CITT-Q assessment. CITT-Q was linearly related to ICG-Q (r = 0.82, CITT-Q = 0.876 × ICG-Q + 3.638, P < 0.001; limits of agreement ranging from -1.43 to 3.07 L/min) and BTD-Q (r = 0.91, CITT-Q = 0.822 × BTD + 4.481 L/min, P < 0.001; limits of agreement ranging from -1.01 to 2.63 L/min). Compared with ICG-Q and BTD-Q, CITT-Q overestimated cardiac output by 1.6 L/min (≈ 10% of the mean ICG and BTD-Q values, P < 0.05). For Q between 20 and 28 L/min, we estimated an overestimation < 5%. The coefficient of variation of 23 repeated CITT-Q measurements was 6.0% (CI: 6.1-11.1%). In conclusion, cardiac output can be precisely and accurately determined with constant infusion transpulmonary thermodilution in exercising humans.


[Mathematical anatomy: muscles according to Stensen].
In his Elementorum Myologiae Specimen, Steno geometrizes "the new fabric of muscles" and their movement of contraction, so as to refute the main contemporary hypothesis about the functioning of the muscles. This physiological refutation relies on an abstract representation of the muscular fibre as a parallelepiped of flesh transversally linked to the tendons. Those two features have been comprehensively studied. But the method used by Steno, as well as the way he has chosen to present his physiological results, have so far been neglected. Yet, Steno's work follows a true synthetic order, which he conceives as a tool to separate uncertain anatomical "elements" from the certain ones. We will show that the true understanding of this "more geometrico" order is the only way to avoid frequent misconceptions of the scientific aim pursued by Steno, which is neither to give a mathematical explanation of the functioning of the muscles, nor to reduce the muscles to some mathematical shapes.


Association between long-term PM2.5 exposure and risk of Kawasaki disease in children: A nationwide longitudinal cohort study.
Based on previous studies suggesting air pollution as a potential risk factor for Kawasaki Disease (KD), we examined the association of long-term exposure to childhood fine particulate matter (PM2.5) with the risk of KD. We used National Health Insurance Service-National Sample Cohort data from 2002 to 2019, which included beneficiaries aged 0 years at enrollment and followed-up until the onset of KD or age 5 years. The onset of KD was defined as the first hospital visit record with a primary diagnostic code of M30.3, based on the 10th revision of the International Classification of Diseases, and with an intravenous immunoglobulin (IVIG) prescription. We assigned PM2.5 concentrations to 226 districts, based on mean annual predictions from a machine learning-based ensemble prediction model. We performed Cox proportional-hazards modeling with time-varying exposures and confounders. We identified 134,634 individuals aged five or less at enrollment and, of these, 1220 individuals who had a KD onset and an IVIG prescription during study period. The average annual concentration of PM2.5 exposed to the entire cohort was 28.2 μg/m³ (Standard Deviation 2.9). For each 5 μg/m³ increase in annual PM2.5 concentration, the hazard ratio of KD was 1.21 (95% CI 1.05-1.39). In this nationwide, population-based, cohort study, long-term childhood exposure to PM2.5 was associated with an increased incidence of KD in children. The study highlights plausible mechanisms for the association between PM2.5 and KD, but further studies are needed to confirm our findings.


Suppurative abomasitis associated with Clostridium septicum infection.
A 1-week-old calf and two 1-month-old lambs from different farms in eastern South Dakota had severe abomasitis characterized by diffuse suppurative inflammation, edema, and emphysema. Clostridium septicum in the abomasal wall of each was identified by immunofluorescence and isolation. The lesions and microbiologic findings established the disease as braxy, a condition infrequently reported in the United States and thought to affect sheep only.


[Cervico-arthrotic myelopathies. Treatment and prognosis].
The authors present 50 cases of cervical spondylotic myelopathy treated by anterior or posterior approach. To assess the severity of the pre- and postoperative neurological symptoms, they define an original ten-point classification scale taking into account gait and urinary disturbance, ability to manipulate objects and pain. With C2-C7 laminectomy, 60% of the patients are improved, essentially for walk. A few cases only (14%) are upgraded for upper limbs function. The authors conclude that this surgical treatment should be applied only when there is a multi-level narrowed canal and predominant lower limbs deficits. The efficacy of the anterior approach depends on complete removal of osteophytes. In cases with complete osteophytectomy, this surgical treatment can improve both the upper and lower limbs function and 77.8% good results are obtained. In a few cases it may be necessary to use both approach successively. Discriminant analysis applied to 12 factors shows that pre-operative scores of upper and lower limbs and sagittal diameter of spinal canal are the most important factors for neurological prognosis.


Pediatric ocular melanoma: a collaborative multicenter study and meta-analysis.
To investigate clinical manifestations and prognoses in pediatric patients (≤12 years old) with ocular melanoma. This was a retrospective, multicenter cohort study with individual participant data (IPD) meta-analysis pooling available published cases, and unpublished cases from an international collaboration of seven ocular oncology centers. There were 133 eyes of 133 pediatric patients with choroidal or ciliary body (n = 66 [50%]), iris (n = 33 [25%]), conjunctival (n = 26 [19%]), and eyelid (n = 8 [6%]) melanoma. Overall, the mean patient age at presentation was 7 years (median, 8; range, 1-12 years), with 63 males (49%). The mean age by tumor site was 6.50 ± 3.90, 7.44 ± 3.57, 9.12 ± 2.61, and 5.63 ± 2.38 years, for choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively (P = 0.001). Association with ocular melanocytosis was seen in 15%, 11%, 4%, and 0%, respectively (P = 0.01). Frequency of ocular melanoma family history did not vary by tumor site (7%, 17%, 9% and 12%, resp. [P = 0.26]). After mean follow-up of 74, 85, 50, and 105 months (P = 0.65), metastasis was seen in 12%, 9%, 19%, and 13% of choroid/ciliary body, iris, conjunctiva, and eyelid melanoma, respectively. Death was reported in 5%, 3%, 8%, and 0%, respectively, with survival analysis indicating higher mortality in choroidal/ciliary body and conjunctival melanoma patients. Ocular melanoma in the pediatric population is rare, with unique clinical features and outcomes. Iris melanoma accounts for about one-third of pediatric uveal melanoma cases.


The role of PSA in the radiotherapy of prostate cancer.
Pretreatment prostate-specific antigen (PSA) level is the single most important prognostic factor for patients undergoing radiotherapy for clinically localized prostate cancer. When combined with Gleason score and T-stage, pretreatment PSA enhances our ability to accurately predict pathologic stage. Patients with pretreatment PSA levels > 10 ng/mL are at high risk for biochemical failure when treated with conventional radiation alone. A PSA nadir of > 1 ng/mL and a post-treatment PSA > 1.5 ng/mL are associated with a high risk of biochemical failure. Postoperative radiotherapy delivered while the tumor burden is low (eg, PSA < 1 ng/mL) predicts a favorable outcome. Many of these conclusions about the usefulness of pretreatment PSA are based on the assumption that PSA can be used as a surrogate end point for disease-free and overall survival from prostate cancer. However, this assumption still remains to be validated by phase III trials.


Vascularized compared with nonvascularized fibular grafting for the treatment of osteonecrosis of the femoral head.
We are not aware of any clinical studies in the literature comparing the results of vascularized and nonvascularized fibular grafting for the treatment of osteonecrosis of the femoral head. The purpose of this study was to compare the clinical results of free vascularized fibular grafting with those of nonvascularized fibular grafting. Two hundred patients (220 hips) with osteonecrosis of the femoral head were treated with free vascularized fibular grafting at the University of Pittsburgh Medical Center, and ninety-nine patients (123 hips) were treated with nonvascularized fibular grafting at the Kyungpook National University Hospital in Korea. From these populations, two groups of fifty hips each, followed for a minimum of three years (average, five years), were matched by the stage, size, and etiology of the lesion and by the mean preoperative Harris hip score. A retrospective case-control study of these groups was then performed to compare the postoperative Harris hip scores as well as the prevalences of radiographic progression and collapse of the femoral head following free vascularized fibular grafting with those measures following nonvascularized fibular grafting. The mean Harris hip score improved for 70% of the hips treated with free vascularized fibular grafting: seventeen hips (34%) were rated excellent, fourteen (28%) were rated good, nine (18%) were rated fair, and ten (20%) were rated poor. The mean Harris hip score improved for 36% of the hips treated with nonvascularized fibular grafting: five hips (10%) were rated excellent; nine (18%), good; sixteen (32%), fair; and twenty (40%), poor. The rate of survival at seven years for the Stage-I and II hips (precollapse) was 86% after treatment with free vascularized fibular grafting compared with 30% after nonvascularized fibular grafting. The results of this study strongly suggest that vascularized fibular grafting is associated with better clinical and radiographic results.


Neural networks for advanced control of robot manipulators.
Presents an approach and a systematic design methodology to adaptive motion control based on neural networks (NNs) for high-performance robot manipulators, for which stability conditions and performance evaluation are given. The neurocontroller includes a linear combination of a set of off-line trained NNs, and an update law of the linear combination coefficients to adjust robot dynamics and payload uncertain parameters. A procedure is presented to select the learning conditions for each NN in the bank. The proposed scheme, based on fixed NNs, is computationally more efficient than the case of using the learning capabilities of the neural network to be adapted, as that used in feedback architectures that need to propagate back control errors through the model to adjust the neurocontroller. A practical stability result for the neurocontrol system is given. That is, we prove that the control error converges asymptotically to a neighborhood of zero, whose size is evaluated and depends on the approximation error of the NN bank and the design parameters of the controller. In addition, a robust adaptive controller to NN learning errors is proposed, using a sign or saturation switching function in the control law, which leads to global asymptotic stability and zero convergence of control errors. Simulation results showing the practical feasibility and performance of the proposed approach to robotics are given.


Topical sodium cromoglycate in the treatment of moderate-to-severe atopic dermatitis.
Unsatisfactory treatment results for severe atopic dermatitis have led to many experimental therapies, including cromolyn sodium in various vehicles at concentrations ranging from 1% to 10%. Results suggest that the vehicle used to deliver the cromolyn is relevant to its effectiveness. To test the efficacy of low concentrations of cromolyn in a water-soluble vehicle in the treatment of moderate-to-severe atopic dermatitis in a double-blind, placebo-controlled study. Twenty-six pediatric patients who had failed to respond to conventional therapy were randomized into 2 treatment groups: patients in group A used the study drug for 1 month (phase I), then received the placebo for 1 month (phase II); and patients in group B used the placebo for 1 month, then received the study drug for 1 month. The study drug was cromolyn sodium inhalation solution mixed into a water-based emollient cream to a final concentration of 0.21%. Upon enrollment and at each follow-up visit, every patient was given a severity score based on extent and severity of skin involvement. At enrollment, there were no significant differences between groups A and B in severity scores, age, sex, race, skin test and/or RAST positivity, eosinophil levels, IgE concentrations, or the presence of concomitant rhinitis or asthma. After the first phase of the study treatment, severity scores had decreased significantly for both groups with a significant difference between group A (cromolyn) and group B (placebo). After crossover, both groups had significantly lower severity scores than at entry into the study. Treatment with topical cromolyn in a hydrophilic emollient vehicle has a significant anti-inflammatory effect on moderate-to-severe atopic dermatitis. We have now incorporated this treatment into our clinical practice.


Aberrant brain network connectivity in presymptomatic and manifest Huntington's disease: A systematic review.
Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to shed light on the pathophysiological mechanisms of Huntington's disease (HD), paving the way to new therapeutic interventions. A systematic literature review was conducted in three online databases according to PRISMA guidelines, using keywords for HD, functional connectivity, and rs-fMRI. We included studies investigating connectivity in presymptomatic (pre-HD) and manifest HD gene carriers compared to healthy controls, implementing seed-based connectivity, independent component analysis, regional property, and graph analysis approaches. Visual network showed reduced connectivity in manifest HD, while network/areas underpinning motor functions were consistently altered in both manifest HD and pre-HD, showing disease stage-dependent changes. Cognitive networks underlying executive and attentional functions showed divergent anterior-posterior alterations, possibly reflecting compensatory mechanisms. The involvement of these networks in pre-HD is still unclear. In conclusion, aberrant connectivity of the sensory-motor network is observed in the early stage of HD while, as pathology spreads, other networks might be affected, such as the visual and executive/attentional networks. Moreover, sensory-motor and executive networks exhibit hyper- and hypo-connectivity patterns following different spatiotemporal trajectories. These findings could potentially help to implement future huntingtin-lowering interventions.


The role of maternal stress in early pregnancy in the aetiology of gastroschisis: an incident case control study.
The incidence of gastroschisis, a congenital anomaly where the infant abdominal wall is defective and intestines protrude from the abdominal cavity, is increasing in many countries. The role of maternal stress in some adverse birth outcomes is now well established. We tested the hypothesis that major stressful life events in the first trimester are risk factors for gastroschisis, and social support protective, in a case-control study in the United Kingdom. Gastroschisis cases and three controls per case (matched for maternal age) were identified at routine 18-20 week fetal anomaly ultrasound scan, in 2007-2010. Face to face questionnaire interviews were carried out during the antenatal period (median 24 weeks gestation) asking about serious stressful events and social support in the first trimester. Data were analysed using conditional logistic regression. Two or more stressful life events in the first trimester (adjusted OR 4.9; 95% CI 1.2-19.4), and moving address in the first trimester (aOR 4.9; 95% CI 1.7-13.9) were strongly associated with risk of gastroschisis, independent of behavioural risk factors including smoking, alcohol, and poor diet. Perceived availability of social support was not associated with reduced risk of gastroschisis (aOR 0.8; 95% CI 0.2-3.1). Stressful maternal life events in the first trimester of pregnancy including change of address were strongly associated with a substantial increase in the risk of gastroschisis, independent of stress related high risk behaviours such as smoking, alcohol consumption and poor diet. This suggests that stress pathways are involved in the aetiology of gastroschisis.


Does nephrometry scoring of renal tumors predict outcomes in patients selected for robot-assisted partial nephrectomy?
Robot-assisted partial nephrectomy has emerged as a viable surgical treatment for patients with certain renal tumors. We hypothesized that extirpation of more complex tumors, as graded with the nephrometry score, would result in worse operative and postoperative outcomes when compared with tumors with lower nephrometry scores. We report whether nephrometry-graded tumor complexity impacted operative or postoperative outcomes. A single experienced surgeon at our tertiary-care institution performed more than 100 robot-assisted partial nephrectomies. Istitutional Review Board-approved data collection was available for 95 patients, and nephrometry scores were available for 92 patients. Cases were divided into tertiles, based on their nephrometry score of low, medium, or high. We compared preoperative, operative, and postoperative data to evaluate any differences between the three tertiles. Statistical analysis was performed using JMP 8 software. There were 66, 22, and 4 patients in the low, medium, and high nephrometry score tertiles, respectively. There were no statistically significant differences between the tertiles regarding warm ischemia time, estimated blood loss, operative time, length of stay, change in glomerular filtration rate, Clavien-graded complication rates, or any other metric. Mean follow-up for each tertile was also similar. We have routinely been using the nephrometry scoring system to anatomically describe renal masses before robot-assisted partial nephrectomy. Our findings demonstrate that nephrometry-graded tumor complexity was not related to any differences in outcomes for patients with renal tumors who were selected at our institution to undergo robot-assisted partial nephrectomy. The nephrometry system remains a reproducible standardized classification of renal tumor anatomy, but it remains to be seen if this can be used to predict surgical outcomes.


Pathophysiological effects of Möbius syndrome on speech and hearing.
The effects of Möbius syndrome (MoS) on the functioning of the peripheral speech and hearing mechanisms has not hithertofore been described, to my knowledge. Speech and hearing function of an 8-year-old MoS speaker was studied. Data were obtained from several sources. These included: electromyography of the facial muscles, physical examination of the peripheral speech mechanism, speech and language test batteries, audiological evaluation, and acoustic analyses of the speech signal. A pathologic condition was found to exist in a number of cranial nerves and in structures in the oral cavity. This resulted in consonant and vowel misarticulations, which notably affected speech intelligibility. Middle ear dysfunction was also present. Neurological mechanisms are discussed to account for these pathologies in human communication. Strategies for speech therapy and future research in MoS are presented.


Dynamics-Based Peptide-MHC Binding Optimization by a Convolutional Variational Autoencoder: A Use-Case Model for CASTELO.
An unsolved challenge in the development of antigen-specific immunotherapies is determining the optimal antigens to target. Comprehension of antigen-major histocompatibility complex (MHC) binding is paramount toward achieving this goal. Here, we apply CASTELO, a combined machine learning-molecular dynamics (ML-MD) approach, to identify per-residue antigen binding contributions and then design novel antigens of increased MHC-II binding affinity for a type 1 diabetes-implicated system. We build upon a small-molecule lead optimization algorithm by training a convolutional variational autoencoder (CVAE) on MD trajectories of 48 different systems across four antigens and four HLA serotypes. We develop several new machine learning metrics including a structure-based anchor residue classification model as well as cluster comparison scores. ML-MD predictions agree well with experimental binding results and free energy perturbation-predicted binding affinities. Moreover, ML-MD metrics are independent of traditional MD stability metrics such as contact area and root-mean-square fluctuations (RMSF), which do not reflect binding affinity data. Our work supports the role of structure-based deep learning techniques in antigen-specific immunotherapy design.


Heat shock proteins and their association with major pediatric malignancies.
Heat shock proteins belong to a group of molecular chaperones responsible for the regulation of many intracellular processes. HSPs play a pivotal role in the survival of cells under stressful conditions. Over-expression of these proteins have been found in both healthy and a great number of cancer cells. HSPs may be involved in numerous carcinogenic and chemoresistant processes. Due to that fact, they may be referred to as diagnostic biomarkers of oncogenesis and potential targets for anticancer drugs. Thus, we decided to review the involvement of major HSPs in the most malignant childhood cancers.


Gene-specific signal transduction between microtubules and tubulin genes in Tetrahymena thermophila.
Mammalian cells regulate tubulin mRNA abundance by a posttranscriptional mechanism dependent on the concentration of tubulin monomer. Treatment of mammalian cells with microtubule-depolymerizing drugs and microtubule-polymerizing drugs causes decreases and increases in tubulin mRNA, respectively (D. W. Cleveland, Curr. Opin. Cell Biol. 1:10-14, 1989). In striking contrast to the case with mammalian cells, perturbation of microtubules in Tetrahymena thermophila by microtubule-depolymerizing or -polymerizing drugs increases the level of the single alpha-tubulin gene message by increasing transcription (L. A. Stargell, D. P. Heruth, J. Gaertig, and M. A. Gorovsky, Mol. Cell. Biol. 12:1443-1450, 1992). In this report we show that antimicrotubule drugs preferentially induce the expression of one of two beta-tubulin genes (BTU1) in T. thermophila. In contrast, deciliation induces expression of both beta-tubulin genes. Tubulin gene expression was examined in a mutant strain created by transformation with an in vitro-mutagenized beta-tubulin gene that conferred resistance to microtubule-depolymerizing drugs and sensitivity to the polymerizing drug taxol and in a strain containing a nitrosoguanidine-induced mutation in the single alpha-tubulin gene that conferred the same pattern of drug sensitivities. In both cases the levels of tubulin mRNA expression from the drug-inducible BTU1 gene in the mutant cells paralleled the altered growth sensitivities to microtubule drugs. These studies demonstrate that T. thermophila has distinct, gene-specific mechanisms for modulating tubulin gene expression depending on whether ciliary or cytoplasmic microtubules are involved. They also show that the cytoplasmic microtubule cytoskeleton itself participates in a signal transduction pathway that regulates specific tubulin gene transcription in T. thermophila.


Body mass index, waist circumference and waist-to-hip-ratio in the prediction of obesity in Turkish teenagers.
The aim of this study was to identify the usefulness of body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) in screening for obesity in teenagers by using the receiver operating characteristic (ROC). To select the sample set in this cross-sectional study, a stratified random sampling approach was utilized. Weight, height, WC, hip circumference and body fat percentage (BFP) were measured in 1118 children of both genders (597 boys and 521 girls), aged from 10 to 15 years old. Percentiles of BMI and Centers for Disease Control and Prevention-United States (CDC-US)-growth chart for boys and girls aged from 10 to 15 years old were presented. ROC analyses were then used to evaluate the performances of three anthropometric indices; BMI, WC and WHR had strong positive correlations with BFP (r = 0.49-0.77) in both girls and boys within indicated age group. The area under the curves (AUCs) were high in both girls and boys for BMI, 0.795 and 0.893, respectively, and WC, 0.767 and 0.853, respectively, and were a little lower, 0.747 and 0.783, respectively, for WHR. In conclusion, this study demonstrates that the prevalence of being overweight and obese among teenagers of both sexes in our data set does not differ from CDC-US-growth chart. In addition, BMI and WC are two important predictors for teenagers to become overweight and obese, while WHR is less useful for this purpose.


Spontaneous metastasis of cells of the human prostate carcinoma cell line PC-3 in athymic nude mice.
Spontaneous metastasis and extensive invasiveness were observed in athymic nude mice injected with human prostatic carcinoma cells of the PC-3 line or heterotransplants of nude mouse supported PC-3 tumor. In 3 experimental series, 60, 63 and 50 per cent of the nude mice receiving subcutaneous inoculations of PC-3 cells or tumor heterotransplants developed 1 or more lymphatic tumor metastases. Examination of metaphase-arrested cells recovered from the metastatic sites confirmed the tumor origin as human in each case. Cells recovered from 1 nude mouse supported subline, MPC-3-10, frequently exhibited double minute chromosomes in addition to the typical PC-3 chromosomal profile. These observations provide the foundation for a study of the relationship between prostate carcinoma cell characteristics and lymphatic metastasis in the nude mouse.


Retention behavior of carbohydrates on metal loaded chelating stationary phase under conditions of hydrophilic interaction liquid chromatography.
The chromatographic retention of carbohydrates on chelating stationary phase loaded with different metal ions was studied under conditions of hydrophilic interaction chromatography (HILIC). The chelating stationary phases represented silica microparticles with immobilized 2-hydroxyethyliminodiacetic acid (HEIDA) groups in loose form and saturated with Ca2+, Pb2+, and La3+form. The role of loaded metal ion, the acetonitrile and methanol content in the mobile phase, buffer pH and column temperature on the retention of l-(+)-arabinose, d-(+)-maltose, l-(+)-rhamnose, d-(+)-lactose, d-(+)-xylose, glucose, fructose, sucrose, mannose, maltotriose and d-(+) raffinose was studied. The investigation was mainly focused on possible contribution of the complexation in the stationary phase on retention of carbohydrates as well as on effect of the presence metal ion in HEIDA-silica on resulting HILIC behavior of. It is shown that adsorbents with immobilized metal complexes have a good potential for the separation of organic ligands under HILIC mode.


Balloon dacryoplasty in internal ostium stenosis after endoscopic dacryocystorhinostomy.
To determine the effectiveness of balloon dacryoplasty in the treatment of internal ostium stenosis after endoscopic dacryocystorhinostomy (EnDCR). A retrospective, noncomparative interventional case series of patients who underwent balloon dacryoplasty for post-EnDCR internal ostium stenosis were included. A balloon catheter was used in all procedures, with bicanalicular silicone intubation. Patient records were reviewed and data analyzed. Anatomical success was defined by functional endoscopic dye test, and functional success was defined as a subjective improvement in symptoms at last follow up. Nineteen lacrimal systems of 18 consecutive patients were studied between July 2007 and September 2012. At a mean follow up of 20 months (range, 3-53 months), anatomical success rate was 84% (16/19 systems), whereas functional success was 74% (14/19 systems). No major complication was observed. Balloon dacryoplasty is a minimally invasive procedure in the treatment of post-EnDCR internal ostium stenosis. It is a simple, safe procedure and can provide symptomatic relief to some of these patients. It can be considered as a treatment option for patients demonstrated with internal ostium stenosis after EnDCR.